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CURRENT DIAGNOSIS AND THERAPY FOR HEAD AND NECK

MALIGNANCIES

CONSULTING EDITOR
NICHOLAS J. PETRELLI, MD, Medical Director, Helen F. Graham Cancer Center,
Newark, Delaware; and Professor of Surgery, Jefferson Medical College, Philadelphia,
Pennsylvania

GUEST EDITOR
WESLEY L. HICKS, JR, DDS, MD, FACS, Attending Surgeon, Department of Head and
Neck Surgery, Roswell Park Cancer Institute; Associate Professor of Otolaryngology,
Head and Neck Surgery, and Neurosurgery, School of Medicine and Biomedical
Sciences, State University of New York at Buffalo, Buffalo, New York; and Director,
Head and Neck Surgical Fellowship Program, Roswell Park Cancer Institute

CONTRIBUTORS
RONALD A. ALBERICO, MD, Associate Professor of Radiology, Assistant Clinical
Professor of Neurosurgery, School of Medicine and Biomedical Sciences, State
University of New York at Buffalo; Director of Neuroradiology/Head and Neck
Imaging, Department of Radiology, Roswell Park Cancer Institute, Buffalo, New York;
and Acting Director of Pediatric Neuroradiology, Buffalo Children’s Hospital, Buffalo,
New York

GARTH R. ANDERSON, PhD, Professor of Cellular and Molecular Biology, Department


of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York

JIMMY J. BROWN, DDS, MD, FACS, Assistant Professor, Department of


Otolaryngology–Head and Neck Surgery, Charles R. Drew University of Medicine and
Science, Los Angeles, California

AMOS O. DARE, MD, Clinical Instructor, Department of Neurological Surgery, School of


Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo,
New York

WADE DOUGLAS, MD, Fellow, Department of Head and Neck Surgery, Roswell Park
Cancer Institute, Buffalo, New York

KEVIN J. GIBBONS, MD, Program Director and Director of Skull Base Surgery,
Department of Neurological Surgery, School of Medicine and Biomedical Sciences,
State University of New York at Buffalo, Buffalo, New York

WILLIAM GIESE, MD, JD, Associate Professor, Department of Radiation Oncology,


Roswell Park Cancer Institute, Buffalo, New York

iii
RALPH W. GILBERT, MD, FRCSC, Associate Professor, Head and Neck Surgical
Oncology; Reconstructive Microsurgery, University Health Network; Princess
Margaret Hospital; and Department of Otolaryngology, University of Toronto,
Toronto, Canada

CHRISTINE G. GOURIN, MD, FACS, Assistant Professor, Department of


Otolaryngology–Head and Neck Surgery, Medical College of Georgia, Augusta,
Georgia

PATRICK J. GULLANE, MB, FRCSC, FACS, Otolaryngologist-in-Chief, University Health


Network; Wharton Chair in Head and Neck Surgery, Princess Margaret Hospital; and
Professor and Chairman, Department of Otolaryngology, University of Toronto,
Toronto, Canada

SYED HAMED S. HUSAIN, DO, Radiology Resident, School of Medicine and Biomedical
Sciences, State University of New York at Buffalo, Buffalo, New York

DOMINICK LAMONICA, MD, Director of Nuclear Medicine, Division of Diagnostic


Imaging, Roswell Park Cancer Institute; and Assistant Professor of Radiology and
Clinical Nuclear Medicine, School of Medicine and Biomedical Sciences, State
University of New York at Buffalo, Buffalo, New York

PABLO MOJICA-MANOSA, MD, Fellow, Department of Head and Neck Surgery,


Roswell Park Cancer Institute, Buffalo, New York

JEFFREY N. MYERS, MD, PhD, Associate Professor of Head and Neck Surgery,
Department of Head and Neck Surgery, The University of Texas M.D. Anderson
Cancer Center, Houston, Texas

LARRY L. MYERS, MD, Department of Otolaryngology–Head and Neck Surgery,


University of Texas Southwestern Medical Center, Dallas, Texas

RYAN F. OSBORNE, MD, Director, Head and Neck Oncology, Cedars-Sinai Medical
Center; and Assistant Professor, Department of Otolarynology–Head and Neck
Surgery, Charles R. Drew University of Medicine and Science, Los Angeles, California

LANCE E. OXFORD, MD, Department of Otolaryngology–Head and Neck Surgery,


University of Texas Southwestern Medical Center, Dallas, Texas

CARSTEN E. PALME, MB BS, FRACS, Clinical Fellow, Oncologic Head and Neck
Surgery, Department of Otolaryngology, University of Toronto, Toronto, Canada

JAMES REIDY, DO, Fellow, Department of Head and Neck Surgery, Roswell Park Cancer
Institute, Buffalo, New York

NESTOR R. RIGUAL, MD, FACS, Associate Professor of Clinical Otolaryngology, School


of Medicine and Biomedical Sciences, State University of New York at Buffalo; and
Attending Surgeon, Section of Plastic and Reconstructive Surgery, Department of Head
and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York

JAMES K. SCHWARZ, MD, Assistant Professor, Department of Medicine, Roswell Park


Cancer Institute, Buffalo, New York

iv CONTRIBUTORS
IGOR SIROTKIN, MD, Radiology Resident, School of Medicine and Biomedical Sciences,
State University of New York at Buffalo, Buffalo, New York

DANIEL L. STOLER, PhD, Assistant Professor, Department of Experimental Pathology,


Roswell Park Cancer Institute, Buffalo, New York

MAUREEN SULLIVAN, DDS, Chief, Department of Dentistry and Maxillofacial


Prosthetics, Roswell Park Cancer Institute, Buffalo, New York

DAVID J. TERRIS, MD, FACS, Porubsky Professor and Chairman, Department


of Otolaryngology–Head and Neck Surgery, Medical College of Georgia, Augusta,
Georgia

KEITH WILSON, MD, Associate Professor, ENT/Head and Neck Surgery, University
of Cincinnati, Cincinnati, Ohio

SAM M. WISEMAN, MD, FRCS(C), Assistant Professor of Surgery, University of British


Columbia School of Medicine; and Attending Surgeon, Department of Surgery, St.
Paul’s Hospital, Vancouver, British Columbia, Canada

ROBERT L. WITT, MD, Chief, Section of Otolaryngology, Department of Surgery,


Christiana Care Health System, Newark, Delaware; and Assistant Professor,
Department of Otolaryngology, Jefferson Medical College, Philadelphia, Pennsylvania

MAHER N. YOUNES, MD, Postdoctoral Fellow, Department of Head and Neck Surgery,
University of Texas M. D. Anderson Cancer Center, Houston, Texas

CONTRIBUTORS v
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Surg Oncol Clin N Am
13 (2004) xiii–xiv

Foreword

Current diagnosis and therapy for head


and neck malignancies

Nicholas J. Petrelli, MD
Consulting Editor

Approximately 1,334,100 new cancer cases were diagnosed in 2003. Since


1990, over 17 million new cancer cases have been diagnosed. According to
the American Cancer Society, these new cancer cases do not include carci-
noma in situ of any site except urinary bladder and do not include basal and
squamous skin cancers. In 2003, approximately 556,500 Americans died of
cancer, which is equivalent to more than 1500 people a day.
Cancers of the oral cavity and pharynx were diagnosed in an estimated
27,700 new cases in 2003. These incidence rates are more than twice as high
in men as in women and are greatest in men who are over age 50. Neverthe-
less, incidence rates for cancers of the oral cavity and pharynx continued to
decline in the 1990s in both African American and white males and females.
There were an estimated 7200 deaths in 2003 from oral cavity and pharyng-
eal cancer. The known risk factors for these cancers are cigarettes, cigars,
pipe smoking, and the use of smokeless tobacco. Excessive consumption
of alcohol is also a risk factor.
In this issue of the Surgical Oncology Clinics of North America, under the
direction of Wesley Hicks, Jr., DDS, MD, an outstanding array of authors
has been assembled to discuss many clinical and scientific issues regarding
cancers of the head and neck. Dr. Hicks is a member of the Department
of Head and Neck Surgery at the Roswell Park Cancer Institute in Buffalo,
New York, and an Associate Professor of Surgery at the State University of
New York at Buffalo.

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.soc.2003.12.010
xiv N.J. Petrelli / Surg Oncol Clin N Am 13 (2004) xiii–xiv

The article by Wiseman, Stoler, and Anderson on the role of genomic


instability in the pathogenesis of squamous cell carcinoma of the head and
neck is especially interesting. These researchers are from the Departments of
Surgical Oncology, Experimental Pathology, and Cancer Genetics, respec-
tively. Cancer predisposition genes and the genetic heterogeneity of head
and neck tumors are discussed in detail.
On the clinical side, the article by Osborne and Brown from the Division
of Otolaryngology/Head and Neck Surgery at the University of California–
Los Angeles Medical Center deals with carcinoma of the oral pharynx with
an analysis of subsite treatment heterogeneity. This article provides a clear
discussion of the clinical treatment modalities in relationship to histopatho-
logic characteristics.
As I have stated in previous forewords for the Surgical Oncology Clinics
of North America, this issue is a must-read for trainees in the three major
disciplines of surgery, radiation oncology, and medical oncology. Trainees
in pathology and radiology should also make this issue a part of their educa-
tional matriculation.
I congratulate Dr. Hicks and his colleagues on an outstanding issue of the
Surgical Oncology Clinics of North America.

Nicholas J. Petrelli, MD
Consulting Editor
Helen F. Graham Cancer Center
4701 Ogletown-Stanton Road
Suite 1212
Newark, Delaware 19713, USA
Jefferson Medical College
Philadelphia, Pennsylvania
Surg Oncol Clin N Am
13 (2004) xv–xvi

Preface

Current diagnosis and therapy for head


and neck malignancies

Wesley L. Hicks, Jr, MD


Guest Editor

Squamous cell carcinoma is the most common histologic malignancy of


the head and neck region. Despite this monotonous pathologic presentation,
there are a plethora of treatment options and clinical outcomes based on
both the site and stage of the primary tumor. The recent movement to com-
bined modality therapy has been driven by the clinical need to improve dis-
ease-free survival while minimizing functional and cosmetic morbidity. Here
much more work can and should be done. Advancement in treatment
and survival in head and neck surgery, in our opinion, requires further
translational research efforts melding clinical expertise with bench scientific
discovery.
Oncologic head and neck surgery is one of the most clinically challenging
and complex areas of surgical oncology. This issue of the Surgical Oncology
Clinics of North America presents what we believe is a rational organ-specific
approach to malignancies of this region. This issue is not intended to be an
exhaustive explanation regarding the armamentarium or clinical paradigms
for the treatment of head and neck cancer. We anticipate, however, that it
will serve as a solid foundation for those who wish to pursue a personal clin-
ical interest in head and neck surgical oncology.
We anticipate that this issue will give readers a general overview of head
and neck cancer and the common surgical/medical approaches to this dis-
ease. Each article is a self-contained clinical caveat with a complete explan-
ation of how specific subsites within the head and neck region can be

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doi:10.1016/j.soc.2003.12.009
xvi W.L. Hicks / Surg Oncol Clin N Am 13 (2004) xv–xvi

evaluated and treated. After reviewing the articles in aggregate, my belief


was affirmed that an understanding of the clinical nuances pertinent to each
head and neck subsite must be mastered to obtain effective and improved
clinical outcomes.
I wish to express my sincere gratitude and thanks to the contributing
authors, whose diligent and exacting work made this issue possible.

Wesley L. Hicks Jr, DDS, MD, FACS


Department of Head and Neck Surgery
Roswell Park Cancer Institute
School of Medicine and Biomedical Sciences
State University of New York at Buffalo
Elm & Carlton Streets
Buffalo, NY 14263, USA
E-mail address: wesley.hicks@roswellpark.org
Surg Oncol Clin N Am 13 (2004) 1–11

The role of genomic instability


in the pathogenesis of squamous cell
carcinoma of the head and neck
Sam M. Wiseman, MD, FRCS(C)a,1,
Daniel L. Stoler, PhDb, Garth R. Anderson, PhDa,c,*
a
Department of Surgical Oncology, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA
b
Department of Experimental Pathology, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA
c
Department of Cancer Genetics, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA

Human beings are composed of a highly complex community of cells, and


each cell type has its own role that is defined by the genetic instructions it
expresses. For cells to function normally, their genetic instructions must be
accurately transmitted from one generation to the next. The information
carried by the genetic code must be accurately replicated and efficiently
repaired to ensure the survival of cells, organisms, and species. In humans,
the importance of maintaining the integrity of their genetic blueprint can be
appreciated by the approximately 130 genes involved in DNA repair alone
[1]. When these cellular self-repair mechanisms break down, or when bathed
in an environment of genotoxic compounds, cells become genomically
unstable. Ultimately, this genomic destabilization, or instability, results in
the natural selection of a genomically heterogeneous cellular mass, or
cancer, that threatens the survival of the organism as a whole. The impor-
tance of genomic instability in tumorigenesis and tumor evolution may be
seen in the work of numerous investigators who have demonstrated that
cells must undergo multiple genetic alterations to become neoplastic. Loeb
[2,3] and Jackson and Loeb [4] determined that the normal rate of mutation
is insufficient to allow for the observed genetic change in neoplasms to take

1
Current address: Department of Surgery, St. Paul’s Hospital, 1081 Burrard Street,
Vancouver, British Columbia, Canada, V6Z 1Y6.
* Corresponding author.
E-mail address: garth.anderson@roswellpark.org (G.R. Anderson).

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doi:10.1016/S1055-3207(03)00118-2
2 S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11

place. Genomic instability is now seen as an essential enabling component


that allows tumors to evolve [5].
With a yearly global incidence of 500,000 cases, head and neck squa-
mous cell carcinoma (HNSCC) ranks as the sixth most prevalent cancer
worldwide [6]. The American Cancer Society estimates that there will be
28,900 new cases of oral cavity and pharynx cancers diagnosed and 8900 new
cases of larynx cancer diagnosed in 2002 [7]. Despite advancements in medi-
cine, surgery, and radiation therapy, the long-term survival of individuals
diagnosed with HNSCC has not increased significantly over the past 20 years,
with the 5-year survival rate remaining at 52% in the United States [8]. It is
estimated there will be 11,100 deaths from cancer at these head and neck sites
in 2002 [8]. Mortality from this disease correlates with tumor size and the
presence of local nodal or distant metastatic disease [9–11]. This article
provides an overview of the clinical and experimental evidence, and
implications, of genomic instability as a major force driving HNSCC tumori-
genesis and evolution.

Many patients with head and neck cancer are cancer predisposed
HNSCC arises from a complex interaction between the host (genetic
factors) and the environment. Tobacco exposure has long been recognized
as increasing the risk of developing HNSCC between 2- and 20-fold [12].
More than 50 years ago, Slaughter et al [13] recognized the ‘‘field can-
cerization’’ that occurs in patients with HNSCC as a consequence of pro-
longed carcinogenic exposure of the upper aerodigestive tract. It is this
‘‘field cancerization’’ that is believed to be responsible for the 2% yearly
incidence of second primary tumors that develop in this patient population.
Furthermore, the concurrent consumption of alcohol with tobacco may
have a multiplicative effect on the risk of developing HNSCC [14–16]. In
addition to tobacco and alcohol exposure, other environmental factors that
are currently believed to play a role in HNSCC development include viruses,
radiation exposure, and certain nutritional deficiencies [17–19].
Epidemiologic and experimental evidence suggests that, because of an
inherent inability to maintain their genomic integrity in the presence of specific
environmental stressors, certain individuals demonstrate a predisposition to
developing head and neck tumors. The occurrence of this malignancy, even in
the absence of environmental carcinogen exposure, supports this concept. The
current authors recently described a cohort of 40 nonsmoking, nondrinking
patients with HNSCC treated at Roswell Park Cancer Institute. These
patients tended to be elderly (median age, 60 y), female, and white. In addition,
they had oral cavity primary tumors and were predisposed to second primary
tumor development. Despite a lack of exposure to tobacco and alcohol, 10
patients (25% of study population) eventually developed a second primary
tumor. The occurrence of second primary tumors in this patient population
suggests a possible genetic pre11disposition of these individuals to HNSCC
S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11 3

development [20]. Information concerning whether nonsmoking patients with


HNSCC have a prognosis different from smoking patients with HNSCC is
limited. Koch and McQuone [21] described a cohort of 46 nonsmokers
(individuals who never used tobacco on a regular basis) who developed
HNSCC, and compared them to a large cohort of smokers who developed
HNSCC. Of the 46 nonsmokers in this study, 37 patients (84%) were also
nondrinkers. The overall length of survival of the patients in this study did not
vary significantly with either smoking history or drinking history.
Family members of patients with HNSCC also are predisposed to upper
aerodigestive tract tumor development. In a study performed in The
Netherlands, Copper et al [22] found that first-degree relatives of patients
with HNSCC had an increased risk of developing upper aerodigestive tract
tumors (relative risk [RR], 3.5), with an especially high risk amongst siblings
(RR, 14.6). Foulkes et al [23] performed a similar study in southern Brazil
and found first-degree relatives of patients with HNSCC to have a relative
risk of 3.5 times the general population for developing HNSCC. In this
study, siblings had a relative risk of 8.6 for developing the disease. In a study
performed in the United States, however, Goldstein et al [24] found only
a slight increase in the relative risk of first-degree relatives of patients with
HNSCC for developing these tumors themselves (RR, pharynx, 1.7; RR,
oral, 1.2). In a study examining 26 individuals with multiple primary upper
aerodigestive tract tumors, Foulkes et al [25] demonstrated that the relative
risk of developing HNSCC was significantly higher in relatives of individuals
who developed multiple versus single primary tumors (RR, 7.89 versus 3.53,
respectively). Only the study by Goldstein et al [24] collected smoking
details for relatives, and matching was performed according to racial group.
Thus, epidemiologic studies suggest the families of patients with HNSCC
are themselves genetically predisposed to developing HNSCC, although the
magnitude of this predisposition is limited.
There are several rare ‘‘cancer predisposition’’ syndromes that arise from
genes that maintain genomic integrity. These syndromes have a constellation
of associated malignancies, including HNSCC. These cancer predisposition
syndromes include the genomic instability syndromes, Werner’s syndrome,
Bloom syndrome, Fanconi’s anemia, and ataxia telangectasia. Patients who
have Bloom syndrome or Werner’s syndrome have deficient RecQ-like
DNA helicases [26,27]. Werner’s syndrome is an autosomal recessive dis-
order that has been linked to the WRN locus on chromosome 8p. Homo-
zygous individuals age prematurely and are cancer predisposed [26]. Bloom
syndrome is an autosomal recessive disorder that arises from an alteration
of the Bloom syndrome gene, which encodes a DNA helicase that interacts
with topoisomerase III and plays an important role in DNA repair. Affected
individuals have impaired fertility, immunodeficiency, dwarfism, and are
cancer predisposed [27]. Genomic instability arises in these individuals from
impaired DNA repair, and consequently, these individuals are vulnerable to
DNA damage and subsequent cancer development [26,27].
4 S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11

Fanconi’s anemia is a rare genetic disorder in which affected individuals


are predisposed to developing squamous cell carcinoma (SCC) of the gingiva,
tongue, and mandible. This disorder is also characterized by developmental
abnormalities and a propensity to develop hematologic disorders and bone
marrow failure. It is currently believed that the protein defects that arise in
affected individuals may result in loss of regulation of DNA repair [28].
Ataxia telangiectasia is a rare genetic disorder that arises from a defect in the
ataxia telangiectasia gene (ATM gene). The ATM gene functions in survey-
ing for DNA damage and is responsible for activating DNA repair and
apoptosis genes. Individuals homozygous for the defective gene develop
progressive neuromuscular degeneration, an unsteady gait, and have facial
or conjunctival telangiectasias, and are predisposed to cancer development.
Heterozygous individuals also have a cancer predisposition [29].
Hereditary nonpolyposis colorectal cancer is associated with a high fre-
quency of microsatellite instability. Mismatches of nucleotides may occur
during DNA replication when DNA polymerase inserts the wrong bases into
newly synthesized DNA. Normally, these DNA mismatches are repaired by
mismatch repair enzymes, and individuals with germ-line mutations in the
genes that encode these mismatch repair enzymes have impaired DNA
replication fidelity. The integrity of the mismatch repair enzyme systems is
measured by microsatellite instability, or a measure of the integrity of short,
tandemly repeated DNA sequences (microsatellites) distributed throughout
the human genome [30]. Individuals diagnosed with hereditary nonpolyposis
colorectal cancer have been reported to be at increased risk of developing
HNSCC [31].
Further evidence suggesting patients with HNSCC are cancer predisposed
may be appreciated on experimental studies applying mutagen sensitivity
testing to the HNSCC patient population. Hsu et al [32] developed the
bleomycin mutagen sensitivity test as a method of assessing cellular DNA
repair capacity. This test is performed by exposing lymphocytes in culture to
the drug bleomycin and quantifying the number of chromosome breaks per
lymphocyte in culture. This test has been successfully able to identify
individuals at high risk for developing head and neck tumors [33,34]. The
highest rates of chromosomal breakage are observed in individuals with
a family history of HNSCC and in those with multiple primary tumors
[33,34]. The DNA repair capacity after exposure to the carcinogen
benzo(a)pyrene diol epoxide also is impaired in patients with HNSCC [35].
In addition, investigators have found that certain polymorphisms of the
DNA repair gene XRCC1 are associated with an increased risk for HNSCC
development [36].

Genomic instability and head and neck cancer


Genomic instability may be broadly considered either chromosomal or
intrachromosomal. Intrachromosomal genomic instability, the form most
S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11 5

frequently observed in sporadic disease, consists of amplifications, deletions,


inversions, and oligobase or point mutations. These alterations can be readily
assessed by comparative genomic hybridization (CGH) and microsatellite
instability measurements. Independent measures of intrachromosomal
instability can be assessed by cytogenetic techniques and CGH on ordered
Bac clone arrays. Chromosomal instability, changes in ploidy status, and
chromosomal translocations can be visualized by cytogenetic analytic
techniques. Although not all chromosomes are affected in each tumor, all
autosomal chromosome arms have been described as being affected in head
and neck tumors [17,18,37]. Although clustering aberrations have been
described, consistent cyogenetic abnormalities common to all HNSCCs have
not been demonstrated [17,18,37]. CGH analyses performed on HNSCCs
have demonstrated multiple chromosomal aberrations found in these tumors
[38–40]. Using CGH methodology, Hashimoto et al [40] were able to
demonstrate a correlation between specific chromosomal aberrations and
pathologic tumor stage in 32 patients with HNSCC.
The literature has been conflicting regarding the role of microsatellite
instability in head and neck tumor progression. Piccinin et al [41]
demonstrated low rates of microsatellite instability in patients who had
HNSCC with a single primary or multiple primary tumors. Both groups had
similarly low rates of microsatellite instability. Using makers for 11
chromosomal loci, El-Naggar et al [42] examined microsatellite instability
in peripheral blood, dysplastic tissue, and SCCs. Although microsatellite
instability was absent in the blood, levels were twice as high in the cancers as
in the dysplastic tissue (30% versus 15%, respectively). This finding led these
authors to conclude that microsatellite instability played an important role in
HNSCC progression. Field et al [43], however, were unable to demonstrate
any correlation between microsatellite instability and clinicopathologic
features (tumor site, tumor grade, nodal metastasis, disease stage, history of
prior treatment, or alcohol consumption) in patients. Thus, whereas
measurements of microsatellite instability in HNSCC suggest genomic
instability is driving tumor progression, they have been of limited clinical
applicability.
The study of the fraction of chromosomal arms on which allele loss is
observed, or the fractional allelic loss rate (FAL), has demonstrated how
measurements of genomic instability in patients with HNSCC may be of
clinical value. By studying 80 HNSCCs, Field et al [44] were able to dem-
onstrate a positive correlation between FAL and tumor grade, neck nodal
status, and overall patient prognosis.

Cancer predisposition genes


Cancer predisposition genes may play an important role in the increased
genetic susceptibility observed in patients who have HNSCC. Important
6 S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11

cancer predisposition genes that have been found to be mutated in patients


with HNSCC include p16 and TP53 tumor-suppressor genes.
The p16 tumor-suppressor gene is located on chromosome 9p21 and
encodes a 16kDa protein that binds to the cyclin-dependent kinases (cdk) 4
and 6 and prevents them from complexing with cyclin D1. This inhibition of
D1-cdk 4/6 complex activity does not allow for retinoblastoma phosphory-
lation, and thus blocks the cell cycle G1/S transition. Somatic homozygous
deletions and mutations of the 9p21 region are commonly observed in patients
with sporadic HNSCC [45]. Recently, Yu et al [46] performed molecular
analyses of a family with a high incidence of HNSCC and melanoma, and
identified a germ-line p16 tumor-suppressor gene mutation. These results,
along with this group’s earlier description of a separate, unrelated family
harboring a p16 germ-line mutation and exhibiting a HNSCC predisposition,
suggest a familial HNSCC syndrome may exist [46].
Li-Fraumeni syndrome arises as a consequence of germ-line mutations in
the TP53 gene, which is located on chromosome 17. The affected individual
develops a sarcoma before age 45, has a first-degree relative with cancer
before age 45, and has another first- or second-degree relative with a history
of sarcoma at any age or a cancer diagnosed before age 45. Patients who
have Li-Fraumeni syndrome are at increased risk of developing laryngeal
cancer [47]. The TP53 gene is a well-known tumor-suppressor gene and
represents one of the most common sites for genetic abnormalities to be
found in human tumors [48]. The TP53 gene is frequently mutated in several
human cancers, including lung cancer, colon cancer, and breast cancer [49–
51]. Multiple investigators have demonstrated that 40% or more of sporadic
HNSCC contain TP53 mutations [52–54]. The TP53 gene product, the P53
protein, is believed to have a dual role in protecting the cell from cancer
development. The P53 protein causes cell cycle arrest, allowing damaged
DNA to be repaired; alternatively, it helps prevent DNA damage from being
passed on to the next cell generation by causing damaged cells to undergo
apoptosis before division. Therefore, cells that lack or only produce abnormal
P53 protein are more susceptible to malignant transformation [48].
In sporadic head and neck tumors, TP53 mutation is currently believed
to represent a relatively late step in head and neck tumor evolution. The
incidence of TP53 mutation in premalignant head and neck lesions has been
reported to be much lower (19%) than in invasive lesions (43%) [54]. Shin
et al [55] reported P53 immunohistologic expression by the adjacent normal
epithelium in 6 of 31 (19%) normal epithelium specimens adjacent to
squamous cell carcinomas, in 7 of 24 (29%) hyperplastic lesions, in 12 of 26
(46%) dysplastic lesions, and in 28 of 48 (58%) HNSCCs. In a group of 232
patients with HNSCC, Koch et al [56] described a much higher incidence of
TP53 mutations in smokers (44%) than in nonsmokers (18%). Field et al
[57] correlated tumor TP53 status and the patient’s history of smoking and
alcohol consumption, also suggesting both substances may be linked to
aberrant P53 expression in HNSCC.
S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11 7

Genetic heterogeneity of head and neck tumors


Despite considerable histologic homogeneity, HNSCCs do not all exhibit
uniform biologic behavior. Tumors from different head and neck sites display
a wide range of biologic behaviors, despite often being separated by only a very
small anatomic distance, and they are not treated in a uniform manner.
Recently, investigators have provided evidence that suggests, at the genetic
level, HNSCCs are actually a heterogeneous group of disease entities. Takes
et al [58] studied expression of several proteins (P53, retinoblastoma (Rb),
cyclin D1, myc, bcl-2, epidermal growth factor receptor (EGFR), neuro-
glioblastoma derived oncogene (neu), E-cadherin, epithelial cellular adhesion
molecule (Ep-CAM), desmoplakin 1, and nonmetastatic protein 23 [nm23])
in 33 laryngeal cancers, 31 pharyngeal cancers, and 36 oral cancers. These
authors found that cyclin D1 had a very high level of expression in the pharynx
cancer (P = 0.0004) and EGFR had a very low level of expression in the
larynx cancer (P\0.0001). Rodrigo et al [59] examined 38 laryngeal cancers,
29 oropharyngeal cancers, and 37 hypopharyngeal cancers for the following:
amplification of oncogenes at the 11q13 region (CCND1, FGF3, FGF4,
EMS1), oncogenes MYC and ERBB1, for integration of the human papilloma
virus types 6b and 16, loss of heterozygosity at P53 and NAT2, and cellular
DNA content. This group found that FGF3 and FGF4 had a significantly
higher degree of amplification in the hypopharyngeal tumors (P = 0.006 and
P = 0.0002, respectively). Aneuploid tumors were found in a significantly
lower proportion of larynx tumors than in other sites (P = 0.03). These
observed differences in genes and gene expression, at different head and neck
disease sites, provide early evidence suggesting that HNSCC may actually
represent a genetically heterogeneous group of diseases. Furthermore, there
may be different pathways of tumorigenesis and tumor progression that are
responsible for the observed clinical differences in biologic behavior of disease
originating from different sites. The genetic heterogeneity of head and neck
tumors is not surprising when the genomic instability exhibited by these
tumors is considered. Not only are these tumors genetically heterogeneous
from one tissue site to the next, however, but they may also exhibit
considerable intratumoral heterogeneity. Jacob et al [60] evaluated five tumor
regions in 12 patients who underwent surgery for oropharyngeal carcinoma.
Specimens were each evaluated by immunohistochemical assessment for
proliferation markers (Ki67 and proliferating cell nuclear antigen), for
quantitative DNA content, and morphologic tumor-front grading. Their
results demonstrated a considerable variation of proliferation and differen-
tiation both intratumorally (within the same tumor) and extratumorally
(between different tumors). Consistent with the genomic instability exhibited
by head and neck malignancies, these results suggest that HNSCCs are
genetically heterogeneous tumors. As has been suggested, perhaps head and
neck tumors should be studied in a manner similar to how they are viewed and
treated clinically, as separate and distinct disease entities [59].
8 S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11

Summary
Measurements of genomic instability, or identification of genes respon-
sible for instability, may potentially be used as molecular markers to predict
disease course and response to therapy. Other possible applications include
use of genomic instability measurements, or genes, as tools to screen for
primary or recurrent disease. Methodologies for detection of genetic
mutations in saliva, blood, and sputum have already been described
[61,62]. Brennan et al [63] have described a molecular technique for
analyzing histopathologically negative margins and lymph nodes for the
presence of p53 gene mutation. This study showed that a positive molecular
margin significantly predicted disease recurrence.
The recognition that HNSCC is a genetically heterogeneous disease repre-
sents a major step toward developing an understanding of its underlying
genetic basis. To develop an insight into this genetically heterogeneous
disease, investigators must not only focus their efforts on specific head and
neck disease sites. Laser-capture microdissection represents a powerful tool
for isolating very specific cell populations from tumors [64]. Leethanakul et al
[65] performed laser-capture microdissection on oral cavity SCC to construct
stage-specific cDNA libraries. Sequencing of 96 clones from each of the six
libraries constructed suggested the existence of 132 novel genes, which may
play a role in the pathogenesis of HNSCC.
The current literature suggests that many individuals diagnosed with
HNSCC are genetically predisposed to developing malignancy because of
some inherent deficiency of their capacity to maintain their genome in the
presence of environmental stressors. Head and neck cancers are highly het-
erogeneous tumors and exhibit a wide variety of forms of genomic
instability. Thus, genomic instability may be viewed as a fundamental force
driving head and neck tumorigenesis and evolution. Future study of the
specific genetic mechanisms that underlie genomic instability in the HNSCC
patient population is needed. It is only through study of this fundamental
force that drives the development of these tumors that clinicians may gain
the insight required to develop new diagnostic and therapeutic modalities to
benefit the HNSCC patient population as a whole.

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Surg Oncol Clin N Am 13 (2004) 13–35

Imaging in head and neck oncology


Ronald A. Alberico, MDa,b,*
Syed Hamed S. Husain, DOb, Igor Sirotkin, MDb
a
Department of Radiology, Roswell Park Cancer Institute, Elm and Carlton Streets,
Buffalo, NY 14263, USA
b
State University of Buffalo School of Medicine and Biomedical Sciences, Buffalo VA
Medical Center 3495 Bailey Avenue, Buffalo, NY 14215, USA

Since the initial description of the pathologic distribution and patterns of


spread of tumors in the head and neck, the pretreatment assessment of the
size, extent, and pattern of spread has been necessary for optimal treatment
planning. It has subsequently become apparent that decisions, including the
operative approach, possibility of organ preservation or functional
preservation of tissue, and the appropriateness of an operative role in
patient care, hinge on these important pieces of information. Clinical
examination alone, however, is limited in its ability to properly assess the
extent and size of head and neck tumors, especially for submucosal
extension of disease and extent of nodal metastasis.
Modern radiologic imaging has provided the means to maximize
information available to clinicians during the treatment-planning pro-
cess. The combination of CT, MRI, ultrasound, and positron emission
tomography (PET) has enabled clinicians to obtain a great deal of
information about the patient before planning the surgical approach. Both
CT and MRI have been shown to be superior to clinical examination in
evaluating the size and extent of head and neck tumors and in detailing the
extent of nodal metastases [1–4]. Imaging also has added to the cost and, in
some cases, the controversy of the preoperative assessment and post-
treatment follow-up period. The choice of which imaging modality is
preferred remains controversial and remains part of an ongoing discussion
[5]. This article describes a strategy for imaging head and neck neoplasia in
an effort to simplify the process and emphasizes the strengths and
weaknesses of the available imaging modalities. In addition, the article
emphasizes techniques for imaging and reporting on patients who have head

* Corresponding author.
E-mail address: ronald.alberico@roswellpark.org (R.A. Alberico).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00124-8
14 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

and neck cancer in a manner that maximizes the clinician’s ability to make
appropriate treatment plans and avoid unnecessary complications.
The primary goal in imaging of head and neck oncology is to answer the
pertinent clinical questions. Too often, the radiologist can get caught up in
the collateral findings and provide information that is confusing or
superfluous while omitting key points needed for the treatment plan.
Although the clinician may feel comfortable filling in the blanks, the scan
may not be optimally designed to answer the clinical question, particularly
in postoperative patients. Frequently, the radiology requests provide
insufficient clinical information to adequately plan the scan, possibly
resulting in exclusion of anatomy crucial to the diagnosis. The solution to
these problems is knowledge and communication. The radiologist must be
familiar with the surgical procedures available and the anatomic criteria that
exclude various procedures from consideration. In addition, the radiologist
must be made aware of the clinical findings and concerns to select the
appropriate imaging modality and optimize the imaging technique. The
radiologist’s goal should be not only to answer the questions of size and
extent of tumor but to point out potential surgical complications resulting
from vascular relationships to the tumor, and individual anatomic variants
that may complicate the procedure. The formation of a differential diagnosis
based on lesion location and imaging characteristics plays an important, but
secondary, role in this process. Even with the best modern imaging
available, the radiologist is still relegated to the role of gross pathologist,
with some limited physiologic data, and, as always, the final answer is in the
histology.

Imaging techniques
The radiology and head/neck surgery literature over the last decade has
supported either CT or MRI as the primary technique for evaluating
patients who have head and neck cancer. This situation has divided the
radiology community into two groups, each of which feels passionately
about their respective choices. CT has been shown to be superior to MRI in
evaluating necrosis in nodal metastases [6], whereas MRI is better for
detecting perineural extent of disease and disease at the skull base [5,7,8].
Other authors have shown improved lymph node detection with MRI [3].
Both modalities have advantages and disadvantages in the evaluation of
head and neck cancer. CT has the advantage of increased speed and
availability and better patient tolerance. The bony framework is better
evaluated with CT and small calcifications are more apparent. CT has the
disadvantage of requiring ionizing radiation and iodinated contrast agents.
MRI is more sensitive for subtle spread of disease along nerves and into the
skull base. In addition, MRI has higher soft tissue contrast resolution and
direct multiplanar imaging capability. Disadvantages of MRI include lower
patient tolerance and dangers associated with metallic implants, pacemakers
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 15

and other hardware, and increased expense. MRI is also subject to many
artifacts that can make interpretation more difficult. Patient motion is
always a concern in MRI, particularly in patients who have difficulty
suspending swallowing and lying flat.
PET scanning and ultrasound take a definite back seat to CT and MRI in
evaluating the head and neck. Ultrasound is useful for image-guided biopsy
and can provide the fastest, easiest means to guide the needle to the
appropriate target. Doppler sonography has shown some ability to improve
the specificity and sensitivity of nodal staging in clinically N0 neck disease,
as has PET imaging, but the clinical criteria for exploring N0 neck disease
frequently obviates the need to use PET or ultrasound for this purpose [9].
The current authors have found that, for most patients, CT, when
properly performed, provides a readily available and easily tolerated
assessment of head and neck neoplasia. It is easier to interpret for nodal
staging and successfully completed more often than MRI. Multidetector CT
obtained with thin images (2.5 mm) and contrast is able to detect
perineural disease and is readily reformatted into multiple imaging planes.
The current authors typically assess patients initially with CT and will
obtain MRI only if perineural spread of disease is suspected or ambiguous
on CT, or to better evaluate cartilage or marrow invasion. MRI is also
useful in patients who have tumors that are typically lower in attenuation on
CT, such as liposarcomas, and may provide additional information in
patients with this type of tumor. The current authors also use MRI for
thyroid tumors that may potentially be treated with radio-iodine therapy to
avoid the iodine load inherent in CT contrast media. Gadolinium contrast
agents, which are usually used in MRI, can be used as an alternative for
specific patients in CT who are allergic to iodinated contrast and who have
contraindications to MRI evaluation. When necessary, the current authors
use gadolinium as an alternative contrast agent in CT.
All scans are not equal, and to answer the pertinent clinical questions,
properly performed scans are needed. The current authors begin all CT
imaging for head and neck cancer above the orbit to include the skull base
foramina and pterygopalatine foramen. The authors previously used single
detector helical scanners with 5-mm thick sections at 5 mm intervals with 3
mm sections through the larynx. Currently, with multidetector scanners, it is
possible to scan with 2.5 mm section thickness and 2.5 mm section interval
through the entire neck without significant time constraints. Multiplanar
and three-dimensional models can be readily obtained from these data,
including CT angiography as needed to assess vessel–tumor relationships.
Artifacts on CT at the oral cavity can limit the evaluation of the intrinsic
tongue and hard palate; sections angled through the oral pharynx using
a coronal oblique orientation can result in improved visualization of these
areas with a minimum of effort (Fig. 1). It is important to find an imaging
center that uses techniques such as these, with an effort to guide the
treatment plan of the individual patient in the proper direction.
16 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 1. (A) Scout image from a CT scan of the neck and skull base for SCC shows dental
hardware and the usual scan section orientation. (B) The axial section from the angle scanned in
A at the level of the oral pharynx has extensive artifact from dental hardware, which obscures
the pharyngeal and parapharyngeal structures (arrow). (C) Scout image with coronal oblique
sections planned to avoid dental artifact through the oral pharynx. (D) The oral pharyngeal
walls and tonsils are now visible with associated left-sided mass (arrow).

Imaging the primary tumor


The most important role of imaging in head and neck cancer is to
evaluate the primary tumor and its extent. Although T1 lesions are much
more conspicuous on clinical examination than in images (Fig. 2),
submucosal disease and the extent of tumor across tissue planes and along
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 17

nerves is best seen with imaging [10,11]. The findings may affect the choice of
radiation field needed to cover a lesion and can affect the surgical options
offered to the patient. The extent of tumors can frequently be observed
through the submucosal spaces on the images, resulting in higher tumor
staging than is suspected on clinical grounds, whereas in other cases the
clinical staging is confirmed. The images are key in defining the final extent
of the tumor (Figs. 3 and 4). Invasion of tumor into adjacent structures,
such as the mandible, or along perineural pathways may be clinically
inconspicuous. The sensitivity and specificity of imaging in detecting these
patterns of disease is well described in the literature; MRI is the preferred
method for detecting perineural disease and mandibular invasion [10–19].
Most reports to date have not accounted for recent advances in CT
technology, including multidetector scanning. The current authors have
found that perineural spread, although more obvious on a high-quality,
motion-free MRI, is detectable on CT, in most cases, by loss of the normal
fat signal at the foramen [10,18–19]. Perineural spread of tumor is usually
the result of squamous cell carcinoma (SCC), although this finding is likely
caused by the prevalence of this tumor in the population. Perineural spread
is also commonly seen in adenoid cystic carcinoma, followed by
mucoepidermoid carcinoma [10,18]. Because perineural spread is present
in a higher percentage of cases in these relatively rare tumors, MRI may
provide a more sensitive assessment of the extent of disease for salivary

Fig. 2. Axial section from a contrast-enhanced CT scan with a subtle high-attenuation lesion
(arrow) that represents a T1 SCC. This finding was much more apparent on clinical
examination.
18 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 3. (A) This axial contrast-enhanced CT section reveals a typical-appearing high-


attenuation mass of the right floor of mouth and tongue (arrows). (B) The coronal reformatted
image from the scan in A demonstrates the superior inferior extent of the mass (arrows) and
confirms the lack of extension across the midline.

malignancy. MRI offers advantages in detecting marrow invasion in the


mandible and the cartilage of the larynx (Figs. 5–9).
SCC, which originates in the mucosa, comprises most head and neck
cancer. Imaging can play a roll in the preoperative diagnosis of different
histologic subtypes by placing tumors in different spaces in the neck. The
suprahyoid neck is typically divided into muscosal, parapharyngeal, parotid,
and masticator spaces, with the parapharyngeal space further divided into
pre- and poststyloid components. The mucosal space is composed of the
mucosal surfaces of the nasal and oral pharynx. Lesions in this space are
most likely SCC with minor salivary tumors, including benign, mixed
tumors; mucoepidermoid carcinoma; and possibly adenoid cystic carci-
noma. The mucosal spaces of the oral pharynx, specifically the soft palate,
may provide perineural pathways of tumor spread along the greater palatine
or lesser palatine nerves (Fig. 10). The parotid space includes superficial and
deep lobes of the parotid and involves the space between the styloid process
and posterior mandibular ramus (stylomandibular tunnel). Tumors of the
parotid include the primary salivary tumors listed previously and metastatic
disease and lymphoma involving intraparotid nodes. The parotid space
provides a pathway of perineural spread along cranial nerve VII to the
stylomastoid foramen (see Fig. 9). The poststyloid parapharyngeal space
(carotid space) is defined by the styloid process and fascia anteriorly,
paraspinal musculature posteriorly and medially, and the sternocleidomas-
toid (SCM) muscle laterally. Tumors of this space include schwannomas,
glomus tumors, metastatic adenopathy or lymphoma, and lipomas or
liposarcomas. Perineural spread along the vagus nerve or direct spread
along the carotid artery or jugular vein can lead into the skull base. A mass
within this space can also result in vocal cord paralysis by means of its effect
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 19

Fig. 4. (A) Axial contrast-enhanced CT of the neck reveals a high-attenuation mass in the right
pharyngeal tonsil (arrow). (B) A section lower in patient shown in A demonstrates involvement
of the tongue as the tumor spreads anteriorly along the palatoglossus muscle (arrows). (C) A
section higher than that shown in A reveals some early spread to the soft palate as well (between
arrows).

on the vagus nerve. The prestyloid parapharyngeal space borders the


masticator space anteriorly, the mucosal space medially, and the styloid
process posteriorly. It contains fat and lymphatics and is rarely directly
involved as a primary tumor site. Displacement of this fat by large masses
can give insight as to which space a large mass is originating from, thus
affecting the differential diagnosis. This space communicates with the
pterygopalatine fossa (see Fig. 8) and has access to all perineural routes
associated with the fossa, including spread along the vidian and rotundum
canals and into the inferior orbital fissure. The masticator space is defined
by the muscles of mastication and is affected primarily by sarcomas and
nerve sheath tumors, including rhabdomyosarcoma, liposarcoma, and
schwannomas. Metastatic disease and lymphoma can affect this space as
20 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 5. (A) Sagittal T2-weighted MRI image reveals a large intracranial component to this
esthesioneuroblastoma (arrows). Note the cystic and solid components of the mass, which is
a characteristic of these tumors. (B) The coronal T1 fat-saturated gadolinium-enhanced image
reveals the heterogeneous enhancement of this lesion and its sharp demarcation from the brain,
which is not yet invaded (arrows).

well. Perineural spread from the masticator space usually involves cranial
nerve V and specifically its third division (see Figs. 6 and 7).
Imaging of the infrahyoid neck is less complex overall but requires
knowledge of laryngeal anatomy and operative approaches. Most infra-
hyoid head and neck tumors are SCC or metastatic disease to the lymph
nodes. Three-dimensional and multiplanar modeling of the CT data can
provide the surgeon with a better appreciation of the anatomy pre-
operatively, providing a more surgically oriented perspective of the
pathology and, in some cases, allowing for production of synthetic
prostheses to be prepared preoperatively to fit the patient’s anticipated
surgical defect [20–22]. The normal distribution of adipose tissue in the
larynx allows clinicians to differentiate the false from the true vocal cords on
CT and to see the paraglottic space (see Fig. 10; Fig. 11). The various
surgical approaches to laryngeal cancer include supraglottic and supra-
cricoid laryngectomy and vertical hemilaryngectomy and total laryngecto-
my. Diagrams of these procedures can be modeled from modern CT images
(see Fig. 11; Figs. 12 and 13). For patients with laryngeal tumors, the images
can define extension of a primary neoplasm in the paraglottic space across
the laryngeal ventricle or across the midline that would render supraglottic
or vertical hemilaryngectomy unlikely to provide tumor-free margins. This
finding would affect the potential for operative cure in these patients. With
this information, the head and neck surgeon can have a more informed
discussion with the patient regarding potential operative options and
prognosis. CT provides the best, most rapid, and consistently motion-free
images in this population. MRI is more sensitive for invasion of the thyroid
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 21

Fig. 6. (A) Axial contrast-enhanced fat-saturated T1 image of the suprahyoid neck reveals
a nodule of enhancing tissue (arrow) in the mandibular foramen of this patient who has
a retromolar trigone SCC. (B) Contrast-enhanced axial CT section in the same patient shows
the lack of fat signal typical of perineural spread in the same mandibular foramen imaged 3
weeks earlier (curved arrow). Note the normal fat signal in the foramen of the contralateral side
(straight arrow). (C, D) The invasion of the mandibular marrow space is clearly seen in these
coronal and axial contrast-enhanced T1-weighted MR images from the same patient (arrows).

cartilage and may be useful in certain patients for evaluation of direct


cartilage invasion.
The hypopharynx is readily seen on MRI and CT, and patterns of tumor
spread to the pyriform sinus and retropharyngeal tissues typically can be
defined by high attenuation on contrast-enhanced CT and enhancement on
MRI. Direct invasion of the cervical spine or perivertebral space is best
evaluated with MRI because it is more sensitive for bony invasion than CT.
There is currently no well-defined role for PET or ultrasound in evaluating
the primary tumor site in the infrahyoid neck.
Less common tumors in the infrahyoid neck also include tumors of the
perivertebral space, which includes the cervical spine and cord, and the
perivertebral muscles. These must include all primary and metastatic bone
22 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 7. (A) An axial contrast-enhanced T1-weighted image from an MRI of the neck reveals an
enhancing mass at the top of the right masticator space just below foramen ovale (between
arrows). (B) A coronal contrast-enhanced T1-weighted image reveals the perineural spread of
the tumor into foramen ovale along cranial nerve V3 to involve Meckel’s cave (long arrow).
Compare this to the normal contralateral side (short arrow).

tumors, and neurofibromas, schwannomas, and other central nervous


system tumors. Tumors of the thyroid gland include adenomas and thyroid
malignancies of all subtypes. A detailed discussion of thyroid neoplasm is
beyond the scope of this article; however, imaging of the thyroid is best
obtained with a combination of nuclear medicine thyroid scanning,
ultrasound, and MRI. CT is excellent as well; however, the iodine load
from contrast material can decrease uptake for potential nuclear medicine
scanning and result in delayed therapy, so care must be taken to avoid
unnecessary iodine loads before diagnosis. The poststyloid parapharyngeal
space continues into the infrahyoid neck as the carotid space and is a site for
metastatic disease and lymphoma. Glomus tumors and schwannomas also
can be found in this space.

Nodal staging
Staging of nodal disease in the neck traditionally has been based on
clinical examination; however, limitations in the clinical examination result
in relatively low sensitivity and specificity (60%–70%), leading to an
unacceptably low negative predictive value [3,4,23]. Improved negative
predictive value is important in defining a population that would benefit
from surgery without the need for neck dissection and radiation. Imaging,
including CT and MRI, uses a threshold size to determine if a node is
abnormal. Depending on the reference, this size varies between 1 and 1.5
cm. Morphology of the node is also considered in determining the likelihood
of metastasis, including the transverse-to-longitudinal ratio and the
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 23

Fig. 8. An axial section from a contrast-enhanced CT of the neck reveals loss of the normal fat
attenuation within the left pterygopalatine fossa (arrow). This finding was confirmed to be
perineural spread from the patient’s left tonsillar fossa SCC.

Fig. 9. An axial section from a contrast-enhanced CT of the neck in a patient with


mucoepidermoid carcinoma of the left parotid gland reveals loss of the normal fat attenuation
in the left stylomastoid foramen (thick arrow). Note the normal low attenuation of the
contralateral side (thin arrow).
24 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 10. (A) Axial CT section of the larynx a t the level of the false cords (arrows). Note the low
attenuation of the paraglottic fat. (B) Axial CT section at the level of the paraglottic space
shows the fat within the space to better advantage (arrows). (C) Coronal reformation from the
same scan shows the fatty attenuation in the paraglottic space (long arrow) and false cords (short
arrow) compared with the muscle attenuation of the true vocal cords (curved arrow). (D) Off-
midline sagittal reformat from the same patient clearly shows the air within the laryngeal
ventricle (long arrow). The false cords are above the ventricle with the muscular true cords
below.

attenuation of the node [24,25]. Even with a combined approach, the


literature varies widely on the specificity and sensitivity of nodal staging
with MRI and CT, with sensitivity varying from 40% to 80% and specificity
from 90% to 95%. In a large-scale study by Curtin et al [3], attempts were
made to obtain a negative predictive value of 90% with CT and MRI using
size criteria alone or size criteria in combination with internal morphology.
Although CT could achieve this 90% negative predictive value, it required
a size threshold of 5 mm, which decreased positive predictive value to 44%.
MRI did not achieve a 90% negative predictive criterion in that study,
regardless of size threshold used. Attempts at increasing sensitivity with
PET scanning or Doppler sonography to detect malignancy in normal-size
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 25

Fig. 11. (A) An axial contrast-enhanced CT scan at the level of the true vocal cords (arrow).
Note the high attenuation (muscle) of the true vocal cords compared with the false cords seen in
Fig. 10. The line delineates the surgical resection for a vertical hemilaryngectomy. Because the
cricoid cartilage is preserved by the surgery, extension of tumor into the cricoid or arytenoid
would contraindicate this type of voice-sparing procedure. (B) A color three-dimensional
diagram of the larynx, again showing the surgical plan for a supracricoid laryngectomy. The
thyroid cartilage is blue, the cricoid cartilage is light blue, the epiglottis is red, and the hyoid
bone is white.

nodes have had some success, but the sensitivity is only marginally improved
over that of MRI or CT [25,26]. Combined MRI and CT have approached
90% sensitivity for metastatic node detection in one study [1]. It would seem
that, regardless of imaging technique, negative predictive value has not
achieved a level that would be clinically useful in excluding clinically N0
neck disease without unacceptably low positive predictive values.
Until negative and positive predictive values of nodal disease are
improved, exclusion of patients from treatment of the neck with radiation
or neck dissection based on imaging is not appropriate; however, there are
other uses for nodal assessment with imaging that can affect patient care and
prognosis. The location of nonpalpable adenopathy in the neck in patients
who have disease of any nodal stage can affect the size and extent of
radiation fields and the side and extent of neck dissection. Given the
increased sensitivity of image-based nodal staging compared with clinical
staging, this is sufficient to warrant nodal evaluation with imaging.
The description of nodal locations in the neck requires precise language
to facilitate communication between the head and neck radiologist, the
surgeon, and the pathologist. Without such a system, patterns of nodal
disease and their relationships to tumor prognosis and location would lack
precision and result in inaccuracies in clinicians’ knowledge of disease
prognosis and patterns of spread, limiting their ability to treat patients.
Various classification systems for nodal disease in the neck therefore have
been used in the past, including those of the American Academy of
26 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 12. (A) Sagittal CT reformatted image of the neck reveals the resection plan for
a supraglottic laryngectomy. Note the line goes through the laryngeal ventricle and spares the
vocal cords. (B) Coronal section reformatted from the same scan shows the surgical plan
through the laryngeal ventricle between the true and false vocal cords. (C) Color volume–
rendered model of the larynx again reveals the surgical margin. The thyroid cartilage is blue, the
cricoid cartilage light blue, the hyoid bone is white, and the epiglottis is red.

