Histopathology
The tumor characteristically involves the dermis, with sparing of the epidermis. The tumor cells form irregular trabeculae extending down into the subcutaneous tissue. The tumor may resemble lymphoma, carcinoid, oat cell carcinoma, sweat gland carcinoma, or neuroblastoma. The histologic appearance of the tumor has no predictive value on its clinical aggressiveness. Merkel cell tumors express both neuroendocrine and epithelial markers. They show positive labeling with epithelial membrane antigen and neuron-specific enolase. The tumor cells also stain positive for monoclonal antibodies to cytokeratins 8, 18 and 19, which are characteristic of simple and glandular epithelia.  In contrast to normal Merkel cells, the cells of Merkel cell tumor also express neurofilament proteins in a paranuclear location. Ultrastructurally, the tumor cells contain membrane-bound, dense-core neurosecretory granules in the peripheral cytoplasm.. These granules vary from 80 to 180 nm in diameter, and their presence is an important diagnostic feature. The cells also show characteristic perinuclear filament whorls.
Treatment
Wide local excision with 2.5 to 3.0 cm margins is the standard treatment modality.. Alternatively, local excision with margin control by frozen section histology (Mohs surgery) may be the treatment of choice if the service is available.. Lymph node dissection should be done if the nodes are clinically involved or if there is a single drainage area.. Radiation may be beneficial for local recurrences or for local control after node dissection.  The dosage used is similar to those used for squamous cell carcinoma (5,000–6,000 cGy). Combination chemotherapy has produced limited success. Intralesional tumor necrotic factor has also been evaluated.
Course and Prognosis
The rate of local recurrence is approximately 35 to 43%, with the average time to recurrence of 4.3 months. Lymph node metastasis is present in 41% and visceral metastasis in about 18% at diagnosis. Of patients without local recurrence, 60% develop nodal metastasis, while 86% of patients with local recurrence also develop nodal metastasis. One-third of patients with positive nodes develop visceral or central nervous system metastasis and die of their disease; the average time from diagnosis to death is 2.4 years. Factors associated with a poor prognosis are early age of presentation, male sex, lesion location on the head and neck or trunk, and generalized disease. In view of the high recurrence rate, close follow-up is recommended. Ratner and colleagues recommended monthly visits for the first 6 months, then every 2 to 3 months for the next 2 years, and followed by semiannual to annual visits thereafter.

Int J Radiat Oncol Biol Phys 1990 Sep;19(3):583-91

The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma.

Morrison M. D. Anderson Cancer Center, Houston.

Between 1966 and 1987, 54 patients with non-disseminated Merkel cell carcinoma (MCC) were treated with curative intent at the University of Texas M. D. Anderson Cancer Center. The primary tumor site was in the head and neck in 38 patients. The majority of the patients (57%) were referred with locoregionally recurrent disease. For the whole group, survival was 30% after 5 years. Patients who presented with nodal involvement had a median survival of 13 months compared with 40 months for node-negative patients (p less than .04). Only 4/37 patients treated initially by surgery alone were locoregionally controlled, with a median time to recurrence of 4.9 months. Salvage with radiation therapy was attempted in 18 patients (after additional surgery in 14), but was successful in only four. The predominant failure pattern in this subgroup was distant metastases, occurring as a component of initial recurrence in 12/18 patients. Prior to 1982, the philosophy of initial therapy was to give postoperative irradiation only to patients with large primaries or nodal involvement. Subsequently, postoperative radiotherapy has been recommended routinely, and all five patients treated with this approach remain disease-free. In total, 31 patients (including 10 patients with gross disease) were irradiated at M. D. Anderson; only one developed an in-field locoregional recurrence as an initial site of failure. However, three marginal recurrences occurred. The median dose to the primary tumor, first echelon nodes, and supraclavicular nodes was 60, 51, and 50 Gy, respectively. Our current recommendation for initial treatment is excision of the primary tumor followed by irradiation with generous fields to include the primary tumor site and draining regional lymphatics to doses of 46-50 Gy in 2 Gy fractions. For gross unresected disease, 56-60 Gy is recommended. The role of adjuvant systemic therapy remains to be defined.
 

Radiat Oncol Investig 1998;6(5):233-9

Merkel cell carcinoma of the skin.

Nathu University of Florida College of Medicine, Gainesville, USA.

Merkel cell carcinoma is a rare, aggressive neuroendocrine tumor of the skin with a predisposition for local regional and distant spread. Radiotherapy after wide local excision has improved local control, but distant spread continues to be a significant problem. This is an update of our experience in the treatment of Merkel cell carcinoma at the University of Florida. Of 24 patients who were treated for Merkel cell carcinoma between 1984 and 1996, 18 patients were treated at the time of the initial diagnosis, and six were treated after local-regional recurrence. Of the 18 previously untreated patients, 13 had primary sites in the head and neck region, and five had primary sites elsewhere. Minimum follow-up was 1 year; no patient was lost to follow-up. The 5-year absolute survival, cause-specific survival, and local-regional control rates for the entire group were 27%, 31%, and 78%, respectively. Patients who were treated with radiotherapy at the time of initial presentation had 5-year absolute survival, cause-specific survival, and local-regional control rates of 38%, 44%, and 73%, respectively. Most deaths were due to distant metastasis. Site of the primary tumor (head and neck versus other) was not associated with any difference in the outcome. Of six patients who were treated at the time of local-regional recurrence, five developed distant metastasis at 3-19 months (median 8 months) from the time of treatment. One patient was alive and without evidence of disease 13 months after treatment. All patients who were treated at the time of local-regional recurrence had local-regional control after radiotherapy at 3-30 months (median 8 months). Wide local excision and radiotherapy is effective local-regional treatment for Merkel cell carcinoma of the skin, but distant metastasis remains a significant problem in this disease. The role and effectiveness of chemotherapy as part of the initial treatment remains to be defined.
 

