Pathology Quiz Case 2: Diagnosis

Diagnosis: Merkel cell carcinoma (MCC) of the left auricle

Merkel cell carcinoma, which is an uncommon, aggressive cutaneous neoplasm, was first described in 1972.¹Although MCCs were originally thought to originate from neuroendocrine mechanoreceptor cells, it is now believed that they are derived from pluripotent neural crest cells.^2,3Nearly half of all MCCs present in the head and neck area. Facial areas, including the cheeks, nose, mouth, and eyelids, are the most common sites, while auricular MCC is extremely rare.^1,4Merkel cell carcinoma exhibits rapid growth and aggressive lymphatic spread, and 25% of patients will have local or distant spread at initial presentation.^2,4,5An additional 30% will develop local or distant spread during the disease course.²On physical examination, MCC lesions appear as pink or violaceous subcutaneous nodules. Ulceration is a rare finding.^1,4,6

Although rare, the incidence of MCC has tripled in the past 15 years. This increase may be the result of improved recognition as well as of an aging population and more sun exposure.⁷Risk factors include age (average age at diagnosis, 70 years), male sex, sun exposure, and immunosuppression.^1,2,4,7Merkel cell carcinoma seems to be disproportionally associated with other neoplasms, including skin, hematologic, ovarian, and breast adenocarcinomas.²

The pathogenesis of MCC is multifactorial. Mast cells may mediate several aspects of neoplastic proliferation through several mechanisms, including immunosuppression, angiogenesis stimulation, extracellular matrix degradation, and mitogenesis. The presence of mast cells on microscopic examination of the MCCs can be correlated with an increased risk of death.³Merkel cell polyomavirus has been found in a high percentage of MCCs in several series. Merkel cell polyomavirus integrates into the genome, and 2 oncogenes, LTand ST, are expressed. Acting similarly to the human papillomavirus E6 and E7 proteins, LTinactivates p53 and pRb; STdisrupts a protein phosphatase complex that has been implicated in cellular adhesion.⁷Also, deletions and unbalanced translocations have been identified in the short arm of chromosome 1.²

On microscopic examination, MCC exhibits small round cells arranged in sheets and trabeculae.³Infiltration into surrounding dermal lymphatics is common and indicative of the aggressive nature of this disease.⁵Cytoplasmic granules show similarities to cells of neuroendocrine and amine precursor uptake decarboxylation cell lineage.⁶Intercellular junctions, vesicular nuclei with fine chromatin, high nuclear to cytoplasm ratio, and spinous processes are all characteristic cytologic features.^2,3,6It is common for samples to exhibit large numbers of mitotic figures and numerous apoptotic cells.³

Immunohistochemical analysis can aid the pathologic diagnosis, with MCC demonstrating characteristic peranuclear dotlike immunopositivity for CK20.³Often morphologically similar to metastatic small cell carcinoma of the lung, MCC notably lacks a recently identified marker known as achaete-scute complex–like 1.³Furthermore, small cell carcinoma of the lung is typically positive for thyroid transcription factor 1, whereas MCC is negative.³The absence of S-100 protein and homatropine methylbromide helps rule out malignant melanoma. Immunohistochemical analysis can also serve a prognostic role, with p63 expression associated with (1) a more aggressive clinical course; (2) nuclear expression of the antiapoptotic protein survivin, which is associated with higher mortality and rates of metastasis; and (3) overexpression of matrix-metalloprotein 7, which has been shown to be associated with increased metastasis.³Other pathologic characteristics associated with a worse prognosis include lymphocytic infiltration and a high mitotic index.³

After a pathologic diagnosis, presurgical staging should include a clinical examination and may include a PET scan. A PET scan may contribute useful information about the presence of metastatic lesions, but normal findings on the PET scan do not rule out metastatic disease.⁸Computed tomography is not accurate for detecting nodal disease.²

Wide local excision with 2- to 3-cm margins is the initial treatment of choice. However, such large margins are often difficult to obtain in the head and neck area.^2,4With respect to auricular lesions, auriculectomy may be necessary.¹Sentinel lymph node biopsy has been used but is limited by the dense and irregular lymphatic drainage pattern in the head and neck region.⁹Identification of nodal spread is important for prognostication and adjuvant treatment. However, owing to the high rate of clinically inapparent micrometastases, elective regional lymphadenectomy is often considered.¹⁰Gamma probe–guided lymphadenectomy may help identify the nodes that should undergo rigorous pathologic examination (analysis of fine sections and immunohistochemical staining) for micrometastic disease.⁴Lymphadenectomy has been show to decrease regional recurrence and its associated morbidity but does not seem to increase survival.¹⁰There are no consistent recommendations regarding lymphadenectomy. Chemotherapy has a limited role as a palliative measure only and may actually worsen prognosis in patients with local nodal spread.²It has never been shown to improve survival.¹⁰Although controversial, radiotherapy should be considered.²Merkel cell carcinomas are radiosensitive, and radiation monotherapy has been shown to be effective in inoperable stage I tumors. At least 1 single-institution study has demonstrated effective local control with postoperative adjuvant radiotherapy. Radiation is usually applied to the primary site and the draining regional lymph node bed.⁵Reported rates of local recurrence are around 30%, and for regional recurrence, the rate is approximately 59%.⁴Lymph node involvement is the most robust predictor of survival and distant metastasis. Five-year survival rates range from 40% to 68%.¹⁰

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