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Merkel Cell Carcinoma of the Head and Neck
Effect of Surgical Excision and Radiation on Recurrence and Survival
Ann M. Gillenwater, MD;
Amy C. Hessel, MD;
William H. Morrison, MD;
M. Andrew Burgess, MD;
Elvio G. Silva, MD;
Dianna Roberts, PhD;
Helmuth Goepfert, MD
Arch Otolaryngol Head Neck Surg. 2001;127:149-154.
ABSTRACT
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Background Merkel cell carcinoma is a rare malignant neoplasm of the skin that
most often arises in the head and neck region. Despite the innocuous appearance
of the primary lesion, Merkel cell carcinoma often has an aggressive clinical
course with frequent locoregional recurrences and distant metastases. We evaluated
the association of the width of surgical margins and the use of postoperative
radiation therapy with locoregional control and survival rates.
Methods The medical records of 66 patients with head and neck Merkel cell carcinoma
seen between 1945 and 1995 were retrospectively reviewed. The Fisher exact
test was used to compare outcomes. Kaplan-Meier survival curves were constructed.
Results Eighteen patients for whom there was adequate information were divided
into the following groups according to the width of their surgical margins:
smaller than 1 cm, 1 to 2 cm, and larger than 2 cm. No statistical difference
in locoregional control or survival was found among these groups owing to
the small patient population. In contrast, a comparison of the patients who
did (n = 26) and did not (n = 34) receive postoperative radiation therapy
revealed a significant difference in local (3 [12%] vs 15 [44%], respectively; P<.01) and regional (7 [27%] vs 29 [85%], respectively; P<.01) recurrence rates. There was, however, no significant
difference in the disease-specific survival between these groups (P = .30). Distant disease developed in 36% of all patients regardless
of therapy.
Conclusions Any effect of the width of surgical margins on outcome was not detectable
in the small number of patients analyzed. The use of postoperative radiation
therapy was associated with a significant improvement in locoregional control.
There was no detectable influence of the type of initial therapy on the rates
of distant metastases or on survival. Future therapeutic innovations should
be directed toward controlling the development of distant metastases in patients
with Merkel cell carcinoma.
INTRODUCTION
MERKEL CELL carcinoma (MCC) is an innocuous-appearing malignant neoplasm
that most commonly arises in the skin of the head and neck. It usually appears
as a painless, pink, solitary nodule that can be easily misdiagnosed both
clinically and pathologically (Figure 1).
The differential diagnosis is extensive, and during light microscopy, it is
difficult to distinguish MCC from other small cell carcinomas. Electron microscopy
and immunocytochemical studies are often required to correctly diagnose this
tumor.1, 2, 3, 4, 5, 6
Merkel cell carcinoma is found almost exclusively in white patients who are
usually 65 years old or older. An even sex distribution has been seen in many
studies2, 4, 6 and
a strong male predominance in others.5, 7
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Figure 1. Merkel cell carcinoma of the cheek.
Primary Merkel cell carcinoma lesions are usually pinkish purple cutaneous
nodules without ulceration.
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Merkel cell carcinoma often has an aggressive course, with the development
of early locoregional recurrence and frequent distant metastases (DM).4, 5, 8 Despite maximal surgical,
radiation, and medical therapy, an estimated 25% to 35% of patients with MCC
die of their disease.4 It has been suggested
that the key to increased survival is locoregional control and that the development
of local or regional recurrence is directly related to the adequacy of the
primary treatment.5 Currently, standard treatment
consists of wide local excision (WLE), with some authors advocating up to
2- or 3-cm margins.4, 9 With the
success of radiation therapy (XRT) against this tumor, the necessity of performing
extensive surgical resections needs reevaluation.10
We therefore undertook a retrospective analysis to determine whether excision
of the primary lesion with wider surgical margins affected the locoregional
control rate. We also sought to determine whether postoperative XRT independently
affected locoregional recurrence and survival rates.
