The American Journal of Surgery (2015) 209, 342-346
Merkel cell carcinoma: what makes a difference? Jennifer Tseng, M.D.a, Birat Dhungel, M.D.a, Jane K. Mills, M.B.B.S.b, Brian S. Diggs, Ph.D.a, Roshanthi Weerasinghe, M.P.H.b, Jeanine Fortino, H.I.M.A.b, John T. Vetto, M.D., F.A.C.S.a,b,* a
Department of Surgery and bDivision of Surgical Oncology, Oregon Health & Science University, Portland, OR, USA
KEYWORDS: Merkel cell carcinoma; Lymph node; Chemotherapy; Radiation
Abstract BACKGROUND: Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine tumor that may spread via lymphatics and can therefore be staged with sentinel lymph node biopsy (SLNB). MCC is radiosensitive and chemosensitive, although the role of adjuvant therapy is still unclear. We examined the impact of different treatments on the outcome of MCC. METHODS: We performed a retrospective review of state cancer registry data from California, Oregon, and Washington of patients diagnosed with primary skin MCC between 1988 and 2012 (n 5 4,038). Data were analyzed using Cox regression and Kaplan–Meier methods to examine diseasespecific survival. RESULTS: Patients with positive nodes or no documented nodal evaluation had worse survival compared with node-negative patients. No nodal evaluation had decreased survival compared with lymph node evaluation by SLNB. Completion lymph node dissection conferred improved survival in patients with a positive SLNB. In clinically node-negative patients who had a positive SLNB, radiation and chemotherapy did not affect survival. CONCLUSIONS: Lymph node evaluation is an important component to MCC treatment. The role of adjuvant radiation and chemotherapy needs further evaluation. Ó 2015 Elsevier Inc. All rights reserved.
Merkel cell carcinoma (MCC) is a primary neuroendocrine cancer of the skin, originally termed ‘‘trabecular carcinoma’’ by Toker in 1972.1 The cell of origin is thought to be the dermal neurotactile cell, as described by Merkel in 1875.2 Merkel cells are small cells of neuroendocrine origin, found in the basal layer of the epidermis, where they form Merkel cell-axon-complexes with primary nerve endings and work as slow-acting mechanoreceptors.3–5 Although uncommon, the incidence of MCC is increasing.6 * Corresponding author. Tel.: 11-503-494-5501; fax: 11-503-4947573. E-mail address: [email protected]
Manuscript received January 27, 2014; revised manuscript June 2, 2014 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.06.013
Most patients present with rapidly growing, firm, nontender, painless, and occasionally ulcerated skin nodules, which have a red or bluish color, measuring up to several centimeters in size on predominantly sun-exposed areas of the body.7 MCC is characterized by an aggressive course with regional nodal development, distant metastases, and high rates of recurrence.8 Current treatment recommendations include surgical excision of the primary tumor with wide margins (1 to 3 cm) followed by sentinel lymph node biopsy (SLNB) or elective lymphadenectomy (for clinically node-negative cases), as 25% to 30% patients have regional nodal disease at presentation.7,9–11 In vitro studies have shown that MCC is a radiosensitive tumor.12 Some retrospective analyses have shown regional control as well as survival benefits
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with irradiation, while others have demonstrated no survival advantage.13–19 Because of the relative rarity of MCC, present knowledge is based primarily on single-institution retrospective analyses of small series. The purpose of this study was to examine the prognostic indicators and treatment outcomes for MCC using a large database of pooled data from 3 state cancer registries (California, Oregon, and Washington).
Methods Data sources The study population was obtained from the California, Washington, and Oregon State Cancer Registry databases. A query of the databases from 1988 to 2012 identified 17,853 patients with histological International Classification of Diseases for Oncology codes 8246 (neuroendocrine carcinoma) and 8247 (MCC). Of these, 4,038 patients were found to have a primary cutaneous MCC diagnosis and were selected for analysis. Demographics recorded included patient (age, sex, race/ ethnicity) and tumor (tumor size, primary location, stage, lymph node status, metastatic disease) features. Treatment variables included surgery, radiation therapy (RT), and chemotherapy. Surgery was coded as local excision (local removal of tumor only), wide local excision (WLE) (.1 cm
margin) including Moh’s, and any regional lymph node surgery including SLNB for patients diagnosed after 2004. Adjuvant RT was defined as radiation given after surgical resection. The Extent of Disease codes were used to assess tumor size for those diagnosed before 2004, while the American Joint Committee on Cancer (AJCC) collaborative staging system codes for tumor size were used for primary tumors diagnosed since 2004. Primary tumor size was categorized as follows: less than 2 cm (T1), between 2 and 5 cm (T2), greater than 5 cm (T3), and tumor with deep invasion of extra dermal structures (T4), in accordance with the 2010 AJCC staging criteria for MCC (Table 1).20 Primary tumor sites were evaluated in 4 categories: head and neck, trunk, upper extremity, and lower extremity. For this analysis, combined primary site-specific and disease process-specific causes of death were analyzed. Causes-ofdeath statistics were classified in accordance with the International Classification of Diseases and Related Health Problems, Ninth and Tenth Revisions.
