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Sinonasal carcinoma: clinical, pathological,


genetic and therapeutic advances
Jos Luis Llorente, Fernando Lpez, Carlos Surez and Mario A. Hermsen
Abstract | The sinonasal cavities represent an anatomical region affected by a variety of tumours with clinical,
aetiological, pathological, and genetic features distinct from tumours at the main head and neck cancer
localizations. Together, squamous-cell carcinoma and adenocarcinoma account for 80% of all sinonasal
tumours, and are aetiologically associated with professional exposure to wood and leather dust particles
and other industrial compounds, and therefore, are officially recognized as an occupational disease. Owing
to their distinctive characteristics, sinonasal tumours should be considered as separate entities, not to be
included in the miscellany of head and neck cancers. Sinonasal tumours are rare, with an annual incidence
of approximately 1case per 100,000 inhabitants worldwide, a fact that has hampered molecular-genetic
studies of the tumorigenic pathways and the testing of alternative treatment strategies. Nevertheless, the
clinical management of sinonasal cancer has improved owing to advances in imaging techniques, endoscopic
surgical approaches, and radiotherapy. Genetic profiling and the development of invitro cell lines and animal
models currently form the basis for future targeted anticancer therapies. We review these advances in our
understanding and treatment of sinonasal tumours.
Llorente, J. L. etal. Nat. Rev. Clin. Oncol. advance online publication 17 June 2014; doi:10.1038/nrclinonc.2014.97

Introduction
Although the sinonasal cavities occupy a relatively This article focuses on SNSCC and ITAC, which have
small anatomical space (Figure1), they are the site of been the subjects of an increasing number of publica-
origin of one of the most histologically diverse group tions on multiple oncological aspects. In particular,
of tumours observed in the entire human body. The the advances in endoscopic surgical approaches, radio-
sinonasal region is a complex anatomical area, close to therapy and imaging techniques that have improved the
structures that include the eyes and the brain, which is of clinical management of patients with sinonasal cancer
special relevance to surgery and postoperative treatment, are reviewed. In addition, the progress in genetic profil-
as mutilation and aesthetic deformities are difficult to ing and the development of invitro and animal models
avoid. Epithelial tumours are the predominant form of of sinonasal cancers, which is laying the foundations for
malignancy affecting the sinonasal cavities, represent- future targeted anticancer therapies, are discussed.
ing >80% of all sinonasal tumours.1 The most-common
subtypes of epithelial tumour are sinonasal squamous- The epidemiology of sinonasal tumours
cell carcinoma (SNSCC), which predominantly occur in Sinonasal cancers comprise 5% of all cancers of the head
the maxillary sinus and nasal cavity, and intestinal-type and neck, with a worldwide incidence of approximately
adenocarcinoma (ITAC), which almost exclusively arise 1 case per 100,000 inhabitants, annually.24 The average
in the ethmoid sinus (Figure1; Table1).1 Tumours of age at which patients present with sinonasal tumours is
the frontal and sphenoid sinuses are rare.1 Despite the between 5060years.5 In general, SNSCCs account for
anatomical proximity of the nasopharynx to the sino- 5080% of all sinonasal malignancies, while ITAC rep-
nasal cavities (behind the nasal cavities and above the resents 1020%, although these proportions vary geo-
Department of
soft palate), tumours in these regions are considered graphically;4,6 for both these tumour types, the highest
Otolaryngology, separately. Indeed, the aetiology, epidemiology, clinical incidences are reported in European countries.5
Instituto Universitario features, and genetic profile of sinonasal tumours are SNSCC and ITAC occur more commonly in men,
de Oncologa del
Principado de Asturias distinct from those of the main head and neck cancer with a male-to-female ratio of 2:1 in SNSCC, and up to
(IUOPA), Hospital localizations, such as larynx, pharynx, and oral cavity 6:1 in ITAC.1,4,7 The male predominance of sinonasal
Universitario Central
deAsturias,
cancers. Thus, sinonasal tumours should be considered tumours is probably a result of the aetiological involve-
CelestinoVillamil s/n, unique malignancies not to be included in the miscellany ment of occupational hazards;1,4,7 occupational exposure
33006Oviedo, Spain of head and neck cancers. to several industrial compounds has been attributed to
(J.L.L., F.L., C.S.,
M.A.H.). tumorigenesis in around 40% of all sinonasal cancers,
and 30% of SNSCC and 90% of ITAC specifically.710
Correspondence to:
M.A.H. Competing interests Professionals working with wood have up to 500900-
mhermsen@hca.es The authors declare no competing interests. times and 20-times increased risk of developing ITAC

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geographical variation might reflect the existence of


Key points
currently unidentified genetic susceptibility factors, or
A variety of tumour types can develop in the sinonasal cavities; most common are exposure to different types of wood or other compounds.
sinonasal squamous-cell carcinoma (SNSCC) and intestinal-type adenocarcinoma
Apart from wood and leather dust, chemical substances
(ITAC), which arise in separate sinonasal sublocalizations
Patients with sinonasal tumours often present with nonspecific clinical symptoms such as glues, formaldehyde, chrome, nickel, and various
and with advanced-stage tumours, and therefore, have a poor prognosis compounds used in the textile industry have been
Exposure to wood and leather dusts is a strong aetiological factor associated associated with sinonasal carcinomas, mainly SNSCC.16
with the development of SNSCC and especially ITAC, possibly through tumorigenic In contrast to most head and neck cancers, tobacco
pathways of chronic inflammation smoking does not seem to have a key role in the develop-
SNSCC and ITAC have aneuploid genomesharbouring multiple genetic ment of sinonasal tumours; nevertheless, evidence sug-
aberrationsthat are distinct from each other and from histologically
gests that smoking tobacco can increase the risk of
similar tumours (head and neck squamous-cell carcinoma and colorectal
adenocarcinoma, respectively)
SNSCC twofold to threefold.5 In addition, human papil-
Genetic profiling of sinonasal tumours and studies in relevant invitro cell culture loma virus (HPV) type16 and HPV-18 have been impli-
and animal models are laying the foundations for future targeted therapies cated in the development of SNSCC,17,18 mainly in cases
The clinical management of sinonasal cancer has improved greatly owing to of malignant transformation, which occurs in 316% of
developments in endoscopic surgery and precision radiotherapy inverted papillomas.17

Clinical presentation
and SNSCC, respectively, compared with the general The typical clinical symptoms of sinonasal cancer, such
population.10 In individuals who present with these dis- as nasal obstruction, facial pain, or persistent rhinor-
eases, exposure to such environmental insults usually rhoea (runny nose), or epistaxis (nosebleed), are non-
began at an early age and often persisted for longer specific, and indeed are often indistinguishable from
than 20years.3,11 On the basis of this evidence, in many symptoms of patients with benign sinonasal disease.
European countries ITAC is officially considered a pro- Proptosis (bulging of the eyes), diplopia (double vision),
fessional disease.12 Indeed, the International Agency or neurological symptoms can be present in patients
for Research on Cancer (IARC) designated wood dust with advanced-stage tumours. Owing to thenonspecific
as a human carcinogen in 1995,13 and in 2002, the NIH and the often relatively mild nature of the symptoms
identified wood dust as a known human carcino- at early stages of disease, sinonasal malignancies have
gen.14 Outside of Europe, however, only 20% of patients a prolonged diagnostic latency.7,19 As such, lymphatic
with ITAC have a history of exposure to wood.15 This metastasis at diagnosis occurs in 1020% of patients

EC Intestinal-type
adenocarcinomas
OG
Frontal O
sinus
Sphenoid ES
sinus
Ethmoid S
sinus

Maxillary
sinus NC

MS

OC

Squamous cell carcinomas

Figure 1 | Schematic view of the sinonasal cavities and distribution of the main sinonasal tumour types. Sinonasal
malignancies comprise mostly tumours of epithelial origin, mainly SNSCCs and ITACs, but also esthesioneuroblastomas,
SNUCs, and ACCs.1 Other malignancies affecting the sinonasal region include melanomas, soft-tissue tumours, tumours
ofbone and cartilage, haematolymphoid tumours, germ-cell tumours, and metastases from primary tumours in other
partsof the body. Almost all ITACs are located in the olfactory groove of the ethmoid sinuses, whereas SNSCCs occur
mainly in the nasal cavity and the maxillary sinuses.1 Apart from esthesioneuroblastomas, which originate in the olfactory
epithelium, the other types of sinonasal tumours can occur anywhere within the sinonasal cavities, although tumours with
frontal and sphenoid sinus localizations are rare.1 Given the close proximity of these anatomical areas and the fact that
tumours frequently present at advanced stages,7,19 identifying the exact anatomical localization from which they developed
is often difficult. Of note, the regions affected by sinonasal tumours are situated close to the eyes and brain.
Abbreviations:ACCs, adenoid cystic carcinomas; EC, endocraneum; ES, ethmoid sinuses; ITACs, intestinal-type
adenocarcinomas; MS, maxillary sinus; NC, nasal cavity; O, orbit; OC, oral cavity; OG, olfactory groove; S, septum;
SNSCCs,sinonasal squamous-cell carcinomas; SNUCs, sinonasal undifferentiated carcinomas.