PATIENTS AND METHODS
Through a search of the database maintained by the Department of Medical
Infomatics, M. D. Anderson Cancer Center (MDACC), Houston, Tex, we identified
145 patients who were seen between 1945 and 1995 with a diagnosis of either
MCC or neuroendocrine carcinoma of the skin. Sixty-nine cases were eliminated
from further evaluation because the primary lesion was located in a site other
than the head and neck or because the pathologic diagnosis was not MCC, leaving
76 patients with head and neck MCC. Ten of the 76 patients were excluded from
further analysis for the following reasons: 2 had distant metastasis on presentation;
1 had unresectable disease and had no further treatment; 2 died of other causes
during treatment of their primary lesion; 2 were unavailable for evaluation
before 6 months; and 3 were seen for consultation only and had treatment elsewhere.
Thus, 66 patients with MCC of the head and neck composed the cohort
for this study. Of these 66 patients, 15 presented to MDACC for primary treatment
of their disease, 12 were referred to MDACC after the initial excision of
the primary tumor, and 33 presented to MDACC with locoregional recurrent disease.
Six patients were referred to MDACC for follow-up evaluation after receiving
definitive treatment of their primary tumor elsewhere. All patients included
in the study had at least 6 months of follow-up after the initial diagnosis.
The surgical or biopsy specimens in all cases were reviewed by members of
the pathology department of MDACC, and the diagnosis of MCC was confirmed.
There were sufficient data to determine the size of surgical margins
in only 18 patients, who will be referred to as the margin
group. The patients in the margin group were subdivided into those
with margins smaller than 1 cm (n = 9), 1 to 2 cm (n = 6), and larger than
2 cm (n = 3).
We defined postoperative XRT as the initiation
of XRT within 1 month of the surgical excision without an intervening locoregional
recurrence. This typically consisted of external beam irradiation ranging
between 46 and 66 Gy to generous fields covering the primary tumor site, surgical
bed, and the draining lymphatics.9 Thirty-four
patients, referred to as group A, did not receive
postoperative XRT. The cancer stage in 4 of the 34 patients was clinically
N+ at presentation; the status of the nodes was not given in 2 cases. The
stage in 28 (82%) of the 34 patients was N0 at presentation. Twenty-six patients
received postoperative XRT and are referred to as group
B. Two of these 26 patients had clinically evident nodal metastases;
the status of the nodes was unknown in 4 cases. The stage in 20 (77%) of the
26 patients was clinically N0 at presentation. Twenty of the 26 patients underwent
elective XRT for possible microscopic disease, and 3 had definitive XRT for
positive nodes; the reason for administration of XRT was not stated in 3 cases.
Six patients received XRT as their definitive therapy and are referred to
as group C. Two of these 6 patients had radiation
implants at the primary site.
Patient records were retrospectively reviewed for demographic information,
such as age, sex, and race. The tumor size and location; type of initial therapy;
number, site, and time to onset of recurrences; and final outcome were noted
for the entire study population. The date of last contact with MDACC determined
the length of follow-up. The Fisher exact test was used to compare outcomes.
A P value of less than .05 was considered significant.
Kaplan-Meier survival curves were constructed for the different groups.
RESULTS
DEMOGRAPHICS
All 66 patients in this study were white (2 had Hispanic surnames).
The patients ranged in age from 41 to 91 years (mean age, 68.4 years). There
were 55 men and 11 women (male-female ratio, 5:1). No association was found
between age or sex and outcome.
PRIMARY AND REGIONAL DISEASE
The primary tumors were located throughout the head and neck region,
as shown below:
The sizes of the lesions (diameter) were as follows: 43 tumors, smaller
than 2 cm (67%); 10 tumors, 2 to 5 cm (15%); and 4 tumors, larger than 5 cm
(6%). The diameter could not be determined in 9 cases.
Seven patients (11%) had palpable cervical lymphadenopathy
at presentation (N+); 51 (77%) had no lymphadenopathy (N0); and the status
of the neck could not be determined (NX) in 8 (9%). Neck dissection and/or
parotidectomy was performed as part of the initial procedure in 14 of the
66 cases: 5 of these had pathologically positive nodes, and 6 had no pathologic
nodes; the status could not be determined in 3 cases. Three (43%) of the 7
patients with clinically positive neck disease and 22 (43%) of the 51 patients
with clinically negative neck disease died of disease. The site and size of
the primary lesion and the lymph node status at the time of presentation were
not significant factors for predicting locoregional recurrence or survival
rates.
