ORIGINAL ARTICLE
Merkel cell carcinoma of the head and neck: Favorable outcomes with radiotherapy
Andrew J. Bishop, MD,1 Adam S. Garden, MD,1 G. Brandon Gunn, MD,1 David I. Rosenthal, MD,1 Beth M. Beadle, MD, PhD,1 Clifton D. Fuller, MD, PhD,1
Lawrence B. Levy, MS,1 Ann M. Gillenwater, MD,2 Merrill S. Kies, MD,3 Bita Esmaeli, MD,4 Steven J. Frank, MD,1 Jack Phan, MD, PhD,1
William H. Morrison, MD1*
1
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 2Department of Head and Neck Surgery, The University of Texas MD
Anderson Cancer Center, Houston, Texas, 3Department of Thoracic/Head and Neck Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, 4Orbital
Oncology and Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Accepted 28 January 2015
Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24017
ABSTRACT: Background. The purpose of this study was to report the
outcomes of patients with Merkel cell carcinoma (MCC) of the head and
neck using a radiation-based treatment approach.
Methods. We reviewed records of 106 consecutive patients with MCC of
the head and neck treated with radiation therapy (RT) at our institution
between 1988 and 2011. The Kaplan–Meier method was used to estimate outcomes and hazard ratios (HRs) were calculated.
Results. The 5-year actuarial local and regional control rates were 96%
and 96%, respectively. There were no regional recurrences in 22
patients treated with RT to gross nodal disease without neck dissection.
The 5-year cause-specific survival rate was 76%. Lymphadenopathy at
INTRODUCTION
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine tumor with possible viral etiology
and increasing incidence.1,2 The most common site of origin is the head and neck.2,3 This dermal malignancy is
known to have high rates of regional and distant
progression.
Because of the rarity of MCC, therapeutic recommendations are based primarily on relatively small, single
institution retrospective studies. Treatment is often multimodal, and surgery is usually the preferred initial therapy.
Although no objective evidence supports the need for
“wide” margins, a wide local excision (WLE) with 1 to
2-cm margins is typically performed.4 Unfortunately, in
the head and neck, wide surgical margins can result in
significant cosmetic and functional deformities because of
the close proximity of important organs. After WLE, consideration is given to the use of adjuvant radiation therapy
(RT). Previous reports have demonstrated that adjuvant
RT improves local control.5,6 However, despite evidence
for the benefit of adjuvant local RT, the National Comprehensive Cancer Network (NCCN) guidelines recom-
*Corresponding author: W. H. Morrison, Department of Radiation Oncology,
Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe
Blvd., Houston, TX 77030. E-mail: [email protected]
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presentation impacted distant metastatic-free survival outcomes
(p < .001). Treatment was well tolerated with only 5 patients having
grade 3 toxicities.
Conclusion. For MCC of the head and neck, a management strategy that
includes RT offers excellent locoregional control. Gross nodal disease
C 2015 Wiley Periodicals, Inc. Head
can be successfully treated with RT. V
Neck 38: E452–E458, 2016
KEY WORDS: Merkel cell carcinoma, radiotherapy, head and neck,
adjuvant therapy, cutaneous neuroendocrine
mend either observation or adjuvant RT to the primary
site7; institutional preferences often dictate its use.
Management of the draining lymphatics is less welldefined, and involvement of regional nodes is challenging
to predict.8–10 Therefore, strategies continue to evolve for
the optimal management of potential lymphatic metastases. Recent practice has steered toward histologic evaluation of the clinically negative neck using sentinel lymph
node biopsy.11–14 Although this approach has been widely
adopted, few reports document the outcomes of patients
managed with sentinel lymph node biopsy. The management of clinically positive regional disease is less controversial; treatment options consist of either a lymph node
dissection with or without adjuvant RT or nodal RT
alone. Systemic chemotherapy is also used in select
cases.7
Before 1990, patients with MCC were treated at our
institution with doses similar to those given for squamous
cell carcinoma, and the therapeutic approach for patients
with nodal disease was neck dissection and postoperative
RT. However, an analysis done at that time demonstrated
the impressive radiosensitivity of the disease.15 Thereafter, for primary tumors, while we continued to perform
conservative local excision, the treatment algorithm was
based on RT as the principal therapeutic modality. Postoperative RT was delivered to the primary site, and most
patients presenting with nodal disease received RT to the
neck. Because of the radiosensitivity of MCC, we
MERKEL
decreased the regional dose for patients who presented
without clinical nodal disease from 50 Gray (Gy) to 46
Gy. We did not routinely perform sentinel lymph node
biopsy or nodal dissections; neck dissections were typically reserved for patients with persistent disease after
RT.
