Merkel Cell Carcinoma - Springer Link

Ann Surg Oncol (2013) 20:1365–1373 DOI 10.1245/s10434-012-2779-3

ORIGINAL ARTICLE – MELANOMAS

Merkel Cell Carcinoma: 30-Year Experience from a Single Institution Juan A. Santamaria-Barria, MD1, Genevieve M. Boland, MD, PhD1, Beow Y. Yeap, ScD2, Valentina Nardi, MD3, Dora Dias-Santagata, PhD3, and James C. Cusack Jr. , MD1 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; 2Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 3Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 1

ABSTRACT Background. Merkel cell carcinoma (MCC) is a rare cutaneous malignancy. Few single-institution series have been reported. Methods. Review of MCC patients treated at our institution between 1980 and 2010. Patient, tumor, and treatment variables were analyzed to determine MCC-specific outcomes. Results. We identified 161 patients with MCC. There was a 2.5-fold increase in cases over the last decade. Median length of follow-up was 36 months. Stage at diagnosis was I in 35 %, II in 21 %, IIIa in 12 %, IIIb in 23 %, and IV in 9 %. The 5-year MCC-specific survival rates were 87, 63, 42, and 0 % for stages I, II, III, and IV, respectively. Death from the disease occurred in 10 % of patients with T1 and in 50 % with larger lesions. One-third of patients presented with nodal disease. Sentinel lymph node biopsy (SLNB) identified micrometastases in 9 out of 27 (33 %) earlystage patients. Recurrence developed in 56 % of SLNBpositive and 39 % of SLNB-negative patients. Half of patients recurred after a median time of 9 months. Proportions of first recurrence location were distant (52 %), nodal (27 %), and local (21 %). Adjuvant treatments did not improve recurrence or survival rates. One-third of patients died of the disease. Conclusions. SLNB identifies micrometastasis in onethird of early-stage patients. Negative SLNB may predict

Ó Society of Surgical Oncology 2012 First Received: 21 March 2012; Published Online: 1 December 2012 J. C. Cusack Jr. , MD e-mail: [email protected]

for improved but not necessarily favorable outcome. Initial tumor size and clinical nodal disease predict for poor outcome. High recurrence rates warrant the development of more effective adjuvant therapies, and better markers of recurrence and treatment response for MCC are needed.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy arising from the skin, with estimated incidence of 0.6 per 100,000 person-years.1 The incidence appears to be on the rise, likely due to improved diagnostic techniques, the growing immunosenescent population, and increased exposure to known risk factors, such as chronic immunosuppression and prolonged mutagenic exposure of the skin.2–5 The natural history of MCC is unpredictable, ranging from a localized indolent course, to a regionally more aggressive course with widespread metastases. The rare incidence of the disease, deficient reporting of outcomes, and a relative lack of management consensus have made MCC characterization cumbersome.6–17 MCC treatment recommendations remain inconsistent. The benefit of adjuvant therapies after surgical management in early-stage patients (stage I and II) has not been well established, yet reports of increased locoregional recurrence rates after surgical excision alone support the need for better regional and systemic disease control.10–14 Other studies have shown improved recurrence and survival rates with either adjuvant radiotherapy or chemotherapy.12–17 The goal of this study is to describe the experience with MCC at the Massachusetts General Hospital and examine the evolution of its management and outcomes over a 30-year period. Data concerning patient, tumor, and treatment characteristics were collected and analyzed for their association with recurrence and disease-specific survival.

