2322

Management of Nonsinonasal Neuroendocrine

Carcinomas of the Head and Neck
Jerry L. Barker, Jr., M.D.1
Bonnie S. Glisson, M.D.2
Adam S. Garden, M.D.1
Adel K. El-Naggar, M.D.3
William H. Morrison, M.D.1
K. Kian Ang, M.D., Ph.D.1
K. S. Clifford Chao, M.D.1
Gary Clayman, M.D.4
David I. Rosenthal, M.D.1
1

Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Department of Medical Oncology, The University

of Texas M. D. Anderson Cancer Center, Houston,
Texas.

Department of Pathology, The University of Texas

M. D. Anderson Cancer Center, Houston, Texas.

Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center,
Houston, Texas.

Presented at the 39th Annual Meeting of the American Society of Clinical Oncology (abstract no.
2058), Chicago, Illinois, May 31June 3, 2003.
Address for reprints: David I. Rosenthal, M.D., Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515
Holcombe Boulevard, Houston, TX 77030; Fax: (713)
563-2336; E-mail: dirosenthal@mdanderson.org
Received July 10, 2003; accepted August 26,
2003.
2003 American Cancer Society
DOI 10.1002/cncr.11795

BACKGROUND. Nonsinonasal neuroendocrine carcinomas (NSNEC) of the head

and neck are rare and pose a diagnostic and management challenge. The authors
undertook a retrospective study to gain insights into the spectrum of clinicopathologic characteristics, patterns of failure, and optimal management of patients
with this disease.
METHODS. The authors treated 23 adults with pathologically proven, nonmetastatic,
primary NSNEC from 1984 to 2001. The majority (13 patients) had laryngeal origin
with the following American Joint Committee on Cancer stage distribution: Stage I
disease in 1 patient, Stage II disease in 2 patients, Stage III disease in 6 patients, and
Stage IV disease in 14 patients. Nine patients underwent denitive surgery with or
without postoperative radiation, and 14 patients received denitive radiotherapy. The
median denitive radiation dose was 66 grays (Gy) (range, 44 72 Gy) using conventional fractionation. Fourteen patients received chemotherapy, with two to four cycles
of induction platinum plus etoposide used most commonly.
RESULTS. The median follow-up time for surviving patients was 40 months (range,
15 89 months). The actuarial 2-year and 5-year overall survival (OS) rates were
53% and 33%, respectively; and the disease-free survival (DFS) rates were 41% and
25%, respectively. Both the 2-year OS rate (68% vs. 30%; P 0.002) and the 2-year
DFS rate (55% vs. 17%; P 0.004) were improved with chemotherapy compared
with local therapy alone. Seventy-ve percent of patients with measurable disease
had complete clinical responses to induction chemotherapy. There was 100%
complete clinical response of tumor after radiotherapy. The actuarial 2-year local
failure rate was 23%. Chemotherapy did not reduce local failure (P 0.91). There
was no regional failure. The 2-year and 5-year distant metastasis rates were 54%
and 71%, respectively. The 2-year rates of metastases without and with chemotherapy were 79% and 39%, respectively (P 0.006). The 2-year and 5-year rates of
intracranial metastases were 25% and 44%, respectively, and the 2-year and 5-year
rates of isolated brain metastases were 21% and 41%, respectively.
CONCLUSIONS. Based on these results, the authors treatment strategy for patients
with NSNEC is sequential chemotherapy and radiation. They recommend full-dose
radiotherapy alone for patients with NSNEC who achieve a complete clinical response
to induction chemotherapy. Newer chemotherapeutic regimens or additional adjuvant chemotherapy should be investigated for patients with NSNEC given the high rate
of distant failure. Due to the very high rate of brain metastases among patients in the
current study, the authors now consider incorporating prophylactic cranial irradiation
into primary radiotherapy for individual patients who have complete clinical responses to induction chemotherapy. Cancer 2003;98:2322 8.
2003 American Cancer Society.