Otolaryngology–Head and Neck Surgery and the American Joint Commit-


tee on Cancer. These classification systems did not always precisely define
nodal locations, however, and did not account for retropharyngeal nodes
described in the original anatomic system proposed by Rouviere [27]. The
previous nodal classification systems also have been based on anatomic
landmarks that are not necessarily conspicuous in the axial plane. Because
modern nodal assessment almost always includes imaging, a modern
classification system should refer to anatomic landmarks that are reliably
identified in the axial plane and at the time of surgery.
In 1999, Som et al [27] undertook this considerable task. They defined
level I as submental (IA) and submandibular (IB), with both levels anterior
to the posterior margin of the submandibular gland, above the hyoid bone,
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 27

Fig. 13. (A) An axial CT reformatted image at the level of the true vocal cords demonstrates the
surgical plan for a supracricoid laryngectomy. Note the cricoid cartilage is spared and only one
arytenoid cartilage is resected. (B) A sagittal section of the same scan shows the two possible
plans for the supracricoid laryngectomy, with and without preservation of the epiglottis.

and below the mylohyoid muscle. Level IA is between the anterior bellies of
the digastric muscles, with level IB lateral to the digastric muscle anterior
belly. Level II extends from the skull base to the bottom of the hyoid bone,
posterior to the back of the submandibular gland, and anterior to the back
of the SCM muscle (Fig. 14). Level IIA consists of nodes in the level II
region that are inseparable from the jugular vein by a fat plane, with level
IIB nodes posterior to the vein and separable from it by a fat plane. Level III
nodes are anterior to the back of the SCM muscle and between the bottom
of the hyoid bone and the bottom of the cricoid arch (Fig. 15). Level IV
nodes are located below the bottom of the cricoid arch but above the
clavicles. They are anterior to the line joining the back of the SCM muscle
with the posterolateral margin of the anterior scalene muscle, and lateral to
the common carotid arteries. Level V nodes are posterior to the back of the
SCM muscle from the skull base to the bottom of the cricoid arch (level VA)
and continue posteriorly to the line connecting the back of the SCM muscle
and the posterolateral margin of the anterior scalene muscle to the level of
the clavicle (level VB). Level VI nodes are between the common carotid
arteries from the bottom of the hyoid bone to the top edge of the
manubrium, with level VII nodes located between the carotid arteries below
the top edge of the manubrium to the level of the brachiocephalic vein. The
level of the clavicles is defined as the first axial section in which the clavicles
are visible. The supraclavicular nodes are at the level of the clavicles lateral
to the common carotid arteries. Retropharyngeal nodes are defined as
medial to the internal carotid arteries, within 2 cm of the skull base.
This system provides the precise framework needed to facilitate
communication among and between surgeons, pathologists, and radiolog-
ists. Although all nodal levels may not be commonly used by surgeons in all
28 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 14. An axial contrast-enhanced CT section reveals metastatic adenopathy at level IIA on
the right and the left (arrows). Nodes are above the bottom of the hyoid bone, posterior to the
back of the submandibular gland, and anterior to the back of the SCM muscle, inseparable
from the jugular vein. Note that the nodes are enlarged, abnormal in shape (rounded), and
abnormally low in attenuation.

locations, an effort to adhere to this classification system should improve the


quality of surgical–pathologic correlation and result in research in head and
neck cancer, which has historically been difficult to study because of low
numbers of patients and inconsistencies in language used in the literature
and pathology and radiology reports.

Other applications of head and neck imaging in malignant disease


Other applications of head and neck imaging include CT or ultrasound-
guided biopsy of suspected recurrent or primary disease, evaluation of the
neck post treatment, and assessment of anatomic variants that may impact
the surgical approach. CT-guided percutaneous biopsy has been widely
studied in the literature for virtually all potential targets, including the
brain. The application of this technology to head and neck cancer can result
in safe and efficacious tissue sampling of retropharyngeal, parapharyngeal,
and other deep or difficult-to-palpate regions of the neck [28,29]. With
proper techniques, nodal biopsy with ultrasound or CT guidance can be
performed with minimal risk to the patient [23]. The current authors’
preferred CT technique is to access the face through the buccal space using
a short guide needle to the posterior edge of the pterygoid muscle, allowing
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 29

Fig. 15. An axial contrast-enhanced CT section reveals an enlarged, rounded hypoattenuating


node at level III on the right (arrow). The node is between the bottom of the hyoid bone and the
bottom of the cricoid cartilage, lateral to the carotid artery, and anterior to the back of the
SCM muscle.

for multiple passes with a 22-guage needle into the substance of the mass,
without additional percutaneous passes and with good maintenance of an
entry point close to the tumor margin (Fig. 16). From this approach, the
guide needle can be angled slightly at the skin surface to obtain samples at
different locations within the tumor mass, with minimal additional risk. The
current authors have performed biopsies in 38 patients using this technique
over the last 4 years without complication. Sufficient tissue for diagnosis was
obtained in 98% of patients who underwent biopsy.
The use of imaging in postoperative patients is perhaps the most difficult
part of head and neck imaging interpretation for the radiologist. MRI in the
postoperative setting frequently proves difficult for patients, because motion
and suspension of swallowing can be difficult to control. MRI has been
shown to have a high false-positive rate after radiation, which increases over
time to as high as 58%; CT has a specificity and sensitivity of 80% to 90%
[30,31]. Knowledge of the surgical procedure performed and the type or
location of any operative flap reconstruction, and history of radiation
treatment, will decrease the false-positive rate in MRI. This again
emphasizes the need for communication between surgeons and radiologists
to obtain accurate evaluation of the patient and the optimal imaging
technique [32]. Recognition of the post-treatment appearance of head and
neck cancer on CT is an acquired skill that requires practice and readily
available follow-up information for the radiologist to become proficient.
30 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 16. (A) An axial CT section of the neck without contrast reveals a lateral pharyngeal node
on the left (arrow). The section includes part of the biopsy guide needle in the buccal space.
(B) This section shows the biopsy needle piercing the lateral pharyngeal node. Note the initial
scan was obtained with contrast to locate the carotid artery, which was clearly lateral to the
node before biopsy.

The operative flaps typically contain fat and muscle, with identifiable
vascular pedicles. The postradiation density of tumor is intermediate
between muscle and fat but may maintain the shape of the original neoplasm
(Fig. 17). The initial evaluation of PET scanning in recurrent disease and for
tumor response to chemotherapy has been promising [33–35], with some
articles stating improved sensitivity of PET over MRI and CT for
evaluation of recurrent disease. Overall patient numbers have been low in
these studies, however. Other studies have implied PET has a role during
initiation of chemotherapy to evaluate initial tumor response using glucose
metabolism as an indicator of tumor response. A lack of metabolic change
with initiation of therapy implies therapy may not be effective [31]. This
finding could potentially provide an early indicator that a new therapeutic
regimen should be considered.
The role of any radiologist is to provide the clinician with important
anatomic details about the patient that may affect the difficulty or feasibility
of the planned therapeutic approach. This communication is particularly
important with head and neck malignancies. The use of three-dimensional
and multiplanar reformatted images in CT or MRI to help define tumor
relationships to vessels and the likelihood of vascular, spinal, perineural, or
tracheal invasion is crucial. Controversy still exists as to whether CT or
MRI performs these perspective tasks with higher sensitivity, but the well-
trained eye, and the clinician who is informed of the planned clinical
procedure and is aware of the surgical approach and risks, is the best tool
for alerting the surgeon to potential pitfalls related to anatomic variants in
a specific patient (Figs. 18 and 19).
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 31

Fig. 17. (A) An axial contrast-enhanced CT section through the larynx at the level of the
paraglottic space reveals a high-attenuation mass crossing the laryngeal ventricle through that
space (arrow). (B) The coronal reformatted image from A confirms the paraglottic spread of the
tumor (arrow). This tumor also extended across the midline anteriorly, excluding the patient
from voice-preservation surgery. (C) A follow-up CT scan after radiation therapy in the same
patient reveals the typical low attenuation of treated tumor, which is between muscle and fat
density (arrow). (D) A coronal reformation of C confirms that the paraglottic space also shows
evidence of radiation effect (arrow). Note that the mass effect from the tumor has not yet
subsided and continues to indent the supraglottic airway.

Summary
Evaluation of head and neck cancer with imaging is a topic that is far
more extensive than can be covered in this article. The main reason for head
and neck imaging is to evaluate the true extent of disease to best determine
surgical and therapeutic options. This process includes evaluation of the
size, location, and extent of tumor infiltration into surrounding vascular and
visceral structures. Important anatomic variants must be pointed out so the
surgeon can avoid potential intraoperative complications. These variants
can be evaluated with the appropriate multiplanar and three-dimensional
images to provide as much information as possible to the surgeon
32 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

Fig. 18. (A) An axial contrast-enhanced CT section at the level of the hard palate in a patient
with a superficial palatal carcinoma on clinical examination reveals an asymmetry in
attenuation and size of the greater palatine foramen (solid arrow). Compare this to the normal
side (open arrow) in which the attenuation is normal and the foramen is comparatively small.
(B) A bone window of the same section demonstrates the size asymmetry to better advantage
(arrows). (C) Sagittal reformatted image of the mass demonstrates the lack of fatty attenuation
at the opening of the palatine foramen on the left (arrow). (D) Sagittal reformatted image of the
normal side reveals the expected normal fatty attenuation. This finding is consistent with
perineural spread on the CT and changed the surgical plan from intraoral resection to a split
mandible procedure with partial resection of the maxilla. Perineural tumor in the greater
palatine foramen was found pathologically.

preoperatively. Second, nodal staging should be assessed in an effort to


increase the number of abnormal nodes detected by physical examination
and, more important, to precisely define their location by a standard
classification system that can be understood and consistently applied by the
radiologist, surgeon, radiation oncologist, and pathologist. Although
secondary to the previously described tasks, imaging frequently enables
a limitation of the diagnostic and histologic possibilities based on lesion
location and signal-attenuation characteristics, which may lead the clinical
R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35 33

Fig. 19. (A) A volume-rendered CT laryngoscopy view reveals a posterior bulge in the wall of
the upper hypopharynx (arrows). (B) The cutaway view of the same image reveals a densely
enhancing structure in the submucosa of the retropharyngeal space (arrow). (C) An axial
contrast-enhanced CT section reveals the mass to be secondary to a tortuous carotid artery,
which resulted in a retropharyngeal position of the carotid bifurcation on the right (arrows).
This finding was brought to the attention of the head and neck surgeon.

investigation along a different path, saving the patient unnecessary risk and
shortening the time to diagnosis and ultimate treatment.
This article has attempted to detail the current state of the controversy
between CT, MRI, and other modalities, and has emphasized the constant
evolution of this controversy because of the evolving imaging technology.
Although CT and MRI are both well suited to evaluation of the deep spaces
and submucosal spaces of the head and neck, each has some limitations.
MRI has the advantages of higher soft tissue contrast resolution, the lack of
iodine-based contrast agents, and high sensitivity for perineural and
intracranial disease. The disadvantages of MRI include lower patient
tolerance, contraindications in pacemakers and certain other implanted
metallic devices, and artifacts related to multiple causes, not the least of
which is motion. CT is fast, well tolerated, and readily available but has
34 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

lower contrast resolution and requires iodinated contrast and ionizing


radiation. The current authors’ practice is heavily centered on CT for initial
evaluation, preoperative planning, biopsy targeting, and postoperative
follow-up. They reserve MRI for tumors that are suspicious for perineural,
cartilaginous, or bony invasion on CT, or for tumors such as adenoid cystic
carcinoma that are highly likely to spread by way of these routes. For
patients who have head and neck cancer, a radiologist who is educated in
the treatment options, patterns of tumor growth, and important surgical
landmarks, and who has a well-established pattern of communication with
the head and neck clinical services, including surgery, radiation oncology,
and pathology, is key in providing accurate and useful image interpretation.

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[34] Anzai Y, Carroll W, Quint D, Bradford C, Minoshima S, Wolf G, et al. Recurrence of head
and neck cancer after surgery or irradiation: prospective comparison of 2-deoxy- 2-[F-18]
fluoro-D-glucose PET and MR imaging diagnoses. Radiology 1996;200:135–41.
[35] Greven K, Williams D, Keyes JW Jr, McGuirt W, Watson NE Jr, Randall M, et al.
Positron emission tomography of patients with head and neck carcinoma before and after
high dose irradiation. Cancer 1994;74(4):1355–9.
Surg Oncol Clin N Am 13 (2004) 37–46

The expanding role of dental oncology


in head and neck surgery
Maureen Sullivan, DDS
Department of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA

Dental oncology is the discipline within dentistry that combines general


dentistry, maxillofacial prosthetics, oral medicine, and oral pathology. To
provide state-of-the-art care for patients who have head and neck cancer,
the dental oncologist must play an integral role in all facets of treatment,
whether surgical or nonsurgical. Historically, the maxillofacial prostho-
dontist was the only dental specialist involved in the treatment and reha-
bilitation of patients with head and neck cancer; however, it became
apparent that early intervention by a dentist familiar with the complica-
tions associated with head and neck malignancies was required. The oral
complications secondary to the management of head and neck malignan-
cies have been well described [1–3]. To maximize the possibility of optimal
function and cosmesis, and limit the possibility of complications that can
lead to significant morbidity, a comprehensive dental screening must be
performed during the pretreatment phase. Close communication between
the head and neck surgeon, radiation oncologist, dental oncologist, and
maxillofacial prosthodontist is paramount in achieving function and cure.
There are three treatment modalities involved in eradicating head and neck
cancer: (1) surgery; (2) radiation therapy, with or without chemotherapy;
and (3) combined treatment. Because all of these treatments dramati-
cally affect the oral environment, close scrutiny of the dental condition is
crucial.
With a complete understanding of the role of the dental oncology team
involved in the pretreatment, treatment, and rehabilitation phases of treat-
ing patients with head and neck cancer, the goal of cure with an acceptable
quality of life can be obtained.

E-mail address: maureen.sullivan@roswellpark.org

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00121-2
38 M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46

Dental oncologic assessment


Because radiation therapy is used frequently in the treatment of head and
neck malignancies, prompt attention to the dental condition at the time of
diagnosis can allow time for adequate healing before the onset of radiation,
if oral surgery is required. Frequently, the patient will require procedures
under general anesthesia performed by the head and neck surgeon to
formulate an appropriate plan for tumor removal. These assessment
procedures also provide the dental oncologist an opportunity to perform
necessary dental procedures in the operating room setting, which is
generally preferred by the patient and, more important, allows for longer
healing time if radiation treatment is required.
The oral cavity undergoes monumental insult as a direct result of
radiation therapy to the head and neck. The immediate effects of radiation
include mucositis, pain, trismus, and hypoguesia. These effects are variable,
depending on the type of radiation used, the dose, and the field of involve-
ment. Furthermore, these effects can be minimized with close attention to
the dental condition. The long-term effects may include xerostomia,
rampant dental caries, trismus, soft tissue necrosis, and, potentially the
most devastating effect, osteoradionecrosis (ORN).
Comprehensive evaluation of the dental patient includes Panorex
(Orthopantomograph OP 100, Instrumentarium Corp, Tuusala, Finland)
radiograph, a full-mouth series of intraoral radiographs, and intraoral
examination, including periodontal probing. All teeth deemed unrestorable,
especially those in the field of radiation should be extracted. This procedure
has received much attention in the literature in an attempt to find a formula
for dental extraction requirements before radiation [4,5]. All teeth with
advanced dental decay, with or without pulpal involvement, and advanced
periodontal disease are generally extracted. Partially impacted third molars
with evidence of pericoronitis and any teeth with periapical pathology should
be extracted. The time required for adequate healing should be between 2 to 3
weeks [6]. If third molars are completely impacted without evidence of
pathology, they are left and simply monitored. Again, if oral surgery is ad-
dressed during the head and neck surgeons’ initial treatment-planning phase,
there should be adequate time for healing if radiation therapy is required.
After all obvious sources of infection have been eliminated, the need for
existing restorative dental work is evaluated and any necessary restorative
dentistry is completed. The specific type of restorative material used in
patients that will become xerostomic has been a consideration [7]. There
have been a few studies evaluating the efficacy of fluoride-releasing materials,
and therefore the type of restoration is not as critical as removing a potential
source of mechanical irritation during treatment.
If the patient has not had a thorough periodontal scaling and prophylaxis
within the 3 previous months to diagnosis, these procedures should be
completed. The dental hygienist must be familiar with the secondary
M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46 39

complications associated with head and neck radiation. At this juncture, the
importance of impeccable oral hygiene can be emphasized. Recently, the use
of topical fluoride varnishes containing 5% sodium fluoride (eg, Duraphat,
Ivoclan, NA, Amherst, New York) have been shown to be effective in
preventing decay in the xerostomic population [8]. The topical fluoride varnish
is applied on the surfaces of all teeth. A daily fluoride delivery system is also
recommended. Many different means of fluoride delivery have been explored
in the literature [9,10]; these include the fabrication of custom fluoride carriers,
containing a 0.4% stannous fluoride product, which are worn nightly for 5 to
10 minutes. If this process is perceived to be arduous by the patient, the use of
a 1.1% fluoride paste is prescribed. Also at this time, an evaluation for
xerostomia is rendered based on the location of the tumor and the type of
subsequent radiation required. Historically, the radiation oncologist is
consulted regarding the use of a salivary stimulant, such as pilocarpine
(Salogen, MGI Pharma, Inc., United Kingdom), in an attempt to maintain
salivary function [11–13]. Pilocarpine (Watson Laboratories, Corona,
California) is a parasympathomimetic agent that stimulates exocrine gland
tissue. This action promotes salivation and is believed to be most effective if
administered at the onset of radiation. In a recent study, pilocarpine
administered during and after radiation therapy was found to offer no benefit
[14]. Amifostine (Ethyol, Medimmune, Inc., Gaithersburg, Maryland) has
been investigated for its use as a chemoprotectant, which reduces the severity
of radiation-induced mucositis and maintains salivary function in patients
with head and neck cancer undergoing radiation therapy [15–18]. This agent
must be administered daily throughout radiation therapy, with profound
hydration, to be effective without significant side effects. Although amifostine
shows promise, further controlled clinical studies must be performed.
Patients who are at high risk for developing trismus should be given
instruction for its prevention rather than treatment once it occurs. Patients
requiring resection of part of the mandible without reconstruction are at
considerable risk, especially if postoperative radiation is required. Those
patients who require partial maxillectomy that includes the tuberosity,
hamular notch region and the pterygoid fossa area are at risk, especially
if postoperative radiation is required. For tumors located within the
nasopharynx, in which the muscles of mastication and the temporomandib-
ular joint are within the field of radiation, trismus therapy must not be
overlooked. Daily opening exercises can be a worthwhile task for minimizing
this debilitating complication. Instructing patients on the use of tongue blades
to use as a lever and monitoring the range of opening can be useful as well [19].
The use of chemotherapeutic agents in the treatment of head and neck
cancer historically has not been as widely used as surgery or radiation.
Chemotherapy was reserved for advanced-stage disease or as an adjunct
when front-line treatment failed. For head and neck malignancies, chemo-
therapy can be used before surgery to decrease the possibility of distant
metastases, or it can be used concurrently with radiation therapy.
40 M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46

When chemotherapy is suggested as a course of treatment for head and


neck cancer, the timing of the dental assessment is important. The risk of
infection is great because of a depressed peripheral white blood cell count,
which can occur approximately 1 week after infusion. It is critical that the
patient is made aware of oral hygiene measures to limit the possibility of
bacteremia during cycles of chemotherapy. In addition, all possible sources
of oral infection should be eliminated before the onset of chemotherapy.
In conjunction with the pretreatment dental assessment, a maxillofacial
prosthodontist should evaluate the area to be treated, if prosthetic
rehabilitation is required. The head and neck surgeon should consult with
the maxillofacial prosthodontist before surgery to establish a design for
immediate surgical obturation if resection of the hard palate is unable to be
reconstructed by local or regional flap surgery. When large palatal defects
are anticipated, prosthetic rehabilitation is generally preferred, and there-
fore presurgical impressions and radiographs are required. The quality of
the remaining teeth and alveolar bone adjacent to the surgical defect is im-
portant when predicting the support for prosthesis. The use of split-thick-
ness skin grafts to line the surgical closure of the maxillary defect generally
allows for adequate scar band formation, which provides an optimal sur-
face for engaging the eventual prosthesis [20,21].
Presurgical facial impressions are crucial if tumor eradication involves
total auriculectomy or rhinectomy. Because large facial defects are challeng-
ing to reconstruct surgically, prosthetic reconstruction is frequently required.
At this stage, osseointegrated implants should be considered; this determina-
tion includes CT imaging to evaluate quality and quantity of available
bone. Because the retention of facial prostheses is of great concern, the
possibility of using implants should always be discussed at the pretreatment
phase [22]. The skin overlaying facial implants must be extremely thin and
ideally free of hair follicles.
Communication between the dental oncologist, maxillofacial prostho-
dontist, and the head and neck surgeon is important and should be initiated
at the pretreatment phase to allow for a more predictable reconstructive
outcome.

Dental considerations during treatment


Head and neck surgery that entails mandibulectomy with immediate
reconstruction involving free-tissue grafting is challenging for not only the
head and neck surgical team but the dental team as well. At the time of tumor
removal, the dental oncologist may be required to implement intermaxillary
fixation, with or without occlusal splinting, to ensure appropriate intercus-
pation of the remaining mandible. This procedure ensures that the remaining
mandible is able to function within the confines of the temporomandibular
joint and provides a template for positioning of the grafted bone. In the
M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46 41

immediate postsurgical period, infection is the greatest risk to the graft;


therefore, close observation and meticulous hygiene are required [23].
Osseointegrated implants in free-bone grafts have been used with greater
success in recent years. The placement of implants at the time of free-flap
surgery can be achieved, or at a second-stage surgery once graft viability has
been confirmed [24–27].
Immediate placement of a surgical obturator for defects of the hard
palate can allow the patient to speak and eat. The use of keratinized skin
grafts to line the surgical defect can be beneficial in providing a supportive
surface for a maxillary obturator. After the surgical packing has been
removed, the immediate obturator can be modified and worn by the patient
until complete healing has been achieved.
Close scrutiny during radiation therapy of patients who have head and
neck cancer is required to monitor toxicity. Mucositis is the thinning and
eventual breakdown of the oral mucosa caused by chemotheraputic agents
or head and neck radiation. This condition is first observed within 1 to
2 weeks of therapy and continues until therapy is completed. The severity
of radiation-induced mucositis depends on the tumor location, type of
radiation, and chemotherapy used, in addition to the patient’s ability to
maintain oral hygiene [28,29]. There is currently no means of preventing oral
mucositis, only a means of palliation once it occurs. Patients are at risk of
many types of infection when tissue breakdown occurs, and should be
treated for evidence of bacterial or fungal infections locally to avoid the
possibility of lapse in treatment. Rinsing with topical analgesics, coating
agents, or saliva substitutes can be recommended in addition to systemic
pain management. The use of partial and complete dentures should be
avoided until the acute effects of therapy have improved. It is during the
treatment phase that trismus therapy should be closely monitored if
radiation involves the muscles of mastication. This step is most significant
when surgery is combined with radiation therapy.

Long-term dental oncologic considerations


Following treatment, the dental oncology team must closely monitor
patients who have head and neck cancer to minimize the complications of
treatment. Because the treatment for tumors of the mandible, hard and soft
palate, tongue, and facial structures can significantly compromise a patient’s
ability to function, rehabilitation requires immediate attention to assessing
the patient’s post-treatment status. Evaluation for pain, infection, speech,
and swallowing, and evaluating the quality of the patient’s oral-care regimen
should be performed weekly following the immediate post-treatment phase.
Evaluating the healing of oral tissues before the placement of removable
prosthetics is recommended to decrease the possibility of unnecessary tissue
trauma.
42 M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46

For defects of the mandible caused by resections of the floor of mouth,


tongue, or mandible itself, fabrication of a mandibular resection prosthesis
retained by osseointegrated implants may be required to restore continuity.
If the mandible is reconstructed with a microvascular free flap, osseointe-
grated implants can provide a more reliable means of rehabilitation. The
success of the prosthesis varies significantly with the amount of hard and
soft tissue affected [30,31]. For patients with significant tongue morbidity,
a palatal augmentation prosthesis may provide better tongue contact to the
palate.
The reconstruction of a palatal defect can be extremely challenging
depending on the size of the defect, access to the defect, and the nature of
the residual dentition. Surgical reconstruction of the hard palate is possible;
however, if significant tissue bulk remains, rehabilitation with an intraoral
prosthesis is impossible [32]. If prosthetic rehabilitation is required,
fabrication of a definitive prosthesis can take place following complete the
healing of the surgical defect, which occurs between 3 to 6 months following
surgery. This may be delayed even further if radiation therapy is required.
The management of the surgical removal of some or all of the soft palate
is challenging. Fabrication of a speech-aid appliance attempts to provide
closure of the oral pharyngeal resection, thereby enabling separation of the
nasal and oral cavities. If the patient is edentulous, the retention of
a maxillary speech aid can be difficult; therefore, osseointegrated implants
may be considered. If the soft palate is present but not functioning, either
because of surgery or radiation, a palatal lift prosthesis may elevate an
incompetent soft palate [33].
With initiation of prosthetic rehabilitation, it is important to continue
monitoring patients with head and neck cancer who are at continued risk of
complications secondary to radiation therapy. For example, xerostomia
induced by head and neck radiation is well described in the literature [34,35].
Because there is currently no means of preventing xerostomia when the
salivary glands are in the field of radiation, attention to patient compliance
with oral hygiene protocol cannot be understated. Rampant tooth decay in
patients who have undergone radiation of the head and neck can lead to
significant morbidity.
Trismus therapy must be maintained not only during radiation therapy
but throughout the life of the patient. Patients’ progress can be monitored
at follow-up examination with the dental hygienist. If there is a lapse in
a regular trismus therapy, the ability to wear prostheses, eat, and maintain
posterior teeth becomes difficult. Tongue depressors or custom trismus
screws can be used to monitor patients’ compliance with daily opening
exercises.
Periodontal management is a challenge, especially for the teeth left in the
field of radiation therapy. It has been suggested that radiation increases the
periodontal attachment loss because of disruption in cellularity and
vascularity. It is generally agreed that 3-month recalls are required with
M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46 43

minimal soft tissue trauma, followed by a short duration of chlorhexidine


rinsing [36–38].
Despite efforts to maintain adequate oral health following head and neck
radiation, soft tissue breakdown, periodontal disease, or rampant decay can
necessitate the extraction of teeth in the field of radiation. This situation has
received considerable attention in the literature as a predisposing factor
in the development of ORN. ORN is defined as a radiation-induced
nonhealing wound rather than an osteomyelitis of irradiated bone [39].
ORN can occur spontaneously, from denture trauma, or most often from
trauma caused by dental extraction. It is generally agreed that the mandible
is at greater risk than the maxilla, and it rarely occurs when the total
radiation dose is less than 6000 cGy. The mandibular molar region is
generally the most affected area in most clinical studies. ORN can present as
a small, isolated area of exposed bone or, in advanced cases, progress to
pathologic fracture with profound pain [40–42].
There is a significant amount of controversy surrounding dental
extractions following radiation therapy. Some authors suggest that safe
oral surgery can be performed with nontraumatic techniques on patients
following radiation therapy [43,44]. Recent studies suggest that the risk of
postradiation ORN can be dramatically reduced if hyperbaric oxygen
treatments are used before dental extractions. Hyperbaric oxygen is believed
to promote the revascularization of hypoxic tissues [45,46]. Hyperbaric
oxygen therapy is extremely costly, however, and may be contraindicated in
the patient with compromised respiratory function. Most clinicians agree
that in high-risk patients where all attempts at maintaining the dental
condition have failed, all oral-surgical attempts should be made with
extreme caution.
In cases where ORN develops after head and neck radiation, close
communication between the dental oncologist, radiation oncologist, and
head and neck surgeon is required to determine the best course of treatment.
Clearly, conservative treatment involving local wound care is preferred if the
area involved is small and isolated. In cases of advanced necrotic lesions,
hyperbaric oxygen therapy can be of benefit in conjunction with surgical
resection of the affected area [47,48].

Summary
A comprehensive dental oncologic screening should be part of the
pretreatment workup of patients who have head and neck cancer. This
screening should be performed by a dentist who is familiar with the
pathologic process of disease and type of treatment being rendered; in
addition, he or she should comprehend the various morbidities associated
with eradicating head and neck malignancy. The dental oncologist must
provide the timeline for the surgeon and radiation oncologist in which all
necessary dental treatment will be completed. It is important at this juncture
44 M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46

to educate the patient as to the possible short- and long-term complications,


no matter what treatment course they choose.
Osseointegrated implants used in the rehabilitation of patients who have
undergone head and neck surgery have provided a more reliable means of
retaining intraoral and extraoral prostheses. With close communication
between the head and neck surgeon and dental oncologist, and careful
patient selection, better functional outcomes may be provided.

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Surg Oncol Clin N Am 13 (2004) 47–70

Current treatment options in squamous


cell carcinoma of the oral cavity
Carsten E. Palme, MB BS, FRACS,
Patrick J. Gullane, MB, FRCSC, FACS*,
Ralph W. Gilbert, MD, FRCSC
Department of Otolaryngology, University of Toronto, 610 University Avenue,
Toronto, ON M5G 2M9, Canada

Squamous cell carcinoma (SCC) of the oral cavity is a significant public


health issue, which uses a wide range of resources. It accounts for 14% of
head and neck cancers reported to the National Cancer Data Base each year
[1]. Approximately 29,000 new cases were diagnosed in the United States in
2002, and the mortality rate was approximately 25% [2]. In comparison,
France and Hungary have an annual incidence of 40 per 100,000 individuals,
with mortality in approximately 12 per 100,000 individuals [3]. The incidence
of this disease is even higher in developing nations where it is the third most
common malignancy after both cervical and gastric carcinoma [4].
The anatomic and functional complexity of the oral cavity and because
SCC is locally invasive and can involve adjacent sites make the diagnosis
and management of this disease entity extremely challenging. It is imperative
that physicians adopt a multidisciplinary approach that encompasses both
surgical and medical expertise. This approach necessitates not only onco-
logically sound ablation of the tumor but also timely and state-of-the-art
reconstructive techniques. In addition, adjuvant therapy used by both
radiation and medical oncologists is vital to improve disease-specific
outcome. Ancillary medical specialists, including radiologists, anesthesiol-
ogists, nurses, and nutritionists experienced in head and neck oncology, are
integral in the multidisciplinary approach. Finally, oral rehabilitation is not
complete without the expert assistance from speech pathologists, dentists,
and prothodontists.

* Corresponding author.
E-mail address: patrick.gullane@uhn.on.ca (P.J. Gullane).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00123-6
48 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Etiology
Predisposing factors in the development of oral cavity SCC can be
divided into those that are specific to the patient and those of environmental
origin. Most patients are men with a median age of 60 years [5]. There is an
increasing trend of this disease in women, however, who now account for
approximately 30% of all cases [6]. A recent Canadian report showed that
the incidence of oral SCC in women increased by 84% over the period
from 1983 to 1997 [7]. In addition, the incidence of oral cavity SCC is
approximately 4% in patients younger than 35 years [6].
The dominant causative environmental factor in the development of oral
SCC is smoking. This factor combined with the chronic consumption of
alcohol constitutes a 35-fold greater risk for developing an oral cavity
malignancy [2,8]. A constant and prolonged exposure to these two known
causative factors results in ‘‘field cancerization’’ of the oral mucosa [9]. The
mechanisms are multifactorial and include activation of proto-oncogenes
and deactivation of tumor suppressor genes. Genomic instability develops,
and this results in a chain of events that ends in the development of
malignancy with the potential for local destruction and distant spread
[10,11].
The culturally specific habits of chewing betel nuts and tobacco and
reverse smoking are also implicated in the cause of oral cavity SCC [12,13].
Although lip carcinoma is included within the oral cavity, it is important to
recognize that it may be caused by excessive exposure to ultraviolet
radiation and therefore should be classified more appropriately as a skin
carcinoma [14]. Other factors, such as poor oral hygiene, significant
periodontal disease, and chronic trauma from ill-fitting dentures or jagged
teeth, also have been proposed as potential causative factors. In addition
there are several other oral pathologic conditions that are potential
precursors in the development of malignancy, which include erosive lichen
planus, oral submucous fibrosis, erythroplakia, leukoplakia, and possibly
chronic hypertrophic candidiasis [2]. An association with Epstein-Barr virus
and the human papilloma virus has been suggested, but clear causation has
not yet been established [15–17].

Pathology
SCC accounts for approximately 90% of all oral cavity malignancies [5].
In the differential diagnosis, however, minor salivary gland carcinomas,
lymphoma, melanoma, mesenchymal tumors, and tumorlike conditions
must be considered. Submucosal malignancies arising at the junction of the
hard and soft palate often originate in the minor salivary gland and may
include adenoid cystic, mucoepidermoid, or acinic cell carcinoma. Mucosal
melanoma needs to be considered in the differential diagnosis of a bluish
mass on the alveolus. Other mesenchymal tumors, such as osteosarcoma,
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 49

can occur in younger patients. Tumorlike conditions, such as necrotizing


sialometaplasia, can involve the hard palate and present a diagnostic and
management dilemma. SCC of the oral cavity involves several distinct
subsites, each with its unique diagnostic and management challenges (Fig.
1). The most common site involved is the mobile tongue (ie, anterior two
thirds of the tongue), which accounts for approximately 30% of all oral
cavity SCC [5]. The floor of the mouth is second in frequency, with
approximately 28% of oral cavity SCC, followed by SCC involving the
upper (including the hard palate) and lower alveolar ridge, retromolar
trigone, buccal mucosa, and the lips. Staging of these tumors is classified
according to the Union Internationale Contre le Cancer and the American
Joint Committee on Cancer tumor-node-metastasis (TNM) system (Box 1)
[18].
Tumors of the mobile tongue occur most commonly on its lateral and
ventral surface and tend to spread in both a radial and vertical fashion.
Patients who have these lesions present with discomfort on swallowing;

Fig. 1. Oral cavity subsites. (Modified from Sharma PK, Schuller DE, Baker SR. Malignant
neoplasms of the oral cavity. In: Cummings CW, et al, editors. Otolaryngology–head and neck
surgery. Vol. 3, 3rd edition. St. Louis, MO: Mosby; 1998; with permission.)
50 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Box 1. TNM staging of oral carcinoma


Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor is 2 cm or less in greatest dimension
T2 Tumor is larger than 2 cm but no larger than 4 cm in
greatest dimension
T3 Tumor is larger than 4 cm in greatest dimension
T4 Tumor invades adjacent structures (eg, through
cortical bone, into maxillary sinus, skin, pterygoid
muscle, or deep muscle of tongue)
Nodal involvement (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Single ipsilateral node, 3 cm or less in
greatest dimension
N2a Single ipsilateral node, larger than 3 cm and not
more than 6 cm
N2b Multiple ipsilateral nodes, 6 cm or smaller
N2c Bilateral or contralateral nodes, 6 cm or smaller
N3 Metastasis in a lymph node more than 6 cm in
greatest dimension
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis)

Used with the permission of the American Joint Committee on Cancer


(AJCC), Chicago, Illinois. The original and primary source for this information is
the AJCC Cancer Staging Manual, 6th edition (2002) published by Springer-Verlag
New York (For more information, visit www.cancerstaging.net). Any citation or
quotation of this material must be credited to the AJCC as its primary source.
The inclusion of this information herein does not authorize any reuse or further
distribution without the expressed written permission of Springer Verlag New
York, Inc., on behalf of the AJCC.

these lesions are therefore usually diagnosed at an early stage (ie, T1 or T2).
Neoplasms that originate in the floor of the mouth and along the lower
alveolar ridge tend to invade the mandible early, and patients may present
with loosening of teeth and ill-fitting dentures. The retromolar trigone is
a less common site for oral cavity SCC but deserves special mention. These
tumors spread early to involve adjacent sites such as the mandible, tongue
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 51

base, tonsil, and soft palate. Once these lesions have extended beyond their
site of origin, treatment becomes more complex, with significant ablative
and reconstructive challenges. The hard palate and maxillary alveolus are
involved in approximately 10% of cases [5]. Aggressive local invasion
frequently occurs with extension to involve the paranasal sinuses,
pterygopalatine fossa, infratemporal fossa, orbit, and/or the cranial cavity.
SCC of buccal mucosa may occur de novo or become involved by way of
direct extension from other oral cavity subsites. This site includes all the
intraoral lining of the inner surface of the cheeks and lips from the line of
contact anteriorly to the pterygomandibular raphe posteriorly and attaches
to the superior and inferior alveolus. The buccal mucosa is a common site of
origin in India and the southeastern parts of the United States because of
the high incidence of betel nut chewing in the former and the use of snuff in
the latter [12,13]. SCC of the lip commonly occurs in white individuals who
have a life-long outdoor occupation [2].
Oral cavity SCC presents with regional cervical lymph node involvement
in a significant proportion of patients. The incidence of regional metastases
is associated with subsite, stage, and various histopathologic features (eg,
depth of invasion, malignancy grading of the tumor front, pattern of
invasion, growth pattern, and lymphovascular and perineural invasion) [19–
22]. For example, neoplasms that are larger than 2 cm, have depth of
invasion greater then 3 mm, and tend to invade in small groups of tumor
cells have been associated with a significant rate of occult nodal metastases
[23]. Potential molecular markers (ie, tumor suppressor genes and proto-
oncogenes) have been proposed as indicators for regional involvement, but
their routine application has yet to be proved [11,24].

Management
The management of patients who have oral cavity SCC begins with
a comprehensive history and complete head and neck examination, which
includes an office-based fiberoptic-endoscopic evaluation of the upper
aerodigestive tract. In addition, it is vital to confirm any comorbidities,
degree of functionality, family support, and understanding and personal
wishes of the patient before embarking on any therapeutic path. Treatment
modalities are divided into surgical and nonsurgical options or a combination
of both. Surgery is further subdivided into ablative and reconstructive
approaches. Nonsurgical management includes the use of radiotherapy,
chemotherapy, and ancillary services aimed at functional rehabilitation (Fig.
2). The selection of appropriate therapy depends on certain patient, tumor,
and institutional factors. Patient factors have been outlined previously, and
those pertaining to individual tumor sites are discussed later. Institutional
factors relate to the expertise, resources, and treatment philosophy established
by the multidisciplinary team. Various therapeutic philosophies exist, and
these need to be considered in the management of each individual patient.
52 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Fig. 2. Management algorithm for oral cavity carcinoma.


Abbreviations: MRND, modified radical neck dissection; RFFF, radial forearm free flap.

Investigations
Investigations can be divided into those that are general and specific and
include a complete blood film, biochemistry, ECG, and a chest radiograph.
Specific investigations should include imaging of the primary tumor site and
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 53

regional lymphatics, examination of the upper aerodigestive tract under


general anesthesia, and histopathologic verification of the tumor type.
Before embarking on surgery, anesthetic fitness needs to be confirmed by the
anesthesiologist and other members of the medical team (eg, cardiologist,
respiratory specialist). Finally, the patient’s management should be dis-
cussed within the setting of a multidisciplinary tumor board.
The goal of imaging is to assist in the staging of the primary tumor,
evaluate cervical lymphatics, and detect any bony invasion, which helps in
the planning of the most appropriate therapeutic approach. Pulmonary
imaging in the form of a chest radiograph or CT scan for more advanced
tumors is imperative in the evaluation of any underlying lung disease and in
the exclusion of possible metastatic involvement. CT scanning is widely used
in the management of head and neck malignancy. Its many advantages
include the clear delineation of the bone–soft tissue interface in the
evaluation of the neck and its universal availability. Invasion of the facial
skeleton, including the hard palate, paranasal sinuses, and mandible, is best
visualized using thin slices with bone algorithm (ie, axial and coronal planes)
[25]. Dental CT scans have been developed and, if available, offer more
choice in the assessment of mandibular invasion [26]. Panoramic X-ray or
occlusal view radiographs of the mandible are simple and cost-effective first-
line investigations that have a high specificity but low sensitivity for
excluding mandibular invasion and are therefore useful with gross tumor
involvement only. They can assist, however, in the planning of tumor
resection and in evaluating the remaining dentition [27,28].
MRI is superior in the delineation of soft tissue lesions within the tongue
and in the floor of the mouth. In addition, neural involvement and
intracranial extension can be accurately evaluated with this modality. MRI
allows direct multiplanar evaluation of the pathology and, as an additional
benefit, avoids the distortion seen in patients with heavily restored dentition
[28]. Recent literature has focused on single photon emission CT (SPECT)
scanning in evaluating the mandible. Its sensitivity in excluding invasion
(95%) was far superior to CT or dental CT scans, or Panorex radiographs
[27,28]. Lack of availability, cost, and limited application of this modality,
however, demands that further prospective studies be performed before its
universally acceptance.

Specific sites
Tongue
Surgery is the mainstay of treatment for early-stage disease of the oral
tongue (ie, stages I or II) [29]. Adjuvant radiotherapy improves locoregional
control and disease-specific survival rates in patients with advanced-stage
lesions [30]. Chemotherapy in a neoadjuvant setting has been investigated
and shows promise; however, its use is presently limited to institutional trials
54 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

[31]. Palliative chemotherapy useful and can be offered to patients for whom
definitive curative management is no longer an option.
There are several surgical approaches to disease of the oral tongue. These
include the peroral, degloving, mandibular swing (ie, by means of midline,
paramedian, or lateral osteotomies), lingual release, or cheek flap approach
[32,33]. The approach selected depends on several factors, which include size
of the primary tumor, mandibular invasion, dentition, extent of cervical
lymph node involvement, need for reconstruction, and the expertise and
preference of the individual surgeon. Neoplasms staged T1 or T2 that do not
invade the mandible are best managed using a peroral approach (Fig. 3).
More advanced lesions, however, particularly those that have deep tongue
involvement and extent across the midline require a more radical approach.
Both the mandibulotomy and lingual release afford good access, both for
tumor ablation and subsequent reconstruction [32,33]. The advantage of the
tongue drop is the avoidance of an osteotomy with its associated
complications of malunion and/or nonunion [34]. Prior radiotherapy can
increase the rate of complications that occur with a mandibular swing. In
expert hands, however, complication rates are low, and a recent comparison
of these two approaches showed no significant difference in outcome [35].
Patients treated with a mandibulotomy did report superior ability of speech,
swallowing, and chewing when compared with the lingual release group,

Fig. 3. (A) Right T2 lateral tongue SCC; (B) transoral resection of lesion; and (C) primary
closure with absorbable suture.
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 55

Fig. 4. (A) Lip-split and midline mandibulotomy approach to the oral cavity. (B) Repair with
radial forearm flap and plate.

however. The potential negative impact of a facial scar was not borne out in
this analysis [35].
Mandibular swing with either a midline or paramedian osteotomy is the
current authors’ preferred approach to the oral cavity (Fig. 4). In patients
with teeth, care needs to be taken in placing the osteotomy site between the
tooth roots; however, if there is dental crowding, extraction of one tooth is
preferred. Commercially available plating systems have improved recon-
struction and have diminished morbidity. It is important to reduce the
prominence of the symphyseal region of the mandible using a high-power
burr to compensate for the thickness of the reconstruction plate. Once this
has been achieved, a thin titanium (eg, 2.3-mm) plate is used to stabilize the
56 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Fig. 5. Lag screws for repair of midline mandibular osteotomy.

osteotomy and a tension band splint or circumdental wire help minimize


excess movement. Alternatively, one or two lag screws can be used to
achieve a similar result (Fig. 5) [36].

Floor of the mouth


Tumors in the floor of the mouth are located either anteriorly or laterally
along the oral tongue. The management of these lesions is challenging
because of their proximity to the mandible. Edentulous patients seem to
have less resistance to the advancing tumor front, which tends to invade the
mandible along its occlusal surface at the site of tooth sockets. Once
invasion of the neurovascular canal occurs, the tumor tends to spread to the
skull base along the inferior alveolar nerve. In contrast, dentition does offer
some resistance; however, direct tumor invasion through the lingual cortex
and tooth roots will eventually occur [37]. The state of dentition therefore
plays a significant role in the selection of appropriate surgical treatment.

Retromolar trigone and lower alveolus


Patients who have tumors located on or near the lower alveolus tend to
present with mandibular invasion and advanced-stage disease. These
neoplasms frequently involve adjacent sites, including the oropharynx, with
direct invasion of the pterygopalatine and infratemporal fossa. Surgery is
the primary mode of therapy with the need for complex reconstruction,
which often necessitates composite free-tissue transfer. In addition, adjuvant
radiotherapy is recommended when resection margins are close or involved
[38]. This combined therapy frequently results in significant functional
disability, with resultant dysphagia, lack of speech, xerostomia, and trismus.
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 57

Upper alveolus and hard palate


Tumors arising from the upper alveolus and hard palate tend to involve
important adjacent structures at the time of presentation (ie, paranasal
sinuses, orbit, or brain). Management frequently requires partial or total
maxillectomy with, on occasion, orbital exenteration. Reconstruction is
challenging; however, most defects are repaired using a combination of a skin
graft and maxillary prosthesis, which provide adequate function and ac-
ceptable cosmesis. Alternate options include free-tissue transfer, which is used
in a select number of patients where orbital support and/or repair are ne-
cessary. In addition, resection that transgresses the cranial base mandates the
use of free-tissue transfer to minimize potential postoperative complications,
such as cerebrospinal fluid leak, meningitis, or intracranial abscess [39].

The lip
Most lip cancers occur on the sun-exposed lower lip; approximately 7%
arise from the upper lip and 4% involve the commissure. Simple excision
and primary closure is advocated in defects that involve less than one third
of the lip. Some form of advancement flap is necessary if the defect exceeds
30% of the lip, and the Abbe and Karapandzic flaps are the reconstructive
options of choice (Fig. 6) [40]. Total lip replacement, however, usually
requires free-tissue transfer, and a combination of the radial forearm free

Fig. 6. (A) Lower lip SCC; (B) excision and outline of bilateral Karapandzic advancement
flaps; (C) flap advancement and closure; and (D) Postoperative result.
58 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

flap and the palmaris longus sling has become a popular option [41].
Primary radiotherapy is an alternative form of treatment, especially in
elderly patients and in those who are medically unfit for prolonged
anesthesia and hospitalization. Treatment of the cervical lymphatics (ie,
neck levels I to III) should be considered in patients with neoplasms that
involve either the upper lip, the oral commissure, or in those with advanced
(ie, tumor stage, [T2) or recurrent lesions, because these lesions have
a significant incidence of occult metastases [42].

The mandible
Mandibular involvement has significant implications for both prognosis
and postoperative rehabilitation. In addition, adjuvant radiotherapy is
recommended in most patients with mandibular invasion. Currently, there is
no one diagnostic modality that provides accurate preoperative assessment
of bone invasion. Careful clinical examination is paramount, however, and
studies have shown it to be highly sensitive ([94%) but lacking in specificity
(25%) [27]. In certain situations, including those in which lesions are close to
and abutting the inferior alveolar ridge, immobile lesions of the floor of the
mouth and/or in edentulous patients are highly suggestive of bone invasion.
A combination of Panorex/occlusal views and CT scanning has a high
sensitivity (81%) and specificity (88%) [27]. SPECT and MRI also show
promise, with reported sensitivities of more than 90%, but their limited
availability curtails their routine use [28]. The current authors’ approach to
the evaluation of the mandible includes a thorough clinical examination,
with Panorex/occlusal views, CT scans, and a high index of suspicion.
The goal of resection is to provide a clear margin of more than 1 cm with
removal of all microscopic disease. Where the mandible is involved clinically
and radiologically, the standard of care is usually segmental mandibulec-
tomy (Fig. 7). The reconstructive menu in the current authors’ institution
includes a vascularized osseous free-tissue transfer, but in select cases, where
the bony defect is situated posterolaterally in elderly and edentulous
patients, it may be left unreconstructed. The dilemma arises in lesions that
are close to or abut the mandible. A marginal mandibulectomy is a widely
accepted approach where there is no clear evidence of bone invasion [43].
This procedure involves a resection of either the superior half of the
mandible or the lingual cortex (Fig. 8). Where the resection includes more
than 60% of the height of the mandible, a plate is applied to reduce the
incidence of fracture.
The management of the mandible requires a balanced approach, with
avoidance of unnecessary, excessive resection of normal, uninvolved tissue.
Results support using a marginal mandibulectomy in most patients in whom
no gross clinical and radiologic evidence of mandibular invasion exists.
Ultimate locoregional control and survival rates compare well with those for
segmental mandibulectomy [44,45].
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 59

Fig. 7. (A) T4 right lower alveolar SCC. (B) Composite resection, including lateral segmental
mandibulectomy and radical neck dissection. (C) Repair with free vascularized fibular bone and
overlying skin.

The neck
The management of the neck in patients who have SCC of the oral cavity
is determined by the treatment approach to the primary neoplasm, with
most clinically involved cervical lymph nodes requiring a neck dissection.
The standard is a modified radical neck dissection encompassing levels I to
V. Recent studies, however, have questioned this approach for small, single
lymph node disease involving the upper neck. Andersen et al [46] in a recent
review reported on 106 patients with clinically positive neck disease. The
primary sites were varied with approximately half involving the oral cavity.
60 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Fig. 8. (A) Cheek flap approach. (B) Exposure of the lateral oral cavity. (C) Posterior marginal
mandibulectomy.

All patients were treated with an appropriate selective neck dissection.


Adjuvant radiotherapy was used in 72% of patients, with an overall
locoregional control rate of 94% [46]. Gooris et al [47] evaluated the
therapeutic use of performing a supraomohyoid neck dissection followed by
radiotherapy in patients with primary lip SCC and concomitant neck disease
(ie, stage N1 or N2) involving only level I. Locoregional control exceeded
90%. Although these studies were retrospective and relied heavily on
adjuvant radiotherapy, a selective neck dissection as part of a combination
approach may be adequate treatment of clinically positive neck disease.
The management of clinically negative neck disease provides further con-
troversy. There are three accepted treatment approaches: close observation,
elective neck surgery, or radiotherapy [48,49]. Physical examination, CT
scanning, MRI and positron emission tomography are used in the
evaluation of clinically negative neck disease in head and neck carcinoma
[50–52]. The combination of clinical examination and CT compares well
with the ‘‘ gold standard ‘‘ of elective neck dissection (sensitivity, >90%)
[50]. A significant number of patients have occult disease, however, and the
goal is to detect those patients who have occult or positive disease to avoid
any unnecessary morbidity associated with elective neck surgery.
The technique of sentinel node biopsy as used in the management of
melanoma has been proposed in an effort to identify those patients with
occult disease [53]. Ionna et al [54] recently reported the use of sentinel node
biopsy in patients with oral cavity SCC staged T1 or T2. The sentinel node
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 61

was identified in 95% of patients, and the overall sensitivity of this approach
was 100%. Ross et al [55] recently presented the results of a multicenter trial
on the feasibility of this technique in the management of patients with head
and neck SCC and concluded that sentinel node biopsy identified 95% of
sentinel nodes with an overall sensitivity of 90%. The sensitivity dropped
significantly in centers performing fewer than 10 sentinel node biopsies per
year, however. Although results of this approach are promising, further
multi-institutional trials need to be performed to evaluate and test this
modality before it can become part of the routine workup in patients who
have clinically N0 neck disease. The management of clinical negative neck
disease therefore continues to be controversial, and the selection of
treatment modality generally depends on the approach to the primary
tumor. Treatment of early-stage disease is adequate with single-modality
therapy. The importance of including the neck in the treatment regime rests
on the fact that oral cavity SCC has a significant rate of occult metastases.
Even T2 lesions have a known incidence of occult disease of more than 15%,
necessitating treatment of the N0 neck. Neck dissections encompassing
levels I to III are generally adequate; however, Byers et al [56] reported that
‘‘skip metastases’’ involving only levels III or IV exist in up to 15% of
patients with oral tongue SCC. In addition, midline lesions (eg, anterior
floor of mouth) usually require bilateral neck treatment. The current
authors’ approach in the management of clinically N0 neck disease is to
perform either unilateral or bilateral selective neck dissections encompassing
levels I to IV. In addition, adjuvant radiotherapy is recommended if occult
disease is identified.

