The challenge of diagnosing neuroendocrine neoplasms: experience from a national reference center

Correctly diagnosing neuroendocrine neoplasm (NEN) has become increasingly challenging, given that more histomorphologic and immunophenotypic NEN mimics have been identified in recent years. A systemic review was conducted on the 4795 consult cases submitted with initial diagnoses of NEN to a national reference center in China from 2013 to 2021. Among them, 443 cases were misdiagnosed as epithelial NENs after reevaluation with the help of immunohistochemical and/or molecular tests, ranging from 7.1 to 13.2%, with yearly increases. The misdiagnoses varied among age groups and tumor sites. Exocrine carcinoma was the most common (63.2%), followed by mesenchymal tumors. Other common tumors that were misdiagnosed included hepatocellular carcinoma, salivary gland tumor, and gastrointestinal stromal tumor. Aberrant expression of neuroendocrine markers was frequent (218/408, 53.4%), with diffuse positivity ranging from 8.2 to 51.7% for synaptophysin, chromogranin A, and INSM1 stains in all non-NEN cases. Selecting appropriate immunohistochemical stains based on H&E morphology is the key to avoiding diagnostic pitfalls. Medical history and molecular genomic information greatly assist in correctly diagnosing NENs and their mimics.