Merkel cell carcinoma: high recurrence rate despite aggressive treatment

j o u r n a l o f s u r g i c a l r e s e a r c h 1 7 7 ( 2 0 1 2 ) 7 5 e8 0

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Merkel cell carcinoma: high recurrence rate despite aggressive treatment Michael C. Soult, MD,a Eric C. Feliberti, MD,a Marc L. Silverberg, MD,b and Roger R. Perry, MDa,* a b

Eastern Virginia Medical School, Department of Surgery, 825 Fairfax Avenue, Hofheimer Hall, Suite 610, Norfolk, Virginia 23507 Department of Pathology, Sentara Norfolk General Hospital, 600 Gresham Drive, 2nd Floor, Norfolk, Virginia 23507

article info

abstract

Article history:

Background: Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cancer of the

Received 7 January 2012

skin whose incidence has been increasing. The objective of the study was to evaluate

Received in revised form

current treatment modalities, including sentinel lymph node (SLN) biopsy and outcomes

21 March 2012

and identify prognostic factors in patients with MCC.

Accepted 28 March 2012

Methods: A retrospective chart review of patients with MCC. Clinical, pathologic, treatment

Available online 16 April 2012

characteristics, disease status, and survival were collected. All slides were reviewed by a single pathologist, and additional pathologic elements were evaluated for prognosis.

Keywords:

Results: Twenty-six patients were identified in the study period. All patients were Cauca-

Merkel cell carcinoma

sian with an average age of 71.3 y. Twenty-one patients had tumors in sun-exposed

Sentinel lymph node biopsy

locations, and 13 had a prior history of skin cancer. All nonmetastatic patients under-

Recurrence

went wide excision. SLN biopsy was successful in 19 patients. The SLN was positive in 21%

Treatment

of patients. Radiation therapy was used in 13 patients. Average follow-up was 26 mo, and

Outcomes

median survival was 29 mo. Recurrence occurred in eight patients: four locoregional, two distant, one combined, and one unknown. Recurrence occurred in five patients with stage I disease. Five patients with negative SLN later developed recurrence. The presence of metastasis to the nodes was significant for recurrence. No other pathologic factor was found to have prognostic significance. Conclusions: Despite aggressive surgical and radiation treatment, MCC has a high rate of locoregional recurrence, even in early stage disease. SNLB is useful for the staging and management of patients. Further research is needed to identify better prognostic markers. ª 2012 Elsevier Inc. All rights reserved.

1.

Introduction

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma of the skin. First described in 1972 by Toker [1] as trabecular carcinoma, it shares characteristics

similar to that found in Merkel cells. The incidence of MCC continues to rise, but overall it remains low at less than 0.50 per 100,000 persons-years [2e4]. MCC is frequently found in older patients with a significant history of sun exposure. Its course is often aggressive leading to

* Corresponding author. Department of Surgery, Eastern Virginia Medical School, 825 Fairfax Avenue, Hofheimer Hall, Suite 610, Norfolk, VA 23507. Tel.: þ1 757 446 8950; fax: þ1 757 446 8951. E-mail address: [email protected] (R.R. Perry). 0022-4804/$ e see front matter ª 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jss.2012.03.067

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treatment failure with early locoregional recurrence and metastasis [3,5,6]. The optimal therapy for patients with MCC remains unclear, with large variations in treatment strategies. Primary treatment includes wide local excision (WLE), without clear evidence of the appropriate margin [7,8]. Those with clinically involved nodes and distant metastasis have a worse prognosis, with recent studies advocating nodal evaluation by sentinel lymph node biopsy (SLNB) [4,9e12]. Radiation therapy is often used in treatment of MCC, and chemotherapy has limited activity in patients with metastatic disease. The optimal role of both therapies is still being debated [13e18]. The American Joint Committee on Cancer (AJCC) recently released its first MCC-specific staging system [19]. In the previous edition, patients with MCC were staged as nonmelanomatous carcinomas of the skin, along with basal and squamous cell carcinomas [20]. The AJCC has recommended that additional pathologic elements be collected to help evaluate their role as future prognostic factors. Several of these elements were adopted as part of the MCC staging protocol developed by the College of American Pathologist (CAP) [21]. The purpose of this study was to evaluate the treatment of MCC at our institution. We sought to study clinical and tumor characteristics of patients with MCC and evaluate current treatment modalities, including SLNB. We also sought to evaluate a variety of pathologic factors, including the optional elements recommended in the current AJCC staging guidelines and the CAP protocol to determine if they had prognostic utility.

2.