Reconstruction
A wide variety of reconstructive options are currently available to repair
surgical defects of the oral cavity [57]. The simplest approach is to permit the
defect to heal by secondary intention, and this is certainly appropriate for
small lesions of the tongue, floor of the mouth, or buccal mucosa. Split-
thickness skin grafting is an alternative; however, in large defects, there
exists a significant rate of fistula formation, trismus, and graft failure [58].
Local mucosal, tongue, or skin flaps (eg, nasolabial) are alternate options,
and these are best suited for defects that involve the anterior floor of the
mouth, especially in edentulous patients [59]. The gold standard in soft
tissue reconstruction of the oral cavity is the radial forearm free flap [60]. It
provides significant flexibility to the surgeon because of the size of the
potential skin paddle and adequate length of its vascular pedicle. It is thin,
pliable, and potentially sensate and therefore well suited for intraoral
reconstruction, with minimal failure rates (Fig. 9) [61].
Three options are available for managing segmental mandibular defects.
The first option is to leave posterolateral defects unreconstructed (eg, in
62 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Fig. 9. (A) Cosmetic result of the lip-split approach. (B) Postoperative appearance of the radial
forearm free flap for the repair of lateral oral tongue defects.

elderly and edentulous patients) and manage these defects with only soft
tissue replacement (eg, pedicled mycocutaneous or free soft tissue flap).
Simple plate reconstruction is another alternative; however, this modality is
associated with high extrusion rates despite adequate soft tissue cover (eg,
pedicled mycocutaneous or free soft tissue flap) and therefore is usually not
recommended as a primary reconstructive approach (Fig. 10) [62–64]. The
gold standard approach today is the use of an osseocutaneous free-tissue
transfer (eg, fibula, iliac crest, or scapular free flap) [65].

Radiotherapy and chemotherapy


Radiotherapy is an integral part of the management of oral cavity SCC.
In select patients, it may form the primary therapeutic option if
comorbidities and patients’ wishes preclude the use of surgical excision.
Primary radiotherapy is not the treatment of choice for early-stage oral
cavity SCC, however, because of significant morbidity, including xerostomia
and dysphagia [66,67]. Furthermore, studies have demonstrated that a return
to normal oral function is achieved more often with primary surgery when
compared with radiotherapy alone [68]. A significant number of patients will
develop a metachronous neoplasm and therefore it is important to reserve
radiotherapy for the treatment of tumor sites that are less amenable to
function-preserving surgery [69]. In addition, locoregional control and
survival rates for early-stage oral cavity SCC with surgery alone are
comparable to radiotherapy, and therefore the current authors advocate
primary surgery in these patients [29].
Many patients require postoperative radiotherapy if certain adverse
features exist. These features may include positive or close margins, sig-
nificant perineural/perivascular invasion, bone involvement, multiple nodal
involvement, and/or extracapsular spread [70]. In addition, patients with
advanced malignancies staged III or IV are best treated with a combined
approach, and survival rates have been improved in those for whom com-
plete surgical resection is possible [30,38].
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 63

Fig. 10. Reconstruction plate extrusion 3 years following therapy.

Brachytherapy is an alternative for both primary and recurrent lesions


[71]. Marsiglia et al [72] recently published a series of 160 patients with floor
of mouth and tongue SCC (ie, T1 or T2) treated with primary
brachytherapy (ie, iridium-192 wires). The survival rates were 88% and
74%, respectively, comparing favorably to results obtained with surgery
and/or external beam radiotherapy. Significant local complications, in-
cluding soft tissue and bone necrosis occur with this modality, however, and
have resulted in limited application of this form of management.
Chemotherapy for the treatment of oral cavity SCC is presently reserved
either for palliation or within the setting of institutional trials. Licitra et al
[31] examined the use of cisplatin and 5-fluorouracil in a neoadjuvant
setting. They compared toxicity and outcome in two treatment arms:
chemotherapy and surgery versus surgery alone. Adjuvant radiotherapy was
given in those patients with adverse factors (eg, positive margins, soft tissue
involvement, multiple nodal disease, or extracapsular spread). The results
64 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

revealed no survival advantage with neoadjuvant chemotherapy. The


authors reported a decreased need for adjuvant radiotherapy, however,
and less need for mandibular resection in those patients who received
chemotherapy. It may be possible in the future to adopt a less aggressive and
organ-sparing approach if further studies support the findings by these
authors. Schuller et al [73] reported the use of pre- and postoperative
cisplatin concurrently with slightly accelerated hyperfractionated radiother-
apy in an attempt to reduce treatment toxicity and improve disease control.
The results showed that this combined treatment is well tolerated and may
form part of a future treatment regime for patients with advanced and
resectable oral cavity carcinoma. At present, chemotherapy is not part of the
first-line management of patients who have oral cavity SCC, and its
application is reserved for palliative purposes only.
The future may rest on the development of novel treatment strategies that
seek to exploit the molecular characteristics of the tumor. Myers et al [74]
recently targeted epidermal growth factor receptor in an experimental
xenograft animal model. Overexpression of this receptor is associated with
a poorer prognosis in patients with head and neck cancer, and it was
postulated that blocking this receptor would control the malignant potential
and form the basis of targeted molecular therapy. The results have been
promising in blocking the growth of human oral cavity SCC, providing hope
for the possible use of this technique in the future.
Chemoprevention is a strategy that aims at preventing the development
of invasive carcinoma. Certain agents have been isolated that curtail the
development of lower gastrointestinal carcinoma. Among the possible
targets is cyclooxygenase-2 (COX-2), which is expressed in premalignant
tissue and certain cancers. This finding probably reflects the action of
various oncogenes and growth promoters that induce the expression of
COX-2. Certain transgenic mouse models have been developed to test the
role of COX-2 in tumorigenesis [11]. Celecoxib, a cyclooxygenase inhibitor,
has been shown to be effective in the prevention and treatment of colon
cancer. It has potent antiangiogenic properties and has been shown to
reduce oral cavity SCC tumor volume in vivo. These findings suggest that
this agent may someday assist in the prevention and treatment of oral cavity
cancer [75]. Extensive human trials are required before this agent becomes
part of the routine management, however.

Rehabilitation
Post-treatment rehabilitation is vital in patients with oral cavity SCC
because significant functional morbidity is encountered that affects speech,
swallowing, and/or mastication. Oral rehabilitation commences at the time
of initial consultation and is coordinated by a speech pathologist. Input
from a dentist and prosthodontist, however, is also vital for successful and
expedient rehabilitation in these patients.
C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70 65

Prognostic factors and outcome


The overall disease-specific survival rate for patients who have oral cavity
SCC is approximately 50% [5]. Patients with early-stage tumors (T1 or T2)
have survival rates of 70% to 90% [29,38,76,77]. Those with more advanced
stage (ie, stage III or IV) of disease have survival rates of less than 25%. The
addition of radiotherapy has significantly improved disease-specific outcome
in these patients, however [78]. The most important factor for prognosis is
the state of the cervical lymphatics, with survival rates halved in the presence
of pathologic nodal involvement [79].
Factors other than those included within the TNM staging system have
been found to be significant for prognosis. These factors include his-
topathologic features, such as grade of tumor, depth of invasion, type of
tumor front, extracapsular spread, and the presence of perineural/perivas-
cular invasion [19,70]. In a recent analysis, the most important predictive
factor for occult nodal disease in oral tumors staged T1 or T2 was depth of
invasion in excess of 3 mm [23]. This finding compares well with a pre-
vious report by Spiro et al [21], who found that depth of invasion of
greater then 2 mm was associated with increased regional failure and
reduced survival. A recent multivariate analysis found that a high combined
Byrne’s invasive front grading score and tumor invasion characterized by
small groups of dissociated cells were independent, poor prognostic factors
in a group of 102 patients with oral cavity SCC [22]. In addition to these
tumor factors, incomplete surgical resection is significantly associated with
an adverse outcome [22]. Young age also has been postulated to affect
prognosis; however, recent analysis has not substantiated this. Patients aged
40 years or younger had a superior outcome when compared with those
aged 66 years or older [5,80]. Certain ethnicities seem to have more
aggressive disease. African Americans have a significantly greater risk of
presenting with advanced-stage disease and therefore have a worse overall
survival rate when compared with whites (35% versus 51%, respectively).
Presentation with advanced-stage disease was associated with low socio-
economic status in white patients. This finding was not mirrored in the
African American population, however, suggesting features other than
environment may be responsible for the poor outcome in this group [5]. The
answer may lie with molecular markers, such as cyclin D1 and p16. These
nuclear proteins are important in controlling the cell cycle and over-
expression of cyclin D1 and loss of p16 have been found to be common
genetic events in head and neck cancer. Bova et al [24] found that these
factors were present in 55% to 68% of oral tongue SCC and predicted
advanced neck disease, increased tumor grade, and reduced disease-specific
survival on multivariate regression analysis [24]. The presence of over-
expression of cyclin D1 and loss of p16 were complementary in predicting
for a greater relapse rate and reduced disease-specific survival rate. These
results show promise that routine evaluation of these parameters
66 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

may become useful in the management of patients who have oral cavity
SCC.

Summary
Oral cavity SCC remains a significant health problem and requires
a multidisciplinary approach. Treatment with surgery alone or in
combination with adjuvant radiotherapy for more advanced lesions is the
standard of care. Major advances have been made in surgical approaches,
reconstructive options, and the rehabilitation of patients who have oral
cavity SCC. These advances have significantly improved disease-specific
outcome and quality of life. The future may lie in the development of
treatment regimes that combine early detection with organ preservation and
result in improved cure rates and quality of life.

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Surg Oncol Clin N Am 13 (2004) 71–80

Carcinoma of the oral pharynx:


an analysis of subsite treatment
heterogeneity
Ryan F. Osborne, MDa,b,
Jimmy J. Brown, DDS, MD, FACSb,*
a
Head and Neck Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard,
Los Angeles, CA 90048, USA
b
Department of Otolaryngology–Head and Neck Surgery,
Charles R. Drew University of Science and Medicine, 12021 South Wilmington Avenue,
Room 5004, Los Angeles, CA 90059-3051, USA

The treatment of malignant tumors of the oropharynx is far from


straightforward, and is compounded by the wide variability in treatment to
the different subsites of the oropharynx as shown by reports from the major
centers that treat this disease. There seems to be no consensus as to the best
mode of primary treatment, and selection of the various treatment
modalities is largely center driven.

Relevant anatomy
The superior and inferior boundaries of the oropharynx are marked by
horizontal planes at the levels of the hard palate and vallecula or hyoid
bone, respectively. The muscular pharyngeal wall between these two planes
defines the posterior limits. The circumvallate papillae and palatoglossal
muscle mark the anterior limits. Most of the lateral wall of the oropharynx
is primarily composed of the tonsil and the tonsillar fossa. A small
contribution comes from the lateral extensions of the posterior pharyngeal
wall. The oropharynx can be divided into four subsites: (1) the posterior
pharyngeal wall, (2) the soft palate, (3) the tonsil complex (ie, tonsil,
tonsillar fossa, and pillars), and (4) the base of tongue. The limits of the
oropharynx as a whole can usually be easily appreciated during clinical

* Corresponding author.
E-mail address: jimbrown@cdrewu.edu (J.J. Brown).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00117-0
72 R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80

examination. In comparison, clearly visualizing the limits of the subsites of


the oropharynx can be more of a challenge, especially in the presence of
gross disease.

Histopathology
In general, the histopathologic entities seen in the oropharynx represent
a derivation of tissue normally present there. Because the oropharynx is
lined with stratified squamous epithelium, 85% to 90% of carcinomas seen
are squamous cell in origin. The presence of minor salivary glands,
neurovascular and fibromuscular structures, and lymphoid aggregates in the
Waldeyer’s ring opens the possibility to a wide variety of mesemchymally
derived sarcomas and carcinomas. A discussion of the management of all
malignancies found in the oropharynx is beyond the scope of this article.
Therefore, the remainder of the article pertains to the management of
squamous cell carcinomas (SCCs) at the various subsites of the oropharynx.

Assigning tumor to subsite of origin


Determining the subsite of origin in oropharyngeal carcinomas can be
a daunting task and frequently comes down to an educated guess based on
subjective and objective information. The reason for the great difficulty is
twofold. The first factor relates to mucosal continuity between subsites,
making it difficult to strictly demarcate one subsite from another. For
example, the soft palate, which includes the uvula is continous with the
anterior tonsillar pillar. Similarly, the lateral extension of the postpharyn-
geal wall merges almost imperceptibly with the posterior tonsillar pillar.
The second factor rests with the size and position of a given lesion, which
may encompass more than one subsite. Lesions located at transition zones,
such as between the soft palate and anterior tonsillar pillar, or large lesions
involving contiguous subsites may present a diagnostic dilemma.
Some authorities have attempted to use histologic differentiation,
imaging studies, or patient symptoms to discern lesion subsite of origin.
Approximately 60% of soft palate lesions have been found to be moderately
differentiated, 20% poorly differentiated, and 20% well differentiated [1].
This distribution is fairly uniform throughout the other subsites of the
oropharynx. MRI with gadolinium provides the highest soft tissue
resolution but rarely does much better than the examination of an
experienced clinician in positively identifying the subsite of origin. Patient
symptoms are perhaps the least helpful markers of subsite origin, because
dysphagia, odynophagia, and otalgia are common complaints of oropharyn-
geal disease in general. It is therefore not unusual for a clinician to be
incapable of making a definitive subsite designation.
R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80 73

Posterior pharyngeal wall


Tumors that are isolated to the posterior pharyngeal wall are very
uncommon. They tend to be asymptomatic unless they become bulky. They
rarely extend laterally to other subsites of the oropharynx but rather
infiltrate deeply into the retropharyngeal and prevertebral tissues. They are
known for their early metastases to bilateral jugular and retropharyngeal
nodes because of their posterior and relatively midline location. The biologic
characteristics of these tumors are the same as those of tumors of the
hypopharynx. As such, the treatment philosophies and approaches are the
same as those used for tumors of the hypopharynx.

Soft palate
The soft palate functions to prevent air escape during phonation and
nasal regurgitation during deglutition. Of all the subsites of the oropharynx,
it may provide the least challenge to routine examination. Thus, despite the
relatively asymptomatic presentation of carcinomas in this region, they are
usually identified early and referred for definitive management.
SCC of the soft palate is a relatively uncommon malignancy and remains
virtually asymptomatic because of its location, until a lesion reaches
a substantial size. At first glance, these lesions give the impression that they
can be readily encompassed by a surgical procedure without compromise of
function. Because of the relative infrequency of these lesions, however,
many clinicians have limited experience in their management.
The soft palate forms a mucosa-covered muscular bridge from one side of
the oropharynx to the other. There exists no true barrier to lateral tumor
spread, and the aponeurosis of the underlying musculature provides
a transient barrier at best. The lymphatic drainage is weighted in an
ipsilateral direction, yet there are well-recognized lymphatic drainage
patterns that permit contralateral spread. Therefore, even the smallest
lesions have the capability of seeding both sides of the neck with metastatic
disease. This possibility becomes more of a reality as lesions approach or
cross the midline. The effect of location on prognosis is well documented.
The overall 5-year survival rate for patients presenting with unilateral
lesions is 70.8% and drops to 51% for patients with midline or bilateral
lesions [2]. Approximately 25% of patients treated for a soft palate tumor
will present with a second primary tumor, with the floor of the mouth being
the most common secondary site [3–8].
Although early-stage soft palate lesions readily lend themselves to
primary surgical treatment, the submucosal nature of the disease demands
that adequate margins be taken to minimize recurrences. Thus, the
treatment of a small lesion often results in a large defect, which results in
functional difficulties. Modern palatal obturators and surgical reconstruc-
tive efforts have reduced the degree of functional deficits; however, these
74 R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80

deficits are not reduced to an appreciable level such that the resultant
functional status matches that of patients treated with primary irradiation
[4]. Because the local control rates for T1 and T2 lesions remains the same at
91% to 100% and 70% to 75%, respectively (American Joint Committee on
Cancer. Manual for Staging Cancer, 5th edition. Philadelphia: Lippincott-
Raven, 1997. pp. 29, 37.), for either surgery or radiotherapy [2,3], primary
radiotherapy is considered the treatment of choice for early-stage soft palate
lesions [3–6]. Importantly, to achieve similar control rates as radiotherapy,
the surgeon must not be conservative with surgical margins out of fear of the
functional and reconstructive challenges that may present postoperatively.
Advanced soft palate lesions portend a poor prognosis. The 5-year
disease-free survival rates for T3 and T4 lesions are 39% to 56% and 32% to
39%, respectively, for any treatment modality. Studies that have attempted
to analyze the modality which offers the best control rates are limited by
small numbers and many patient selection biases [9]. Despite these
limitations, there is strong support that surgery combined with radiotherapy
probably offers the best chance for obtaining locoregional control.

Tonsillar complex
Tonsillar carcinoma represents approximately 75% of all carcinomas
presenting in the oropharynx. Among carcinomas of the aerodigestive tract,
it ranks second only to laryngeal cancer. Unlike the soft palate, the more
cryptic locations of the tonsillar complex places this region at high risk for
being poorly visualized or overlooked by the casual examiner. This is one
reason the source of many unknown primary tumors is ultimately found to
originate in the tonsil. Furthermore, its relatively ‘‘out of the way’’ lateral
location permits normal speech and swallowing functions to carry on in the
presence of early-stage lesions (T1 and T2). Thus, the asymptomatic nature of
this disease causes many patients to present with more advanced lesions (T3
and T4) after the presence of pain, dysphagia, or dysarthria may prompt them
to seek help. Trismus or the restriction of tongue mobility usually indicates
advanced disease (T4). This symptom is likely caused by disease extension
into the musculature of the pterygoids or base of tongue, respectively.
In general, lesions involving the anterior tonsillar pillars tend to be less
invasive and rarely bulky. These lesions spread rapidly across broad
muscosal surfaces and frequently involve adjacent subsites of the
oropharynx, such as the soft palate or tongue base. In comparison, tumors
involving the posterior pillar or tonsil proper tend to be far more exophytic
and invasive but are less likely to spread to adjacent subsites until an
advanced stage of disease.
As with palatal primary tumors, early-stage tonsillar carcinomas (T1 and
T2) that remain confined to that subsite can be treated with either
radiotherapy or surgical modalities, with comparable locoregional control
and overall 5-year survival results [10,11].
R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80 75

In these cases, treatment decisions are based on multiple factors: patient


health profile, patient preferences, availability of adequate radiation or
surgical services, patient compliance, and the presence or absence of nodal
disease.
Despite the single-modality treatment chosen, control rates at the
primary site for T1 lesions approximate 83% to 90% and 70% to 78%
for T2 lesions. The overall disease-free 5-year survival rates remain
acceptable and similar at 75% to 85% for T1 and 55% to 80% for T2
lesions using either surgery or radiation for treatment [10,11].
Because surgical resection of these lesions offers no curative advantage,
irradiation largely has become the first-line treatment for early-stage
tonsillar carcinomas. Treatment in this manner allows the reservation of
surgery for salvage, which improves disease-free 5-year survival rates to
85% to 100% for T1 tumors and 80% to 92% for T2 tumors, thus
minimizing the morbidity associated with treatment of these tumors and
maximizing the locoregional control [12].
The treatment option for advanced (T3 and T4) tonsillar tumors that
provides the greatest chance of disease control involves both surgery and
radiotherapy. Debate continues to revolve around whether surgery should
be used up front or for the purposes of salvage, however.
In an effort to spare patients the significant morbidity associated with
surgical resection, especially with large primary tumors, radiotherapy with
surgical salvage has been advocated. The enthusiasm for this treatment
approach must be tempered with the reality that many of these patients’
tumors may not be surgically salvageable after failure of primary
radiotherapy.
The effects of radiation on the soft tissues can alter the sensitivity of the
clinical examination to such an extent that a partial response to therapy can
easily be mistaken for a complete response. This situation therefore can
decrease the early detection rate of persistent or recurrent disease, leading to
recurrences that have extended beyond the scope of surgical resection. Less
than 25% of patients who fail radiotherapy have tumors that are considered
surgically salvageable, and only half of patients with salvaged tumors
survive more than 48 months [13,14].
Patient selection is paramount when considering primary radiotherapy
for advanced cancers of the tonsil. All T3 lesions are not the same. For
instance, a study from the University of Texas M.D. Anderson Cancer
Center attempted to identify patient or tumor factors that may predict
patients’ responsiveness to radiotherapy [15]. The degree of histologic
differentiation had no influence on locoregional control. Local extension to
other oropharyngeal subsites, such as the base of tongue in particular,
decreased the curative effects of radiotherapy, however. When lesions were
limited to the tonsillar fossa, radiotherapy controlled 89% of T3N0 lesions.
When base of tongue involvement was noted, the control rate dropped to
63%. The recurrence rate of tonsil-confined lesions approximated 10%
76 R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80

versus a 47% recurrence rate when there was tongue base invasion. These
findings have been mirrored in other studies in the literature [16–18].
Therefore, the mainstay of treatment for T4 and T3 lesions that
demonstrate ulceroinfiltrative features and involve adjacent subsites of the
oropharynx has been combination therapy. The classic composite resection
with postoperative radiation offers improved locoregional control and
survival over any single-modality treatment.
A review of the literature showed that combination therapy can decrease
the rate of local recurrence by 25% to 50% when compared with
radiotherapy or surgery alone [10,14,18–20]. Perez et al [20] found a 52%
recurrence rate when patients with advanced tonsillar lesions were treated
with single-modality radiotherapy. This rate of recurrence was 33% when
combination therapy was instituted, which further supports the concept of
combined-modality therapy for advanced tonsillar carcinomas.

Tongue base
Treatment selection for base of tongue carcinomas is institutionally
driven. Some centers primarily use surgery with or without radiotherapy
[21–28]; others use primary radiotherapy and reserve surgery for salvage
[29–31]. The role of brachytherapy remains controversial. Brachytherapy
combined with external beam radiotherapy (EBRT) was initially believed to
be a superior treatment option to EBRT alone for base of tongue lesions. It
has since fallen out of favor because of the lack of data that supported its
independent use [15–18]. In addition to unacceptable local control rates,
EBRT is time-consuming, costly, requires additional personnel, and
increases the risk of soft tissue necrosis. Interstitial implants, however,
may have a role in patients with residual tongue disease who have completed
a course of EBRT and are not candidates for surgical salvage.
Centers using primary radiotherapy, such as the University of Florida,
are achieving local control rates for T1 and T2 tumors of 75% to 100%
[21,22,32,33]. Similarly, centers that approach T1 and T2 tongue base
tumors with surgery as a first-line therapy report essentially the same control
rates. Therefore, the approach to these early-stage lesions are primarily
based on the wishes of the patient, health status, institutional resources, and
the morbidities associated with each treatment the patient is willing to
accept. Strong arguments have been made from both sides about which
approach is less functionally disabling. In general, most centers favor the use
of radiotherapy to both the base of tongue and neck, followed by planned
interval neck dissection for N1 or greater neck disease. The current authors
prefer this approach as well.
Greater controversy exists in the management of advanced (T3 and T4)
tongue base tumors. Analysis of the literature to objectively compare the
efficacy of surgery with or without postoperative radiotherapy versus
primary radiotherapy is extremely difficult. There seem to be no studies
R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80 77

without significant inherent patient selection bias. To further compound the


problem, these biases vary from one treatment center to another.
At some institutions, patients who have significant comorbidities or have
tumors that are deemed unresectable are referred for radiotherapy. Those
patients with lesions amenable to resection and who are otherwise relatively
healthy are offered surgery with or without postoperative radiotherapy. At
other centers, patients with large lesions are believed to be unlikely to
achieve satisfactory local control with radiotherapy alone and are treated
with a combined approach, reserving primary radiotherapy for smaller, less
infiltrative lesions.
Another reason the literature reveals such disparities in treatment
protocols lies in the inaccurate and varied pretreatment clinical staging of
these lesions. Foote et al [34] showed that, overall, 16% of patients are up-
staged at the time of surgery and 31% are down-staged. Significantly, the
greatest errors in judgment were made in the T1 lesions, in which 46% were
up-staged, and the T3 lesions, in which 58% were down-staged.
Analysis of the 5-year survival rates for patients with T3 and T4 tumors
treated with single-modality radiotherapy shows that these rates equal those
seen in patients treated with surgery alone, although there seems to be a small
improvement in locoregional control when a combined modality is used [33].
When treating patients with large T3 and T4 tumors, radiotherapy alone
offers local control rates of 59% to 73% and 35% to 44%, respectively
[33,35]. The range of these control rates reflects tumor differences in
radiosensitivity. Despite sophisticated scientific efforts to identify which
tumors are likely to be more radiosensitive, clinicians have yet to truly
achieve this goal. Thus, the clinician must use cruder indications of
response, such as gross tumor appearance.
Weber et al [35] showed that T3 and T4 tumor response to radiotherapy
could be predicted from morphologic growth patterns of the tumor. Patients
with exophytic tumors had a 5-year local control rate of 84% and a 5-year
survival rate of 67%. Those patients with ulceroinfiltrative tumors had
a 5-year local control rate of 58% and a 5-year survival rate of 33%.
In general, patients with exophytic lesions, significant comorbid states, or
those who will not accept the functional deficits of large resections, such as
subtotal or total glossectomies, are treated with radiotherapy with or
without chemotherapy, reserving surgery for salvage.
When patients present with tumors that cross the midline, have ulcerative
features, or infiltrate into the deep musculature of the tongue, the best
chance for obtaining local control seems to be a combination of radical
surgery with postoperative radiotherapy.

Approach to management of the neck


Management of the regional lymphatic spread of disease is virtually the
same for all subsites of the oropharynx. The risk of occult cervical
78 R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80

metastases ranges from 15% to 30%; therefore, treatment of N0 neck


lesions is justified for all T stages of disease. Most early-stage primary
lesions are treated with definitive radiotherapy, which is also used to address
clinically negative neck lesions. Elective neck dissections also can be used in
this setting and produce equal control rates with the added advantage of
providing a histologic specimen for diagnostic and prognostic information.
Clinically positive (N+) neck disease can be managed in several ways.
When the primary site is treated with radiation, it is recommended that the
nodal disease is concurrently irradiated. If the pretreatment nodal tumor
burden is significant, a planned interval neck dissection approximately 6 to 8
weeks following radiotherapy is common practice.
When surgery is used as definitive therapy for the primary lesion,
however, the cervical adenopathy can be addressed with surgery as well. In
the presence of extracapsular spread or multiple positive nodes, the use of
postoperative radiotherapy is recommended.

Chemotherapy
In the past, the role of chemotherapy in the treatment of oropharyngeal
carcinoma was generally considered experimental and used for palliation.
Most patients being treated with chemotherapy were either enrolled in
a study or were receiving treatment at a research-based institution.
There are now many promising cytotoxic agents currently under
investigation. There exists no way to ascertain from the literature the true
independent effects of chemotherapy on oropharyngeal carcinomas,
however, because there are no studies in which chemotherapy was used as
the sole treatment modality with curative intent. Most studies of merit used
chemotherapy for induction or concomitant therapy. Very little is known
about its role as an adjuvant therapy.
Cisplastin and 5-fluorouracil continue to be the most commonly used
agents in the treatment of oropharyngeal carcinomas. They have been
shown to improve locoregional control and survival statistics when given
with concomitant radiotherapy [36,37]. In the treatment of very advanced
oropharyngeal lesions, the role of chemotherapy has changed from
experimental to standard of care. The medical oncologist has a justified
role in the team approach to the treatment of advanced oropharyngeal
carcinomas.

Summary
The data indicate that SCC of the various subsites of the oropharynx can
be treated successfully with acceptable locoregional control and survival
rates by using either surgery or primary radiotherapy for T1 or T2 primary
lesions. Treatment success data for late-stage disease (T3 and T4) are less
R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80 79

encouraging, regardless of which modality is used or which treatment center


is administering treatment. This finding may suggest an intrinsic property of
these lesions or the patient that may be going unnoticed.
One problem is that the diversity of approaches to these lesions hinders
any meaningful comparisons between series from different treatment
centers. There exists heterogeneity in patient populations and approaches
to staging and characterization of these diseases. This situation has ensured
the same heterogeneity in treatment philosophy, which is largely institu-
tionally based.

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Surg Oncol Clin N Am 13 (2004) 81–98

Carcinoma of the hypopharynx


Christine G. Gourin, MD, FACS*,
David J. Terris, MD, FACS
Department of Otolaryngology–Head and Neck Surgery, Medical College of Georgia,
1120 15th Street, Augusta, GA 30912, USA

Carcinoma of the hypopharynx is uncommon, accounting for 4% of all


malignancies of the head and neck reported by the National Cancer Data
Base and 7% of all malignancies of the upper aerodigestive tract [1,2].
Squamous cell carcinoma (SCC) accounts for 95% of hypopharyngeal
pathology. Hypopharyngeal carcinoma is associated with the highest mor-
tality of all cancers of the head and neck. Poor survival rates are attributed
to a preponderance of late presentations and to the unique behavior of
tumors occurring in this location. Tumors of this region typically remain
silent until the disease has reached an advanced stage and causes symptoms
from airway or digestive tract obstruction or pain from neural invasion.
Hypopharyngeal carcinoma is associated with a high incidence of sub-
mucosal spread, which can be difficult to detect clinically and can result in
underestimating the extent of disease. Cervical metastases are present in
60% to 80% of patients and signify more advanced disease and a poorer
prognosis [3–7]. More than 75% of patients who have hypopharyngeal
tumors have stage III or IV disease at presentation [1]. The overall 5-year
disease-specific survival rate is approximately 30% to 35% [1,2].
Recent advances in reconstructive techniques and perioperative care have
allowed resection of advanced disease with single-stage reconstruction of
a functional alimentary tract. In addition, improved locoregional control
has been demonstrated with the use of combined-modality therapy. Overall
survival rates remain poor and largely unaffected, however, because of a shift
in the pattern of failure from local to distant disease and the development of
second primary tumors. Therefore, treatment goals are aimed at eradicating
disease and restoration of function, while causing the least morbidity and
the most effective palliation of symptoms.

* Corresponding author.
E-mail address: cgourin@mcg.edu (C.G. Gourin).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00122-4
82 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

Clinical behavior
The hypopharynx is described as the region of the pharynx that begins at
the level of the hyoid bone and extends to the inferior border of the cricoid
cartilage. Within the hypopharynx are three anatomic subsites: the paired
pyriform sinuses, the postcricoid area, and the posterior hypopharyngeal
wall. The pyriform sinus is the most commonly involved site, representing
more than 60% of all cases, and the postcricoid region is least commonly
involved, accounting for fewer than 5% of cases [2]. Isolated early-stage
lesions of the pharyngeal wall or pyriform sinus have the best prognosis and
long-term survival but comprise fewer than 20% of hypopharyngeal
carcinomas [3,7–10]. Tumor staging based on the American Joint
Committee on Cancer classification system (AJCC Cancer Staging Manual,
6th edition; Springer-Verlag: New York, 2003. pp. 33–45.) shows that
contiguous involvement of adjacent sites portends more advanced disease
(Box 1). The proximity of the hypopharynx to the larynx and cervical
esophagus mandates that the extent of disease be accurately determined
before embarking on treatment.
Hypopharyngeal carcinoma is unique in demonstrating a high propensity
for extensive submucosal spread. The true extent of disease may be initially
underestimated because of submucosal extension and the presence of skip
lesions [3]. Using whole organ, serial sectioning studies, Ho et al [11] found
that submucosal tumor extension was present in 60% of specimens. In one
third of patients, submucosal spread was not detectable on gross
examination, appearing histologically as tongues and islands of tumor
infiltration beneath an intact mucosa. The limits of submucosal extension in
this series were 10 mm superiorly to the oropharynx, 25 mm medially, 20
mm laterally, and 20 mm inferiorly toward the esophagus. The incidence
and extent of submucosal spread were higher in patients who had undergone
previous radiation therapy, with macroscopically undetectable submucosal
spread present in 82% of patients [11]. These data provide useful guidelines
for treatment planning.
The hypopharynx is served by an extensive lymphatic network.
Lymphatic drainage proceeds first to the jugular lymphatics and then to
the tracheoesophageal nodes, lateral pharyngeal and retropharyngeal nodes,
and the parapharyngeal space. Tumors that involve the posterior
hypopharyngeal wall and the medial wall of the pyriform sinus have
bilateral nodal drainage and have a high incidence of involvement of the
contralateral neck. Between 60% and 75% of patients will have clinically
involved neck nodes (node-positive [N+]) at presentation, and more than
one third of patients without clinical evidence of nodal disease will harbor
occult metastases [3–8]. In patients with N+ disease, zones II (72%–75%),
III (55%–72%), and IV (21%–45%) are most often affected; zones I (1%–
10%) and V (11%–15%) are less commonly affected [12,13]. Contralateral
occult metastases are present in 37% of patients with N+ disease [14]. In
Box 1. Staging of hypopharyngeal cancer
Tumor stage
Tis: Carcinoma in situ
T1: Tumor limited to one subsite of the hypopharynx and 2 cm or less
in greatest dimension
T2: Tumor invades more than one subsite of hypopharynx or an
adjacent site, or measures [2 cm but not more than 4 cm in
greatest diameter, without fixation of hemi-larynx
T3: Tumor [4 cm in greatest diameter or with fixation of hemi-larynx
T4a: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid
gland, esophagus, or central compartment soft tissue. Note:
central compartment soft tissues includes prelaryngeal strap
muscles and subcutaneous fat
T4b: Tumor involves prevertebral fascia, encases carotid artery, or
involves mediastinal structures
Nodal stage
N0: No regional lymph node metastases
N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in
greatest dimension
N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but
not more than 6 cm in greatest dimension; or in multiple ipsilateral
lymph nodes or bilateral or contralateral lymph nodes, none
greater than 6 cm
N2a: Metastasis in single ipsilateral lymph node more than 3 cm but
not more than 6 cm in greatest dimension
N2b: Metastasis in multiple ipsilateral lymph nodes, none more than
6 cm in greatest dimension
N2c: Metastasis in bilateral or contralateral lymph nodes, none more
than 6 cm in greatest dimension
N3: Metastasis in a lymph node more than 6 cm in greatest dimension
Distant metastasis
M0: No distant metastasis
M1: Distant metastasis present
TNM stage
Stage I: T1, N0, M0
Stage II: T2, N0, M0
Stage III: T3, N0, M0; T1 or T2 or T3, N1, M0
Stage IV: T4, N0 or N1, M0; any T, N2 or N3, M0; any T,
any N, M1

Used with the permission of the American Joint Committee on Cancer (AJCC),
Chicago, Illinois. The original and primary source for this information is the AJCC
Cancer Staging Manual, 6th edition (2002) published by Springer-Verlag New York
(For more information, visit www.cancerstaging.net). Any citation or quotation of
this material must be credited to the AJCC as its primary source. The inclusion of
this information herein does not authorize any reuse or further distribution with-
out the expressed written permission of Springer Verlag New York, Inc., on behalf
of the AJCC.
84 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

patients who have clinically N0 tumors, 36% harbor occult nodal


metastases in the ipsilateral neck, and 27% have occult disease in the
contralateral neck [14].
Metastatic disease involves the retropharyngeal lymph nodes in at least
20% of patients who have hypopharyngeal cancer [15]. The true incidence of
retropharyngeal nodal involvement is probably not known because
dissection of this level is not routinely performed. The incidence of clinically
involved retropharyngeal nodes by imaging criteria in patients with
hypopharyngeal cancer is 5% [16]. Imaging studies may underestimate
retropharyngeal nodal disease based on the small size (\1.5 cm) of nodes in
this location and will miss occult metastases [17]. A histologic study of
routinely dissected retropharyngeal nodes showed metastases in 20%
of patients with hypopharyngeal carcinoma [15]. The highest incidence of
retropharyngeal node metastases was seen in patients with disease
involvement of the posterior wall of the hypopharynx (57%) or the cervical
esophagus (50%). Retropharyngeal nodes were positive for occult
metastases in 15% of patients with stage N0 disease [15].
Metastases to the thyroid gland and paratracheal lymph nodes occur in
30% of patients who have hypopharyngeal tumors [18]. A 20% incidence of
occult nodal metastases to ipsilateral paratracheal lymph nodes has been
reported in patients with postcricoid lesions and tumors that involve the
pyriform fossa apex staged N0 [14]. Occult metastases may involve lymph
nodes in the parapharyngeal space, which has been described as a site of
recurrent disease in 5% of patients when untreated [8]. These data, taken
together, require that both sides of the neck and the retropharyngeal,
tracheoesophageal, and parapharyngeal nodes be included in treatment
planning.
Distant metastases are present in 6% of patients at initial presentation
[2,10]. The most common sites of involvement are the lungs, bone, and liver.
Between 12% and 32% of patients develop clinically apparent distant
metastases during the course of treatment [3,6–8,11,19–23]. The incidence of
distant metastases is increased in patients who have stage IV disease,
advanced-stage neck disease (N2 or N3), involvement of retropharyngeal
nodes, extracapsular spread, and lymphovascular invasion [7,8,17,19,23–25].
Most mortality in the first 2 years following diagnosis is caused by
locoregional recurrence; after 2 years, distant metastatic disease is re-
sponsible for a greater proportion of treatment failures [3,8]. Locoregional
recurrence may eclipse the appearance of distant metastatic disease, and
with improved locoregional control, distant metastatic disease may
subsequently become apparent. Disease control above the clavicles has
been associated with a higher incidence of distant metastases in studies that
reported results of radiation therapy, with or without surgery [7,19]. Others,
however, have shown no correlation between the incidence of distant
metastases and locoregional disease control [20,22,25,26]. Salvage of distant
metastatic disease is possible in only 6% of patients, and more than 90% of
C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98 85

patients die within 2 years of detection of distant metastases [20]. The


incidence of distant metastases may be significantly decreased by the
addition of chemotherapy to radiation therapy according to several reports
and a European Organization for Research and Treatment of Cancer
(EORTC) trial specifically evaluating pyriform sinus cancer [27–30].
Most patients who have hypopharyngeal cancers present with advanced-
stage disease. Early-stage cancer is considered to be any T1 or T2 lesion with
N0 neck disease, whereas T3 or T4 lesions, or any primary lesion associated
with N+ neck disease, are considered to be advanced cancers (Table 1). A
nationwide review of 2939 cases of hypopharyngeal cancer from 1980 to
1992 showed that 9% of patients had stage I disease, 11% had stage II
disease, 22% had stage III disease, and most (56%) had stage IV disease at
presentation [2]. The 5-year disease-specific survival rates by stage was 63%
for stage I, 58% for stage II, 42% for stage III, and 22% for stage IV
disease.
Second primary tumors are present in 7% of patients at the time of initial
diagnosis [2]. Between 10% and 17% of patients will subsequently develop
a second primary tumor, which is a significant cause of mortality in patients
who survive for more than 2 years after the initial diagnosis of
hypopharyngeal cancer [3,7]. A history of previous head and neck cancer
is present in 16% to 23% of patients, and prior treatment, such as radiation
therapy, may significantly limit treatment options available to the patient
[2,7].

Treatment
Currently, several treatment options exist for patients who have
hypopharyngeal cancer. Surgery combined with radiation therapy is the
standard treatment for most patients who have hypopharyngeal carcinoma.
Radiation therapy alone also may be used and seems to be most useful for
small (T1 or T2) lesions. Hyperfractionated radiation therapy seems to
confer some advantages over conventional radiation therapy in improved
locoregional control. Finally, organ preservation therapy using chemo-
radiation is being increasingly studied and may result in larynx preservation
in one third of patients.

Table 1
American Joint Committee on Cancer TNM staging classification
N0 N1 N2 N3
T1 I III IV IV
T2 II III IV IV
T3 III III IV IV
T4 IV IV IV IV
86 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

Surgical treatment
Preoperative evaluation is critical in determining the appropriate surgical
approach for treatment of hypopharyngeal carcinoma. The location and
extent of disease determine the extent of resection required. Accurate
staging is necessary to answer the following questions: Will excision leave
a partial or circumferential hypopharyngeal defect, Will total laryngectomy
be required, and What is the extent of neck dissection that is required?
The predilection of hypopharyngeal carcinoma for submucosal spread
must be kept in mind when planning resection of the primary tumor. Wei
[18] suggested that, based on measurements of submucosal extension in
whole organ studies, an adequate resection margin in patients who have not
received previous radiation therapy is 15 mm superiorly, 30 mm inferiorly,
and 20 mm laterally. Patients who have undergone previous radiation
therapy require resection margins of 20 mm superiorly, 40 mm inferiorly,
and 30 mm laterally. The deep margin in either situation should be greater
than 1 mm to ensure complete removal of the tumor without leaving
residual disease in the prevertebral musculature [18].

Posterior hypopharyngeal wall


Posterior hypopharyngeal wall lesions may be treated with wide local
excision. Endoscopic resection has been described for carefully selected
small lesions that are widely accessible endoscopically [31]. The resulting
defect may be left to granulate secondarily. More commonly, the
hypopharynx may be approached through either a suprahyoid pharyngot-
omy or lateral pharyngotomy; usually a combination of both approaches is
required for adequate exposure and resection, particularly for midline
disease. The lesion is excised down to the prevertebral fascia, keeping in
mind the extent of resection required to address the possibility of
submucosal extension of disease. Prevertebral involvement dooms this
approach to failure. The resulting partial posterior hypopharyngeal wall
defect usually requires coverage with a split-thickness skin graft, local or
regional flaps, or free-skin or visceral flaps. Split-thickness skin grafts
should be used whenever possible because of their ease of harvest and
minimal morbidity to the patient. The graft is sewn to the prevertebral fascia
and musculature and bolstered for 5 days.
Larger defects can be reconstructed using the deltopectoral skin flap or
the pectoralis major myocutaneous flap. The deltopectoral flap is an axial-
pattern skin flap that is based on perforators of the internal mammary
artery. Its use requires a staged procedure. The flap is a medially based skin
paddle from the upper chest and is initially elevated and reset several weeks
in advance of its use when possible, to encourage development of a blood
supply to its most distal tip. Subsequently, the flap is inset into the defect
and divided at yet a later stage. Before modern methods of soft tissue
reconstruction, the deltopectoral flap was widely used. It has been largely
C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98 87

replaced by the pectoralis major myocutaneous flap. The pectoralis flap is


based on the thoracoacromial artery, which provides an extremely reliable
and predictable blood supply. The pectoralis flap may be harvested with or
without an associated skin paddle: harvest of the overlying skin adds to the
bulk of the flap, which, even when used as a muscle-only flap, is significant.
The bulk of the pectoralis flap may interfere with swallowing but undergoes
atrophy with time. Free flaps are a third option for reconstruction. The
radial forearm and lateral thigh flaps may be harvested as free-skin flaps for
use in hypopharyngeal reconstruction. These require microvascular
anastomosis and result in some donor site morbidity but are thin and
pliable and well suited for use in the hypopharynx. The use of any free flap
requires suitable recipient vessels. The jejunal free flap may be used as
a patch graft and has an advantage of providing lubrication to this area, but
it requires a laparotomy for harvest with intestinal anastomosis and thus
increased morbidity.

Pyriform sinus
Lesions of the pyriform sinus, by virtue of their proximity to the larynx,
require at least a partial resection of the larynx for adequate excision. Early-
stage lesions, such as T1 lesions or T2 lesions of less than 2 cm, can be
treated by partial laryngopharyngectomy or extended supraglottic partial
laryngectomy. Transoral CO2 laser excision of pyriform sinus tumors
recently has been reported by one group to be effective, with results
comparable to transcervical approaches [32]. Regardless of the approach
used, aspiration is expected in the postoperative period, and candidates for
partial laryngopharyngectomy must have adequate pulmonary reserve and
be in otherwise good medical condition. Pulmonary function tests may
provide some objective measure of pulmonary function, but far more
physiologically useful is a determination of an active lifestyle and good
exercise tolerance. The ability to climb two flights of stairs (the ‘‘Ogura stair
test’’) is a reliable test of adequate pulmonary reserve [33].
Contraindications to partial laryngopharyngectomy are severe chronic
obstructive pulmonary disease, previous pulmonary resection, an inactive or
bed-ridden patient, or extension of the tumor to within 1.5 cm of the
pyriform apex. Arytenoidectomy is usually required for adequate excision of
the pyriform fossa. This procedure is unsafe for any tumor that is larger
than 2 cm; larger tumors require total laryngectomy with partial
pharyngectomy, which results in a significant partial pharyngeal defect.
Similarly, partial laryngopharyngectomy is unsafe for cancer that involves
the apex of the pyriform sinus. The proximity of the apex of the pyriform to
the postcricoid mucosa requires total laryngectomy and cervical esoph-
agectomy in addition to partial pharyngectomy for removal of the tumor
and results in a circumferential pharyngeal defect [3].
Partial pharyngeal defects may be closed primarily if sufficient mucosa
remains to give a tension-free closure over a #36 Maloney esophageal
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dilator. If insufficient mucosa remains, closure may be achieved with the use
of the pectoralis major myocutaneous flap, or free-skin or visceral flaps. The
pectoralis major flap is the preferred method of reconstruction to patch
partial pharyngeal defects because of its ease of harvest, low morbidity, and
reliability. For posterior defects, the bulk of the pectoralis major flap may
interfere with swallowing, but this seems to be less of a problem with lateral
defects after resection of the pyriform fossa. The radial forearm, lateral
thigh, and jejunal free flaps may be used to fill the defect but carry
significantly higher donor site and surgical morbidity.
Circumferential pharyngeal defects require more involved reconstructive
efforts, with a greater potential for stricture formation and anastomotic
failure. Cervical skin flaps, regional flaps, such as the deltopectoral flap and
pectoralis major flap, and free-radial forearm, lateral thigh, and jejunal flaps
all have been used successfully. Cervical skin-flap reconstruction is a foreign
concept to most recently trained head and neck surgeons, but before the
development of the deltopectoral and pectoralis major flap, medially based
cervical skin flaps were used extensively to reconstruct pharyngoesophageal
defects. Wookey popularized this technique in the 1940s when he developed
a method of pharyngoesophageal reconstruction (the so-called ‘‘Wookey
procedure’’) by elevating a laterally based skin flap to form the new
posterior wall of the pharyngoesophageal defect. At a second staged
procedure several months later, medially based flaps from the original flap
were elevated and closed longitudinally in the midline to create a new
pharyngoesophageal segment [34]. The deltopectoral flap is used in a similar
fashion, by elevating and transposing the flap and, at a second staged
procedure, subsequently dividing the pedicle and closing the defect.
Both the Wookey procedure and the deltopectoral flap are associated with
a significant incidence of flap complications and, because these are staged
procedures, there are an average of three procedures before successful
reconstruction is accomplished. The length of hospitalization and the time to
oral alimentation is measured in week to months. Flap necrosis, fistula
formation, and stenosis have been reported to occur in 90% of patients who
have undergone surgical reconstruction with cervical skin flaps [35]. Because
laterally based cervical skin flaps tend to have marginal circulation at the tip,
partial flap loss occurs frequently. The incidence of complications has been
reported to be 56% with the deltopectoral flap, likely because of better blood
supply compared with cervical skin flaps [35]. Staged reconstruction of
pharyngoesophageal defects has been supplanted by newer methods of
reconstruction but may be useful when multiple reconstructive efforts fail.
The pectoralis major myocutaneous flap allows single-stage reconstruc-
tion of circumferential defects and is widely used for this purpose today. The
bulk of the pectoralis major flap makes tubing the flap difficult, similar to
attempting to roll up a telephone book. Postoperative complications,
including stenosis, stricture, and fistula formation, have been reported in
41% of patients [36]. In addition, the thickness of the pectoralis flap and its
C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98 89

adynamic properties may impair swallowing function. Functional outcome


seems to be better when the pectoralis major is used to reconstruct a partial
defect as opposed to a circumferential defect: patients with circumferential
defects have greater difficulty swallowing after pectoralis major reconstruc-
tion [37,38].
Free-flap reconstruction of circumferential defects can be accomplished
using jejunal free flaps or free-skin flaps, such as the radial forearm, lateral
thigh, and scapular flaps. Jejunal free flaps have the advantage of being
tubular and match the defect closely in caliber; insetting is relatively
straightforward. Free-skin flaps, like the pectoralis flap, must be tubed to
reconstruct a circumferential defect, with a longer suture line resulting and
greater potential for anastomotic complications. The secretory properties of
the jejunum have been believed to be beneficial, particularly in patients
treated with radiation therapy, but in the current authors’ experience, ex-
cessive mucus production often results and interferes with tracheoesoph-
ageal voice restoration. The main disadvantage of the jejunal flap is the
requirement for laparotomy, with three enteric anastomoses resulting from
harvest. Abdominal complications related to laparotomy occur in 6% of
patients, and fistula development and swallowing difficulty occur in 18% of
patients [39]. Jejunal harvesting is contraindicated in patients who have
Crohn’s disease or ascites.
The radial forearm fasciocutaneous flap is based on the radial artery.
Because the radial artery in most patients is the dominant vessel to the deep
palmar arch, it must be determined that there is a patent anastomosis across
the palmar arch between the radial and ulnar arteries before harvest. The
use of the radial forearm free flap, compared with the jejunal flap, is
associated with a shorter hospitalization time and decreased time to oral
alimentation; in addition, most patients are able to successfully achieve full
oral alimentation without the need for supplemental enteral feedings [40,41].
This flap is associated with a somewhat higher incidence of stricture and
fistula formation compared with the jejunal flap, however, presumably
because the suture line is longer in a tubed flap. Donor site morbidity can be
significant, but laparotomy and its attendant risks and longer recovery time
are avoided. The lateral cutaneous thigh flap has gained in popularity as an
alternative method of reconstruction and, unlike the radial forearm flap, the
donor site defect is smaller and associated with less morbidity.

Postcricoid lesions
Postcricoid tumors are usually advanced at the time of presentation and
require total laryngopharyngectomy and cervical esophagectomy. If disease
extends below the lower border of the cricoid, total esophagectomy is
required. The first-line reconstructive technique for the resulting pharyn-
goesophageal defect is gastric transposition, or the gastric pull-up. The
primary advantage of the gastric pull-up is that it allows for reliable single-
stage reconstruction with a single anastomosis. Stricture formation is
90 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

uncommon, because the only anastomosis is high in the neck where stricture
rarely occurs. The entire esophagus is removed and the stomach is
transposed through the superior mediastinum into the neck. The main
disadvantage of the gastric pull-up is a significant morbidity and mortality
from the procedure. The rate of major perioperative complications is 50%,
and the operative mortality is approximately 10% [34]. Organ necrosis
occurs in 3% of patients [38]. In addition, pulmonary complications can
occur from thoracic dissection. The weight of the stomach and gravitational
pull can cause anastomotic tension and suture line disruption. Gastric
transposition entails a complete vagotomy and pyloroplasty, and swallow-
ing after a gastric pull-up can be complicated by early satiety, reflux, and
dumping syndrome. The most common long-term complication is reflux,
which occurs in 20% of patients. Only 30% of patients develop good speech
with available techniques of voice restoration [42]. Gastric pull-up is not
warranted when disease is limited to the cervical esophagus.
Colon transposition is a second-line method of pharyngoesophageal
reconstruction when total esophagectomy is required. The right or left colon
may be used, based on the superior mesenteric artery or middle colic artery,
respectively. The distal anastomosis is made between the distal colon and
stomach. Colon interposition has been associated with a high incidence of
postoperative infection, and therefore the colon is usually placed in
a subcutaneous pocket anterior to the sternum to avoid mediastinal
complications if necrosis occurs. Colon interposition has fallen out of favor
because of a 45% incidence of major medical complications; a 25%
incidence of reconstructive complications, including necrosis, fistula and
stricture; and an overall perioperative mortality rate of 20% [35,43]. Gastric
transposition is considered the reconstructive technique of choice for total
esophageal defects, with colon interposition reserved for patients with
contraindications to gastric surgery or as a salvage technique.