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PATIENTS AND METHODS Patient, Tumor, and Treatment Characteristics We performed a search of the Massachusetts General Hospital clinical records to identify patients with a confirmed histological diagnosis of MCC who received treatment at out institution between January 1, 1980 and December 31, 2010. Approval from the institutional review board was obtained before accessing the databases and conducting the study. Biographical characteristics and relevant past medical history were collected. Review of individual pathological and surgical records helped us to identify the primary tumor location and size. The majority of patients were referred to us after newly discovered lymphadenopathy or MCC pathology results. Patients were staged using the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual.18 We classified immunosuppressed patients as those with some degree of immunocompromise (e.g., chronic leukemia, lymphoma, liver or renal diseases, acquired or congenital immunodeficiencies, long-standing diabetes, immunosuppressive or chemotherapeutic drugs, transplant recipients, etc.). Treatment characteristics of the initial management of the primary lesion included surgery, adjuvant radiation, chemotherapy or combination of these modalities. We did not include margin status after resection because the very few number of positives did not impact analysis. Additional data including clinical lymph node status at diagnosis, operative staging of regional lymph nodes, and treatments of the draining nodal basin were collected.

J. A. Santamaria-Barria et al.

date of last follow-up in the recurrence-free survival analysis. Patients who died due to non-MCC causes were censored at their date of death in the disease-specific survival analysis. These curves were compared using the logrank Mantel–Cox test. All statistical tests were two-tailed. Statistical significance was established at P \ 0.05. RESULTS Patient and Tumor Characteristics Table 1 summarizes patient and tumor characteristics. We identified 161 patients with confirmed histological diagnosis of MCC who received treatment at our institution between 1980 and 2010. When compared with the 1990 s decade, there was a 2.5-fold increase in cases over the last 10 years (patients, 41 vs 102). Nearly half of our cohort was diagnosed since 2005 (43 %; n = 70). MCC was more common in men (61 vs 39 %). Median age at diagnosis was 72 years. More than half of patients presented with early local disease (stage I or II, 56 %; n = 90), one-third presented with regional nodal spread TABLE 1 Patient and tumor characteristics from 161 patients treated for Merkel cell carcinoma at the Massachusetts General Hospital between 1980 and 2010 Variable

No. of patients

%

Age (years) Median

72

Range

28–97

Sex

Recurrence and Survival The date and type of the first recurrence after initial treatment, the management rendered for the recurrence, and the date and cause of death were determined. Sufficient follow-up information was acquired to establish adequate recurrence-free and disease-specific survival rates. Outcomes were analyzed for patient, tumor, and treatment characteristics. Statistical Analysis

Male

98

61

Female

63

39

Immunosuppression Yes

90

56

No

71

44

65 36

40 22

Location of primary lesion Head and neck Lower extremity Upper extremity

26

16

Unknown

22

14

Trunk

12

8

Size of primary (cm) (n = 141)

Fisher’s exact test was used to determine proportion differences on outcomes and patient, tumor, and management characteristics. Means of continuous variables were compared using the unpaired t test. Recurrence-free and disease-specific survival times were measured from the date of confirmed histological diagnosis of MCC. Kaplan–Meier survival curves were obtained to determine recurrence-free and disease-specific survival probabilities. Patients who were alive with no evidence of disease were censored at their

