Subtyping non-small cell lung cancer: relevant issues and operative recommendations for the best pathology practice.

Morphology still remains the cornerstone in lung cancer classification and cytology and small biopsy samples should be interpreted by morphology, whenever feasible, according to shared and widely agreed-upon diagnostic schemes. However, as novel therapy strategies are being offered on the basis of the diverse tumor characteristics, pathologists are now challenged by the need to offer clinicians more detailed typing of non-small cell lung cancer, not otherwise specified (NSCLC-NOS), especially when dealing with limited diagnostic material or poorly differentiated tumors. Close integration of morphology, immunohistochemistry, and clinical data is highly warranted according to a multidisciplinary approach to limit the category of NSCLC-NOS as much as possible or exclude unsuspected metastases, so rendering more definite and clinically useful diagnoses. Among the many proposed immunohistochemical markers, which as a whole are more practical and diagnostically useful than cumbersome and expensive molecular assays, a 2-hit model including thyroid transcription factor-1 (TTF-1) and p40 (the latter more specific for squamous differentiation than p63) seems to be the most effective to basically highlight adenocarcinoma (positivity for TTF-1 regardless of p63) and squamous (always strongly and diffusely positive for p40 or p63 and negative for TTF-1) differentiation. This minimalist 2-hit diagnostic approach paves the way to novel perspectives in clinical trials on lung cancer, and it is also in keeping with the need of strategically preserving diagnostic material for molecular assays that are essential for personalizing therapies.