September 20007

Fig.3

Fig.4

Fig.5

Fig.6

Diagnosis: Merkel Cell Carcinoma

Original Histopathology: Large pedunculated basal cell carcinoma with focal squamous differentiation and superficial ulceration, completely removed

Due to discrepancy between clinical findings and histopathology, further evaluation was requested by dermatology. The slide was reevaluated and special stains were obtained because of concern for Merkel cell carcinoma.

Final Histopathology: Positive stains for the tumor cells included CK-20, NSE, Synaptophysin, and Chromogranin. CK-5/6 is focally positive. The final diagnosis is a small cell neuroendocrine carcinoma (Merkel cell carcinoma) of the skin with foci of squamous differentiation. The tumor is completely removed.

Discussion: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that occurs most frequently on sun-exposed skin in elderly Caucasians . The incidence of MCC appears to have tripled between 1986 and 2001 , possibly due to an aging population, increased exposure to ultraviolet light, and improved histopathologic recognition (the disease was first described in 1972 ). There is an epidemiological link to an immunocompromised state ­ in one large series, 14.5% of MCC occurred in patients who had received immunosuppressive therapy .

MCC usually presents as a painless, rapidly-growing, red-to-blue, firm, exophytic nodule. However, this is highly variable, and ulcerated lesions and plaques are also common.

The presumed cell of origin is the epidermal neuroendocrine Merkel cell, which functions as a mechanoreceptor. MCC only rarely involves the epidermis, leading some authors to postulate a pleuripotent dermal stem cell as the cell of origin . Histologically, MCC appears as small round blue cells with hyperchromatic nuclei and scant cytoplasm. Immunohistochemistry is necessary to distinguish MCC from other small round blue cell tumors such as metastatic small cell lung cancer. The most important markers are cytokeratin-20 (CK-20, a cytoskeletal intermediate filament protein), neuron-specific enolase, chromogranin A, and synaptophysin.

The following staging and survival information is adapted from a 2005 Memorial Sloan-Kettering Cancer Center publication :

Stage Definition Patients 5-Year Survival
I Max diameter < 2cm 44% 81%
II Max diameter > 2cm 26% 67%
III Regional metastasis 24% 52%
IV Distant metastasis 6% 11% (2-year)

A recent critical review from the University of Michigan, offers evidence-based management guidelines . The primary treatment for localized disease is wide local excision with 1-2cm margins depending on size of lesion. Mohs micrographic surgery has a comparable cure rate and is appropriate when tissue sparing is a high priority or if surgical margins are close or positive7, , .
Sentinel lymph node biopsy with anti-CK-20 immunohistochemical analysis is prognostically significant, and is recommended for staging and treatment planning in all clinically lymph node-negative patients . If Mohs micrographic surgery is being considered, it should be done after the patient has undergone sentinel lymph node biopsy7. Multiple retrospective studies show an association between post-excision adjuvant radiation therapy and a marked reduction in local recurrences and a trend towards increased survival. Post-excision radiotherapy to the wound bed should be considered in lesions larger than 2cm and when clear margins cannot be obtained7, .

MCC is considered a chemosensitive tumor; however the median duration of response is only 8 months , . Adjuvant chemotherapy currently is not supported for routine use in the treatment of MCC due to its increased risk of mortality, significant morbidity, development of resistance to chemotherapy, lack of data to support survival benefit, and immune suppression11.
Combination chemotherapy with a platinum agent plus etoposide is a reasonably effective option for patients with inoperable or metastatic MCC and a good performance status7,14.

Stage III patients ­ those with clinical lymphadenopathy or positive sentinel lymph node biopsy ­ should have a complete lymph node dissection. Adjuvant radiation therapy is appropriate in patients with extensive lymph node involvement or with extracapsular spread, and chemotherapy may be considered, but good data is lacking7.

Our patient in this case received further evaluation with a chest CT and an axillary lymph node aspiration. The chest CT revealed bilateral apical scarring, which was consistent with old inflammatory disease, and numerous enlarged left axillary lymph nodes with central hypodensities possibly indicating necrosis. The lymph node aspirate was positive for MCC. Therefore, our patient was diagnosed with stage III Merkel cell carcinoma. After discussion at a multidisciplinary tumor board, the plan for the patient includes complete lymph node dissection followed by adjuvant radiation therapy to the primary site and the affected regional lymph node basin and chemotherapy.

References:

1.Agelli M, et al. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:832-841.
2.Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2005;89:1­4.
.Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972;105:107-110.
4.Medina-Franco H, et al. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2001;8:204-208.
5.Ferringer T, et al. Merkel cell carcinoma in situ. J Cutan Pathol 2005;32:162­165.
6.Allen PJ, et al. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:2300-2309.
7.Bichakjian CK, et al. Merkel Cell Carcinoma: Critical Review With Guidelines for Multidisciplinary Management. Cancer 2007;110:1-12.
8.Boyer JD, et al. Local control of primary Merkel cell carcinoma: Review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002;47:885-892.
9.Senchenkov A, et al. Predictors of Survival and Recurrence in the Surgical Treatment of Merkel Cell Carcinoma of the Extremities. J Surg Oncol 2007;95:229-234.
10.Gupta SG, et al. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 2006;142:685-690.
11.Garneski KM and Hghiem P. Merkel cell carcinoma adjuvant therapy: Current data support radiation but not chemotherapy. J Am Acad Dermatol 2007;57:166-169.
12.Voog E, et al. Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 1999;85:2589­2595.
13.Tai PT, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 2000;18:2493­2499.
14.Davis MP, et al. The use of VP16 and cisplatin in the treatment of Merkel cell carcinoma. J Dermatol Surg Oncol. 1990:16:276-278.

This case is presented by Drs. David Lortscher, Pooja Dorward, and David Smith.
Special Thanks to Dr. Hyung Doo Chung for providing the histopathology.