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Merkel Cell Carcinoma Treated with Wide Local Excision with or without Radiotherapy and Chemotherapy: A Multi-Institutional Retrospective Analysis

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    • Merkel Cell Carcinoma Treated with Wide Local Excision with or without Radiotherapy and Chemotherapy: A Multi-Institutional Retrospective Analysis

    Morteza Dowlatshahi MD, Reza Shirazi MD, Ly Do MD, Tri Do MD, Arash Salari BS, Lawrence Huan MD, and Robert A. Kagan MD

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    Purpose: The purpose of this study was to evaluate the treatment of Merkel cell carcinoma with or without radiotherapy and chemotherapy. In order to gain a better understanding of management and assess prognostic factors, data from 3 California cancer centers was pooled and retrospectively analyzed.

    Materials and Methods: We reviewed 26 consecutive cases of Merkel cell carcinoma from June 2000 to October 2010. There were 16 male and 10 female patients. The majority of the cases involved the upper extremities (54%), followed by the head and neck (35%), and finally lower extremities (11%). No tumors were noted in the trunk. Twenty-seven percent of the patients presented with stage I disease (localized with a tumor <2 cm), 31% with stage II disease (localized with a tumor >2 cm), and 42% percent with stage III disease (nodal metastasis). No patients presented stage IV (distant metastasis). All patients were surgically treated with wide local excision and lymph node dissection when appropriate. Radiotherapy was administered with curative intent in 18 patients (69%). 6 patients (23%) additionally received radiotherapy after a recurrence. 2 patient (8%) did not receive radiotherapy at all. In addition, four patients were treated with chemotherapy.

    Results: With an average follow-up time of 32 months, 10 patients (38%) had recurrent disease. The median time to recurrence was 8.8 months with a mean of 11.8 months. Although tumor size and site of presentation were not observed to be statistically significant, significant results were observed based on lymph node involvement and post-operative radiation therapy. Patients with positive lymph node status at the time of diagnosis had a statistically significant (P < 0.05) lower overall survival rate [mean 21 months] as compared to patients having no lymph node involvement [mean 44 months]. Also, the recurrence rate was 85% in patients treated with surgery alone as compared to 17% for surgery + adjuvant radiation (P < .05). Patients treated with chemotherapy were not statistically analyzed because the systemic effect of chemotherapy would have been less clear due to the small number of patients. 2 and 5-year survival rates were 70% and 53% respectively.

    Conclusion: Adjuvant radiation therapy is recommended in all patients undergoing surgical management of MCC. Lymph node metastasis carries a dismal prognosis. Early detection is vital in the management of Merkel cell carcinoma.

    Introduction

    Merkel cell carcinoma (MCC) first described by Toker in 1972 is an aggressive cutaneous malignancy of neuroendocrine origin.1 Due to the rarity of MCC, it is often misdiagnosed as basal cell carcinoma, squamous cell carcinoma, melanoma, angiosarcoma, or cutaneous lymphoma. Regardless, the incidence rate for Merkel cell carcinoma has been on the rise from 0.15 per 100,000 in 1986 to 0.6 per 100,000 in 2012.2-3 This increase may be credited to many reasons, including increased clinical awareness, improved testing, and an increasing elderly population.2, 4-6 Environmental factors such as an increase in sun exposure have also been attributed to the increase in the malignancy. Immunocompromised patients exhibit higher rates of MCC.2, 7-8

    The danger in Merkel cell carcinoma is that the cancer is clinically aggressive. Tumors larger than 2 cm and clinically positive lymph nodes have revealed to have a poor prognostic outcome for recurrence.6-7, 9-11 The SEER results (2003) in the United States for five year survival of metastatic MCC is a poor 25%.6 Because of these various reasons more clinical awareness needs to be observed to this specific type of skin cancer.

    However, due to the rarity of MCC, there is still a significant lack of information surrounding the best practices and outcomes. Experience gained from retrospective studies like this one can help the optimal treatment of these uncommon types of cancer. This article presents 26 consecutive cases that were treated with surgery, radiotherapy, and/or chemotherapy. We will evaluate the effectiveness of our different treatment options and compare our results to the literature. Survival and prognostic factors will be statistically analyzed and discussed.

