Respiratory cytology in the era of molecular diagnostics: a review

Carcinoma of the lungs remains one of the primary causes of cancer mortality in the United States and represents a significant diagnostic challenge. Current diagnostic protocols depend substantially on cytology as an initial diagnostic modality. Pulmonary cytology can be diagnostically challenging with false positive and false negative diagnoses being relatively frequent. False positive diagnoses remain a significant problem for the cytologist with benign conditions including reactive atypia of type II pneumocytes, reactive bronchial respiratory epithelium, basal cell hyperplasia, and reactive metaplastic squamous cells being potentially misinterpreted as carcinoma. False negative diagnoses also occur usually attributable to sampling. Traditionally, cytopathologists were expected to recognize carcinoma when present and subdivide it into small cell or nonsmall cell varieties. With the advent of targeted therapy, expectations now include separation of adenocarcinoma from squamous cell carcinoma. Additionally, molecular testing for EGFR mutations and ALK rearrangements is now required as an accompaniment to morphologic diagnosis. This review summarizes the morphologic appearances of the common and diagnostically important carcinomas of the lung and discusses diagnostic pitfalls responsible for false positive and false negative diagnoses. Molecular testing for selection of targeted therapy is also reviewed.