An Unusual Clinical Presentation of An Unusual Clinical Presentation of Merkel Cell CarcinomaMerkel Cell Carcinoma

Deba P. Sarma, , Dawn E. Heagley, , Julianne Chalupa, , Meredith Cox, and , and James M. Shehan

Creighton University Medical Center, OmahaCreighton University Medical Center, Omaha

AbstractAbstract IntroductionIntroduction. Merkel cell carcinoma is a rare, aggressive . Merkel cell carcinoma is a rare, aggressive

neuroendocrine cell carcinoma arising in the sun-exposed neuroendocrine cell carcinoma arising in the sun-exposed skin of elderly patients. Most of these tumors are located in skin of elderly patients. Most of these tumors are located in the dermis. An unusual clinical presentation of such a the dermis. An unusual clinical presentation of such a tumor in the subcutis, if not biopsied, may be easily tumor in the subcutis, if not biopsied, may be easily mistaken as a benign lesion. mistaken as a benign lesion. Case PresentationCase Presentation. An 83-. An 83-year-old white woman presented with a several-month year-old white woman presented with a several-month history of a painless 7 mm subcutaneous mass that was history of a painless 7 mm subcutaneous mass that was initially thought to be a lipoma. A conservative follow-up initially thought to be a lipoma. A conservative follow-up was planned. At the insistence of the patient, an excisional was planned. At the insistence of the patient, an excisional biopsy of the mass was performed revealing a biopsy of the mass was performed revealing a subcutaneous Merkel cell carcinoma. The tumor cells subcutaneous Merkel cell carcinoma. The tumor cells stained positively for CK 20, chromogranin, and stained positively for CK 20, chromogranin, and synaptophysin. No other primary or metastatic tumors synaptophysin. No other primary or metastatic tumors found after a thorough work-up. The patient was treated found after a thorough work-up. The patient was treated with local irradiation. She remains disease free at her six-with local irradiation. She remains disease free at her six-month follow-up visit. month follow-up visit. ConclusionConclusion. When a new growth is . When a new growth is encountered in the sun-exposed skin of elderly patients, a encountered in the sun-exposed skin of elderly patients, a biopsy is warranted even if the lesion clinically appears biopsy is warranted even if the lesion clinically appears benign.benign.

1. Case Presentation1. Case Presentation An 83-year-old white American woman of European An 83-year-old white American woman of European

descent presented to the Dermatology clinic complaining descent presented to the Dermatology clinic complaining of a small painless lump on her left cheek that had been of a small painless lump on her left cheek that had been present for several months. She did not have a past history present for several months. She did not have a past history of any significant medical illness including any neoplastic of any significant medical illness including any neoplastic disease.disease.

Physical examination revealed a 7-mm soft papule with Physical examination revealed a 7-mm soft papule with overlying intact skin on the left cheek. There was no overlying intact skin on the left cheek. There was no evidence of any sun-induced skin lesion. There were no evidence of any sun-induced skin lesion. There were no palpable lymph nodes in the neck. Clinical impression was palpable lymph nodes in the neck. Clinical impression was that of a benign subcutaneous nodule such as a lipoma. that of a benign subcutaneous nodule such as a lipoma. The patient was advised of conservative follow-up, but the The patient was advised of conservative follow-up, but the patient insisted on having the lesion removed. patient insisted on having the lesion removed.

An excisional biopsy was performed. The excised An excisional biopsy was performed. The excised specimen was an ovoid fragment of adipose tissue specimen was an ovoid fragment of adipose tissue measuring 1-cm in size attached to an ellipse of normal measuring 1-cm in size attached to an ellipse of normal skin measuring 1.9 X 0.5 cm.skin measuring 1.9 X 0.5 cm.

