High expression of insulinoma‐associated protein 1 ( INSM1 ) distinguishes colorectal mixed and pure neuroendocrine carcinomas from conventional adenocarcinomas with diffuse expression of synaptophysin

• Published in: The journal of pathology. Clinical research Vol. 9; no. 6; pp. 498 - 509
• Main Authors: Litmeyer, Anne‐Sophie, Konukiewitz, Björn, Kasajima, Atsuko, Foersch, Sebastian, Schicktanz, Felix, Schmitt, Maxime, Kellers, Franziska, Grass, Albert, Jank, Paul, Lehman, Bettina, Gress, Thomas M, Rinke, Anja, Bartsch, Detlef K, Denkert, Carsten, Weichert, Wilko, Klöppel, Günter, Jesinghaus, Moritz
• Format: Journal Article
• Language: English
• Published: Oxford John Wiley & Sons, Inc 01.11.2023; Wiley
• Subjects: Cancer; Classification; Cloning; Colorectal cancer; Colorectal carcinoma; conventional adenocarcinoma; Diagnosis; INSM1; Insulinoma; Medical prognosis; Morphology; neuroendocrine carcinoma; Neuroendocrine tumors; Original; Patients; Survival; Synaptophysin; Tumors
• ISSN: 2056-4538; 2056-4538
• DOI: 10.1002/cjp2.339

Abstract Complementary to synaptophysin and chromogranin A, insulinoma‐associated protein 1 (INSM1) has emerged as a sensitive marker for the diagnosis of neuroendocrine neoplasms. Since there are no comparative data regarding INSM1 expression in conventional colorectal adenocarcinomas (CRCs) and colorectal mixed adenoneuroendocrine carcinomas/neuroendocrine carcinomas (MANECs/NECs), we examined INSM1 in a large cohort of conventional CRCs and MANECs/NECs. In conventional CRC, we put a special focus on conventional CRC with diffuse expression of synaptophysin, which carry the risk of being misinterpreted as a MANEC or a NEC. We investigated INSM1 according to the immunoreactive score in our main cohort of 1,033 conventional CRCs and 21 MANECs/NECs in comparison to the expression of synaptophysin and chromogranin A and correlated the results with clinicopathological parameters and patient survival. All MANECs/NECs expressed INSM1, usually showing high or moderate expression (57% high, 34% moderate, and 9% low), which distinguished them from conventional CRCs, which were usually INSM1 negative or low, even if they diffusely expressed synaptophysin. High expression of INSM1 was not observed in conventional CRCs. Chromogranin A was negative/low in most conventional CRCs (99%), but also in most MANECs/NECs (66%). Comparable results were observed in our independent validation cohorts of conventional CRC ( n  = 274) and MANEC/NEC ( n  = 19). Similar to synaptophysin, INSM1 expression had no prognostic relevance in conventional CRCs, while true MANEC/NEC showed a highly impaired survival in univariate and multivariate analyses (e.g. disease‐specific survival: p  < 0.001). MANECs/NECs are a highly aggressive variant of colorectal cancer, which must be reliably identified. High expression of INSM1 distinguishes MANEC/NEC from conventional CRCs with diffuse expression of the standard neuroendocrine marker synaptophysin, which do not share the same dismal prognosis. Therefore, high INSM1 expression is a highly specific/sensitive marker that is supportive for the diagnosis of true colorectal MANEC/NEC.