Neck dissection
Because of the high incidence of nodal metastases, ipsilateral neck
dissection is warranted in all patients who have hypopharyngeal cancer.
Selective neck dissection of zones II through IV is recommended for all
patients with clinically N0 neck disease. The scarcity of metastases to zones I
and V supports sparing these zones in this scenario [12,44]. Ipsilateral
paratracheal node dissection (zone VI) should be included as part of
selective neck dissection for all patients who have postcricoid tumors and
tumors that involve the pyriform fossa apex [14]. Patients with clinical
evidence of neck disease (N+) require modified radical neck dissection or
radical neck dissection of zones I through VI.
Contralateral neck dissection is indicated in patients who have midline
lesions of the posterior hypopharyngeal wall and postcricoid tumors
because of the increased incidence of occult contralateral metastases.
Patients who have laterally situated tumors are usually treated with
C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98 91

ipsilateral neck dissection alone, but T4 lesions may require bilateral neck
dissection when involvement of the medial wall of the pyriform sinus or
postcricoid mucosa is suspected. Tumors that involve the medial wall of
the pyriform sinus have a higher incidence of regional failure in the
contralateral neck compared with lateral wall lesions, and require bilateral
neck dissection [6]. Bilateral zone VI dissections are rarely performed
because of the risk of postoperative hypocalcemia [7].

Results
Limited data exist regarding the results of surgical treatment alone,
because the combination of surgery and postoperative radiation therapy has
become the standard of care for all but very small primary lesions with
negative margins and no histologic evidence of nodal metastases [7].
Postoperative radiation therapy is superior to preoperative radiation
therapy, with better locoregional control and fewer surgical complications,
and avoids the loss of important prognostic information obtained from
a nonirradiated surgical specimen [45]. Most patients who have hypophar-
yngeal cancer have histologic indications for adjuvant postoperative
radiation therapy, such as perineural invasion, lymphovascular invasion,
more than two lymph nodes with metastatic disease, extracapsular spread,
or close or positive margins. For most patients, surgery alone does not
provide sufficient disease control. Retrospective reviews comparing surgical
treatment alone with surgery plus postoperative radiation therapy have
shown decreased locoregional recurrence rates (11%–14% versus 39%–
57%, respectively) and improved 5-year disease-specific survival rates
(40%–48% versus 18%–25%, respectively) with the addition of post-
operative radiation therapy [8,46].
Surgery with postoperative radiation therapy is associated with local
recurrence rates of 4% to 18% and regional recurrence rates of 17% to 47%
[3,6,7,11,46]. Locoregional recurrence has been reported to be higher in
patients with postcricoid lesions compared with those who have lesions in
other sites [2]. No significant difference has been shown in local or regional
control rates between pyriform lesions and posterior wall lesions, with the
exception that T4 lesions of the posterior wall seem to have a higher
incidence of local recurrence when compared with lateral lesions, probably
because of prevertebral muscle involvement [23]. Within subsites, medial
wall pyriform sinus lesions have a higher incidence of failure in the
contralateral neck when compared with lateral pyriform lesions but have
equivalent local and regional recurrence rates [6].
Advanced-stage neck disease is significantly associated with increased
locoregional recurrence rates and poorer 5-year disease-specific survival
rates. N2 or N3 neck disease is associated with 5-year disease-specific
survival rates of 0% to 20% compared with 28% to 57% in patients with N0
or N1 disease [3,7]. The presence of extracapsular spread is associated with
92 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

poorer survival rates among patients with nodal disease [8]. In patients with
indications for elective treatment of the neck, the combination of surgery
and radiation therapy seems to result in better regional control rates
compared with reliance on postoperative radiation therapy alone to sterilize
N0 neck disease [6,7]. In patients who have clinically staged N0 disease, the
presence of occult metastatic disease results in poorer 5-year disease-specific
survival rates compared with patients who have N0 disease without occult
nodal disease (32% versus 50%, respectively) [7].
Surgical resection results in loss of the larynx in 56% to 79% of patients
and pharyngoesophagectomy in 27% to 44% of patients [2,7,10,27,47].
These numbers have driven the search for effective organ-sparing methods
of treatment.

Primary radiation therapy


The results of treatment with primary radiation therapy for curing
patients who have hypopharyngeal cancer are not as favorable as they are
for those who have tumors in other sites. Locoregional control has been
reported to occur in 35% to 40% of patients in several nonrandomized
single-institution trials [8,9,21–23,27,48]. Early-stage T1 or T2 lesions have
the best prognosis for locoregional control with radiation therapy alone,
with rates comparable to those obtained with combined surgery and
radiation therapy [9,49]. Local control rates for early-stage disease have
been reported to range from 77% to 89%, with 5-year disease-specific
survival rates as high as 69% [2,3,7–10]. Advanced-stage primary disease
(T3 and T4) and advanced-stage nodal disease (N2 or N3) are associated
with dismal rates of laryngeal preservation and 5-year disease-specific
survival rates of 0% to 12%. Surgical salvage after failure of radiation
therapy is successful in less than 10% of patients, and larynx preservation is
rarely possible [50,51]. Fewer than one third of patients are alive at 5 years
with a functional larynx [48]. Because of the prevalence of nodal disease and
the poor results of surgical salvage, primary radiation therapy is not
considered a first-line treatment for most patients with advanced-stage
hypopharyngeal cancer. Some of these studies, however, suffer from an
inherent selection bias by including patients referred for radiation therapy
because of inoperable disease or poor patient condition, thus contra-
indicating surgery or chemotherapy [21].
The addition of a neck dissection following radiation therapy for patients
who have N2 or N3 disease improves regional control rates and may cure
a subset of patients with residual microscopic regional disease [23,52–56].
More than 30% of patients who have N2 or N3 disease harbor residual
occult microscopic disease in cervical lymph nodes after definitive radiation
therapy. Neck dissection following radiation therapy may provide
prognostic information, because residual disease may be more likely to
recur locally [56]. Most surgeons believe postradiation neck dissection is
C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98 93

indicated for residual neck disease and for patients with N2 and N3 neck
disease who seem to have had a complete response to treatment [57].
Several nonrandomized studies have reported that hyperfractionated
radiation therapy provides a 15% to 25% improvement in local control
rates for larger tumors [9,23,27]. It has been suggested that doses of 7680 to
7920 cGy administered by twice-daily fractionation are required to
demonstrate benefit: the larynx must be shielded at doses greater than
7440 cGy to prevent laryngeal complications from treatment [23]. There is
an increased incidence of treatment-related complications on this schedule
when compared with conventional radiation therapy and these seem to be
dose related [9,23]. Hyperfractionated radiation therapy seems to improve
local control rates but incurs socioeconomic and time constraints and does
not seem to result in improved survival when compared with conventional
radiation therapy [9,23]. Prospective randomized studies are needed to
separate out selection bias to determine the efficacy of radiation therapy
alone in patients who have hypopharyngeal cancer compared with other
modalities of therapy.

Chemoradiation therapy
Chemotherapy sometimes yields impressive initial tumor responses, but it
is not a curative modality and does not improve survival rates in patients
who have head and neck cancer. Multiple chemotherapeutic agents have
been tried in combination with surgical therapy or radiation therapy. The
response of SCC to cisplatin, particularly in combination with 5-fluorouracil
(5-FU), has resulted in more widespread interest in chemotherapy as
adjunctive treatment. Patients who respond to chemotherapy show a sub-
sequent response to definitive radiation therapy, suggesting that tumors that
are sensitive to chemotherapy are radiosensitive. Induction chemotherapy
consists of the administration of two or three cycles of chemotherapy
initially, to distinguish between responders who are likely to benefit from
radiation therapy and nonresponders who are more likely to fail and require
surgery. In 1990, the use of chemoradiation for organ preservation
was established by the Department of Veterans Affairs Laryngeal Cancer
Study Group in a landmark prospective randomized trial [58]. Induction
chemotherapy with cisplatin and 5-FU, followed by definitive full-course
radiation therapy in responders, resulted in larynx preservation in two thirds
of patients who otherwise would have required total laryngectomy, without
compromising survival. These findings resulted in the acceptance of organ
preservation therapy in the treatment of laryngeal cancer and have led to
interest in determining whether these findings hold true for other sites in the
head and neck.
The only randomized, prospective phase 3 trial to date investigating
chemoradiation in patients who have hypopharyngeal cancer was conducted
by the EORTC Head and Neck Cancer Cooperative Group [29]. Patients
94 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

with T2 to T4 lesions who required total laryngectomy as part of definitive


surgical treatment were randomized to receive either induction chemother-
apy with cisplatin and 5-FU followed by definitive radiation therapy, or to
surgery with postoperative radiation therapy. This trial found no significant
difference between the chemoradiation arm and the surgery arm in local
(12% and 17%, respectively) or regional (19% and 23%) recurrence rates
and 5-year disease-free survival rates. A decreased incidence of distant
metastases was identified in the organ preservation group compared with the
surgery group (25% versus 36%, respectively). The 5-year estimate of
retaining a functional larynx for the chemoradiation group was 35% [29]. A
similar incidence of laryngeal preservation with the use of platinum-based
chemotherapy and radiation therapy has been reported by other institutions
[27,28,59–61]. These data suggest that larynx preservation with chemo-
radiation is far less likely for hypopharyngeal cancer than for laryngeal
cancer but can be attempted without compromising survival.
More recently, concurrent chemoradiation, the simultaneous administra-
tion of chemotherapy with radiation therapy, has been used to take advantage
of the effects of simultaneously administered chemotherapy as a radiation
enhancer. The administration of chemotherapy and radiation therapy
concurrently may result in a synergistic effect, which is suggested by impressive
initial complete response rates [62]. Concurrent treatment with chemotherapy
potentially treats distant disease and locoregional disease and may improve
survival rates [63]. Prospective randomized trials to test this hypothesis are in
progress. Acute side effects of treatment, particularly mucositis, seem to be
more severe with concurrent regimes compared with induction chemotherapy
and subsequent radiation therapy; however, there seems to be no difference in
long-term side effects between either modality of chemotherapy delivery [30].
Although larynx preservation is possible with chemoradiation, the pre-
served organ is not always functional. Significant laryngeal and pharyn-
geal dysfunction has been reported following chemoradiation [64–68].
Dysphagia may have a slow onset during treatment and a prolonged
recovery period: at 1 year after chemoradiation, 60% of patients treated with
this modality have moderate to severe impairment in swallowing ability and
a restricted diet caused by pharyngeal dysfunction [64–66]. Pretreatment vocal
cord fixation seems to be the strongest predictor of a poor functional outcome,
with more than 50% of patients requiring a feeding tube or tracheostomy 6
months after the completion of therapy compared with patients without vocal
cord fixation [69]. Patients who present with a fixed vocal cord should be
counseled accordingly as to expectations about treatment and results.
When surgical salvage is required after treatment with organ-preserving
techniques, the postoperative complication rate is significant. Neck
dissection after chemoradiation is associated with a complication rate of
38% [70]. Primary resection without free-flap reconstruction is associated
with a 77% incidence of postoperative complications, including wound
breakdown and fistulas [71]. When free flaps are used for reconstruction, the
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incidence of wound complications following chemoradiation has been


reported to be 20%, and less severe with an average hospital stay of 8 days
[72]. These data suggest that free-flap reconstruction should be performed
when salvage surgery of the primary site is required.

Summary
Despite advances in surgical and nonsurgical treatment, overall survival
rates for patients who have hypopharyngeal carcinoma have not improved,
and this disease still has a poor prognosis. The best results are obtained with
multimodality therapy, but at best, two thirds of patients are palliated rather
than cured of disease. Radical surgery with postoperative radiation therapy
remains the standard of care. Organ preservation strategies have not been as
successful in hypopharyngeal cancer as for cancers of other head and neck
sites. Chemoradiation is an effective alternative method of aggressive
treatment but may be associated with significant dysfunction of the end
organ when preservation is possible. Because of poor long-term survival
rates, local control remains the most important factor in planning
treatment, to provide meaningful palliation and best possible quality of life.

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Surg Oncol Clin N Am 13 (2004) 99–112

Larynx squamous cell carcinoma: concepts


and future directions
Pablo Mojica-Manosa, MDa,*, James Reidy, DOa,
Keith Wilson, MDb, Wade Douglas, MDa
a
Department of Head and Neck Surgery, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA
b
University of Cincinnati, Medical Science Building, P.O. Box 670528, Cincinnati,
OH 45267, USA

The larynx is a sphincter and is therefore one of the most important


structures in the upper aerodigestive tract. Functional impairment of the
larynx is a burden to patients who suffer from laryngeal carcinoma, the
second most common cancer of the head and neck region after the oral cavity.
The American Cancer Society estimated that there would be 8900 cases
of laryngeal carcinoma in 2002, with 3700 deaths. Spain has one of the highest
rates in the world—some regions reach a rate of 20 cases per 100,000 persons.
Other countries with high incidence are France, Italy, and Poland. Men are
affected four times more frequently than women [1]. The male/female ratio is
greater in glottic carcinoma than supraglottic carcinoma, and is often a disease
of the elderly. The peak incidence is in the sixth and seventh decade of life.
Less than 1% of the cases developed in patients under 30 years of age [2].
As with most tumors, multiple factors contribute to the development
of this cancer, tobacco being the single most important risk factor. There
are more than 30 known carcinogens in tobacco. The most well-known
are polycystic aromatic hydrocarbons and nitrosamines [3]. Cessation of
smoking for more than 15 years decreases the risk to nearly that of non-
smokers [4,5]. Another risk factor for developing larynx carcinoma is
alcohol use. The relationship to alcohol and larynx carcinoma is unclear,
but most studies show that it has a synergistic effect with tobacco use [6,7].
In addition, certain occupations and exposures increase the risk of
developing carcinoma of the larynx, such as: painters; metal-working
and plastic-working machine operators; construction workers; and those

* Corresponding author.
E-mail address: pablo.mojica@roswellpark.org (P. Mojica-Manosa).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00130-3
100 P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

exposed to diesel and gasoline fumes, therapeutic radiation, wood dust,


or asbestos [8]. Dietary factors that predispose an individual to laryngeal
carcinoma include intake of salt-preserved meat and high dietary fats and
chronic gastric reflux disease.

Anatomy
The larynx is divided anatomically and clinically into three areas: supra-
glottic, glottic, and subglottic. This section describes how the anatomy re-
lates to cancer origin and spread. Treatment options are often based on
the anatomic site of laryngeal cancer.

Larynx
The supraglottic larynx extends from the epiglottis down to the lateral
angle of the ventricles. This includes the epiglottis, pre-epiglottic space, the
hyoid bone and arytenoids cartilage mucosa. The supraglottis is derived
from midline wedge-shape structures and ultimately has bilateral blood
supply and lymphatic drainage.
The hyoid bone is the most superior structure of the supraglottic larynx.
It is the point of attachment of numerous muscles and ligaments. It is
composed of the greater cornu laterally and lesser cornu medially.
The epiglottis is composed of elastic cartilage. It is widest at the top and
tapers down to the petiole. There is a suprahyoid, infrahyoid, and petiole
portion. The suprahyoid portion is covered by mucosa in both sides. The
infrahyoid portion is covered by mucosa posteriorly and abuts the fat of
the preepiglottic space anteriorly. It is a fenestrated structure that pro-
vides a pathway for the extension of normal structures like lymphatics,
submucosal glands, blood vessels, and nerves. In addition, these perfo-
rations provide a route of spread for supraglottic carcinoma from the mu-
cosa to the pre-epiglottic space [9]. The most inferior aspect is the petiole,
which is attached to the thyroid cartilage by way of the thyroepiglottic
ligament. The hyoepiglottic ligament is the roof of both the paraepiglottic
and preepiglottic spaces. It provides a formidable barrier for carcinoma
invasion to the base of the tongue [9].
The pre-epiglottic space is surrounded by the hyoepiglottic membrane
superiorly, the epliglottis posteriorly, the thyrohyoid membrane anteriorly,
and the thyroepiglottic ligament inferiorly. This space is continuous laterally
with the para-epiglottic space. This space is bounded anterolaterally with
the thyroid cartilage and thyrohyoid membrane and medially with the quad-
rangular membrane. These spaces are important because they provide the
route for superior and inferior spread in the larynx [9].
The glottic larynx extends from the lateral angle of the ventricle down to
one centimeter below the apex of the ventricles. It contains the true vocal
cords, the posterior and anterior commissure. It arises from lateral cell masses
that come together, and the lymphatic drainage tends to be ipsilateral.
P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112 101

The lamina propia of the true vocal cords has a superficial layer com-
posed of loose fibrous tissues that makes up Reinke’s space. An interme-
diate and deep layer consisting of elastic and collagenous fibers forms the
vocal ligament. Blood vessels and lymphatics are almost absent in this space,
which creates resistance to tumor invasion [9].
The true vocal cords meet anteriorly in the anterior commissure tendon,
which is attached to the thyroid cartilage. This area is devoid of peri-
chondrium, which is a pathway of less resistance to tumor progression. This
commisure extends superiorly from the thyroepliglottic ligament.
Another structure that makes tumor invasion more resistant is the conus
elasticus. This membrane extends from the true vocal cord down to the
upper border of the cricoid cartilage. The most anterior aspect is the crico-
thyroid membrane. This area contains the paraglottic space, which is a
pathway for tumor progression through the larynx [9].
The subglottic larynx extends from the bottom of the glottic to the inferior
aspect of the cricoid cartilage. It is a rare site for primary tumor origin, but is
more commonly associated with subglottic extension from the glottis. Because
of the proximity of the cricothyroid membrane and the rich postcricoid,
lymphatics have a higher propensity for extralaryngeal extension.

Lymphatic and distant spread


Lymphatic spread from the primary tumor of the larynx is of great
importance because of its impact on treatment options and survival. The
overall metastatic rate to cervical lymph nodes for larynx squamous cell
carcinoma in general for all subsites is: T1, 6% to 25%; T2, 30% to 70%; T3
and T4, 65% to 80% [10–12]. The occult metastasis ranges from 20% to
50% base on the T stage.
The lymph nodes that are more commonly involved are levels II, III, and
IV [13,14]. Past studies have shown that levels I and V have been involved in
6% and 1%, respectively, with most of the patients also presenting nodal
involvement at levels II to IV [15].
The lymphatic spread has also been studied by site. In the supraglottic
larynx, the rate of nodal involment depends on the T stage. For T1/T2
the rate for clinical or occult metastasis is 30% to 70%, having 50% of
those with contralateral disease. The rate of lymph nodes metastasis is
also influence by the subsite in the supraglottis. The incidence of clinical or
occult node metastasis in tumors presenting at the marginal zone or large
size tumors is greater when compared with centrally located or transglottic
tumors. However, the rate of bilaterally disease in the neck is higher in
centrally located and large tumors [16].
In glottic tumors, the rate of node metastasis differs from that of the
supraglottic. The rate of neck metastasis overall is less than 5% for T1, 5%
to 10% for T2, 10% to 20% for T3, and 25% to 40% for T4 tumors [12].
Bilateral and contralateral neck metastasis is rare except in subglottis and
102 P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

supraglottis extension of the tumor. In addition, with this type of extension


delphian node involvement and thyroid invasion are evident [12].
Little is known about primary subglottis tumors, because their incidence
is less than 1% of all larynx tumors. One important aspect to consider with
this type of tumor is the high rate of paratracheal node involvement (65%)
and low rate of cervical node involvement (20%) [17]. Mediastinal node
involvement has also been described [17].
The clinical development of distant metastasis for larynx tumors of the
supraglottis and glottis are 15% and 3%, respectively, after a follow-up of
2 years [18]. The most common affected organ is the lung, followed by the
mediastinum, bone, and liver. The incidence of distant metastasis without
local recurrence is greater for supraglottis tumors than for glottis tumors.
Second primary malignancies develop in 11% to 19% of patients, usually
within the first 5 years after treatment [19].

Staging and prognosis


In the United States, larynx tumors are classified using the American
Joint Committee for Cancer guidelines. They are staged according to the
tumor size (T stage), presence of cervical lymph node metastasis (N stage),
and presence of distant metastasis (M stage) (Table 1) [20].
Factors that portend a poor prognosis include: increasing T stage, pre-
sence of cervical nodal metastasis, extracapsular spread of the cancer, and
presence of distant metastasis [21–24].
With an increased understanding of the molecular biology of cancer, much
research has been directed in characterizing this tumor type. There have been
studies pointing to DNA aneuploidy as a factor for increased recurrence
when compared with diploidy tumors [25,26]. Overexpression of the c-myc
oncogene has been correlated with a resistance to radiation and chemotherapy
and increased metastatic potential [27]. Expression of int-2 has been associated
with decreased survival [28]. Mutations in p53 and ras genes have been
associated with high-grade tumors and increased metastatic potential [29].

Diagnosis
The diagnosis of laryngeal cancer should be suspected when hoarseness
is present for more than 2 to 3 weeks. Tumors in the glottic usually present
early because of vocal cord involvement; tumors of the supraglottis usually
present later because of a lack of symptoms in the early stages. Other
symptoms associated with laryngeal tumors are hemoptysis, airway insuffi-
ciency upon exertion, halitosis, and the so-called ‘‘hot potato’’ voice. Dys-
phagia, airway compromise, stridor, and neck mass are more common in
advance disease.
Accurate examination by way of indirect or direct laryngoscopy is
of most importance to staging and treatment planning [30]. A critical
P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112 103

Table 1
TNM staging of larynx carcinoma
Primary tumor (T)
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Supraglottis
T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility
T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis, glottis,
or region outside the supraglottis (eg, mucosa of base of tongue, valleculla,
medial wall of pyriform sinus) without fixation of the larynx
T3 Tumor limited to larynx with vocal cord fixation or invades any of the following:
postcricoid area, pre-epiglottic tissues, paraglottic space, or minor thyroid
cartilage erosion (eg, inner cortex)
T4a Tumor invades through the thyroid cartilage or invades tissues beyond the larynx
(eg trachea, soft tissues of neck including deep extrinsic muscle of the tongue,
strap muscle, thyroid, or esophagus)
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal
sturctures
Glottis
T1 Tumor limited to the vocal cords (may involve anterior or posterior commissure)
with normal vocal cord mobility
T1a Tumor limited to one vocal cord
T1b Tumor involves both vocal cords
T2 Tumor extends to supraglottis or subglottis, or there is impaired vocal cord mobility
T3 Tumor limited to the larynx with vocal cord fixation or invades paraglottic space,
or minor thyroid cartilage erosion (eg, inner cortex)
T4a Tumor invades through the thyroid cartilage or invades tissues beyond the
larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of
the tongue, strap muscles, thyroid, or esophagus)
T4b Tumor invades prevertebral space, encases carotid artery, or invades
mediastinal structures
Subglottis
T1 Tumor limited to the subglottis
T2 Tumor extends to vocal cords with normal or impaired mobility
T3 Tumor limited to larynx with vocal cord fixation
T4a Tumor invades through the thyroid cartilage or invades tissues beyond the
larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of the
tongue, strap muscles, thyroid, or esophagus)
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal
structures
Regional lymph nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Single ipsilateral node, 3 cm or less in greatest dimension
N2a Single ipsilateral node, greater than 3 cm and less than 6 cm
N2b Multiple ipsilateral nodes less than 6 cm
N2c Bilateral or contralateral nodes less than 6 cm
N3 Metastasis in a lymph node more than 6 cm in greatest dimensions
(continued on next page)
104 P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

Table 1 (continued )
Distant metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Data from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original
and primary source for this information is the AJCC Cancer Staging Manual, 6th edition (2002)
published by Springer-Verlag New York (For more information, visit www.cancerstaging.net).
Any citation or quotation of this material must be credited to the AJCC as its primary source.
The inclusion of this information herein does not authorize any reuse or further distribution
without the expressed written permission of Springer Verlag New York, Inc., on behalf of the
AJCC.

component of evaluation is an assessment of the size and location of the


tumor, vocal cord involvement, extralaryngeal spread, and regional lymph
node in the neck.
Adjunct to the history and physical examination is the use of radiologic
studies to ascertain the depth of the tumor involvement. These studies help
evaluate the presence of pre-epiglottic space extension, paraglottic space
extension, cartilage involvement, and extralaryngeal involvement. Both CT
and MRI provide adequate assessment. Involvement of the soft tissue,
subglottis extension, and early cartilaginous invasion is better evaluated with
MRI, while invasion of bony or cervical lymph nodes is better evaluated
with CT [31,32]. PET imaging can be used to differentiate postchemotherapy
and radiation changes of sterilized tumor and fibrosis from recurrence in
comparison with CT and MRI in those nonsurgical or organ-preserving
patients. It is also helpful for surveillance for second primary malignancies
[33,34].
Operative endoscopy is the gold standard for pretreatment staging.
Direct visualization can assess the size, location, and mucosal extent of the
tumor. Under general anesthesia, digital palpation of the base of the tongue
and vallecula may reveal areas of extensive submucosal spread. A biopsy of
the lesion should be performed in this case. With a suction catheter tip,
areas of friable mucosa and submucosal firmness—which may represent
submucosal extension—may be identified. The status of laryngeal ventricles
and the subglottic extend of the tumor are the two most challenging aspects
of direct laryngoscopy, especially with bulky tumors. The esophagous,
trachea, and bronchial tree should be evaluated to rule out any synchronous
tumors in the upper aerodigestive tracts. A chest X ray and liver function
test is sufficient for a metastatic survey in the absence of systemic
complaints [35]. The true extent of the tumor is fully evaluated during
surgical exploration, which could reveal the need for a total laryngectomy;
patients must be warned of this possibility when conservation surgery is
contemplated.
P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112 105

Pathology
Only 1% of all laryngeal tumors are of the nonsquamous type. The most
common tumor types include cystic adenoid (adenocarcinoma), neuroen-
docrine, and carcinoid. Sarcomas have been reported, of which chondro-
sarcomas predominate. Other tumor types include pseudosarcoma, fibrous
histiocytoma, leiomyosarcoma, liposarcoma, synovial sarcoma, and giant
cell tumors. The vast majority of laryngeal tumors are squamous cell car-
cinomas. This article concentrates on the management of this type of tumor.

Treatment
Treatment of this type of tumor should focus on providing an ade-
quate oncologic chance of cure while attempting to minimize morbidity.
Important secondary goals of treatment include a serviceable voice and the
ability to swallow without aspiration.
Several factors may affect treatment. For example, exophytic tumors
tend to respond better to radiation than endophytic tumors, and poorly
differentiated tumors tend to metastasize more readily than well-differen-
tiated ones [36]. Tumor location and extent and the patient’s general medical
condition may also dictate the treatment option.

Supraglottic carcinoma
Treatment options for carcinoma of the supraglottis varies widely for
local control, cure rates, and 2- to 5-year survival rates for surgery, radia-
tion, or combination therapy, depending on the stage.
For early (T1, T2) tumors, surgery and radiation treatment are equivalent
in terms of locoregional control and survival. The control rates for surgery
and radiation in T1 tumors are 90% to 95% and 80% to 90%, respectively;
in T2 tumors, they are 80% to 90% and 70% to 80%, respectively [37–40].
Surgical salvage for radiation failure equalizes locoregional control for both
modalities.
It is important to consider the patient’s age and general medical condition.
The most common approaches to stage I and II are vertical partial laryng-
ectomy, supraglottic laryngectomy, supracricoid subtotal laryngectomy, and
total laryngectomy. The type of procedure is influenced by the site of the
tumor, extension, nodal status, and surgeon’s expertise. Although conserva-
tion surgery may be planned, is important to inform the patient that it may
ultimately change to a total laryngectomy if the tumor extension goes beyond
the previous examination studies.
Cure rates are lower for advanced tumors (T3, T4), with stage III at
40% and stage IV at 20% [8]. The mainstay of treatment for advanced supra-
glottic carcinoma is combination modality therapy that includes surgery
and radiation. Chemotherapy and radiation is an alternative that is under
106 P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

evaluation. Many factors can influence the decision regarding optimal


treatment. Clinical consideradtions include endophytic versus exophytic,
extensive cartilage invasion, involvement of soft tissue in the neck, presence
of cervical node metastasis, and involvement of the airway. The most
common surgical treatment is total laryngectomy. In rare cases, conservation
surgery may be attempted. If a nonsurgical approach is chosen, the
combination of chemotherapy with radiation is an effective treatment and
will conserve the larynx 60% of the time. For cases in which nonsurgical
treatment yields a response of less than 50%, salvage with surgery may be
indicated [41].

Glottic caricinoma
Locoregional control in glottic carcinoma differs from the supraglottic
carcinoma because of its embryology. Locoregional control after surgery or
radiation for T1 is 98% and 85% to 95%, respectively; for T2 it is 82% and
65% to 75%, respectively [8]. Treatment options will be affected by
decreased vocal cord mobility, anterior commissure involvement, subglottic
extension, and total size of the tumor. Vocal cord impairment will decrease
local control from 77% to 50% in 3 years, especially if both cords are
diseased. Radiation therapy is less effective with vocal cord mobility
impairment [42]. Anterior commissure invasion may change the T stage
from T1 to T4 in a few millimeters. Subglottic extension may increase
recurrence from 12% to 32% if extension is greater than 5 mm posteriorly
or 10 mm anteriorly [43].
For advanced glottic cancer (T3, T4), the local control rates for radiation
therapy range from 40% to 60%. Local control rates for surgery are greater,
ranging from 84% to 96%, and the 2-year disease-free survival is 79% for
T3 and 58% for T4 [8]. The ultimate decision to treat advanced glottic
carcinoma depends on the tumor specifics and the patient’s desires and
general medical condition. Combined modality therapy is considered supe-
rior to either surgery or radiation alone. Total laryngectomy is usually per-
formed, while near total laryngectomy or supracricoid laryngectomy may
be used in certain cases. Laryngeal preservation can be achieved with the
combination of chemotherapy and radiation 60% of the time [41].

Subglottic carcinoma
Primary subglottic carcinoma is rare. Most cases are a subglottic exten-
sion from glottic carcinoma. Involvement of the subglottic space increases
the risk of extralaryngeal spread. Treatment usually involves the combina-
tion of surgery and radiation therapy. It is recommended that surgery
include laryngectomy, thyroidectomy, and paratracheal node dissection.
Radiation therapy is recommended for advance cases. Elective neck dis-
section is recommended when the risk of cervical nodal metastases is greater
than 25%.
P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112 107

For the supraglottis, the location of the tumor influences the incidence
of nodal metastasis. In the clinically negative neck, the risk of pathologic
metastatic node involvement ranges from 15% to 48% depending on the site
and size of the tumor [8]. For lesions in the marginal zone, the rate is higher
when compared with more centrally located tumors. One important aspect
of supraglottic carcinoma is the fact that as the tumor size increases, so does
the risk of bilateral neck spread. For T2 tumors, the risk of pathological
or clinically involved nodes is between 30% and 70%, with contralateral
disease occurring 50% of the time. With this in mind, it is recommended
that both sides of the neck be included in the treatment planning for tumors
T2 or higher, whether with surgery or radiation.
Because of the embryology of glottic carcinoma, the incidence of nodal
spread differs and the rate of contralateral disease is lower. Because the rate
of occult metastases for T1 and T2 lesions is between 1% to 8%, there is
little role for elective neck treatment [44,45]. The rate of occult disease is
approximately 15% for T3 and approximately 30% for T4 [46]. Elective
neck treatment in the form of surgery or radiation is recommended for T3
or T4 glottic lesions. Bilateral or contralateral disease will be seen with
subglottic and supraglottic extension of the tumor.
These nodal patterns support the removal of levels II, III, and IV in the
clinically negative neck. If there is extension beyond the subglottis, level IV
should be included in the dissection [47–49]. A comprehensive neck dis-
section should be performed for the clinically positive neck. For cases in
which there is pathologic node involvement of only one node, selective node
dissection can be adequate treatment.
Radiation can be considered for definitive treatment of cervical nodal
metastases in patients presenting with N0 or N1 disease [50]. Postoperative
radiation to the neck should be considered for patients who present with
multinodal disease or extracapsular spread [51].

Radiotherapy and chemotherapy in the treatment of laryngeal cancer


Radiation therapy may be used in the treatment of laryngeal cancer
in a variety of ways. Radiation can be used as primary, adjuvant, or
neoadjuvant modality. In the last decade, chemotherapy has played a more
important role as neoadjuvant therapy in combination with radiation to
treat advanced laryngeal carcinoma. The goal of this approach is to preserve
the larynx in those patients who would otherwise need a total laryngectomy.
Many study protocols using chemotherapy and radiation to preserve
laryngeal function have demonstrated that the larynx can be preserved
without compromising survival. The most significant of these protocols
comes from the multi-institutional trail performed by the Department
of Veterans Affairs Laryngeal Cancer Study Group [41]. In this study,
induction chemotherapy was administered with cisplatin and 5-FU, fol-
lowed by radiation. The experimental arm consisted of two initial cycles
108 P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

of chemotherapy; if the tumor responded with more than 50% reduction,


the patient completed a third cycle of chemotherapy followed by radiation.
If the tumor had less than 50% reduction or progression of the disease,
a total laryngectomy was performed with adjuvant radiation. The survival
and locoregional control was equivalent between both arms, and 64% of the
patients retained their larynx in the chemotherapy/radiation therapy arm.
Studies that followed that of the Department of Veterans Affairs
Laryngeal Cancer Study Group have tried to identify the combination and
sequence schedule that will yield the best responses for organ preservation
and morbidity without compromising survival. More recent studies show that
complete clinical response has been seen 59% to 68% of the time [52–54].
There have been studies investigating the differences between sequential
and concomitant chemotherapy/radiation therapy, different chemotherapy
combinations (most cisplatin-based), and conventional fractionation versus
accelerated fraction radiotherapy. Some studies suggest that concomitant
chemotherapy and radiation therapy may provide better locoregional control
when compared with sequential chemotherapy/radiation therapy [55]. At
present, no study has demonstrated conclusively that either concomitant
chemotherapy/radiation therapy or accelerated fractionation is better than
standard sequential chemotherapy followed with conventional fractionation
radiation therapy in demonstrating a difference in overall survival.
The major drawback for the induction concurrent chemotherapy/
radiation therapy is the substantial morbidity, particularly if radiation is
administered in the therapeutic range. Protocols have decreased total
radiation dosages in an attempt to minimize this. Toxicities include mu-
cositis, diarrhea, dermatitis, renal failure, and myelosuppression. This ap-
proach has prevented 7% to 18% of patients from completing a full course of
neoadjuvant therapy [56,57]. In addition, mortality has been reported with
chemotherapy and radiation in the range of 0.6% to 6% [58,59]. Neverthe-
less, it should be mentioned that preservation does not translate into function
automatically. Problems in function after chemotherapy and radiation have
been reported, such as reduced laryngeal closure, reduced laryngeal
elevation, and reduced posterior tongue base movement [60].

Complications, outcomes, and future directions


Complications after surgery can be classified as acute or chronic. Acute
complications include wound infection, hematoma, seroma, pneumonia,
and pharyngocutaneous fistula (PCF) formation (5% to 15%) [61,62].
Complications increase when radiation therapy is used preoperatively; the
most troublesome is PCF, with incidence rates increasing to 20% to 30%.
Conservation management with appropriate wound care, early detection,
and cessation of oral intake will promote fistula closure most of the time. In
those cases where PCF persists despite conservative therapy, local, regional,
or free flaps may be used to correct the defect [63–65].
P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112 109

The most common chronic complication after total laryngectomy is stric-


ture formation. If a stricture is identified, it can be treated with dilation. In
dilation failures, consideration of tissue transfer is recommended to correct
the stricture [66].
Acute radiation reactions characteristically present as skin dermatitis and
mucositis. These are managed symptomatically with adequate oral hygiene.
Late complications include xerostomia, skin dermatitis, and osteoradionec-
rosis [66]. For xerostomia, patients should be instructed to take adequate
amounts of fluids orally to maintain humidification of the oral cavity.
Osteoradionecrosis sometimes can present severe enough to cause impair
swallowing. Aggressive debridement is recommended occasionally.
Laryngeal cancer historically has been treated with surgery or radiation
alone for early disease and combination therapy with surgery followed by
adjuvant radiation reserved for advance disease [22]. Location of the tumor,
determination of its size, and nodal involvement are important consi-
derations for optimal treatment. Of these, nodal involvement is the most
important prognostic factor for recurrence and long-term survival [24,67,68].
Future directions focus on optimizing locoregional control and survival
while preserving the organ. Protocol modalities, including combination
chemotherapy and radiation treatment, are under intense investigation to
achieve this goal. The approach of multimodal treatment with incorporation
of biological markers and novel biologic and genetic techniques may in the
future increase long-term survival and organ preservation for this population.

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Surg Oncol Clin N Am 13 (2004) 113–127

Major salivary gland cancer


Robert L. Witt, MDa,b,*
a
Section of Otolaryngology, Department of Surgery, Christiana Health Care Systems,
Newark, DE, USA
b
Department of Otolaryngology, Jefferson Medical College, Philadelphia, PA, USA

Salivary gland tumors represent 3% of head and neck tumors and 0.6%
of all tumors in the body. Parotid gland tumors constitute 70% to 80% of
tumors of the salivary gland, and 20% of parotid gland tumors are
malignant. Four fifths of the parenchyma of the gland lies lateral to the
facial nerve, in the superficial lobe, and 90% of parotid neoplasms present in
the superficial lobe. Approximately 80% of parotid tumors occur in the
lower part of the gland. Parotid pleomorphic adenoma is the most common
parotid neoplasm, accounting for 60% to 70% of parotid tumors.
Malignant salivary gland tumors have an incidence of less than 1 per
100,000 individuals. Most malignant salivary gland tumors arise from the
excretory or intercalated duct reserve cells [1]. Their origin is largely
unknown. Genetic alterations, including allelic loss, chromosomal trans-
locations, and absence or addition of a chromosome, may be factors in some
cases. A heightened risk after radiation exposure [2] is not uniformly
reported [3]. Malignant parotid tumors are slightly more common in
women, with a peak incidence in the fifth through seventh decades of life.
Malignant salivary gland tumors generally present as painless, slow-
growing tumors that are indistinguishable from benign tumors. The overall
detection rate for salivary gland malignancy based on clinical features is
approximately 30%; palpable cervical lymph nodes, facial nerve palsy, and
deep fixation and rapid enlargement of the tumor are significant parameters
for parotid gland tumors [4]. Both benign and malignant tumors can present
with pain in a small percentage of patients. Approximately 10% of patients
who have parotid gland malignancies present with facial paralysis, which is
associated with a poor prognosis. Patients who have deep-lobe parotid
tumors may present with distortion of the lateral pharyngeal wall on intraoral
examination. Trismus may represent infratemporal fossa involvement.

* 2401 Pennsylvania Avenue, Suite 112, Wilmington, DE 19806.


E-mail address: robertlwitt@aol.com

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00126-1
114 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

Cervical lymph node metastasis is observed in 10% to 20% of malignant


cases. Most parotid cancers are high-grade tumors, with a global 5-year
survival rate of 45% to 50%.
Submandibular gland tumors are malignant in 50% of cases, constituting
10% of all salivary gland malignancies. Fixation to the mandible or skin
infiltration suggest extraparenchymal extension. Weakness or numbness of
the tongue indicates perineural involvement of the hypoglossal or lingual
nerve. The 5-year survival rate has recently been reported to be as high as
50% [5], but generally, submandibular gland cancers are regarded as more
aggressive and are associated with a lower survival rate compared with
parotid gland tumors of the same histologic type. Sublingual gland tumors
are very rare; approximately 80% are malignant. They present as
a submucosal mass on the anterior floor of the mouth, and survival rates
are similar to those in patients who have submandibular gland tumors of the
same histologic type.
The American Joint Commission on Cancer 2002 classification of major
malignant salivary gland tumors follows the tumor-node-metastasis (TNM)
system of staging (AJCC Cancer Staging Manual, American Joint Committee
on Cancer, 6th edition. Springer-Verlag: New York; 2002.) (Box 1).

Imaging and fine-needle aspiration


Preoperative CT, MRI, or ultrasonography rarely alters the clinical
course for small tumors of the superficial parotid lobe. Management of
parotid tumors with fixation, facial nerve dysfunction and cervical lymph
node metastasis, and deep-lobe tumors with parapharyngeal extension is
enhanced with imaging. Imaging is helpful for submandibular and sublingual
gland tumors. MRI provides superior resolution of soft tissue structures and
is the preferred modality for evaluating a parotid tumor and neck metastasis.
MRI may indicate an inferior tail of parotid mass, when clinical presentation
would suggest an upper cervical nonparotid neck mass. Infiltration of the
tumor into muscle or bone on MRI is predictive of malignant disease. High-
resolution MRI may detect perineural involvement. Positron emission
tomography categorizes only 69% of parotid tumors correctly when
attempting to distinguish benign from malignant parotid masses [6].
Fine-needle aspiration (FNA) for a small, mobile mass of the tail of the
parotid gland is not mandatory. The breadth of histologic subtypes in
parotid tumors makes cytologic diagnosis a formidable goal. Furthermore,
histologic patterns of pleomorphic adenoma are variable, and they can be
mistaken for mucoepidermoid carcinoma or adenoid cystic carcinoma [7,8].
There is difficulty in distinguishing a benign oncocytic tumor from an acinic
cell carcinoma, and a Warthin’s tumor (adenolymphoma) from a low-grade
mucoepidermoid carcinoma [8]. The accuracy of FNA in broadly distin-
guishing benign and malignant tumors, however, is more than 90% in most
series [7]. In elderly, debilitated patients with a parotid neoplasm, such as
R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127 115

Box 1. TNM staging system for salivary gland tumors


T: tumor
T1 tumor smaller than 2 cm
T2 tumor 2 to 4 cm
T3 tumor 4 to 6 cm or tumor with extraparenchymal extension
T4a tumor invading skin, mandible, ear canal, or facial nerve
T4b tumor invading skull base or pterygoid plates or encasing
carotid artery
N: regional lymph nodes
N1 single ipsilateral node smaller than 3 cm
N2a single ipsilateral node 3 to 6 cm
N2b multiple ipsilateral nodes smaller than 6 cm
N2c bilateral or contralateral node smaller than 6 cm
N3 node larger than 6 cm
M: distant metastases
M0 no distant metastases
M1 distant metastases present
Staging
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3,
T1/T2/T3 N0, N1 M0, M0
Stage IVa T4a,
T1/T2/T3 N0/N1/N2 M0, M0
N2
Stage IVb T4b,
any T N3, any N M0, M0
Stage IVc any T any N M1

Data from the American Joint Committee on Cancer (AJCC), Chicago,


Illinois. The original and primary source for this information is the AJCC Cancer
Staging Manual, 6th edition (2002) published by Springer-Verlag New York (For
more information, visit www.cancerstaging.net). Any citation or quotation of
this material must be credited to the AJCC as its primary source. The inclusion
of this information herein does not authorize any reuse or further distribution
without the expressed written permission of Springer Verlag New York, Inc.,
on behalf of the AJCC.

a Warthin’s tumor, FNA may obviate the need for surgery. In addition, the
use of FNA may avoid parotid gland surgery in sarcoidosis, tuberculosis,
histoplasmosis, lymphoma, and benign cervical adenopathy in patients with
HIV and in children. FNA can distinguish an upper cervical neck mass from
a low tail of parotid tumor. It also is helpful in patients who have
116 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

submandibular neoplasms, and can distinguish a salivary gland neoplasm


from a metastatic occult upper respiratory tract primary tumor in a patient
who has a painless mass that does not enlarge with oral intake. Preoperative
diagnosis is helpful to advise patients about the extent of surgery that may
be required or that operative findings may dictate sacrifice of the facial
nerve. More rigorous attention to the operative margin may be required when
results of preoperative cytologic tests reveal malignancy. The type of
malignant tumor is much more difficult to classify correctly by FNA. Finally,
there have been no reports of seeding of tumor along the needle tract.

Histology, immunohistochemistry, and molecular biology


In 2002, the World Health Organization suggested the histologic typing
of malignant salivary gland tumors listed in Box 2.

Mucoepidermoid carcinoma
Mucoepidermoid carcinoma is the most common malignant tumor of the
parotid gland and the second most common malignant tumor of the

Box 2. Histologic typing of malignant salivary gland tumorsa


Acinic cell carcinoma
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Polymorphous low-grade adenocarcinoma
Epithelial-myoepithelial carcinoma
Basal cell adenocarcinoma
Sebaceous carcinoma
Papillary cystadenocarcinoma
Mucinous adenocarcinoma
Oncocytic carcinoma
Salivary duct carcinoma
Adenocarcinoma
Myoepithelial carcinoma
Carcinoma ex pleomorphic adenoma
Squamous cell carcinoma
Small cell carcinoma
Other carcinomas

Data from: Seifert G in collaboration with Sobin LH, and pathologists in


6 countries. World Health Organization international histological classification
of tumors. Histological typing of salivary gland tumors, 2nd edition.
Springer-Verlag: Berlin, 1991.
a
World Health Organization, 2002.
R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127 117

submandibular and sublingual glands. There is a slight female predilection.


Mucoepidermoid carcinoma is located in the parotid gland in 80% to 90% of
patients, comprising approximately one third of parotid malignancies.
Mucoepidermoid carcinomas contain mucin-producing cells and epithelial
cells. Differentiation between high-grade mucoepidermoid carcinoma and
poorly differentiated squamous cell carcinoma (SCC) may require special
staining with periodic acid–Schiff stain for the presence of glycogen in the
mucin or positive staining for mucicarmine in the mucous cells. Sub-
classification includes low-grade, intermediate-grade, and high-grade tumors.
Low-grade tumors are circumscribed but not encapsulated and have
a predominance of mucin cells (Fig. 1), whereas high-grade tumors are
dominated by poorly differentiated squamous cells with poorly defined
margins, high mitotic activity, neural invasion, and tumor necrosis. Most
mucoepidermoid carcinomas are low grade, with less than 10% of patients
presenting with facial nerve dysfunction. Wide excision without radiation
therapy results in 5-year survival rates for low-grade tumors that approach
75%. High-grade mucoepidermoid carcinoma presents with facial nerve

Fig. 1. Photomicrograph of low-grade mucoepidermoid carcinoma (magnification 40 with


H&E stain). (From Ellis GL, Auclair PL. Tumors of the salivary gland. In: Rosai J, editor. Atlas
of tumor pathology. Washington, DC: Armed Forces Institute of Pathology; 1996. p. 164; with
permission.)
118 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

dysfunction in 25% of patients and has a propensity for locoregional and


distant recurrence. Recommended treatment is surgery and radiation therapy,
which yields a 5-year survival rate of 50%. Grading is not as successful in
predicting clinical outcome in submandibular mucoepidermoid carcinoma.

Adenoid cystic carcinoma


Adenoid cystic carcinoma is the second most common salivary gland
malignancy, representing 10% to 20% of major salivary gland cancers.
Women are more commonly affected. It is the most common malignancy of
the submandibular gland and sublingual glands: half of all sublingual
tumors are adenoid cystic carcinomas. Perineural involvement by direct
invasion is the hallmark of adenoid cystic carcinoma, allowing distant
spread, including the skull base in 42% of patients [8]. Invasion into salivary
gland parenchyma and soft tissues is common. The incidence of facial nerve
dysfunction in adenoid cystic carcinoma is 20%, although most of these
tumors present as an asymptomatic mass. Lymphatic spread is less common
than distant metastasis to bone and lung. Histologic subtypes include the
most common ‘‘Swiss cheese–appearing’’ cribriform pattern (Fig. 2). The
tubular subtype, with a more glandular histology, has the best prognosis.
The solid subtype has sheets of cells and is associated with a grim prognosis.
Most tumors display more than one histologic subtype, with the classi-
fication depending on the predominant subtype. Recurrences generally de-
velop within 5 years, but late recurrences develop 10 to 20 years later. The
factors with the greatest impact on survival are the stage of the disease and
histologic grade; other significant factors include the site of origin, surgical

Fig. 2. Photomicrograph of the cribriform type of adenoid cystic carcinoma demonstrating the
‘‘Swiss cheese’’ appearance (magnification 100 with H&E stain). Arrows show pseudolumens
that are in continuity with the stroma of the tumor. (From Ellis GL, Auclair PL. Tumors of the
salivary gland. In: Rosai J, editor. Atlas of tumor pathology. Washington, DC: Armed Forces
Institute of Pathology; 1996. p. 206; with permission.)
R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127 119

margin, and previous radiation therapy. The 10-year survival rates for the
solid and cribriform subtypes have been reported as 0% and 62%,
respectively [9]. Many patients survive for several years after recurrence,
but up to 80% ultimately succumb to this malignancy.

Acinic cell carcinoma


Acinic cell carcinoma constitutes 10% to 15% of malignant salivary
gland tumors. Two thirds of the patients are female. Approximately 3% of
acinic cell carcinomas occur bilaterally, making this tumor second only to
Warthin’s tumor for bilateral presentation [10]. This low-grade tumor
occurs primarily in the parotid gland and rarely presents with facial nerve
dysfunction (Fig. 3). Regional lymph nodes are the most likely site of
metastasis. There are numerous subtypes, including solid, papillary cystic,
follicular, medullary, and microcystic, which do not correlate with

Fig. 3. Photomicrograph of acinic cell carcinoma (magnification 200 with H&E stain). (From
Ellis GL, Auclair PL. Tumors of the salivary gland. In: Rosai J, editor. Atlas of tumor pathology.
Washington, DC: Armed Forces Institute of Pathology; 1996. p. 186; with permission.)
120 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

prognosis. Surgery without radiation is recommended for this well-circum-


scribed tumor. Five-year survival rates of 75% are achieved but these rates
decrease with longer follow-up periods. Local recurrences are treated with
further surgery. Acinic cell carcinoma is the second most common pediatric
salivary gland malignancy after mucoepidermoid carcinoma.

Malignant mixed tumors


Malignant mixed tumors comprise 5% to 10% of salivary gland
malignancies, with most occurring in the parotid gland. Gender is not
a factor in presentation. The most common of the three types of malignant
mixed tumors, carcinoma ex pleomorphic adenoma (CEPA), arises from
a pleomorphic adenoma that has been untreated for many years or from
a previously treated pleomorphic adenoma that has recurred. Sudden
enlargement may represent malignant transformation. Clinical findings and
histologic features at the initial diagnosis that indicate a greater likelihood
of malignant transformation are as follows: older patient age, large tumor
size, submandibular gland location, and prominent zones of hyalinization or
at least moderate mitotic activity [11]. The rate of malignant transformation
approaches 10% in tumors that have been present for 15 years [12]. Only the
epithelial component metastasizes, typically presenting as an adenocarci-
noma. A noninvasive subtype with either complete encapsulation or only
limited microscopic invasion has an excellent prognosis, but the invasive
subtype is associated with regional and distant metastasis [13]. Immunohis-
tochemistry has demonstrated that activation of c-myc and ras p21 proto-
oncogenes and the involvement of the p53 mutation may play an important
role in the malignant transformation of pleomorphic adenoma [14]. Ploidy
results do not predict tumor behavior in CEPA. Cervical neck node metastasis
occurs in 25% of patients. Surgery and postoperative radiation therapy are
recommended and lead to an overall 5-year survival rate of 40%. In addition,
the degree of invasion and histologic grade have an impact on survival.
The malignant mixed tumor also can present as a true carcinosarcoma
from the beginning, with both epithelial and mesenchymal metastasizing
components. The most common epithelial types are SCC and adenocarci-
noma, and the most common mesenchymal tumor is chondrosarcoma,
a lethal tumor with few survivors. Finally under this category is the rare
histologic curiosity known as benign metastasizing pleomorphic adenoma.
These tumors have an absence of cytologic atypia, and they are
histologically indistinguishable from pleomorphic adenoma; however, these
tumors are associated with a mortality rate of 22% [15].

