Lung carcinoma–‘nonsmall cell’ is no longer an option

Abstract

Current diagnostic issues concerning nonsmall cell lung carcinoma (NSCLC) include subtyping as encountered in cytology and small biopsy samples, and the requirement to strike a balance between histology and immunohistochemistry (IHC) for discrimination between squamous (SCCs) and adenocarcinomas (ADCs), versus the requirement for conservation of material for molecular studies (i.e., for recognition of ADCs with EGFR, EML4-ALK, or other mutations). There is a problem for pathologists in subtyping of NSCLC from small biopsies, in relation to: (i) a minimal sample of poorly differentiated tumour for histological and IHC assessment; (ii) biopsy artefact; (iii) conservation of tissue for molecular studies. A minimalist IHC workup of p63 and TTF1 can facilitate discrimination between SCC versus nonmucinous ADC, respectively. However, about one-third of proven ADCs show expression of p63, so that a p63+/TTF1+ immunoprofile is still considered to favour ADC. Alternatively, p40 can be substituted for p63 and labels ADCs less often than p63, or CK5 or CK5/6 can be added to p63 to facilitate diagnosis of SCC. Invasive mucinous ADC has an immunoprofile different from nonmucinous ADC (usually CK7+/CK20+/TTF1–). Other pitfalls exist: TTF1+/p63– in small cell carcinoma and metastatic thyroid carcinoma; TTF1–/p63– in lymphomas and melanoma; and TTF1–/p63+ in metastatic uro-thelial carcinoma. In this context, IHC studies need to take into account the clinical background and medical history for each case. Even now, up to about 30% NSCLCs are not further classifiable beyond NSCLC NOS, on the basis of IHC on small biopsy samples. EGFR antibodies are commercially available, and can be used to screen for such mutations, whereas ALK antibodies used at present for diagnosis of ALK positive large cell lymphomas are insensitive for diagnosis of most EML4-ALK ADCs. ALK positive ADCs reported to date have been positive for TTF1, and positive/negative TTF1 labelling may represent an inclusionary/exclusionary boundary for molecular testing. Even so, EGFR and ALK ADCs represent a small proportion of ADCs in Western societies, so that histological/IHC subtyping appears to retain prognostic and clinical relevance for most ADCs.