    Materials and Methods

    Patients

    Patients were identified searching the EMR databases of three California cancer centers. The databases were pooled for patients receiving treatment for Merkel cell carcinoma between June 2000 and October 2010. All patients who were included in the analysis had histologically confirmed MCC. (Further eligibility of patients? Metastatic, nonmetastatic, age? Other malignancies?)

     

    Staging

    Our study used the four-tier staging system developed by the Memorial Sloan-Kettering Cancer Center (MSKCC). A patient’s tumor was initially biopsied and clinically evaluated. If further testing was appropriate the adjacent lymph nodes were biopsied and a computer tomography (CT) of the chest, abdomen, and regional areas were performed. The MSKCC staging for MCC is consistent with the staging system used by the American Joint Committee on Cancer.12 Another predominant staging system, proposed by Yiengpruksawan et al. was also found and both staging systems have been presented in Table 1 for clarity.13

    Surgical Treatment

    After positive biopsy the primary tumor was surgically removed by wide local excision. Adjacent lymph nodes were also clinically evaluated and biopsied when appropriate. Treatment after a positive lymph node was based on patient and treating physician preference. Various studies are suggesting a routine biopsy of the sentinel lymph node (SLNB) in MCC patients to detect a spread that would otherwise have been clinically undetected.11, 14-15 Due to the aggressive nature of MCC elective LN dissection (LND) with clinically negative lymph nodes are still being debated by surgical oncologists.16-17

    Radiation Therapy

    Radiation therapy usually consisted of > 50 greys (Gy) of external-beam radiation for 5 days per week over a 5 to 6-week course. Radiation was administered to the primary tumor excision site and/or draining LN basin. In our study adjuvant RT is defined as RT to the primary tumor site and/or regional LN basin within 4 months of wide local excision and/or LN dissection.

    Chemotherapy

    Chemotherapy consisted of a platinum agent in combination with an etoposide. One patient’s chemotherapy regimen consisted of a platinum agent and an irenotecan. Treatment was administered for a total of 4 to 6 cycles over 6 to 8 weeks. Patients received chemotherapy as an adjuvant treatment or after a recurrence. ( What was the clinical indication for chemotherapy?)

    Follow-Up

    Patients were seen in the clinic every few months for 2 years and once or twice a year thereafter. Patients not followed in person were contacted by telephone. Recurrence was defined as a clinically or histologically discovered return of tumor. Recurrences were categorized as local, regional, or distant. The date of recurrence was defined as the first clinically positive account indicating the return of carcinoma. The time to recurrence was defined as the interval from the concluding date of therapy to the date of confirmed recurrent carcinoma.

    Statistical Analysis

    Statistical analysis was performed using the statistical software JMP (version 10 for PC; SAS Institute, Inc., Cary, NC). Log-Rank and Wilcoxon tests were used to statistically analyze survival time in the two different cohorts (patients receiving adjuvant RT and patients not receiving adjuvant RT). A chi-square analysis was used to examine the etiological differences of disease. Overall survival was determined by the Kaplan-Meier method. Patients who died during the course of the study were censored to not bias the outcome of analysis. P-values of < .05 were considered to be statistically significant.

    Results

    Patient Characteristics

    Twenty-six patients with stage I through stage III MCC were clinically identified and treated within 4 months of diagnosis at the Cancer Care Institute of San Jose, Radiation Medical Group of California, and the Valley Medical Center of California. Table 2 lists patient demographic information, tumor/pathology, and follow-up information from our study population.

    The median age of diagnosis was 78 years (range of 47 to 99 years). About 70% of our patients were over the age of 70. There was an overall male predominance with 16 male patients (62%) and 10 female patients (38%). An overwhelming majority of our patients were white, 23 patients (88%) and the remaining 3 patients (12%) were Hispanic.

    The most common sites of occurrences were in sun-exposed areas: 8 (30%) in the head and neck region, 14 (54%) in the upper extremities, and 2 (8%) in the lower extremities. No tumors were found in the trunk region. The median size of tumor was 2.1cm with a range of 0.7cm-5.2cm. Two patients (8%) presented with no primary tumor.