We conducted the present study with the following
goals: (1) to confirm that delivering adjuvant RT to the
primary tumor site resulted in high local control rates; (2)
to determine whether RT delivered to the neck in lieu of
surgical staging of stage I and II disease resulted in comparable or enhanced regional control rates; (3) to evaluate
the results of lowering the elective RT dose (46 Gy) to
the draining lymphatics; and (4) to determine whether
delivering definitive RT to patients presenting with gross
nodal disease can eliminate the need for neck dissection.
MATERIALS AND METHODS
Patients
With permission from the Institutional Review Board,
databases were queried for eligible patients with MCC of
the head and neck diagnosed between 1988 and 2011 and
treated with RT at The University of Texas MD Anderson
Cancer Center. Pathologic confirmation of the diagnosis
of MCC was made by institutional pathologists. Patients
were excluded from this study if initial RT was delivered
at an outside institution or if patients were treated with
palliative intent.
The patient characteristics coded included: demographics, pathologic markers, recurrence status at presentation, tumor site, features and stage, distant metastatic
workup, treatment modalities, radiation technique and
dose, chemotherapy delivered, and date of last follow-up,
death, and disease-specific death.
Tumor stage was determined using the American Joint
Committee on Cancer seventh edition, 2010 staging system for MCC. A primary lesion was coded as recurrent if
it had been excised with a negative margin but was clinically or radiographically apparent before receiving RT or
if it had recurred after surgical excision without receiving
adjuvant RT; the RT was coded as salvage in these scenarios (vs adjuvant or definitive).
CELL CARCINOMA OF THE HEAD AND NECK
graphic imaging, and/or pathologic biopsy, and then
categorized as local, regional (nodal), or distant failures.
Furthermore, patterns of local and regional recurrences
were subcategorized as occurring in-field, at the field
margin, or out-of-field based on the site of recurrence and
the borders of the RT fields. Date of death was recorded,
and MCC was coded as the cause of death if notated in
the medical records or if the patient had developed recurrent disease before death. Toxicity was retrospectively
scored based on the Radiation Therapy Oncology Group
scoring criteria.
Statistical analysis
Descriptive statistics were used to evaluate baseline
characteristics and categorical data were analyzed by
using Fisher’s exact test. Survival times were calculated
from the start of RT to the event. The Kaplan–Meier
method was used to estimate local control, regional control, locoregional control, distant metastasis-free survival,
progression-free survival, overall survival (OS) and
cause-specific survival (CSS) of the entire cohort. Logrank tests were used to evaluate differences in survival
functions. A 2-sided 5% significance level was used for
analysis. Hazard ratios (HRs) were estimated with Cox
models and reported with 95% confidence intervals. Statistics were carried out using SAS/STAT v 9.3 user’s
guide (SAS Institute, Cary, NC).
RESULTS
Patient and tumor characteristics
One hundred six patients met criteria for the study.
Patient characteristics are summarized in Table 1. The
median age was 71 years (range, 37–93 years) with a
median tumor size of 10 mm (range, 2–40 mm). The
American Joint Committee on Cancer T classifications
were: TX-9, T0–4, T1–71, T2–20, and T4-2. The type of
initial biopsy varied (excisional, 41; incisional, 42; shave,
20; and unknown, 3). Microscopic and gross nodal disease was present in 36 patients (cN0–58, pN0–11, N1a-5,
N1b-31, and N2 [in-transit metastasis]-1). Primary sites
and tumor stages are listed in Table 1.
Treatment characteristics
Local therapy
The treatment regimen for each patient was detailed.
For the analysis, excisional biopsies were classified as
surgical excisions if margins were negative. Sentinel
lymph node biopsies and neck dissections were notated.
When administered, chemotherapy consisted of cisplatin
or carboplatin and etoposide for 3 to 4 cycles.
Radiation dose and field design were based on departmental guidelines, but ultimately were determined by the
individual treating physician. Treatment fields included
the primary site and ipsilateral neck down to the clavicle.
The treatment modality (electron vs photon), RT dose,
and fractionation were recorded.