Adenocarcinoma and related classifications


Adenocarcinoma is a shrinking category (as is undifferentiated carcinoma).
These tumors have been reclassified into subtypes with similar histopathology
R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127 121

and biologic behavior based on electron microscopy and immunohistochem-


istry. Carcinomas with ductal features without other distinguishing character-
istics are termed ‘‘adenocarcinoma, not otherwise specified.’’ Adeno-
carcinoma is generally an aggressive tumor. Approximately 20% of patients
present with facial nerve dysfunction, with frequent regional and distant
metastasis. Treatment consists of wide excision and postoperative radiation
therapy. A 5-year survival rate of less than 50% is generally predicted.
Immunoreactivity of smooth muscle–specific proteins helps differentiate
adenocarcinoma from the high-grade salivary duct carcinoma. Salivary duct
carcinoma, which originates from the excretory duct reserve cell and
resembles intraductal carcinoma of the breast, is an extremely aggressive
tumor with low survival rates [16].
Differentiating salivary duct carcinoma from the more indolent poly-
morphous low-grade adenocarcinoma (PLGA) is important. PLGA has
a female predominance (2:1) and arises primarily from intraoral minor
salivary glands. PLGA has a varied histologic (polymorphic) appearance of
papillae, glandular structures, and solid aggregates. Local and regional
spread is limited, and this tumor is associated with low recurrence rates and
a high rate of expected survival. Perineural involvement can make
distinction from the more aggressive adenoid cystic carcinoma difficult.
The immunoreactivity of smooth muscle–specific proteins also helps
differentiate adenoid cystic carcinoma from PLGA [16]. Invasion helps
distinguish PLGA from the benign pleomorphic adenoma, for which it can
also be mistaken. Before histologic refinements, salivary duct carcinoma and
PLGA were classified as adenocarcinoma.

Squamous cell carcinoma


Primary SCC of the parotid gland is rare, representing 1% of cases. There
is a 2-to-1 male preponderance. Metastatic disease to an intraparotid lymph
node from a skin primary tumor, contiguous spread of SCC from an
adjacent skin primary tumor, poorly differentiated mucoepidermoid
carcinoma (mucin stains must be negative to exclude mucoepidermoid
carcinoma), and squamous metaplasia must be excluded. Primary SCC
arises from metaplastic parotid duct epithelium. These tumors often act in
an aggressive fashion, widely infiltrating the parotid gland. Up to 60% of
patients who have this SCC present with cervical lymph node metastasis and
facial nerve dysfunction. With advanced-stage disease, survival rates are less
than 50%. Radical surgery and postoperative radiation therapy are required
for this highly malignant tumor.

Melanoma
Most malignant melanomas arise from cutaneous primary sites, with the
parotid gland being a frequent metastatic location. The prognosis is
generally poor. Mucosal and ocular primary sites also must be considered.
122 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

Identifying the primary tumor of a parotid metastasis can be exceptionally


difficult when the rare spontaneous regression of the primary tumor occurs.
The complex lymphatic drainage of the head and neck has slowed the use of
sentinel node biopsy. Many patients have multiple positive nodes, and
primary melanomas may be near or overlap the nodal basin in the head and
neck. Preoperative lymphoscintigraphy using intradermal injections of
technetium Tc 99m antimony trisulfide colloid, followed within 4 hours by
intraoperative handheld gamma-probe localization, has been used to
improve sentinel node biopsy. This procedure can be coupled with
intraoperative injection of 1% isosulfan blue dye. Technical success rates
have risen to 95%. The routine elective use of superficial parotidectomy for
patients who have primary melanoma of the scalp, auricle, and face has been
questioned. Sentinel node biopsy in the parotid gland has been performed
without facial nerve dissection, with a 2.6% rate of facial nerve dysfunction
(and one case of temporary facial nerve paresis) [17]. Further study to define
the role of sentinel neck nodes in the parotid gland and the surgical
procedures to address them is required.

Lymphoma
Lymphoma of the parotid gland represents 1% to 2% of parotid
malignancy presenting either primarily or as part of disseminated disease.
The incidence is equal in men and women, and this tumor rarely occurs before
the age of 50. Patients with Sjögren’s syndrome have a 40-fold greater risk for
a parotid lymphoma than the general population. Most are B-cell, non-
Hodgkin’s lymphomas, with 80% of patients presenting in stage I or II disease
[18]. Primary lymphomas are usually low grade; however, even intermediate-
and high-grade lymphomas of the parotid gland can have a satisfactory
prognosis with chemotherapy and radiation therapy. Immunohistochemical
analysis can help differentiate the low-grade mucosa-associated lymphoid
tissue lymphoma from myoepithelial sialadenitis. In many cases, lymphoma
can be diagnosed with FNA using immunohistochemistry.

Undifferentiated carcinoma
Undifferentiated carcinomas include large cell undifferentiated carci-
noma, small cell undifferentiated carcinoma, and lymphoepithelial carci-
noma. Primary lymphoepithelial carcinoma may arise from a benign epithelial
lesion. It has been reported in Asians and Greenland Eskimos, with an
associated Epstein-Barr virus infection [19].

Molecular biology
DNA flow cytometry can assist in the characterization and diagnosis of
salivary gland malignancies, which can be difficult to diagnose. Bang et al
[20] reported that 43% of salivary gland tumors were reclassified after DNA
R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127 123

flow cytometry. The development and progression of cancer are regulated


by various oncogenes and tumor-suppressor genes. Genetic alterations, such
as those involving p53 and c-erbB-2, play an important role in the
progression of malignant salivary gland tumors, specifically adenocarci-
noma, CEPA, and salivary duct carcinoma [21]. The p53 tumor-suppressor
gene may be involved in salivary gland carcinogenesis, and its oncoprotein
expression is an independent indicator of clinical aggressiveness in parotid
cancer [22]. Collagen IV and tenascin are extracellular matrix constituents.
Weak immunoreactivity for collagen and intense staining of tenascin are
determinants of recurrent disease. Tenascin immunoreactivity is intimately
associated with c-erbB-2 positivity and weak staining of collagen IV [23].
DNA aneuploidy noted in undifferentiated adenocarcinoma or squamous
carcinomas is associated with reduced survival times compared with those of
predominantly diploid tumors, such as mucoepidermoid, acinic cell, and
adenoid cystic carcinomas [20].

Treatment
Salivary gland surgery
Surgery is the primary treatment for salivary gland malignancy. The
minimal operation for a parotid mass is superficial parotidectomy with facial
nerve dissection. Enucleation will result in higher rates of recurrence and facial
nerve dysfunction. Low-grade parotid tumors may be treated with superficial
parotidectomy. Facial nerve monitoring for a mobile tumor of the superficial
lobe will not decrease the rate of facial nerve dysfunction [24]. Deep-lobe
tumors, facial nerve dysfunction, recurrent tumors, fixed tumors, tumors
larger than 4 cm, and nodal metastasis are indications for nerve monitoring.
The incision in the preauricular skin curves gently 2 mm below the ear
lobule to prevent distortion of the ear lobule, and subsequently 3 cm below
the mandible so as not to traumatize the marginal mandibular branch of the
facial nerve. Electrosurgical dissection is eschewed. The sternocleidomastoid
muscle is separated from the parotid gland. The facial nerve trunk
emanating from the stylomastoid foramen is superior to the cephalic
margin of the digastric muscle. The cartilaginous tragal pointer leads to the
tympanomastoid suture. The pes anserinus of the facial nerve is invariably
located 2 mm to 4 mm inferior to this most important anatomic landmark.
Facial nerve dissection can be performed atraumatically with a fine
hemostat, bipolar coagulation, and plastic scissors. Bipolar scissors, the
harmonic scalpel, and hemostat/stimulator probes with a dedicated nerve
monitor have been advocated.
Deep-lobe dissection or total parotidectomy is indicated for deep-lobe
tumors, superficial tumors that extend to the deep lobe, high-grade tumors,
and tumors involving the parapharyngeal space. After completion of the
superficial parotidectomy, the facial nerve branches are elevated from
surrounding parotid tissue or tumor, and the deep lobe is separated from the
124 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

masseter and other muscles. Parapharyngeal parotid tumors can present as


an oropharyngeal submucosal mass and can pass posteroinferiorly or
posterosuperiorly to the stylomandibular ligament. The cervical-parotid
approach is successful for most cases. Anterior or lateral mandibulotomy is
required more commonly for malignant tumors approaching the skull base.
Suction drainage will minimize the risk of hematoma and allow the wound
to be readily observed without a dressing. Infrequently, retrograde
identification of peripheral nerve branches is required for large, bulky
tumors or for surgical procedures for recurrent tumors. Cortical mastoid-
ectomy can be used to identify the intratemporal course of the facial nerve
and to follow it to the stylomastoid foramen. Involvement of the middle
cranial fossa and medial neurovascular structures of the jugular foramen
may require subtotal petrosectomy.
A balance between eradicating the tumor and preserving the facial nerve is
warranted. Facial nerve branches should be spared unless they are involved
with tumor. In cases in which the tumor extends close to the nerve, the tumor
potentially can be peeled off the nerve and treated with postoperative
radiation therapy. Although this procedure transgresses the classic oncologic
principle that malignant tumors should be resected with a wide margin, high
rates of survival confirm the efficacy of postoperative radiation therapy in
eradicating microscopic remnants of tumor after surgery. Preoperative facial
nerve weakness suggests a very high likelihood of facial nerve sacrifice
intraoperatively. A facial nerve surrounded by tumor is best treated with
resection. If direct neurorrhaphy is not possible, cable nerve graft re-
construction is performed, most commonly with the greater auricular or sural
nerve. Facial skin involvement requires reconstruction with local or regional
flaps or free-tissue transfer. Complications include facial nerve dysfunction,
Frey’s syndrome, ear numbness, hematoma, and salivary fistula.
Submandibular gland tumor resection calls attention to the following
anatomic sites: the marginal mandibular branch of the facial nerve deep to the
platysma (ligation of the facial vein and upward traction protects this branch);
the lingual nerve, identified by its looping course along the hyoglossus muscle;
and the hypoglossal nerve deep to the posterior belly of the digastric muscle.
En bloc excision may require resection of the floor of the mouth or marginal or
segmental mandibulectomy. Sublingual gland resection should proceed with
cannulation of Wharton’s duct using a lacrimal probe and identification of the
lingual nerve. These structures, the mucosa of the floor of the mouth, and the
associated alveolar mandible may require resection if sublingual gland cancer
is present. Complications of submandibular and sublingual gland surgery
revolve around the cranial nerves dissected.

Neck dissection
Neck metastases are present in 10% to 20% of parotid gland
malignancies. These generally occur in levels II and III. The survival rate
R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127 125

for parotid gland malignancies without metastasis is 75%. Nodal metastasis


reduces the survival rate by 50%. Clinically positive neck metastases are
treated with neck dissection. In N0 neck disease, the odds of neck micro-
metastasis being present are increased in adenocarcinoma, SCC, high-grade
mucoepidermoid carcinoma, CEPA, high-grade tumors (excluding adenoid
cystic carcinoma, in which lymph node metastasis is rare), facial nerve
involvement, and extraglandular tumor extension. T1 and T2 tumors have
a reported 12% risk of metastasis, and T3 and T4 tumors have a 27% risk of
nodal metastasis [25]. Selective neck dissection at levels IB, II, III, and the
upper part of level V should be considered in patients who have high-risk
N0 disease. Selective neck dissection may assist in determining the need for
postoperative radiation therapy. The risk of neck recurrence is higher in
patients with node-positive disease [25].
Immunohistochemistry, molecular analysis, cell culture techniques, and
serial sectioning of lymph nodes have increased the rate of reported
micrometastasis. Neck dissection for N0 neck disease remains a debated
topic. In a reported series of N0 parotid gland malignancies treated with
parotidectomy and radiation therapy without neck dissection, the risk of
subsequent nodal metastasis was only 4% (7 of 164 cases) [26].

Radiation therapy
Patients who have advanced-stage disease, positive margins, nodal me-
tastasis, preoperative facial nerve dysfunction, and high-grade tumors are
candidates for postoperative radiation therapy. Combined therapy with
surgery followed by radiation therapy has resulted in improved 5-year
disease-free survival rates as high as 77%, with few sequelae from radiation
[27]. Retrospective reviews have not defined a radiation dose–response
relationship, and treatment has ranged from 50 to 70 Gy. Radiation therapy
as the primary treatment may be appropriate for patients with unresectable
tumors or those with overwhelming comorbidities. Postoperative radiation
therapy for patients with positive surgical margins was reported to be
effective for T1 and T2 disease but not for advanced-stage disease [28].
Chemotherapy or combined radiation therapy and chemotherapy have not
improved survival (excluding lymphoma), although chemotherapy has been
used in palliative settings.

Recurrence
The pattern of recurrence for most parotid gland malignancies, in order
of frequency, is local recurrence, cervical neck metastasis, and distant
metastasis [26]. Significant factors for survival are as follows: advanced age,
tumor stage, positive nodal disease, facial nerve involvement, high-grade
tumors, extraparenchymal spread, and positive margins.
126 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

Recurrence in submandibular gland cancer is most significantly related to


the initial stage at presentation, with most deaths caused by metastatic
disease. Other factors include clinical skin or soft tissue invasion, lymph
node metastasis, and perineural growth. Lower recurrence rates with
positive margins can be achieved with postoperative radiation therapy.
Survival rates for sublingual gland cancer are similar to those for
submandibular gland malignancy. All salivary gland malignancies require
follow-up periods of 20 years for true measures of clinical outcomes.

Summary
Major salivary gland cancers are rare, with many histologic types and
subtypes. The tumor stage at presentation will dictate the need for imaging,
FNA, and facial nerve monitoring. Immunohistochemistry has enhanced
diagnosis. In addition, precise attention to surgical landmarks and technique
will reduce complications. Tumor stage, histologic type, tumor grade,
surgical margin, facial nerve dysfunction, perineural involvement, extra-
parenchymal spread, and nodal metastasis are factors influencing the indi-
cation for neck dissection, postoperative radiation therapy, and survival rate.

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Iodine 131 (131I) as adjuvant therapy


of differentiated thyroid cancer
Dominick Lamonica, MDa,b,*
a
Department of Nuclear Medicine, School of Medicine and Biomedical Sciences,
State University of New York at Buffalo, Parker Hall, Room 105, 3435 Main Street,
Building 10, Buffalo, NY 14214-3007, USA
b
Department of Nuclear Medicine, Division of Diagnostic Imaging, Roswell Park Cancer
Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA

Thyroid carcinoma is the most common endocrine malignancy in the


United States, with 22,000 new cases and 1400 deaths projected for 2003 [1].
For unclear reasons, the annual incidence of thyroid carcinoma has risen
over the last quarter century [2]. In the management of patients who have
thyroid cancer, nuclear medicine and surgical oncology often interface. The
discovery and use of radioactive iodine are major reasons that nuclear
medicine originally achieved its specialty standing and central role in the
management of thyroid disease.
Nearly 90% of malignant tumors involving the thyroid are differentiated
thyroid carcinomas (DTCs). Approximately 75% to 80% of these carcinomas
can be categorized as papillary and 15% to 20% as follicular [3]. DTC
typically has a low incidence and a good prognosis. Nevertheless, some
factors separate patients into low and high risk for recurrence and adverse
outcome, and numerous classification systems have been proposed to assess
overall risk. Fig. 1 summarizes cumulative mortality rates over a 20-year
period for Mayo Clinic patients with papillary carcinoma that is judged to be
high (25%–40%) or low risk (1%–ÿ2%) using four of these scoring systems:
European Organization of Research and Treatment of Cancer (EORTC) [4],
Union Internationale Contre le Cancer (UICC) [5], AGES a staging system
with origins at the Mayo Clinic that stands for Age, Grade, Extent and Size
[6], and AMES a staging system originating in the Lahey Clinic which is an
acronym for Age, Metastases, Extent and Size [7,8]. Cumulative survival rates
at 20 years are even more impressive for Mayo Clinic patients at low (survival

* Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.
E-mail address: dominick.lamonica@roswellpark.org

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00129-7
130 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

Fig. 1. Mayo Clinic patients with papillary carcinoma judged to be at high (25%–40%) or low
(1%–2%) risk for mortality using EORTC (upper left), UICC (upper right), AGES (lower left),
and AMES (lower right) classification systems. (From Hay ID. Papillary thyroid carcinoma.
J Endocrinol Metab Clin North Am 1990;19:561; with permission.)

rate, 88%–90%) versus high (survival rate,\10%) risk from follicular tumors
in a system incorporating age and the presence of vascular invasion and
distant metastases at diagnosis [9]. Although follicular carcinomas are
typically smaller when discovered, they are usually found later in life and are
more advanced, with a propensity for hematogenous dissemination and
distant metastasis. Survival statistics for equally staged papillary tumors are
also poor. A recent large-scale retrospective analysis comprising patients
from the Ohio State University (OSU) and US Air Force (USAF) who had
both papillary and follicular cancers focused principally on tumor-specific
factors associated with disease recurrence and cancer-specific mortality [10].
As a part of this study, tumor variables alone were used in a system for the
clinical staging of thyroid malignancies. In addition to age at diagnosis and, to
a lesser degree, patient gender, tumor features, such as size, extrathyroidal
extension, multifocality, and the presence of distant metastases were all
shown to affect outcomes. From a clinical standpoint, all of the previously
mentioned factors warrant review at the time of initial consultation. From
a nuclear medicine perspective, we believe that it is most important to base
decisions regarding adjuvant 131I therapy on anatomic staging at the time of
diagnosis.

Patient-specific prognostic factors


For reasons that are poorly understood, both the age and gender of the
patient at diagnosis influence disease behavior and outcome to initial
therapies.
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 131

Age at diagnosis is included in nearly all series as a factor influencing


mortality in DTC. Thyroid carcinoma is more often a fatal illness in patients
older than 40 years when first diagnosed. Mortality further increases when it
is diagnosed over subsequent decades [11,12].
A different overall pattern emerges when disease recurrence is examined
relative to age. Although the incidence of tumor recurrence from midlife on
is high, it is even more frequent among children (Fig. 2), despite the more
favorable outcomes in this age group. Long-term survival statistics for the
pediatric population are usually good, although children more often present
with advanced-stage tumors, which typically recur [13–15]. Some risk of
recurrence and cancer-specific mortality remains well beyond 20 years from
initial diagnosis for all patients (Fig. 3), emphasizing the need for adequate
early treatment and careful follow-up examinations.
A second patient-specific factor that is believed to affect outcome is
gender. Although gender holds variable statistical weight in different study
populations, there is evidence throughout the literature that the prognosis
from thyroid carcinoma is less favorable among male patients. Two large-
scale studies have reported that male gender has an overall negative effect on
survival [4,10]. Most physicians therefore agree that these patients warrant
careful attention, particularly when lesions are diagnosed in midlife and
beyond.

Fig. 2. Recurrence and cancer death based on age at diagnosis. (From Mazzaferri EL, Jhiang
SM. Long-term impact of initial surgical and medical therapy on papillary and follicular cancer.
Am J Med 1994;97:422.)
132 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

Fig. 3. Recurrence and cancer death based on time from initial diagnosis. (From Mazzaferri
EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and
follicular cancer. Am J Med 1994;97:421.)

Tumor-specific prognostic factors


The size and extent of the tumor at diagnosis have been shown repeatedly
in series both in the United States and abroad to have statistical bearing on
outcome in DTC.
The size of the primary tumor is a major factor affecting disease control
in both papillary and follicular tumors. It is included in seven of the nine
scoring systems compiled in Table 1. Most small carcinomas contained
within the thyroid gland rarely recur. This finding is particularly true for
lesions located below the limits of palpation (\1.0 cm). The OSU/USAF
series described the 30-year recurrence rate for lesions smaller than 1.5 cm to
be one third that of larger tumors, with a cancer-specific mortality rate of
0.4% compared with 7.0% for tumors larger than 1.5 cm (P > 0.001) [10].
Papillary microcarcinomas are often uncovered as a result of surgery for
benign conditions, and these almost never recur. Although they are less
common, more aggressive forms of microcarcinoma do exist [19]. These
microcarcinomas can be a source of locoregional and distant metastatic
tumor [20]. They are usually multifocal tumors at presentation, however,
and it is most often the spread of disease that first brings them to clinical
attention [21].
The invasion of perithyroidal tissues by tumor also has a clear statistical
bearing on recurrence and mortality from DTC. Gross or microscopic
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 133

evidence of direct extension to local tissues signals an increased risk for


recurrence. All recognized scoring systems list direct tumor invasion beyond
the gland capsule as a major risk factor for cancer-related death (see Table 1).
More controversy exists concerning the relevance of locoregional lymph
node metastases in DTC. More than one third of patients (35%) who have
papillary carcinoma present with locoregional lymph node metastases, and
a lower percentage (13%) of patients with follicular tumors [3]. A major
clinical and pathologic feature of DTC in children is spread to regional
lymph nodes [13]. Some series have reported the incidence of cervical
metastases in children with DTC to be as high as 90% [15]. Some
investigators claim that regional lymph node metastases have little impact
on overall outcome [7,22,23]. Others, however, consider this finding a risk
factor for both disease recurrence and cancer-specific mortality [10,24,25].
This pattern of spread is considered even more worrisome when disease has
extended to contralateral or bilateral neck nodes, or to mediastinal nodes
[10]. The spread of metastatic tumor beyond the lymph node capsule is an
especially worrisome finding, as is extension of the primary tumor to tissues
outside of the thyroid gland [26].
Finally, there is little debate over the impact of distant metastatic tumor
on overall survival rates. One large-scale review of 13 series comprising 1231

Table 1
Risk stratification systems for differentiated thyroid carcinoma
Recognized risk factors
Scoring system Patient-specific Tumor-specific
United States
AMES [7] (Lahey Clinic) Age Metastasesa, extentb, sizec
AGES [6] (Mayo Clinic) Age Graded, extent, size
MACIS [23] (Mayo Clinic) Age, completeness Metastases, extent (invasion
of resection beyond gland), size
University of Chicago [16] — Metastases, lymph node statuse,
extent
OSU/USA [10] — Metastases, lymph node status,
extent, size
MSKCC [17] Age Metastases, extent, size
AJCC [18] Age Metastases, extent, size
Europe
EORTC [4] Age, sex Metastases, lymph node status,
cell typef, extent
UICC [5] Age Metastases, extent, size
Abbreviations: AJCC, American Joint Committee on Cancer; MACIS, Metastases, Age,
Completeness of resection, Invasion, Size.
a
Metastases, distant tumor in sites outside of neck (ie, lung, bone, brain).
b
Extent invasion, extension of tumor to extrathyroidal soft tissues.
c
Size, size of primary tumor.
d
Grade, histologic grade of primary tumor.
e
Lymph node status, tumor-positive cervical lymph nodes.
f
Cell type, medullary, poorly differentiated follicular, anaplastic, all other.
134 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

patients estimated that 5% of papillary carcinomas and 13% of follicular


carcinomas have extended beyond the neck at diagnosis. This distant spread
of tumor was most common within the lung (49%), which was followed in
order of frequency by metastases in bone (25%), lung and bone (15%), and
the central nervous system (CNS) or other tissues (10%). Overall, close to
50% of these patients die of their disease within 5 years [27]. Although some
forms of pulmonary spread may be compatible with long-term survival and
even ‘‘cure,’’ macroscopic tumor within the lung, skeleton, or brain is
typically difficult to treat and often fatal [28,29].
In summary, although differences exist in the various staging and
prognostic scoring systems used at clinics in the United States and in
Europe, these are outweighed by similarities. Emphasis is given to tumor
size, local soft tissue invasion, and the presence of distant metastases. All of
these characteristics have a clear bearing on the risk of tumor recurrence and
cancer-specific mortality. Furthermore, these same factors can be used to
tailor therapy to individual disease risk both in the operating room and in
the clinic following surgery. Although age is weighted by many physicians,
the current author does not include it in treatment decisions for the
individual patient. Although young patients often demonstrate more
favorable outcomes to treatment, the reasons are not well understood.
The current author does not believe that age alone should override the red
flags of anatomic staging. Improved mortality figures are not sufficient cause
to ignore data that clearly point to an increased incidence of tumor
recurrence and associated morbidity.

131
Postsurgical I remnant ablation
When the surgical team intends to perform total or near-total
thyroidectomy, patients are typically referred for a postoperative 131I scan
for assessment for remnant thyroid tissue and adjuvant administration of
radioactive iodine. Total resection of the thyroid is a difficult proposition,
and attention to critical structures within the neck usually interferes with
complete surgical removal of glandular tissues. The term ‘‘radioiodine
ablation’’ refers to the use of 131INa to destroy what is presumed to be
normal thyroid tissue remaining within the neck following operation. The
current author has found that more than 90% of patients referred for
radioiodine scan in the weeks following surgery show uptake within the neck
indicative of some thyroid remnant. Radioiodine ablation of residual
thyroid tissue in the setting of intermediate-stage tumor is advised for the
following reasons:
1. It has been shown to reduce the risk of tumor recurrence and thereby
lessen the chances of adverse outcome relating to treatment failure [10,30].
2. It clearly increases the sensitivity of diagnostic 131I scans and the efficacy
of further 131I treatments. DTC is typically less iodine-avid than is the
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 135

normal glandular epithelium. The radioiodine localization that enables


both tumor detection and effective therapy is enhanced by thyroid-
stimulating hormone (TSH) release, which can be difficult to stimulate
with significant postsurgical remnant in place.
3. Finally, postoperative 131I ablation greatly improves disease monitoring
by facilitating the use of serum thyroglobulin (Tg) as a tumor marker
and eliminating the variable ‘‘background’’ Tg levels that persist with
normal thyroid remnant and often confound accurate interpretation of
laboratory results.
The current author’s initial postoperative ablation doses of radioactive
iodine for papillary or follicular tumors usually follow a regimen comprising
two levels, provided there has been surgical removal of all gross and
microscopic evidence of tumor.
1. Fixed ‘‘low-dose’’ ablation, 1850 to 4625 MBq (50–125 mCi), is
performed following surgery for solitary tumors smaller than 4.0 cm
in diameter without pre- or postsurgical evidence of spread to
locoregional lymph nodes or extension to extrathyroidal soft tissue.
(Dosing is based on age, patient size, tumor characteristics, and uptake
within thyroid remnant.)
2. Fixed ‘‘high-dose’’ ablation, 5550 MBq (150 mCi), is reserved for
patients with lesions larger than 4.0 cm or with any of the following in
the operative specimen: multifocal tumor, spread to locoregional lymph
nodes, prominent vascular invasion, or extension of tumor to
extrathyroidal soft tissue.
Radioiodine ablation is ordinarily performed following a 131I diagnostic
survey demonstrating persistent radioiodine concentration within the
surgical bed 6 to 8 weeks after the operation. Following surgery,
levothyroxine sodium (T4) is withheld in preparation for 131I scanning and
ablation. To postpone and alleviate the effects of a T4 deficit, liothyronine
sodium (T3) is given for 3 to 4 weeks. T3 has a much shorter half-life and
may be discontinued 10 to 14 days before 131I dosing. At the same time,
a low-iodine diet is initiated, which is intended to further enhance uptake of
the radioisotope. Pre- or postsurgical findings that suggest persistent tumor
(local or distant) have clear therapeutic relevance and such patients warrant
safe augmentation of the 131I dose.

131
I therapy of differentiated thyroid carcinoma
The approach to radioiodine therapy of metastases from DTC varies in
many clinics within the United States. The demonstration of iodine-
concentrating tumor outside the operative bed on preablation 131I imaging
often calls for an increase in the 131I doses typically used for the ablation of
normal postsurgical thyroid remnant. Persistent or recurrent tumor seen on
136 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

postablation imaging may also be most effectively addressed with additional


131
I. Dose augmentation for treatment can take one of three forms:
1. Fixed dosing: This is an approach that was first introduced and
effectively applied to the management of patients with DTC by a team
of physicians at the University of Michigan, and it may be the treatment
system most commonly used in clinics throughout the United States
today [31]. Fixed-dose augmentation does not involve measurement of
radiation dose to thyroid remnant or to functioning metastatic lesions
but instead focuses on the empiric dosing of radioiodine based on
knowledge of the extent and location of tumor. A sliding scale is used in
accordance with the operative report and visualization of disease on
diagnostic scans within limits determined to be safe for most adult
patients. A documented tumor that is limited to lymph nodes within the
neck that are not obviously involved by disease or that are beyond the
reach of the surgeon’s knife is usually treated with 5500 to 6475 MBq
(150–175 mCi) of 131I. Tumor invading soft tissues within the neck that
may have been incompletely excised is most often addressed with 131I
doses in the range of 5500 to 7400 MBq (175–200 mCi). Finally, patients
who have clear evidence of distant metastatic disease are usually safely
administered doses in the 7400 to 9250 MBq (200–250 mCi) range. Dose
reduction may be warranted for unusually large remnants or extensive
diffuse lung tumor that strongly retains 131I to avoid prolonged count
reductions or possible lung injury.
2. Type I (remnant/tumor) dosimetry: Investigators who have looked at
some of the issues surrounding effective radioiodine therapy of DTC
have determined that normal glandular remnant requires a radiation-
absorbed dose of at least 300 Gy for likely ablation (80%) and that
iodine-concentrating tumor limited to lymph nodes within the neck
should receive at least 80 to 100 Gy for similar efficacy [32]. Although it
is necessary to measure the volume of larger lesions treated with 131I to
accurately estimate the absorbed dose from systemic radiotherapy, the
current author has found that many of the lymph nodes first detected on
a postoperative radioiodine scan are at or below the radiographic size
criterion (1 cm) for characterization as abnormal. This is a fact that
increases the likelihood of effective treatment with radioiodine. In
addition to some anatomic estimate of lesion dimension, a calculation of
the radiation dose delivered to a glandular remnant or metastatic lesion
requires serial measurement of the uptake of 131I at 2 or optimally 3
times over a 1-week period. There is evidence to suggest that
a radioiodine dose that is not sufficient to deliver at least 35 Gy will
be ineffective and that such lesions should be addressed surgically or by
external beam radiotherapy [33,34].
3. Type II (blood-based) dosimetry: It is frequently difficult, if not
impossible, to estimate radiation delivery to sites of metastatic tumor.
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 137

Iodine-avid metastatic disease may be distributed in such a way that


volume cannot be measured. To increase the likelihood of effective
delivery of 131I, systems have been developed for maximum delivery of
targeted systemic radiotherapy within limits that will protect what has
been determined to be the dose-limiting organ for most patients, the
bone marrow [35]. This system requires serial blood sampling and
measurement of retained activity over a 1-week period. The system was
originally proposed and validated by Benua et al [35] and Leeper and
Shimoaka [36] of the Memorial Sloan-Kettering Cancer Center
(MSKCC). Serious complications from dose maximization were avoided
by using this approach and limiting blood exposure to 200 cGy while
keeping whole body retention under 4440 MBq (120 mCi) at 48 hours or
under 2960 MBq (80 mCi) in patients with diffuse lung disease.
Enhanced radioiodine uptake outside the confines of the surgical bed on
postoperative examination often indicates metastases from DTC. If this
pattern is first evident on the initial postoperative survey, the current
author’s approach is to maximize the ablative dose within the previously
noted fixed-dose guidelines for 131I therapy. The patient is then reimaged in
6 to 12 months with formal blood-based dosimetry, which will allow safe
administration of a maximum permissible dose of 131INa for therapy of
metastatic tumor. Prior knowledge of distant metastases or of persistent
tumor within the neck will prompt the physician to include dosimetry in the
initial postoperative evaluation. Post-therapy imaging is included for all
patients undergoing ‘‘high-dose’’ remnant ablation or therapy for locore-
gional or distant metastases. Imaging is done not only to document effective
uptake within thyroid remnant and tumor but to gain added information
about the extent of disease. It has been estimated that as many as 20% to
25% of patients will demonstrate lesions not evident on pretreatment studies
[37]. This finding is more frequent in cases where patients with negative
pretreatment imaging are treated empirically with 131I based on rising serum
Tg levels. There are probably few situations where the results will
significantly alter treatment plans [38].

131
Acute and long-term effects of I therapy
Early effects
Although 131I is lethal to the cells most able to concentrate it, it is not
without immediate and long-term effects on background tissues free of
disease.
Mild, acute radiation symptoms have been described in the immediate
post-treatment period in close to two thirds of patients receiving 131I therapy
[39,40]. These symptoms are usually reported for doses in excess of 5550 MBq
(150 mCi), and this post-treatment period is often marked by fatigue, loss of
138 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

appetite, headache, nausea, and occasional vomiting. The gastrointestinal


component that is often described also may reflect the direct effect of
physiologic localization of radioiodine within normal salivary tissues and
gastric mucosa. This symptom constellation usually resolves over a 48-hour
period.
Radiation thyroiditis, characterized by throat discomfort, cervical
swelling, and difficulty swallowing, can result when high doses of radiation
are delivered to large gland remnants [41]. Patients also may experience
symptoms of transient hyperthyroidism caused by release of stored hormone
from large remnants or from extensive functioning follicular tumor [42].
Physicians should be wary of this effect, particularly in patients with
documented coronary artery disease or compromised cardiovascular
function. All such patients should be made euthyroid before treatment
and should be observed carefully for signs of thyroid storm within 10 days
of 131I therapy, because this situation requires prompt attention [43]. Rarely,
local swelling may be sufficient to precipitate vocal cord dysfunction [44].
Such effects are usually limited to patients who have an invasive tumor
involving the vocal cords or who have large thyroid remnants adjacent to
the recurrent laryngeal nerves. These are situations that call for careful
monitoring, and treatment will likely involve the systemic administration of
corticosteroids. It is important to appreciate that large gland remnants will
compete for finite doses of administered 131I. Such competition is believed to
interfere with the detection and effective treatment of a tumor that may have
been incompletely excised [45,46]. The current author therefore recommends
re-operation for patients known to have large gland remnants and residual
tumor that requires the upfront, effective delivery of 131I.
Cytopenias are frequently observed following high-dose radioiodine
therapies for DTC. A reduction in platelet and white blood cell counts may
be witnessed over the weeks following 131I therapy based largely on the dose
administered and on the effective half-life of radioiodine in the individual
patient. A University of Michigan study reported anemia (35%), leucopenia
(10%), and thrombocytopenia (3%) in 157 patients treated with an average
dose of 207 mCi. Count reductions can be expected to resolve by 1 year,
with red cell declines persisting slightly longer than white cell and platelet
effects [47]. Weekly monitoring of counts over an 8- to 12-week period is
advocated, particularly for patients receiving doses in excess of 9250 MBq
(250 mCi) for treatment of widespread disease. Long-term hematologic
effects are not likely if the red marrow dose is kept within the
aforementioned 200 cGy exposure limit.
Finally, the salivary effects from 131I treatment can sometimes be
prominent. Tenderness and swelling may result from radiation effect on the
lingual, parotid, and submandibular salivary glands following 131I
administration. These effects have been reported to occur in up to one
third of individuals treated with 131I doses, with a direct correlation to the
radiation dose received [48]. Symptoms usually become evident over a 24- to
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 139

48-hour period following administration of therapy and have been described


as reflecting the radiation effect of large 131I doses in patients with minimal
thyroid remnant. Transient alteration or loss of taste sensation can result,
most often resolving spontaneously over an 8- to 12-week period.
Emphasizing hydration and encouraging salivary flow through use of
lemon drops or chewing gum over the early post-treatment period may
reduce these symptoms. Despite these measures, longstanding adverse
effects are possible, particularly in patients receiving repeated high-dose 131I
treatments for refractory tumor. These effects include dry mouth, altered
taste and conjunctival irritation, and ear and jaw pain caused by
intermittent salivary obstruction from desquamation of glandular epithe-
lium [49]. The latter symptom complex is often precipitated by eating and
may persist for some months.

131
Late effects of I treatment
Although most of the immediate effects described previously resolve
during the weeks following 131I therapy, the chances of long-term organ or
tissue injury increase with the cumulative dose of radioactivity required for
treatment.
Female reproductive function is usually unaffected by single admin-
istrations of 131I. Permanent reproductive organ impairment may result
from repeated therapies for this disease, however. One study noted that the
miscarriage rate after 131I ablation that used doses in excess of 100 mCi was
nearly double the increase observed following thyroidectomy alone [50]. The
reasons for this finding are not entirely clear, although this observation
suggests a possible relation to irradiation of the ovaries. It seems that there
is no increase in risk of birth defects from treatment of children or women of
childbearing age. This same study of women and pregnancy before and after
131
I therapy for thyroid carcinoma revealed no evidence for increased risk of
congenital malformation, stillbirth, or prematurity following treatment of
this disease. Long-term studies suggest that fertility is unaffected for women
younger than 30 years at the time of therapy [51]. Such statistics are usually
directly correlated to cumulative radiation dose, however. Although
permanent sterility has not been recorded for premenopausal women
receiving less than 11,100 MBq (300 mCi) of 131I, it has been reported in
nearly 60% of women receiving 131I doses in excess of 29,600 MBq (800
mCi) [10,52]. Patients should be aware of this finding. Women treated in the
current author’s clinic are advised to avoid pregnancy during the 12 months
following 131I therapy.
A different situation exists for men undergoing 131I therapy for thyroid
cancer, because the testes are especially vulnerable to the effects of radiation.
A single 131I treatment involving only moderate doses of radioiodine (1850–
3700 MBq [50–100 mCi]) is sufficient to cause reduction in sperm count [53].
The testicular effects described from 131I therapy in men are proportional to
140 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

the total dose of radioactivity received over the course of treatment [54].
Permanent sterility has been described in men receiving cumulative doses
greater than 29,600 MBq (800 mCi) [55]. Sperm banking should be
considered for young men who have extensive disease.
Lung fibrosis is often a concern for physicians treating patients who have
diffuse pulmonary spread of iodine-avid thyroid tumor; however, it is
uncommon. Lung fibrosis was originally reported in the early experience of
the MSKCC group [32]. Based on five events in 59 patients, dosimetry
guidelines were adjusted to ensure retained activities were kept under 4440
MBq (120 mCi) at 48 hours in all patients and under 2960 MBq (80 mCi) at
48 hours in those who had diffuse lung metastases [56]. It is the current
author’s experience that, on average, 30% to 50% of the administered 131I
dose is excreted within 24 hours in athyrotic patients who have normal renal
function. Exceptions to this are patients with large thyroid remnants or
those with an overwhelming mass of persistent, functioning tumor. The
standard fixed-schedule dose of 7400 MBq (200 mCi) usually advocated for
treatment of lung metastases is therefore safe for treatment of pulmonary
disease in the overwhelming majority of patients. An approach that uses
dosimetry would safely permit the upfront augmentation of therapy, which
is particularly needed for disease outside the neck. It would also be recom-
mended in therapies for those patients who have compromised renal function.
Radiation-induced malignancy is probably the most serious among the
potential late effects of 131I treatment. Permanent count reductions and white
cell and platelet abnormalities are sometimes seen in patients receiving more
than 37 GBq of 131I for treatment of thyroid cancers. A large-scale meta-
analysis comprising 13 series and 2753 patients reported a slight increase in
prevalence of acute myelogenous leukemia (AML) for patients who had
received 131I therapy for thyroid cancer [57]. Many of the patients received
high doses of radioiodine over short time intervals, a fact that only enhances
the mutagenic properties of ionizing radiation for both normal and diseased
tissues. A small increase in deaths from bladder cancer and leukemia has
been reported with cumulative 131I doses in excess of 37 GBq [51]. Again, the
risk is proportional to cumulative dose of radioactivity and underscores the
need for attention to bowel and bladder function in the days following
therapy. In view of these effects, 131I treatments are normally spaced at 12-
month intervals and are usually not repeated any sooner than 6 months for
the more aggressive tumor variants. Placed in perspective, the lifetime risk of
leukemia is small enough so that, even with the added radiation exposure
from 131I treatment, this risk does not exceed the risk of dying from
metastatic thyroid cancer [2].

131
I imaging and follow-up
Following radioiodine ablation of thyroid remnant or treatment of
iodine-concentrating thyroid tumor, the current author recommends
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 141

a minimum of one follow-up 131I study to assess the efficacy of the


radioiodine dose. For reasons described previously, once normal thyroid
remnant has been eliminated, unrecognized areas of disease may become
apparent on whole body survey. The initial postoperative radioiodine survey
is done to assess the presence of normal thyroid remnant following total or
near-total thyroidectomy. Uptake in the neck is likely in this setting, and
this study is therefore performed using only a small 37-MBq (1-mCi) dose of
131
I. Once remnant ablation is achieved, patients are re-imaged to detect any
persistent or recurrent tumor. Diagnostic scans for this application are
acquired with 74-MBq (2-mCi) doses of 131INa. The tracer dose is doubled
but is kept below 111 MBq (3 mCi) because of a concern that the diagnostic
dose of 131I might interfere with radioiodine concentration for subsequent
therapy, a concept termed ‘‘stunning’’ [58,59]. 131I studies in the current
author’s clinic are accompanied by stimulated serum Tg assays, allowing
serial comparison of this tumor marker in the assessment of a patient’s
disease as well. Serum Tg is usually undetectable (\0.5 ng/mL) in patients
free of disease following successful postsurgical 131I remnant ablation.
In patients who are at increased risk for recurrence, the current author
ordinarily advocates obtaining at least two negative 131I scans over the first 5
years following initial 131I administration to increase the chances of early
detection and prompt treatment of recurrent tumor at a time when it is most
likely to be discovered. This imaging schedule is accompanied by regular
follow-up examinations within the clinic, with a physical examination every
3 to 6 months for the first 2 to 3 years, thyroid function testing at 3 months
and 6 months, then annually, and serum Tg assay at 6 and 12 months and
annually thereafter. Once two negative 131I surveys have been documented,
the current author believes it is appropriate for patients to enter long-term
follow-up, with clinic visits every 6 to 12 months and further diagnostic
studies based on the results of serial examination and laboratory testing.
Recently, it has been suggested that regularly repeating the 131I whole body
scan adds little to the DTC workup in this setting. In place of serial 131I
scans at 3- to 5-year intervals used in the past for disease monitoring,
recombinant human thyroid-stimulating hormone (rhTSH) -stimulated Tg
testing has been suggested as an even more sensitive indicator of disease
recurrence, highlighting a need for further workup to determine the most
effective and appropriate therapy [60]. Although in the past eligibility for
131
I therapy was principally determined by uptake on radioiodine scans
alone, this paradigm has recently changed. Several investigators have
demonstrated post-treatment evidence of tumor uptake in more than one
half of patients with negative diagnostic 131I studies when they were treated
empirically with 3700 MBq to 5550 MBq (100–150 mCi) of 131I based only
on elevated serum Tg [61,62]. A lowering of serum Tg levels also has been
recorded in 30% to 50% of such patients in response to treatment [62].
The current author has also seen benefit from the empiric administration of
131
I, both in terms of lowering of tumor marker and resolution of
142 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

anatomic findings on CT without clear evidence of uptake on pretreatment


images.
If a surgically treatable lesion cannot be identified on diagnostic studies
(eg, CT, MRI, or ultrasound) that are done for rising Tg levels, one might still
consider moving ahead with additional empiric 131I therapy based on a rising
tumor marker alone. This is an approach further strengthened by concerns
over lesion stunning. In this situation, the post-treatment surveys acquired 7
to 10 days following 131I therapy often provide the image evidence of DTC
missing from the interim diagnostic studies. The Tg thresholds for
consideration of additional 131I therapy of DTC are in evolution. Serum
Tg levels of more than 10 ng/mL in patients who are off thyroid hormone
replacement or levels greater than 5 ng/mL in patients undergoing T4
treatment are currently used by some clinicians to determine the need for
additional 131I therapy [37]. An rhTSH-stimulated Tg level of more than 2 ng/
mL recently has been described as having a sensitivity of 100% for the
detection of recurrent disease [60,63].

131
I therapy of differentiated thyroid carcinoma: outcomes
A beneficial effect has been demonstrated from the use of 131I for the
postoperative ablation of thyroid remnant in patients at intermediate risk
for disease recurrence [10,30]. Patients who have disease outside the neck
who respond to 131I therapy have significantly longer survival times than
those who do not [11]. There can be considerable impact for the 131I
treatment of distant metastases within the lung. The 10-year survival rate for
patients treated with 131I for lung metastases evident only on post-treatment
whole body survey has been reported to be 100%. The numbers are lower
but still impressive for disease seen either on pretherapy 131I imaging alone
(91%) and/or with an accompanying micronodular pattern on radiographic
study (63%) [64]. Macronodular lung tumor is considerably more difficult to
treat with 131I, and bone metastases represent an even greater challenge.
Dominant or solitary skeletal sites optimally require a multidisciplinary
team approach centering on surgery or external beam radiotherapy [65].
Here as well, however, 131I can have a role for the treatment of residual
disease (Fig. 4). A similar application for 131I is anticipated for rare
individuals with isolated CNS lesions [66].

Further management
L-thyroxine therapy
Following surgery and initial radioiodine therapy for DTC, patients are
begun on T4 replacement and enter a regular schedule of clinical follow-up
based largely on surgical findings and results of post-therapy imaging.
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 143

Fig. 4. (A) Skeletal metastases (arrowheads) from papillary thyroid carcinoma on initial
postoperative 131I scan. (B) Positive post-treatment images 1 week after 131I therapy. (C)
Negative follow-up 131I images 1 year post therapy.
144 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

Fig. 4 (continued)

Studies have suggested that the recurrence rate of DTC is reduced by the
augmented administration of T4. The degree of TSH suppression required
remains controversial, however. A retrospective European investigation
showed degree of TSH suppression as an independent predictor of disease
recurrence [67]. A more recent prospective study in the United States,
however, reported that, when it was measured against other variables, the
degree of TSH suppression taken alone did not predict those individuals at
greater risk for recurrent disease [68]. Despite ongoing debate, it is
recommended that intermediate-stage patients be started on a dose of T4
sufficient to maintain serum TSH levels just below the lower limit of the
normal range 0.1–0.4 micro-International Units per mililiter (uIU/mL) [69].
If there is documentation of residual neck disease or distant metastatic
D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149 145

tumor following initial therapy, the replacement dose of T4 is usually further


augmented to limit or remove evidence of circulating TSH (\0.02 uIU/mL)
from serum samples on second-generation assays. Here, as elsewhere, it is
important to stress that patient management must be individualized, and
that there may be patients who cannot tolerate such dose augmentation. An
initial TSH assay is usually obtained at 12 weeks or on the first follow-up
visit following postoperative 131I ablation and initiation of hormone
replacement. Using these results, the T4 dose is further adjusted.

Serum Tg testing and rhTSH


It is the current author’s practice to perform a stimulated Tg assay at the
time of the initial postoperative 131I scans. This assay is repeated at 6 months
on hormone replacement and again at 12 months, both on and off
supplementation at the usual time of the first follow-up 131I imaging.
Laboratory testing and 131I scans are obtained to determine the efficacy of
the ablative or therapeutic dose. These are both done in the TSH-stimulated
state either following hormone withdrawal or rhTSH administration.
Although the current author attempts to lessen the ill effects of hormone
withdrawal by routinely using T3 during T4 withdrawal for imaging and
therapy, he still cannot downplay the morbidity associated with the cessation
of thyroid hormone. At present, the current author does not use rhTSH
stimulation for patients who are expected to receive therapeutic doses of 131I,
because this approach has not been proved equally effective. Thus, the choice
of scan preparation is based largely on risk and on the probability that
a patient will require additional treatment with 131I. Moreover, there are
other factors that need consideration in the decision to substitute rhTSH for
the standard imaging preparation. Two large-scale studies of rhTSH show
that less disease may be detected on 131I scans following rhTSH injection
versus with T4/T3 withdrawal [70,71]. A more recent investigation showed
the difference between the two techniques to be less marked, provided greater
attention was paid to scanning technique [63]. The proposed technical
modification involved a doubling of the tracer dose of 131I from 74 MBq to
148 MBq (2 mCi to 4 mCi) to account for the increased renal clearance of
free iodide in the rhTSH-stimulated patient. This is a change that some
clinicians are reluctant to make because of considerations regarding possible
stunning of iodine-concentrating tumor and a potential for reduction in
efficacy of subsequent radioiodine therapy. The more important point of this
study was that the addition of a stimulated Tg level to rhTSH-simulated
imaging allowed detection of all patients who had recurrent tumor without
the negative effects of hormone withdrawal. Serum Tg should be undetect-
able when persistent thyroid tissue or thyroid carcinoma is not present.
From these results, the current author believes that using this combined
method for the follow-up of DTC is worthwhile to reduce morbidity for
patients at relatively low risk for tumor recurrence requiring therapy.
146 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

Moreover, rhTSH is a welcome and necessary option for those who cannot
mount a TSH response to hormone withdrawal (ie, functioning tumor,
pituitary insufficiency) and a needed, although as yet unproven, alternative
for treatment of patients unable to tolerate the prolonged effects of
profound hypothyroidism (ie, CNS critical lesions, cardiac insufficiency). A
situation that would not allow use of this dual approach using rhTSH
imaging and Tg would be the patient with autoantibodies to Tg, because
these would likely invalidate the added information obtained with this
laboratory assay.

Summary
The importance of the optimization of the upfront management of DTC
cannot be underestimated. An aggressive approach is advocated, except in
situations widely accepted to be low risk (ie, female patients \40 y, with
tumors \1.0 cm confined to the gland). Distant tumor greatly reduces the
chances for survival in all patients. The loss of iodine-concentrating ability
removes systemic radioiodine from the therapeutic equation and thereby
virtually eliminates chances for cure. The role of chemotherapy in noniodine
responsive DTC is still in question, and a benefit in advanced disease has not
been established. For non–iodine-concentrating tumor that cannot be
approached surgically, external beam therapy remains an option, both
within the neck and for dominant foci of distant metastatic tumor (ie, brain
and bone). Any distant lesion demonstrating the capacity for radioiodine
uptake also should be addressed with 131I, because this will potentially treat
tumor not evident on diagnostic survey.
In conclusion, 131I has demonstrated efficacy for the postsurgical
management of DTC. Although its acute and long-term side-effect profile
is not especially worrisome relative to other forms of systemic cancer
therapy, the administration of 131I is not entirely without risk. Taking into
account many of the issues described in this article, the administration of
131
I should in every case be optimized. It also should be applied carefully
and judiciously to patients expected to derive benefit.

