Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm known for its propensity to develop early regional and distant metastasis. Fewer than 400 cases occur annually in the United States. MCC ranks as the most deadly of cutaneous malignancies, with a fatality rate of approximately 25%. Because of its aggressive nature, MCC is often resistant to surgery, radiation, and chemotherapy regimens. Standardized treatment patterns have not been established, and difficulty arises finding appropriate treatment for the elderly, who comprise the majority of patients with MCC.
Merkel cell carcinoma (MCC) is a neuroendocrine tumor that has been described as a primary neuroendocrine carcinoma of the skin or "cutaneous APUDoma." Alternatively, MCC has been called a primary small cell carcinoma of the skin1 because of its morphologic and behavioral similarities to small cell carcinoma of the lung.
Merkel cells are slowly adapting mechanoreceptors in epidermal nerve endings. Although they are found in ectoderm-derived skin and mucosa, recent evidence places their origin as neural crest.2 Merkel cells contain cytokeratins and neuropeptide-containing eosinophilic granules. These cells combine with nerve terminals to form mechanoreceptors. It remains unclear if MCC originates from the same developmental lineage as Merkel cells. Recent research suggests these tumors originate from epidermal epithelial cells that are not in contact with nerve terminals but that have similar cytoskeletal filaments and a neuroendocrine origin.2 Although the pathogenesis of MCC has not been completely illuminated, it is agreed that UV exposure is an important risk factor. UVB-induced C · T transitions have been found, as well as p53 missense mutations. For this reason, risks include fair skin (as evidenced by the higher incidence in Caucasian populations), advanced age, and previous or concurrent sun-related skin malignancies such as squamous cell carcinoma and basal cell carcinoma.3 MCC also is linked to immunosuppression, with a higher incidence in transplant recipients and patients receiving chemotherapy.4 In addition, there is an increased incidence in patients with psoriasis who were treated with psoralen-UVA. Reports link MCC to a history of prolonged arsenic exposure,1 as well as to congenital dysplasia syndrome and chronic lymphocytic leukemia.5 MCC most often presents in fair-skinned patients 65 years and older as a solitary firm nodule on the head or neck. Its gross appearance is often nonspecific, being misdiagnosed as basal cell carcinoma or metastasis of a small cell carcinoma elsewhere.2 Even when diagnosed at its earliest stage, MCC has a 2-year fatality rate of 10%. Its 5-year survival rate is 50% to 68%. Regional metastasis occurs in 50% to 60% of patients. When metastasis does occur, regional lymph nodes are involved 65% of the time,6 with the majority (70%) occurring within 2 years of diagnosis. Nearly 40% will develop distant metastasis.7 Metastases most commonly involve the skin, lymph nodes, liver, lung, and bone.1 A primary lesion larger than 2 cm denotes a poor prognosis. There have been rare reports of spontaneous regression.
Histopathology Microscopically, MCC can be difficult to identify. The epidermis may show bowenoid or squamous cell carcinoma-like changes, but they are not characteristic. Under low power microscopy, small round blue cells are evident in the dermis; the cells appear uniform and are often arranged to form either sheets or clusters that create a trabecular appearance or that of a group of grapes. On high power, the cells will appear to be pale and empty. Numerous mitoses can be identified, and evidence of metastasis can be found in the lymphatic or blood vessels. Neurosecretory granules that range from 80 to 120 nm and look like small blue dots5 are membrane bound in the paranuclear regions. Because traditional hematoxylin-eosin (H&E) staining demonstrates morphologic features of both epithelial and neuroendocrine tumors, H&E results cannot distinguish MCC from other small round blue cell tumors such as melanoma, lymphoma, neuroblastoma, and metastatic small cell lung carcinoma.7 Cytokeratin staining and immunohistologic markers are required to make the definitive diagnosis; cytokeratin 20, chromogranin A, and synaptophysin are among those used. Other markers include neuron-specific enolase and, most recently, CD56, a marker for neural cell adhesion molecule.8
In August 2002, an 86-year-old white man presented for evaluation of an 8-mm friable pink nodule on the right ear of uncertain duration (Figure 1). No cervical or peripheral adenopathy was appreciated. The man had an extensive history of prior basal cell carcinoma and squamous cell carcinoma on sun-exposed areas, having undergone excisions and Mohs micrographic surgery for many of these lesions.
An excisional biopsy was performed, and the pathology results revealed aggregates of neoplastic cells with indistinct nucleoli with granular nucleoplasms and scant cytoplasms separated by fibrous septa or trabeculae (Figure 2). Also, numerous mitotic figures and areas of focal necrosis were present. In our patient, cytokeratin 20 and chromogranin A results were strongly positive (Figures 3 and 4); although other entities can demonstrate either of these markers, when found together they confirm the diagnosis of MCC. Our patient also demonstrated CD56 positivity and a weakly positive reaction to synaptophysin (Figure 4). Cytokeratin 7 and CD45 results were negative, which also confirmed the diagnosis of MCC (Figure 5).