Median

2.3

Range

0.4–11.3

Stage at presentation I

56

35

II

34

21

IIIa

19

12

IIIb

37

23

IV

15

9

Merkel Cell Carcinoma at a Single Institution

(stage IIIa or IIIb, 35 %; n = 56), and a small percentage with disseminated disease beyond the regional draining lymph nodes (stage IV, 9 %; n = 15). Two-thirds of stage III patients exhibited clinically evident lymphadenopathy (macrometastases, stage IIIb; n = 37). SLNB or lymph node dissection (LND) identified the remaining third (micrometastases, stage IIIa; n = 19). The most common primary lesion site was the head and neck (40 %), followed by the lower and upper extremities (22 and 16 %, respectively). The median size of the primary tumor was 2.3 cm (range 0.4–11.3 cm; n = 141). Nodal disease was less frequent with upper extremity primaries (15 vs 50 % trunk, 42 % lower extremities, and 43 % head and neck). T1 lesions (B2 cm) were significantly less likely to harbor nodal disease than T2 ([2 cm but B5 cm) and T3 ([5 cm) lesions (22 vs 46 %; P = 0.006). There were 22 patients presenting with unknown primaries: 13 with stage IIIb and 9 with stage IV. At least half of patients had some degree of immunocompromise (56 %; n = 90). Treatment Figure 1 summarizes treatment characteristics. At presentation, 109 patients (68 %) presented without clinically evident lymphadenopathy or distant metastasis (stage I, II, and IIIa). Wide local excision was performed on 104 patients. Five patients were treated with radiotherapy only. Forty-one of these apparently early-stage patients underwent operative nodal staging (LND, n = 14; SLNB, n = 27), on which almost half (46 %; n = 19) were discovered to harbor nodal micrometastases and hence were upgraded to stage IIIa. Patients undergoing LND had larger lesions than patients undergoing SLNB (mean, 3.75 vs 2 cm; P = 0.003). LND performed on 14 patients found micrometastases in 10 patients, of whom 7 received adjuvant chemoradiation and 2 received radiotherapy only. Twentyseven patients underwent SLNB at our institution (20 since 2005), revealing micrometastases in nine patients (33 %). SLNB-positive patients showed a trend to have larger lesions than SLNB-negative patients (mean, 2.58 vs 1.72 cm; P = 0.078). Five SLNB-positive patients were further managed with completion LND of the nodal draining basin, all nine patients with micrometastases in the sentinel node received adjuvant radiotherapy to in-transit and draining nodal basins, and four received chemotherapy. Wide excision of the known primary tumor and LND were performed on 30 patients with stage IIIb disease (81 %; n = 37). Adjuvant chemoradiation was given to 14 of these patients, and adjuvant radiation to 12. Seven stage IIIb patients did not undergo LND: four received combined chemoradiation, two received radiation, and one deferred treatment (Fig. 1).

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Adjuvant radiotherapy was administered to 78 patients who presented with local or nodal disease (53 %; n = 146): 16 stage I (29 %; n = 56), 18 stage II (53 %; n = 34), 18 stage IIIa (95 %; n = 19), and 26 stage IIIb patients who underwent LND (86 %; n = 30). Adjuvant chemotherapy was administered to 43 patients who presented with local or nodal disease (29 %; n = 146): 6 stage I (11 %), 11 stage II (32 %), 11 stage IIIa (63 %), and 14 stage IIIb patients (38 %). The most commonly used regimen was a combination of platinum and etoposide. Recurrence Outcomes are summarized in Fig. 1. Half of patients with local or nodal disease recurred after primary treatment (48 %, 70 recurrent patients; n = 146) with median time to recurrence of 9 months (range, 1.3–75 months). The 1-, 3-, and 5-year recurrence-free survivals for these patients were 64, 48 and 42 %, respectively (Fig. 2a). The most common type of first recurrent event was distant metastasis beyond the regional draining lymph nodes, followed by regional lymphadenopathy and local recurrences (52 27 and 21 %, respectively). Recurrences developed in 34, 50, 47 and 68 % of stage I, II, IIIa, and IIIb patients, respectively. Approximately one-fifth of early-stage patients recurred initially in regional lymph nodes (22 %, 20 patients; n = 90): 13 stage I (23 %, n = 56) and 7 stage II patients (21 %, n = 34). Recurrence developed in 56 % of SLNBpositive (5, n = 9) and 39 % of SLNB-negative (7, n = 18) patients. Only 1 out of 10 SLNB-negative stage I patients recurred locally. However, 7 out of 12 SLNBnegative or LND-negative stage II patients recurred: 1 locally, 4 to the nodal basin, and 2 distantly. Recurrence occurred in 21 T1 (B2 cm; 31 %, n = 68), 26 T2 ([2 but B5 cm; 58 %, n = 45), and 14 T3 lesions ([5 cm; 50 %, n = 28). These differences were significant (P = 0.013). Distant metastasis developed in 4, 33, and 46 % of patients with T1, T2, and T3 lesions, respectively (P \ 0.0001). The 2-year recurrence-free survivals of T1, T2, and T3 lesions were 66, 37 and 35 %, respectively (Fig. 2a). Local or nodal recurrence rates were not different for stage I or II patients who underwent surgery alone versus surgery with adjuvant radiotherapy to the primary site and draining nodal basin (stage I: surgery only, 27 % vs adjuvant radiotherapy, 32 %; P = 0.765; stage II: surgery only, 60 % vs adjuvant radiotherapy, 39 %; P = 0.433). There was no local or nodal recurrence-free survival improvement among early-stage patients who underwent adjuvant radiotherapy (Fig. 3a, b). Nodal or distant recurrence rates were not different in stage IIIa and IIIb patients who received chemotherapy (stage IIIa: no chemotherapy, 25 % vs chemotherapy,

