May 2019 Case

KristineAstvatsaturyan,MD(fellow),DavidFrishberg,MD(attending)

A woman aged 82 years presented with shortness of the breath, atrial fibrillation, and enlarged supraclavicular lymph node. The patient had a remote (>10 years) history of bilateral lung adenocarcinomas (Figure 1) and was status post wedge resection with no subsequent therapy. There also was a history of low-grade B-cell lymphoma in 2014 (Figure 2).

Physical examination revealed 2.0 x 2.0cm, palpable, non-tender left scalene lymph node. Review of systems was otherwise unremarkable.

Computed tomography of the chest demonstrated significant diffuse mediastinal and subcarinal lymphadenopathy, as well as extensive lytic bone lesions, and was presumed to represent recurrent metastatic lung cancer vs progressive lymphoma. Flow cytometry analysis of supraclavicular lymph node showed no monoclonal B-cell or abnormal T-cell population.

A supraclavicular lymph node fine needle aspiration was performed. The aspirate was hypercellular, demonstrating abundant small, round-to-oval cells with stippled chromatin, inconspicuous nucleoli and numerous mitoses (Figure 3). Cell block preparation with immunohistochemistry performance revealed tumor cells negative for CD20, TTF-1 and Melan-1 immunostains (Figure 4). Most of the neoplastic cells expressed dot-like staining with antibodies to Pancytokeratin AE1/AE3 and CAM 5.2. Similar crisp, dot- like perinuclear immunoreactivity with antibodies to cytokeratin 20 and positive cytoplasmic immunoexpression of synaptophysin (Figure 4) established the diagnosis of metastatic Merkel cell carcinoma (MCC).

Figure 1. Lung adenocarcinoma on Hematoxylin & Eosin stain (A-C), confirmed by TTF-1 immunoreactivity (D)

Figure 2. Low grade B-cell lymphoma on Hematoxylin & Eosin (A, B), confirmed by CD20 immunopositivity (C), absence of CD3 immunoexpression (D).

Figure 3. Fine needle aspiration specimen from a supraclavicular lymph node shows population of small, round- to-oval neoplastic cells with stippled chromatin. Diff-Quick stain (A, B) and Papanicolaou stain (C, D)

Figure 4. Cell block. Hematoxylin & Eosin (A). Neoplastic cells show negative CD20 (B), TTF-1 (C) and Melan A (D) immunoreactivity, which rule out the differential diagnosis of lymphoma, metastatic carcinoma and melanoma. Dot-like immunoexpresion of Cytokeratin 20 (E) and diffuse positive synaptophysin cytoplasmic immunoreactivity (F) support diagnosis of Merkel cell carcinoma

Metastatic Merkel cell carcinoma (MCC).

A subsequent lymph node excision histologically confirmed MCC. The patient was referred for medical and radiation oncology and started chemotherapy but was lost to follow-up approximately 6 months later.

This patient illustrates the protean clinical presentations of MCC and the clinical and cytologic challenges associated with this neoplasm. There was no known primary site of the tumor. Lymphadenopathy was interpreted radiologically as metastatic carcinoma or progressive lymphoma. Cytologic misinterpretation also can occur, especially in the clinical view of prior malignancies.

The cytologist must learn to suspect MCC in FNA samples that demonstrate features of a high-grade neuroendocrine tumor in elderly. Perinuclear dotlike immunoreactivity with AE1/AE3, CAM5.2, and CK20 is useful.

MCC is a relatively rare but highly aggressive cutaneous neuroendocrine neoplasm that was described first by Cyril Toker in 1972.¹ MCC is most commonly located in the head and neck regions (37%-50%) and the extremities (40%-44%).^2,3 Less commonly, MCC arises in the buttocks (9%-16%) and trunk (4%- 8%).^3,4 Most cases occur in elderly patients (age range, 60-70 years); however, MCC may present earlier in immunosuppressed patients.⁵ MCC occurs mainly in Caucasians, with few reports in African Americans.⁶ Most reports indicate a slightly higher incidence among men.^3,6 The data also indicate that MCC incidence rates have increased 3-fold over the last 20 years.⁷ MCC is more common in immunosuppressed patients than in the normal population. This includes patients on chronic immunosuppressive therapy, patients with HIV, transplantation recipients, and patients with hematologic malignancies.⁸

The exact etiology of MCC remains unclear but is likely multifactorial. The recently described Merkel cell polyomavirus (MCV) is suspected to be an agent important in the oncogenesis of MCC.⁵

Sunlight may also be a factor, because MCC is identified primarily in areas that receive actinic damage, suggesting that ultraviolet radiation may play a role.⁹ However, a significant number of tumors arise on non-sun-exposed regions.