Eighty-eight patients underwent primary surgical excision with 47 patients having a completion WLE after a
positive margin biopsy, and 41 patients had a negative
margin biopsy upfront. The other 18 patients did not
undergo surgical reexcision after a positive-margin
biopsy. Instead, these primarily T1 lesions (n 5 13) were
treated with RT to doses between 60 and 66 Gy. Eleven
patients had gross primary disease at the time of RT.
All patients (n 5 106) received RT to the primary site
(Table 1). Field margins around the primary site were
location and clinician-dependent, but usually consisted of
at least 3 cm. Treatment types and median doses are
listed in Table 2. Dose was predominantly delivered at 2
Gy per fraction (n 5 103). Electron beam treatments were
prescribed to a median isodose line of 90% (range, 85%
to 100%) and photons to a median isodose of 98% (range,
89% to 99.5%).
Follow-up
Patients were followed every 3 to 6 months for the first
2 to 3 years and then typically yearly thereafter. Recurrences were identified by physical examination, radio-
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TABLE 1. Patient and treatment characteristics (n 5 106).
Variables
TABLE 2. Radiation doses and modalities to the primary site and neck.
Value or no. (%)
Follow-up time, mo
Median
Range
Sex
Male
Female
Ethnicity
White
Hispanic
Asian
Extensive sun exposure
Immunocompromised
Leukemia/lymphoma
Transplant
Psoriasis
Previous skin cancer
Site of primary tumor
Cheek
Forehead/temple
Eyelid/orbital ridge
Other
Nose
Helix
Workup
Chest X-ray
CT/MRI head and neck
CT chest
PET scan
Stage
IA
IB
IIB
IIC
IIIA
IIIB
TX
Recurrence before RT
Local treatments (n 5 106)
Surgery 1 postoperative RT
RT only*
Regional treatments for N0 (n 5 70)
Surgery 1 postoperative RT
RT only
Sentinel lymph node biopsy only
No surgery or RT
Regional treatments for N1 (n 5 36)
Surgery 1 postoperative RT
RT only†
Sentinel lymph node biopsy (n 5 12)
Positive
Negative
Systemic treatment (n 5 18)
Neoadjuvant
Adjuvant
39
1–233
71 (67)
35 (33)
94 (89)
11 (10)
1 (1)
19 (18)
6 (6)
3 (3)
1 (1)
42 (40)
27 (25)
19 (18)
17 (16)
11 (10)
10 (9)
8 (8)
99 (93)
87 (82)
56 (53)
27 (25)
9 (8)
39 (37)
8 (8)
1 (1)
5 (5)
33 (31)
9 (8)
17 (16)
88 (83)
18 (17)
2 (3)
62 (89)
4 (5)
2 (3)
14 (39)
22 (61)
5 (42)
7 (58)
12 (67)
6 (33)
Abbreviations: PET, positron emission tomography; TX, primary tumor could not be assessed
and was unable to be staged; RT, radiation therapy.
* Radiation only for the primary means there was either residual microscopic disease (n 5 7)
or gross disease (n 5 11) at the time of RT.
†
Ten patients were treated with neoadjuvant chemotherapy before RT without nodal
dissection.
Nodal and neck management
Sentinel lymph node biopsy was performed in 12
patients and lymphoscintigraphy alone in 2 patients. Five
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Variables
Radiation dose delivered, Gy
Gross
Margin (1)
Margin (2)
Subclinical
Radiation modality used
Electrons
Photons
Mixed
No radiation
Primary site RT
Median (range)
or no. (%)
Neck RT
Median (range)
or no. (%)
65 (60–66)
60 (52–64)
56 (50–62)
–
66 (60–68)
56 (50–60)
56 (46–60)
46 (44–60)
87 (82)
17 (16)
2 (2)
–
70 (66)
30 (28)
–
6 (6)
Abbreviations: RT, radiation therapy; Gy, Gray.
patients had a positive sentinel lymph node and underwent surgery followed by postoperative RT. Of the 7
patients who had negative sentinel lymph node biopsy, 3
were treated with neck RT and 4 were not.
Thirty-six patients had clinical or pathologic evidence
of nodal disease; 17 patients had only 1 lymph node
involved and 19 had 2. The most commonly involved
lymph nodes were intraparotid (n 5 11) and preauricular
(n 5 8), and were at levels II (n 5 11) and IB (n 5 9).
Regional treatment for N1a (n 5 5) or N1b (n 5 31) disease included RT without dissection (n 5 22), parotid or
preauricular lymph node excision followed by postoperative RT (n 5 8), and neck dissections followed by RT
(n 5 6).
