Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Merkel Carcinoma Cell of the Skin Merkel cell carcinoma is an uncommon cutaneous neuroendocrine carcinoma first described by Toker in 1972. Tang and Toker in 1978 studied the ultrastructural features and described intracytoplasmic dense-core granules closely similar to those seen in the neuroendocrine cells and noted the presence of neuron specific enolase, a marker for cells in the neuroendocrine system. The Merkel cell is named for Fredrick Sigmund Merkel who discovered a particular round cell in the basal layers of the epidermis in 1875 and observed that these cells were associated with terminal nerve endings and reasoned that its function was related to the perception of mechanical stimuli. Current understanding of the Merkel cells is that they surround tactile hair follicles in organized innervated clusters and are believed to function as touch receptors. These cells have also been identified as isolated cells in the dermis without obvious neural connections. Clinically these tumors are usually painless, firm, raised, nodular masses that are red, pink or occasionally blue in color. The overlying skin is usually intact, however in advanced lesions the skin may be ulcerated. The tumors range in size from 0.3cm to 14cm and average 2cm. It primarily develops on sun exposed areas of the body with the head and neck being the most common site accounting for 53% of cases in the review of the literature by Pitale, et al. It is equally distributed between males and females and typically appears in the 6th or 7th decade of life. The location of these tumors within the skin and subcutaneous tissues is influenced by its size with small lesions confined to the dermis. It is very unusual for these tumors to be contiguous with the epidermis and tumor cells are only occasionally found within the epithelium. By light microscopy the cells of Merkel cell carcinoma are round to ovoid with scanty cytoplasm and the nuclei are round to ovoid and measure 14 to 20 microns with chromatin that is fine and dispersed. Mitotic figures are usually numerous as reported by Silva, et al in which 76% of their cases had 4-9 mitotic figures per high power field, 18% had 10 or more and 6% had less than 3. There is also a small cell variant of Merkel cell carcinoma in which the cytoplasm is particularly inconspicuous and the nuclei measure only 10 to 14 microns and the chromatin appears more dense. Some authors stress the importance of recognizing a small cell variant of Merkel cell carcinoma because these tumors appear to pursue a more aggressive clinical course. Immunocytochemistry can be helpful in differentiating Merkel cell carcinoma from other tumors such as lymphoma, melanoma, metastatic oat cell carcinoma and undifferentiated carcinoma. The most useful markers in Merkel cell carcinoma are cytokeratin and neuron specific enolase. Cytokeratin is positive in a large percentage of Merkel cell carcinomas as well as oat cell carcinoma and undifferentiated carcinoma. The presence of ball-like immunostaining resembling an inclusion body is seen only in Merkel cell carcinoma and is useful in differentiating it from metastatic oat cell carcinoma. Neuron specific enolase is found in Merkel cell carcinoma and oat cell carcinoma but not melanoma, lymphoma, or undifferentiated carcinoma. Ultrastructural studies play a significant role in the recognition of Merkel cell carcinoma. Although the light microscopic features are well documented and it is often possible to establish the identity of the tumor by paraffin section, confirmation from electron microscopy is usually desirable and may be essential when the diagnosis is uncertain by light microscopy. The most helpful features on electron microscopy are cytoplasmic extensions which are short and tapering and usually not longer than one cell diameter, dense-core granules measuring 75 to 200nm which are characteristically concentrated in cytoplasmic processes, and round paranuclear aggregates of cytoplasmic intermediate filaments. Merkel cell carcinoma is often associated with other neoplasms, the most frequent of which is squamous cell carcinoma in which it has either been resected earlier from the skin of the same anatomic site involved by the Merkel cell carcinoma or the two tumors coexist. It has also been associated with Bowen's disease, sweat gland tumors and basal cell carcinoma. Tumors that need