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a

b

FIG. 1 Staging, treatment and outcomes for MCC patients who presented with localized disease (a) and clinically evident lymphadenopathy or metastatic disease (b). MCC Merkel cell carcinoma, XRT radiotherapy, ADJ surgical resection with adjuvant treatment, SUR

surgical resection, Chem chemotherapy, REC recurrence, LOC local recurrence, NOD nodal recurrence, MET distant metastasis, DOD died of disease

54 %; P = 0.352; stage IIIb: no chemotherapy, 58 % vs chemotherapy, 56 %; P = 1.00). Stage III patients receiving chemotherapy demonstrated no significant recurrence-free survival advantage (Fig. 3c). Current MCC staging guidelines define stage IV disease as metastatic spread beyond the regional draining lymph nodes.18 Distant metastasis was the most common first recurrence event, occurring in 36 of 146 patients who presented with local or nodal disease (1 on stage I, 2 %; 7 on stage II, 21 %; 8 on stage IIIa, 42 %; 20 on stage IIIb, 54 %).

n = 68), 18 (40 %; n = 45), and 18 (64 %, n = 28) patients with T1, T2, and T3 lesions, respectively. These differences were significant (P \ 0.001). The 2-year disease-specific survivals of patients with T1, T2, and T3 lesions were 86, 69, and 45 %, respectively (Fig. 2c). At last follow-up, 13 early-stage patients had died of the disease: 5 stage I patients (9 %, n = 56) and 9 stage II patients (26 %, n = 34). The five stage I patients who had died of the disease had not undergone surgical nodal staging, whereas none of those who underwent surgical nodal staging with a negative result had died of the disease (0 %, SLNB-negative; n = 10). Likewise, 6 stage II patients who had died of the disease had not undergone pathological nodal staging, whereas 3 out of 12 who underwent surgical nodal staging with a negative result had died of the disease (25 %; SLNB-negative, n = 8; LNDnegative, n = 4). Early-stage patients who received adjuvant radiation showed no significant disease-specific survival advantage (Fig. 3d). Finally, 26 patients who presented with nodal disease had died of the disease: 7 stage IIIa patients (37 %, n = 19) and 19 stage IIIb patients (51 %, n = 37).

Survival The median length of follow-up was 36 months among surviving patients. The 1-, 3-, and 5-year disease-specific survival rates were 81, 61, and 56 %, respectively (Fig. 4a). At last follow-up, 63 (40 %) patients had no evidence of disease, 55 (34 %) had died from the disease, 31 (19 %) had died of other causes, and 12 (7 %) were alive with the disease (Table 2). The 5-year MCC-specific survival rates were 87, 63, 42, and 0 % for stage I, II, III, and IV, respectively (Fig. 4b). Disease-specific death occurred in 7 (10 %;


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b

a

c

FIG. 2 Recurrence-free survival of local and nodal MCC at presentation (stages I, II and III) (a) Recurrence-free survival (b) and diseasespecific survival (c) stratified by T stage of primary: T1: B2 cm, T2: [2 and B5 cm, T3: [5 cm