Statistical analysis Disease-specific survival (DSS) was measured from the date of initial diagnosis to the date of death attributed to initial cancer diagnosis. Survival functions were estimated using the Kaplan–Meier method and compared using the
AJCC seventh edition staging for Merkel cell carcinoma
IA T1 IB T1 IIA T2/T3 IIB T2/T3 IIC T4 IIIA Any T IIIB Any T IV Any T Primary tumor cannot be assessed No evidence of primary tumor In situ primary tumor %2 cm maximum tumor dimension .2 cm but %5 cm maximum tumor dimension .5 cm maximum tumor dimension Primary tumor invades bone, muscle, fascia, or cartilage Regional lymph nodes cannot be assessed No regional lymph node metastasis Nodes negative by clinical examination Nodes negative by pathologic examination Metastasis in regional lymph node(s) Micrometastasis Macrometastasis In transit metastasis No distant metastasis Metastasis beyond regional lymph nodes
Stage Stage Tx T0 Tis T1 T2 T3 T4 NX N0 cN0 pN0 N1 N1a N1b N2 M0 M1
AJCC 5 American Joint Committee on Cancer.
N0 pN0 cN0 pN0 cN0 N0 N1a N1b/N2 Any N
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log-rank test. Multivariate analyses were performed using the Cox proportional hazards model. The chi-square test was used to compare differences in percentages between categorical variables. A 2-sided P value of less than .05 determined statistical significance for all tests. All statistical analyses were performed using SPSS 21.0 software (SPSS, Inc, Chicago, IL).
Results Demographics and tumor characteristics Table 2 summarizes the clinical and pathologic characteristics of 4,038 patients. There were 2,469 men (61.1%) and 1,569 women (38.9%). Median age at diagnosis was 73 years (range 14 to 105 years). Eighty-eight percent of patients were white (Table 2). MCCs were primarily located on the head and neck region (1,905; 47%), followed by the extremities (1,515; 37%) and trunk (350; 9%). The mean tumor size was 27.7 mm (Table 3). Male sex, age greater than 60 years, and tumor size greater than 21 mm were predictors of lower DSS (P 5 .0001).
Treatments Patients with positive nodes or no documented nodal evaluation had worse 5-year DSS compared with patients who were node negative (P 5 .0001). No nodal evaluation had decreased DSS (hazard ratio 5 1.72, 95% confidence interval 1.38–2.15) compared with lymph node evaluation by SLNB. Of the 1,140 patients who underwent SLNB, 567 patients had completion lymph node dissection for positive findings. Completion lymph node dissection conferred improved DSS in patients with a positive SLNB (P 5 .0001; Fig. 1). In clinically node-negative patients who had a positive SLNB, DSS was not affected by radiation (P 5 .16; Fig. 2) or chemotherapy (P 5 .50; Fig. 3). Table 2
Tumor features Number (%)
Tumor size (cm) Tis T1 (%2) T2 (.2–%5) T3 (.5) T4 (extracutaneous invasion) Unspecified Stage I II III IV Unspecified Primary tumor site Head and neck Trunk Upper extremity Lower extremity Unspecified Lymph node involvement Present Absent Unspecified
2 719 387 115 5 2,810
(0%) (18%) (10%) (3%) (0%) (70%)
562 334 236 47 2,859
(14%) (8%) (6%) (1%) (71%)
1,905 350 948 567 268
(47%) (9%) (23%) (14%) (6%)
422 (10%) 2,623 (65%) 993 (25%)
In this 3 state review of 4,038 patients with Merkel cell carcinoma, completion lymph node dissection conferred improved DSS in patients with a positive SLNB. In clinically node-negative patients who had a positive SLNB, radiation and chemotherapy did not affect survival.