For ipsilateral neck irradiation, the RT fields extended
down to the clavicle in 99 patients. In the other 7
patients, 1 patient was treated with a field that only covered the upper neck, and 6 patients were not treated with
neck RT. Eighty patients were treated with 46 Gy to the
elective neck. Radiation doses to the neck are listed in
Table 2. For neck fields treated with electron beam, the
isodose prescription was uniformly 90% and the photon
median isodose prescription was 98% (range, 96.5% to
99.5%).
Managing recurrent disease
Seventeen patients had recurrent tumors at the time of
RT after a previous negative margin excision. Lymph
nodes were involved in 53% of the recurrent cases
(n 5 9), with 7 patients having disease in the preauricular
or parotid lymph nodes at minimum. Eleven patients had
re-resections before proceeding with adjuvant RT; 6
patients received RT alone. Four of these patients
received systemic chemotherapy as part of their treatment
regimen.
Chemotherapy
Multiagent chemotherapy was used as a component of
a multimodality approach for 18 patients (neoadjuvant,
12; adjuvant, 6). Neoadjuvant chemotherapy was administered to a third of the patients who were designated stage
III, using combined cisplatin or carboplatin and etoposide
(n 5 11) or taxol/ifosfamide/carboplatin (n 5 1) for 3
MERKEL
CELL CARCINOMA OF THE HEAD AND NECK
FIGURE 1. Survival curves generated using the Kaplan–Meier method representing cumulative incidences of outcomes. (A) Locoregional control;
(B) distant metastatic-free survival; (C) cause-specific survival; and (D) overall survival.
cycles. Ten patients with N1b disease were treated with
neoadjuvant chemotherapy followed by RT without neck
dissection. Adjuvant chemotherapy was given to 14% of
the patients with stage III disease (n 5 5) and 1 patient
with stage IA disease in 4 cycle schedules.
Outcomes
The median follow-up was 39 months (range 5 1–233
months) for the entire cohort and 44 months (range 5 3–
162 months) for all living patients. The 5-year local control and regional control were both 96% with a 5-year
locoregional control rate of 92%. Distant metastases were
more common with a 5-year distant metastasis-free survival of 73%. The 5-year OS rate was 58%, and the 5year CSS rate was 76% (see Figure 1).
There were 4 local recurrences (1 in-field and 3 at the
radiation field margin) that occurred within 4 to 7 months
after irradiation (median, 5.5 months). Three patients had
regional recurrences (1 in-field, 1 out-of-field, and 1 in
the unirradiated contralateral neck) within 7 to 32 months
(median, 14 months); distant metastases were identified in
24 patients within 3 to 59 months (median, 9 months).
The liver was the first site of distant recurrence in 12 of
the patients (50%) developing metastases.
Recurrence status at presentation was significantly associated with lower 5-year local control (recurrent 5 82%,
not 5 99%;
p 5 .001)
and
locoregional
control
(recurrent 5 75%, not 5 96%; p 5 .002). Furthermore, on
multivariate analysis, recurrence status maintained significance as a variable associated with subsequent local
recurrence (HR 5 16.35; p 5 .008), but not OS or CSS.
Our preferred strategy for patients presenting with
involved neck nodes was definitive RT (delivered after
neoadjuvant chemotherapy in 10 patients), with surgery
reserved for patients with persistent disease after the completion of irradiation. No regional recurrences occurred in
patients treated with definitive RT (1/2 chemotherapy)
for gross nodal disease (5-year regional control 100%;
Table 3). Nodal status at presentation was significantly
associated with 5-year distant metastasis-free survival
rates (N1 5 53% vs N0 5 87%; p < .001) and with an
increased risk of distant metastasis (HR 5 3.99; p 5 .001).
When compared to node-negative patients, those patients
with multiple nodes and/or a single node larger than 3 cm
had worse outcomes (distant metastasis: HR 5 4.77;
p < .001; CSS: HR 5 3.90; p 5 .007).
Radiation therapy toxicity
There were 5 patients with grade 3 late toxicities: 4
ocular and 1 mandibular. Radiation retinopathy (periorbital primary; definitive, 65 Gy), recurrent corneal ulceration requiring corneal transplant (upper eyelid;
postoperative, 56 Gy), chronic cicatricial retraction and
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TABLE 3. Nodal management and outcomes for patients presenting with
N1 disease.