KEYWORDS: head and neck carcinoma, neuroendocrine carcinoma, prophylactic

cranial irradiation, chemoradiation.

rimary neuroendocrine carcinomas are uncommon head and

neck malignancies. They present with a varied histopathologic
spectrum in sinonasal and nonsinonasal head and neck subsites. The

Nonsinonasal Neuroendocrine Carcinomas/Barker et al.

sinonasal carcinomas are more diverse, with four major histologic phenotypes: esthesioneuroblastoma, sinonasal undifferentiated carcinoma, neuroendocrine
carcinoma, and small cell undifferentiated carcinoma.1
These tumors occur with enough frequency that specic
treatment strategies have emerged.25 The nonsinonasal
neuroendocrine carcinomas (NSNECs), however, are
represented predominantly by small cell undifferentiated carcinomas, followed by moderately differentiated
(atypical carcinoid) carcinomas and well-differentiated
(typical carcinoid) carcinomas. The NSNECs are rare
enough that they are represented in the literature primarily by sporadic case reports.6 We contend that the
differences in tumor types and treatment strategies for
sinonasal and nonsinonasal sites justify a separate analysis. We reviewed our institutional experience in patients
with NSNEC to determine the optimal management parameters for this disease.

2323

Pathologic Analysis
Combined cytomorphologic and immunohistochemical features of neuroendocrine differentiation formed
the basis for diagnosis. All tumors that had small cells
(well differentiated, moderately differentiated, and
undifferentiated) with positive staining for keratin,
neuron-specic enolase, and chromogranin were included in this study. There was 1 well-differentiated
carcinoma (typical carcinoid), 1 moderately differentiated carcinoma (atypical carcinoid), and 19 small cell
undifferentiated carcinomas. Two tumors were hybrids, with a component of squamous cell carcinoma
within an extensive background of small cell carcinoma. Tumors that potentially could be confused8
with NSNEC (including paraganglioma,9 medullary
carcinoma,10 basaloid squamous cell carcinoma,11
melanoma,12 pituitary adenoma/carcinoma,13 or Merkel cell carcinoma14) were excluded from the current
analysis.

MATERIALS AND METHODS

Statistical Analysis

Patient Population

Estimated rates of local failure (LF), distant failure,

disease-free survival (DFS), and overall survival (OS)
were calculated using the KaplanMeier method. Survival estimates were calculated from date of diagnosis.
Clinical and pathologic variables were assessed using
the Mantel log-rank test for univariate analysis, and
the Cox proportional hazards model was used for multivariate analysis. Retrospective categorization of late
treatment toxicity was determined according to the
National Cancer Institute Common Toxicity Criteria
Version 2.0 (which includes the Radiation Therapy
Oncology Group/European Organization for Research
and Treatment of Cancer Late Radiation Morbidity
Scoring Schema).15

We reviewed the medical records of 23 adults who

were treated for primary NSNEC of the head and neck
at The University of Texas M. D. Anderson Cancer
Center (UTMDACC; Houston, Texas) between 1984
and 2001. The patient population was identied
through a search of the Tumor Registry database
maintained by the Department of Medical Informatics. All patients had newly diagnosed, nonmetastatic
tumors arising from nonsinonasal head and neck subsites and were treated with curative intent. Patients
who were seen at UTMDACC for consultation only or
for treatment of recurrent disease were excluded. Histopathologic slides prepared from archived blocks
were reviewed, and immunohistochemical and electron microscopic ndings were reevaluated by an experienced head and neck pathologist for every patient.
This retrospective review received Institutional Review
Board approval, and patient data were maintained
condentially throughout the study.
Staging evaluation for these patients included history and physical examination, screening laboratory
studies, chest X-ray, contrast-enhanced computed tomography (CT) scan or magnetic resonance image of
the head and neck, and biopsy of primary or lymph
node disease in all patients. Abnormalities on chest
X-rays were evaluated further (with chest CT or biopsy) as necessary to exclude metastatic disease. Tumors were restaged according to the American Joint
Committee on Cancer (AJCC) staging manual,7 based
on documented clinical, imaging, and pathologic ndings.