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Table 1 | Summary of sinonasal tumour subtypes* also essential because they enable the complete extent of
the tumour to be established and can potentially provide
Histological subtype Proportion of 5-year overall
sinonasal cancers (%) survival rate (%)
information on the benign or malignant nature of the
tumour. Currently, when malignancy is suspected, both
Sinonasal squamous-cell carcinoma 50 50
CT imaging and MRI must be performed to obtain precise
Intestinal-type adenocarcinoma 13 60 anatomical details regarding the tumour localization and
Mucosal melanoma 7 35 extension, which are critical in determining operability
Esthesioneuroblastoma 7 70 or in planning radiotherapy (Figure2). MRI is consid-
Adenoid cystic carcinoma 7 70
ered the standard imaging modality for postoperative
surveillance. The value of PETCT in the assessment of
Sinonasal undifferentiated carcinoma 3 35
sinonasal tumours has not been clearly defined, but this
Other 13 Variable imaging modality is especially important in evaluating
*These data come from a study of patients with sinonasal cancer in the USA; 1 however, similar data have patients with suspected metastasis or tumour recurrence;
been obtained in patient populations in Europe and other regions.5
up to one-third of sinonasal tumours might be accurately
upstaged because of neck or distant-site involvement dis-
with SNSCC (especially if the tumour erodes through the covered using PETCT.22 Once the appropriate imaging
maxillary gingiva), but is a rare occurrence in patients data have been obtained, clinical staging of sinonasal
presenting with ITAC,20,21 perhaps becausethe pattern tumours is performed based on location and extent,
of tumour spread is largely dependent of thesinus according to the current Union for International Cancer
origin and lymphatic drainage. During the follow-up Control (UICC) classificationsystem.23
period after treatment of the primary tumour, 10%
of patients with sinonasal tumours develop distant Tumour histology
metastasis; however, this seldom occurs in absence of The sinonasal cavities are lined with a pseudostratified
locoregionalrecurrence.1921 respiratory epithelium, which changes into pseudo-
Clinical examination of patients with suspected sino- stratified olfactory epithelium at the roof of the nasal
nasal tumour should begin with a thorough medical cavity (Figure3ab); the main difference between these
history and a complete ear, nose, and throat (ENT) epithelia is the presence of olfactory neurons in the latter,
exploration, including assessment of the cranial nerves with the axons of these neurons forming unmyelinated
and neck. Anterior rhinoscopy generally provides limited nerve bundles that traverse the cribiform plate andtrans-
information and, therefore, rigid nasal endoscopy with mit signals to the olfactory bulb. Goblet cellsand sub-
optics at 0 or 45 is mandatory. Nasofibroscopy can also mucosal secretory glands within these epithelia produce
provide useful data, but the image quality is usually worse mucous that captures bacteria and other foreign matter,
than with rigid endoscopes. Noninvasive imaging tests are and is moved toward the pharynx by coordinated

a b c

O O ES
O
ES * ES
MS
MS
MS

*
Figure 2 | Imaging approaches for diagnosis of sinonasal tumours. CT imaging in axial and coronal sections, preferably with
contrast enhancement, enables accurate assessment of sinonasal cancers, especially in terms of bone destruction.
Features of malignancy are invasion of soft tissue and the presence of reactive osteogenesis. MRI is generally indicated
forassessing extension beyond the sinonasal cavities (orbital, intracranial or infratemporal fossa invasion), evaluating
perineural tumour spread, and differentiating tumour from postobstructed secretions. MRI protocols generally include axial
and coronal T1-weighted, T2-weighted, STIR and T1-weighted gadolinium-enhanced scans. a|Coronal CT image showing an
aggressive left maxillary SNSCC with destruction of the maxillary sinus walls. Erosion of the floor of the maxillary sinus and
extension of the tumour into the maxillary alveolus (arrow), buccal space (asterisk), and hard palate (arrowhead) is evident.
b | Coronal CT image of a woodworker, which led to the early diagnosis of a small ITAC of the left olfactory cleft (arrow). The
left olfactory cleft is closed by a slight bulging of the corresponding nasal septum (asterisk) to the right and of the conchal
lamina (arrowhead) to the left. Note the thinning of the left cribiform plate (dotted arrow). c | 3D IR-prepared gradient-echo
sequence coronal MRI image demonstrating a large, heterogeneous ITAC occupying the nasal cavity and ethmoid sinuses
bilaterally, with extension into the anterior cranial fossa (arrow). Abbreviations: ES, ethmoid sinuses; IR, inversion recovery;
ITAC, intestinal-type adenocarcinoma; MS, maxillary sinus; O, orbit; SNSCC, sinonasal squamous-cell carcinoma;
STIR,short tau inversion recovery.

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a b Figure 3 | Histological features of normal, benign


metaplastic and various sinonasal tumour tissues.
a|Thesinonasal cavities are lined with pseudostratified
respiratory epithelium containing occasional melanocytes,
and basal, ciliated, and goblet cells. Seromucous secretory
glands and lobular ducts lie below the surface epithelium
in the lamina propria. b | The roof of the nasal cavity is
lined with the olfactory epithelium, which differs from the
respiratory epithelium mainly by the presence of olfactory
neurons (brown stain). In the olfactory epithelium, basal
cells are thought to produce olfactory neurons as well as
c d sustentacular and ensheathing cells, and tubuloalveolar
Bowmans glands below the surface epithelium.
c|Abnormal cell differentiation can lead to squamous
metaplasia, a precursor to SNSCC. d | SNSCCs are graded
as well-differentiated, moderately differentiated, and poorly
differentiated tumours, all of which are characterized by
extracellular or intracellular keratin fibres and intercellular
bridges. e | Abnormal cell differentiation can also lead to
intestinal metaplasia. f | Cuboidal metaplasia is also
e f
possible. These histological samples demonstrating
intestinal and cuboidal metaplasia come from patients
with occupational exposure to wood dust, which is a known
risk factor for sinonasal cancer, and particularly ITAC.
Indeed, intestinal and cuboidal metaplasia are both
precursors to ITAC, which occurs in four main subtypes:
g|well-differentiated papillary-typeITAC, characterized
bytall columnar monomorphic cells and a low number
ofmitotic figures; h|moderately differentiated colonic-
g h typeITAC, which is associated with a mixed tubulopapillary
pattern and increased mitotic rate; i | poorly differentiated
solid-typeITAC, in which tubules are infrequent and highly
hyperchromatic nuclei are common; j | mucinous-typeITAC,
comprising alveolar goblet cells or signet-ring cells and
mucin lakes. In parts a and b, immunohistochemical
staining with anti-III-tubulin antibodies with haematoxylin
counterstain was used to identify neurons. In parts cj
standard haematoxylin and eosin staining was performed.
Magnification was 20 in all images, except parts g and j
i j
in which a magnification of 10 was used. Abbreviations:
ITAC, intestinal-type adenocarcinoma; SNSCC, sinonasal
squamous-cell carcinoma.

type is colonic (40%), followed by mucinous (22%), solid


(20%), and papillary (18%).24 ITACs can also show mix-
tures of two or more of these four histological subtypes.24
Irrespective of the histological type, ITACs demonstrate
sweeping of ciliated cells on the surface of the epithelium. elevated production of intracellular or extracellular
This protective layer of mucous also contains antimicro- mucins, and might also contain argyrophilic, endocrine,
bial peptides and factors that regulate the local immuno- enterochromaffin, and Paneth cells.24
logical defence mechanisms. In the stroma, leukocytes,
lymphocytes and mononuclear cells lie ready and form Tumorigenesis of sinonasal tumours
a second line of defence. Chronic inflammation
Aberrant cell differentiation in the sinonasal epithelia The pathogenic molecular pathways that result in
can result in various forms of metaplasia, some of which sinonasal cancer remain unknown. The organic dusts
might subsequently evolve to malignant transformation associated with tumour development are not considered
to form SNSCC (Figure3cd), or ITAC (Figure3ef). directly mutagenic, but these materials mightthrough
Similar to other mucosal sites in the head and neck, continuous irritation of the mucosaillicit chronic
SNSCCs are graded into well-differentiate, moderately inflammation, which is a recognized mechanism of
differentiated (Figure3d), and poorly differentiated tumorigenesis in several types of cancer.27
tumours according to the WHO tumour classification A role for chronic inflammation in sinonasal tumori-
system,24 although histological grade does not seem to genesis is supported by the findings of various studies.
have any clinical relevance.25,26 Four histological subtypes Invitro, phagocytosis of inhaled organic dust, mineral
of ITAC are recognized (Figure3gj), the most frequent fibres, or fungal spores induced activated alveolar