LOCOREGIONAL RECURRENCES AND DM
Fifty-one (77%) of the 66 patients with MCC had a total of 109 recurrences.
Ninety-six (88%) of these occurred within 2 years, and 104 (95%) occurred
within 5 years. Of those patients who had recurrences, 31 (60%) died of disease.
Nineteen patients (29%) had a single recurrence; 10 (53%) of the 19 died of
disease. Multiple recurrences were common, with 32 patients having 2 or more
recurrences (49% of the total population, and 63% of the patients who had
a first recurrence). Twenty-one (66%) of these 32 patients died of disease.
Local recurrence was the first site of recurrence in 17 patients, 9
(53%) of whom died of disease. Regional lymphadenopathy was the first site
of recurrence in 25 patients. Thirteen (52%) of the 25 patients died of disease.
It was not uncommon for multiple regional recurrences to develop in a single
patient. Distant metastasis occurred in 24 patients. In 9 patients (38%),
DM developed as the first recurrence without locoregional recurrence; 1 of
these 9 patients also had a simultaneous regional recurrence. All died of
disease. Fifteen patients developed DM after a local or regional recurrence.
Twenty-one patients with DM (88%) died of disease; 2 (8%) were living with
disease; and 1 (4%) died of other causes with disease.
IMPACT OF SURGICAL MARGIN SIZE ON RECURRENCE AND SURVIVAL
In 18 cases, sufficient information was found in the patient records
to establish the size of the surgical margins. Seven of the 18 patients remained
disease free after their initial therapy. The recurrence rates for each group
are given in Table 1. Two of the
18 patients in the margin groups had clinically evident regional disease at
presentation (1 patient each in the <1- and >2-cm groups). Both patients
were treated with WLE, neck dissection, and postoperative XRT and did not
have a recurrence. The cancer stage was N0 in 15 patients in the margin groups
at presentation; the status was unknown in 1 patient (<1-cm group) at presentation.
Eight of the 15 patients were treated with WLE only; 5 (33%) were treated
with WLE and postoperative XRT; and 2 (13%) were treated with WLE, neck dissection,
and postoperative XRT.
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Table 1. Effect of Margin Size on Recurrence
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In this small group of patients, there was no significant difference
detected in local, regional, or distant disease control among the 3 margin
groups. Furthermore, if the number of groups was reduced from 3 to 2 (margins
<1 cm vs >1 cm or <2 cm vs >2 cm), significant differences in disease
control still could not be detected. There was no detectable trend toward
larger margins in larger sized primary lesions. Interestingly, the patients
in the smaller-than-1-cm-margin group had a significantly better survival
than those in the 1- to 2-cm-margin group (P = .006);
the larger-than-2-cm-margin group was too small to make any comparisons.
IMPACT OF POSTOPERATIVE XRT ON RATES OF RECURRENCE AND SURVIVAL
Of the 34 patients who were treated with WLE and no postoperative XRT
(group A), only 1 patient (3%) was free of recurrence. Fifteen (44%) of these
34 patients developed a local recurrence at some point (13 of the recurrences
were a first recurrence). Regional recurrence developed in 29 patients (85%).
In 20 patients (59% of group A), regional disease was the first site of recurrence,
without any evidence of local or distant disease. No one in group A had DM
as the first recurrence, but 11 (32%) eventually developed distant disease.
Of the 26 patients who were treated with WLE and postoperative XRT (group
B), 13 (50%) had no recurrences. Three patients (12%) developed a local recurrence
(all recurrences were a first recurrence). Seven patients (27%) developed
a regional recurrence; in 3 cases, this was the first site of recurrence.
Distant metastases occurred in 11 patients (42%). In 7 patients, DM was the
first recurrence.
In summary, there was a significant improvement in group B (postoperative
XRT) over group A in overall disease control (50% group B vs 3% group A; P<.001), as well as in local recurrence rates (12% of
group B vs 44% of group A; P<.01) and regional
recurrence rates (27% of group B vs 85% of group A; P<.001).
