Clonal relationship in a rare pulmonary mixed tumor: shared ALK fusion in atypical carcinoid and adenocarcinoma—a case report

Background: Pulmonary mixed neuroendocrine and non-neuroendocrine neoplasms (MiNENs) are currently described in the World Health Organization (WHO) classification primarily as combinations of non-small cell lung cancer (NSCLC) and high-grade neuroendocrine carcinomas, such as small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC). The coexistence of NSCLC with typical or atypical carcinoid (TC/AC) tumors is not officially recognized in the current classification and remains an exceptionally rare entity, with limited information on its pathogenesis. We sought to delineate the molecular alterations underlying a rare case of MiNEN composed of AC and adenocarcinoma. Case Description: A 62-year-old male with a history of prostate cancer underwent a right apical segmentectomy for a suspicious lung nodule detected on follow-up computed tomography (CT). The resected 1.4 cm tumor was histologically diagnosed as a MiNEN, comprising an AC component (60%) and a well-differentiated invasive adenocarcinoma component (40%). Next-generation sequencing (NGS) performed on the distinct components identified a KIF5B-ALK gene fusion shared by both the neuroendocrine and adenocarcinoma elements. Furthermore, both components harbored identical mutations in the PMS1, PXDNL, TMEM132C, and NQO1 genes. ALK immunohistochemistry confirmed strong, diffuse cytoplasmic positivity in both tumor populations. The identification of a shared ALK rearrangement and overlapping mutational profiles in morphologically distinct components strongly supports a monoclonal origin from a common progenitor cell, rather than a collision of independent tumors. Conclusions: These findings suggest that MiNEN-associated carcinoids may share molecular drivers with NSCLC, distinct from the genetic landscape of sporadic carcinoids, and may be responsive to targeted therapies such as ALK inhibitors. Expanding the current WHO classification to include these low-grade neuroendocrine combinations is warranted to facilitate better diagnostic definition and clinical management.