Case Report: Neuroendocrine-marker-negative high-grade neuroendocrine carcinoma mimicking squamous cell carcinoma: an underrecognized diagnostic pitfall.

High-grade neuroendocrine carcinoma (NEC) can be difficult to diagnose, particularly when conventional neuroendocrine (NE) markers are weakly expressed or absent. This challenge is particularly pronounced in NE-low tumors with lineage-defining transcription factor profiles (e.g., POU2F3 and/or YAP1), which may exhibit squamoid (basal-like) morphology and reduced or absent expression of synaptophysin (Syn), chromogranin A (CgA), and CD56, thereby phenotypically overlapping with non-small cell lung cancer (NSCLC) and increasing the risk of misclassification. In this case, needle biopsies from the lung and liver both showed a poorly differentiated carcinoma with squamoid morphology and squamoid/basal-like immunohistochemical features. Syn, CgA, and CD56 were negative in both specimens, leading to an initial diagnosis of poorly differentiated squamous cell carcinoma. However, the subsequent clinical course revealed discordant clinicobiologic features, including rapid progression of the liver metastases, markedly elevated NSE levels, and a high Ki-67 labeling index (60-80%). These discrepancies prompted further molecular evaluation, and 90-gene expression profiling (90-GEP) supported a neuroendocrine lineage assignment. Retrospective immunohistochemistry further demonstrated positivity for POU2F3 and YAP1, whereas INSM1 was negative in both specimens, supporting classification as an NE-marker-negative high-grade NEC with an NE-low NEC/SCLC-like lineage profile. The patient subsequently showed a marked response to etoposide plus carboplatin, consistent with the known chemosensitivity of high-grade NEC/SCLC to platinum-based chemotherapy. This case highlights an underrecognized diagnostic pitfall of NE-marker-negative high-grade NEC with squamoid mimicry. When morphology, immunophenotype, and clinical behavior are discordant, integration of expanded immunohistochemistry (including lineage-defining transcription factors), molecular lineage assays (e.g., GEP), and treatment response may help avoid misdiagnosis and guide appropriate therapy.