Comments MCC was previously regarded as a rare entity, likely because earlier reports were single-institution studies consisting of small series of patients.13–19 We analyzed a larger, more modern sample of MCC, consisting of 4,038 patients diagnosed with pathologically confirmed primary skin neuroendocrine carcinoma between 1988 and 2012 from the state cancer registries of California, Oregon, and Washington. Our study allowed for the identification of statistical relationships that cannot be demonstrated with smaller, single-institutional studies. In terms of prognostic indicators, male sex, age greater
Number (%) Sex Male Female Age (years) %60 61–79 R80 Ethnicity/race American Indian/Alaska Native Asian/Pacific Islander Black Hispanic White Other/unspecified
2,469 (61%) 1,569 (39%) 447 (11%) 1,954 (48%) 1,637 (41%) 9 87 32 249 3,548 113
(0%) (2%) (1%) (6%) (88%) (3%)
Figure 1 Improved survival with completion lymph node dissection with positive sentinel lymph node biopsy (P 5 .0001).
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Figure 2 Radiation did not affect survival in node-negative patients (P 5 .16).
than 60 years, and tumor size greater than 21 mm were all associated with lower DSS (P 5.0001). These data are comparable with previously cited literature by Tarantola et al20 in their retrospective study and suggest possible future refinements to the current AJCC staging criteria for T stage, which currently only includes size (Table 1).20 Treatment with WLE has been shown to improve disease-free survival, with margins of 1 to 3 cm recommended.21–23 Nonpalpable microscopic nodal involvement occurs in about one third of clinically localized MCC.24 Therefore, SLNB is advised if the patient can tolerate the additional operation.25,26 Our data analysis confirmed that patients with positive nodes or no documented nodal evaluation had decreased DSS. Those patients who did undergo SLNB evaluation of nodal disease had a survival benefit with completion lymph node dissection. This can likely be attributed to removal of micrometastatic disease within the lymph nodes that may improve DSS and possible stage migration with patients more accurately staged by pathological than clinical or radiographic results.20 MCC is a radiosensitive tumor. Currently, adjuvant RT is advocated because MCC has a high incidence of nodal and metastatic disease.27,28 A previously unaddressed question was whether RT was beneficial in those patients specifically known to be node negative. Our study found that there was
345 no statistical survival advantage to giving adjuvant RT to patients with a negative SLNB. Presumably, the risk of nodal failure in our SLN-negative patients was low enough to obviate the need for RT. In their review, Ellis and Davis suggested that RT should be optional for patients at lowest risk for locoregional failure, including immunocompetent patients with primary tumors less than or equal to 1 cm with no adverse histologic features, whose WLEs show clear margins and whose SLNB is negative.28,29 Chemotherapy has traditionally been reserved as more of a palliative and salvage option, although MCC is considered to be chemosensitive. Although high remission rates of up to 70% are seen, there has been no survival benefit.21,30 Poulsen et al31 failed to confirm a statistically significant advantage to chemotherapy in multivariate analysis, although originally the univariate analysis did suggest an overall survival advantage of receiving chemotherapy (52% vs 31% 5-year survival). Furthermore, chemotherapy can be fairly toxic in MCC patients, who tend to be older and more immunocompromised than the general population. No broadly accepted treatment algorithm exists and there are no randomized studies comparing different chemotherapy regimens.32 Limitations with our analysis include the inherent downsides associated with the use of the state tumor registry databases, such as an unknown incidence of disease-specific recurrence. Data on SLN biopsy were available only after 2004 and we also did not have any information on patient comorbidities such as immunosuppression, which can influence individual outcomes. This study also does not address potential newly targeted therapies for MCC aimed at the Merkel cell polyomavirus or other monoclonal antibody targets.21 In conclusion, our study, the largest review of MCC in the literature, further clarifies demographic features of MCC and found that male sex, age greater than 60 years, and tumor size greater than 21 mm were predictors of lower DSS. We found a survival benefit to SLNB and for completion node dissection when the SLN was positive for tumor. RT and chemotherapy provided no survival advantage to nodenegative patients.
Figure 3 Chemotherapy did not affect survival in node-negative patients (P 5 .50).
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