RESULTS
Patient Characteristics
The median patient age at diagnosis was 64 years
(range, 38 86 years), and males were diagnosed as
commonly as females (Table 1). Eighty-three percent
of patients were current or former smokers, with a
median 50 pack-years (range, 0 160 pack-years) of
tobacco use reported. The majority (13 patients) had
laryngeal primary tumors. Most patients presented
with locoregionally advanced disease. The distribution
according to the AJCC staging system was as follows:
Stage I in 1 patient, Stage II in 2 patients, Stage III in
6 patients, and Stage IV in 14 patients.

Treatment Characteristics
Prescribed therapy varied during the long study interval, as is expected for a rare disease. Nine patients had

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CANCER December 1, 2003 / Volume 98 / Number 11

TABLE 1
Patient Characteristics
Characteristic
Gender
Male
Female
Primary site
Larynx
Supraglottic
Glottic
Subglottic
Oropharynx
Oral cavity
Hypopharynx
Nasopharynx
Parotid gland
Tumor status
T1
T2
T3
T4
Tx
Lymph node status
N0
N1
N2
N3
AJCC stage
I
II
III
IV

No. of patients (%)

12 (52)
11 (48)
13 (56)
11 ()
1 ()
1 ()
3 (13)
1 (4)
2 (9)
2 (9)
2 (9)

FIGURE 1. Overall survival (all patients).

4 (17)
5 (22)
6 (26)
5 (22)
3 (13)
5 (22)
4 (11)
10 (44)
4 (17)
1 (4)
2 (9)
6 (26)
14 (61)

AJCC: American Joint Committee on Cancer.

denitive surgery (with or without postoperative radiotherapy [RT]), and 14 patients had denitive RT.
The median denitive radiation dose was 66 grays (Gy)
(range, 44 72 Gy) using conventional fractionation.
RT treatment volumes included the primary tumor
and bilateral cervical/supraclavicular lymph nodes for
nearly all patients; contralateral lymph nodes were
excluded for highly selected patients with well-lateralized primary tumors (e.g., parotid gland). No patient
received prophylactic cranial irradiation (PCI).
Fourteen patients received chemotherapy in addition to local therapy. Nine patients had induction
chemotherapy followed by denitive RT or chemoradiation; one of those patients received additional cycles of adjuvant chemotherapy. Eight of nine patients
who were treated with induction chemotherapy were
evaluable for clinical disease response; one patient
had no evaluable disease after generous biopsy of the
primary lesion. Six of 8 evaluable patients (75%) had
complete clinical responses to induction chemotherapy; the remaining 2 patients had stable disease.
There was 100% tumor clearance after RT, however.

FIGURE 2. Overall survival according to use of any chemotherapy (induction,

concurrent, or adjuvant).
Two to four cycles of platinum/etoposide comprised
the most common induction regimen. Two patients
were treated with denitive chemoradiation (without
induction). Two patients had adjuvant chemotherapy
after local treatment, and a single patient was treated
with postoperative, concurrent chemoradiation.

OS and DFS
The median follow-up time for surviving patients was
40 months (range, 15 89 months). The actuarial
2-year and 5-year OS rates were 53% and 33% (Fig. 1),
respectively; and the DFS rates were 41% and 25%,
respectively. Both 2-year OS (68% vs. 30%; P 0.003)
and 2-year DFS (55% vs. 17%; P 0.004) were improved with use of chemotherapy compared with local
therapy alone (Fig. 2). AJCC stage (Stage IIII vs. Stage
IV) and cervical lymph node status (positive vs. negative) also signicantly predicted 2-year OS in a univariate analysis (Table 2). The use of chemotherapy, how-

Nonsinonasal Neuroendocrine Carcinomas/Barker et al.