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macrophages to secrete a variety of cytokines and chemo- Differentiation or reprogramming the sinonasal epi-
kines involved in the development and maintenance of thelium towards an intestinal-type epithelium, incorpor-
the inflammatory response, including tumour necrosis ating resorptive, goblet, neuroendocrine, and Paneth cells,
factor (TNF).28 The cytokines TNF and IL-1 can result occurs before the development of ITAC (Figure3ef),24
in activation of the transcription factor nuclear factorB but is not unique to the sinonasal cavities: this process
(NFB), which is implicated in tumorigenesis, thus has been reported to precede the development of tumours
connecting inflammation with cancer development.27 at a number of locations, including the stomach, oeso-
Of note, expression of both NFB and downstream phagus, and lung.36,37 Both cuboidal and intestinal meta-
prostaglandin G/H synthase2 (also known as cyclo- plasia have been proposed to be a precursor to ITAC, as
oxygenase-2 [COX2]) have been found to be elevated these metaplastic tissues have been observed adjacent to
in sinonasal carcinomas.29 In addition, upon stimulation such tumours and in sinonasal mucosa of individuals with
by wood dust, alveolar macrophages released reactive exposure to aetiological risk factors (Figure3ef).3840
oxygen species (ROS) and reactive nitrogen species Immunohistochemically, this metaplasia can be detected
(RNS), such as peroxynitrites and nitrogen oxides, which as a switch from a normal cytokeratin-7 (CK-7)+/CK-20/
can generate mutagenic DNA adducts.30,31 Under acute CDX-2/villin sinonasal epithelial cell phenotype to an
inflammatory conditions, these free radicals are released abnormal CK-7/CK-20+/CDX-2+/villin+ intestinal epi-
to combat pathogenic organisms, but in chronic inflam- thelial cell phenotype.41 Expression of p53, which is absent
matory conditions, they can have detrimental effects on in the normal respiratory epithelium, has been also been
the host tissues. A strong relationship between nitric observed, mainly in squamous metaplasia, and seems to
oxide (NO) production through inducible nitric oxide be related to wood-dust exposure.39,40 This observation
synthase (iNOS) activity and G>A nucleotide transi- might be indicative of upregulated expression of func-
tions in the TP53 gene was demonstrated in colorectal tional p53 in response to inflammatory signals in the
cancer.31 Likewise, a dominance of TP53 G>A transitions wood-dust-exposed sinonasal epithelium, rather than of
has been observed almost exclusively in nonsmoking TP53 genemutation.
woodworkers, whereas G>T transversions associated
with tobacco smoking were considerably less frequently Cancer stem cells
observed.3234 Furthermore, G>A transition in KRAS was Another method of investigating the origin of sino-
the most-frequent mutation found in patients with ITAC nasal cancer is the analysis of cancer stem cells (CSC), as
who had a history of exposure to wood and leatherdust.35 proposed for other head and neck tumours.42,43 To our
Together, these data implicate chronic inflammatory knowledge, no research has been published on the role
processes as a causal or promoting factor in the tumori- of CSC in sinonasal cancer. Nevertheless, normal stem
genesis of both SNSCC and ITAC, particularly in indivi- cells in the olfactory epithelium have captured the atten-
duals exposed to industrial compounds. However, more tion of stem-cell researchers, especially with regard to the
studies are needed to confirm this relationship, and ability of these cells to form new olfactory neurons after
also to explain why none of the known sinonasal cavity tissue damage sustained during adulthood.44 The same
inflammatory pathologies, such as rhinitis and polyps, olfactory neuroepithelium stem cells were also found to
seem to be associated with an increased cancer risk. be precursors of non-neuronal, epithelial cell types.44 In
addition to the olfactory epithelium, stem cells have been
Precursor lesions isolated from respiratory epithelium of the lower and
Multistep carcinogenesis through various histological middle turbinate, and these cells were capable of differ-
changes accompanied by accumulating genetic altera- entiating into cells with either neuroectodermal or meso-
tions has not been demonstrated for sinonasal carcino- dermal phenotypes.45 On the basis of specific neuronal
mas. However, any premalignant histological changes markers, esthesioneuroblastoma is the only type of sino-
might be obscured by growth of the tumour mass, which nasal tumour demonstrated to derive from the olfactory
is often detected at advanced stages of progression. At epithelium. Clinical and radiological evidence suggests
an early stage of development of both SNSCCs and that ITACs also originate from the olfactory epithelium
ITACs, the normal respiratory or olfactory epithelium lining the olfactory cleft (Figure1 and Figure2), whereas
undergoes metaplasia, redirecting the normal cell dif- SNSCCs might develop in other sinonasal areas, such
ferentiation pathways toward tissue types that do not as respiratory mucosa in the maxillary sinus or in the
normally exist in the sinonasal cavities. One could specu- pterigopalatine fossa.46,47 Thus, these tumour types could
late that such metaplasia is a histopathological change potentially result from expansion of CSCs localized in
reflecting cellular and tissue responses to a chronic these particular regions.
inflammatorymicroenvironment. Sinonasal tumours could be hypothesized to derive
Squamous metaplasia and subsequent dysplasia are from CSCs capable of undergoing differentiation into
histological changes that precede the development of various cell types, rather than from differentiated, lineage-
SNSCC (Figure3cd).24 In addition, inverted papilloma specific cells that acquire stem-cell properties. Support-
is associated with a small proportion of SNSCCs; HPV- ing this suggestion, many sinonasal tumours have been
16 infection has been described in 38% of benign and described that demonstrate more than one histologi-
31% malignant tumours,17,18 suggesting that inverted cal appearance; for example, adenoid cystic carcinoma
papilloma is a precursor to this subset of SNSCCs. with adenocarcinoma or undifferentiated carcinoma, or

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Table 2 | Genetic alterations in SNSCCs/ITACs, and possible targeted therapies adenocarcinomas that arise in patients with inflam-
Genetic aberration ITAC SNSCC Targeted therapeutic agents* matory bowel disease.63,64 Furthermore, mutations in
APC (encoding adenomatous polyposis coli protein) or
EGFR overexpression59,6668 2033% 40% Cetuximab and TKIs
CTNNB1 (encoding -catenin), key components of the
ERBB2 overexpression59,68 ND 37% Trastuzumab and TKIs Wnt cascade that are frequently mutated in colorectal
KRAS mutation 35,58,71,72
15% 1% Deltarasin cancer,65 have not been identified in sinonasal carcino-
Overexpression of ND 50% Sunitinib and TKIs mas.58 Thus, although activation of the Wnt pathway
VEGFR-encoding genes59,116 probably contributes to the development of certain
Overexpression of 36% ND Solithromycin ITACs, the specific mechanisms remain to be identified
NFKB-encoding genes29 and are likely to differ from those underlying the histolo-
FGFR1 amplification73 ND 20% Dovitinib gically similar spontaneous colorectal adenocarcinomas.
PTGS2 (also known as COX2) 4060% 8% NSAIDs In SNSCC, nuclear -catenin expression is rare and the
overexpression29 Wnt pathway is unlikely to have a role in the development
*The list of drugs is not exhaustive and only provides examples of specific agents or classes of agents of this tumour type (unpublished data, M.A.Hermsen).
that target the druggable genetic alterations demonstrated in SNSCC and ITAC to date. Abbreviations: Several studies have demonstrated EGFR overexpres-
ITAC,intestinal-type adenocarcinoma; ND, not determined; NFKB, nuclear factor KB; NSAIDs, non-steroid
anti-inflammatory drugs; SNSCC, sinonasal squamous cell carcinoma; TKIs, tyrosine kinase inhibitors; sion in about 40% of SNSCCs and in 2033% of ITACs
VEGFR,vascular endothelial growth factor receptor.
(Table2).59,6668 Again, these frequencies are lower than
those reported for the histologically similar head and
SNSCC with neuroendocrine carcinoma.48,49 Further- neck and colorectal cancers.69,70 Interestingly, EGFR
more, recurrent tumours can have a different histologi- mutations that have been observed in lung adenocarci-
cal type than the original primary tumour, with reports noma were not found in ITAC. 66 Overexpression of
of ITAC recurrence as undifferentiated carcinoma or HER2 (also known as ErbB2) has also been detected in
esthesioneuroblastoma.50 <10% of SNSCCs.59,68 Mutations in KRAS and HRAS,
The CSC hypothesis provides a model that accommo- which encode proteins downstream of EGFR in the EGF
dates the multiple causes of tumour heterogeneity.51 signalling pathway, have been found in approximately
Accord ing to this hypothesis, tumorigenesis can be 1% in SNSCCs and 15% of ITACs,35,58,71,72 whereas BRAF
considered as a dynamic and plastic process regulated mutations have not been detected in these tumours.71
by microenvironmental factors, rather than as a hier- In SNSCC, 21% of tumours overexpressed p16 INK4A
archical or static concept.52 The study of CSCs and the (also known as cyclin-dependent kinase inhibitor 2A),
tumour microenvironment might, therefore, have clini- and high expression levels of this protein were a surrogate
cal implications for sinonasal cancer, particularly as these marker of a subset of HPV-positive cases.18,73 Conversely,
cells have been implicated in disease recurrence and epigenetic silencing of p16INK4A was reported in 67% and
resistance to chemotherapy,5356 which are both notable loss of heterozygosity at the 9p21 locuswhich har-
characteristics of sinonasal carcinomas.1921 bours the gene encoding this proteinin 45% of ITAC
cases studied.33 Furthermore, microsatellite instability
Genetic characterization can occur in a small proportion of SNSCCs, but does
Sinonasal-cancer-related genes not seem to have a role in ITAC oncogenesis. 62,72,74 In
Studies of the involvement of specific genes in SNSCC addition, using fluorescence insitu hybridization, gene
and ITAC have often been guided by findings from amplification of FGFR1 and SOX2 was demonstrated
more-frequent and better-studied tumours with similar in 20% and 37% of SNSCC cases, respectively, whereas
histology, such as head and neck squamous-cell carci- 0% and 8% of ITACs had amplification of these genes,
noma and colorectal carcinoma, respectively. Mutation respectively (Table2). 73,75 Several studies have also
of the TP53 gene has been associated with exposure to reported NFB and COX2 overexpression in sinonasal
wood dust, with frequencies of TP53 mutation ranging carcinomas, particularly in ITAC, suggesting a role for
from 70% in SNSCC and up to 86% in ITAC. 33,34,57,58 chronic inflammation in tumorigenesis.29
Overexpression of p53 has also been reported in around
50% of SNSCCs and 72% of ITACs.29,33,5860 Interestingly, Genomic profiling of ITAC and SNSCC
the frequency of p53 overexpression seems to be mark- Genome-wide genetic studies have shown that both
edly lower in mucinous-typeITAC compared with the SNSCC and ITAC generally have complex, aneuploid
other ITAC subtypes.60 genomes that carry a wide variety and a large number
Aberration of the canonical Wnt signalling pathway has of chromosomal aberrations (Figure4),7679 similarly to
also been implicated in sinonasal cancer. Activation of most solid tumours. An exception is papillary-typeITAC,
this pathway, detected as nuclear expression of -catenin, which seems to be predominantly diploid with few
has been reported in 3153% of ITACs, with a higher pro- genetic aberrations.76,77 SNSCC and ITAC each have both
portion of activation of Wnt signalling observed in papil- shared and unique genetic abnormalities compared with
lary and colonic ITAC subtypes than in solid-type and other head and neck tumours, such as larynx, pharynx,
mucinous-typeITAC.6062 This proportion is, however, or oral cavity squamous-cell carcinomas, but have a con-
substantially lower than the 90% of sporadic colorectal siderably different genetic profile compared with salivary
adenocarcinoma that demonstrate activation of the Wnt gland tumours, which have characteristic chromosomal
pathway, but is similar to the 40% frequency in colorectal translocations and relatively few geneticchanges.48,80,81