Int J Radiat Oncol Biol Phys 1995 Jan 15;31(2):325-31

The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma.

Meeuwissen. Queensland Radium Institute, Royal Brisbane Hospital, Australia.

Eighty patients with MCC of the skin were treated with curative intent at the Queensland Radium Institute between 1981 and 1991. Fifty-one patients (63.7%) were referred after initial biopsy for further treatment and 29 patients (36.3%) were referred with locally recurrent disease following primary surgery elsewhere. Thirteen patients (16.3%) presented with nodal disease without a clinically definable primary skin lesion. RESULTS: Of the 80 patients, 38 had undergone surgery (S) alone, 34 surgery plus radiotherapy (S + RT), 7 RT after incomplete S, and 1 patient had chemotherapy (CT) plus RT. Overall survival at 36 months for all patients was 68%. All of the 38 patients treated with S alone relapsed. The median time to recurrence was 5.5 months. Ten of the 34 patients treated with S + RT relapsed. The median time to recurrence was 16.5 months. Of the 80 patients, 55 have relapsed after primary treatment, 25 have developed systemic metastases, and 26 patients have died as a direct result of MCC. CONCLUSION: Our large series confirms earlier reports from this Institute and highlights the importance of S + RT over S alone in preventing local recurrence of this highly malignant skin cancer.Strahlenther Onkol 1999 Dec;175(12):611-5

Merkel cell carcinoma: the role of radiation therapy in general management.

Bischof M, University of Heidelberg

Merkel cell carcinoma (MCC) is a rare malignant, locally aggressive tumor of the skin. Because few data exist about the clinical course of irradiated patients, we reviewed the 17 patients treated at our institution since 1982.The median overall survival after first diagnosis was 45 months. Three-year overall survival was 57%, 5-year cause-specific survival was 73% (Kaplan Meier). Local control could be achieved in the 5 patients irradiated immediately after surgical treatment of the primary tumor. In contrast, an in-field recurrence occurred in 5 of 12 patients irradiated after surgical excision of relapsed disease. Five patients developed distant metastases. None of these patients was irradiated immediately after surgical excision of the primary tumor. CONCLUSIONS: With respect to our experience, a local control can be achieved with an immediate postoperative radiotherapy of the primary tumor site and the adjacent lymph nodes.

Arch Surg 1999 Apr;134(4):388-92; discussion 392-3

Multimodality management of Merkel cell carcinoma.

Ott MJ, Harvard Medical School
Merkel cell carcinoma is a rare dermal neuroendocrine carcinoma whose optimal treatment and prognostic factors are poorly defined. We hypothesize that high-risk patients with Merkel cell carcinoma are best treated with multimodality therapy. DESIGN: A retrospective review of all patients (N = 33) with Merkel cell carcinoma treated at the Massachusetts General Hospital from January 1, 1980, to August 24,1997. Median follow-up time was 37 months (range, 6-157 months). PATIENTS: Adequate data for evaluation were available for 31 patients. Male to female distribution was 14 men and 17 women, with a median patient age of 68 years. MAIN OUTCOME MEASURE: Stage at presentation; factors associated with recurrence; and the effects of surgery, radiation therapy (XRT), and chemotherapy on recurrence, salvage, and survival rates. RESULTS: There were 12 extremity, 11 head and neck, and 8 truncal tumors. There were 22 isolated primary tumors, 8 with additional clinically positive lymph nodes, and 1 with distant disease. Therapy was local excision with or without XRT in 19 patients, local resection and lymphadenectomy with or without XRT in 8 patients, and XRT alone in 4 patients with head and neck tumors. Fifteen patients developed recurrences (7 local, 8 nodal, and 10 distant). Median time to recurrence was 8 months (range, 3-48 months). There were 7 tumor-related deaths, 6 of which were associated with truncal lesions (P<.001). No locoregional recurrences occurred in patients with margins of resection of 2 cm or greater or adequate XRT. A multivariate analysis selected truncal location (P = .005) and nodal disease (P = .05) as predictors of mortality. Remission was possible in 5 patients with locoregional and 2 patients with distant recurrences. CONCLUSIONS: Merkel cell carcinoma is an aggressive dermal cancer with frequent nodal metastases; truncal tumors have the worst prognosis. Locoregional recurrence correlates with inadequate margins and lack of XRT, but remission is possible with multimodality therapy.

