INSM1 Is Less Sensitive but More Specific Than Synaptophysin in Gynecologic High-grade Neuroendocrine Carcinomas: An Immunohistochemical Study of 75 Cases with Specificity Test and Literature Review

Insulinoma-associated protein 1 (INSM1) has emerged as a promising diagnostic marker for high-grade neuroendocrine carcinomas (HGNECs); however, it is controversial whether INSM1 is more sensitive than conventional markers chromogranin, synaptophysin, and CD56. Here, we investigated immunohistochemical expression of INSM1 in 75 gynecologic HGNECs using full tissue sections (30 small-cell carcinomas [SmCCs], 34 large-cell neuroendocrine carcinomas [LCNECs], and 11 mixed SmCC and LCNEC), with specificity analysis in 422 gynecologic non-neuroendocrine tumors (410 in tissue microarrays and 12 full sections) and comparison with conventional neuroendocrine markers for their sensitivity and specificity. Positive INSM1 staining was seen in 69 (92%) HGNECs, whereas chromogranin, synaptophysin, and CD56 staining was seen in 61 (81%), 72 (96%), and 44 (69%) tumors, respectively (INSM1 vs. chromogranin, P=0.09; INSM1 vs. synaptophysin, P=0.4942; and INSM1 vs. CD56, P<0.001). The mean percentage of INSM1-positive tumor cells was 54% (median: 60%, range: 0% to 100%), similar to chromogranin (58%, P=0.2903) and higher than CD56 (30%, P=0.00001) but significantly lower than synaptophysin (89%, P<0.00001). INSM1 showed no staining difference among SmCCs, LCNECs, and mixed SmCC-LCNECs. Among the 422 non-neuroendocrine tumors, positive staining was seen in 5% tumors for INSM1, 18% for chromogranin, 19% for synaptophysin, and 25% for CD56. Our study indicates that INSM1 is a highly specific marker (95% specificity) for gynecologic HGNECs with high sensitivity (92%), but it is less sensitive than synaptophysin (96% sensitivity). INSM1 is more specific than chromogranin, synaptophysin, and CD56 for gynecologic HGNECs. Our literature review reveals that INSM1 has consistently (the same antibody clone A8 used for all reported studies) shown higher or similar sensitivity to chromogranin (for all 3 chromogranin antibody clones LK2H10, DAK-A3, DAKO polyclonal); however, whether INSM1 is more or less sensitive than synaptophysin or CD56 for HGNECs is highly dependent on the antibody clones used for synaptophysin (clones MRQ-40 and SNP88 showing higher sensitivity than clones 27G12 and DAK-SYNAP) or CD56 (clones CD564, MRQ-42, and MRQ-54 showing higher sensitivity than clones 123C3D5, 1B6, and Leu243).