FIG. 3 Comparison of local and nodal recurrence-free survival between stage I (a) and stage II (b) patients who underwent adjuvant radiation versus surgery alone, * Patients who recurred distantly as first event were excluded from the analysis: 5 stage I and II patients who received adjuvant chemotherapy only and 6 who received radiotherapy without surgery. Comparison of recurrence-free survival between stage III patients who underwent adjuvant chemotherapy versus no chemotherapy (c). Comparison of disease-specific survival between early stage patients who underwent radiation versus surgery alone (d)

a

b

c

d

At diagnosis, 15 patients presented with stage IV metastatic disease. They all died of the disease. The median and average time to death were 6 and 7.8 months,

respectively. Finally, patients who were defined as having some degree of immunocompromise showed a trend for improved survival outcomes (Fig. 5).

1370 FIG. 4 Disease-specific survival of all MCC stages (a). Disease-specific survival stratified by stage at presentation according to the 7th edition of the AJCC staging manual (b)


a

DISCUSSION To the best of our knowledge, this is the third largest single-institution MCC series to be reported.19–21 Our institution had previously reported a smaller series prior to 2000.6 Since then, MCC cases at our institution have increased by almost threefold. MCC was first described in 1972 as ‘‘trabecular carcinoma’’ by Toker.22 It was not until the early 1980 s that ultrastructural studies led to the adoption of its present name.22–24 The accurate identification of MCC histologically was facilitated by the introduction of immunostaining cytokeratin 20 positive and thyroid transcription factor-1 negative to rule out metastatic small cell lung cancer.25–27 Our cohorts from earlier years may be underrepresented, since these techniques were gradually introduced in the late 1990s. Early lymphatic spread is the cornerstone of MCC natural history and affects prognosis dramatically. Together with stage and size, lymph node status has been found to be an independent predictor of survival in the largest reported series, and several studies have highlighted the relevance of node-positive disease.6,9,19,28–32 Notably, distant, and not regional, recurrence was the most frequent first site of recurrence. This finding suggests that MCC cells had already disseminated via the lymphatic and/or hematogenous route beyond the regional nodal basin at the time of diagnosis. Over the last decade, numerous studies have highlighted the utility of SLNB in MCC.8,28,32–39 The first SLNB for MCC at our institution was performed in 1994. Over the last decade, SLNB has gradually become incorporated into the management algorithm for early-stage MCC patients. Our SLNB-positive rate (33 %) is comparable to others reported in the literature (20–40 %).8,15,19,36–39 A recent study compiled 5,823 MCC patients from the National Cancer Data

b

Base, and found that SLNB-negative patients had improved overall survival when compared with patients who did not undergo SLNB.32 This study was limited by the inability of the database to establish MCC-specific survival. We believe overall survival to be an unreliable measure of MCC mortality, since the typical MCC population is both polypathological and senescent. Fields et al. recently reported a 153 SLNB series for MCC.38 In this study, there was no difference in recurrence or survival between SLNB-positive and SLNB-negative patients. Consistent with this report, 5 out of our 9 SLNB-positive patients have recurred to date (56 %): 4 recurred distantly and 1 locally; and 7 of our 18 SLNB-negative patients have recurred (39 %): 2 recurred distantly and 5 locoregionally. A negative SLNB may predict for improved yet not intrinsically favorable outcome. However, false-negative SLNBs could be numerous, since SLNB is technically difficult in the head and neck area and MCC occurs more commonly in this area. In contrast, clinically evident lymphadenopathy and size seem to have a clearer negative impact on outcome. Lastly, emerging evidence points towards histological characteristics as potential predictors of outcomes, wherein tumor growth pattern, depth, mitotic rate, and most notably lymphovascular invasion (LVI) may be better predictors of SLNB result and prognosis.29,38,39 Our study is limited in that it was not until recent years that LVI status and other histopathologic features were included in our pathology reports. The role of adjuvant therapy in MCC is not well defined. Many studies have shown improved local control and outcomes with adjuvant radiotherapy, including a metaanalysis and pooling from a national database.7,12–14,16,40–44 Administration of adjuvant radiotherapy is recommended by the national comprehensive cancer network guidelines for advanced local and regional disease.45 Our findings failed to


