Cytologic Features Across Molecular Subtypes of Small Cell Lung Carcinoma: Classical Uniformity With Exceptions in...

Small cell lung carcinoma (SCLC) comprises molecular subtypes defined by transcription factor expression, but cytologic correlates of these groups remain poorly characterised. We investigated whether cytomorphologic features differ across subtypes and identified variants that may confound diagnosis.

We conducted a single-center, retrospective study of 30 SCLC cases diagnosed between 2021 and 2024. Molecular subtypes were assigned on histologic tissue using immunohistochemistry and classified as SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-P (POU2F3) and SCLC-I (inflamed subtype). Paired cytology specimens, including conventional smears stained with Papanicolaou and Giemsa as well as liquid-based cytology, were reviewed. Classical morphology was defined by established SCLC criteria, and non-classical morphology by deviations such as enlarged nuclei with prominent nucleoli, increased cytoplasm and reduced nuclear moulding.

Twelve tumours were classified as SCLC-A, 6 as SCLC-N, 9 as SCLC-P and 3 as SCLC-I. Cytomorphology was uniformly classical in 28 cases, encompassing all SCLC-A, SCLC-N and SCLC-I tumours. Two SCLC-P cases demonstrated non-classical morphology with relatively abundant cytoplasm and conspicuous nucleoli, imparting an appearance more reminiscent of non-small cell carcinoma.

Cytomorphology is largely conserved across molecular subtypes of SCLC, but a minority of POU2F3-positive tumours may display non-classical features. Recognition of this variant is important to avoid misclassification, particularly when only limited cytology material is available. These findings suggest that lineage-defining programs may occasionally imprint the cytologic phenotype and highlight the value of considering subtype-oriented ancillary testing in challenging cases.