Methods

A retrospective review of the MCC database maintained by the Division of Surgical Oncology at Eastern Virginia Medical School (EVMS) was performed. Patients were diagnosed within 6 mo of presentation to EVMS and were treated between January 1998 and December 2010. All patients had histologically confirmed MCC. Charts were reviewed for patient age at diagnosis, sex, race, history of sun exposure, tumor location, tumor size, clinical and pathologic nodal status at presentation, management of primary lesion, margin status, management of draining nodal basin, tumor invasion, use of chemotherapy or radiation therapy, and current disease status. Patients were staged using the AJCC criteria from both the sixth and the seventh editions. A single pathologist reviewed pathologic samples based on current AJCC guidelines and CAP protocol. Additional elements examined include mitotic index, tumor thickness (depth), lymph-vascular invasion, tumor-infiltrating lymphocytes (TILs), tumor growth pattern, extra nodal extension, tumor base transection status, size of tumor nests in regional lymph nodes (LNs), and isolated tumor cells in LN. All patients were seen in follow-up for complete history and physical examination, including skin and LNs, every 3e6 mo for the first 2 y after excision. After 2 y patients underwent complete history and physical examination for surveillance every 6e12 mo. Imaging and laboratory studies were obtained selectively based on clinical indications. Overall survival (OS) was defined, in months, as the time from diagnosis to death; disease-specific survival (DSS) was

defined as the time from diagnosis to death from disease. Patients were categorized as no evidence of disease (NED), deceased with NED (DNED), alive with disease (AWD), or deceased with disease (DWD). Data were analyzed using MedCalc (MedCalc Version 12.1.4.0, MedCalc Software, Belgium). Categorical variables were described as a percentage. Median and mean were used for continuous variables. Mann-Whitley U and Fisher’s exact tests were used for comparison of pathologic variables. Logrank test and the Kaplan-Meier survival curve were used for evaluation of survival. The Institutional Review Board at EVMS approved the study.

3.

Results

3.1.

Patient and tumor data

MCC was diagnosed and treated in 26 patients at EVMS from 1998 to 2010. Median age at diagnosis was 71.3 y with a maleto-female ratio of 1.2:1. All patients were Caucasian. Patient characteristics are listed in Table 1. Sixteen had previous history of cancer (62%); three had breast and 13 had skin cancer. Of those with history of skin cancer, 12 had nonmelanoma skin cancer and one had melanoma. No patients were found to be immunosuppressed. Average length of follow-up was 25.6 (range 1e141) mo. Tumors were found in sun-exposed areas in 23 (89%) patients. Three patients presented with clinically positive nodes; one patient had distant metastasis on presentation. Sixteen (62%) patients had stage I disease, one (4%) patient had stage II disease, eight (31%) patients had stage III disease, and one (4%) patient had stage IV disease based on the older AJCC sixth edition staging guidelines. Two patients were downstaged from stage III to stage II based on the current AJCC seventh edition staging guidelines. Tumor, nodes, metastasis, and stage grouping are found in Tables 2 and 3.

3.2.

Treatment

The primary tumor was treated with WLE in 25 patients. WLE was generally performed with a minimum of 2 cm margins except in the face where margins of 1 cm, if necessary, were

Table 1 e Patient and clinical characteristics. Age (y) Median Range Sex Male Female Race Caucasian Location of primary Extremity Head/neck Trunk Diameter of primary (cm) Median Range

71.3 25e90 14 (54%) 12 (46%) 26 (100%) 9 (35%) 14 (54%) 3 (11%) 1.99 0.2e4.5

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Table 2 e TNM and staging. Primary tumor T1 T2 T3 T4 Regional LNs cN0 pN0 cN1 pN1 pN1a pN1b pN2 Distant metastasis M0 M1

17 4 2 3 4 15 1 5 3 2 1 25 1

TNM ¼ Tumor, nodes, metastasis.

permitted to prevent a major cosmetic defect. One patient refused surgical management because of widely metastatic disease but underwent palliative radiation therapy. Tumor margins were negative in all 25 patients. Four (16%) patients had their primary tumor invading into surrounding skeletal muscle. At the time of presentation 23 had no clinical evidence of nodal disease. SLNs were successfully identified on 19 of 20 (95%) patients. One patient failed lymphoscintigraphy, and three refused SLNB. Patients successfully undergoing SLNB had an average of two (range 1e4) SLNs. Four (21%) patients undergoing SLNB had histologically positive nodes, and none underwent completion LN dissection (LND). Two patients refused completion dissection, and the remaining two underwent radiation therapy to the affected nodal basin based on National Comprehensive Cancer Network (NCCN) guideline recommendations [22]. Five (31%) patients with negative SLNB later developed recurrence; two had local recurrence, two had nodal recurrence, and one had distant recurrence. Clinically positive nodes were palpable in three patients. One patient with clinically positive LNs underwent LND. That patient had 18 histologically positive nodes on dissection. The other two patients refused operative LND; however, one of them had a LN biopsy to help confirm the initial diagnosis. Postoperatively radiation therapy was used in 13 (52%) of the 25 patients without widely metastatic disease. Radiation therapy was delivered to the primary site and pertinent nodal basins. Seven (54%) of 13 patients receiving radiation therapy had stage I disease; 10 (77%) of the 13 not receiving radiation had stage I disease (P ¼ 0.4110). Two of the three patients with clinically positive nodes did not receive radiation therapy. After recurrence, two patients subsequently underwent

Table 3 e AJCC staging. Stage I II III IV

Sixth edition

Seventh edition

16 1 8 1

16 3 6 1

radiation therapy. None of the nonmetastatic patients underwent adjuvant systemic therapy. The patient who initially presented with metastatic disease refused chemotherapy. Systemic therapy was used in three patients after recurrence.