Microscopic examination revealed an intact atrophic Microscopic examination revealed an intact atrophic epidermis, solar elastosis of the dermis, and several dark epidermis, solar elastosis of the dermis, and several dark tumor nodules in the subcutaneous adipose tissue tumor nodules in the subcutaneous adipose tissue (Figures (Figures 1 and and 2). The neoplasm was composed of dark, ). The neoplasm was composed of dark, small undifferentiated cells with ill-defined cell borders small undifferentiated cells with ill-defined cell borders showing large hyperchromatic nuclei with numerous showing large hyperchromatic nuclei with numerous mitotic figures (Figure mitotic figures (Figure 3). The tumor cells stained ). The tumor cells stained positively for CK 20 showing a dot-like pattern (Figure positively for CK 20 showing a dot-like pattern (Figure 4) ) and were also positive for chromogranin (Figure and were also positive for chromogranin (Figure 5) and ) and synaptophysin (Figure synaptophysin (Figure 6). They were negative for CK 5/6, ). They were negative for CK 5/6, S-100, and LCA immunostains. The diagnosis of S-100, and LCA immunostains. The diagnosis of subcutaneous Merkel cell carcinoma (MCC) was made.subcutaneous Merkel cell carcinoma (MCC) was made.

Figure 1: Dermal solar degeneration and dark tumor nodule in the subcutaneous tissue.

Figure 2: Undifferentiated dark epitheliod neoplastic infiltrates within the adipose tissue.

Figure 3: The neoplastic cells show vague cell borders, large pleomorphic nuclei, and numerous mitotic figures.

Figure 4: The tumor cells are positive for CK20 and show a “dot-like” pattern of staining.

Figure 5: The tumor cells are positive for chromogranin.

Figure 6: The tumor cells are positive for synaptophysin.

A thorough clinical and radiological workup was A thorough clinical and radiological workup was undertaken to exclude other possible primary undertaken to exclude other possible primary neuroendocrine carcinomas, especially that of lung. neuroendocrine carcinomas, especially that of lung. The patient was found to be free of other primary or The patient was found to be free of other primary or metastatic tumors.metastatic tumors.

The patient refused surgical intervention and was The patient refused surgical intervention and was treated with local irradiation at the biopsy site. At the treated with local irradiation at the biopsy site. At the six-month follow-up visit, the patient remains six-month follow-up visit, the patient remains asymptomatic and free of tumor.asymptomatic and free of tumor.

2. Discussion2. Discussion Merkel cell carcinoma (MCC) is a rare, aggressive Merkel cell carcinoma (MCC) is a rare, aggressive

cutaneous carcinoma arising from neuroendocrine cells of cutaneous carcinoma arising from neuroendocrine cells of the dermis. Clinically, MCC is found in sun-exposed areas the dermis. Clinically, MCC is found in sun-exposed areas such as the face or neck and presents as a small (less than such as the face or neck and presents as a small (less than 2 cm), red or violet raised nodule with intact overlying skin. 2 cm), red or violet raised nodule with intact overlying skin. The lesion is usually painless and rapidly growing. The The lesion is usually painless and rapidly growing. The populations most commonly affected are Caucasians over populations most commonly affected are Caucasians over the age of 70 and the immunosuppressed [the age of 70 and the immunosuppressed [1--4].].

Microscopically, the tumor nodule of MCC is comprised of Microscopically, the tumor nodule of MCC is comprised of small cells with scant cytoplasm, large nuclei, finely small cells with scant cytoplasm, large nuclei, finely granular chromatin, and numerous mitotic figures. MCC is granular chromatin, and numerous mitotic figures. MCC is best differentiated from other cutaneous tumors by best differentiated from other cutaneous tumors by immunohistochemical stains. MCC cells stain positively for immunohistochemical stains. MCC cells stain positively for cytokeratin 20 in a characteristic dot-like pattern and stain cytokeratin 20 in a characteristic dot-like pattern and stain negatively for S-100 (positive in melanoma), TTF-1 and negatively for S-100 (positive in melanoma), TTF-1 and CK7, (positive in small cell lung carcinoma), and LCA CK7, (positive in small cell lung carcinoma), and LCA (positive in lymphoma) [(positive in lymphoma) [4]. Additionally, MCC cells stain ]. Additionally, MCC cells stain positively for neuroendocrine markers chromogranin and positively for neuroendocrine markers chromogranin and synaptophysin. Electron microscopy shows characteristic synaptophysin. Electron microscopy shows characteristic intracytoplasmic neurosecretory granules [intracytoplasmic neurosecretory granules [1].].