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Surg Oncol Clin N Am 13 (2004) 151–166

Neck dissection: current concepts


and future directions
Nestor R. Rigual, MD, FACSa,b,*,
Sam M. Wiseman, MD, FRCS(C)c,1
a
School of Medical and Biological Sciences, State University of New York at Buffalo,
Buffalo, NY 14263, USA
b
Section of Plastic and Reconstructive Surgery, Department of Head and Neck Surgery,
Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
c
Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets,
Buffalo, NY 14263, USA

This article discusses the classification, rationale, and future directions


pertaining to neck dissections in the management of cancers of the head and
neck. Most head and neck cancers arise from the squamous epithelium of
the upper aerodigestive tract. In this article, the term ‘‘head and neck
cancer’’ refers to squamous cell carcinoma (SCC) of the upper aerodigestive
tract.
The development of lymph node metastasis is a critical factor in guiding
the treatment and determining the prognosis of individuals diagnosed with
head and neck carcinoma. The presence of lymphatic metastases is asso-
ciated with a decrease in the survival rate of up to 50% of patients [1,2].
Radical neck dissection (RND), first described by Crile [3] in 1906, and
popularized by Martin et al [4], has remained the cornerstone of the surgical
treatment of cervical lymph node metastasis throughout most of the 20th
century. The classic RND requires en bloc resection of the cervical lymph
nodes, internal jugular vein, sternocleidomastoid muscle (SCM), and spi-
nal accessory nerve. This operative procedure has significant long-term
morbidity, including shoulder dysfunction, cosmetic deformity, cutaneous
paresthesia, and chronic neck and shoulder pain syndrome. These morbid-
ities are exacerbated when postoperative radiotherapy is added. For these
reasons, and because of a lack of rationale for removing all cervical lymph

1
Current address: Department of Surgery, St. Paul’s Hospital, 1081 Burrard Street,
Vancouver, British Columbia, Canada, V6Z 1Y6.
* Corresponding author.
E-mail address: nestor.rigual@roswellpark.org (N.R. Rigual).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00119-4
152 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

nodes, a change in the surgical approach to managing cervical metastasis


was initiated by Suarez [5] in the late 1950s. In anatomic studies, Suarez
demonstrated that cervical lymphatics are contained within well-defined
fascial compartments, separate from muscles, nerves, blood vessels, and
other visceral structures of the neck. Thus, he proposed that muscles, blood
vessels, and nerves that were routinely removed during an RND could be
preserved without compromising regional disease control in patients who
had limited neck disease. Bocca et al [6] subsequently popularized this
‘‘functional neck dissection’’ concept, or neck dissection with the pre-
servation of vital structures. The development of a better understanding of
lymph node drainage patterns [7,8], the discovery of fascial compartments
separating cervical lymph nodes from neck structures commonly removed in
RND, and an improved understanding of the role of adjuvant radiation
therapy [9,10] have been the impetus for the development of current modi-
fications of the RND.
In response to a need for an organized approach for describing and
classifying neck dissection, the Committee for Head and Neck Surgery and
Oncology of the American Academy of Otolaryngology/Head and Neck
Surgery standardized neck dissection terminology in 1991 [11], and a more
recent update was published in 2002 [12]. Neck dissection classification
categories are shown in Box 1.
In the current classification schema, the location of cervical lymph node
groups is delineated by the level system [11]. This system is easy to remember
and has become widely accepted (Fig. 1).
Recently, the concept of neck sublevels has been introduced into the
classification schema, because areas have been identified within the six neck
levels that seem to have independent oncologic significance [12]. These
sublevels include level IA (submental nodes), level IB (submandibular
nodes), levels IIA and B (upper jugular nodes), level VA (spinal accessory
nodes), and level VB (supraclavicular nodes). The lymph node groups
contained in these levels and the anatomic boundaries of the six neck levels
are shown in Table 1. Lymph node groups not located within these regions
should be referred to by their specific nodal group name. Examples include
retropharyngeal, periparotid, and suboccipital nodal groups.
The structures defining the anatomic boundaries of the neck levels and
sublevels are depicted in Fig. 2. Most of these anatomic boundaries are

Box 1. Neck dissection classification


 Radical neck dissection
 Modified radical neck dissection
 Selective neck dissection
 Extended neck dissection
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166 153

Fig. 1. The levels of the neck. (Drawing by Paul Tomljanovich, MD, medical illustrator.)

familiar and well-defined anatomic structures, with few exceptions. The


posterior boundary of levels II through IV is delineated by the posterior
border of the SCM or by the sensory branches of the cervical plexus. These
cervical plexus sensory nerve branches also define the anterior boundary of
level V. The anterior border of level IIA is defined by the stylohyoid muscle
(see Table 1).

Imaging-based classification of cervical lymph node groups


Imaging studies were not used in the initial neck dissection classification
scheme in 1991 [11].
Radiologists therefore have recently identified landmarks that accurately
define the location of lymph nodes and have devised an imaging-based
classification scheme for the cervical lymph node groups [13]. This
radiologic classification was designed as an adjunct to the clinically based
nodal classifications. Using imaging landmarks, level IA includes the lymph
nodes that are located between the medial margin of the anterior belly of
the digastric muscles, superior to the body of the hyoid bone, and below
the mylohyoid muscle. Level IB includes nodes that also lie below the
154
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166
Table 1
Neck level anatomic landmarks
Level Superior Inferior Medial (anterior) Lateral (posterior)
IA Mandibular symphysis Hyoid bone body Contralateral digastric muscle, Ipsilateral digastric muscle,
anterior belly anterior belly
IB Mandibular body Posterior belly of digastric Anterior belly of digastric Stylohyoid muscle
muscle muscle
IIA Base of skull Plane (horizontal) defined by Stylohyoid muscle Plane (vertical) defined by
inferior border of hyoid bone spinal accessory nerve
IIB Base of skull Plane (horizontal) defined by Plane (vertical) defined by Sternocleidomastoid muscle,
inferior border of hyoid bone spinal accessory nerve lateral border
III Plane (horizontal) Plane (horizontal) defined by Sternohyoid muscle, Sternocleidomastoid muscle,
defined by inferior border inferior border of cricoid lateral border lateral border, or cervical
of body of hyoid cartilage plexus sensory branches
IV Plane (horizontal) defined Clavicle Sternohyoid muscle, lateral Sternocleidomastoid muscle,
by inferior border of cricoid border lateral border, or cervical
cartilage plexus sensory branches
VA Apex of the point of convergence Plane (horizontal) defined Sternocleidomastoid muscle, Trapezius muscle,
of the trapezius and by inferior aspect posterior border, or cervical anterior border
sternocleidomastoid muscles of cricoid cartilage plexus sensory branches
VB Plane (horizontal) defined by Clavicle Sternocleidomastoid muscle, Trapezius muscle,
inferior border posterior border, or cervical anterior border
of cricoid cartilage plexus sensory branches
VI Hyoid bone Sternum Common carotid artery Common carotid artery
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166 155

Fig. 2. The sublevels of the neck. (Drawing by Paul Tomljanovich, MD, medical illustrator.)

mylohyoid muscle and above the hyoid bone but are posterior and lateral to
the anterior belly of the digastric muscles and anterior to the posterior
border of the submandibular gland. Level II nodes are contained in the
space defined superiorly by the skull base, inferiorly by the hyoid bone,
anteriorly by the posterior border of the submandibular gland, and
posterior to a transverse line drawn on each axial image through the
posterior edge of the SCM. The deep border of level II is defined by the
internal carotid artery in that any nodes lying medially to this vessel are
considered to belong to the retropharyngeal nodal group. Level III nodes
are located between the lower border of the hyoid bone and the lower
margin of the cricoid cartilage. These nodes lie laterally to the common
carotid artery. On both sides of the neck, the medial margin of the carotid
arteries separates the level III nodes, which are located laterally to level IV
nodes, which lie medially to the vessels. Level IV nodes lie inferiorly to the
lower border of the cricoid cartilage and superiorly to the clavicle. The
boundaries of levels V and VI are the same as in the clinical classification.

Neck dissection classification


The neck dissection classification system has arisen because radical neck
dissection remains the standard procedure for cervical lymphadenectomy,
156 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

with other operations representing alterations of this classic operation (see


Box 1). The term ‘‘modified radical neck dissection’’ (mRND) is used when
one or more nonlymphatic structures routinely removed in an RND is
preserved. In general, currently preserved structures include the SCM, the
accessory nerve, and the internal jugular vein. If one or more lymph node
levels that are routinely removed in an RND are preserved, the procedure is
termed a ‘‘selective neck dissection’’ (SND). Finally, if the procedure includes
removal of additional nonlymphatic structures or lymph node groups
(relative to the RND), the operation is termed an ‘‘extended neck dissection.’’
The anatomic boundaries of the RND include the following: superiorly,
the inferior border of the mandible; inferiorly, the clavicle; medially, the
midline; and posteriorly, the anterior border of the trapezius muscle. Included
within these boundaries are lymph node levels I through V, the SCM, the
internal jugular vein (IJ), and accessory spinal nerve (cranial nerve XI), which
are removed at surgery (Fig. 3).
An mRND refers to the removal of lymph node levels I through V, with
preservation of one or more nonlymphatic structures that are routinely
removed during the course of an RND. In describing an mRND, the
anatomic structure or structures preserved should be clearly specified (eg,
mRND with preservation of the internal jugular vein).
SNDs are commonly used in the staging and treatment of the clinically
undetectable (or N0) neck tumor. In this type of neck dissection, one or

Fig. 3. Radical neck dissection. (Drawing by Paul Tomljanovich, MD, medical illustrator.)
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166 157

more lymph node levels are preserved. The lymph node levels removed
are based on the location of the primary tumor because the clinical
patterns of cervical lymphatic metastasis from head and neck tumors have
been shown to be predictable in multiple, large-scale, retrospective studies
[8,14,15].
The lymph nodes at risk for laryngeal, hypopharyngeal, and oropharyn-
geal carcinomas are usually found within levels II, III, and IV. For thyroid
cancer and subglottic cancers, the nodes in level VI are at greatest risk of
harboring metastatic disease. Lymph nodes in levels I, II, and III are at
greatest risk of harboring microscopic metastatic disease in patients who
have oral cavity primary cancers. Skip metastasis to level IV may potentially
represent a problem in patients who have oral tongue carcinoma [16].
The most significant paradigm shift in the management of cervical lymph
node disease over the past decade has been the selective removal of lymph
node groups that are at greatest risk of harboring metastases. Although this
change in treatment philosophy has been applied mostly to patients with N0
nodal disease, SND also has a role in the treatment of N-positive neck
tumors [17,18].

Selective neck dissection for oropharyngeal, laryngeal,


and hypopharyngeal cancer
The lymphadenectomy of choice in the treatment of cancers affecting
these anatomic sites includes the removal of lymph node groups in levels II,
III, and IV (SND II–IV). Patients who have SCC of the larynx rarely
present with metastases at the submandibular triangle (level I) [19]. Data
from two recent studies support the use of SND II–IV for the treatment
of N0 laryngeal and hypopharyngeal carcinomas [20] and transglottic
carcinomas (supraglottic tumors that cross the laryngeal ventricle and
invade the glottis) [21]. The anatomic limits of this lymphadenectomy are as
follows: the clavicle inferiorly, the skull base superiorly, the lateral border of
the sternohyoid muscle medially, and the posterior border of the SCM and
cutaneous sensory branches of the cervical plexus posteriorly (Fig. 4).
With the exception of the glottic larynx, cancers of the oropharynx,
hypopharynx, and larynx have bilateral lymphatic drainage patterns. Thus,
the procedure of choice for patients with N0 primary tumors in these locations
is a bilateral SND II–IV in cases where the neck is managed surgically. In
cancers involving the walls of the hypopharynx and oropharynx, the
retropharyngeal nodes may harbor metastatic disease. Therefore, in this
circumstance, removal of this nodal group should be considered. The
procedure would be termed SND II–IV, retropharyngeal nodes. In laryngeal
and hypopharyngeal carcinomas extending below the glottic larynx, level VI
lymph nodes are usually included in the neck dissection (SND II–IV, VI),
because they are at risk [21].
158 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

Fig. 4. Selective neck dissection II–IV. (Drawing by Paul Tomljanovich, MD, medical
illustrator.)

Selective neck dissection for cancer of the oral cavity


In oral cavity cancer, the nodal groups at risk are located in levels I, II,
and III [8]. The procedure of choice is SND I–III (Fig. 5). Some evidence
suggests that, in cancer of the anterior tongue, level IV nodes may contain
metastatic disease [16]. Therefore, it is recommended that lymph nodes in
level IV be removed in patients who have cancer of the tongue (Fig. 6). In
cancers involving midline structures, including the floor of the mouth, the
indicated procedure is a bilateral SND I–III, because the lymph nodes on
both sides of the neck are at risk for containing metastases. The adequacy
of SND I–III for treating clinically negative neck tumors in patients who
have oral carcinomas has been examined thoroughly [9,10,22]. In addition,
investigators have demonstrated that, in patients with pathologically posi-
tive lymph nodes, the addition of postoperative radiotherapy following SND
I–III can achieve regional control comparable to that of level I–V dissection
and postoperative radiotherapy [9].

Anterior neck dissection (selective neck dissection VI)


Level VI, central compartment neck dissection refers to the removal of
bilateral, paratracheal, delphian, and perithyroiidal lymph nodes, including
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166 159

Fig. 5. Selective neck dissection I–III. (Drawing by Paul Tomljanovich, MD, medical
illustrator.)

Fig. 6. Selective neck dissection I–IV for oral tongue cancer. (Drawing by Paul Tomljanovich,
MD, medical illustrator.)
160 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

nodes adjacent to the recurrent laryngeal nerves [7]. The superior boundary
of the dissection is the body of the hyoid bone, and the inferior margin is the
suprasternal notch. The lateral margins are defined by the common carotid
arteries. SND VI is most commonly indicated in the treatment of thyroid
cancer, advanced laryngeal cancer with subglottic extension, and cervical
esophageal carcinoma (Fig. 7). In thyroid cancer where there is clinical
evidence of nodal metastases in the neck, either preoperatively or
intraoperatively, the procedure of choice also would include levels II to V,
and is designated SND II–VI.

Extended neck dissection


Extended neck dissection is by definition more extensive than an RND.
Extended neck dissection involves the removal of additional lymph node
groups or nonlymphatic structures not included in an RND. The anatomic
structures and lymph node groups removed during the course of this oper-
ation must be documented. Examples of such lymph node groups include
the retropharyngeal, suboccipital, and paratracheal nodes. Examples of
nonlymphatic structures that may be removed include the vagus nerve,
carotid artery, and the strap muscle (Fig. 8).

Fig. 7. Selective neck dissection VI, or central compartment neck dissection. (Drawing by Paul
Tomljanovich, MD, medical illustrator.)
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166 161

Fig. 8. Extended neck dissection (common carotid artery, digastric muscle, hypoglossal nerve).
(Drawing by Paul Tomljanovich, MD, medical illustrator.)

Posterolateral neck dissection


Posterolateral neck dissection is an SND that involves removal of the
suboccipital lymph nodes, postauricular lymph nodes, and lymph nodes in
levels II through V (Fig. 9). SND II–V (postauricular, suboccipital) is the
procedure of choice to treat the neck in patients with cutaneous carcinomas
of the posterior scalp and neck [23].
The superior limit of the dissection is the base of skull and the nuchal
line. The inferior limit of the dissection is the clavicle. The anterior (medial)
limit of the dissection is the lateral border of the sternohyoid muscle. The
lateral (posterior) limit is the anterior border of the trapezius muscle
inferiorly and the midline of the neck superiorly [24,25].

Sentinel lymph node biopsy: a new paradigm for staging N0 neck tumors
Sentinel lymph node biopsy (SLNBX) has become an accepted technique
for staging the first extratumoral echelon of draining lymph nodes in
individuals diagnosed with melanoma or breast cancer. Similar to SND,
SLNBX is based on the principle that lymphatic metastases do not occur in
a random manner, but rather predictably, in accordance with preexisting
lymphatic anatomy. As discussed, the practice of Staging SND, performed
162 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

Fig. 9. Selective neck dissection II–V (postauricular, suboccipital), or posterolateral neck


dissection. (Drawing by Paul Tomljanovich, MD, medical illustrator.)

by removing nodal levels with the highest probability of harboring metastatic


disease, is based on studies examining the pattern and incidence of metastases
in large patient cohorts. Unlike SND, however, SLNBX is a lymphatic
mapping technique that allows for the direct evaluation of the lymph node or
nodes that initially receives metastatic disease, in a specific individual, with
a tumor at a specific location.
Patients who have N0 head and neck cancer may benefit most from
SLNBX. Approximately 20% to 40% of patients who have N0 disease
harbor microscopic tumor foci [26–28]. Thus, approximately two thirds of
patients who have N0 head and neck cancer will have no pathologic
evidence of metastatic disease [26,29]. Taking a ‘‘wait and see’’ approach in
patients with N0 cancer has been associated with disease recurrence and
a worsened prognosis [26]. SLNBX has the potential of avoiding either
overtreatment or undertreatment of the neck. In addition, SLNBX has the
added benefit of improved disease staging by directing the pathologist to the
‘‘highest risk’’ lymph node or nodes, which may be more extensively eval-
uated by either immunohistochemical or molecular techniques. Hamakawa
et al [30] determined that routine histologic evaluation of neck dissection
specimens miss micrometastatic disease in up to 28% of patients. It is this
group of ‘‘understaged’’ patients with head and neck cancer that may espe-
cially benefit from SLNBX.
Recently, Wiseman et al [31] presented the results of a pilot study using
an isosulfan blue dye technique to carry out SLNBX in patients with early-
N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166 163

stage N0 oral cavity head and neck cancer. Although SLNBX was
technically feasible, and no adverse effects were observed in the authors’
patient population, the sentinel node identification rate was only 57%, and
when identified, the sentinel node accurately predicted the pathologic status
of the neck in 75% of patients. The negative predictive value for the absence
of cervical metastases was 67% [31]. The authors’ experience was similar
to that of other investigators who found that a vital dye technique alone
had a low rate of sentinel node identification (0%–67%), and even when
identified, the sentinel node often did not accurately predict the pathologic
status of the neck (0%–75%) [32,33]. The poor clinical utility of the vital
dye methodology is a sharp contrast to the high rate of sentinel node
identification reported when a radiotracer technique is used (in most series,
100% of sentinel nodes were identified) [34–44]. In addition, using the
radiotracer technique, the sentinel node almost always accurately reflected
the pathologic status of the neck. Other investigators have used a combined
vital dye/radiotracer technique and have reported that these methodologies
complement one another and also have high rates of sentinel node iden-
tification (90%–100%) and accurate nodal staging (97%–100%) [43–45].
Recently, Ross et al [46] reported pooled results, from 22 centers, of
SLNBX being performed on 316 patients who had N0 head and neck
cancer. Although this study was not prospective, and the study population
was treated heterogeneously, these investigators reported a 95% rate of
sentinel node identification and an overall sensitivity of 90% for this
procedure. At centers that performed 10 or fewer procedures, the sensitivity
was 57%; centers that performed more than 10 procedures had a sensitivity
of 92% [46].
Although the data reported by Ross et al [46] are provocative, they must
be interpreted with caution because this study was performed in a patient
cohort that was nonrandomized, uncontrolled, retrospectively collected, and
heterogeneous. The results reported in the current literature are encourag-
ing, however. SLNBX does seem to be a technically feasible and accurate
method for staging N0 neck cancer. There remain many issues that must
be addressed before SLNBX becomes integrated into the management
algorithm of N0 neck cancer. Critical unresolved issues include the identi-
fication of patient/tumor characteristics appropriate for this methodology
(eg, stage, site, subsite) and a determination of the technique (eg, radio-
tracer, vital dye, or combination technique) most appropriately applied to
these individuals.

Summary
For individuals diagnosed with head and neck cancer, neck dissection
may be performed for therapy or disease staging. The classification of neck
dissection and the definition of precise anatomic landmarks have allowed
164 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

for this operation, and its many variations, to become standardized world-
wide. SLNBX shows promise in its ability to accurately stage N0 head and
neck cancer and may allow patients with no micrometastatic disease to
avoid neck dissection. Before this technique becomes adopted into routine
clinical practice, however, it must first be prospectively scrutinized in large
patient populations. Regardless of the future role of SLNBX in the man-
agement of head and neck cancer, currently it is only through a complete
understanding of the clinical, theoretic, and technical aspects of neck dis-
section that surgeons may benefit individual patients and the head and neck
cancer patient population as a whole.

Acknowledgment
The authors thank Paul Tomljanovich, MD, for his excellent artwork.

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Surg Oncol Clin N Am 13 (2004) 167–186

Differential diagnosis and treatment


options in paranasal sinus cancers
Larry L. Myers, MD*, Lance E. Oxford, MD
Department of Otolaryngology–Head and Neck Surgery, University of Texas Southwestern
Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9035, USA

Despite major advances in the diagnosis and treatment of paranasal sinus


cancers, these rare malignancies remain a complex and difficult problem.
Improved surgical techniques, including the ability to safely reconstruct
large, complex defects with free-tissue transfers, multimodality therapies
and radiation therapy and chemotherapy protocols have had little impact on
improving the traditionally poor prognosis. Paranasal sinuses are in-
accessible on routine examination and cancers of this region typically do not
become manifest until critical adjacent structures are involved. The poor
overall and disease-free survival rate is commonly attributed to the
advanced stage at presentation of most tumors. This article presents the
diagnosis, staging, treatment options, and outcomes for these heterogeneous
neoplasms arising from the anatomically complex region of the paranasal
sinuses, with an emphasis on epithelium-derived malignancies.

Anatomy
A fundamental knowledge of the anatomy of the paranasal sinuses is
crucial in any discussion of malignancies of this region. The paranasal
sinuses consist of the paired maxillary, ethmoid, sphenoid, and frontal
sinuses (Figs. 1 and 2). Each sinus is named according to the bone that it
pneumatizes. The frontal sinus is located between the outer and inner tables
of the frontal bone. Each frontal sinus drains inferiorly by way of the
nasofrontal duct, which continues inferiorly to drain into the medial meatus
of the lateral nasal wall. The middle meatus is the area found inferior to the
middle turbinate and superior to the inferior turbinate. The dura of the

* Corresponding author.
E-mail address: larry.myers@utsouthwestern.edu (L.L. Myers).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00115-7
168 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

Fig. 1. Sagittal section of head, depicting position of paranasal sinuses and sectioning planes
1 and 2 of Fig. 2. AE, anterior ethmoid; ME, middle ethmoid ostium; OB, olfactory bulb; PE,
posterior ethmoid; SO, sphenoid ostium.

anterior cranial fossa is located immediately posterior to the sinus. The


ethmoid sinuses consist of 3 to 18 thin-walled air cells. The lateral border is
formed by the lamina papyracea of the medial orbital wall. The ethmoid
sinuses are divided into anterior and posterior ethmoid cells by the basal
lamella, a bony structure that supports the middle turbinate by attachment
to the lamina papyracea and anterior skull base. The anterior cranial base
forms the superior border of the ethmoids, and the nasal cavity is located
medially. The sphenoid sinus is the most posterior of the paranasal sinuses. It
is surrounded by numerous vital structures. The internal carotid artery and
optic nerve are located along its lateral wall. Its superior surface forms the
sella turcica and contains the pituitary gland. Each of the sphenoid ostia is
located on the anterior wall of the sphenoid sinus, which also forms the
posterior wall of the nasal cavity superior to the choanae. The sphenoid sinus
and posterior ethmoid cells drain into the sphenoethmoid recess in the
posterior superior lateral nasal cavity. The maxillary sinuses are the largest
sinuses and are the only ones separated from the skull base. Each maxillary
sinus is shaped similar to a pyramid, with a base formed by the lateral nasal
wall and an apex projecting toward the zygomatic arch. The superior
boundary is formed by the orbital floor, and the inferior boundary is formed
by the alveolar and palatine process of the maxilla. The pterygopalatine
fissure is located immediately posterior to the sinus. The soft tissues of the face
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 169

Fig. 2. Coronal section of head to illustrate relationships of paranasal sinuses (see Fig. 1 for
planes of sections 1 and 2).

are located anteriorly and laterally to the sinus. The maxillary sinuses and the
anterior ethmoid cells drain into the middle meatus [1,2]. The normally air-
filled sinuses surround the nasal cavity and are lined by ectodermally derived
respiratory epithelium, consisting of ciliated, pseudostratified, columnar
epithelial cells and interspersed mucus producing goblet cells. The lining of
the sinuses is continuous with the mucosa of the nasal cavity. The sinus
mucosa is thinner, however, and more adherent to the surrounding bone [1].

Incidence
Paranasal sinus cancers account for less than 1% of all malignancies and
comprise 3% of all head and neck malignancies [3]. The incidence rate is 0.3
to 1.0 case per 100,000 people per year in Western populations [4–6]. The
incidence is 2 to 3 times higher in Japan [7]. In the United States, the overall
male-to-female incidence is 3 to 2, with a strong predilection for whites. The
incidence rate of sinonasal cancer progressively increases after age 35.
Epithelium-derived neoplasms are almost nonexistent in children [5,6].

Etiology
The precise cause of paranasal sinus malignancies is unknown. Known
risk factors for the development of cancer in this region, however, include
170 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

wood and leather dust, smoke, and heavy metals, including nickel. Most
patients have a history of exposure to carcinogens for more than 10 years [8].

Pathology
The paranasal sinuses contain diverse components: schneiderian mucosa,
minor salivary glands, neural tissue, lymphatics, vessels, and bone. A
neoplasm may arise from any type of tissue present in the paranasal sinuses.
This article discusses epithelium-derived malignant neoplasms, including
lymphomas.

Epithelium-derived malignancies
Squamous cell carcinoma
Non–squamous cell carcinoma
Adenocarcinoma
Adenoid cystic carcinoma
Mucoepidermoid carcinoma
Melanoma
Olfactory neuroblastoma
Sinonasal undifferentiated carcinoma

Presenting symptoms/history
Patients typically present after symptoms have been present for several
months and the tumor has involved adjacent structures. Small tumors are
often asymptomatic but may present with nasal obstruction, epistaxis, or
symptoms consistent with chronic sinusitis, such as headache or rhinorrhea.
With involvement of surrounding structures, patients may experience
diplopia or vision changes, infraorbital nerve deficits, maxillary dental
symptoms, or possibly neurologic deficits secondary to intracranial
extension.

Evaluation
A suspected paranasal sinus malignancy requires a thorough head and
neck examination complemented by imaging studies. Office nasal endoscopy
under topical anesthesia allows assessment of the extent of a mass and its
fixation to surrounding structures. A biopsy can usually be performed in the
office setting. If there is concern for bleeding or the lesion is not easily
accessible, then endoscopic or open biopsy is best performed in the
operating room. A complete cranial nerve examination may disclose skull
base or direct nerve involvement by the tumor. A formal ophthalmologic
evaluation is recommended if there is concern for orbital involvement.
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 171

CT imaging, with at least 3-mm cuts, allows the best assessment of


involvement of surrounding bone. Coronal imaging readily demonstrates
the anatomy of the paranasal sinuses, including fine bony structures such as
the lamina papyracea, orbital floor, and cribiform plate. The extension of
a paranasal sinus malignancy through the skull base is best evaluated with
fine-cut coronal imaging. Contrast infusion may help demonstrate regions
of enhancement containing neoplasm. Often on CT scans, it is difficult to
determine the soft tissue extent of a malignancy. Sinus opacification on CT
images may be secondary to tumor infiltration or the result of accumu-
lations of mucus from obstruction of the sinus. MRI with gadolinium is
superior in delineating soft tissue detail, both intra- and extracranially. This
modality provides the best assessment of tumor extent and can easily
differentiate between tumor and inspissated mucus (Fig. 3). In addition,
MRI has the advantage of avoiding dental filling artifacts, imaging in the
sagittal plane, and not exposing the patient to ionizing radiation. Plain
radiographs are generally not useful in assessing a sinus malignancy. A 6-ft
Caldwell view is occasionally used to create a template of the outline of the
frontal sinus to guide frontal bone osteotomies.

Staging
Staging paranasal sinus malignancies as a whole is imprecise and
controversial. A formal staging system has been developed only for maxillary
sinus carcinomas. In 1933, Ohngren [9] differentiated maxillary sinus tumors
based on whether they primarily involved the suprastructure or the
infrastructure of the maxillary sinus. Ohngren’s line runs from the medial
canthus inferiorly and laterally to the angle of the mandible. The
infrastructure of the maxillary sinus lies anterior and inferior to the line and
the suprastructure lies posterior and superior. Tumors of the infrastructure
are associated with a better prognosis because of decreased involvement of the
orbit and cranial base. In 1997, the American Joint Committee on Cancer
revised its 1977 criteria to more accurately correlate tumor stage and survival
[10]. The 1997 staging system is described in the following sections [11].

Tumor classification
T1: Tumors limited to antral mucosa, without bone erosion or destruction
T2: Tumor causing bone erosion or destruction, except for the posterior
wall, including extension into the hard palate or middle nasal meatus
T3: Tumors invading any of the following: posterior wall, subcutaneous
tissue, skin of the cheek, floor, or medial wall of the orbit,
infratemporal fossa, pterygoid plate, or ethmoid sinuses
T4: Tumors invading orbital contents beyond the floor or medial wall,
including any of the following: orbital apex, cribiform plate, base of
skull, nasopharynx, and sphenoid and frontal sinuses
172 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

Fig. 3. Axial contrast-enhanced MRI depicting actual extent of left posterior ethmoid sinus
adenocarcinoma. Black arrow indicates actual tumor. White arrow indicates inspissated mucus.

Node classification
N0: No regional node metastasis
N1: Metastasis to single ipsilateral node, less than 3 cm in greatest
dimension
N2a: Metastasis to single ipsilateral node, more than 3 cm and less than 6
cm in greatest dimension, or in multiple ipsilateral lymph nodes,
none more than 6 cm in greatest dimension
N2b: Metastasis to multiple ipsilateral nodes, all less than 6 cm in greatest
dimension
N2c: Metastasis to bilateral or contralateral nodes, all less than 6 cm in
greatest dimension
N3: Metastasis of more than 6 cm

Metastasis classification
M0: No distant metastasis
M1: Distant metastasis present
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 173

Disease stage
Stage I: T1N0
Stage II: T2N0
Stage III: T3N0 or T1-3N1 in greatest dimension
Stage IV: T4N0 or T1-4N2-3

Squamous cell carcinoma


Squamous cell carcinoma (SCC) is the most common paranasal sinus
neoplasm, accounting for 58% to 73% of malignancies [12–14]. The maxillary
sinus is the most common location for paranasal sinus SCC, followed by the
ethmoid sinuses. The frontal and sphenoid sinuses each account for 1% of
SCC [1,12]. The neoplasm more commonly affects men and typically presents
in the sixth and seventh decades of life [1]. Reported risk factors include
a history of inverted papilloma and exposure to radioactive thorium dioxide
(thorotrast) contrast and nickel [1]. SCC typically presents at an advanced
stage; more than 80% of patients present with stage III or IV tumors
[10,12,13]. Lymph node or distant metastases are rare on presentation [15].
SCC arises from the respiratory ciliated columnar epithelium of the
paranasal sinuses. Histologically, 80% of cases demonstrate keratinization
and the remainder are the nonkeratinizing subtype. The tumors may exhibit
either papillary, exophytic, or inverted growth patterns [1].
The standard treatment of paranasal sinus SCC is combined therapy
involving resection and radiation [10,13]. Tiwari et al [13] reviewed 35 cases
of SCC of the maxillary sinus. Twenty-six patients were treated with surgery
and postoperative radiation and nine were treated with chemotherapy and
radiation therapy. Resections included 12 maxillectomies, 7 infrastructure
maxillectomies with preservation of the orbital floor, 6 radical maxillec-
tomies with orbital exenteration, and 1 craniofacial resection. The surgical
group demonstrated a significantly higher 5-year disease survival rate of
64%, compared with the chemotherapy/radiation therapy group; however,
22.5% of patients treated with resection developed a local recurrence, most
commonly in the infratemporal fossa. Duelguerov et al [12] reported a 58%
5-year survival rate for 126 patients treated at the University of California–
Los Angeles and Geneva University Hospital. The most common treatment
approach used was surgery and radiation therapy. The authors reviewed the
literature and demonstrated a significant improvement in survival compared
with previous publications. The reported survival rates in articles published
in the 1960s through 1990s were 25%, 34%, 45%, and 50%, for each decade
respectively.
The favorable response of head and neck SCCs to the chemotherapeutic
agents 5-fluorouracil (5-FU) and cisplatin recently has been reported, and the
use of these agents may be an effective adjuvant treatment for paranasal sinus
SCC. Nibu et al [15] reported an overall 5-year survival rate of 86% in 33
patients with maxillary sinus SCC. Even with skull base involvement, a 60%
174 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

survival rate was achieved. Multimodality treatment included preoperative


cisplatin, 5-FU, and radiation therapy, surgical resection; and postoperative
radiation therapy. Orbital contents were preserved in 67% of patients. Nine
patients developed a local recurrence; three of these recurrences were
salvaged with repeat resection [15]. In addition, a University of Chicago
study reported 11 of 12 patients with no evidence of disease at a median
follow-up period of 55 months after preoperative chemotherapy, surgical
resection, and postoperative radiation therapy [16].

Adenocarcinoma
Paranasal sinus adenocarcinomas differ from SCC in risk factors and
typical location. Chronic exposure to wood or leather dust has been cited as
a risk factor for the development of sinonasal adenocarcinoma in numerous
studies. Woodworkers in England have greater than a 1000-fold increased
incidence of ethmoid adenocarcinoma [17–24]. Adenocarcinomas account
for 17% to 90% of ethmoid malignancies, depending on geographic location
and occupational risk factors [25–27].
Sinus adenocarcinomas may develop from either minor salivary gland
tissue or the epithelium. Histologically, adenocarcinomas are classified as
low grade, high grade, or intestinal type. Low-grade adenocarcinomas
contain numerous glands lined by a single layer of cuboidal to columnar cells
with uniform nuclei. Papillary formations or large, irregular cystic spaces
may be present. High-grade lesions may demonstrate glandular structures
but are characterized by a solid growth pattern containing pleomorphism
and increased mitotic activity. Intestinal- or colonic-type adenocarcinoma
resembles intestinal adenocarcinoma and may contain goblet or signet ring
cells. All intestinal types are considered to be high-grade lesions [1].
Ethmoid adenocarcinoma typically requires a craniofacial approach for
resection. Postoperative radiation therapy is recommended for positive
margins, dural or cribiform plate invasion, and high-grade lesions adjacent
to the cribiform plate [28]. Wax et al [27] reported on eight patients with
adenocarcinoma of the ethmoid sinuses who were treated with craniofacial
resection, with follow-up periods ranging from 9 months to 5 years. Four
patients received postoperative radiation therapy. Seven patients have no
evidence of disease, including five patients who were observed for more than
3 years. Only one patient had positive margins secondary to brain
involvement and died of local recurrence at 8 months. The 5-year survival
rates after craniofacial resection ranged from 39% to 57% [29–31]. Knegt
et al [32] reported a 5-year survival rate of 87% in 70 patients treated with
surgical debulking and topical chemotherapy with 5-FU. The patients
received biweekly packing changes, removal of necrotic tissue, and topical
chemotherapy for 4 weeks. Selection bias likely contributed to the high
survival rate, however, because advanced tumors with invasion of dura or
the orbit were excluded from the protocol.
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 175

Adenoid cystic carcinoma


Adenoid cystic carcinoma (ACC) most commonly develops in the major
salivary glands. It may arise from minor salivary gland tissue located
throughout the upper respiratory tract, however, including the paranasal
sinuses. ACC is the second most common malignancy of the paranasal
sinuses in some series [33,34]. It is an aggressive neoplasm characterized by
early neural invasion and a high incidence of local recurrence and distant
metastases, which may develop years after initial resection. Although the 5-
year survival rate of ACC of all head and neck sites is 75%, the 20-year
survival rate is only 13% [1]. ACC of the paranasal sinuses has the highest
incidence of local recurrence, likely secondary to its advanced stage at
presentation and vicinity to cranial nerves and the skull base [35,36]. The
most common location of ACC of the sinonasal tract is the maxillary sinus,
accounting for 66% of cases [36].
Histologically, ACC is characterized by varied growth patterns, including
cribiform, tubular, and solid arrangements of hyperchromatic cells with
indistinct cell borders. The neoplastic cells may form nests of ducts or
tubules, which are sharply demarcated from the surrounding myxoid or
hyalinized interstitial stroma [1].
The standard treatment for ACC of the paranasal sinuses is combined
therapy with resection and radiation therapy [36–38]. Pitman et al [36]
reviewed 35 patients with ACC of the sinonasal tract and reported a 46%
disease-free survival rate with a median follow-up of 40 months. Approx-
imately 71% of patients developed a recurrence, however, including 21%
with distant metastases. Salvage therapy yielded no evidence of disease for at
least 2 years in only 1 of 17 patients with a local recurrence. Craniofacial
resection in 23 patients allowed a similar rate of control of advanced tumors
compared with patients treated with a maxillectomy for limited tumor
extension. In a longer-term follow-up period of 22 patients with ACC of the
maxillary antrum, Kim et al [37] reported a 10-year survival rate of 37.6%
and a 10-year disease-free survival rate of 13.6%. All 12 of the patients
treated with a single modality developed local recurrence, compared with
a local recurrence rate of 40% in patients receiving resection and radiation
therapy. With a median follow-up period of 8 years, the median survival time
for all patients was 7.5 years. Negative predictors for survival were perineural
invasion and single-modality treatment. Patients with unresectable ACC or
residual disease after resection should be evaluated for neutron radiotherapy.
Neutron therapy delivers a higher linear energy transfer compared with
conventional radiotherapy. Five-year survival rates of approximately 50%
have been reported for advanced cases of ACC [39,40].

Melanoma
Sinonasal melanomas are rare neoplasms characterized by a poorer
prognosis than cutaneous melanomas. Malignant melanoma occurs in the
176 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

sinonasal tract in less than 1% of cases [41], and sinonasal melanoma


accounts for less than 4% of sinonasal malignancies [42]. The incidence of
sinonasal melanoma is much higher in certain populations. It accounts for
more than 25% of melanoma cases in Japan and 7% to 11% of sinonasal
neoplasms [43–45]. There is an equal male-to-female incidence, and most
patients present in their sixth or seventh decade of life [46]. Sinonasal
melanoma most commonly develops in the nasal cavity, especially the lateral
nasal wall. The ethmoid and maxillary sinuses are the most common
location for paranasal sinus melanomas [47].
Sinonasal melanomas develop from neural crest–derived melanocytes
found in the lamina propria of respiratory epithelium and around sinonasal
minor salivary glands [48]. Histologically, melanomas may exhibit various
growth patterns, including epithelioid and spindle cell formations, with
variable melanin deposition [1]. Immunohistochemical staining for S-100
protein and HMB45 allows the diagnosis to be made with amelanotic
melanomas [1,49].
Surgical resection is the standard treatment for sinonasal melanomas. In
a review of 72 cases of sinonasal melanoma, Lund et al [47] reported a 5-year
survival rate of 28%. There was no improvement in local control or survival
rates with the addition of radiotherapy or chemotherapy compared with
surgical resection. Brandwein et al [46] reviewed 25 cases from Mount Sinai
Hospital and performed a meta-analysis of 163 reported cases. The overall
5-year survival rate was 36%. Despite advances in chemotherapy and
radiation therapy, there was no improvement in survival in patients reported
before 1980 compared with patients from 1980 to 1995. Despite initial
resection with negative margins, patients may develop local recurrences or
distal metastases years later [50,51]. Recurrences amenable to surgery should
be resected to help prolong survival [46].

Olfactory neuroblastoma (esthesioneuroblastoma)


Olfactory neuroblastomas, also known as esthesioneuroblastomas, are
aggressive, rare neoplasms derived from the olfactory mucosa present on the
superior septum, cribiform plate, and upper surface of the superior
turbinate [52]. The ethmoid sinuses are the most common paranasal sinuses
to be affected by this neoplasm. The tumor displays a bimodal distribution
for patient age, with peaks in the second and sixth decades of life. Olfactory
neuroblastomas commonly extend intracranially and are associated with
a high local recurrence and metastatic incidence. The cervical lymphatics are
the most common site of metastasis, but distant spread may involve the
brain, bones, viscera, and lungs [53].
On histology, low-grade olfactory neuroblastomas exhibit lobular
architecture with pseudorosette formations, prominent neurofibrillary
material, variable calcification, and well-differentiated cells. Higher-grade
neoplasms are characterized by anaplastic tumor cells with increased mitotic
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 177

activity. High-grade olfactory neuroblastomas may retain a lobular con-


figuration with rosette formation [1].
Standard treatment consists of combined therapy with surgical resection
and postoperative radiation therapy. Craniofacial resection is frequently
necessary because of the high incidence of anterior cranial fossa involvement.
Broich et al [54] reported a 5-year survival rate of 72.5% with combined
therapy. The survival rates with surgery or radiation alone were 62.5% and
53.85%, respectively. Chao et al [55], at Washington University Medical
Center, observed a 5-year local control rate of 87.4% for combined therapy
and 51.2% for irradiation alone. Others proposed that craniofacial resection is
sufficient treatment when negative margins are obtained with limited tumors.
Resto et al [53], at Johns Hopkins, obtained complete surgical resection in
62% of patients with craniofacial resection. Approximately 80% of patients
with negative margins had no evidence of disease at a median follow-up period
of 5.6 years. In patients with unresectable tumors, chemotherapy may be given
in conjunction with radiation therapy for palliation.

Sinonasal undifferentiated carcinoma


Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive
neoplasm, which was not described until 1986 [56]. The mean age of
presentation is the sixth decade of life, and there is a male-to-female
incidence of approximately 2.5 to 1 [57,58]. Patients present with rapid onset
of symptoms, such as epistaxis, nasal obstruction, cranial nerve deficits, or
proptosis. The tumor typically presents with involvement of multiple sinuses
and extension through the skull base and into the orbit. The most common
locations are the ethmoid sinuses and the nasal cavity. Proposed risk factors
include smoking and prior radiation therapy [56–58]. Histologically, SNUC
is characterized by nests of small- to medium-sized cells with extensive
necrosis. Cells contain numerous mitotic figures, a high nuclear-to-
cytoplasmic ratio, and moderate pleomorphic, hyperchromatic nuclei [57].
In a recent review of 36 cases of SNUC, Jeng et al [57] reported a high
incidence of metastasis. Approximately 17% of patients had cervical node
involvement and 31% had distant metastasis, most commonly to the liver,
lungs, or bone. Various protocols, including surgery, chemotherapy, and
radiation therapy, yielded only a 10-month median survival time. All five of
the patients with no evidence of disease at a median follow-up time of 31
months received surgical resection as part of their treatment. Despite
advances in craniofacial resection, radiation therapy, and chemotherapy,
there has not been an improvement in survival times. Duelguerov et al [12]
reviewed 30 cases and reported a 10-year survival rate of 33%. The authors
performed a meta-analysis of cases reported since 1960 and demonstrated
no significant improvement in survival rates during the past 40 years. The
survival rates for articles from the 1960s through the 1990s were 23%, 42%,
30%, and 28%, for each decade respectively.
178 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

Lymphoma
Lymphomas of the paranasal sinuses are rare but are the most common
non–epithelial-derived neoplasm of the sinuses. Lymphomas of the
sinonasal tract account for less than 0.2% to 2% of extranodal lymphomas
in Western populations [59,60]. There is significant geographic diversity in
the incidence and histology of paranasal sinus lymphomas. In Asian
populations and in Peru, most cases are T-cell derived neoplasms affecting
young men. Most Western cases, however, are large B-cell–type lymphomas
diagnosed in elderly men [59–66]. The maxillary sinus is the most common
site of involvement. Orbital extension is more often associated with diffuse,
large B-cell lymphomas, whereas T-cell lymphomas more commonly involve
the nasal cavity [62].
If lymphoma is suspected, it is necessary to send biopsy specimens in
formalin and in saline to allow permanent section analysis and flow
cytometry. A combined modality approach with chemotherapy and
radiation therapy is the treatment of choice. A review of 70 patients who
had sinonasal lymphoma and who were treated at M.D. Anderson Cancer
Center reported improved prognosis with combined therapy versus
radiotherapy alone, yielding a 67% overall survival rate [61]. Cuadra-
Garcia et al [62] reported a significantly improved prognosis with patients
who had T-cell/natural killer cell lymphomas treated at Massachusetts
General Hospital compared with Eastern reviews. Approximately 11 of 15
patients were alive at a median follow-up period of 10 years, compared with
a median survival time of 6 to 25 months in Asian populations [67–69].
Because T-cell–derived lymphomas are associated with Epstein-Barr virus,
diversity of Epstein-Barr strains in the different populations may contribute
to the marked difference in disease course [62].

Treatment
Surgical treatment
A multidisciplinary approach is often used before resection of a paranasal
sinus cancer. Patients are presented to a tumor board consisting of
specialists in head and neck oncologic surgery, medical oncology, and
radiation therapy. Imaging studies are reviewed by a neuroradiologist. A
neurosurgeon is consulted if there is skull base involvement and
a craniofacial resection is anticipated. Formal ophthalmologic evaluation
is helpful when there is concern for orbital involvement. If a patient is
expected to require radiation therapy, the patient is referred to an oral
surgeon so that any needed dental extractions may be performed at the time
of surgery.
The goal of surgical resection is to remove the cancer en bloc, with
margins clear of neoplastic cells. For maxillary sinus neoplasms, maxillec-
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 179

tomy is the standard surgical procedure. Numerous modifications, such as


medial maxillectomy, subtotal maxillectomy, infrastructure maxillectomy,
suprastructure maxillectomy, and radical maxillectomy, may be used
depending on tumor extent. Neoplasms involving the ethmoid, frontal, or
sphenoid sinuses usually require a craniofacial approach because of skull
base involvement.
Before beginning surgical resection, patients receive broad-spectrum
intravenous antibiotics. Cefuroxime and metronidazole are most commonly
given upon entering the operating room and every 8 hours for at least 24
hours postoperatively. In addition, 2 to 4 units of blood are made available
for the patient. After general endotracheal anesthesia, the extent of the
tumor is assessed with rigid telescopes and indirect mirror examination of
the nasopharynx.
The two most commonly used incisions for approaches to the midface and
anterior skull base are the lateral rhinotomy and the facial degloving
technique. The lateral rhinotomy technique provides access to the nasal
cavity, medial third of the maxilla, and the ethmoid sinuses. The incision
begins in the inferior hairs of the medial one third of the eyebrow. The incision
curves downward midway between the nasion and the medial canthus. It
continues slightly on the nasal side of the nasofacial groove until it curves
around the ala and into the floor of the nose. The incision is carried deep
through the periosteum. The medial canthal ligaments may be detached from
the lacrimal crest in the subperiosteal plane. After periosteal elevation,
a curved osteotome is used to make low lateral osteotomies through the
frontal process of the maxilla. The lateral nasal wall may then be out-fractured
and retracted medially. If a total maxillectomy is required, a Weber-Ferguson
incision may be made, which combines the lateral rhinotomy incision with an
upper lip–splitting incision. Placing the vertical component of the incision on
the philtral crest minimizes the visibility of the subsequent scar [70–72].
The midfacial degloving technique offers the advantage of avoiding facial
incisions. Exposure is compromised, however, in patients with decreased
distance between the oral commissures [73]. This technique provides access
to the midfacial skeleton, nasal cavity, sinuses, and clivus. Bilateral
intranasal incisions include a transfixion, an intercartilaginous incision
along the cephalic border of the lower lateral cartilage, and an incision along
the nasal floor. The medial nasal floor incision may include a small Z-plasty
or triangular incision to decrease postoperative stenosis. The hemitrans-
fixion incisions are connected, and the nasal tip and dorsal nasal soft tissues
are elevated as with a rhinoplasty. The mucosa of the gingivobuccal sulcus is
incised between the maxillary tuberosities. The maxillary soft tissues may
then be elevated in a subperiosteal plane to the orbital rims, with exposure
of the pterygopalatine fissure. The infraorbital neurovascular bundle is
preserved, if possible, and may be freed with osteotomies [74].
Anterior craniofacial resection is most commonly used for resection of
tumors originating in the sinonasal tract with invasion of the floor of the
180 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

antezrior cranial fossa. This approach combines a bifrontal craniotomy with


transfacial exposure of the nasal cavity, ethmoid, maxillary, and orbital
regions. If a total maxillectomy is also planned, an upper lip incision is
included with the lateral rhinotomy incision. The periosteum is elevated
from the maxilla, nasal bones, and medial and inferior orbital rims. A
contralateral Lynch incision facilitates elevation of the contralateral
periorbita, control of anterior and posterior ethmoid vessels, and exposure
for osteotomies.
Once transfacial exposure has been obtained, a neurosurgeon performs
the bifrontal craniotomy. An osteoplastic frontal sinus flap may be used in
patients with large frontal sinuses to avoid cosmetic deformity from the
placement of burr holes in the forehead region. A diamond burr may then be
used to remove the posterior table to expose the dura. In patients with small
frontal sinuses, a guarded osteotome is introduced by means of burr holes
above the hairline or in the temporal regions to create the frontal bone
flap. Cutting the anterior horizontal bone inferiorly within 1 cm of the
supraorbital rims minimizes the amount of subsequent brain retraction
required. In the midline, care is taken to separate the superior sagittal sinus
contained in the dural folds from the frontal bone before making the lower
horizontal bone cut. Once the bone flap is removed, the frontal lobe is then
elevated from the cranial base. The olfactory nerves are severed at the
cribiform plate. The dura is then elevated to expose the planum sphenoidale,
fovea ethmoidales, orbital roofs, and the base of the anterior clinoid
processes. If the posterior limit of resection involves the planum
sphenoidale, the optic nerve should be decompressed. Removing the optic
canal allows an osteotomy to be made in the planum sphenoidale with
decreased risk of injury to the optic nerve. Optic nerve decompression is not
required if the posterior limit of resection is limited to the cribiform region.
Osteotomies of the zygoma and palate are included if a total maxillectomy is
required.
Once margins have been cleared and the dura is closed, attention is
directed at reconstruction of the anterior skull base defect. A vascularized,
anterior-based pericranial flap is placed over the defect, and the distal end
may be sutured to dura. Because the pericranial flap traverses the frontal
sinus, the frontonasal duct should be obliterated. The frontal sinus may
either be obliterated or cranialized. During closure of the facial wound, the
medial canthal ligaments are resuspended to the medial orbital wall. Stents
may be placed in the canalicular system to help prevent dacrostenosis [75,76].
A less aggressive approach toward orbital exenteration with resection of
sinonasal malignancies has developed during the past century. In the early
1900s, all resections for maxillary sinus carcinomas included an orbital
exenteration [77]. With the realization that the entire orbit is lined by a
periosteum (periorbita), which is resistant to tumor infiltration [78], orbital
preservation became more accepted. Traditionally, if the tumor involves the
periorbita or other intraorbital structures, orbital exenteration is indicated
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 181

[79]. Recent articles report similar local control rates with orbital
preservation in selected cases of infiltration of the periorbita. At the
University of Virginia, the invaded periorbita is resected, and the defect is
closed primarily or with temporalis fascia, without reconstruction of the
bony orbital wall [80].

Radiation therapy
Radiation therapy is often used with combination therapy, including
surgical resection. Multiple studies have demonstrated improved survival
with paranasal sinus malignancies with combined therapy compared with
single-modality treatment. Patients who have advanced lesions, positive
margins of resection, or regional metastasis should be evaluated for
radiation therapy. Before referral for radiation therapy, patients are
evaluated by an oral surgeon for extractions of diseased dentition to
decrease the risk of osteoradionecrosis. Patients are counseled regarding
potential adverse effects, such as xerostomia, hypothyroidism, middle ear
effusions, and blindness. Radiation therapy is typically started approxi-
mately 4 weeks after surgical resection.

Chemotherapy
In general, chemotherapy is of limited use for most sinus malignancies.
Chemotherapy regimens may be used with radiation therapy for palliation
of unresectable neoplasms. Chemotherapy is the primary treatment for
paranasal sinus lymphomas, however. Recent studies for aggressive cancers,
such as SNUC, have included chemotherapy, in addition to surgery and
radiation therapy. Thus far, however, no improvement in overall survival
rates has been demonstrated with such regimens compared with surgery and
radiation therapy.

Management of cervical nodes


Regional metastasis to cervical nodes is less common with paranasal
sinus malignancies compared with other head and neck sites, such as the
nasopharynx, oral cavity, oropharynx, and hypopharynx. Approximately
10% of paranasal sinus cancers are found to have regional spread at the
time of diagnosis. The most common locations for cervical involvement are
the submandibular and jugulodigastric nodes [81,82]. Nodal metastasis
should be treated with neck dissection at time of surgical resection of the
primary cancer. The neck should be included in the postoperative radiation
field if there are two or more pathologic nodes or if one node exhibits
extracapsular spread. There are no standard criteria for the treatment of N0
neck tumors. The 5-year incidence of post-treatment regional nodal failure
with N0 disease is reported to range from 12% to 29% [81–83]. The risk of
regional failure is higher with SCCs and undifferentiated carcinomas. Jiang
182 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

et al [84] reported a regional recurrence rate of 38% with SCC and SNUC at
the M.D. Anderson Cancer Center. Several centers have reported improved
regional control with elective neck irradiation. Patients presenting with T3
or T4 maxillary sinus carcinomas routinely receive cervical radiation
therapy [81], whereas physicians at Loyal University of Chicago Medical
Center use radiation therapy with all maxillary sinus carcinomas [82].
Jeremic et al [85] achieved a 10-year regional control rate of 97% with
elective radiation and surgical salvage in 44 patients.

Prognosis/outcome
The overall survival prognosis for paranasal sinus malignancies remains
poor. Five-year survival rates range from 35% to 40% [12,86,87]. In Myers
et al’s [14] series of 141 patients with paranasal sinus malignancies, an ad-
vanced stage, nodal metastasis, and distant metastasis negatively influenced
survival. Survival rates are higher for maxillary sinus neoplasms compared
with other paranasal sinuses because of decreased incidence of skull base in-
volvement. There is a wide variety in the clinical courses of paranasal sinus
malignancies depending on the histopathologic type. Melanoma and SNUCs
are both aggressive neoplasms associated with a dismal prognosis, charac-
terized by local recurrence and metastatic spread. In contrast, patients who
have ACC often seem to have no evidence of disease during the first 5 years
after treatment. With a long-term follow-up period of 20 years, the most of
these patients develop a local recurrence or a metastasis.