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TABLE 2 Recurrence and follow-up characteristics Variable

No. of patients

%

I (n = 56)

19

34

II (n = 34)

17

50

IIIa (n = 19)

9

47

IIIb (n = 37)

25

68

Total

70

48

Recurrence (n = 146)

Time to recurrence (months) Median

9

Range

1.3–75.0

Type of first recurrent event (n = 70) Local Nodal

15 19

21 27

Distant

36

52

Follow-up (months) Median

36

Status at last follow-up NED

63

39

DOD

55

34

DOC

31

19

AWD

12

7

MCC mortality 1980–1990 (n = 19)

7

34

1990–2000 (n = 40)

11

27

2000–2010 (n = 102)

37

36

NED no evidence of disease, DOD died of disease, DOC died of other causes, AWD alive with disease

FIG. 5 Comparison of MCC-specific survival between patients who presented with some degree of immunocompromise, such as chronic leukemia or lymphoma, liver or renal diseases, acquired or congenital immunodeficiencies, long-standing diabetes, immunosuppressive drugs, transplant recipients, etc

find convincing benefits from adjuvant treatment regimens. However, our review is limited by the intrinsic drawbacks of a retrospective review and underpowered by a small sample size. Caution should be taken when interpreting our data. We found no significant improvement in recurrence or survival for early-stage patients who received radiotherapy (Fig. 3a, b, d). Adjuvant radiation continues to be given selectively under experienced clinical judgement to patients with nodal disease, larger tumors, and more aggressive pathological features.46 The role of adjuvant chemotherapy is less controversial. We failed to find benefit from adjuvant chemotherapy among node-positive patients (Fig. 3c). Several studies have explored the role of adjuvant chemotherapy in MCC, but despite reported chemosensitivity, responses are not durable and have failed to correlate with improved outcomes.47–52 The low incidence of MCC has to date precluded controlled, prospective randomized trials to better address these questions. Patients with some degree of immunocompromise showed a trend to have better MCC-specific survivals (Fig. 5). We do not have an explanation for this phenomenon. Lastly, in 2008, Feng et al.53 described a previously unknown polyomavirus integrated into the tumor genome of patients with MCC. The polyomavirus is reported to be present in roughly 50–80 % of MCC.54–58 The definitive role of the polyomavirus in MCC has yet to be elucidated. Recently published findings from our group described a subset of tumors with activating PI3 KCA mutations that may be sensitive to PI3 K pathway inhibitors in clinical development.59 We also found improved stage-adjusted outcomes in those patients harboring the polyomavirus. The activation of PI3 K/AKT signaling in MCC has also been reported by another group.60 In conclusion, our review illustrates the 30-year experience with MCC at our institution and characterizes MCC as an aggressive and heterogeneous malignancy. MCC cases have increased at our institution 2.5-fold. Approximately one-half of patients recurred, one-third presented with nodal disease at diagnosis, and in similar proportion, one-third died of the disease. Surgery remains the mainstay of treatment for localized MCC, and operative nodal staging (i.e., SLNB) is important, since one-third of patients will harbor occult nodal micrometastases. However, SLNB-positive and SLNB-negative patient outcomes were variable. SLNB result may not have such a paramount prognostic role as it does in melanoma or breast cancer; a negative result may predict for an improved yet not entirely favorable outcome. Stage and tumor size remain vital predictors of recurrence and survival. Although underpowered, our review failed to find convincing recurrence or survival benefits from current adjuvant therapies. MCC recurred regionally but, more frequently, spread distantly. As the search for molecular targets continues, improvements in the understanding of the

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tumor biology that dictates MCC dissemination and treatment resistance are needed. DISCLOSURES to disclose.

The authors have no potential conflicts of interest

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