Diagnostic issues with cytopathologic interpretation of lung neoplasms displaying high-grade basaloid or neuroendocrine morphology.

Basaloid squamous cell carcinoma (BSQCC) and high-grade neuroendocrine carcinomas (HGNEC) including small cell carcinoma (SMCC) and large cell neuroendocrine carcinoma (LCNEC) can be difficult to differentiate on lung cytology. This problem is particularly true in scant specimens where immunoperoxidase stains cannot be adequately performed. Sixty-six cases of BSQCC, LCNEC, and SMCC (22 cases of each) on lung or mediastinal cytology were retrospectively reviewed from the cytopathology archives of two hospitals. Common cytomorphologic characteristics were; hypercellularity, small to intermediate round blue (hyperchromatic) cells, lack of prominent nucleoli, lack of three dimensional architecture, karyorrhexis/necrosis, mitoses, naked nuclei, nuclear crush artifact, and nuclear molding. Distinctive features included: larger cell size with pleomorphism, more cohesive architecture, syncytial aggregation, slightly coarser chromatin texture, rare keratinized malignant cells, and a granular smear background seen more often in BSQCC as opposed to HGNEC. Larger cells with prominent nucleoli and more cytoplasm with focal rosette formation were helpful in distinguishing LCNEC from SMCC and BSQCC. Finally, SMCC displayed uniform small cells with extensive necrosis, and higher mitotic rate. Immunoperoxidase (IPOX) staining using p63, CK5, 6, neuroendocrine markers (chromogranin, synaptophysin and CD56) and TTF-1 were helpful. BSQCC showed p63 expression and was mostly negative for neuroendocrine markers and TTF-1. HGNEC showed immunoreactivity for neuroendocrine markers with variable immunoreactivity for TTF-1. BSQCC, SMCC, and LCNEC share overlapping cytomorphologic features and can be difficult to differentiate on limited cytology specimens. Careful consideration to subtle but definite cytomorphologic clues and attention to selective IPOX stains can lead to a definitive diagnosis.