Summary
Paranasal sinus malignancies are challenging to treat. Most patients
present with advanced lesions, often with intracranial or intraorbital
extension, and have a poor overall prognosis. Given the low incidence
and diverse pathologies of paranasal sinus cancers, it is extremely difficult to
perform prospective, randomized clinical trials to compare different
treatment approaches. Improving the prognosis of these cancers continues
to be a difficult task, even in light of advances in surgical techniques,
radiation delivery techniques, and new chemotherapeutic agents. Cranio-
facial resection techniques developed in the past few decades have cured
many patients with skull base invasion, who would have been considered
unresectable in the past. Furthermore, improvements in radiation therapy
can allow more accurate administration to the desired region, with
decreased damage to surrounding structures such as the orbit and brain.
Aggressive and oncologically sound surgical resection combined with
radiation therapy remains the treatment of choice for most patients.
Finally, advances in the diagnosis and staging by use of molecular or DNA
markers of tumor behavior may allow for more directed therapy.
L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186 183

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Surg Oncol Clin N Am 13 (2004) 187–199

Organ preservation in patients with


squamous cancers of the head and neck
James K. Schwarz, MDa,*, William Giese, MD, JDb
a
Department of Medicine, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA
b
Department of Radiation Oncology, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA

In recent years, significant progress has been made in improving survival


in some types of malignancies. In many cancers, survival times have not
increased significantly, but progress has been made in lessening the nega-
tive impact that cancer treatments may have on patients. Examples of
this progress include preoperative chemotherapy and radiation followed by
sphincter-sparing surgery for rectal cancer, and multimodality therapy and
limb-sparing surgery for sarcoma. This article addresses issues of organ
preservation in the treatment of patients who have head and neck cancers.
The issue of organ preservation in patients who have head and neck
cancers often is centered on the larynx. This article, however, adapts a
broader perspective to include several head and neck functions that are im-
pacted significantly in patients who undergo treatment for head and neck
cancer. Box 1 lists physiologic functions that can be altered significantly by
either head and neck cancer or its treatment. This article addresses only
a subset of these issues.
Anatomic organ preservation does not necessarily equate to functional
preservation. This situation is fairly obvious in the case of radiation-induced
xerostomia, in which the salivary glands are anatomically intact, yet
functionally impaired. It is less clear in the case of a patient with persis-
tent swallowing or speech difficulties after treatment with radiation and
chemotherapy.
Furthermore, issues of organ preservation are inexorably linked with
quality of life, and this is the impetus for development of treatment regimens
that result in maximum functional organ preservation. Therefore, this article

* Corresponding author.
E-mail address: james.schwarz@roswellpark.org (J.K. Schwarz).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00120-0
188 J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

Box 1. Functions impacted by head and neck cancers and


their treatment
Speech
Swallowing
Salivary function
Hearing
Dental function
Neuromuscular function
Taste
Cosmetic function

briefly addresses the issue of quality of life in patients who have head and
neck cancer before discussing specific functions.
Finally, an article of this type should be able to make recommendations
as to what treatment regimens would be most appropriate for a given
situation. For organ preservation for head and neck cancer, this is a difficult
task. Some reasons for this difficulty include the following: the number of
randomized trials (particularly trials of surgery versus a nonsurgical modal-
ity) are limited, specific functional assessment (subjective and objective) is
not routinely performed in treatment trials, different assessment tools have
been used in different studies, patients have been assessed at different inter-
vals in different studies, and new technical changes in modalities of treat-
ment (ie, new surgical techniques, new radiation techniques) have not been
compared with each other.

Radiation as an alternative to surgery: the nature of side effects


and complications
Head and neck irradiation, whether adjuvant or definitive, has certain
side effects and complications. Irradiation does result in anatomic organ
preservation; however, the larger issue of whether that preserved organ
remains functional is tainted by patient perception. Although the patient
may be seduced by an alternative that does not include the surgical extir-
pation of their tongue or larynx, the risks of full-course head and neck ir-
radiation are not trivial. It is therefore important that the advising physician
be cognizant of the potential temporary and permanent side effects and
complications of radiation, and that they be fully disclosed.
First, it is necessary to realize that although irradiation may eradicate the
primary tumor and sterilize nodal metastases, it often will not restore
function of an organ destroyed by tumor. In addition, radiation can have
significant, long-term detrimental effects on speech and swallowing. Among
J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199 189

the other significant radiation-associated factors that affect a patient’s


quality of life are acute mucositis and acute and long-term xerostomia.
Acute oral mucositis is painful. Good oral hygiene seems to help reduce
the temporal appearance and severity of the reaction. Treatment has been
largely based on patient symptoms, using salt and baking soda gargles/rinses
and antifungal and antibiotic therapy. Preventative measures under inves-
tigation include systemic or topical prostaglandins, growth factors, amifos-
tine, certain amino acids (glutamine), and photodynamic therapy. The issue
is important, because severe mucositis can result in breaks in treatment that
may translate into a reduced cure rate.

Quality of life in patients with head and neck cancer


Numerous articles have been published on quality of life in patients who
have head and neck cancer [1]. It is difficult to draw definitive conclusions
from much of this work, however, for the following reasons: the patient
populations and their treatments are varied, the tools (subjective and
objective) are varied, and often the patient groups studied are selected from
a single institution. In addition, treatment trials (randomized and non-
randomized) rarely include prospective and ongoing assessment of organ
function. What is clear is that the quality of life of patients who have head
and neck cancer is profoundly impacted by the disease and its treatment,
and that treatment choices made by patients and providers are influenced by
perceptions of the impact of treatments on the patients’ quality of life [1–4].

Speech
In the early 1980s, the most aggressive treatment option (in terms of
survival) for patients with advanced larynx cancers was total laryngectomy,
possibly followed by adjuvant radiation therapy. Several phase 2 trials
demonstrated that some patients with advanced larynx and hypopharynx
cancer who responded to induction chemotherapy could be subsequently
treated successfully with radiation therapy and avoid a total laryngectomy
[5–7]. These studies provided the rationale for three trials in which patients
were randomized between initial surgery or induction chemotherapy fol-
lowed by radiation for those patients who responded to chemotherapy.
The Veterans’ Administration (VA) trial was initiated in 1985 and
randomized 332 patients with larynx cancer to primary laryngectomy or
a nonsurgical approach [8]. The nonsurgical approach started with two
cycles of cisplatin and 5-fluorouracil (5-FU) chemotherapy. Patients who
did not have a 50% or greater decrease in the primary lesion after two
cycles of chemotherapy underwent surgery. Patients with a 50% or greater
response (and no progression in neck disease) received a third cycle of
chemotherapy followed by definitive radiation. Approximately 64% of the
190 J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

patients assigned to the induction chemotherapy arm had an anatomically


intact larynx at a median follow-up time of 33 months. There was a slightly
decreased overall survival rate in the induction chemotherapy group, but
this was not statistically significant.
A second randomized trial of similar design was performed by the
European Organization for Research and Treatment of Cancer in 194
patients who had resectable cancers of the aryepiglottic fold or pyriform
sinus [9]. A complete clinical response to two to three cycles of cisplatin and
5-FU chemotherapy was required for patients randomized to the nonsurgical
arm to proceed to radiation. Approximately 54% of the patients assigned to
the induction chemotherapy arm achieved a complete response. The 3- and
5-year estimates of having an intact larynx in the patients assigned to
induction chemotherapy were 42% and 35%, respectively. Again, there was
no statistical difference in survival between groups assigned to surgery or
induction chemotherapy.
A third trial randomized 68 patients who had laryngeal cancers to either
induction chemotherapy followed by radiation or upfront surgery [10].
Larynx preservation was achieved in 41% of the 36 patients randomized to
induction chemotherapy, but there was a decreased survival rate for patients
randomized to the nonsurgical arm. This trial has been criticized for its
small size, lack of CT scan assessment of the tumor extent at the beginning
of the trial, and less stringent evaluation of response after chemotherapy and
after radiation.
A meta-analysis that pooled updated survival data from these three trials
concluded that there was not a statistically significant difference in the
survival rates of patients randomized to the two different arms in each of
these studies [11]. The conclusion from these trials was that, for patients
with large, resectable cancers of the hypopharynx or larynx, a strategy of
induction chemotherapy followed by radiation for those patients who
respond to chemotherapy is a reasonable treatment option. This strategy
may provide comparable survival rates to a strategy of upfront surgery and
result in rates of anatomic larynx sparing of approximately 50%.
Given that these trials were performed to provide support for a larynx-
sparing approach, it is important to confirm the benefits of anatomic larynx
preservation in the patients whose larynx was spared versus those who
underwent laryngectomy. The VA trial assessed patients periodically for
2 years after treatment for parameters related to speech, swallowing, and
employment [12]. There were no significant differences in swallowing and
employment in the two groups. There was a difference in parameters for
speech and voice, however, favoring the group that received induction
chemotherapy.
Long-term (mean, 10.5 y) follow-up of 46 patients from the VA trial also
has been reported [13]. Twenty-five of the patients had been randomized
to initial surgery and 21 to induction chemotherapy. In addition, 8 of the
21 patients had undergone laryngectomy at some point. The 21 patients
J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199 191

randomized to the induction chemotherapy arm had significantly better


quality of life scores for mental health and pain compared with those
randomized to surgery. This finding was also true of the 13 patients with
anatomically preserved larynges. Furthermore, patient-reported assessment
of speech was not significantly different between any of the groups. Thus,
although the self-reported quality of life was better in those patients ran-
domized to initial chemotherapy, this could not be attributed to speech.
Two things are worth mentioning: (1) the laryngectomy patients may have
learned to adapt well to their state and (2) differences in the domain scores
for speech were partly minimized because the speech scores for patients with
an intact larynx were well below that of healthy control subjects.
Induction chemotherapy followed by radiation (in those who respond to
chemotherapy) is currently considered a reasonable treatment option for
patients with larynx and hypopharynx sinus cancers who would otherwise
require total laryngectomy. Close monitoring of these patients by a head
and neck surgeon (particularly during the assessment of response to chemo-
therapy) is an intrinsic part of this strategy.

Technical improvements and larynx-preservation strategies


Numerous advances in treatment modalities have been made since the
previously discussed randomized trials were initiated. With respect to sur-
gery, the use of hemilaryngectomy, supraglottic laryngectomy, or supracri-
coid laryngectomy may allow for laryngeal voice preservation while still
providing a sound oncologic operation [14].
Radiation therapy has evolved to include altered fractionation schedules
and powerful new planning techniques, such as intensity-modulated
radiation therapy (IMRT). In addition, the use of chemotherapy concurrent
with radiation has been demonstrated to be superior to radiation alone in
several randomized trials. The Intergroup Trial R91-11 randomized 547
patients with larynx cancers to radiation alone, induction chemotherapy fol-
lowed by radiation, or concurrent chemotherapy and radiation [15]. Pre-
liminary analysis suggests that concurrent chemotherapy may be superior
to induction chemotherapy followed by radiation or radiation alone for
larynx preservation. It is too early to tell if concurrent chemotherapy and
radiation should be considered a standard larynx-sparing approach.

Comparing voice quality in patients treated with different modalities


Numerous studies have been performed documenting quality of speech
and voice in patients after treatment for larynx cancers. Few studies have
assessed speech prospectively, however, and measurement of vocal function
is generally not part of treatment trials. It is generally assumed that patients
with an intact larynx will have more favorable speech function than patients
192 J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

who have undergone a total laryngectomy. This assumption has not been
clearly documented, however. As noted previously, in long-term follow-up
from the VA trial, patient-reported speech quality of life was similar in
patients with and without an intact larynx [13].
Whether radiation therapy can have adverse effects on larynx function is
not clearly known. Poor vocal function after radiation for larynx cancer
could be caused by the treatment or by irreversible damage from the cancer.
In patients who have small- to moderate-sized larynx cancers, improvement
in self-assessed speech has been shown to occur at 6 months after treatment
with radiation [16].
As mentioned previously, newer surgical techniques involving less than
a total laryngectomy may allow for reasonable voice production [14]. This
type of surgery can also obviate a permanent tracheostomy. Because a
tracheostomy contributes significantly to negative quality of life [17], sur-
gical options that avoid this procedure will result in improved quality of life,
regardless of vocal function.
Options for speech rehabilitation in patients who have undergone a total
laryngectomy include an electrolarynx, esophageal voice, and esophageal
voice with augmentation by a tracheoesophageal prosthesis (TEP) [18].
Voice function in patients who have larnyx cancer treated with radiation
has been compared with voice function in patients who have had a total
laryngectomy and speech rehabilitation with a TEP [19,20]. The perception
of speech by trained and untrained listeners was higher in patients who had
received radiation, but the difference was not large. In addition, there were
clear differences in patients who had received radiation compared with
control subjects who did not have larynx cancer. Most of the poor voice
quality in the patients who received radiation is likely caused by irreversible
damage from the cancer rather than the radiation, but this is not known
with certainty [21]. Furthermore, although a TEP can result in good voice
quality, this approach has not been successful in some patients.
Patients who have advanced larynx cancer, in whom a total laryngectomy
traditionally would be considered, often have significant impairment of
voice before treatment. Oncologically successful treatment of this popula-
tion with radiation should not be expected to restore excellent vocal
function in most of these patients. Surgical procedures that preserve some
form of laryngeal voice and avoid a permanent tracheostomy have the
potential to be associated with quality of life that might equal that asso-
ciated with nonsurgical treatments.

Swallowing
There are at least two basic considerations when evaluating swallowing
function in patients who have head and neck cancer: (1) the ability to
swallow itself and (2) whether there is aspiration.
J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199 193

Patients who have head and neck cancer often have abnormal swallowing
before treatment. In one study using videofluoroscopy, 11 of 27 patients
with advanced head and neck cancers were found to have aspiration [22].
Impairment of swallowing was more closely associated with hypopharynx
and larynx cancers in another study [23], whereas in a third series, patients
with larynx cancers did not have the worst swallowing function [24]. Thus,
patients who have advanced head and neck cancers often have abnor-
mal swallowing function before treatment, and a nonsurgical treatment ap-
proach may not result in restoration of function, even if the treatment is
effective.

Swallowing after surgery for patients with head and neck cancers
Much of the literature concerning swallowing function after surgery has
focused on patients who have base of tongue cancer. Harrison et al [25]
reported that, in patients with base of tongue cancer, swallowing function
was better in those patients treated with radiation rather than surgery. A
later series from the same institution noted that patients treated surgically
may have swallowing function that is more comparable to patients treated
with radiation [26]. The extent of surgical resection for the base of the
tongue is hard to quantify, however, and the experience and opinion of the
consulting surgeon is invaluable in estimating the degree of swallowing func-
tion to be expected after surgery.
Surgery for head and neck cancer in sites other than the tongue of head
and neck cancer surgery can result in difficulty swallowing, but modern
methods of reconstruction have had reasonable functional outcomes [27–30].
Radiation can have detrimental effects on swallowing function (discussed
later), and patients treated with postoperative radiation have had swal-
lowing function that is inferior to patients treated by either surgery or radia-
tion alone [31].

Radiation effects on swallowing


Swallowing symptoms after radiation in patients who have head and
neck cancercan been separated into those symptoms that are caused by
xerostomia versus a mechanical problem with the tongue or pharyngeal
function [32,33]. Patients with xerostomia may or may not have difficulties
with the mechanical act of swallowing.
Swallowing abnormalities after radiation have been documented [34–36].
Swallowing changes have been attributed to decreased compliance in tissues
after radiation.
Several randomized trials have demonstrated that administration of
chemotherapy concurrent with radiation has been associated with more
favorable outcomes for control of disease and survival compared with
radiation alone. This type of treatment also has been clearly associated with
194 J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

more severe short-term toxicity, particularly mucositis. It is possible that


long-term swallowing problems are more prevalent in patients treated with
concurrent chemotherapy and radiation.
Severe, long-term swallowing problems also have been noted in several
phase 2 trials of concurrent chemotherapy and radiation [35,37–41]. In some
of these trials, the chemotherapy regimens are experimental and may re-
sult in greater toxicity than more commonly used regimens. For example,
in a trial in which gemcitabine was used concurrent with radiation (in pa-
tients with mostly oropharynx and nasopharynx cancers), 14% of patients
aspirated pretreatment versus 62% post treatment.
The randomized trials of concurrent chemotherapy and radiation versus
radiation alone did not report long-term swallowing function, however.
Thus, although the results of concurrent chemotherapy and radiation are
attractive from a survival standpoint, quality of life and swallowing in par-
ticular need to be carefully evaluated in these patients [42].

Salivary function
Radioprotective agents
The concept that certain agents taken systemically might render a pro-
tective effect against ionizing radiation is not new [43]. WR-2721 (com-
monly known as amifostine; trade name, Ethyol) was developed circa World
War II by the US Army at the Walter Reed facilities with the hope it might
prove protective to troops in the field when and if they became exposed to
atomic fallout. The prodrug form becomes dephosphorylated to form an
activated free thiol, WR-1065 [44]. This free-radical scavenger is concen-
trated preferentially by normal rather than tumor cells [45]. The precise
reasons for this behavior is unclear, but may be because of the lower con-
centration of alkaline phosphatase in tumor tissue [46].
Data from randomized trials have concluded that amifostine reduces
both acute and chronic xerostomia in patients who have head and neck
cancer, with no evident tumor protection [47]. The drug has received Food
and Drug Administration approval to be marketed for that purpose, but is
limited to intravenous administration at 200 mg/m2 daily, given just before
irradiation. The drug may be useful for radiation-induced mucositis as well.
Practically, the drug seems to be tolerable for some patients, although
hypotension, nausea, and rash (both in and outside the irradiated portals)
limit its use in others. Pretreatment hydration and antiemetic agents seem to
be helpful.
Another agent with a differing mode of action touted as potentially useful
in the prevention or treatment of radiation-induced xerostomia is pilocarpine
hydrochloride. This parasympathomimetic agent stimulates secretion from
salivary glands. The theory is that stimulation of output from those acini
that remain functional translates into a reduction in the sensation of dry-
J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199 195

ness. A recent phase 3 placebo-controlled trial failed to demonstrate a benefit


with respect to subjective parameters of swallowing and taste. This was
despite statistically significant presence of salivary output in the pilocarpine
arm [38]. This study limited eligibility to a planned dose of more than 50 Gy
to at least 50% of both parotid glands. The output of major salivary glands
decreases with doses of 10 Gy and worsens with dose escalation. If IMRT can
be used to limit a significant portion of the total volume of major salivary
gland tissue to below this dose, this output stimulation may prove beneficial.

Limiting salivary gland exposure to radiation


Another avenue for the reduction of the xerostomia inherent to head and
neck irradiation is to limit the dose that the salivary gland receives. It has
been theorized that this may be accomplished through the use of computer-
generated three-dimensional dose distributions that conform to the tumor
and tissues deemed at risk, while limiting dose to a sufficient volume of the
saliva-producing organs. Although research has largely focused on the
major salivary glands (parotids and submandibular/sublingual complex),
the sparing of minor salivary gland–rich tissues is also protective.
IMRT uses sophisticated computer algorithms to design a treatment
beam array. It is the intersection of multiple noncoplaner beams that results
in the dose delivered to any one point. The physician must first define the
acceptable radiation exposure to all tissues, both those that are normal and
those at risk. The computer modulates fluence as a function of entry angle
for each defined point and simply ‘‘grinds out’’ a plan by shear power of
repetition in a trial-and-error format, a function uniquely suited to this tool.
Cheng et al [48] compared the fractional volume of parotid gland receiv-
ing 30 Gy by conventional versus other techniques and showed that IMRT
nearly reduced this volume by half (from 93% to 48%). Chao et al [49]
noted that, whereas limiting parotid gland dose resulted in both an objective
(stimulated and unstimulated salivary flow rate) and subjective improve-
ment of quality of life scores (by quality of life questionnaire), both current
IMRT and non-IMRT techniques could achieve this.
There exist logistical constraints to these approaches, however. Perhaps
most important, it remains unclear just what daily and overall dose is
appropriate for closely juxtaposed structures heretofore similarly exposed.
Although the appropriate doses should become clearer with the test of time
and analysis of failure patterns, close follow-up and frequent reimaging
are mandatory. Physicians need to weigh the risk of locoregional failure,
a potentially life-threatening event, to the possible benefit of some degree of
salivary gland sparing that, although uncomfortable, remains tolerable.
A current technique to reduce xerostomia is to physically transfer the
submandibular gland to a region of the head and neck outside the
anticipated irradiation portal. Surgical relocation of this gland to the sub-
mental space is technically feasible; however, it applies to those patients
196 J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

deemed surgical candidates and, perhaps more significantly, is limited to


those in which the submental space can safely be shielded. In general,
eligibility criteria limit applicability to squamous cell carcinomas of the
oropharynx, hypopharynx, and larynx, with either no or unilateral neck
node involvement [50]. This technique is also limited to those surgeons
familiar with how to move the particular gland with limited trauma to the
gland duct. In experienced hands, this technique seems to be useful.

Neuromuscular function
Neck function can be significantly altered by surgery and radiation.
Radiation can result in long-term decreased mobility of the neck tissues [51].
Surgical morbidity associated with neck dissection depends largely on the
extent of surgery; sparing of the spinal accessory nerve, sternocleidomastoid
muscle, and internal jugular vein are associated with improved function
[52–55].
In patients who have advanced head and neck cancers (ie, the patients for
whom the question of organ preservation is an issue), treatment decisions
concerning the neck often necessitate using both surgery and radiation.
Thus, the development of treatment strategies that result in improved
outcomes in neck function have lagged behind that of the primary sites.
For example, a clinically complete response to primary radiation alone in
patients with N2 or N3 disease in the neck would typically require a neck
dissection. It is not known if a neck dissection is required after a complete
response following concurrent chemotherapy and radiation for patients with
N2 or N3 nodal disease [56].

Summary
Treatment strategies that have the potential to improve functional organ
preservation in patients who have head and neck cancer are emerging. Clin-
ical research in this field, however, has been limited by the lack of stan-
dardized, objective criteria of organ function post treatment and by lack of
prospective assessment of organ function in treatment trials [56]. Advances
in surgical techniques, radiation techniques, radiation protectants, and
combined-modality therapies are promising, but well-planned and executed
clinical trials are necessary to determine how best to apply these techniques
to patient care.

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Surg Oncol Clin N Am 13 (2004) 201–229

Melanoma of the head and neck: current


concepts in staging, diagnosis, and
management
Maher N. Younes, MD, Jeffrey N. Myers, MD, PhD*
Department of Head and Neck Surgery, University of Texas M.D.
Anderson Cancer Center, Box 441, 1515 Holcombe Boulevard,
Houston, TX 77030-4009, USA

Cutaneous malignant melanoma (CMM) is an aggressive malignant


neoplasm of the melanocytes. CMM is less common than basal cell and
squamous cell carcinoma (SCC), but far more fatal. Therefore, early
detection is paramount and is associated with a high chance of cure. In
contrast, late-stage disease has a dismal chance for cure. Because as many as
one third of CMMs arise from the skin of the head and neck region, it is
critical that head and neck surgeons have a thorough understanding of the
natural history, diagnosis, staging, and treatment of CMM. It is also
important that clinicians are aware of the less common types of melanoma
arising in the head and neck, including mucosal melanoma and desmoplastic
melanoma.

Epidemiology
It is estimated that cutaneous melanoma of the skin comprised 5% and
4% of all new cancer cases in the United States among men and women,
respectively, in 2002 [1]. This statistic makes CMM the fifth and the sixth
most common cancer in the United States among men and women,
respectively [1]. In 2002, it was estimated that 53,600 new cases of CMM and
about 34,300 new cases of melanoma in situ were diagnosed. In the United
States, the lifetime risk for developing CMM is 1.72% (1 in 58) for men and
1.22% (1 in 82) for women. This lifetime risk increases with age (0.13%
at birth, up to 0.97% at 60–79 y for men; 0.19% at birth, up to 0.49% at

* Corresponding author.
E-mail address: jmyers@mdanderson.org (J.N. Myers).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00125-X
202 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

60–79 y for women) [1]. The overall incidence of CMM is increasing at a


disturbing rate of 5% per year. In 1935, the estimated lifetime risk of develop-
ing CMM was 1 in 1500. In 2001, it was estimated that 1 in 75 Americans
developed CMM (Fig. 1) [2].
Primary melanoma of the head and neck accounts for approximately
25% to 35% of all melanomas, although the head and neck region accounts
for a mere 9% of the total body surface area [3]. There are many reasons for
that predilection to the head and neck area, including sun exposure and the
regional variation in the skin distribution of melanocytes, because the
melanocytic content in the head and neck is 2 to 3 times higher than it is
elsewhere in the body [4].
There are different sites in the head and neck region where CMM can be
found. The most common sites in decreasing order are the skin of the cheek
(46%), neck (20%), scalp (18%), external ear (125), nose (2%), and eyelids

Fig. 1. Incidence and mortality rates by gender. (From Ries LAG, Eisner MP, Kosary CL,
Hankey BF, Miller BA, Clegg LX, Edwards BK. The Surveillance, Epidemiology, and End
Results [SEER] Cancer Statistics Review 1973-1997; National Cancer Institute: Bethesda, MD,
2000. NIE pub. no. 00-2789; with permission.)
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 203

(1%) [5]. In addition, the survival rates differ depending on the specific
location of the melanoma in the head and neck, with the skin of the scalp
tumors with the worst rate, followed by those of the temple, ear, cheek, and
neck (Fig. 2) [6].

Mortality
The number of deaths attributed to melanoma was projected to be
approximately 7400 persons in the United States for 2002 [1]. This
represents a 2% annual surge in total mortality since 1960. The explanation
for this increase in mortality is a parallel increase in incidence. Despite of the
increase of melanoma, the 5-year survival rates for all ethnic groups in
the United States for CMM is on the rise: from 80% for 1974 to 1978, to

Fig. 2. Actuarial survival rates by site of primary tumor for patients with melanoma of the head
and neck. (From Ames FC, Sugarbaker EJ, Ballantyne AJ. Analysis of survival and disease
control in stage I melanoma of the head and neck. Am J Surg 1976;132:484–89; with
permission.)
204 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

85% for 1983 to 1995, to 89% for 1992 to 1997 [1]. These rates can be
attributed to an increase in earlier detection of the disease, allowing more
effective treatment in the earliest stages, rather than to a true improvement
in treatment.

Causes and risk factors


Sun exposure
The most important predisposing factor in the development of CMM is
exposure to sunlight. Studies have shown that excessive lifetime exposure to
sunlight, intermittent exposure to sunlight, and a history of sunburns are
risk factors for developing CMM later in life. Whether cumulative exposure
versus early exposure is more important is still a debatable issue. Many
investigators believe that intermittent, acute exposure during childhood and
adolescence is more damaging to the skin [7].
Ultraviolet (UV) B radiation (280–320 nm) has long been believed to be
the most critical factor in the pathogenesis of CMM; however, recent
evidence shows that UV-A (320–400 nm), and even visible light radiation,
may also play a role [8].
Because of the pivotal role of sunlight exposure in the development of
CMM, much interest has been focused on prevention strategies, including
the use of sunscreens. Although there is an expanding body of epidemiologic
evidence for the effectiveness of sunscreens in the prevention of CMM [9],
there is also evidence for their inefficiency. The conclusions drawn from
a European case control study [10] and one animal study [11] suggest that
sunscreens may not be protective. There are several reasons behind this
counterintuitive finding. First, sunscreens help in preventing or, at least
delaying, the development of sunburns, the body’s alarm system against
sunlight overexposure. This in turn induces a ‘‘safe’’ feeling among users,
which results in longer time exposures to sunlight. Second, most sunscreens
are effective against UV-B, not UV-A or the visible light spectrum, both of
which have been implicated in the pathogenesis of CMM.
Despite the conflicting data, there is a consensus that sun protection in its
different forms: sunscreens, protective clothing [12] and hats, and a decrease
in daily exposure to sunlight, particularly between 10 AM and 2 PM, is an
integral part of an overall sun protection regimen [13,14]. These practices
have been tested in Australia, where it has been shown that the incidence of
CMM can be decreased and the melanomas that develop can be diagnosed
earlier by raising public awareness through education [15].

Precursor lesions
Most patients who have head and neck melanoma have a history of a pre-
existing lesion. One report found that one third of melanomas arise from
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 205

congenital nevi, one third arise in nevi present for more than 5 years, and
one third arise in newly acquired nevi (nevi present for \5 y) [16].
Three types of lesions are known to be precursors to CMM. Congenital
nevi are usually present at birth. Patients with large congenital nevi (>20
cm) have a lifetime risk between 5% and 20% for developing CMM [17].
Dysplastic nevi may either occur sporadically or as a part of a familial
syndrome called dysplastic nevus syndrome (DNS). The lifetime risk for
CMM in the sporadic form is unknown, but the lifetime risk of CMM in the
DNS is believed to be close to 100% [18]. Lentigo maligna is considered to
be a preinvasive lesion of lentigo maligna melanoma and frequently occurs
on the head and neck region. The rate of progression of lentigo maligna to
melanoma is between 5% and 33% [18].

Patient characteristics
Certain phenotypic characteristics increase the risk for developing CMM.
These characteristics include blue or green eyes, blonde or red hair, a fair
complexion, a freckling pattern, and an inability to tan [19]. Rigel [20] used
multivariant analysis to identify six independent risk factors for CMM:
family history, freckling of upper back, blonde or red hair, history of 3 or
more years at an outdoor job as a teenager, history of 3 or more blistering
sunburns before the age of 20 years, and presence of actinic keratosis.
Individuals with one or two of these risk factors had a fivefold increased risk
of developing CMM, whereas those with three or more factors has
a twentyfold increased risk [20].

Genetics
Familial melanoma/dysplastic nevus syndrome
Members of familial melanoma and DNS families have a lifetime risk for
developing CMM approaching 100% [21]. Linkage analysis has shown the
involvement of several genes. An early, unconfirmed study that showed a
linkage of familial melanoma to chromosome 1p36 was followed by multiple
studies that demonstrated linkage to chromosome 9p21 [22–25]. Subsequent
investigations showed that the gene of interest at 9p21 was the previously
described p16 gene [26].

Xeroderma pigmentosum
Xeroderma pigmentosum (XP) is a hereditary syndrome that predisposes
individuals to the development of skin cancers. This rare autosomal-recessive
disease increases the risk of skin cancer in individuals with this syndrome by
1000 times more than that of the general public. Clinical features of XP
include early onset of freckling (by age 2 y) and multiple skin cancers,
including SCC, basal cell carcinoma, and melanoma. The onset of skin
cancers often occurs in individuals younger than 10 years who are affected
with this syndrome [27].
206 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

Patients with XP are hypersensitive to the sun, and skin cells in these
patients exhibit decreased survival and increased mutagenesis after UV
radiation because of defects in nucleotide excision repair [28]. The
pathogenesis of skin cancers in XP patients highlights the important role
for UV-induced DNA damage in the development of all three types of skin
cancer.

Pathology
Lentigo maligna melanoma
Lentigo maligna melanoma is the least common subtype of melanoma,
comprising 5% to 10% of all cases. Its main characteristics include
a prolonged radial growth phase, which may last for decades. Therefore,
these tumors are fairly slow to invade. The neoplastic melanocytes remain at
the dermoepidermal junction, and the intraepithelial growth is along hair
follicles and sweat ducts. A differentiating feature of lentigo maligna
melanoma from lentigo maligna lies in the requirement of this melanoma to
invade into the papillary dermis.

Superficial spreading melanoma


Superficial spreading melanoma is the most common subtype, accounting
for 75% of cases. It is marked by an initial radial growth spread that is
eventually followed by a vertical growth, which can be heralded by ulceration
and bleeding. The melanocytic neoplastic cells are uniform, forming
aggregates in all levels of the epidermis. The hallmark feature of this form
of melanoma is that all tumor cells, although atypical, maintain a uniform
appearance throughout the epidermis.

Nodular melanoma
Nodular melanoma accounts for 10% to 15% of all melanoma cases. It is
characterized by a lack of radial growth and early vertical growth. It is
invasive almost from the onset.

Desmoplastic melanoma
This subtype of melanoma is characterized by a dermal population of
spindle cells among a fibrous stroma, a pattern that has been likened to
a ‘‘school of fish.’’ These lesions are often not pigmented. These lesions also
have been found to infiltrate and expand nerves and may show neural-like
differentiation. When this occurs, the term ‘‘neurotropic melanoma’’ is often
used. This affinity for perineural spread is crucial to consider during
evaluation and treatment [29].
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 207

Diagnostic evaluation
History
The key to effective treatment of malignant melanoma lies in early
recognition and diagnosis. Either the patient or a family member detects
approximately 75% of the cases, with the remaining 25% detected by
physicians [30]. The most common presenting signs are color change or
growth of a pre-existing lesion. In addition, other signs may include itching,
bleeding, ulceration, paresthesis, and pain. These signs usually are ominous,
late signs, which occur more often in thick melanomas rather than thin ones.
Physicians need to ask patients about overall sun exposure, family history of
melanoma, and about their history of sunburns.

Physical examination
A comprehensive assessment of the total number and types of moles
present is required. Physicians should look for congenital nevi, dysplastic
nevi, and lentigo malignas. On examination, a bright light and a magnifying
lens are needed to assess the size, color, border, and surface characteristics
(irregularly raised) of moles. Hallmarks of melanoma include the following:
(1) variation in color, (2) irregularly raised surface, (3) an irregular border,
and (4) ulceration. These features are what characterize benign from
malignant lesions.

ABCD checklist
The ABCD checklist is used by clinicians to identify potentially
malignant lesions [31]. The following clinical factors are included:
Assymetry. Assymetric growth patterns are caused by uneven growth
rates.
Border irregularities. Lesions that show border irregularities are likely to
be melanoma.
Color variegation. Differential coloring and shading indicates malignant
potential, especially red, white, and blue [32].
Diameter. Any increase in the size of a lesion, or a diameter greater than
6 mm, is suspicious.
All these factors have been found to predict malignant lesions to a varying
degree, with border irregularity being the strongest predictor [33].

Biopsy
All suspicious lesions should undergo biopsy to confirm the diagnosis of
melanoma and for accurate staging once the diagnosis is established. In
addition, the biopsy method of choice should not interfere with subsequent
208 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

resection and reconstruction efforts if needed later on. Several methods of


biopsy are available to clinicians to choose from.
If the lesion is small and the location is amenable, excisional biopsy with
1- to 2-mm margins is recommended. Patients who underwent excisional
biopsy have had better overall survival rates [34]. Furthermore, excisional
biopsy does not interfere with or affect subsequent staging procedures, such
as lymphoscintigraphy, compared with wide local excision (WLE). WLE
before lymphscintigraphy makes it difficult to accurately access sentinel
lymph nodes (SLNs) and drainage basins [35].
For lesions that are either large or inaccessible to excisional biopsy
without significant disfiguration, incisional biopsy through the thickest part
of the tumor is recommended. Punch biopsies, if they encompass the entire
thickness of the tumor, are sufficient and easy to perform in the office or the
clinic. Needle and shave biopsies of the primary tumor are strongly
discouraged because they do not properly assess the thickness, which is
critically important for further treatment options. Needle biopsies are useful
to assess suspicious lymph nodes or distant metastasis, however.

Staging
Anatomic location of the primary tumor
Numerous studies have shown the prognostic significance of anatomic
site of the primary tumor on survival rates. In an analysis of prognostic
factors in 8500 patients with CMM, Balch et al [36] showed that patients
with head and neck primary tumors are believed to have a worse prognosis
than patients with extremity tumors. Although controversial, several studies
have revealed that patients with tumors arising in the so-called ‘‘BANS’’
region (upper back, upper arm, posterior neck, and scalp) have lower
survival rates than those individuals with tumors arising in non-BANS
regions [37,38].
A review from the M.D. Anderson Cancer Center revealed that
melanoma lesions on the scalp do significantly worse than lesions on the
ear, face, and neck (see Fig. 2) [39]. This finding has been confirmed by other
studies [40,41].

Depth of invasion
During the 1960s, the landmark histologic staging of Clark [42], who
defined the levels of invasion, was set. The depth of invasion became the
most important prognostic factor for stage I and stage II melanoma tumors.
Breslow [43], however, demonstrated the importance of tumor thickness.
Currently, Breslow thickness represents a more powerful prognostic tool
than do Clark’s levels, although both remain widely used in the literature
and in clinical practice (Table 1).
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 209

Table 1
Histopathologic staging systems—Clark’s levels and Breslow thickness
Classification Characteristics
Clark’s levels
I Lesions involving only the epidermis (in situ melanoma); not an
invasive lesion
II Invasion of the papillary dermis but does not reach the papillary-
reticular dermal interface
III Invasion fills and expands the papillary dermis but does not penetrate
the reticular dermis
IV Invasion into the reticular dermis but not into the subcutaneous tissue
V Invasion through the reticular dermis into the subcutaneous tissue
Breslow thickness stage
I 0.75 mm
II 0.76–1.50 mm
III 1.51–4.0 mm
IV 4.0 mm

American Joint Committee on Cancer


First published in 1978, the American Joint Committee on Cancer
(AJCC) staging system of CMM has undergone several changes in an effort
to incorporate current knowledge into each version. It is based on the
tumor-node-metastasis (TNM) classification and incorporates the Breslow
system into the primary tumor stages.
In 2002, the AJCC published a new staging system for CMM (Box 1) [44].
This new melanoma staging system includes five major changes from the
1997 version as follows [45]:
1. Level of invasion (Clark’s level) is replaced by tumor thickness, with
cutoff levels of 1 mm, 2 mm, and 4 mm, as the prognostic variable of
primary tumor invasion that best predicts survival.
2. Ulceration of the primary tumor is included in this system, and patients
with ulceration in each T-stage subgroup are upstaged accordingly.
3. The number of lymph nodes involved in staging replaces the size of
lymph nodes.
4. Patients are categorized into clinical and pathologic staging to
incorporate lymphatic mapping data and micrometastatic disease.
5. Subcategorization of stage IV metastatic disease is based on anatomic site
and inclusion of an elevated serum lactate dehydrogenase (LDH) [46,47].
6. Distinct definitions for clinical and pathologic staging incorporate the
new staging information gained from intraoperative lymphatic mapping
and SLN biopsy [48].
Staging: clinical versus pathologic
In the past, the TNM classification system of melanoma had been
broadly based on a clinical staging system that recognized three general
categories: (1) localized melanoma (stages I and II), (2) regional disease
210 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

Box 1. Revised AJCC TNM classification


T classification
T1: 1.0 mm or less
(a) without ulceration
(b) with ulceration or level IV or V
T2: 1.01 to 2.0 mm
(a) without ulceration
(b) with ulceration
T3: 2.01 to 4.0 mm
(a) without ulceration
(b) with ulceration
T4: greater than 4.0 mm
(a) without ulceration
(b) with ulceration
N classification
N1: one lymph node
(a) micrometastasisa
(b) macrometastasisb
N2: two to three lymph nodes
(a) micrometastasis
(b) macrometastasis
(c) in-transit metastasis/satellites without metastatic lymph
nodes
N3: four or more lymph nodes, matted lymph nodes, or
combinations of in-transit metastasis/satellites and
metastatic lymph nodes
M classification
M1: distant skin, subcutaneous, or lymph node metastasis;
normal LDH levels
M2: lung metastasis, normal LDH levels
M3: all other visceral or any distant metastasis, elevated LDH
levels
a
Micrometastases are diagnosed after sentinel or elective lymphadenectomy.
b
Macrometastases are defined as clinically detectable lymph node metastases
confirmed by therapeutic lymphadenectomy or when any lymph node
metastasis exhibits gross extracapsular extension.
From Balch CM, Buzaid AC, Atkins MB, Cascinelli N, Coit DG, Fleming ID,
Houghton A Jr, et al. A new American Joint Committee on cancer staging system
for cutaneous melanoma. Cancer 2000;88(6):1484–91; with permission.
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 211

(stage III), and (3) distant disease (stage IV) [49]. Because of major advances
in the diagnosis and staging of CMM brought about primarily by the
development of SLN mapping and/or biopsy for the identification of
micrometastases, however, the new AJCC staging system incorporates
clinical and pathologic staging (Table 2).
The AJCC melanoma staging committee recommends that, when
possible, nodal staging should be performed and that, for clinical trials,
nodal staging is particularly important. Early-stage (I and II) localized
melanoma is a primary tumor without evidence of lymph node metastasis.
Ulceration of the primary tumor up-stages each T stage [50]. A new staging
category of IIC was designed for ulcerated T4 lesions. The IIC patients have
an equivalent prognosis as those with multiple metastatic lymph nodes [51].
The hallmark of stage III is the involvement of regional lymph nodes. The
presence of micrometastasis in the lymph nodes using SLN biopsy is
differentiated by the pathologic staging [52]. Patients with multiple lymph
node metastases and ulcerated primary tumors do worse are categorized as
having stage IIIC disease. Similarly, satellite or intransient metastases have
a poor prognosis and are up-staged to IIIB. Stage IV is defined by distant
metastasis and remains the same in the new system.

Pretreatment evaluation by stage


Although there are general stage-specific guidelines, each patient’s
evaluation and treatment should be individualized. The general guidelines
followed at the M.D. Anderson Cancer Center are summarized in Table 3
and are available at www.mdanderson.org. Similar guidelines are available
from the National Comprehensive Cancer Network at www.nccn.org and
the National Cancer Institute at www.nci.nih.gov.
In situ and/or Clark’s level I lesions are effectively treated with WLE and
require no further workup. In asymptomatic patients with primary
melanoma (stage I or II), a chest radiograph and an evaluation of LDH
levels is recommended [50]. For patients with lesions of intermediate
thickness (1–4 mm) and thin lesions that are either ulcerated or extend into
Clark’s level IV, preoperative lymphoscintigraphy is warranted, especially if
elective lymph node dissection may be part of the treatment plan. For patients
with thick lesions (>4 mm) or those who have regional metastatic or
recurrent locoregional disease, a more comprehensive workup is recom-
mended. For this patient population, there is a high risk for distant
metastasis, and therefore consideration should be given to a metastatic
workup (complete blood count; liver function tests, including alkaline
phosphatase and LDH levels; a CT of the chest, abdomen, and pelvis; and
MRI of the brain). All patients with clinically evident regional disease (stage
III) must undergo imaging of the cervical lymphatics and metastatic screening
(CT or ultrasound of the head and neck, chest radiograph, and LDH). For
patients with signs or symptoms of metastatic disease, selective metastatic
212 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

Table 2
New stage groupings for cutaneous melanoma
Clinical staginga Pathologic stagingb
Stage T N M T N M
0 Tis N0 M0 Tis N0 M0
1A T1a N0 M0 T1a N0 M0
1B T1b N0 M0 T1b N0 M0
T2a N0 M0 T2a N0 M0
IIA T2b N0 M0 T2b N0 M0
T3a N0 M0 T3a N0 M0
IIB T3b N0 M0 T3b N0 M0
T4a N0 M0 T4a N0 M0
IIC T4b N0 M0 T4b N0 M0
IIIc Any T N1 M0 — — —
— N2 — — — —
— N3 — — — —
IIIA — — — T1–4a N1a M0
— — — T1–4a N2a M0
IIIB — — — T1–4b N1a M0
— — — T1–4b N2a M0
— — — T1–4a N1b M0
— — — T1–4a N2b M0
— — — T1–4a/b N2c M0
IIIC — — — T1–4b N1b M0
— — — T1–4b N2b M0
— — — Any T N3 M0
IV Any T Any N Any M1 Any T Any N Any M1
a
Clinical staging includes microstaging of the primary melanoma and clinical/radiologic
evaluation for metastases. By convection, it should be used after complete excision of the
primary melanoma with clinical assessment for regional and distant metastases.
b
Pathologic staging includes microstaging of the primary melanoma and pathologic
information about the regional lymph nodes after partial or complete lymphadenopathy, except
for pathologic stage 0 or stage 1A patients, who do not need pathologic evaluation of their
lymph nodes.
c
There are no stage III subgroups for clinical staging.
Data from Balch CM, Buzaid AC, Atkins MB, Cascinelli N, Coit DG, Fleming ID,
Houghton A, Jr, et al. A new American Joint Committee on Cancer staging system for
cutaneous melanoma. Cancer 2000;88(6):1484–91.

imaging should be performed. Finally, patients with known systemic disease


(stage IV) should be more comprehensively evaluated. Accordingly, they
require a full metastatic workup, including the following: chest radiograph;
LDH levels; CT or ultrasound of the head and neck; CT of the chest,
abdomen, and pelvis; and MRI of the brain. Other studies (eg, gastrointes-
tinal series, bone scan) are performed according to symptoms [53].
Newer modalities, including positron emission tomography (PET), and
their role in the detection of melanoma of the head and neck are currently
being investigated. PET is one of the new modalities that has shown promise
in detecting regional and metastatic lesions; however, its role in the evaluation
and follow-up of patients with CMM awaits further studies [54–56].
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 213

Table 3
Recommendations for workup based on stage
Stage Workup
Melanoma in situ None
Stage I or II CXR, LDH
Stage I or II with ulceration or T3 CXR, LDH; consider lymphoscintigraphy
T4 or recurrent primary melanoma CXR, LDH
Consider metastatic imaging (CT of chest, abdomen,
pelvis, MRI of brain)
Stage III CXR, LDH (CT or US of the neck for regional
lymphatics); consider metastatic imaging for patients
with signs and symptoms of metastatic disease
Stage IV CXR, LDH, metastatic imaging (CT or US of
the head and neck, CT of abdomen, pelvis, chest,
MRI of brain)
Abbreviations: CXR, chest X ray; US, ultrasound.
Data from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original
and primary source for this information is the AJCC Cancer Staging Manual, 6th edition (2002)
published by Springer-Verlag New York (For more information, visit www.cancerstaging.net).
Any citation or quotation of this material must be credited to the AJCC as its primary source.
The inclusion of this information herein does not authorize any reuse or further distribution
without the expressed written permission of Springer Verlag New York, Inc., on behalf of the
AJCC.

Management
General treatment options
Surgery
Surgery is well accepted as the primary treatment modality for CMM.
Complete surgical excision is recommended in most patients who have local
or regional disease in the absence of systemic disease. Recent studies have
indicated that a 2-cm margin around the primary tumor for intermediate-
thickness melanoma is sufficient [57]. For thinner lesions, 1-cm margins
provide equivalent local control and survival [58]. A crucial reminder is that
these recommendations are derived from studies of truncal and extremity
melanoma and that, in the head and neck, the surgeon may not have the
luxury of being able to take 1- to 2-cm margins without running the risk of
significant functional disability or cosmetic deformity.
A sound knowledge of the anatomy of the pathways of lymphatic spread
for CMM of the head and neck is essential. It is generally accepted that
clinically positive neck disease requires surgical treatment. In these patients,
it is important to address all the intervening lymphatics between the primary
tumor and the positive node or nodes. The type of neck dissection must be
tailored to the disease.
The treatment for clinically N0 neck disease is less definite. Patients with
stage I disease have a low rate of occult metastasis and thus may not need
surgical treatment of the neck. In contrast, a substantial number of patients
214 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

with stage II disease harbor an occult regional metastasis and need to be


considered for elective treatment. To date, there are no prospective data to
support the use of any elective neck dissection for N0 neck disease to
improve either locoregional control or overall survival.
The most commonly used elective treatment is elective neck dissection
(END). If END is undertaken, it should be guided by a comprehensive
knowledge of the pathways of lymphatic spread (Fig. 3). In general, tumors
arising on the scalp and the forehead anterior to a line drawn through the
external auditory canal most commonly spread to the parotid/periparotid
lymph nodes and upper jugular lymph nodes; thus, a parotidectomy and
lateral neck dissection are recommended. Tumors arising on the scalp and
occiput posterior to a line drawn through the external auditory canal most
commonly spread to postauricular, suboccipital, and posterior triangle
lymph nodes; therefore, a posterolateral neck dissection is recommended
[59]. Tumors located anteriorly on the face and neck tend to spread to the
facial, submental, submandibular, and deep cervical nodes; consequently,
a supraomohyoid neck dissection is advocated.
A newer option for elective treatment of the neck is sentinel lymph node
biopsy (SLNB). The rationale behind SLNB is as follows. There exists
a limited set of regional lymph nodes as a first stop along the route of

Fig. 3. Predicted patterns of lymphatic drainage from primary sites in the head and neck.
Location of nodes: A, submental; B, submandibular; C, preauricular; D, jugular chain; E,
occipital; F, posterior cervical; G, retroauricular; H, jugulodigastric; and I, supraclavicular.
(From Byers RM. Cervical and parotid node dissection. In: Balch CM, Houghton AN, Milton
GW, et al, editors. Cutaneous melanoma. 2nd edition. Philadelphia: JB Lippincott; 1992. p. 377;
with permission.)
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 215

lymphatic drainage. Using dyes, radiographic contrasts agents, or radioactive


tracers, these ‘‘sentinel’’ lymph nodes can be localized and surgically removed.
Based on the result, a decision can be made as to whether to perform a more
extensive lymphadenectomy or provide systemic adjuvant therapy.
SLNB has proved to be a well-accepted method in the treatment of
truncal and extremity melanoma. It provides accurate staging and impor-
tant prognostic information [60]. In a multi-institutional study, Gershen-
wald et al [61] showed the status of SLNs was the strongest predictor of
disease-free survival in patients who have stage I and II disease (Fig. 4). The
same group of investigators also has shown that among the benefits of
this method is that it allows the pathologist to focus on fewer lymph
nodes than found in an END, which allows for a more comprehensive

Fig. 4. Disease-free survival and disease-specific survival according to sentinel lymph node
status. Kaplan-Meier survival for patients undergoing sentinel lymph node biopsy. (A) Disease-
free survival. (B) Disease-specific survival. (From Gershenwald JD, Thompson W, Mansfield
PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;17:976–83;
with permission.)
216 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

search for metastasis by applying molecular methods to increase the


sensitivity of detection [62,63].
Despite its promise in truncal and extremity melanoma, the role of SLNB
in the management of CMM of the head and neck has yet to be defined. This
situation is attributed to many factors: (1) the complexity of the lymphatic
drainage patterns in the head and neck; and (2) the frequent need for the
removal of the SLN from the parotid gland, thus placing the facial nerve at
risk of injury. Currently, the data from head and neck studies concerning
SLNB are conflicting. Most studies have reported that SLNs can be
identified in almost 95% of cases and that false-negative results are low
[63,64]. Also, CMMs of the head and neck were found to metastasize to
clinically predicted nodal groups in 92% of patients, and that postauricular
and contralateral metastatic node involvement was uncommon [65]. Other
studies, however, have shown disturbingly high rates of regional recurrence
in patients with negative SLNB results [66]. Moreover, there seems to be
a steep learning curve associated with the technique and potential risks to
the facial nerve and other cranial nerves during the biopsy procedure.
To properly assess the accuracy and applicability of the SLNB in the
management of CMM of the head and neck, investigators at M.D.
Anderson Cancer Center designed a prospective trial of intraoperative
lymphatic mapping and SLN identification in 43 patients who had head and
neck CMM. This trial showed that intraoperative lymphatic mapping
accurately depicts the SLN and that false-negative results were 0% (no
patient who had a negative SLN had a positive nonsentinel lymph node [67].
The multiplicity of the nodes, their widespread distribution (42% with
noncontiguous nodal basins), and their frequent location within the parotid
gland (44%), however, may preclude SLNB in many patients. Thus, the
recommendations from that study are that selective lymphadenectomy of
the SLN basins allows histologic staging of the regional lymphatics with
limited morbidity. More studies are warranted to establish the role of SLNB
in the management of head and neck CMM [67].

