Asymptomatic Indurated Plaques on the Anterior Thigh

An 84-year-old man presented with a 6-month history of large indurated, asymptomatic plaques on right anterior thigh. Previous treatment consisted of triamcinolone cream. His past medical history was unremarkable. Findings from the review of systems were negative, and his weight remained stable. The patient took no medications, “occasional” pipe or cigar, did not consume alcohol, and appeared younger than his stated age.

Upon exam, multiple violaceous, indurated nontender plaques distributed in an agminated pattern along the proximal half of the right anterior thigh were observed (Figure 1). The lesions were surrounded by numerous telangiectasia. Mild right inguinal lymphadenopathy was palpated.  A punch biopsy specimen was obtained for histologic evaluation, and laboratory tests were ordered.

Microscopic Findings

Light microscopy. Permanent sections from the punch biopsy show findings of a malignant small cell tumor. The overlying epidermis was uninvolved, but the dermis was extensively infiltrated by cords, nests, and nodules of small cells that extensively intercalated between collagen bundles. The tumor was composed of cells, which were compactly arranged and round-to-polygonal shaped. The cells had large hyperchromatic vesicular nuclei with a small rim of cytoplasm, and some clusters of cells showed gland-like organization. Mild pleomorphism was noted as well as several mitotic figures. Several necrotic cells were present. Mucin deposition surrounded some of the tumoral clusters. Perineural invasion and endolymphatic involvement were not identified.

Immunohistochemical studies. The tumor cells had strong staining for cytokeratin-20 (CK20) and neuron-specific enolase with a mixed pattern of 50% perinuclear dot staining and 50% with globular cytoplasmic staining. A chromogranin stain was positive on 50% of the tumor cells with a perinuclear dot pattern. Stains for pan-keratin (AE-1/AE-3), S-100 protein, cytokeratin-7, cytokeratin 5/6, p63, prostate-specific antigen, and thyroid transcription factor-1 were all negative. A Ki-67 stain showed almost 100% labeling of tumor cells. Positive and negative controls were all valid.

Clinical Course

The initial biopsy revealed metastatic neuroendocrine carcinoma, and the immunohistochemical stain revealed positive Ki-67 between the ranges of 40% to 50%. The patient was diagnosed with neuroendocrine carcinoma of the groin/leg area, or Merkel cell carcinoma (MCC), with metastatic pelvic node involvement. Positron emission tomography (PET) scan revealed several prominent right inguinal nodes with no significant fludeoxyglucose (FDG) avidity and large external iliac chain lymph nodes on the right (largest = 7 cm with FDG avidity of 3.8) favoring metastatic disease along the right lower extremity. The pathology was reviewed and was consistent with neuroendocrine carcinoma with Merkel cell type.

The patient underwent two cycles of chemotherapy with cisplatinum and VP-16 (etoposide). The first treatment was complicated by pneumonia with associated prolonged hospitalization. Subsequent doses were reduced and despite four treatments with combination therapy, follow-up scanning revealed progression of disease. He had two surgical resections of the lymph nodes and large lesions initially that was again followed by chemotherapy.

The patient received subsequent treatment with topotecan for two cycles, but the disease further progressed. He was started on cyclophosphamide, doxorubicin, and vincristine (CAV) chemotherapy and pegfilgrastim for associated leukopenia. The patient underwent two cycles of CAV for 2 months. Clinically he had significant worsening on examination, as evidenced by worsening of plaques (Figure 2), and computed tomography (CT) of the pelvis and right upper thigh confirmed worsening of disease. Oral etoposide was initiated. The patient was offered octreotide scanning. He declined further treatment and entered hospice care, and he died 14 months after diagnosis.

Discussion

MCC (cutaneous neuroendocrine tumor) is a malignant solid tumor derived from the Merkel cell. The Merkel cell is a mechanoreceptor that is present as a “clear cell” in the basal layer of the epidermis and surrounds the hair follicles (disk of Pinkus). The tumor usually presents as a solitary lesion on the head or neck but may present as multiple lesions and on any area. The incidence of MCC in the United States is approximately 1500 cases per year.¹ As of 2005, the disease incidence had more than tripled over the previous 20 years.¹   

It is generally a tumor of the elderly (>65 years), male, immunosuppressed, and fair-skinned patients with chronic UV exposure. Merkel cell cancer is a rare carcinoma with a high mortality rate; MCC has a 5-year relative mortality of 46% vs only 15% with melanoma.² When MCC is localized to the skin with no nodal involvement (stage 1A), the survival rate is 79%, emphasizing the need for early detection.³

MCC generally presents as a rapidly growing, nontender, erythematous to violaceous nodule that has a shiny appearance. The diagnosis is rarely suspected clinically prior to biopsy.  It is generally associated with overlying telangiectasia. At the time of diagnosis, lymph node involvement is 33%.⁴ There also is an association with the Merkel cell polyomavirus (MCPyV); 80% of MCC have MCPyV vs only 20% in uninvolved, nonmalignant skin.⁵ Studies confirm that patients with MCC who harbor the MCPyV have a better prognosis then those who do not.⁵

Patients with MCC should be staged with the four-tiered system (American Joint Committee on Cancer).³ Sentinel lymph node and all palpable lymph nodes should be biopsied prior to the excision of the primary tumor to allow for staging. The sample should be examined for CK20 to determine micrometastases. PET and CT scanning are adjunctive tools in staging.

Histologically, MCC is a dermal tumor that may extend into the subcutaneous tissue. The cells have scanty cytoplasm and are about 15 µm in diameter, with dense hyperchromatic nuclei and a distinctive smudged chromatin pattern. Mitosis and apoptotis are abundant, and cells tend to be arranged in cords and sheets and lymphovascular invasion may be seen.² It is important to distinguish MCC from other small-cell neuroendocrine tumors such as:

• Small cell (oat cell) lung carcinoma neuroblastoma
• Ewing sarcoma
• Lymphoma
• Basal cell carcinoma
• Melanoma

Immunoperoxidase confirmation is required for diagnosis of MCC; the tumor should be CK20 positive with characteristic perinuclear dot pattern and thyroid transcription factor-1 negativity. Additional neuroendocrine immunohistochemical markers that are frequently positive in MCC are synaptophysin, chromogranin, and neuron-specific enolase. Other immunohistochemical markers to exclude other small cell cancers include negativity for CK7, S-100, and leukocyte common antigen.

This case represents the need for increased awareness of MCC, a reduced threshold for biopsy with persistent asymptomatic lesions, and the need for staging in guiding appropriate therapies.

Dr Haycraft is a dermatology nurse practitioner based in Hannibal, MO, and a member of Diversity in Dermatology. Dr Cooke is a dermatologist and owner of Riverside Dermatology in Hannibal, MO. Dr Graham is a dermatologist and dermatopathologist at US Dermatology Partners of Tyler, TX.

Disclosures: The authors report no relevant financial relationships.

References
1. Uchi H. Merkel cell carcinoma: an update and immunotherapy. Front Oncol. 2018;8:48. doi:10.3389/fonc.2018.00048

2. Merkel cell carcinoma. In: Rigel DS, Robinson JK, Ross M, et al, eds. Cancer of the Skin, 2nd ed. Saunders; 2011.

3. Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008;58(3):375-381. doi:10.1016/j.jaad.2007.11.020

4. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096-1100. doi:10.1126/science.1152586

5. Rastrelli M, Del Fiore P, Buja A, et al. A therapeutic and diagnositic multidisciplinary pathway for Merkel cell carcinoma patients. Front Oncol. 2020;10:529. doi:10.3389/fonc.2020.00529