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a 5 are less frequent, but some have been reported at 1q, 5p,
7q, 8q2324, 12p, 13q14, and 20q.76,77
4 Using an expression array of 6,864 genes, and vali-
Tumour DNA:normal DNA log2-ratio

dated by RT-PCR and immunohistochemistry, two


3 genes with marked differential expression compared with
matched normal nontumour sinusal tissue were identi-
2
fied in nine ITACs.82 Specifically, LGALS4encoding
galectin-4was highly upregulated, particularly in
1
well-differentiated tumours; and CLU, which encodes
clusterin, was downregulated in all tumours.82 However,
0
these findings await validation and, therefore, the
1
potential implications of these data remain unknown.
Two SNSCC, one HPV-positive and one HPV-negative,
2 were included as part of a large exome-sequencing study
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
18
19 21 23
20 22 of head and neck squamous-cell carcinoma, and both
were discovered to be among the tumours with the lowest
b 5
number of mutations.83 TP53 was the only mutated gene
identified in the HPV-positive SNSCC, whereas the other
4
HPV-negative tumour was found to harbour two mutated
Tumour DNA:normal DNA log2-ratio

genes, SYNE1 and NOTCH3, which have both been impli-


3
cated in the regulation of nuclear polarity and terminal
2
differentiation of squamousepithelia.83

1 Models of sinonasal cancer


In the past 3years, the first immortalized ITAC cell
0 line and a number of new SNSCC cell lines have been
established and characterized.84,85 In addition, a mouse
1 orthotopic sinonasal cancer model has been developed by
implanting cells from a human sinonasal undifferentiated
2 carcinoma (SNUC) into the maxillary sinus of mice.86
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 19 21 23

Chromosomes
18 20 22 This model suggests that development of mouse ortho-
topic models of SNSCC and ITAC might also be feasi-
Figure 4 | Microarray CGH analysis demonstrating profiles characteristic of SNSCC
and ITAC. The data for each chromosome are ordered continuously from left to ble. These invitro and invivo models, which retain the
right, pter to qter, as chromosomes 1 up to chromosomes X and Y (numbered as biological properties of sinonasal cancer,8486 are impor-
23 and 24, respectively), with the boundaries between chromosomes defined by tant tools for functional studies on the role of CSCs and
dashed vertical lines. All data points are expressed as tumour DNA:normal DNA processes such as proliferation, differentiation, invasion,
log2-ratios; a log2-ratio of 0 is interpreted as a normal copy number, and log2-ratios and metastasis in sinonasal tumours, and might facilitate
of >0 and <0 indicate copy-number gains and losses, respectively. a | CGH analysis the development and testing of new therapeuticagents.
profile of a DNA aneuploid, stage T4aN2bM0, poorly differentiated SNSCC of the
right maxillary sinus with copy-number alterations for most chromosomes. This
case demonstrates many of the recurrent alterations observed in SNSCC (arrows):
Sinonasal-cancer prognosis
high-level amplification at 3q263qter (including SOX2) and at 11q13 (including Independent of the treatment type used, the progno-
CCDN1, EMS1), copy-number gains at 7p, 8q, 17q, 19p, and 20q, and losses at 3p, sis of patients with sinonasal carcinomas is poor, with
8p, 13q, and 17p. b | CGH profile of a DNA aneuploid, stage T3N0M0, colonic- an overall 5-year survival rate of 3050% (Table1).1,2,5
typeITAC of the right ethmoid sinus with copy-number alterations in many The 5-year survival rates depend on disease stage and
chromosomes. This case demonstrates many of the recurrent alterations observed drops from 80% in patients with T1 disease to 30% in
in ITAC (arrows): copy-number gains at 5p, 7p, 8q, 12p, and 20q, and losses at 4q, patients with T4 tumours.1,2,5 Histological grade does
5q, 8p, 17p, and 18q. Abbreviations: CGH, competitive genomic hybridization;
not have prognostic value in patients with SNSCC;25,26
ITAC,intestinal-type adenocarcinoma; SNSCC, sinonasal squamous-cell carcinoma.
among patients with ITACs, however, papillary-type
and colonic-type tumours are associated with more-
In SNSCC, DNA copy number gains are found fre- favourable clinical outcome than the solid or mucinous
quently at chromosomal regions 3q, 7p, 8q, 11q13, 17q, subtypes.24 Molecular markers of poor prognosis include
19p, and 20q, with losses at 3p, 8p, 9p, 13q, 17p, 17q, and EGFR expression and HPV-negativity in SNSCC,17,18,59
18q, whereas recurrent DNA copy number gains in and p53 and nuclear -catenin expression in ITAC.57,61
ITAC genomes include 5p, 6p, 7p, 7q, 8q, 12p, and 20q, Local recurrence often occurs within 2years of follow-
and losses are commonly seen at 4q, 5q, 8p, 17p, and up and is the main contributor to sinonasal cancer
18q (Figure4).7679 Recurrent high-level amplifications mortality.19,21 Lymph node and distant metastases are
of chromosomal loci detected in SNSCC include 7p12, infrequent; however, sinonasal tumours should not be
11p13, 11q13, and 17q21, which contain the suggested considered exclusively as a locoregional disease and
candidate oncogenes EGFR, CD44, CCND1/CTTN, and wider anatomical imaging studies such as PET-CT can
ERBB2, respectively;78 in ITAC high-level amplifications help proper staging.

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a FS b c

B FS
B
D O
O O
SS
*
* N * CL
M
PS

Figure 5 | Endoscopic surgery for the treatment of sinonasal tumours. a|Endoscopic nasal view of the anterior cranial
fossa during an endoscopic craniofacial surgery in a patient with ITAC. After debulking the tumour, the cribriform plate, the
dura mater (D), and the tumour implantation area are resected with proper tumour-free margins. The resection limits are:
the frontal sinus (FS), the planum sphenoidale (PS), and sides of the both orbits (O). The frontal lobes (asterisk), falx
cerebri (arrowhead), and dural resection margin (arrow) are indicated. b | Postoperative coronal CT image of a total
endoscopic resection of a bilateral ITAC showing one single sinonasal cavity (asterisk) free of tumour, leaving only the two
inferior turbinates and part of the septum directly below the sinonasal cavity. c | A postoperative sagittal CT image provides
an alternate view of the same resection (asterisk). Abbreviations: B, brain; CL, clivus; D, dura mater; FS, frontal sinus;
ITAC,intestinal-type adenocarcinoma; M, mouth; N, nose; O, orbit; PS, planum sphenoidale; SS, sphenoid sinus.

Treatment of sinonasal cancer of endoscopic surgery in sinonasal malignancies was the


Complete surgical resection with postoperative radio- fact that tumours could not be removed in monobloc;
therapy is the mainstay of sinonasal-cancer management however, overwhelming evidence indicatesthat mono-
(Figure5), although the therapeutic modality used should bloc procedures are not always essential and thattumours
be tailored individually according to tumour stage, histo- can be fragmented if radical removal of the tumour at the
logy, patient age, and previous treatments. More-effective end of the intervention is guaranteed.87,89 One example is
treatments that are also associated with less morbidity endoscopic laryngeal surgery using a CO2 laser, which has
than the currently available options are needed, especially been shown to be as effective as open approaches.93 At the
for advanced-stage tumours. Strategies to improve treat- beginning of an intervention, dissection and fragmenta-
ment outcome should focus on local disease control and tion of the sinonasal tumour are commonly performed to
reducing distant metastasis. facilitate its removal. In addition, the anterior skull base
(dura mater and olfactory tracts),the site of ITAC origin in
Surgery many cases, can be removed safely in monobloc by endo-
A detailed description of the different potential surgi- scopic approaches (Figure5, Supplementary Video1).
cal approaches to the treatment of the various sinonasal The ability to control bleeding has beenimproved owing
carcinomas is beyond the scope of this Review. However, to the numerous haemostatic techniques that are now
minimally invasive endoscopic approaches are increas- available.94 Another challenge in endoscopic resection of
ingly used, and deserve special attention, because they sinonasal tumours in patients with intracranial extension
can reduce the number of complications and morbid- has been the reconstruction of the dura mater to separate
ity associated with surgery.8789 In addition, traditional the aseptic brain area from the septic nasal cavity region
open surgical approaches, such as maxillectomy, have and also to prevent cerebrospinal fluid leakage. The dura
become less destructive, with surgeons disguising the mater can be reconstructed with good results through
incisions using degloving facial approaches and regional inlay and overlay procedures using different tissue grafts
or free-flap reconstructions.90 comprising fascia lata, collagen matrix or abdominal fat
Resection of sinonasal tumours with wide margins is (Supplementary Video 1). One improvement in the repair
not always possible, as doing so would affect the cranial of dural defects after skull-base surgery was the introduc-
nerves, eyes, internal carotid artery, or brain. Thus, such tion of vascularized local flaps, with the repair performed
attempts to remove tumour with wider surgical margins using vital tissue;95 currently, most surgeons use the so-
could cause unacceptable morbidity and would be tech- called septal mucosal flap, with some modifications.95
nically difficult, if not impossible, either by open or These flaps are especially useful in pituitary pathology, but
endoscopic techniques. Moreover, no evidence suggests in the case of malignant tumours some safety limitations
that this approach would substantially increase survival. restrict use of this approach, for example when a sinonasal
For decades, open craniofacial resection and maxillec- tumour invades or grows in proximity to tissues compri-
tomy was the mainstay treatment for sinonasal tumours.91 sing the harvest flap, such as the septum or choanas. In
In the late 1980s and early 1990s endoscopes began to be such cases, for oncological reasons, this type of procedure
used for the removal of benign nasal tumours and this should beavoided.
endoscopic surgery has now culminated in the resection More data are needed from larger studies of endo-
of sinonasal malignancies, including those affecting the scopic surgery with longer follow-up periods, or prefer-
anterior cranial base.89,92 The first challenge to the utility ably from randomized studies directly comparing open

