Small-cell lung carcinoma (SCLC) is a high-grade aggressive disease that belongs to the neuroendocrine (NE) group of lung tumors that also includes typical carcinoid, atypical carcinoid, and large-cell NE carcinoma. SCLC has specific histological diagnostic criteria that are sometimes troublesome to be assessed in cytological samples that indeed represent the most frequent source of diagnostic material due to the typical advanced presentation at the onset of SCLC. However, cytological preparations could be in some instances more reliable than histology due to the better preservation of nuclear details. Cytological criteria for diagnosis of SCLC include high cellularity, small cell size, scant cytoplasm, coarsely granulated chromatin with “salt-and-pepper” appearance, inconspicuous or absent nucleoli, Azzopardi crush effect, and necrotic debris in the background. Despite being distinctive, these features could be incomplete to differentiate SCLC with other small-cell neoplasia. Therefore, immunocytochemical determination of diagnostic biomarkers is crucial to achieve a confident diagnosis. Furthermore, recent findings on molecular and transcriptomic studies of SCLC revealed the potential rise of new predictive and prognostic biomarkers that, whenever validated by immunocytochemistry, may potentially assist to tailor the best therapy, including immune checkpoint inhibition.

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