K homology domain containing protein overexpressed in cancer (KOC) is a member of the insulin-like growth factor (IGF) messenger RNA-binding protein family and is expressed during embryogenesis and in certain malignancies. KOC, known as L523S and IGF messenger RNA-binding protein 3, was shown to be frequently expressed in high-grade neuroendocrine carcinomas of the lung in our immunohistochemical studies using a monoclonal antibody against human KOC. Specifically, all 10 small cell lung carcinomas (SCLCs) exhibited strong cytoplasmic staining, 9 with diffuse positivity and 1 with focal positivity. Among 14 large cell neuroendocrine carcinomas (LCNECs), 9 exhibited strong and diffuse cytoplasmic staining, and 5 cases showed focal immunoreactivity. In contrast, no KOC was detected in 21 typical and atypical carcinoids, except for one atypical carcinoid with oncocytic cells showing weak cytoplasmic staining. Although SCLCs exhibited a strong and diffuse staining pattern more frequently (90%) than LCNECs (64%), the difference did not reach statistical significance (P = .3408). Interestingly, our immunohistochemical studies demonstrated that IGF-II, reportedly regulated by KOC, was comparably expressed in SCLC, LCNEC, and typical and atypical carcinoids, irrespective of KOC expression status of the tumors. These results support the formulation that KOC may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas. In addition, detection of KOC expression may be diagnostically useful in distinguishing high-grade neuroendocrine carcinomas from carcinoid tumors. Our findings of equivalent IGF-II expression in KOC-positive SCLC and LCNEC and KOC-negative carcinoid tumors suggest different regulatory mechanisms involved in the control of IGF-II expression in these tumors.