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a b In summary, most surgeons agree that in experienced


hands and for selected patients, endoscopic surgery in
adherence with the general principles of oncological
surgery, with adequate exposure, margins, and reconstruc-
tion, is suitable for the treatment of sinonasal tumours.87,99
Contrary to false assumptions, choosing an endoscopic
approach to surgical management of sinonasal tumours
does not mean that a radical resection cannot be achieved
(Figure5). In fact, improvements in instrumentation and
the introduction of robotic technology, together with
generalization of navigation systems, are expected to
expand the indications of endoscopicapproaches.100

Precision radiotherapy
Another aspect of sinonasal-cancer therapy that has wit-
nessed undoubted improvements in the past decade is
radiotherapy.8,101 The main difficulty facing radiotherapy
for the treatment of sinonasal tumours, whether used
Figure 6 | Precision radiotherapy for the treatment of sinonasal tumours.
instead of surgery or postoperatively, is the low radi-
a|Coronal CT section showing the clinical target volumes for radiotherapy with ation tolerance of the nearby optical structures (eyes,
VMAT in a patient with a recurrent ITAC of the ethmoid sinus after endoscopic and optic nerves and chiasm) and other adjacent organs,
craniofacial resection. Clinical target volumes were 60 Gy (yellow contour) in the such as the lachrymal glands, the cochlea, the pituitary
high-risk subclinical disease area, and 66 Gy (red contour) in the tumour gland, the frontal and temporal brain lobes, the brain-
implantation area; isodose lines of 57 Gy (brown), 54 Gy (dark blue), 45 Gy stem, the spinal cord, the parotid glands, the mandible,
(mid-blue), 30 Gy (light blue), and 20 Gy (turquoise), as well as the optic nerves and the oral cavity (Figure1). New radiation techniques
(orange contours), are also shown. b | Axial CT section showing the VMAT
such as intensity-modulated radiation therapy (IMRT),
radiation-dose distribution in a patient with a T4bN0 ethmoid ITAC after endoscopic
craniofacial resection. Note the close vicinity of the 60 Gy clinical target volume volumetric modulated arc therapy (VMAT), tomo-
(redcontour) to the optic-system apparatus (eyes and optic nerves, indicated by therapy, and proton-beam therapy enable the achieve-
thegreen and orange contours, respectively). The lachrymal glands are shown ment of well-defined and steep dose gradients close to
bythe pink contours. Isodose lines of 57 Gy (brown), 54 Gy (dark blue), 45 Gy the target volumes.102105 The greater conformality of these
(mid-blue), 30 Gy (light blue), and 20 Gy (turquoise) are also depicted. Abbreviations: new techniques also results in a lower rate of radiation-
ITAC,intestinal-type adenocarcinoma; VMAT, volumetric modulated arc therapy. induced toxicity and increases therapeutic efficiency
compared with conventional approaches.102 Image-guided
and endoscopic surgical approaches. However, endo- radiation therapy (IGRT) has also been introduced
scopic techniques offer a number of advantages over to complement these approaches in ensuring the safe
open surgical methodologies: the endoscope enables a delivery of a highly conformal treatment, by facilitating
more direct approach to the tumour, without altering or convenient and frequent imaging of the patient anatomy
injuring healthy tissues; patient recovery is generally faster throughout the treatmentcourse.106
and less-complicated compared with open surgery; and Indeed, the precision of these sophisticated radiation
facial incisions are avoided, resulting in better cosmetic techniques stresses the importance of proper target
outcomes and the potential prevention of further compli- delineation during the planning process. Thus, a good
cations in irradiated tissues, including naso cutaneous understanding of the patterns of tumour spread and
fistula. To date, the results of many case series support the recurrence by the multidisciplinary teams involved in
endoscopic resection of malignant sinonasal tumours, the management of patients with sinonasal tumours
rather than open surgical treatment.88,96,97 Despite difficul- is required. Such knowledge facilitates not only surgi-
ties associated with standardization of reported outcomes, cal planning, but also the delineation of the treatment
asystematic review that included all types of sinonasal volumes for postoperative radiotherapy to avoid under-
malignancies indicated that the 5-year overall survival rate treatment of areas at risk of microscopic tumour inva-
was considerably increased among patients whounder- sion, while minimizing the radiation dose applied to the
went endoscopic surgery compared with those who unaffected tissues and vital organs (Figure6). With IMRT
were treated using open surgical approaches.98 In some and VMAT, microscopic tumour spread can be targeted
circumstances, however, an open surgical approach will around the site of the primary tumour and through-
be more appropriate than endoscopy, in particular, when out the lymphatic channels to the lymph nodes in the
the tumour (especially SNSCC) has infiltrated the orbital neck, as well as along other routes of dissemination.101
fat or extraocular muscles, orbital apex, the brain, or the In tumours with risk of perineural spread, the nerves at
facial skin, in which case special reconstructive surgery risk can be safely treated.101 Endoscopic surgery and CT
is needed. It must also be recognized that, when properly imaging can precisely define the tumour implantation
indicated, open surgery can be performed with limited site. For example, an ethmoid ITAC involving the whole
subsequent morbiditycertainly without the mutilation nasal cavity on CT scans could be pedicled at only a small
erroneously suggested in many papersand lowmortality. implantation area on the olfactory surface.

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Given the new possibilities to deliver different doses not recommended because of toxicity concerns.107,110112
of radiation simultaneously to different anatomical areas Alternative therapeutic schemes for the treatment of
while minimizing the dose at adjacent normal tissues, sinonasal carcinoma are weekly intra-arterial infusions
further studies are need to address a number of clini- of cisplatin delivered rapidly to the tumour bulkwith
cal questions. Firstly, would a higher dose delivered to conventional external-beam irradiation in patients
the tumour implantation area improve local control withSNSCC. Despite encouraging organ-preservation
and patient survival? Secondly, would irradiation of the rates, these approaches have been associated with sub-
hypothetical location of the CSC niches, possibly respon- stantial toxicity, particularly those using intra-arterial cis-
sible for tumour maintenance and recurrence, increase platin and conventional intravenous chemotherapy.107,110
the therapeutic efficiency? Finally, could precision Good results have been reported for patients with ITAC
radiotherapy be applied to modify the microenviron- by combining surgical debulking and repeated topical
ment in the surgical field in a way that blocks or reduces chemotherapy with 5-fluorouracil. 114 Never theless,
the chance of residual tumour regrowth or reseeding of safer and more-effective adjuvant therapies for sino-
circulating tumour cells? nasal tumoursor induction therapies for unresectable
tumoursare clearly needed.
Chemotherapy The use of molecular markers predictive of response
Owing to the low incidence of these tumours, few clini- to adjuvant treatment in patients with sinonasal tumours
cal trials have been performed specifically in patients would represent an important therapeutic advance. For
with sinonasal carcinomas; therefore, chemotherapy or instance, chemotherapy was demonstrated to be highly
chemoradiotherapy protocols are usually administered effective in patients with ITACs carrying wild-type TP53,
by extrapolation of the approaches taken in similar, but ineffective in those carrying TP53 mutations.57 Some
more-common tumours, such as laryngeal-preservation biomarkers, such as low DNA excision repair protein
protocols. In addition, several institutions have experi- ERCC1 scores, have been shown to reflect favourable
mented with regional chemotherapy for sinonasal cancer, responses to chemotherapy.115 In addition, genetic pro-
mainly SNSCC, to try and minimize the complications filing of SNSCCs and ITACs have indicated a number
of radical surgical treatments. of frequently altered genes, such as those encoding
The classic indication for chemotherapy in sinonasal COX2, EGFR, ErbB2, FGFR1, NFB, B,
B, and VEGFR pro-
malignancies is the palliative treatment of patients with teins,29,58,59,6673,116 that could potentially be targets for
locally advanced or metastatic tumours when surgery and treatment with specific antibodies or small-molecule
radiotherapy are contraindicated or no longer control inhibitors (Table1). At present, however, no relevant
the disease effectively. However, new developments in case studies or clinical trials of such approaches to the
radiotherapy techniques have renewed interest in the treatment of sinonasal cancer have been published.
use of chemotherapy as a primary therapy for sinonasal
tumours. Chemotherapy can be used before, concurrent Future directions
with, or as an adjuvant to radiotherapy, depending on the As technology improves, robot-assisted surgery might be
tumour histology or the radiotherapy and chemotherapy the next breakthrough in sinus and skull-base surgery.
protocol used. Currently, patients with advanced-stage With increasing miniaturization of instrumentation to fit
SNSCC have been shown to respond to neoadjuvant the sinonasal area and skull base, imaging-guided, robot-
chemotherapy, and the response to this initial treatment assisted surgery will become more useful, less invasive,
might be predictive of the ultimate outcome of therapy and more precise. Improved radiation therapy techniques,
and prognosis.107 Evidence also suggests that concomi- such as proton-beam and light ions radiotherapy, could
tant radiotherapy and chemotherapy increases survival potentiallyowing to their physical characteristics
and enables locoregional control,108,109 but comparative reduce toxicity and achieve better quality-of-life, and
studies have not been performed and are, therefore, a might improve survival outcomes compared with the
requirement in the future; thus, at present, no clear statis- current standard methodologies; these possibilities might
tically significant survival benefit has been demonstrated be especially relevant in patients with tumours that have
for concomitant chemoradiotherapy versus neoadjuvant dural involvement or that affect structures such as the
chemotherapy protocols. optic nerves and/or chiasm, cavernous sinus, or carotid
The choice of chemotherapy regimen should be indivi- artery. The development of novel approaches to systemic
dualized based on patient characteristics and disease chemotherapy, intra-arterial chemotherapy, and molecu-
presentation. Among the varied regimens used in the lar targeted therapy (guided by genomic profiling of
treatment of sinonasal tumours, induction chemotherapy tumours), alone or in combination with other therapeutic
usually involves docetaxel, cisplatin, or 5-fluorouracil modalities (neoadjuvant, concomitant or adjuvant),
protocols.107,110112 Following induction therapy, weekly might contribute to improve disease control and minimize
carboplatin is used in concurrent chemoradiation proto- the associated morbidity if vital organs are affected.
cols.107,110112 In addition, targeted therapy with cetuximab
every 2 weeks in patients overexpressing EGFR has been Conclusions
described after induction therapy. 113 Cisplatin-based Sinonasal tumours arise in an anatomically complex
induction chemotherapy followed by chemoradiotherapy region of the body. Furthermore, the low incidence of such
with high-dose cisplatin administered every 3 weeks is tumours and their histological diversity have hampered