Interestingly, there was no significant difference between group A and group
B in the development of DM (43% of group B vs 32% of group A; P = .59) (Table 2).
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Table 2. Effect of Radiation Therapy on Recurrence
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Survival curves for the patients in groups A and B are shown in Figure 2. As illustrated, there was no significant
difference in disease-specific survival between these 2 groups (P>.30). Among those patients who were treated with surgical excision
and postoperative XRT, there was no difference in recurrence or survival rates
for those who received XRT at MDACC compared with those who were treated elsewhere
(P = .11).
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Figure 2. Comparison of survival in patients
treated with or without postoperative radiation therapy (XRT).
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IMPACT OF NODAL STATUS AND REGIONAL THERAPY ON RECURRENCE AND SURVIVAL
There were 51 patients who presented with no clinical evidence of nodal
metastases. Of these patients, 24 underwent WLE only and did not receive elective
treatment to the draining lymphatics. In this group, 19 patients (79%) had
a regional recurrence (in 14 cases [58%], this was the first recurrence).
Only 1 (4%) of the 24 patients remained free of disease, and 10 patients (42%)
died of disease.
Only 2 (4%) of the patients with N0 disease underwent WLE and prophylactic
neck dissection. Both eventually developed a regional recurrence (1 had regional
disease as the first recurrence), and 1 died of disease. Sixteen patients
(31%) underwent WLE with elective postoperative XRT. Only 3 patients (19%)
had a regional recurrence, 1 of which was the first recurrence. Eleven patients
(69%) remained free of disease, and 5 patients (31%) died of disease. Four
patients (8%) underwent WLE and both elective neck dissection and postoperative
XRT; none of these 4 patients developed a regional recurrence. However, all
4 developed DM, and all 4 died of disease (Table 3).
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Table 3. Outcome of Patients Based on Nodal Status and Treatment
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Among the patients with N0 disease, statistical analysis could be performed
only on the WLE-only group (n = 24) and the WLE-with-postoperative-XRT group
(n = 16) because of the insufficient patient numbers in the other treatment
subsets. A significant decrease in first regional recurrence (P = .001), overall regional recurrence (P
= .003), and all recurrences (P<.001) was found
in the patients who were treated with WLE and postoperative XRT compared with
those who were treated with WLE only. However, there was no difference in
the percentage of patients in these 2 treatment groups who died of disease
(P = .74).
There were only 7 patients (11%) who had clinically evident neck disease
at the time of presentation. One of these patients had XRT as the definitive
treatment, developed DM, and died of disease. For reasons not disclosed in
the medical record, 1 patient underwent WLE only, without recorded treatment
of the neck. The patient developed a regional recurrence as well as DM and
died of disease. Three of these 7 patients underwent WLE and neck dissection.
All 3 patients eventually developed a regional recurrence (1 of which was
a first recurrence), and 2 of these patients died of disease. Two patients
underwent WLE with neck dissection and postoperative XRT. Neither patient
developed recurrence or died of disease.
COMMENT
Merkel cell carcinoma is a rare, aggressive skin malignancy; only approximately
600 cases have been documented in the literature since MCC was first described
by Toker1 in 1972. The annual age-adjusted
incidence of MCC per 100 000 is estimated to be 0.23 for whites.11 The etiology of MCC remains unclear. Miller and Rabkin11 found an increased incidence of MCC with an increase
in the solar UV-B index, similar to that of melanoma, suggesting an etiologic
role for sun exposure in MCC carcinogenesis. This finding is in agreement
with clinical series that have reported an association of MCC with UV exposure
and other skin neoplasms.6, 12
Merkel cell carcinoma has also been reported to occur more frequently in persons
with immunosuppression as a result of B-cell malignancies or after transplantation.11, 13
The histogenesis of MCC also has not been clearly elucidated. Tang and
Toker3 first postulated that MCC arose from
neural crest cells, whereas other investigations have suggested an epidermal
origin with subsequent neuroendocrine differentiation.14, 15
Molecular analyses have implicated genetic alterations at 1p36,16, 17
a site of frequent genetic changes in other neuroendocrine tumors, including
neuroblastomas, pheochromocytomas, and melanomas.