    Fifteen patients (58%) presented with clinically localized MCC [7 patients (27%) with clinical stage I disease and 8 patients (31%) with clinical stage II disease]. Eleven patients (42%) presented with clinical stage III disease. Final pathologic stage included 1 patient (4%) with stage IA disease, 6 patients (23%) with stage IB disease, 4 patients (15%) with stage IIA disease, 4 patients (15%) with stage IIB disease, 1 patient (4%) with IIIA disease, and 10 patients (38%) with IIIB disease. No patients presented with distant metastasis (stage IV).

    Surgical Treatment

    A wide local excision was performed on all patients presenting with a primary tumor (n=24, 2 patients presented without a primary tumor). 18 patients underwent a margin-negative excision while 6 patients had clinically positive margins. Of the 15 patients who presented with clinically negative lymph nodes, 5 patients elected to have a sentinel lymph node biopsy (SLNB) and 2 elected to have an optional lymph node dissection (LND). The remaining 8 patients had no further LN treatment or evaluation. Of the 11 patients who presented with clinically positive LN’s and no evidence of metastatic disease, all underwent total lymph node dissection (TLND).

    Radiotherapy

    Radiotherapy with curative intent was administered in 18 patients. In our cohort, 6 of 7 patients with stage I MCC and 5 of 8 patients with stage II MCC received adjuvant RT. 5 of 11 stage III patients received adjuvant RT to the draining lymph node basin in addition to the primary tumor site. An additional 2 stage III patients received adjuvant RT to the tumor bed only having presented with no primary tumor.

    The median dose of adjuvant radiation to the primary tumor site was 5870 cGy with a range of 4000cGy-6040cGy. The average dose was about 5600 cGy. The median dose of adjuvant radiation to the LN bed was 5250 cGy with a range of 5000cGy-6000cGy. The average dose to the LN bed was about 5460 cGy.

    Six of the 8 patients in the surgical group eventually received radiation after a recurrence. Their median dosage was 5500 cGy with a range of 5000 cGy – 7020 cGy. The average does for this group was 5840 cGy.

    Chemotherapy

    Chemotherapy was received by 4 of 26 patients. The median age was 74 years of age (range 60years-84years). Three of the 4 patients were stage III; the fourth patient was stage I. All patients received carboplatin or cisplatinum. Three patients received a concurrent etoposide and one patient received a concurrent irenotecan. Chemotherapy was received as an adjuvant therapy by two patients and as salvage therapy in two patients who experienced a recurrence.

    At Last Follow-Up

    The median follow-up time was 32 months (range of 4months-102months). At last follow-up 10 patients (38%) had recurrent disease. The median time to recurrence was 8.8 months with a mean of 11.8 months. Recurrence occurred locally in one patient, regionally in three, and distantly in three. One patient had a locoregional recurrence and two patients had a combination of regional and distant metastasis. The recurrence rate was 17% for surgery + adjuvant radiation as compared to 85% in patients treated with surgery alone. (p < 0.05). The effect of systemic chemotherapy on recurrence was not statistically analyzed because the outcome would be less clear as a result of the small number of patients (only four). Patients with positive lymph node status at the time of diagnosis had a statistically significant (P < 0.05) lower overall survival rate noted [mean 21 months] as compared to patients having no lymph node involvement [mean 44 months]. Gender, age, location, and tumor size were not statistically found to affect overall survival. The mean overall survival of the whole cohort was 3.1 years with 2 and 5-year survival rates of 70% and 53% respectively as summarized in Figure 1.

    Discussion

    MCC will typically present as a colored, painless, firm subcutaneous nodule with or without ulceration or telangiactasias.3 The lesion is often clinically mistaken and an acronym “AEIOU” has been proposed to raise awareness [Asymptomatic/lack of tenderness, Expanding rapidly (doubling in < 3 months), Immunosuppresion, Older than 50 years, Ultraviolet exposed skin site].4 There are many benign lesions though that can meet several of the conditions for the AEIOU acronym. To avoid confusion, suspicious lesions should always be biopsied.