2325

TABLE 2
Prognostic Factors for Survival in Patients with Nonsinonasal
Neuroendocrine Carcinomas of the Head and Neck: All Patients
P value
Factor
Age (continuous variable)
Gender
Male
Female
Cervical lymph node status
Negative
Positive
AJCC stage
IIII
IV
History of cigarette use
Yes
No
Primary tumor site
Larynx
Other
Denitive local treatment
Surgerya
Radiotherapyb
Chemotherapy used
Yesc
No

No. of
patients

Two yr
OS (%)

Univariate

Multivariate

23

N/A

0.71

12
11

59.9
45.5

0.82

5
18

100.0
40.1

0.031

0.07

9
14

85.7
33.3

0.028

0.43

19
4

75.0
48.5

0.64

13
10

59.3
45.7

0.94

9
14

40.0
61.4

0.25

0.15

14
9

68.1
29.6

0.003

0.009

FIGURE 3. Freedom from distant metastases (all patients).

OS: overall survival; N/A: not available; AJCC: American Joint Committee on Cancer.
a
Includes patients who received postoperative radiotherapy.
b
Includes patients who underwent planned neck dissection after radiotherapy.
c
Includes patients who were treated with induction, concurrent, and/or adjuvant strategies.

FIGURE 4.
ever, was the only signicant factor (P 0.009) in a
multivariate analysis of OS that included AJCC stage,
lymph node status, local treatment modality, and use
of chemotherapy.

Patterns of Failure
Four patients had LF, yielding actuarial 2-year and
5-year LF rates of 23% and 23%, respectively. Chemotherapy did not reduce the LF rate (P 0.91); however,
the 2 nonresponders to induction chemotherapy represented 50% of the patients who had LF. Among
patients who were treated denitively with RT, the
prescribed total dose in the range of 44 72 Gy was not
correlated with LF (P 0.23). There was no regional
cervical lymph node failure.
The 2-year and 5-year distant metastasis (DM)
rates were 54% and 71%, respectively (Fig. 3), and the
2-year DM rates without and with chemotherapy were
79% and 39%, respectively (P 0.006). All patients
who were not treated with chemotherapy failed distantly by 25 months (Fig. 4). The 2-year and 5-year
rates of intracranial metastases were 25% and 44%,

Freedom from distant metastases according to use of any

chemotherapy (induction, concurrent, or adjuvant).

respectively. The brain was the only site of DM at

2-year and 5-year rates of 21% and 41%, respectively
(Fig. 5).

Late Effects of Treatment

Grade 12 high-frequency hearing loss was documented among patients who were treated with multiple cycles of cisplatin-based chemotherapy; this
prompted a change to carboplatin for 1 patient. After
locoregional RT, Grade 12 xerostomia (8 patients),
Grade 2 hypothyroidism (1 patient), Grade 2 serous
otitis (1 patient), and Grade 2 esophageal stricture (1
patient) were reported. None of the patients developed Grade 35 late toxicity.

DISCUSSION
NSNECs of the head and neck are uncommon and
previously were characterized poorly. Prior studies of
these tumors were limited in scope and number and

2326

CANCER December 1, 2003 / Volume 98 / Number 11

FIGURE 5. Freedom from intracranial metastases (all patients).