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diagnosis, genetic analyses, classification, and staging, completed trials in patients with other more-common
and prevented the accumulation of clinical experi- tumours that have the same druggable genetic aberra-
ence at individual institutions. Nevertheless, the clini- tions. In addition, invitro and mouse models of sinonasal
cal management of these cancers has improved due to tumours have been developed and are now available for
advances in surgery and radiotherapy, although limited preclinicalstudies.8486
progress has been made in chemotherapy, partly owing Occupational exposure to wood and leather dust is
to the difficulty of recruiting a sufficient number of a strong aetiological factor for SNSCC and especially
patients for clinical trials. Importantly, however, because ITAC, possibly through tumorigenic pathways of chronic
of their distinctive characteristics, sinonasal tumours inflammation. Further investigation of this field is
should not be included in the miscellany of head and needed and might yield tools for chemoprevention (such
neck cancers, as occurs in many published case series. as anti-inflammatory drugs) and for early detection of
Moreover, SNSCCs and ITACs originate in different tumours in individuals at risk. In the case of SNSCC,
sinonasal sublocalizations, and both tumour types have routine HPV-testing in biopsies of patients with inverted
different clinical manage ment options. Many of the papilloma might also be advisable.
advances, improvements, and strategies discussed in this To provide the best possible care, patients with sino-
Review can be applied to other sinonasal tumours, such nasal cancer should be treated in clinical referral centres
as SNUCs, adenoid cystic carcinomas, neuroendocrine specialized in skull-base pathologies; such centres should
carcinomas, or esthesioneuroblastomas; however, these include a multidisciplinary team consisting of ENT sur-
tumours have different clinicopathological and molecu- geons, neurosurgeons, radiotherapists, medical oncolo-
lar genetic features, hence, the therapeutic strategies gists, and pathologists. Local hospital ENT physicians
used might have some peculiarities that would demand need to be aware of the possibility of sinonasal tumours
a separate review. despite their nonspecific symptoms. Outside of local
Currently, increasing knowledge of the genomics of clinical and referral centres, the study of molecular
sinonasal cancer enables a new approach to tumour tumorigenic pathways and the testing of alternative treat-
classification, which is more-refined than classic anato- ment strategies would greatly benefit from wider multi-
mical and histological grouping. Furthermore, genetic institutional collaboration, and we strongly support such
analyses comprising at least of a panel of druggable gene collaborative efforts.
products, if not genome-wide, would be a promising
addition to open up possibilities for targeted anticancer
therapy. On the basis of these advances, combined with Review criteria
the development of novel targeted therapies, personal- Data for this manuscript were obtained by searching the
ized therapeutic opportunities are becoming available. PubMed database for papers published before 27 January
In this context, the low numbers of patients with sino- 2014; the search terms used were sinonasal cancer,
nasal tumours such as SNSCC and ITAC who are avail- sinonasal squamous cell, sinonasal adenocarcinoma,
able for clinical trials might not be an issue, as targeted paranasal sinuses cancer, and nasal cavity.
OnlyEnglish-language articles were considered.
therapy could be based on the results of ongoing or

1. Turner, J.H. & Reh, D.D. Incidence and survival 8. Hoppe, B.S. etal. Treatment of nasal cavity and http://www.nih.gov/news/pr/dec2002/
in patients with sinonasal cancer: a historical paranasal sinus cancer with modern niehs-11.htm (2002).
analysis of population-based data. Head Neck radiotherapy techniques in the postoperative 15. Blot, W.J., Chow, W.H. & McLaughlin, J.K.
34, 877885 (2012). settingthe MSKCC experience. Int. J. Radiat. Wood dust and nasal cancer risk. A review of
2. Ansa, B. etal. Paranasal sinus squamous cell Oncol. Biol. Phys. 67, 691702 (2007). the evidence from North America. J. Occup.
carcinoma incidence and survival based on 9. Cantu, G. etal. Intestinal type adenocarcinoma Environ. Med. 39, 148156 (1997).
Surveillance, Epidemiology, and End Results of the ethmoid sinus in wood and leather 16. World Health Organization International Agency
data, 1973 to 2009. Cancer 119, 26022610 workers: a retrospective study of 153 cases. for Reseach on Cancer. IARC Monographs on
(2013). Head Neck 33, 535542 (2011). theEvaluation of Carcinogenic Risks to Humans:
3. Mensi, C. etal. Sinonasal cancer and 10. IARC Working Group on the Evaluation of Tobacco smoke and involuntary smoking Vol. 83
occupational exposure in a population-based Carcinogenic Risks to Humans. Arsenic, metals, (IARC Press, 2004).
registry. Int. J. Otolaryngol. 2013, 672621 fibres, and dusts. IARC Monogr. Eval. Carcinog. 17. Syrjnen, K. & Syrjnen, S. Detection of human
(2013). Risks Hum. 100, 11465 (2012). papillomavirus in sinonasal papillomas:
4. Kuijpens, J.H. etal. Trends in sinonasal cancer 11. Hayes, R.B., Gerin, M., Raatgever, J.W. systematic review and meta-analysis.
in the Netherlands: more squamous cell cancer, &deBruyn, A. Wood-related occupations, Laryngoscope 123, 181192 (2013).
less adenocarcinoma. A population-based study wooddust exposure, and sinonasal cancer. 18. Bishop, J.A. etal. Human papillomavirus-related
19732009. Eur. J. Cancer 48, 23692374 Am.J.Epidemiol. 124, 569577 (1986). carcinomas of the sinonasal tract. Am. J. Surg.
(2012). 12. Bonzini, M. et al. Prevalence of occupational Pathol. 37, 185192 (2013).
5. Youlden, D.R. etal. International comparisons hazards in patients with different types of 19. Cantu, G. etal. Anterior craniofacial
of the incidence and mortality of sinonasal epithelial sinonasal cancers. Rhinology 51, resectionfor malignant paranasal tumors:
cancer. Cancer Epidemiol. 37, 770779 (2013). 3136 (2013). amonoinstitutional experience of 366 cases.
6. Choussy, O. etal. Adenocarcinoma of ethmoid: 13. World Health Organization International Agency Head Neck 34, 7887 (2012).
aGETTEC retrospective multicenter study for Reseach on Cancer. IARC Monographs on the 20. Bhayani, M.K. etal. Sinonasal adenocarcinoma:
of418 cases. Laryngoscope 118, 437443 Evaluation of Carcinogenic Risk of Chemicals to a 16-year experience at a single institution. Head
(2008). Humans: Wood dust and formaldehyde Vol. 62 Neck http://dx.doi.org/10.1002/hed.23485.
7. Sanghvi, S. etal. Epidemiology of sinonasal (IARC press, 1995). 21. Haerle, S.K., Gullane, P.J., Witterick, I.J.,
squamous cell carcinoma: a comprehensive 14. NIH News Release. New Federal Report Zweifel, C. & Gentili, F. Sinonasal carcinomas:
analysis of 4,994 patients. Laryngoscope 124, onCarcinogens Lists Estrogen Therapy, epidemiology, pathology, and management.
7683 (2014). Ultraviolet,Wood Dust [online], Neurosurg. Clin. N.Am. 24, 3949 (2013).