to be differentiated from Merkel cell carcinoma are metastatic oat cell carcinoma, lymphoma, metastatic adult neuroblastoma, basal cell carcinoma and malignant melanoma. There are no reliable microscopic features that will differentiate between Merkel cell carcinoma and metastatic oat cell carcinoma, therefore it is always necessary to rule out metastatic oat cell carcinoma from the lung to the skin by radiologic studies. There is currently no standardized treatment for this tumor due to the relatively small number of cases. The initial evaluation should consist of a thorough physical examination to rule out regional lymph node involvement, multiple primary tumors and distant metastases. The goal in treating these tumors is to excise them with clear margins followed by radiation with or without chemotherapy depending on the particular situation. Due to the highly invasive nature and frequent dermal and subcutaneous extension of this tumor most authors recommend wide local excision with a 2 to 3 centimeter margin of normal tissue. Regional lymphadenectomy is agreed upon in situations where there is palpable regional nodes, massive primary tumor or recurrent disease. Prophylactic lymphadenectomy is controversial, however it is advocated by many authors due to the high rate of regional recurrence that ranges from 35 to 65%. In addition bilateral nodal dissections should be considered when the primary tumor is found in or near the midline. Merkel cell carcinoma is a radiosensitive tumor and is recommended for all patients due to its aggressive nature, the high rate of locoregional recurrence and the association of distant metastases with the initial locoregional recurrence. The fields of treatment need to be generous and include the primary tumor site and draining regional lymphatics with doses of 46 to 60 Gy for resected tumors and 56 to 60 Gy for grossly unresected disease. Merkel cell carcinoma is also reported to be chemosensitive and a wide variety of chemotherapeutic agents have been used successfully. Its current role in the management of this tumor is for palliation of patients with distant metastases and advanced disease of the neck. Pitale et al reviewed the literature for head and neck sites and reported a 40% local recurrence rate, 50% nodal recurrence rate and a 34% incidence of distant metastases. They also noted that patients usually develop nodal and distant metastases in parallel and that death in these patients is usually a result of distant disease. The most common sites of distant metastases in order of decreasing frequency as reported by Hitchcock et al are lymphatics, liver, bone, brain, lung and skin. Factors that have been noted to portend a poor prognosis includes tumors composed of small cells, the presence to lymph node metastases at the time of presentation, particularly if more than 30% of the resected lymph nodes are involved and male gender. Case Presentation A 66-year-old white man presented with a history of actinic skin damage and removal of multiple skin cancers by the Dermatology service. The patient originally presented to Dermatology with a 2 to 3 month history of a painless, slowly enlarging left infra-auricular subcutaneous mass. Punch biopsy was consistent with Merkel cell carcinoma and the patient was referred to the Otolaryngology service for further evaluation and management. Thorough head and neck examination was remarkable for a 2 cm, well circumscribed, pink, subcutaneous mass inferior to the left ear lobule and a 1 cm lesion with raised borders over the left zygomatic region reported to be actinic keratosis from a shave biopsy performed by Dermatology. Evaluation for metastatic disease was unrevealing and CT scan of the neck revealed a 1.5 cm lesion confined to the dermis without evidence of lymphatic involvement. After presentation at the multidisciplinary head and neck tumor conference the patient underwent wide local excision of the primary tumor with 2 cm margins, left superficial parotidectomy, left supraomohyoid neck dissection, split thickness skin graft coverage of the primary site and elliptical excision of the zygomatic lesion on 5/4/94. On final pathologic evaluation, the infra-auricular lesion was confirmed to be Merkel cell carcinoma and the zygomatic lesion was a basal cell carcinoma. The Merkel cell carcinoma measured 1.6 cm in greatest dimension, all margins were free of tumor and there was no lymphatic