Variables
Nodal disease
N1a
N1b
Median node size, cm
Node size range, cm
Lowest nodal level
Auricular/parotid
I
II
III
IV
V
Regional management
Surgery 1 postoperative RT
RT alone
Chemotherapy
Neoadjuvant
Adjuvant
Regional recurrences
Distant recurrences
All N1 disease
(n 5 36)
Value or no. (%)
N1 treated
with RT
alone (n 5 22)
Value or no. (%)
5 (14)
31 (86)
1.5
0.6–6
0 (0)
22 (100)
1.5
0.9–4.3
13 (36)
8 (22)
5 (14)
3 (8)
3 (8)
4 (11)
7 (32)
7 (32)
2 (9)
3 (14)
2 (9)
1 (5)
14 (39)
22 (61)
–
22 (100)
12 (33)
5 (14)
1 (3)
15 (42)
10 (45)
5 (23)
0 (0)
9 (41)
Abbreviation: RT, radiation therapy.
keratopathy (upper eyelid; postoperative, 60 Gy), and eye
enucleation secondary to RT/surgical complications
(upper eyelid; postoperative, 60 Gy) were late orbital toxicities that occurred despite use of eye shielding. The
median time to orbital toxicity was 16 months. One
patient developed osteoradionecrosis requiring mandibulectomy after dental manipulation approximately 4 years
after radiation to 66 Gy.
DISCUSSION
This is the largest single institution analysis describing
the outcomes associated with definitive and adjuvant RT
for MCC of the head and neck. Our excellent locoregional control rates emphasize the importance of a multimodality approach to MCC and indicate that RT should
remain an integral component of treatment.
The need for adjuvant radiation to the primary site in
patients with stage I and II disease is controversial. Fields
et al13 at Memorial Sloan–Kettering Cancer Center
(MSKCC) reported that of 221 patients with pathologic
stage I and II disease with MCC at all anatomic sites,
81% were treated to the local tumor bed with surgery
alone. Their crude local and in-transit recurrence rate was
8%. At Massachusetts General Hospital (MGH), 49% of
the patients with stage I and II disease at all sites were
selected for treatment with surgery alone, and the crude
local recurrence rate was 9%.12 These local recurrence
rates are considerable despite occurring in well-selected
patients with early stage disease. Our series, by contrast,
reports on only head and neck cases in which wide margins can be more difficult to achieve because of anatomic
constraints and perhaps a higher rate of local recurrence
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would be expected. Furthermore, our cohort was comprised of all stages of patients (nearly 40% stage III) and
included 18 patients with positive surgical margins, 11 of
whom had macroscopic local disease at the time of RT.
Our actuarial local recurrence rate was only 4% at 5 years
among a population of patients with probable higher risk
for local recurrence than those reported at MSKCC and
MGH.
Lok et al6 described a series of 48 patients treated with
RT at MSKCC and also reported that RT was both welltolerated and effective. Local control in the radiation field
was 100%; 2 patients (4%) recurred at the field margin,
reinforcing the need to irradiate with wide margins. Relative indications for adjuvant local irradiation, according
to Lok et al,6 include larger tumors (eg, T2–T4 disease),
positive/close surgical margins, and invasive histologic
patterns or the presence of lymphovascular invasion. Considering the favorable therapeutic ratio, we recommend
irradiating the primary tumor site in nearly all patients. In
those patients with midline scalp or upper eyelid lesions,
additional consideration is warranted because RT to the
bilateral salivary glands or upper eyelid can cause significant morbidity.
Optimal management of the draining lymphatics for
MCC is more controversial and inadequately analyzed. It
has been argued that, given the prognostic importance of
nodal status and the high rate of occult metastasis, histopathologic analysis of the nodes should be standard.11–13,16 The NCCN and others have recommended
histologic evaluation of lymph nodes with sentinel lymph
node biopsy in all patients who present with clinical N0
disease, although objective data supporting this position
are limited.7,9,11 Some suggest that high rates of occult
metastases (29% to 50%)11,17 and identifying lymphatic
drainage patterns to direct regional treatment justify sentinel lymph node biopsy. However, many of the primary
lesions are excised before lymphoscintigraphy, which
brings into question the accuracy of the sentinel node
biopsy. Few centers have reported their long-term
regional control rates after sentinel lymph node biopsy.