NATURE REVIEWS | CLINICAL ONCOLOGY ADVANCE ONLINE PUBLICATION | 11


2014 Macmillan Publishers Limited. All rights reserved
REVIEWS

22. Lamarre, E.D. etal. Role of positron emission 40. Vivanco, B. etal. Benign lesions in mucosa alterations of histogenetic significance.
tomography in management of sinonasal adjacent to intestinal-type sinonasal Mod.Pathol. 18, 315319 (2005).
neoplasmsa single institutions experience. adenocracinoma. Patholog. Res. Int. 2011, 59. Takahashi, Y. etal. Comprehensive assessment
Am. J. Otolaryngol. 33, 289295 (2012). 230147 (2011). of prognostic markers for sinonasal squamous
23. Sobin, L.H., Gospodarowicz, M.K. & 41. Kennedy, M.T., Jordan, R.C., Berean, K.W. cell carcinoma. Head Neck http://dx.doi.org/
Wittekind,C.H. (eds) International Union Against &Perez-Ordoez, B. Expression pattern of CK7, 10.1002/hed.23423.
Cancer (UICC) TNM Classification of Malignant CK20, CDX-2, and villin in intestinal-type 60. Franchi, A. etal. Immunohistochemical
Tumors 7th edn (Wiley-Blackwell, 2009). sinonasal adenocarcinoma. J. Clin. Pathol. 57, investigation of tumorigenic pathways in
24. Barnes, L., Eveson, J.W., Reichart, P. & 932937 (2004). sinonasal intestinal-type adenocarcinoma.
Sidransky,D. (eds) World Health Organization 42. Cabanillas, R. & Llorente, J.L. The Stem Cell Atissue microarray analysis of 62 cases.
Classification of Tumours Vol. 9: Pathology and Network model: clinical implications in cancer. Histopathology. 59, 98105 (2011).
Genetics of Head and Neck Tumours (IARCPress, Eur. Arch. Otorhinolaryngol. 266, 161170 61. Daz-Molina, J.P. etal. Wnt-pathway activation
2005). (2009). inintestinal-type sinonasal adenocarcinoma.
25. Nazar, G., Rodrigo, J.P., Llorente, J.L., 43. Chinn, S.B. etal. Cancer stem cells mediate Rhinology 49, 593599 (2011).
Baragao,L. & Surez, C. Prognostic factors of tumorigenesis and metastasis in head and neck 62. Perez-Ordonez, B., Huynh, N.N., Berean, K.W.
maxillary sinus malignancies. Am. J.Rhinol. 18, squamous cell carcinoma. Head Neck http:// &Jordan, R.C.K. Expression of mismatch repair
233238 (2004). dx.doi.org/10.1002/hed.23600. proteins, -catenin, and E-cadherin in intestinal-
26. Kang, J.H. etal. Treatment outcomes between 44. Leung, C.T., Coulombe, P.A. & Reed, R.R. type sinonasal adenocarcinoma. J. Clin. Pathol.
concurrent chemoradiotherapy and combination Contribution of olfactory neural stem cells 57, 10801083 (2005).
of surgery, radiotherapy, and/or chemotherapy totissue maintenance and regeneration. 63. Claessen, M.M. et al. Wnt-pathway activation
instage III and IV maxillary sinus cancer: Nat.Neurosci. 10, 720726 (2007). inIBD-associated colorectal carcinogenesis:
multi-institutional retrospective analysis. J.Oral 45. Hauser, S. etal. Isolation of novel multipotent potential biomarkers for colonic surveillance.
Maxillofac. Surg. 70, 17171723 (2012). neural crest-derived stem cells from adult Cell. Oncol. 32, 303310 (2010).
27. Ben-Neriah, Y. & Karin, M. Inflammation meets human inferior turbinate. Stem Cells Dev. 21, 64. Shenoy, A.K. etal. Transition from colitis to
cancer, with NF-B as the matchmaker. 742756 (2012). cancer: high Wnt activity sustains the tumor-
Nat.Immunol. 12, 715723 (2011). 46. Jankowski, R. Revisiting human nose anatomy: initiating potential of colon cancer stem cell
28. Mtt, J. etal. Characterization of oak and birch phylogenic and ontogenic perspectives. precursors. Cancer Res. 72, 50915100
dust-induced expression of cytokines and Laryngoscope 121, 24612467 (2011). (2012).
chemokines in mouse macrophage RAW 264.7 47. Georgel, T. etal. CT assessment of 65. Cancer Genome Atlas Network. Comprehensive
cells. Toxicology 215, 2536 (2005). woodworkers nasal adenocarcinomas confirms molecular characterization of human colon and
29. Holmila, R. etal. COX-2 and p53 in human the origin in the olfactory cleft. Am. J. rectal cancer. Nature 487, 330337 (2012).
sinonasal cancer: COX-2 expression is Neuroradiol. 30, 14401444 (2009). 66. Garca-Incln, C. etal. EGFR status and KRAS/
associated with adenocarcinoma histology 48. Costa, A.F. etal. Analysis of MYB oncogene in BRAF mutations in intestinal-type sinonasal
andwood-dust exposure. Int. J. Cancer 122, transformed adenoid cystic carcinomas reveals adenocarcinomas. Cell. Oncol. (Dordr.) 35,
21542159 (2008). distinct pathways of tumor progression. 443450 (2012).
30. Pylkknen, L., Stockmann-Juvala, H., Alenius, H., Lab.Invest. 94, 692702 (2014). 67. Franchi, A. etal. Epidermal growth factor
Husgafvel-Pursiainen, K. & Savolainen, K. 49. Franchi, A. etal. Primary combined receptor expression and gene copy number
Wooddusts induce the production of reactive neuroendocrine and squamous cell carcinoma insinonasal intestinal type adenocarcinoma.
oxygen species and caspase-3 activity in human ofthe maxillary sinus: report of a case with OralOncol. 45, 835838 (2009).
bronchial epithelial cells. Toxicology 262, immunohistochemical and molecular 68. Lpez, F. etal. Gene amplification and protein
265270 (2009). characterization. Head Neck Pathol. http:// overexpression of EGFR and ERBB2 in sinonasal
31. Hold, G.L. & El-Omar, E.M. Genetic aspects dx.doi.org/10.1007/s12105-013-0513-5. squamous cell carcinoma. Cancer 118,
ofinflammation and cancer. Biochem. J. 410, 50. Kang, S.Y., McHugh, J.B., Sullivan, S.E., 18181826 (2012).
225235 (2008). Marentette, L.J. & McKean, E.L. 69. Temam, S. etal. Epidermal growth factor
32. Prez-Escuredo, J. etal. Wood dust-related Sinonasalundifferentiated carcinoma and receptor copy number alterations correlate with
mutational profile of TP53 in intestinal-type esthesioneuroblastoma recurring as poor clinical outcome in patients with head and
sinonasal adenocarcinoma. Hum. Pathol. 43, nonintestinal adenocarcinoma. Laryngoscope neck squamous cancer. J.Clin. Oncol. 25,
18941901 (2012). 123, 11211124 (2013). 21642170 (2007).
33. Perrone, F. etal. TP53, p14ARF, p16INK4a and 51. Valent, P. etal. Cancer stem cell definitions and 70. Ljuslinder, I. etal. Increased epidermal growth
H-RAS gene molecular analysis in intestinal-type terminology: the devil is in the details. Nat. Rev. factor receptor expression at the invasive margin
adenocarcinoma of the nasal cavity and Cancer. 12, 767775 (2012). is a negative prognostic factor in colorectal
paranasal sinuses. Int. J. Cancer 105, 196203 52. Barcellos-Hoff, M.H., Lyden, D. & Wang, T.C. cancer. Int. J.Cancer 128, 20312037 (2011).
(2003). Theevolution of the cancer niche during 71. Lpez, F. etal. KRAS and BRAF mutations in
34. Holmila, R. etal. Mutations in TP53 tumor multistage carcinogenesis. Nat. Rev. Cancer 13, sinonasal cancer. Oral Oncol. 48, 692697
suppressor gene in wood dust-related sinonasal 511518 (2013). (2012).
cancer. Int. J. Cancer 127, 578588 (2010). 53. Visvader, J.E. & Lindeman, G.J. Cancer stem 72. Frattini, M. etal. Phenotype-genotype correlation:
35. Bornholdt, J. etal. K-RAS mutations in sinonasal cells in solid tumours: accumulating evidence challenge of intestinal-type adenocarcinoma
cancers in relation to wood dust exposure. and unresolved questions. Nat. Rev. Cancer 8, ofthe nasal cavity and paranasal sinuses.
BMCCancer 8, 53 (2008). 755768 (2008). HeadNeck 28, 909915 (2006).
36. Mackinnon, A.C. Jr etal. Cribriform 54. Zhang, Z., Filho, M.S. & Nr, J.E. The biology 73. Schrck, A. etal. Fibroblast-growth-factor-
adenocarcinoma of the lung: clinicopathologic, ofhead and neck cancer stem cells. Oral Oncol. receptor-1 as a potential therapeutic target in
immunohistochemical, and molecular analysis 48, 19 (2012). sinonasal cancer? Head Neck http://dx.doi.org/
of 15 cases of a distinctive morphologic 55. Sayed, S.I. etal. Implications of understanding 10.1002/hed.23443.
subtype of lung adenocarcinoma. cancer stem cell (CSC) biology in head and neck 74. Martnez, J.G. etal. Microsatellite instability
Mod.Pathol.http://dx.doi.org/10.1038/ squamous cell cancer. Oral Oncol. 47, 237243 analysis of sinonasal carcinomas. Otolaryngol.
modpathol.2013.227. (2011). Head Neck Surg. 140, 5560 (2009).
37. Shen, B. etal. Human defensin 5 expression 56. Reers, S., Pfannerstill, A.C., Maushagen, R., 75. Schrck, A. etal. Sex determining region Y-Box2
inintestinal metaplasia of the upper Pries, R. & Wollenberg, B. Stem cell profiling (SOX2) amplification is an independent indicator
gastrointestinal tract. J.Clin. Pathol. 58, inhead and neck cancer reveals an Oct-4 of disease recurrence in sinonasal cancer.
687694 (2005). expressing subpopulation with properties PLoSONE 8, e59201 (2013).
38. Choi, H.R. etal. Sinonasal adenocarcinoma: ofchemoresistance. Oral Oncol. 50, 155162 76. Hermsen, M.A. etal. Genome-wide analysis
evidence for histogenetic divergence of the (2014). ofgenetic changes in intestinal-type sinonasal
enteric and nonenteric phenotypes. Hum.Pathol. 57. Bossi, P. etal. TP53 status as guide for the adenocarcinoma. Head Neck 31, 290297
34, 11011107 (2003). management of ethmoid sinus intestinal-type (2009).
39. Valente, G. etal. Evidence of p53 adenocarcinoma. Oral Oncol. 49, 413419 77. Korinth, D. etal. Chromosomal imbalances in
immunohistochemical overexpression (2013). wood dust-related adenocarcinomas of the inner
inethmoidal mucosa of woodworkers. 58. Yom, S.S. etal. Genetic analysis of sinonasal nose and their associations with pathological
CancerDetect. Prev. 28, 99106 (2004). adenocarcinoma phenotypes: distinct parameters. J. Pathol. 207, 207215 (2005).