3.3.

Pathologic review

Tissue samples were available for pathologic review in 20 (77%) patients. The average mitoses per square millimeter were 13 (range 0e36), whereas the average depth was 13.7 mm (range 0.5e45 mm). The base of the tumor was transected in four (20%) patients, and the tumor invaded the surrounding muscle/fascia in three (15%) patients. Tumor growth pattern was nodular in 10 (50%) patients, infiltrative in eight (40%) patients, and unknown in two (10%) patients. TILs were brisk in eight (40%) patients, nonbrisk in six (30%) patients, and not identified in six (30%) patients. Eight (40%) patients were found to have lymphatic or vascular invasion. No patients had isolated tumor cells in the LN. LNs were positive in six (30%) of the 20 patients with tissue available for review: four patients had microscopically positive nodes and two had clinically positive nodes. Extracapsular extension of LN was seen in four patients. Tumor nests were found in four patients, with average size of 1.43 cm (range 0.2e2.8 cm). The association of pathologic variables and recurrence is shown in Table 4. The presence of metastasis to the LN was associated with a significant increase in recurrence (P ¼ 0.0498). Thick tumors were more common in those without recurrence than in those with recurrence (P ¼ 0.0129).

3.4.

Recurrence and survival

Recurrence occurred in eight (31%) patients with MCC, and all occurred within 2 y of primary diagnosis. Local recurrence

Table 4 e AJCC and CAP protocol pathologic variables.

Mitosis (1/mm2) Tumor thickness (>4 mm) Lymphatic vessel invasion Present TIL growth pattern Brisk Tumor growth pattern Infiltrative Base transected Present Tumor invasion Muscle LN metastasis Present

Recurrence/ metastasis (N ¼ 9)

No recurrence (N ¼ 11)

P value

9 (100%) 3 (33%)

9 (82%) 10 (91%)

0.2714 0.0129

3 (33%)

4 (36%)

0.8959

4 (44%)

4 (36%)

0.7328

3 (33%)

5 (45%)

0.6086

1 (11%)

3 (27%)

0.4232

2 (22%)

1 (9%)

0.4796

5 (56%)

1 (9%)

0.0498

TIL ¼ Tumor-infiltrating lymphocytes; LN ¼ Lymph node. P values in bold in this chart are those that reached significance (P < 0.05).

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occurred in two (25%) patients, regional recurrence in two (25%) patients, distal recurrence in two (25%) patients, combined recurrence in one (12.5%) patient, and one (12.5%) patient had an unknown location of recurrence (Table 5). Three (23%) patients receiving radiation therapy developed locoregional recurrence, whereas two (15%) patients who did not receive radiation therapy developed locoregional recurrence (P ¼ 0.6507, Table 6). Of the five patients with locoregional recurrence, four had undergone SLNB. Three patients received radiation therapy only after locoregional recurrence. The median OS was 29 mo. The 5-y OS rate was 40% (95% CI 18%e63%), and the 5-y DSS was 60% (95% CI 34%e87%). Stagespecific median survival is seen in Table 7. Eleven (42%) patients had NED, seven (27%) patients were DWD, six (23%) patients were DNED, and two (8%) were AWD at last follow-up (Table 4). Those with nodal disease were significantly more likely to be DWD than those without nodal involvement (P ¼ 0.0018).

4.

Discussion

Our case series of patients with MCC continues to add to the slowly growing body of literature trying to better characterize patient, tumor, and pathologic factors to develop better treatment strategies. Our current series is consistent with previous reports in which MCC patients tend to be older than 65 and Caucasian, with primary tumor site in sun-exposed locations [2,4,23]. Half of our patients had a previous history of a malignancy of the skin, which is consistent with published results [24]. MCC is an aggressive carcinoma with poor prognosis. We found that 50% of our patients were deceased by the completion of the study. Of these, 27% died with disease, whereas the remaining 23% died from other causes. This is in part responsible for the seemingly short follow-up intervals. The median OS of 29 mo and 5-y OS rate of 40% are lower than

Table 5 e Disease status. Length of follow-up (mo) Average Range Disease-free survival (mo) Average Range Recurrence Yes No Site of recurrence Local Nodal Distant Combined Unknown Status at last follow-up NED DWD DNED AWD

25.6 1e141 19 0e141 8 (31%) 18 (69%) 2 2 2 1 1 11 7 6 2

(25%) (25%) (25%) (12.5%) (12.5%) (42%) (27%) (23%) (8%)

NED ¼ no evidence of disease; DWD ¼ deceased with disease; DNED ¼ deceased no evidence of disease; AWD ¼ alive with disease.