included heterogeneous sites and histologies as well
as patients with DM.16 20 These shortcomings were
compounded by the lack of ancillary markers for the
unequivocal diagnosis of neuroendocrine derivation.
Our study was limited to patients with locoregionally
conned disease who were diagnosed and treated
since 1984; this insured that all patients were diagnosed accurately using modern immunohistochemical and electron microscopic techniques, and these
were reviewed and conrmed individually. Patients
received their treatment at a single, high-volume, tertiary cancer care center. There were only 23 patients in
17 years who met these strict criteria. Although this
relatively small denominator makes sweeping conclusions less reliable, to our knowledge, this is the largest
reported homogenous data set that can be used to
direct treatment strategies based on patterns of failure
without resorting to meta-analysis.21
In this series, the use of combination chemotherapy approximately doubled the 2-year OS and DFS
rates and reduced by one-half the 2-year rate of DM.
NSNEC is highly responsive to cisplatin/etoposide
combination chemotherapy, and it was found that the
use of this treatment regimen was the single most
important factor in the improvement of treatment
outcomes. Responses to chemotherapy typically were
not durable, however, and 80% of patients ultimately succumbed to DM (Fig. 3). It is possible that
newer agents, such as camptothecin derivatives or
taxanes, may produce better responses and more durable control, but this will require additional study.22
The 23% 2-year local failure rate for patients with
NSNEC is approximately one-half of the rate seen in
patients with similarly staged squamous carcinomas.23 In contrast, DMs represent the major pattern of
failure for NSNEC, occurring at a rate nearly double
that of local failure. Therefore, we recommend non-

surgical therapy for most patients using combined

chemotherapy and RT. The single patient in our series
who had a well-differentiated neuroendocrine carcinoma (typical carcinoid) underwent a supraglottic laryngectomy and remains free of disease at 32 months.
This is consistent with the nding that surgery alone
may be adequate for the very rare carcinoid and carcinoid-like tumors of the head and neck, as it is for
carcinoid and carcinoid-like tumors at other body
sites.24 The extreme rarity of head and neck carcinoids
(fewer than 20 patients are reported in the published
literature6) makes it impossible to make any different
treatment recommendation for those arising in head
and neck sites different from those arising at any other
body site.
The local control rates in this series also were
higher compared with the rates reported for patients
with small cell carcinoma of the lung. This may have
been due to the higher total RT doses used in the head
and neck (60 70 Gy), although we could not establish
clearly a dose-response relation, the higher response
to induction therapy, or both. Although there is evidence that concurrent chemoradiation rather than sequential chemoradiation is a more effective method
for inducing a complete clinical response in patients
with small cell lung carcinoma,2527 sequential chemoradiation appears to be an adequate and less toxic
means of securing local control for most patients with
NSNEC.
The high rates of isolated intracranial metastases
suggest that the central nervous system may be a
sanctuary site for NSNEC. PCI after patients achieve a
complete response to locoregional therapy is used for
other tumor systems that manifest high rates of brain
metastases, and it has been demonstrated that PCI
reduces the frequency of brain metastases and improves OS in patients with small cell lung carcinoma.28 30 By analogy, we now consider PCI for patients
with NSNEC who have had a complete clinical response to induction therapy. Because matching
whole-brain RT elds to prior head/neck elds is complex at best, it is advantageous theoretically to incorporate PCI into primary RT. This may be accomplished by treating large initial elds that include
whole brain, primary tumor site, and draining regional
lymph nodes to a dose of 28 30 Gy at 2 Gy per day
(Fig. 6). This approach is supported by the previous
successful application of PCI regimens using conventional 2-Gy fractions.31,32
In conclusion, we recommend treating patients
who have NSNEC with induction chemotherapy followed by RT alone for complete responders. Concurrent chemoradiotherapy does not necessary appear to
improve early complete response, local control, or

Nonsinonasal Neuroendocrine Carcinomas/Barker et al.

5.

6.

7.

8.

9.

10.

11.

12.

FIGURE 6.

Hypothetical primary radiotherapy eld (including prophylactic

cranial irradiation) for a patient with laryngeal or hypopharyngeal neuroendocrine carcinoma.

survival, and it is a more toxic induction technique. An

induction approach is most likely to deliver the
planned dose intensity of systemic chemotherapy, the
single most important factor driving survival in our
analysis. Finally, the sequential use of chemotherapy
and RT allows for the potential incorporation of PCI
into denitive radiation elds. If concurrent chemoradiation is used, then PCI cannot be administered
simultaneously without a signicant increase in toxicity.33 If there is a less than complete response to
induction therapy, however, then the problem of local
control dominates, and concurrent chemoradiation or
surgery should be considered; the use of PCI becomes
a less relevant issue in this setting.

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