    MCC and other malignancies such as: small cell lung carcinoma, carcinoid tumors, malignant lymphoma, and small-cell melanoma share similar histological characteristics. MCC usually appears as a dermal tumor extending into the subcutaneous fatty tissue with the papillary dermis and adnexa usually being spared.18-19 Further evaluation shows positive stains for epithelial and neuroendocrine markers, but negative stains for lymphoid and melanoma markers.19-20 It has been hypothesized that MCC originates from a slow-acting pressure receptor within the skin. Increasing evidence suggests that malignant transformations occur in the pluripotent neuroendocrine stem cells within the dermis.21-22

    It is understood that MCC is generally a disease of elderly Caucasian individuals with a slight male predominance.2, 4, 6-7, 23 This observation is consistent with our results as a majority of our patients were white and male (88% and 62% respectively) with a median age of 78 years. Furthermore, patients with immunosuppresion have been reported to have an increased risk of MCC as compared to immunocompetent patients. 24-25 In our study only one patient was immunosuppressed (CLL). Other possible risk factors are arsenic exposure and prior irradiation.26-27 Recently, a polyomavirus [MCPyV] has been linked to Merkel cell carcinoma. Advanced research and the development of a specific monoclonal antibody has detected the polyomavirus currently in 97% of tumors.28-29 With innovative research and increased detection further novel treatments can be discovered to treat this carcinoma. For example, in one study subcutaneous interferon-beta proteins were reported successfully in inducing apoptosis in MCC cells.30

    Unfortunately, due to the exceeding rarity of this tumor, there is a lack of definitive date  (data?) regarding MCC and its treatment. Combination therapies consisting of surgical excision, lymph node dissection, radiotherapy, and/or chemotherapy are commonly used. Wide local excision with negative margins is the preferred surgical intervention.31-32 Bajetta et al. found margin status in surgically treated patients to be significantly (P < 0.001) associated with recurrence.31 A problem with MCC is that it regularly presents in the head and neck regions where clear margins are unattainable. Combination radiotherapy has proven effective in treating MCC tumors and controlling the rates of local recurrence.10, 32-36 In our study all patients (24) presenting with a primary tumor were treated with wide local excision. Of those 24, 6 (25%) had positive margins. Clear margins were not attained on these patients because clear margins were not surgically feasible in their presenting locations. Half of the six patients with positive margins were treated with adjuvant radiotherapy and experienced no recurrence. The other half of the six patients not receiving adjuvant radiotherapy all experienced a recurrence either locally, regionally, or distally. Overall in our study the recurrence rate was 17% for surgery + adjuvant radiation as compared to 85% in patients treated with surgery alone (P < .05). This leads to our recommendation that all patients with MCC be treated with adjuvant radiotherapy following surgical excision.

    The most accurate predictor of prognosis is the involvement of regional lymph nodes. Given this information sentinel lymph node biopsy is gaining favor in determining the extent of disease and detecting microscopic metastases that may have gone clinically unnoticed.11,15,17 As shown in Figure 2, patients in our study with positive lymph nodes had a statistically significant (P < 0.05) lower overall survival [mean 21 months] as compared to patients with no lymph node involvement [mean 44 months]. Our suggestion is every patient presenting with MCC be administered a SLNB to search the adjacent lymph nodes for microscopic disease. Due to the aggressive nature of this cancer complete lymph node dissection for clinically negative lymph nodes has proven beneficial for high-risk tumors such as those that are larger than 1.0cm, located in the head or neck, have a high mitotic rate, or tumors that have invaded the lymphatics or vasculature.16,17,38 It is still being debated in the literature if a complete lymph node dissection is necessary in all MCC cases due to its high morbidity.37