Table 6 e Locoregional recurrence by stage. Stage I II III IV

Radiation therapy 3/7 0/3 0/2 0/1

(43%) (0%) (0%) (0%)

No radiation therapy

P value

2/10 (20%) 0/2 (0%) 0/1 (0%) N/A

0.3569

N/A ¼ Not applicable.

the reported median OS of 6 y reported from Memorial SloanKettering Cancer Center and the reported 50%e74% 5-y survival in other studies [3,4,8,12]. MCC is found in an aging population, and the patients often have multiple comorbidities. Indeed, 23% of our patients died of other causes, which is demonstrated in our 5-y DSS being 20% higher than OS. This is in agreement with other studies, which reported a 7%e20% higher DSS than OS [3,4,8,11,12,25]. Our study supports the routine use of SLNB as a valuable staging tool in patients with MCC. We found that SLNB had a positive rate of 21%, which is consistent with the reported rate of 19%e38% [4,8,12]. The locoregional recurrence rate was 27% for those with negative SLNB, which is higher than the recently published recurrence rate of 13% [11,12]. The reason for this difference is not clear. We found that patients with clinically or microscopically positive nodes had a significantly higher rate of death from disease. This is in contrast to recent reports of a larger series from a single institution, which found that SLN status is not predictive of recurrence or MCC-specific death [4,12]. We are unable to explain the difference with our study, demonstrating that further investigation is warranted to evaluate the prognostic impact of LN status. Of note, nodal staging is felt to be predictive of prognosis by the AJCC as nodal status is part of the recently developed staging system [19]. Some interesting patterns emerge when examining the use of radiation therapy and recurrence by stage. The radiation treatment group had a smaller proportion of stage I patients when compared with the group not receiving radiation therapy (54% versus 77%). This suggests that those who underwent radiation therapy were felt to be at a higher risk for recurrence by their treating physicians. Surprisingly, the five patients with locoregional recurrence were all stage I. This demonstrates that even with aggressive treatment, early stage

Table 7 e Stage-specific survival. Seventh edition Stage

N

Median OS (mo)

I II III IV Overall Median Overall Survival (OS) not reached

16 3 6 1 26

32 ea 9.0 4.0 29 P ¼ 0.1560

a Unable to calculate median due to stage not reaching 50% of events.

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MCC has a high rate of recurrence and poor OS. This supports the use of a multidisciplinary team approach in the treatment of MCC patients [8]. Current NCCN guidelines emphasize that surgery is the primary treatment modality for those with MCC [22]. They advocate the use of SLNB for staging purposes, which our data and recently reported data support [4,12,26]. The NCCN panel also included radiation as a treatment option for all stages of MCC based on limited data showing lower locoregional recurrence with the use of radiation therapy. Differences in opinion exist on the routine use of radiation therapy. In our study, radiation therapy use was left to the discretion of the treating physician. Radiation therapy did not decrease the locoregional recurrence rate, but this difference may reflect selection bias as previously noted. In addition to standard staging information, a variety of pathologic factors were evaluated to determine if they might be helpful in predicting prognosis. These factors included the “optional” elements in both the most recent AJCC Staging Manual and the CAP protocol [19,21]. The literature is mixed on the usefulness of these additional factors [7,27e30]. No study has previously looked at all these factors to determine their usefulness for prognosis. We found that those with nodal metastasis have a high rate of recurrence. Tumor thickness did not correlate with recurrence risk as those with thick tumors paradoxically had lower recurrence risk. This demonstrates that tumor thickness may be less important in MCC than in melanoma patients, where the importance of tumor thickness has been well established. The remaining pathologic factors that were studied did not appear to have a significant effect on prognosis. A limitation of this study is the small number of patients reviewed, but our study is similar in size to many other single institutional studies of this rare tumor. This study also is retrospective in nature. Although the follow-up interval appears short, this in part reflects the significant early mortality of MCC, as well as death from other causes in this elderly population. This study adds to the slowly growing body of literature evaluating treatment and outcomes of those with MCC. Although a prospective randomized study is the gold standard, such a study is unlikely given the rare nature of MCC. In conclusion, despite aggressive surgical and radiation treatment, our study confirms that MCC continues to have a high rate of locoregional recurrence, even in early stage disease. SNLB is useful for the staging and management of patients. Further research is needed to identify better prognostic markers.

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