12 | ADVANCE ONLINE PUBLICATION www.nature.com/nrclinonc


2014 Macmillan Publishers Limited. All rights reserved
REVIEWS

78. Lpez, F. etal. Genomic profiling of sinonasal 94. Kassam, A., Snyderman, C.H., Carrau, R.L., paranasal sinuses. Arch. Otolaryngol. Head
squamous cell carcinoma. Head Neck 33, Gardner, P. & Mintz, A. Endoneurosurgical NeckSurg. 137, 7881 (2011).
145153 (2011). hemostasis techniques: lessons learned from 108. Homma, A. etal. Superselective high dose
79. Ariza, M. etal. Comparative genomic 400 cases. Neurosurg. Focus 19, E7 (2005). cisplatin infusion with concomitant radiotherapy
hybridization of primary sinonasal 95. Hadad, G. etal. A novel reconstructive technique in patients with advanced cancer of the nasal
adenocarcinomas. Cancer 100, 335341 after endoscopic expanded endonasal cavity and paranasal sinuses: a single institution
(2004). approaches: vascular pedicle nasoseptal flap. experience. Cancer 115, 47054714 (2009).
80. Persson, M. et al. Clinically significant copy Laryngoscope 116, 18821886 (2006). 109. Papadimitrakopoulou, V. A. etal. Intraarterial
number alterations and complex rearrangements 96. Nicolai, P., Villaret, A.B., Bottazzoli, M., Rossi, E. cisplatin with intravenous paclitaxel and
of MYB and NFIB in head and neck adenoid & Valsecchi, M.G. Ethmoid adenocarcinoma ifosfamide as an organ-preservation approach in
cystic carcinoma. Genes Chromosomes Cancer from craniofacial to endoscopic resections: patients with paranasal sinus carcinoma. Cancer
51, 805817 (2012). asingle-institution experience over 25years. 98, 22142223 (2003).
81. Leemans, C. R., Braakhuis, B. J. & Otolaryngol. Head Neck Surg. 145, 330337 110. Hoppe, B.S. etal. Unresectable carcinoma of
Brakenhoff,R.H. The molecular biology of head (2011). the paranasal sinuses: outcomes and toxicities.
and neck cancer. Nat. Rev. Cancer 11, 922 97. Kasemsiri, P. etal. Endoscopic endonasal Int. J. Radiat. Oncol. Biol. Phys. 72, 763769
(2011). technique: treatment of paranasal and anterior (2008).
82. Tripodi, D. etal. Gene expression profiling in skull base malignancies. Braz. J. 111. Rosen, A. et al. Locoregionally advanced
sinonasal adenocarcinoma. BMC Med. Genomics Otorhinolaryngol. 79, 760779 (2013). paranasal sinus carcinoma. Favorable survival
2, 65 (2009). 98. Higgins, T.S., Thorp, B., Rawlings, B.A. & with multimodality therapy. Arch. Otolaryngol.
83. Stransky, N. etal. The mutational landscape Han,J.K. Outcome results of endoscopic vs Head Neck Surg. 119, 743746 (1993).
ofhead and neck squamous cell carcinoma. craniofacial resection of sinonasal malignancies: 112. Lee, M. M. et al. Multimodality therapy in
Science 333, 11571160 (2011). a systematic review and pooled-data analysis. advanced paranasal sinus carcinoma: superior
84. Prez-Escuredo, J. etal. Establishment and Int. Forum Allergy Rhinol. 1, 255261 (2011). long-term results. Cancer J. Sci. Am. 5, 219223
genetic characterization of an immortal tumor 99. Castelnuovo, P. et al. Quality of life following (1999).
cell line derived from intestinal-type sinonasal endoscopic endonasal resection of anterior skull 113. Kies, M.S. et al. Induction chemotherapy and
adenocarcinoma. Cell. Oncol. (Dordr.) 34, 2331 base cancers. J. Neurosurg. 119, 14011409 cetuximab for locally advanced squamous cell
(2011). (2013). carcinoma of the head and neck: results from a
85. Garca-Incln, C. etal. Establishment and 100. Eichhorn, K.W. & Bootz, F. Clinical requirements phase II prospective trial. J. Clin. Oncol. 28, 814
genetic characterization of six unique tumor cell and possible applications of robot assisted (2010).
lines as preclinical models for sinonasal endoscopy in skull base and sinus surgery. 114. Knegt, P.P., Ah-See, K.W., vd Velden, L.A. &
squamous cell carcinoma. Sci. Rep. 4, 4925 ActaNeurochir. Suppl. 109, 237240 (2011). Kerrebijn, J. Adenocarcinoma of the ethmoidal
(2014). 101. Spratt, D., Cabanillas, R. & Lee, N.Y. The sinus complex: surgical debulking and topical
86. Takahashi, Y. etal. Establishment and Paranasal Sinuses in Target Volume Delineation fluorouracil may be the optimal treatment.
characterization of novel cell lines from and Field Setup in A Practical Guide for Arch.Otolaryngol. Head Neck Surg. 127,
sinonasal undifferentiated carcinoma. Conformal and Intensity-Modulated Radiation 141146 (2001).
Clin.Cancer Res. 18, 61786187 (2012). Therapy (eds Lee, N.J. & Lu, J.J.) 4549 115. Choi, I.J., Kim, D.W., Kim, D.Y., Lee, C.H. &
87. Lund, V.J. etal. European position paper on (Springer, 2013). Rhee, C.S. Predictive markers for neoadjuvant
endoscopic management of tumours of the 102. Duprez, F. etal. IMRT for sinonasal tumors chemotherapy in advanced squamous cell
nose, paranasal sinuses and skull base. minimizes severe late ocular toxicity and carcinoma of maxillary sinus: preliminary report.
Rhinol.Suppl. 22, 1143 (2010). preserves disease control and survival. Int. J. Acta Otolaryngol. 133, 291296 (2013).
88. Su, S.Y. etal. Endoscopic resection of Radiat. Oncol. Biol. Phys. 83, 252259 (2012). 116. Bandoh, N. etal. VEGF and bFGF expression and
sinonasal cancers. Curr. Oncol. Rep. 16, 369 103. Spiotto, M.T. & Weichselbaum, R.R. microvessel density of maxillary sinus
(2014). Comparison of 3D conformal radiotherapy and squamous cell carcinoma in relation to p53
89. Snyderman, C.H. etal. Endoscopic skull base intensity modulated radiotherapy with or without status, spontaneous apoptosis and prognosis.
surgery: principles of endonasal oncological simultaneous integrated boost during concurrent Cancer Lett. 208, 215225 (2004).
surgery. J. Surg. Oncol. 97, 658664 (2008). chemoradiation for locally advanced head and
90. Llorente, J.L. etal. Outcomes following neck cancers. PLoS ONE 9, e94456 (2014). Acknowledgements
microvascular free tissue transfer in 104. Marta, G.N. etal. Intensity-modulated radiation The authors thank R. Cabanillas for his assistance
reconstructing skull base defects. J. Neurol. therapy for head and neck cancer: systematic with radiotherapy issues and images, B. Vivanco
Surg. B Skull Base. 74, 324330 (2013). review and meta-analysis. Radiother. Oncol. 110, forpreparing the pathological images shown herein,
91. Ketcham, A.S., Wilkins, R.H., Vanburen, J.M. 915 (2014). andJ. Prez-Escuredo, C. Garca-Incln and
&Smith, R.R. A combined intracranial facial 105. Alonso-Basanta, M., Lustig, R.A. & C.lvarez-Marcos for their active collaboration.
approach to the paranasal sinuses. Am. J. Surg. Kennedy,D.W. Proton beam therapy in skull
106, 698703 (1963). base pathology. Otolaryngol. Clin. North Am. 44, Author contributions
92. Castelnuovo, P., Dallan, I., Battaglia, P. & 11731183 (2011). J.L.L., F.L. and M.A.H. contributed to all stages of the
Bignami, M. Endoscopic endonasal skull base 106. Chen, A.M. etal. Utility of daily image guidance preparation of the manuscript. C.S. made substantial
surgery: past, present and future. Eur. Arch. with intensity-modulated radiotherapy for tumors contributions to discussion of content and review/
Otorhinolaryngol. 267, 649663 (2010). of the base of skull. Head Neck 34, 763770 editing of the manuscript before submission.
93. Ambrosch, P. The role of laser microsurgery (2012).
inthe treatment of laryngeal cancer. Curr. Opin. 107. Hanna, E.Y. etal. Induction chemotherapy Supplementary information is linked to the online
Otolaryngol. Head Neck Surg. 15, 8288 (2007). foradvanced squamous cell carcinoma of the version of the paper at www.nature.com/nrclinonc.

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