Few authors see sufficient numbers of patients with this disease to
publish comparative analyses of treatment outcomes.5, 10, 18
We therefore analyzed our series of patients with head and neck MCC to determine
the impact of surgical and XRT on locoregional disease control and survival.
Merkel cell carcinoma has a propensity for recurrence and metastasis.19 Our overall 29% local recurrence rate, 59% regional
recurrence rate, and 36% DM rate are comparable to those in previous series.9, 18 It has been suggested that inadequate
excision of primary MCC lesions will lead to locoregional recurrence and eventually
DM. Bourne and O'Rourke20 recommend that 3-cm
margins be performed but comment that it is impractical in all sites. Thus,
what constitutes an adequate surgical margin in the head and neck has not
been assessed. Our evaluation of the impact of surgical margin width on outcome
was hindered by the retrospective nature of the data collection, which produced
only a small population with enough information to determine margin size.
In the 18 evaluable patients, no statistically significant difference in locoregional
control or outcome could be detected. Unfortunately, the small patient numbers
do not give sufficient statistical power to detect any small incremental advantage
to wide surgical margins. Although we found no evidence that wider margins
were taken around larger, more "malignant-appearing" lesions, this also would
mask a small improvement in disease control associated with wider surgical
margins. From our analysis, we conclude that the width of surgical margin
around the primary site does not have a major impact on recurrence or survival
rates, but we were unable to definitively determine the effect of margin size
on locoregional control. Allen et al,21 in
a retrospective analysis of 102 patients with MCC in all sites, also found
no specific size of surgical margin that correlated with a decrease in local
recurrence.
The treatment of the draining lymphatics has evolved over the years.
In 1984, Goepfert et al5 recommended elective
treatment to the draining lymphatics after finding a 75% failure rate in patients
with untreated necks. In 1988, it was suggested that outcome improves when
both the primary and the draining lymphatics are treated regardless of the
initial neck stage.20 In 1991, Shaw and Rumball22 noted that the combination of elective neck dissection
and XRT was associated with a significant drop in locoregional recurrence
rates. Morrison et al10 and Meeuwissen et al18 demonstrated the efficacy of elective XRT alone for
controlling the regional lymphatics. Our findings also confirmed the importance
of electively treating the draining lymphatics with XRT. We found a 19% regional
recurrence rate among those patients who received postoperative XRT compared
with 79% among those who underwent WLE only (P<.001).
Only 2 patients underwent elective neck dissections without XRT, so we could
not assess the effectiveness of elective surgical management of the neck.
There were also an insufficient number of patients to compare the combination
of elective neck dissection plus XRT with elective XRT alone.
An investigation of the use of intraoperative lymphatic mapping and
sentinel lymph node biopsy in 18 patients with MCC (including 1 patient with
MCC in the head and neck region) was conducted by Hill et al.23
Two patients were found to have metastatic disease in the sentinel nodes and
no further involved nodes on subsequent nodal dissections, suggesting the
possibility that the concept of a "sentinel node" as a predictor of the disease
status of the entire nodal basin may be applicable for MCC. The 16 patients
who were negative for sentinel nodes in this study and who received no further
elective treatment to the draining lymphatics have not developed locoregional
recurrence. However, the follow-up period (median length of follow-up, 7 months)
is too short to assess any effect on locoregional control. Without further
studies in patients with MCC of the head and neck, it is difficult to know
what future role lymphatic mapping and sentinel lymph node biopsy may play
in the treatment of these patients.
Merkel cell carcinoma is a very radiosensitive tumor.24
Several series have demonstrated increased rates of locoregional recurrence
in patients treated with surgery alone compared with those treated with surgery
and XRT.10, 18, 19
However, the few patients who were treated with XRT alone had high rates of
locoregional recurrence and DM, possibly because of a selection bias.10 In our study, there were 6 patients who received
XRT as definitive therapy. One of the 6 had no recurrences and remained free
of disease. Of the 5 patients who had recurrences (1 locoregional, 2 regional,
and 2 distant), 4 died of disease and 1 died with disease. For the present,
it seems that complete surgical excision is warranted before postoperative
XRT.