The chromosomal abnormality most frequently reported in MCC is a deletion of the short arm of chromosome 1 (1p36).¹⁰ Deletions involving 1p35-36 are similar to those described for malignant melanoma, pheochromocytoma, and neuroblastoma, tumors known to originate from neural crest cells.¹¹

MCC typically presents as a painless, solitary, pink-purple to red-brown, dome-shaped papule or plaque ^2,3 on sun exposed skin of elderly or immunocompromised individuals. MCC size at presentation ranges from 0.2 cm to 23 cm.¹² Most MCCs are diagnosed from biopsies submitted as suspected basal cell carcinoma, squamous cell carcinoma, adnexal tumors, pyogenic granuloma, lymphoma, or melanoma^.13,14,15 One-third of patients with MCC develop a local recurrence within after 1 year of excision.¹⁶ In 10% to 20% of patients with metastatic MCC, the primary tumor is not identified.

FNA can be a useful tool for diagnosing MCC but requires awareness of the tumor’s ability to mimic other neoplasms. Aspirate smears are moderately to highly cellular and contain singly or loosely cohesive, relatively monomorphic cells with scanty-to-inapparent cytoplasm resembling small cell neuroendocrine carcinoma. Cell nuclei are rounded with smooth nuclear membranes. Apoptosis and mitotic figures are apparent, but their frequency varies. Aggregates of intermediate filaments (blue bodies), similar to those observed in pulmonary small cell carcinoma, are sometimes present. These features may be an enormous challenge because of the wide range of differential diagnosis, including the "small round blue cell tumors": small cell carcinoma, lymphoma, and other skin-associated tumors like melanoma, basal cell carcinoma, and adnexal tumors.¹⁷

Differentiating MCC from its mimics requires the use of immunohistochemistry (Table 1). MCC tumor cells typically express both epithelial and neuroendocrine markers. Several epithelial markers, such as CAM 5.2, AE1/AE3, CK20, and epithelial membrane antigen (EMA) react with MCC.^18,19 The majority of MCCs are at least focally positive for CK20, typically in a paranuclear, dot-like pattern.²¹ Neuroendocrine markers (chromogranin, synaptophysin, CD56, and neurofilament) also are positive in most tumors.²¹ Flow cytometry is useful if there is a history of or suspicion of coexisting lymphoma, as illustrated in our patient.

The MCC staging system is based on tumor size, lymphatic spread, and distant metastasis and is used to determine primary, adjuvant, and palliative therapy.^4,22

Some studies showed that 10-year relative survival rate for patients with localized MCC was 71% and the rate for those with distant disease was 20%. The 10-year relative survival rate based on tumor size is 60% for patients with tumors < 2 cm and approximately 40% for patients with tumors >2 cm. Recurrence reportedly is common at a rate of approximately 40%.²³

Findings that had a statistically significant correlation with poor outcome included depth of tumor invasion, diffuse growth pattern, and lymphovascular invasion.^2,24 Factors that are associated with an improved prognosis include tumor size <2 cm, women, and local radiation treatment.²⁵ Patients who have tumors located in the upper extremities fare better than patients with tumors located in the head and neck, trunk, and lower extremities.¹³ Tumors on mucosal surfaces also appear to have a worse prognosis, probably because of greater access to vascular and lymphatic channels.²⁶ Distant metastasis indicates a very poor prognosis and is the most important predictor of survival. The most common metastatic sites are lymph nodes followed by liver, bone, brain, lung, and gastrointestinal tract.⁹

The optimal treatment for patients with MCC remains unclear. Current treatment includes Mohs or wide surgical excision and regional lymphadenectomy of any suspicious lymph nodes.²⁷ Many protocols also advocate adjuvant chemotherapy and radiation therapy.²⁸ Even with treatment, MCC has a strong propensity toward local recurrence, lymphatic spread, and distant metastasis.²⁹

In conclusion, the incidence of MCC is rising. It is diagnosed most commonly in elderly or immunocompromised patients, and it has higher mortality than melanoma.³⁰ Because of its nonspecific clinical presentation, MCC is rarely suspected before biopsy. Cytopathologists need to be aware of the deceptive presentation of this neoplasm and its cytologic and immunochemical features to correctly diagnose this insidious neoplasm.

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