Head Neck 1995 Mar-Apr;17(2):96-101

Radiotherapy for Merkel cell carcinoma of the skin of the head and neck.

Suntharalingam University of Florida College of Medicine, Gainesville, USA.

BACKGROUND. Merkel cell carcinoma is a relatively rare neuroendocrine carcinoma of the skin. It arises in the head and neck region in approximately 50% of cases. Its aggressive behavior predisposes patients to local-regional recurrence and distant metastases after surgical excision alone. In this article, we describe our experience with Merkel cell carcinoma of the head and neck. METHODS. Of 18 patients with Merkel cell carcinoma treated in the Department of Radiation Oncology at the University of Florida, 12 patients who had primary tumors in the head and neck region are reported. Eight patients were treated at initial diagnosis (group A), and four were treated at the time of local-regional recurrence (group B). RESULTS. Local-regional control was achieved in seven of eight patients in group A and all four patients in group B. One patient in group A and all patients in group B developed distant metastases and eventually died of their disease. Bone exposure developed in one patient, requiring surgical debridement and hyperbaric oxygen treatment. CONCLUSION. Patients with Merkel cell carcinoma of the head and neck should be treated aggressively. Our data suggest that local-regional recurrence is a harbinger of distant metastases. We recommend that these patients receive treatment to both the primary site and draining lymphatics at initial presentation. The role of chemotherapy remains unclear.

Cancer 1991 Sep 1;68(5):1004-8

Merkel cell carcinoma. Improved locoregional control with postoperative radiation therapy.

Wilder University Medical Center, Tucson, Arizona 85724.

Between April 1981 and May 1990, 11 patients with Merkel cell carcinoma were treated with radiation therapy in Tucson, Arizona. The length of follow-up time from the time of irradiation ranged from 6 to 64 months. Locoregional control was maintained in seven of eight patients treated with surgery and postoperative radiation therapy for primary or recurrent cancer. The other three patients had bulky metastatic disease at the time of referral. Palliation was achieved in all three patients with radiation therapy. Hyperthermia also appeared to be beneficial in the one patient in which it was used, and chemotherapy achieved responses in two of four patients. These results, combined with a review of the literature, suggest that the administration of radiation therapy postoperatively to both the surgical bed and the draining lymph nodes improves locoregional control and may result in long-term disease-free survival when administered after the initial surgical resection.

Aust N Z J Surg 1998 May;68(5):354-8

Clinical management and treatment outcomes of Merkel cell carcinoma.

Wong Sydney, New South Wales, Australia.

BACKGROUND: Merkel cell carcinoma (MCC), first described in 1972, is an uncommon, highly malignant tumour of skin. Its aetiology is unknown although the tumour occurs most frequently in sun-exposed sites. This skin cancer is characterized by a high incidence of metastases, local and regional recurrence and has a high mortality. Few survival data beyond 3 years are available. Treatment strategies include wide local excision of the primary and lymph node dissection, as indicated together with adjuvant radiotherapy. The tumour has also been shown to be chemosensitive. Definitive treatment is inconclusive due to the relative rarity of this malignancy. METHODS: A retrospective study was undertaken between the years 1985 and 1996 of 33 patients with MCC at Concord Repatriation General Hospital (CRGH). Demographic details were noted, together with the site and appearance of the primary lesion and the sites and date of metastases. The response and outcome to various modalities of treatment were documented. RESULTS: There were 27 men and six women with an average age of 80 years (range: 60-86 years). The primary lesion in the present series most often resembled a basal cell carcinoma (BCC), with 53% occurring in the head and neck region. Twenty-seven patients (82%) developed metastatic disease, with an average interval of 13.4 months between diagnosis of the primary lesion and the development of metastases. The incidence of locoregional recurrence in the present series was 42%. Radiation combined with surgery achieved locoregional control in 15 of 19 patients with primary, regional or recurrent locoregional disease. Fourteen patients died of MCC and five others from unrelated causes. The 14 survivors have a mean survival of 54 months with six patients surviving more than 5 years. CONCLUSIONS: Local excision together with regional lymph node clearance as indicated, combined with adjuvant radiation treatment was associated with an improved survival. The role of chemotherapy remains unclear.

J Clin Oncol 2000 Jun 1;18(12):2493-2499

Chemotherapy in Neuroendocrine/Merkel Cell Carcinoma of the Skin: Case Series and Review of 204 Cases.

Tai PT, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, Gilchrist J

London Regional Cancer Center, London, Ontario, Canada.

Cyclophosphamide/doxorubicin (or epirubicin)/vincristine combination +/- prednisone was the most commonly used chemotherapy regimen (47 cases), with an overall response rate of 75.7% (35.1% complete, 35.1% partial, and 5.4% minor responses). Etoposide/cisplatin (or carboplatin) was the next most commonly used regimen (27 cases), with an overall response rate of 60% (36% complete and 24% partial responses). The difference in response rate was not statistically significant (P =.19). Among the 204 cases, there were seven (3.4%) toxic deaths. CONCLUSION: Chemoradiation for locally recurrent or advanced disease may be an option for patients with a good performance status.