Radiotherapy
In the past, melanoma was believed to be a radioresistant tumor. The
past 20 years, however, have shown that different dosimetric and
fractionation schemes are needed for CMM treatment than those used to
treat other tumors. For example, significant improvements in locoregional
control have been noted with the use of adjuvant radiotherapy [68].
At M.D. Anderson Cancer Center, data reveal the possibility of attaining
a locoregional control rate of 88% in patients with stages II and III disease
when postoperative radiotherapy is used at a dose of 30 Gy given in 5
fractions [69]. In this trial, three groups of patients were investigated: (1)
those who underwent excision of stage III primary tumors, (2) those with
palpable lymphadenopathy who underwent WLE and neck dissection, and
(3) those with nodal relapse who underwent neck dissection. The locore-
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 217

gional control rates in all three groups were higher than in historical control
subjects. Moreover, the overall survival rate in patients with stage II disease
was higher than in historical control subjects (Fig. 5) [69].
In a more recent study, a retrospective analysis of 338 patients with lymph
node involvement who underwent complete lymph node dissection (LND) of
the nodal basin, which had pathologically involved lymph nodes, was
performed. The study showed that patients who have malignant melanoma
with nodal involvement have significant risk of nodal basin failure after LND
if they have cervical involvement, extracapsular extension, more than three
positive lymph nodes, clinically involved nodes, or any node that is larger
than 3 cm. Overall and disease-specific survival rates for all patients at 10
years was 30% and 36%, respectively. The rate of cervical nodal basin
recurrence at 10 years was 43%. This study concluded that patients with such
risk factors should be considered for adjuvant radiotherapy to the lymph
node basins to reduce the incidence of recurrence [70].
The M.D. Anderson Cancer Center recommends postoperative radio-
therapy for all patients with stage II lesions in which regional lymph nodes
are not treated surgically and in patients with pathologically proven nodal
disease or nodal recurrence, after nodal dissection has been performed.
Clinicians should bear in mind, however, that dosimetry is harmful to
nervous tissues and cannot be used for lesions near the eyes or central
nervous system.

Chemotherapy
Traditionally, chemotherapy served two main purposes: (1) as a palliative
therapy for patients with stage IV disease and (2) as an adjuvant therapy in
high-risk patients. The use of chemotherapy as an adjuvant therapy for
CMM still needs to be substantiated by prospective randomized trials.
Three major randomized trials have been performed using adjuvant
chemotherapy postoperatively [71–73]. In two of these studies, there was
no difference in disease-free interval or overall survival rates with
chemotherapy [71,72], and in the third study, worse overall survival rates
were found with chemotherapy [73]. Currently, the single most effective
chemotherapeutic agent approved for the treatment of advanced melanoma
is decarbazine. Response rates to decarbazine alone are 10% to 20%,
however. Using combination chemotherapy leads to a small, insignificant
improvement in response rates.

Immunotherapy
Because melanoma is the most immunogenic type of solid tumor, it serves
as a primary model for immunotherapy, both in animal models and in the
clinic. The approaches used to boost the body’s immune system include the
following: (1) biologic response modifiers (interleukins and interferons),
(2) immunostimulants, and (3) vaccines. All three approaches, though
promising, remain investigational. As in chemotherapy, the use of
218
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229
Fig. 5. Locoregional control and survival rates of patients treated with elective or adjuvant radiotherapy. (A) All patients. (B) Group 1, treated with elective
irradiation. (C) Group 2, treated with adjuvant irradiation after WLE plus neck dissection. (D) Group 3, treated with irradiation after nodal recurrence. (From
Ang KK, Peters LH, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys
1994;30:296–8; with permission.)
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 219

immunotherapy has been primarily in the form of adjuvant therapy for


high-risk patients or for patients with metastasis or recurrent disease.
Biologic response modifiers have been extensively studied; interferon a2b
(IFN-a2b) is the most promising of these agents [74]. The Eastern
Cooperative Oncology Group (ECOG) trial E1684 is a prospective
randomized trial that revealed significant improvements in relapse-free
and overall survival rates in patients who had node-positive disease treated
with high-dose IFN-a2b as a postoperative adjuvant drug [74]. A more
recent ECOG trial (number 1690) aimed at verifying these results and
assessing the efficacy of low-dose IFN-a2b [75]. This study confirmed the
improvement in the relapse-free survival rate in patients given the high-dose
INF-a2b; however, the difference was not as significant as was found in the
ECOG 1690 trial. Moreover, low-dose IFN-a2b showed no efficacy. The
lack of difference in the overall survival rate, however, was because of
a significant increase in the survival rate in the trial’s observation group:
patients in this group who had experienced a relapse had been given INF-
a2b as salvage therapy. Thus, the effect of adjuvant INF-a2b therapy on
overall survival rate awaits further investigation.
Other immunostimulants include Calmette-Guérin bacillus [76], Co-
rynebacterium parvum [77], and levamisole [78], although their use has
yielded either negative or conflicting data. These agents do not yet play a role
in the treatment of melanoma [79].
Melanoma vaccines seem to be promising. Furthermore, many advances
in melanoma vaccination have been made during the past 15 years.
Consequently, many clinical trials of melanoma vaccines are now underway
and include carbohydrate-based vaccines, antibody-based vaccines, DNA
vaccines, dendritic cell–based vaccines, peptide vaccines, and heat-shock
protein vaccines [80]. Several phase 2 trials have shown feasibility and
suggested efficacy; however, no phase 3 trial has yet established any im-
provements in disease-free survival or overall survival rates in vaccinated
patients [80,81].

Biochemotherapy
Biochemotherapy is the combination of two modalities of treatment:
immunotherapy and chemotherapy. This form of therapy attempts to
achieve responses higher than those achieved when either treatment is used
alone. At the M.D. Anderson Cancer Center, trials have usually combined
cisplatin, vinblastine, and decarbazine with interleuken 2 and IFN-a2b
[82]. The few prospective randomized trials showed similar survival rates,
higher response rates, and increased toxicity as compared with immuno-
therapy and chemotherapy alone [83–85]. Several large-scale trials
are currently underway to further evaluate the potential role of biochemo-
therapy, both as a postoperative adjuvant treatment and for treatment of
systemic disease.
220 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

Treatment by stage
Three different aspects need to be addressed in the management of CMM
of the head and neck: the primary tumor, the regional lymphatics, and
distant metastasis. Although an acceptably high rate of locoregional control
has been established, many patients who have stage II disease and higher
eventually die of distant disease. The recommendations for treatment on the
basis of stage are presented in Table 4.

Melanoma in situ
For patients with melanoma in situ, the treatment of choice is surgical
excision with conservative margins (0.5–1cm) because the risk of metastasis
is essentially zero. No regional or metastatic workup is required.

Stage I
The recommended treatment in patients with stage I melanoma is WLE
[6]. Margins of 1 cm are generally acceptable. The defect can be closed
primarily or reconstructed using local flaps or skin grafts. Delayed
reconstruction is often advisable, given the limitations of frozen section
analysis of margins for pigmented lesions. As in melanoma in situ, no
regional or metastasis workup is needed because of the low risk of
metastasis in this group.

Table 4
Recommendations for treatment based on stage
Stage Treatment
I Primary tumor: WLE
II Primary tumor: WLE
Regional lymphatics: observation vs, END vs SLNB vs ENI
III Primary tumor: WLE
Regional lymphatics: neck dissection +/ÿ parotidectomy
Consider postoperative radiotherapy
IV Primary tumor: WLE
Regional lymphatics: neck dissection +/ÿ parotidectomy if node-positive
Metastasis site–directed surgery or radiotherapy
Consider systemic adjuvant therapy trials
Supportive care
Abbreviations: END, elective neck dissection; SLNB, sentinel lymph node biopsy; WLE,
wide local excision.
Data from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original
and primary source for this information is the AJCC Cancer Staging Manual, 6th edition (2002)
published by Springer-Verlag New York (For more information, visit www.cancerstaging.net).
Any citation or quotation of this material must be credited to the AJCC as its primary source.
The inclusion of this information herein does not authorize any reuse or further distribution
without the expressed written permission of Springer Verlag New York, Inc., on behalf of the
AJCC.
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 221

Stage II
The adopted treatment in patients with stage II melanoma is WLE. If
possible, 2-cm margins are taken. If 1-cm or smaller margins are obtained,
adjuvant radiotherapy should be contemplated. As in stage I lesions, the
defect can be closed either primarily or reconstructed using local flaps or skin
grafts.
Given the substantial percentage of patients with stage II disease
harboring occult regional metastasis, elective neck treatment is often
considered. There are, however, no prospective trials to support the use of
any type of elective neck treatment for improving the locoregional control
and the overall survival rates. Once elective neck treatment is decided on,
there are several options to choose from.
END is the most widely adopted treatment option. The nodes of interest
are those considered to be at risk. A major advantage to END is the
prognostic information it provides. If occult metastasis is present, then
patients can be up-staged and are eligible for adjuvant systemic treatment
(immunotherapy, chemotherapy, or biochemotherapy).
Elective neck irradiation constitutes the second option. Locoregional
control rate is achieved in 85% of stage III patients who were given
irradiation to the primary site after WLE [68].
Finally, SLNB is still under investigation as a possible modality for the
evaluation of patients who have stage II melanoma.

Stage III
The recommendations for stage III disease include treating the primary
tumor by WLE and obtaining, if possible, a 2-cm margin. In addition, to
attain locoregional control, regional disease can be addressed by neck
dissection. If the disease allows, a selective or modified radical neck
dissection is advised rather than a classic radical neck dissection. In
addition, postoperative radiotherapy seems to increase locoregional control.
Unlike with stage I and stage II disease, systemic therapy, in the form of
chemotherapy, immunotherapy, or biochemotherapy, should be contem-
plated in patients with stage III disease because of the high risk for distant
metastasis.

Stage IV
Despite the dismal prognosis in this subgroup of patients, locoregional
control remains an important consideration because of the devastating
effects of uncontrolled locoregional disease. The overall treatment approach
in the treatment of stage IV metastatic melanoma is best determined by
a multidisciplinary team, including a surgeon, radiation oncologist, and
medical oncologist, and is often best performed in the context of
a prospective clinical trial. Palliative and supportive care is also an
important issue to address in these patients.
222 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

Recurrent disease
Recurrent disease is usually associated with a poor prognosis. The
recurrence can be locoregional or distant. For locoregional recurrence, re-
excision [86], if possible, and adjuvant radiotherapy (if it has not been
administered before) are indicated. If surgery is not an option, radiotherapy
and systemic therapy are secondary options, but they can only be palliative
at this stage. Distant metastases that are surgically resectable should
be aggressively treated because, in rare instances, a cure or long-term
progression-free interval can be achieved. Sometimes, however, isolated
distant metastases are kept in place to initially ‘‘monitor’’ the response to
systemic treatment, and then depending on the result, excised later on. The
prognosis for pulmonary metastasis is better than brain and liver metastasis,
which carries with it a dismal expected survival time of 2 to 4 months [87].
Even in the context of recurrent disease, every effort should be made to
achieve locoregional control, if only to improve the patients’ quality of life.

Follow-up
Because CMM is a disease of young people (average age, 45 y), both the
clinical and financial aspects of the patient’s follow-up are important and
need to be addressed. Weiss et al [88] reported that intensive follow-up in the
post-treatment phase (5 y) costs around $421,000 for laboratory tests alone
[88]. Thus, the need arises to establish equilibrium between what can be
called an ‘‘adequate’’ surveillance and fiscal responsibility. An estimated
28% to 56% of recurrences are usually detected by physicians [89,90].
Therefore, physical examination when supplemented with periodic labora-
tory testing and radiologic assessment is a good basis for follow-up. At the
M.D. Anderson Cancer Center, the follow-up depends on the stage of the
disease at diagnosis (Table 5).

Special issues in melanoma


Mucosal melanoma
Mucosal melanoma of the head and neck is rare (1%–2% of melanomas).
In the head and neck, the most common sites of occurrence include the nose,
paranasal sinuses, oral cavity, and nasopharynx. If located in the sinonasal
cavity, mucosal melanoma typically presents with symptoms of nasal
obstruction, epistaxis, pain, visual disturbances, or facial deformity. Patients
who have mucosal melanomas of the oral cavity most often present with
asymptomatic masses; however, symptoms of dysphagia are not un-
common. Because most of these symptoms are indolent and nonspecific,
there is often a delay in presentation and a worse prognosis.
Mucosal melanoma tumors may lack melanin, making the diagnosis
difficult from the histopathologic standpoint. The 5-year disease-specific
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 223

Table 5
Recommendations for follow-up based on stage
Stage Physical examination Radiology Labs
Melanoma in situ Every 6 mo4 y, then annually None None
Stage 1 or II (no ulceration, Every 6 mo4 y, then annually CXR LDH
thickness \1.0 mm)
Stage I or II (with ulceration Every 6 mo2 y, then every CXR LDH
or thickness >1.0 mm) 6 mo2 y, then annually
Stage III or recurrent primary Every 3 mo2 y, then every CXR LDH, CBC
melanoma 6 mo3 y, then annually
Stage IV Individualize Individualize Individualize
Abbreviations: CBC, complete blood count; CXR, chest X-ray.
Data from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original
and primary source for this information is the AJCC Cancer Staging Manual, 6th edition (2002)
published by Springer-Verlag New York (For more information, visit www.cancerstaging.net).
Any citation or quotation of this material must be credited to the AJCC as its primary source.
The inclusion of this information herein does not authorize any reuse or further distribution
without the expressed written permission of Springer Verlag New York, Inc., on behalf of the
AJCC.

survival rates depend on the anatomic site of the primary lesion [91] and are
40% for oral lesions and 47% for sinonasal lesions [93]. In addition, most of
the staging criteria for CMM, including depth of invasion and regional
lymphadenopathy, fail to impact or affect the prognosis in mucosal
melanoma. The only significant and independent predictors of the
development of distant failure and death in patients who have mucosal
melanoma of the head and neck are as follows: the clinical stage at
presentation, whether the tumor thickness is greater than 5 mm, whether
there is vascular invasion on histologic studies, and the development of
distant failure [92,93].
As a group, mucosal melanomas of the head and neck are highly
aggressive and rapidly fatal [91]. Radical surgery with aggressive resection of
the primary tumor is the primary treatment used to achieve locoregional
control [93]. Adjuvant radiotherapy does improve locoregional control;
however, it probably does not affect overall survival rates because of the
high rates of distant metastasis at the time of initial presentation [94].
Overall 5-year survival rates are usually between 15% and 20%, although
rates as high as 40% have been reported [92,95].

Desmoplastic melanoma
Desmoplastic melanoma (DM) was first described by Conley et al [29], in
1971, as a rare variant of spindle cell melanoma. These lesions are often
nonpigmented and may appear only slightly abnormal or harmless when
actually an aggressive malignant lesion is present. The seemingly benign
appearance of this tumor can be misleading to patients and physicians alike,
causing a delay in proper therapy. Previous studies have noted that DM was
224 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

more commonly diagnosed in elderly men [91,96] and more frequently


reported in the head and neck region [97,98]. At presentation, the lesions are
usually thicker (median tumor thickness, 2.5 mm; Clark’s level IV or V)
[103] than other forms of melanoma; however, the thickness of DM lesions
is not as useful a predictor of prognosis as it is in other forms of melanomas.
This subtype of melanoma is characterized by its neurotropism. This trait is
of critical importance in the head and neck because even small DM lesions
can spread to cranial nerves, causing palsies and leading to intracranial
spread. The particularly high rate of local recurrence with these tumors has
been attributed to this propensity for perineural spread [99], which is
a strong adverse factor for prognosis [100,101]. WLE with a 2-cm margin, if
possible [96], and a meticulous analysis of the specimen for evidence of
perineural spread are important. Adjuvant radiotherapy is also recom-
mended for patients with this pathologic finding. Finally, the rate of
regional lymph node metastasis in DM (15.4%) is lower than for other
forms of CMM [101], regardless of tumor thickness. The overall survival
rates, however, tend to be similar to other forms of CMM [102].

Metastatic melanoma of unknown origin


In rare cases, melanoma is discovered in the cervical and parotid lymph
nodes without evidence of a primary tumor. The hypothesis is that, in most
cases, these metastases result from primary melanomas that have regressed
spontaneously. Clinicians must first rule out mucosal or ocular melanoma,
however. The treatment of choice is appropriate lymphadenectomy and
postoperative radiotherapy. These patients also need to be considered for
clinical trials of adjuvant systemic therapy. The prognosis for this group of
patients is similar to that for other patients who have stage III disease [104].

Summary
Major advances in the understanding of the causes and risk factors for
melanoma and for the prevention and management of this tumor have taken
place since the beginning of the past century, when the diagnosis of
melanoma was synonymous with death. As many as 80% of early
melanomas can be cured, and a high rate of locoregional control for even
far-advanced melanoma is plausible. The major challenge for the years to
come lies in curtailing the steady rise in the incidence of melanoma by
increasing patient education and adopting measures to prevent the
increasing mortality rates associated with this disease. Cure rates can be
improved by early diagnosis by physicians and instant referral to ex-
perienced oncologists. Finally, new advances in diagnostic and treatment
strategies carry the hope for further improvements in locoregional control
and survival rates.
M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229 225

Acknowledgments
The authors thank Bradley A. Schiff, MD, for his review and critique and
Ms. Yolanda Luna for her administrative assistance.

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Surg Oncol Clin N Am 13 (2004) 231–239

The integration of neurosurgical


techniques in current head and neck
skull base surgery
Kevin J. Gibbons, MD*, Amos O. Dare, MD
Department of Neurological Surgery, School of Medicine and Biomedical Sciences,
State University of New York–Buffalo, 3 Gates Circle, Buffalo, NY 14209, USA

Skull base surgery requires integrating surgeons of differing specialties,


and appropriate techniques specific to each specialty, to complete a
technically difficult surgery without complication. Neurosurgical techniques
have evolved over the past 60 years, from a point in time when any cranial
surgery involved great uncertainty and risk, to surgery in the modern era in
which complex operations are routinely performed to treat lesions that were,
until recently, considered inoperable.
This article initially focuses on the avoidance and management of
cerebrospinal fluid (CSF) leak and wound reconstruction. These problems
greatly limited early efforts in cranial base surgery, with complication rates
approaching 40% to 50% in some early series, and remain pertinent for
skull base surgeons today.
Malignant disease involving the internal carotid artery (ICA) limits the
resectability of disease; even if the ICA is not invaded directly, proximity by
preoperative imaging or by direct operative inspection prevents adequate
oncologic margins. A significant number of patients, particularly those who
have recurrent, advanced head and neck malignancies, are not considered
candidates for resection because of concerns about stroke or residual
disease. This article reviews current protocols for assessment and man-
agement of these patients.
The major advance in cranial base surgery, and neurosurgery in general,
is the integration of imaging into the operative suite for surgical planning,
localization, and real-time image acquisition. This apparent revolution in
technique application is actually more of an evolving step, albeit a large one,

* Corresponding author.
E-mail address: kgibbons@Buffns.com (K.J. Gibbons).

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00116-9
232 K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239

in the neurosurgical challenge of localization. Most patients who have skull


base malignancies now undergo multimodality multiplanar preoperative
imaging to aid in surgical planning. Select cases undergo intraoperative
localization, with a combination of preoperative images and intraopera-
tive localization with computer-assisted navigation (frameless stereotaxy).
In many centers, intraoperative imaging is available, with real-time data
acquisition, using MRI obtained in the operative theater and updated as
needed to demonstrate location and extent of residual disease.

Cerebrospinal fluid leaks


In most patients, skull base surgeons link the intracranial subdural space
with the nasapharyngeal compartment. CSF leaks seemed to be a near-
insurmountable problem early in the development of the specialty, however.
These leaks resulted in, or may have presaged, serious wound complications,
such as dehiscence and infection. The development of CSF diversion,
multilayered closures, and fibrin sealant has resulted in significant im-
provement in avoiding this problem.

Cerebrospinal fluid diversion


The first step in prevention and treatment of fistula formation is
elimination of any pressure gradient between compartments. In skull base
surgery, this step generally involves temporary lumbar CSF diversion. In
cases of persistent hydrocephalus, permanent diversion may be required, but
this is generally delayed until any question of perioperative contamination
or postoperative infection has been resolved.
A series describing the role of lumbar CSF diversion was reported by
Shapiro and Scully [1] in 1992. The authors reported a 94% success rate,
with a 5% infection rate and a 3% rate of temporary decline from
overdrainage. Lumbar root irritation, again only temporary in this series,
was reported in 14% of patients. Subgroups included 25 patients with
documented postcraniotomy fistulae, with an 87% success rate, and 38
patients who experienced successful augmentation of ‘‘tenuous dural
closure.’’. Similar results were subsequently reported by McCutcheon et al
[2] in 1996, with a 4% rate of transient CSF leak, an overall 7% rate of
pneumocephalus, and a 4% incidence of symptomatic pneumocephalus
requiring intervention. All patients were treated with primary dural closure
or cadaveric dural reconstruction, pericranial flap base reconstruction, and
4 days of lumbar drainage.
The role, risk, and benefit of postoperative CSF diversion remains
controversial, however. Complications of overdrainage include pneumo-
cephalus, acute foramen magnum syndrome, and uncal and other herniation
syndromes. A report by Dagnew et al [3] described three cases of acute
foramen magnum syndrome with arrest and quadriplegia secondary to
K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239 233

lumbar drainage. The authors also reviewed the syndrome and its
management, the theory of cranial spinal pressure gradients, and the
practical details of successful lumbar drainage (eg, minimal duration;
volume drainage targets; and careful frequent nursing care, ideally in an
ICU setting).. An important practical point is the need to clamp the catheter
at the first sign of neurologic decompensation, as opposed to removing the
catheter, which could result in uncontrolled drainage into the soft tissues of
the back and further herniation.
Another study reported two patients with coma associated with
overdrainage from a lumbar catheter, with the recommendation to attempt
cranial catheter placement, either subarachnoid or intraventricular, to avoid
the pressure gradient across the foramen magnum when possible [4]. Uncal
or transtentorial herniation syndromes occur in the setting of temporal lobe
edema or hemorrhage and lumbar drainage, with potentially devastating
results. Ventriculostomy placement is not without risk, however. Risks
include intraparenchymal hemorrhage and, in particular, serious central
nervous system (CNS) infection, which is uncommon with lumbar drains. A
recent review of ventriculostomy-related infection and specific risk factors
was published by Lozier et al [5].
The decision to place a lumbar drain is usually made before surgery, in
cases where significant dural reconstruction is likely to be required. The
placement of a catheter into the subarachnoid space before craniotomy,
after induction of general anesthesia, is advantageous for the following
reasons:
1. The lumbar subarachnoid space is easily and safely entered before
drainage of large amounts of CSF at the primary surgical site (dry taps
are more likely to result in root injury or irritation).
2. Controlled drainage during surgery facilitates exposure and minimizes
brain retraction.
3. Large-bore (14- or 16-gauge) Tuohy needles are more comfortably
placed in patients under general anesthesia (from both the patient’s and
surgeon’s perspective).
4. Securing the catheter at multiple sites by suture fixation of the looped
catheter is often essential to maintain a working catheter for 5 days or
more; this procedure is easier to perform under general anesthesia.
5. The most tenuous cranial/dural base repairs can be disrupted by even
brief periods of intracranial hypertension associated with Valsalva’s
maneuvers and other events during emergence from anesthesia; CSF
drainage may avoid these periods of intracranial hypertension.

Dural repair and multilayered closure


Adequate resection of lesions extensively involving the skull base requires
meticulous wound closure and repair for several reasons, including the
234 K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239

avoidance of CNS infection, CSF leaks, cosmetic deformity, and structural


support of the CNS and important end organs. Numerous techniques have
been developed to optimize closure and repair. Although the findings at
surgery may require a deviation from the planned approach and procedure,
in most cases with proper preoperative imaging and planning, techniques of
repair and tissue acquisition for repair are determined in advance of surgery.
Preparing the closure during the exposure is a hallmark of the successful
surgeon.
Most of the literature regarding closure of complex wounds after skull
base surgery, and the predominance of cases in most surgeons’ personal
series, involves anterior cranial fossa surgery. In this location, a watertight
dural closure and a viable tissue barrier providing separation from the upper
respiratory tract are essential. Temporal bone and lateral skull base cases
are less likely to involve difficult or impossible dural repairs in direct
connection with a sinus. Posterior fossa cases are usually neurosurgical
cases, with complex repair schemes rarely necessary.
The goal, when possible, is primary dural closure. Primary dural closure
is possible in limited situations in skull base surgery, when the opening is
limited and the adjacent dura is substantial and able to be mobilized: an
example is primary closure or oversewing of the subfrontal dura after
division of an olfactory tract involved with a small esthesioneuroblastoma.
More extensive defects can be repaired primarily with mobilization of
surrounding dura, if viable. Viability in this instance describes dura that is of
adequate thickness and has been kept hydrated during the procedure up
until closure. The dura should be kept moist during any lengthy procedure,
a practice aided by well-positioned irrigation catheters, a moist collagen
sponge over exposed dural surfaces, and general attention to detail.
When dural grafting is required because of an extensive defect, the next
issue is to determine whether a margin of native dura exists circumferentially
around the defect such that a graft can be sewn in a watertight fashion. If so,
the next question is which type of graft to place. When available, autogenous
pericranium is ideal. It may be harvested early on in the procedure and kept
moist on the table as a free devascularized graft. The current authors’
preference is to mobilize as large a pericranial flap as possible, maintaining
attachment and vascular supply during the procedure. This method allows
the alteration of the size of both the free graft used for dural closure and the
vascularized graft used as a sling for floor reconstruction. The grafts are
secured with 4-0 silk or polyglactin 910 (Vicryl) sutures for the dural patch,
and 3-0 and 4-0 silk for attachment of the sling to the surrounding bone of
the defect (usually the orbital roofs for anterior craniofacial resections).
Drill holes are placed with a 2-mm round bit in the adjacent bone. A recent
report described a sutureless fixation, using autologous fascia or peri-
cranium, and anchoring it with titanium screws, with or without titanium
mesh. The repair is reinforced with fibrin glue [6]. This method may be useful
when the dural margin is inadequate to place or hold a suture.
K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239 235

Dural substitutes and allogenic cadaveric dura may be used, particularly


if native tissue is not available because of prior surgery or radiation.
Although these substitutes are acceptable for dural closure in limited
circumstances, they should not be used, even as a dural patch, if there is not
enough vascularized native tissue to provide a viable barrier between the
airway and the subdural compartment. Vascularized muscle flaps may be
used if rotated in (temporalis, latissimus) with adequate tissue and length. In
certain instances, the use of vascularized free flaps is increasing. Radial
forearm free flaps are used for smaller defects, and rectus abdominis free
flaps, with or without subcutaneous fat and/r skin, are placed for larger
defects.

Carotid artery assessment, preservation, sacrifice, and bypass


Tumor involving the ICA presents a major surgical management issue.
Traditionally, tumor involvement of the ICA relegated the patient to
palliative care for malignancies in which surgical resection was the main
therapy. Considerable work in the past 10 years has reported on the
preoperative assessment of adequate collateral circulation, assessment of
adequate cerebral vascular reserve, and the safety of elective carotid
occlusion and sacrifice.
Carotid involvement seen on preoperative imaging limits intervention to
the following options: debulking without oncologic margins (peeling tumor
off the ICA), resection with carotid sacrifice (preoperative with endovascular
balloon occlusion or intraoperative), resection after revascularization
(bypass), and delegation to nonoperative therapy (often palliative care)
[7]. For squamous carcinoma of the head and neck nonoperative treatment
is associated with a dismal prognosis of 1-year survival time.
The decision process is aided in many centers with preoperative
assessment of collaterals and reserve. Collaterals are located by means of
the circle of Willis and the external carotid branch anastomosis to the
intracranial vasculature. Although identification of an isolated hemisphere
or middle cerebral artery (ie, those without apparent collaterals by means of
the circle of Willis) may be obtained with conventional angiography with the
addition of simple cross compression tests (further testing has been
advocated and used) [7,8]. Balloon test occlusion with hypotensive challenge
is an accepted means of assessing cerebrovascular reserve and is used by the
authors in selected patients.
This technique and subsequent ICA sacrifice has been used successfully
for more than a decade. Before routine incorporation into a surgical head
and neck oncology practice, however, there are several key issues to
understand. First, the series that have reported testing and carotid sacrifice
were primarily in patients before elective ICA occlusion for aneurysms:
vascular complications in patients who have skull base tumor occur at
a higher rate (eg, 22%, in one large-scale series) than in aneurysm patients
236 K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239

after a simple hunterian ligation [9]. Second, establishing the presence of


adequate collaterals does not eliminate the risk of embolic stroke. Stump
emboli occur at a higher rate during and following extensive tumor
resection, likely from a transient hypercoagulable state. The current authors
have reported a single case of a stump embolus resulting in a fatal dominant
hemisphere stroke, which occurred after permanent balloon occlusion, after
successful test occlusion with hypotensive challenge, before a scheduled
tumor resection [7].
The routine use of bypass surgery to prevent ischemic complications of
carotid sacrifice is intuitively attractive. This practice does not seem to
reduce or eliminate the risk of stroke, however. In a series reported by
Abruzzo et al [10], 7 of 15 patients undergoing bypass suffered an ischemic
event. Anticoagulation may have lessened the risk of stroke in carotid
sacrifice with or without bypass; antiplatelet agents were not protective. In
patients who have head and neck cancer, prior radiation and surgery are
likely to impair and, in many cases, eliminate the donor and recipient
vasculature. Crossover bypass from the contralateral side (bonnet bypass)
may be an option in selected cases.
Despite careful assessment of collaterals and cerebrovascular reserves,
and the use of extensive revascularization procedures, cerebral ischemia of
varying degrees of severity may affect 20% to 50% of patients undergoing
elective ICA occlusion and represents a major ongoing area of concern in
the treatment of patients with head and neck cancer.
In view of these results, a novel approach for carotid artery management
has been proposed and tested in animal models. Endoluminal stenting of the
ICA, followed by a delay to allow in-stent endothelialization, followed by
‘‘exarterectomy’’ has been tested [11]. This method involves the removal of
the diseased ICA around the endothelialized stent. The stent itself may be
removed. Before routine application, the risks of pseudoaneurysm
formation, carotid blowout, and occlusion need to be determined, and the
durability of this construct needs to be established.

Imaging
Neurosurgeons relied on clinical acumen and knowledge of neurology
and anatomy to guide surgery for the first 70 years of the specialty, from the
days of Harvey Cushing until the advent of CT in the 1970s. Until CT
became available, neurodiagnostic testing included air ventriculograms,
pneumoencephalograms, and contrast angiography, with toxic agents
delivered by direct carotid puncture. With the introduction of CT and
subsequently MRI, the location and extent of lesions were no longer in
doubt. Neurosurgery as a specialty was reborn based on modern neuro-
imaging. Standard CT acquisition was slow, however, with thick (5–10 mm)
slices, significant volume averaging, and very limited nonaxial slice imaging
or reconstruction capability. MRI provided better views of nonosseous
K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239 237

structures in three standard planes but required lengthy scan times and
a cooperative patient, and often included significant artifacts.
The introduction of improved hardware and software in both CT and
MRI modalities greatly aids modern-day skull base surgeons. Thin-slice
high-resolution CT with multiplanar reconstruction and workstation
capabilities allows the surgeon to rotate, magnify, and adjust windows
and plan approaches before incision. CT had been relegated to a distant
second place in terms of value to the surgeon; however, improved computer
capabilities has returned the modality to equal footing with MRI,
particularly in cranial base surgery.
CT and MRI have advanced the specialty of neurosurgery in general and
skull base surgery in particular. Those images initially were only pre-
operative, however, and although of great use to the surgeon, were only
images on a light box in the operating room, not always readily or
accurately transferable in the surgeon’s mind to the three-dimensional field
in which he or she must work. Now, imaging is available with three-
dimensional reconstruction, thin-slice multiplanar imaging, intraoperative
localization (frameless stereotaxy), and intraoperative MRI.
Framed stereotactic techniques in neurosurgery involve the application of
a head frame and localizer ring, image acquisition in the ring, and transfer to
the operating suite with frame attached. Image fusion permits accurate
localization and target identification, as described later. Operative
localization of a predetermined target is useful; however, framed stereotactic
surgery did not allow for reorienting the surgeon. In addition, operating
around a frame is difficult for extensive or lengthy procedures. The concept
of frameless stereotaxy involves preoperative imaging with fixed reference
points, either anatomic structures or fiducials, which are then referenced in
the operating room with a system that allows the surgeon to reorient the
location of a probe or any surgical instrument to a three-dimensional
display in the operating suite. The use of frameless systems for intra-
operative navigation is increasing in neurosurgery and otolaryngology, and
numerous systems are available [12,13]. These systems include those with
reference points with fixed arcs attached to typical neurosurgical head
frames; those with localized skull pins, dental stents, or reference blocks and
less invasive localizing points; and, in surgery, those with tool localization
based on ultrasound, optics, and articulated arms that allow the surgeon to
know where in three-dimensional space he or she is working.
Combining these modalities in overlaid sections and rendered three-
dimensional images is the result of image fusion. The use of fusion
techniques in preoperative frameless guidance combines the submillimetric
accuracy of CT with the tissue-imaging capabilities of MRI, and more
accurately displays the information than either modality alone [14]. This
fusion technique, with accurate three-dimensional renderings, provides
better depiction of individual anatomic structures and key structural
relationships (eg, tumor–bone and tumor–vessel) [15].
238 K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239

Incorporating frameless image–guided surgical technique involves in-


creased cost initially, from equipment and prolonged setup and operative
time; these disadvantages are generally eliminated with routine use, with
several studies documenting no increases or actual decrease in operative time,
and hospital length of stay [16,17]. The use of frameless guidance clearly is
more surgeon-friendly and quicker than framed stereotactic systems, with the
possible exceptions of simple biopsy, in which framed systems are both
accurate and quick, and uncomplicated primary transphenoidal surgery, in
which image guidance is likely to prolong surgery [16,18]. The authors’
practice is to use frameless guidance in cases of repeat operation and tumors
involving multiple anatomic compartments. Frameless guidance is particu-
larly useful in repeat operations in which normal, adjoining anatomic
reference points are distorted or destroyed. In intradural, intraparenchymal
surgery of primary brain tumors, brain shift is a particular problem. This
hindrance is far less likely to occur in skull base surgery [19].

Intraoperative MRI
The latest and potentially most useful imaging modality in the surgical
suite is real-time intraoperative image acquisition that demonstrates the
surgical anatomy and remaining pathology as the procedure evolves.
Intraoperative MRI is now available, with intraoperative magnets of 0.12-
to 1.5-T field strengths now available. MRI surgical suites and compatible
operating equipment, consisting of anesthetic and surgical instruments, are
now available [20]. The transition period from research tool to widespread
clinical applications is now upon us. The use of updated images eliminates
the concern of brain shift and should reduce the occurrence of unsuspected
tumor remnants and the need for return trips to the operating room. In the
future, the routine use of intraoperative MRI may provide intraoperative
quality assurance in neurosurgery and skull base surgical procedures.

Summary
The recent advances in neurosurgery, applied to the growing field of skull
base surgery, provide surgeons with new techniques to avoid the devastating
complication of CSF leak, to improve patient selection by reducing the risk
of stroke while expanding the operative options available to patients with
head and neck malignancies, and to aid operative care through improved
surgical planning and intraoperative localization.

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Surg Oncol Clin N Am 13 (2004) 241–247

Index
Note: Page numbers of article titles are in boldface type.

A Cerebrospinal fluid leaks, integration of


Acinic cell carcinoma, salivary gland, 119 neurosurgical techniques into skull
base surgery for head and neck cancer,
Adenocarcinoma, of paranasal sinuses, 174 232–233
salivary gland, 120–121
Cervical lymph nodes, anatomic landmarks
Adenoid cystic carcinoma, of paranasal for identification of, 153–154
sinuses, 175
salivary gland, 118 Chemoradiation therapy, for
hypopharyngeal carcinoma, 93–94
Adjuvant therapy, iodine 131 for well-
differentiated thyroid cancer, 129–149 Chemotherapy, dental oncology and, in
head and neck cancer, 39–40
Alveolus, squamous cell carcinoma of, for laryngeal carcinoma, 107–108
surgical treatment of, lower, 56 for oropharyngeal carcinoma, 78
upper, 56–57 in management of oral cavity
Amifostine, to protect salivary function squamous cell carcinoma,
during radiation therapy of head and 63–64
neck cancer patients, 194–195 of cutaneous melanomas of head and
neck, 218
Anatomic landmarks, for identification of
cervical lymph nodes, 153–154 Chermotherapy, for paranasal sinus
cancers, 181
Anatomy, of paranasal sinuses, 168–169
Complications, of laryngeal carcinoma,
108–109
B of radiation therapy, as alternative to
Biochemotherapy, of cutaneous melanomas surgery for head and neck
of head and neck, 219 cancers, 188–189

Biopsy, imaging-guided, in head and neck Computed tomography (CT), imaging in


oncology, 28–29 head and neck oncology, 13–35
of cutaneous melanomas of head and in skull base surgery, 236–237
neck, 207–208 Cutaneous malignant melanoma. See
sentinel lymph node, for staging N0 Melanoma.
neck tumors, 161–163

D
C
Dental oncology, expanding role in head
Cancer predisposition, in patients with and neck surgery, 37–46
squamous cell carcinoma of head and assessment, 38–40
neck, 2–4 considerations during treatment,
genes for, 5–6 40–41
genomic instability and, 4–5 long-term considerations, 41–43
Carotid artery, assessment, preservation, Desmoplastic melanoma, 206, 223
sacrifice, and bypass of, in skull base
surgery for head and neck cancer, Differentiated thyroid carcinoma. See
235–236 Thyroid carcinoma.

1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1055-3207(03)00146-7
242 Index / Surg Oncol Clin N Am 13 (2004) 241–247

Dysplastic nevus syndrome, as risk factor other applications, 28–31


for cutaneous malignant melanoma, techniques, 14–16
205–206 melanoma, 201–229
neck dissection, 151–166
neurosurgical techniques in skull base
E surgery, 231–239
Esthesioneuroblastoma, of paranasal paranasal sinus cancers, 167–186
sinuses, 176–177 salivary gland cancer, major, 113–127
squamous cell carcinoma, genomic
instability, role in pathogenesis
F of, 1–11
Familial melanoma/dysplastic nevus of hypopharynx, 81–98
syndrome, as risk factor for cutaneous of larynx, 99–112
malignant melanoma, 205–206 of oral cavity, current treatment
options, 47–70
Fine-needle aspiration, of salivary gland
of oral pharynx, subsite
tumors, 114–116
treatment heterogeneity,
Floor of mouth, squamous cell carcinoma 71–80
of, surgical treatment of, 55–56 organ preservation in patients
with, 187–199
Function, preservation of, in head and neck thyroid cancer, iodine 131 as adjuvant
cancer patients, 187–199 therapy for well-differentiated,
neuromuscular function, 196 129–149
salivary function, 194–196
speech, 189–192 Hypopharyngeal wall, posterior, surgery for
swallowing, 192–194 carcinoma of, 86–87
Hypopharynx, carcinoma of, 81–98
G chemoradiation therapy, 93–94
clinical behavior, 82–85
Genes, for cancer predisposition, in patients
primary radiation therapy, 92–93
with squamous cell carcinoma of head
selective neck dissection for, 157
and neck, 5–6
surgical treatment, 85–92
Genetics, risk factors for cutaneous
malignant melanoma, 205–206
familial melanoma/dysplastic I
nevus syndrome, 205 Imaging, in head and neck oncology, 13–35
xeroderma pigmentosum, anatomic landmarks for
205–206 identification of cervical
lymph nodes, 153–154
Genomic instability, role in pathogenesis of integration of neurosurgical
squamous cell carcinoma of head and techniques into skull base
neck, 1–11 surgery in, 236–238
Glottic carcinoma, surgical treatment of, nodal staging, 22–28
105–106 of primary tumor, 16–22
of salivary gland tumors,
114–116
H other applications, 28–31
Hard palate, squamous cell carcinoma of, techniques, 14–16
surgical treatment of, 56–57 with iodine 131, as follow-up to
radioiodine ablation of
Head and neck cancer, 1–239 thyroid remnant or tumor,
dental oncology, expanding role of, 140–142
37–46
assessment, 38–40 Immunotherapy, of cutaneous melanomas
considerations during treatment, of head and neck, 218–219
40–41
Internal carotid artery. See Carotid artery.
long-term considerations, 41–43
imaging in, 13–35 Intraoperative magnetic resonance imaging
nodal staging, 22–28 (MRI), in skull base surgery for head
of primary tumor, 16–22 and neck cancers, 238
Index / Surg Oncol Clin N Am 13 (2004) 241–247 243

Iodine 131, for adjuvant therapy of Mandible, squamous cell carcinoma of,
well-differentiated thyroid carcinoma, surgical treatment of, 58
129–149
Maxillofacial prosthodontics, dental
acute and long-term effects of
therapy, 137–140 oncology in head and neck cancer, 40
further management, L-thyroxine Melanoma, of head and neck, 201–229
therapy, 142–144 causes and risk factors,
serum Tg testing and 204–206
rhTSH, 145 diagnostic evaluation, 207–208
imaging and follow-up, epidemiology, 201–203
140–142 follow-up, 222
outcomes, 142 management, 213–222
postsurgical remnant ablation, biochemotherapy, 219
134–135 by stage, 219–221
therapy of metastases from, chemotherapy, 218
135–137 immunotherapy, 218–219
radiotherapy, 216–218
surgery, 213–216
L mortality, 203
L-Thyroxine, therapy with, after iodine 131 of paranasal sinuses, 175–176
therapy for differentiated thyroid pathology, 206
carcinoma, 142–144 recurrent disease, 221
Larynx, squamous cell carcinoma of, salivary gland, 121–122
99–112 special issues, 222–224
anatomy, 100–101 desmoplastic melanoma,
complications and outcomes, 223
108–109 metastatic melanoma of
diagnosis, 102–104 unknown origin,
lymphatic and distant spread, 223–224
101–102 mucosal melanoma,
pathology, 104 222–223
preserving speech in patients staging, 208–213
with, 189–192 Metastases, imaging of nodal disease in
radiotherapy and chemotherapy head and neck oncology, 16–22
in treatment of, 107–108 metastatic melanoma of unknown
selective neck dissection for, 157 origin, 223–224
staging and prognosis, 102 of paranasal sinus cancers, 181–182
surgical treatment, 104–107 to neck, of hypopharyngeal
Lentigo maligna melanoma, 206 carcinoma, 90
to neck, of oropharyngeal carcinoma,
Lip, squamous cell carcinoma of, surgical 77–78
treatment of, 57–58
Molecular biology, of salivary gland
Lymph nodes, cervical, anatomic landmarks cancers, 122–123
for identification of, 153–154
sentinel, biopsy of for staging N0 neck Mortality, due to melanoma of head and
tumors, 161–163 neck, 203–204

Lymphoma, of paranasal sinuses, 178 Mucoepidermoid carcinoma, salivary gland,


of parotid salivary gland, 122 116–117
Mucosal melanoma, 222–223
M
Magnetic resonance imaging (MRI), N
imaging in head and neck oncology,
13–35 Neck, cancer of. See Head and neck cancer
in skull base surgery, 236–238 dissection of. See Neck dissection.
intraoperative, 238 levels of, 152–153
squamous cell carcinoma of, surgical
Malignant melanoma. See Melanoma. treatment of, 58–61
244 Index / Surg Oncol Clin N Am 13 (2004) 241–247

Neck dissection, current concepts and Organ preservation, in patients with


future directions, 151–166 squamous cancers of head and neck,
anterior (selective VI), 158–160 187–199
classification systems, 152–157
imaging-based, 153–155 Oropharynx, carcinoma of, analysis of
extended, 160 subsite treatment heterogeneity,
71–80
for cancer of oral cavity,
assigning tumor to subset of
157–158
origin, 72
for oropharyngeal, laryngeal, and
chemotherapy, 78
hypopharyngeal cancer, 157
posterolateral, 160–161 histopathology, 72
sentinel lymph node biopsy for management of regional spread
to neck, 77–78
staging N0 neck tumors,
posterior pharyngeal wall, 73
161–163
relevant anatomy, 71–72
for salivary gland cancers, 124–125
selective neck dissection for, 157
Neuroblastoma, olfactory, of paranasal soft palate, 73–74
sinuses, 176–177 tongue base, 76–77
tonsillar complex, 74–76
Neuromuscular function, preservation of, in
head and neck cancer patients, 196 Osteoradionecrosis, dental oncology in head
and neck cancer, 43
Neurosurgical techniques, integration of in
current head and neck skull base Outcome, in laryngeal carcinoma,
surgery, 231–239 108–109
carotid artery assessment, in oral cavity squamous cell
preservation, sacrifice, and carcinoma, 65–66
bypass, 235–236 of paranasal sinus cancers, 182
cerebrospinal fluid leaks, 232–233 with iodine 131 therapy of
imaging in, 236–238 differentiated thyroid carcinoma,
wound closure, 233–235 142
Nodal disease, imaging of, in head and neck
oncology, 16–22 P
Nodular melanoma, 206 Palate, hard, squamous cell carcinoma of,
surgical treatment of, 56–57
Palate, soft, carcinoma of, 73–74
Paranasal sinus cancers, differential
O diagnosis and treatment options,
Olfactory neuroblastoma, of paranasal 167–186
sinuses, 176–177 anatomy, 167–169
epithelium-derived malignancies,
Oral cavity, squamous cell carcinoma of,
170–178
47–70
etiology, 169–170
etiology, 48
incidence, 169
management, 51–66
lymphomas, 178
diagnostic investigations,
pathology, 170
51–53
prognosis and outcome, 182
prognostic factors and
treatment, 178–182
outcome, 65–66
chemotherapy, 181
radiotherapy and
management of cervical
chemotherapy, 62–64
nodes, 181–182
reconstruction, 61–62
radiation therapy, 181
rehabilitation, 64
surgical, 178–181
selective neck dissection for,
157–158 Pharyngeal wall, posterior, carcinoma
specific sites, 53–61 of, 73
pathology, 48–51
Pharynx, hypopharynx, see Hypopharynx
Oral pharynx. See Oropharynx. oral, see Oropharynx
Index / Surg Oncol Clin N Am 13 (2004) 241–247 245

Pilocarpine hydrochloride, to protect Radical neck dissection. See Neck dissection.


salivary function during radiation
Radioiodine ablation. See Iodine 131
therapy of head and neck cancer
patients, 194–195 Reconstruction, after surgery for squamous
cell carcinoma of oral cavity, 61–62
Positron emission tomography (PET),
imaging in head and neck oncology, Recurrence, of salivary gland cancers,
13–35 125–126
Postcricoid tumors, surgery for, 89–90 Rehabilitation, after treatment of oral
Postoperative evaluation, in head and neck cavity squamous cell carcinoma, 64
oncology, use of imaging in, 29 Retromolar trigone, squamous cell
Precursor lesions, risk factor for cutaneous carcinoma of, surgical treatment of, 56
malignant melanoma, 204–205 Risk factors, for cutaneous malignant
melanoma, 204–206
Predisposition, to cancer, in patients with
squamous cell carcinoma of head and
neck, 2–4 S
genes for, 5–6
Salivary function, preservation of, in
genomic instability and, 4–5
patients with head and neck cancers,
Primary tumor, imaging of, in head and 194–196
neck oncology, 16–22 limiting salivary gland exposure,
195–196
Prognostic factors, in oral cavity squamous radioprotective agents, 194–195
cell carcinoma, 65–66
in well-differentiated thyroid Salivary gland tumors, major, 113–127
carcinoma, patient-specific, acinic cell carcinoma, 119
130–131 adenocarcinoma and related
tumor-specific, 131–134 classification, 120–121
adenoid cystic carcinoma, 117
Prosthodontics, dental oncology in head imaging and fine-needle aspiration,
and neck cancer, 40 114–116
Pyriform sinus, surgery for carcinoma of, lymphoma, 122
87–89 malignant mixed tumors, 120
melanoma, 121–122
molecular biology, 122–123
Q mucoepidermoid carcinoma, 116–117
recurrence, 125–126
Quality of life, in patients with head and squamous cell carcinoma, 121
neck cancers, 189 treatment, 123–125
neck dissection, 124–125
radiation therapy, 125
R salivary gland surgery, 123–124
Radiation therapy, dental oncology and, in undifferentiated carcinomas, 122
head and neck cancer, 38 Selective neck dissection. See Neck
for laryngeal carcinoma, 107–108 dissection.
for paranasal sinus cancers, 181
for salivary gland cancers, 125 Sentinel lymph node biopsy, for staging N0
in management of oral cavity neck tumors, 161–163
squamous cell carcinoma, 62–63 Side effects, of radiation therapy, as
of cutaneous melanomas of head and alternative to surgery for head and
neck, 216–218 neck cancers, 188–189
primary, for hypopharyngeal
carcinoma, 92–93 Sinonasal undifferentiated carcinoma, 177
side effects of, as alternative to surgery
Sinus cancers. See Paranasal sinus cancers.
for head and neck cancers,
188–189 Skull base surgery, for head and neck
xerostomia induced by, strategies to cancer, integration of neurosurgical
reduce, 194–196 techniques in, 231–239
246 Index / Surg Oncol Clin N Am 13 (2004) 241–247

Skull (continued) skull base surgery for head and neck


carotid artery assessment, cancer, integration of
preservation, sacrifice, and neurosurgical techniques in,
bypass, 235–236 231–239
cerebrospinal fluid leaks, 232–233 carotid artery assessment,
imaging in, 236–238 preservation, sacrifice, and
wound closure, 233–235 bypass, 235–236
cerebrospinal fluid leaks,
Soft palate, carcinoma of, 73–74
232–233
Speech, preservation of, in patients with imaging in, 236–238
head and neck cancers, 189–192 wound closure, 233–235
technical improvements in, 191
Swallowing, preservation of, in patients
voice quality with different
with head and neck cancer, 192–194
treatment modalities, after radiation, 193–194
191–192 after surgery, 193
Squamous cell carcinoma, of head and neck,
genomic instability, role in
pathogenesis of, 1–11 T
of hypopharynx, 81–98 Thyroglobulin assay, after postoperative
of larynx, 99–112 iodine 131 therapy for differentiated
of oral cavity, current treatment thyroid carcinoma, 145
options, 47–70
of oral pharynx, subsite Thyroid carcinoma, iodine 131 as adjuvant
treatment heterogeneity, therapy of well-differentiated, 129–149
71–80 acute and long-term effects of
of paranasal sinuses, 173–174 therapy, 137–140
of salivary gland, 121 further management, L-thyroxine
organ preservation in patients therapy, 142–144
with, 187–199 serum Tg testing and
rhTSH, 145
Staging, of cutaneous melanomas of head imaging and follow-up, 140–142
and neck, 208–213 outcomes, 142
Subglottic carcinoma, surgical treatment of, postsurgical remnant ablation,
106–107 134–135
therapy of metastases from,
Sun exposure, risk factor for cutaneous 135–137
malignant melanoma, 204 prognostic factors, patient-specific,
Superficial spreading melanoma, 206 130–131
tumor-specific, 131–134
Supraglottic carcinoma, surgical treatment
of, 105 Thyrotropin administration, after
postoperative iodine 131 therapy for
Surgical treatment, dental oncology and, differentiated thyroid carcinoma, 145
40–41
for hypopharyngeal carcinoma, Thyroxine, L-, therapy with, after iodine
85–92 131 therapy for differentiated thyroid
for laryngeal squamous cell carcinoma, 142–144
carcinoma, 104–107 Tongue, squamous cell carcinoma of,
for oropharyngeal carcinoma, surgical treatment of, 53–54
according to subsite, 71–80
for salivary gland cancers, 123–125 Tongue base, carcinoma of, 76–77
for squamous cell carcinoma of oral Tonsillar complex, carcinoma of, 74–76
cavity, 53–62
neck dissection in head and neck
cancers, 151–166
of cutaneous melanomas of head and U
neck, 213–216 Undifferentiated carcinoma, of salivary
of paranasal sinus cancers, gland, 122
178–181 sinonasal, 177
Index / Surg Oncol Clin N Am 13 (2004) 241–247 247

V X
Voice, preservation of. See Speech. Xeroderma pigmentosum, as risk factor for
cutaneous malignant melanoma,
205–206
W
Wound closure, integration of neurosurgical Xerostomia, preservation of salivary
techniques into skull base surgery for function in patients with head and
head and neck cancer, 233–235 neck cancer, 194–196