Fields et al11 at MSKCC documented a false-negative
sentinel lymph node biopsy rate of 15%, similar to that
described for melanoma of the head and neck (20%).18
Santamaria–Barria et al12 published a 30-year experience
from MGH and reported a 39% rate of recurrence in 18
patients with sentinel lymph node biopsy-negative disease; 5 of these 18 patients recurred in locoregional sites.
These data suggest that a number of patients are harboring regional disease despite having a negative sentinel
lymph node biopsy.
Our data provide evidence for an alternative approach
to sentinel lymph node biopsy with excellent tumor control outcomes and minimal toxicity. We have consistently
treated the node-negative neck with a low dose of RT to
manage occult metastases. The elective dose delivered to
these patients was primarily 46 Gy to subclinical at-risk
lymphatic drainage basins down to the clavicle. Our 5year regional control rate demonstrates the efficacy of
this approach. Furthermore, the acute toxicity was limited
to radiation dermatitis and mild odynophagia, and the late
toxicity associated with this approach is less than that of
other head and neck radiation regimens because of the
lower dose and depth of treatment.
MERKEL
The efficacy of prophylactic RT to subclinical lymphatic channels has also been demonstrated in a multicenter prospective randomized trial conducted by the French
Cooperative Dermatology Group. Eligible patients were
those who had local disease only. All patients had local
excision and radiation of the primary tumor site; they
were randomized to either neck radiation to 50 Gy or
observation. The study was terminated early after enrollment of 83 patients because of a decline in accrual attributed to the increasing use of sentinel lymph node biopsy.
Nevertheless, patients treated with regional RT had a significantly reduced rate of regional recurrence (16.7% vs
0%; p 5 .007).19
We demonstrated that RT, sometimes given with neoadjuvant chemotherapy, is effective initial therapy for
patients presenting with macroscopic (N1b) nodal disease.
In the current series, 22 patients presented with gross
nodal disease and were treated with definitive RT; 10 of
these patients also received neoadjuvant chemotherapy.
All 22 patients were regionally controlled. Our results
indicate that RT is an appropriate initial approach to
treatment of the N1 neck, and that neck dissection and
parotidectomy can be reserved for salvage therapy if
needed.
As reported in other series, patients with MCC have a
propensity for the development of distant metastasis. Our
rate of distant metastasis further emphasizes that improvement in systemic control is clearly needed. This study
showed that the presence of nodal disease correlated with
distant metastases and significantly predicted for worse
outcomes. However, because MCC most often develops
in the elderly (the median age of patients in our series
was 71 years), many patients may not be candidates for
chemotherapy. A review article focusing on the role of
chemotherapy for MCC has recently been published,20
and the potential role of chemotherapy or targeted agents
is actively being investigated.
Patients who were treated with postoperative RT for
recurrent disease in our series had a significantly worse
locoregional control rate compared with patients who
were treated with adjuvant or definitive RT. It is important to emphasize this point because RT is sometimes
reserved for salvage therapy in MCC. One reason for
delaying RT may be out of concern regarding treatmentrelated toxicity. In the present cohort, however, there
were few (n 5 5; 5%) recorded clinically significant longterm toxicities (graded 3), several of which were anticipated potential morbidities because of proximity of the
high-dose fields to critical structures, particularly the
orbit. We suggest that achieving upfront locoregional control is important and multimodality therapy at the time of
initial presentation should be used to maximize locoregional control.
This study had potential limitations. We retrospectively
reviewed the outcomes of a heterogeneous cohort of
patients making the study vulnerable to the inherent bias,
as with any retrospective analysis. Arguably, these
patients were treated over 2.5 decades, which could
potentially introduce some selection bias. However,
despite the fact that patients were treated over a wide
range of years, our institutional approach to treating MCC
of the head and neck has remained consistent, ensuring
uniformity in treatment philosophy.
CELL CARCINOMA OF THE HEAD AND NECK
The NCCN committee, reflecting the views of some
academic centers, has recommended that all patients with
node-negative MCC be treated initially with sentinel
lymph node biopsy. We continue to investigate this
approach in selected patients.7 Outcomes for a substantial
number of patients treated with upfront sentinel lymph
node biopsy at various institutions should eventually be
available for analysis, and the outcomes achievable with
this approach, along with the false-negative rate, will
become evident. In the meantime, we present an alternative approach that yields high local and regional control
rates and is associated with minimal toxicity.
CONCLUSION
This single institution study represents one of the largest series of patients with MCC reported in the literature
and, to the best of our knowledge, is the largest single
institution series of head and neck MCC treated with RT.