In the current study, the use of postoperative XRT significantly improved
locoregional control rates, yet there was no improvement in DM rate or disease-specific
survival. The development of DM was the most important factor for predicting
survival; 88% of those who developed DM died of disease. A multimodality management
approach incorporating adjuvant systemic therapy that can maintain locoregional
control and prevent DM needs to be developed. Studies of chemotherapeutic
agents that are active against small cell carcinoma of the lung, such as etoposide
and cisplatin or cyclophosphamide, methotrexate, and fluorouracil, have shown
promising short-term results in patients with established DM.25
Fenig et al25 showed that chemotherapy used
in a palliative setting had complete responses in 69% of patients, most remarkable
for locoregional disease and less for visceral metastases. They noted that
the response was short-lived unless the chemotherapy was followed by consolidation
XRT. Voog et al,7 through a review of the literature,
found a 60% response rate (57% for DM and 69% for locoregional disease) to
chemotherapy in patients with MCC. The median overall survival after starting
chemotherapy was 9 months for patients with DM and 24 months for patients
with locoregional disease. The conclusion reached by the investigators was
that recurrent and metastatic MCC is chemosensitive but not chemocurable.
The use of chemotherapy in the adjuvant setting has not been thoroughly investigated.
In the current study, the role of chemotherapy could not be evaluated.
CONCLUSIONS
We evaluated the effectiveness of surgical resection margin width and
use of postoperative XRT for locoregional control and survival in this retrospective
analysis of 66 patients with head and neck MCC seen at a single institution.
The number of patients in whom margin size could be accurately determined
was too small to enable us to detect any effect of the width of surgical margins
on outcome. Postoperative XRT to the primary tumor site and draining lymphatics
did have a significant impact on locoregional control, but not on the incidence
of DM or on long-term survival rates. The only factor affecting survival in
this study was the development of DM.
Merkel cell carcinoma of the head and neck region has proved to be an
aggressive skin cancer with a poor prognosis. Like that of melanoma, the incidence
of MCC may be on the rise, possibly owing to greater UV exposure in the population
or to the increased numbers of patients surviving with immunodeficiency disorders.
Unfortunately, the optimal treatment for this disease continues to elude us.
The currently recommended treatment at MDACC is conservative surgical excision
of the primary tumor with microscopically negative margins on frozen section,
followed by postoperative XRT to the primary and draining lymphatics. While
we found that XRT improved locoregional disease control, survival rates remained
poor: almost 50% of patients died of their disease within 3 years of diagnosis.
Further therapeutic innovations incorporating systemic therapy are needed
to reduce the development of DM and to increase survival rates.
AUTHOR INFORMATION
Accepted for publication June 28, 2000.
From the Departments of Head and Neck Surgery (Drs Gillenwater, Hessel,
Roberts, and Goepfert), Radiation Oncology (Dr Morrison), Medicine (Dr Burgess),
and Pathology (Dr Silva), University of Texas M. D. Anderson Cancer Center,
Houston.
Corresponding author and reprints: Ann M. Gillenwater, MD, Department
of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center,
Box 441, Houston, TX 77030.
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Merkel cell cancer of the skin
Pectasides et al.
Ann Oncol 2006;17:1489-1495.
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Adjuvant Local Irradiation for Merkel Cell Carcinoma.
Lewis et al.
Arch Dermatol 2006;142:693-700.
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Merkel Cell Carcinoma: Prognosis and Treatment of Patients From a Single Institution
Allen et al.
JCO 2005;23:2300-2309.
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Radiotherapy Alone for Primary Merkel Cell Carcinoma
Mortier et al.
Arch Dermatol 2003;139:1587-1590.
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Merkel Cell Carcinoma Treatment With Radiation: A Good Case Despite No Prospective Studies
Longo and Nghiem
Arch Dermatol 2003;139:1641-1643.
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