Pulmonary squamous cell carcinoma and lymphoepithelial carcinoma - morphology, molecular characteristics and differential diagnosis.

Squamous cell carcinoma (SCC) comprises one of the major groups of non-small-cell carcinoma of the lung, and is subtyped into keratinising, non-keratinising and basaloid SCC. SCC can readily be diagnosed using histomorphology alone in keratinising SCC. Confirmatory immunohistochemical analyses should always be applied in non-keratinising and basaloid tumours to exclude differential diagnoses, most prominently adenocarcinoma and high-grade neuroendocrine carcinoma, which may have important therapeutic consequences. According to the World Health Organisation (WHO) classification 2015, the diagnosis of SCC can be rendered in resections of morphologically ambiguous tumours with squamous immunophenotype. In biopsies and cytology preparations in the same setting the current guidelines propose a diagnosis of 'non-small-cell carcinoma, favour SCC' in TTF1-negative and p40-positive tumours to acknowledge a possible sampling bias and restrict extended immunohistochemical evaluation in order to preserve tissue for molecular testing. Most SCC feature a molecular 'tobacco-smoke signature' with enrichment in GG > TT mutations, in line with the strong epidemiological association of SCC with smoking. Targetable mutations are extremely rare but they do occur, in particular in younger and non- or light-smoking patients, warranting molecular investigations. Lymphoepithelial carcinoma (LEC) is a poorly differentiated SCC with a syncytial growth pattern and a usually prominent lymphoplasmacytic infiltrate and frequent Epstein-Barr virus (EBV) association. In this review, we describe the morphological and molecular characteristics of SCC and LEC and discuss the most pertinent differential diagnoses.