    Chemotherapy does not have a clearly defined role in the treatment of MCC. One study advises chemotherapy for locally recurrent or advanced disease patients who have a history of good performance status.39 In our study we treated 4 patients with chemotherapy: adjuvant therapy in 2 patients and salvage therapy in 2 patients. Three of these 4 patients were not cured by chemotherapy and at last follow-up were either alive with disease or dead of disease. To note, these three patients all had advanced disease (stage III) at time of presentation. The one patient who did respond well to chemotherapy had early stage disease (stage I) and was treated very aggressively (surgery, radiation, and chemotherapy). With such a small patient pool statistical analysis was not carried out on these four patients. Our hypothesis to why chemotherapy didn’t work in our three patients is it was administered after a recurrence or the possibility the right combination may not have been used. In the Tai et al. study ( notation?) cyclophosphamide/doxorubicin/ (or epirubicin)/vincristine combination +/- prednisone was the most commonly used regimen (47 patients) with the highest overall response rate of 75.7%.39 Our patients were treated with a combination etoposide/cisplatin (or carboplatin). Tei et al. reported a 60% overall response in our combination, but regardless a statistically significant difference in effectivity was not noted between the two groups (P=.19).39 Another hypothesis proposed by Garneski et al. explains chemotherapeutic ineffectiveness in MCC  could be due to the suppression of the immune system.40 The immune system plays a large role in defending the host from the development and progression of MCC.3,8,24-25 Due to these conflicting arguments the only way to truly confirm whether chemotherapy improves the results in high-risk MCC is to run a larger randomized study.

    Conclusion

    While our small study contributes to the data published about Merkel Cell carcinoma, there is still much left to be investigated with this aggressive malignancy. The results show early detection and combination therapies being a predictor of good prognosis. Based on our study, all patients presenting with MCC should be treated with wide local excision and be administered a SLNB to detect microscopic lymph node metastasis. In addition all patients should be treated with radiotherapy to the tumor bed and regional lymph nodes.

    Table 1. Staging Systems for Patients with Merkel Cell Carcinoma12-13

    Staging System Criteria
    Memorial Sloan-Kettering Cancer Center TNM staging system  
    T  
    1 Primary tumor < 2cm
    2 Primary tumor > 2cm
    N  
    0 Negative regional lymph node involvement
    1 Positive regional lymph node involvement
    M  
    0 No evidence of distant metastatic disease
    1 Presence of distant metastatic disease
    Stage  
    I T1, N0, M0
    II T2, N0, M0
    III Any T, N1, M0
    IV Any T, Any N, M1
    Yiengpruksawan et al. three-tiered staging system  
    IA Primary tumor < 2cm
    IB Primary tumor > 2cm
    II Regional lymph node metastasis
    III Distant metastases

    Figure 1. Kaplan-Meier Curve for Overall Survival

    Figure 2. Kaplan-Meier Curve for Overall Survival in Patients Presenting with Involved Lymph Nodes

    Table 2. Patient Characteristics of the Patients Diagnosed with Merkel Cell Carcinoma (Cancer Care Institute of San Jose, Radiation Medical Group of California, and Valley Medical Center of California Health Databases, 2000-2010)

    Characteristic Number of Patients Percentage
    Median Age at Diagnosis: 78 years 26 100%
    Gender    
    Male 16 62%
    Female 10 38%
    Ethnicity    
    White 23 88%
    Hispanic 3 12%
    Location of primary, n=26    
    Head and Neck 8 30%
    Upper Extremity 14 54%
    Lower Extremity 2 8%
    Trunk 0 0%
    No primary 2 8%
    Primary tumor diameter, cm n=24    
    Median 2.1cm  
    Range 0.7cm-5.2cm  
    Stage at diagnosis per MSKCC system, n=26    
    I 7 27%
    II 8 31%
    III 11 42%
    IV 0 0%

    Table 3. Treatment Profiles of Patients Diagnosed with Merkel Cell Carcinoma in the Cancer Care Institute of San Jose, Radiation Medical Group of California, and Valley Medical Center of California Health Databases, 2000-2010

      Number of Patients Percentage
    Type of surgical resection, n=26    
    Wide Local Excision 24 92%
    Total Lymph Node Dissection 11 42%
    Adjuvant therapy    
    RT to Primary Site, Median Dosage 5870 cGy 18 69%
    RT to LNB*, Median Dosage 5250 cGy 5 19%
    RT+Chemotherapy 2 8%

    *Lymph node Basin

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