Is Ectopic Cushing Syndrome Commonly Associated with Small Cell Lung Cancer (SCLC)? Critical Review of the Literature and ACTH Expression in Resected SCLC

The literature emphasizes that pulmonary ectopic Cushing syndrome (ECS) is associated not only with neuroendocrine tumors (NETs), but also with small cell lung carcinomas (SCLCs). This statement is debatable, because extrapulmonary ECS is associated with NETs in the vast majority of cases and very rarely with neuroendocrine carcinomas (NECs). Therefore, we critically reviewed the literature on SCLCs associated with ECS (ECS-SCLC) and performed immunohistochemical analysis of ACTH expression in 155 resected SCLCs and 158 pulmonary NETs. The literature search revealed that 90% of the 205 ECS-SCLC patients identified between 1952 and 2023 had no or poor-quality histologic images, so the diagnosis of SCLC could not be confirmed. Review of the 20 reports (10%) with histologic images revealed that 18/20 (90%) had to be reclassified as "probable NET", of which 5/18 (28%) showed spindle cell morphology, while only 2 cases were qualified as "SCLC compatible" due to their pleomorphic cell features. Immunohistochemically, 5/155 (3%) resected SCLCs, all without ECS, showed weak single cell ACTH expression, whereas in the NET cohort, 61/158 (39%) tumors expressed ACTH, of which 4 (3%) were associated with ECS. Both observations, the literature review, which casts doubt on previously reported data regarding the frequency of SCLC in ECS, and the immunohistochemical study, suggest that there is limited evidence that SCLC is the cause of ECS.