involvement. The patient had an unremarkable postoperative course and is currently undergoing external beam radiotherapy to the primary site and draining lymphatics to a total dose of 50Gy. Bibliography Battifora H, Silva EG. The use of antikeratin antibodies in the immunohistochemical distinction between neuroendocrine (Merkel cell) carcinoma of the skin, lymphoma, and oat cell carcinoma. Cancer 1986;58:1040-1046. Bielamowicz S, Smith D, Abemayor E. Merkel cell carcinoma: an aggressive skin neoplasm. Laryngoscope 1994;104:528-532. George TK, Di Santagnese PA, Bennett JM. Chemotherapy for metastatic Merkel cell carcinoma. Cancer 1985;56:1034-1038. Goepfert H, Remmler D, Silva E, Wheeler B. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 1984;110:707-721. Grosh WW, Giannone L, Hande KR, Johnson DH. Disseminated Merkel cell tumor. Treatment with systemic chemotherapy. Am J Clin Oncol 1987;10:227-230. Hanke WC, Conner AC, Temofeew RK, Lingeman RE. Merkel cell carcinoma. Arch Dermatol 1989;125:1096-1100. Hitchcock CL, Bland KI, Laney RG 3d, Franzini D, Harris B, Copeland EM 3d. Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment. Ann Surg 1988;207:201-207. Kroll MH, Toker C. Trabecular carcinoma of the skin: further clinicopathologic studies and morphologic studies. Arch Pathol Lab Med 1982;106:404-408. Leong AS, Phillips GE, Pieterse AS, Milios J. Criteria for the diagnosis of primary endocrine carcinoma of the skin (Merkel cell carcinoma). A histological immunochemical and ultrastructural study of 13 cases. Pathology 1986;18:393-399. Matsuo K, Sakamoto A, Kawai K, Tschiyama H, Miyata A. Small cell carcinoma of the skin "non-Merkel cell type." Acta Pathol Jpn 1985;35:1029-1036. Moll I, Moll R, Franke WW. Formation of epidermal and dermal Merkel cells during human fetal skin development. J Invest Dermatol 1986;87:779-787. Morrison WH, Peters LJ, Silva EG, Wendt CD, Ang KK, Goepfert H. The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1990;19:583-591. O'Brien PC, Denham JW, Leong AS. Merkel cell carcinoma: a review and behaviour patterns and management strategies. Aust N Z J Surg 1987;57:847-850. O'Rourke MG, Bell JR. Merkel cell tumor with spontaneous regression. J Dermatol Surg Oncol 1986;12:994-996. Pettinato G, De Chiara A, Insabato L, Angrisani P, Saurel J, Morard JL, et al. Neuroendocrine (Merkel cell )tumor of the skin: fine-needle aspiration cytology, histology, electron microscopy and immunohistochemistry of 12 cases. Appl Pathol 1988;6:17-27. Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope 1992;102:244-249. Pople IK. Merkel cell tumour of the face successfully treated with radical radiotherapy. Eur J Surg Oncol 1988;14:79-81. Raaf JH, Urmacher C, Knapper WK, Shiu MH, Cheng EW. Trabecular (Merkel cell) carcinoma of the skin. Treatment of primary, recurrent, and metastatic disease. Cancer 1986;57:178-182. Rice RD Jr, Chonkich GD, Thompson KS, Chase DR. Merkel cell tumor of the head and neck. Five new cases with literature review. Arch Otolaryngol Head Neck Surg 1993;119:782-786. Saurat JH, Didierjean L. The epidermal Merkel cell is an epithelial cell. Dermatologica 1984;169:117-120. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A clinicopathologic and ultrapathologic study of 43 cases. Am J Surg Pathol 1985;9:95-108. Sibley RK, Dahl D. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 cases. Am J Surg Pathol 1985;9:109-116. Silva EG, Mackay B, Goepfert H, Burgess MA, Fields RS. Endocrine carcinoma of the skin (Merkel cell carcinoma). Pathol Annu 1984;19:1-30. Von Moll L, McEwan AJ, Shapiro B, Sisson JC, Gross MD, Lloyd R, et al. Iodine-131 MIBG scintigraphy of neuroendocrine tumors other than pheochromocytoma and neuroblastoma. J Nucl Med 1987;28:979-988. Warner TF, Uno H, Hafez GR, Burgess J, Bolles C, Lloyd RV, et al. Merkel cells and Merkel cell tumors. Ultrastructure, immunocytochemistry, and review of the literature. Cancer 1983;52:238-245. Weymuller EA Jr, Marks M, Ridge D. Merkel cell carcinoma of the ear. Head Neck 1991;13:68-71. Wick RM, Goellner JR, Scheithauer BW, Thomas JR 3d, Sanchez NP, Schroeter AL. Primary neuroendocrine carcinomas of the skin (Merkel cell tumors). A clinical, histologic, and ultrastructural study of 13 cases. Am J Clin Pathol 1983;79:6-13. Zakzouk MS, Ramsay AD, Buchanan G. Merkel cell tumour of the skin. J Laryngol Otol 1986;100:561-572.
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