SATB2, CKAE1/AE3, and synaptophysin as a sensitive immunohistochemical panel for the detection of lymph node metastases of Merkel cell carcinoma

Histopathological evaluation of lymph nodes in Merkel cell carcinoma has become crucial in progression estimation and treatment modification. This study was undertaken to determine the most sensitive immunohistochemical panel for detecting MCC nodal metastases. We included 56 patients with 102 metastatic MCC lymph nodes, which were tested with seven antibodies: cytokeratin (CKAE1/AE3), CK20, chromogranin A, synaptophysin, INSM1, SATB2, and neurofilament (NF). Tissue microarrays (TMA) composed of 2-mm tissue cores from each nodal metastasis were constructed. A semiquantitative 5-tier scoring system (0%, < 25%, 25-74%, 75-99%, 100% positive MCC cells with moderate to strong reactivity) was implemented. In the statistical assessment, we included Merkel cell polyomavirus (MCPyV) status and expression heterogeneity between lymph nodes from one patient. A cumulative percentage of moderate to strong expression >= 75% of tumoral cells was observed for single cell markers as follows: 91/102 (89.2%) SATB2, 85/102 (83%) CKAE1/AE3, 80/102 (78.4%) synaptophysin, 75/102 (75.5%) INSM1, 68/102 (66.7%) chromogranin A, 60/102 cases (58.8%) CK20, and 0/102 (0%) NF. Three markers presented a complete lack of immunoreactivity: 8/102 (7.8%) CK20, 7/102 (6.9%) chromogranin A, and 6/102 (5.9%) NF. All markers showed expression heterogeneity in lymph nodes from one patient; however, the most homogenous was INSM1. The probability of detecting nodal MCC metastases was the highest while using SATB2 as a first-line marker (89.2%) with subsequential adding CKAE1/AE3 (99%); these results were independent of MCPyV status. Synaptophysin showed a superior significance in confirming the neuroendocrine origin of metastatic cells. This comprehensive analysis allows us to recommend simultaneous evaluation of SATB2, CKAE1/AE3, and synaptophysin in the routine pathologic MCC lymph node protocol.