Merkel cell carcinoma almost always arises in the dermis, Merkel cell carcinoma almost always arises in the dermis, but there has been one reported case in the literature of but there has been one reported case in the literature of MCC arising in subcutaneous fat [MCC arising in subcutaneous fat [2]. Our case represents ]. Our case represents the second reported case, to our knowledge, of MCC the second reported case, to our knowledge, of MCC arising in subcutaneous adipose tissue. arising in subcutaneous adipose tissue.

Treatment of MCC includes wide excision, sentinel lymph Treatment of MCC includes wide excision, sentinel lymph node biopsy, and local radiation. Neoadjuvant node biopsy, and local radiation. Neoadjuvant chemotherapy is not recommended. Prognosis is variable chemotherapy is not recommended. Prognosis is variable and most dependent on stage of disease at presentation. and most dependent on stage of disease at presentation. Overall, local recurrence after excision occurs in about 40 Overall, local recurrence after excision occurs in about 40 percent of cases, while regional lymph node metastasis percent of cases, while regional lymph node metastasis occurs in about 30 percent of patients [occurs in about 30 percent of patients [4].].

Identified risk factors associated with MCC are: age Identified risk factors associated with MCC are: age greater than 50 years, European ancestry, ultraviolet (UV) greater than 50 years, European ancestry, ultraviolet (UV) radiation, immunocompromised state, or infection with radiation, immunocompromised state, or infection with Merkel Cell Polyomavirus (MCPyV). Frequency of MCC Merkel Cell Polyomavirus (MCPyV). Frequency of MCC increases dramatically in patients after the age of 50 increases dramatically in patients after the age of 50 years suggesting an accumulation of oncogenic events. years suggesting an accumulation of oncogenic events. Regarding UV radiation, MCC tumors are present in sun-Regarding UV radiation, MCC tumors are present in sun-exposed areas such as the head and neck. Patients who exposed areas such as the head and neck. Patients who have undergone prior psoralen and PUVA treatment are at have undergone prior psoralen and PUVA treatment are at higher incidence. Those of European decent are higher incidence. Those of European decent are genetically more susceptible to this radiation and genetically more susceptible to this radiation and therefore have an increased prevalence of MCC. An therefore have an increased prevalence of MCC. An association is also noted in patients who are association is also noted in patients who are immunocompromised; an 11-fold increase in incidence of immunocompromised; an 11-fold increase in incidence of MCC has been seen in patients with AIDS and a 5-fold MCC has been seen in patients with AIDS and a 5-fold increase in patients who have undergone organ increase in patients who have undergone organ transplantation. Finally, a correlation between MCPyV and transplantation. Finally, a correlation between MCPyV and MCC has been established [MCC has been established [5, , 6].].

Recent research has strengthened the correlation Recent research has strengthened the correlation between MCPyV and MCC. MCPyV DNA is found in the between MCPyV and MCC. MCPyV DNA is found in the majority of MCC tumors but is also commonly found in majority of MCC tumors but is also commonly found in normal tissue including saliva and tissues of the upper normal tissue including saliva and tissues of the upper digestive tract. A recent study suggests that the MCPyV digestive tract. A recent study suggests that the MCPyV integrates into the Large T antigen prior to clonal integrates into the Large T antigen prior to clonal expansion, and this interruption of the Large T antigen is expansion, and this interruption of the Large T antigen is not seen in nontumor cells [not seen in nontumor cells [5]. Another study indicates ]. Another study indicates that lower mortality of MCC is associated with MCPyV viral that lower mortality of MCC is associated with MCPyV viral integration versus those MCCs without MCPyV [integration versus those MCCs without MCPyV [6]. This ]. This data suggests the possibility of different mechanisms for data suggests the possibility of different mechanisms for inducing oncogenesis. MCPyV DNA is ubiquitous in nature inducing oncogenesis. MCPyV DNA is ubiquitous in nature and MCC is relatively rare suggesting that this may be and MCC is relatively rare suggesting that this may be one of many cofactors involved in the oncogenic one of many cofactors involved in the oncogenic transformation to MCC.transformation to MCC.

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