INSM1: A highly sensitive marker for primary and metastatic Merkel cell carcinoma, superior to SOX11, pancytokeratin, and CK20.

Detection of Merkel cell carcinoma (MCC) micrometastases in sentinel lymph nodes (SLNs) often necessitates immunohistochemical studies like pancytokeratin (panCK) or CK20. However, panCK can label non-epithelial cells, particularly dendritic reticulum cells, complicating interpretation, while CK20 is absent in up to 24 % of MCCs, leading to potential false negatives. Recent evidence suggests SOX11 and INSM1 as sensitive nuclear neuroendocrine markers, though their comparative performance in this setting remains unclear. We assessed the expression of panCK (AE1/AE3, CK8/18, Cam5.2, and MNF116), CK20, SOX11, and INSM1 in 25 primary MCCs and 8 nodal metastases. SOX11 and INSM1 demonstrated the highest median H-scores (both 297), significantly outperforming panCK and CK20 (both 255) (p < 0.001). Although median H-scores for SOX11 and INSM1 were similar, 9 % (3/33) of cases lacked SOX11 expression. Direct comparison revealed significant differences in proportion and median H-score between SOX11 and INSM1 (p = 0.020 and p = 0.012, respectively), while intensity did not differ significantly (p = 0.317). When used alongside panCK, INSM1 yielded the highest combined sensitivity (100 %), surpassing panCK/CK20 and panCK/SOX11 combinations. These findings support the use of a panCK/INSM1 panel as a highly sensitive approach for detecting MCC micrometastases in SLNs. While INSM1 demonstrates robust performance, interpretation must account for background immunoreactivity in hematolymphoid elements, a possible and important diagnostic pitfall when using this marker in clinical practice. Further prospective studies with larger and more diverse cohorts may be needed to confirm these results and refine the optimal immunohistochemical strategy for MCC detection in SLNs.