Our excellent locoregional control rates emphasize the
importance of a multimodality approach to this radiosensitive disease and also confirm that radiation should be an
integral component of treatment. Sentinel lymph node
biopsy has a role for risk stratification and lymphatic
drainage mapping, but the ultimate locoregional control
rate using this approach has not yet been established.
Given the excellent regional control rates achievable and
mild toxicity of 46 Gy, we suggest that using RT to treat
the node-negative neck instead of performing a sentinel
lymph node biopsy is a reasonable alternate approach.
For patients presenting with clinically evident nodal disease, RT, with or without neoadjuvant chemotherapy, can
be used, with the expectation of achieving high regional
control rates. Delivering salvage RT for recurrent MCC
yielded inferior local and regional control results compared to treating with adjuvant RT, implying that maximizing upfront disease control should be a therapeutic
goal.
REFERENCES
1. Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg
Oncol 2005;89:1–4.
2. Pellitteri PK, Takes RP, Lewis JS Jr, et al. Merkel cell carcinoma of the
head and neck. Head Neck 2012;34:1346–1354.
3. Lee J, Poon I, Balogh J, Tsao M, Barnes E. A review of radiotherapy for
Merkel cell carcinoma of the head and neck. J Skin Cancer 2012;2012:
563829.
4. Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of
the head and neck: effect of surgical excision and radiation on recurrence
and survival. Arch Otolaryngol Head Neck Surg 2001;127:149–154.
5. Clark JR, Veness MJ, Gilbert R, O’Brien CJ, Gullane PJ. Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary? Head Neck
2007;29:249–257.
6. Lok B, Khan S, Mutter R, et al. Selective radiotherapy for the treatment of
head and neck Merkel cell carcinoma. Cancer 2012;118:3937–3944.
7. National Comprehensive Cancer Network. Merkel cell carcinoma (version
1.2014). Available at: http://www.nccn.org/professionals/physician_gls/
pdf/mcc.pdf. Accessed May 23, 2014.
8. Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel
cell carcinoma: analysis of 240 cases. J Am Acad Dermatol 2013;68:425–
432.
9. Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph
node positivity in Merkel cell carcinoma. J Clin Oncol 2011;29:1036–
1041.
10. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel
cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:2300–2309.
11. Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients
undergoing sentinel lymph node biopsy for Merkel cell carcinoma: analysis
HEAD & NECK—DOI 10.1002/HED
APRIL 2016
E457
BISHOP ET AL.
12.
13.
14.
15.
of 153 patients from a single institution. Ann Surg Oncol 2011;18:2529–
2537.
Santamaria–Barria JA, Boland GM, Yeap BY, Nardi V, Dias–Santagata D,
Cusack JC Jr. Merkel cell carcinoma: 30-year experience from a single
institution. Ann Surg Oncol 2013;20:1365–1373.
Fields RC, Busam KJ, Chou JF, et al. Recurrence after complete resection
and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma. Cancer 2012;118:3311–3320.
Howle JR, Hughes TM, Gebski V, Veness MJ. Merkel cell carcinoma: an
Australian perspective and the importance of addressing the regional lymph
nodes in clinically node-negative patients. J Am Acad Dermatol 2012;67:
33–40.
Morrison WH, Peters LJ, Silva EG, Wendt CD, Ang KK, Goepfert H. The
essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1990;19:583–591.
E458
HEAD & NECK—DOI 10.1002/HED
APRIL 2016
16. Lewis KG, Weinstock MA, Weaver AL, Otley CC. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 2006;142:693–700.
17. Howle J, Veness M. Sentinel lymph node biopsy in patients with Merkel
cell carcinoma: an emerging role and the Westmead hospital experience.
Australas J Dermatol 2012;53:26–31.
18. de Rosa N, Lyman GH, Silbermins D, et al. Sentinel node biopsy for head
and neck melanoma: a systemic review. Otolaryngol Head Neck Surg
2011;145:375–382.
19. Jouary T, Leyral C, Dreno B, et al. Adjuvant prophylactic regional
radiotherapy versus observation in stage I Merkel cell carcinoma: a
multicentric prospective randomized study. Ann Oncol 2012;23:1074–
1080.
20. Desch L, Kunstfeld R. Merkel cell carcinoma: chemotherapy and emerging
new therapeutic options. J Skin Cancer 2013;2013:327150.