Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine Carcinoma

Background: Merkel cell carcinoma (MCC) is a rare and aggressive primary cutaneous neuroendocrine carcinoma. Because MCC cannot be reliably distinguished morphologically from small cell carcinomas from other sites, immunohistochemistry is required to confirm cutaneous origin. Expression of cytokeratin-20 (CK20), especially in a paranuclear, dot-like pattern, is commonly used to confirm the diagnosis of MCC, but is negative in 5-10% of cases. Diagnostic challenges also arise in the setting of metastatic neuroendocrine carcinoma of unknown primary. Design: Neurofilament and CK20 expression was evaluated in 53 MCC specimens from 37 unique patients, including 8 previously characterized CK20-negative MCC tumors. Twelve cases had results from previously performed Merkel cell polyomavirus (MCPyV) immunohistochemistry. Neurofilament and CK20 expression was also assessed in 60 non-cutaneous neuroendocrine carcinomas (NEC) with primary sites including lung (27), bladder (18), cervix (3), gastrointestinal tract (3), sinonasal tract (2), or other sites (7). CK20 and neurofilament immunohistochemistry was scored as either negative or positive (with or without paranuclear dot staining). Results: Neurofilament expression was observed in 40/53 (75.5%) MCC cases, including 6/8 (75.0%) CK20-negative MCC cases. Neurofilament was expressed in 9/9 (100%) MCPyV-positive tumors and 2/3 (66.7%) MCPyV-negative tumors. Neurofilament expression was observed in 2 non-cutaneous NEC cases (one sinonasal and one lung); the specificity of neurofilament for MCC versus non-cutaneous NEC was 96.7%. CK20 expression was observed in 25/60 (41.7%) NEC cases. Specificity of CK20 immunostaining for MCC versus noncutaneous NEC was 58.3%; specificity was only slightly improved (65.0%) by considering only cases with paranuclear dot-like CK20 staining to be positive. Because CK20 expression was a controlled variable in our MCC cohort, sensitivity of CK20 staining for MCC was not calculated. Conclusions: Neurofilament expression has superior specificity to CK20 expression in distinguishing MCC from non-cutaneous NEC. Neurofilament is a useful diagnostic marker in the majority of CK20- negative MCC cases and may be expressed in MCPyV-negative MCC tumors. Limitations of neurofilament immunohistochemistry include predicted lower sensitivity than CK20 and subtle staining in some tumors. However, our findings indicate neurofilament is a useful addition to diagnostic panels for excluding non-cutaneous NEC.