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Keith Kerr

WHO classification of lung carcinomas 2015 – update on subtyping and the role of IHC and molecular pathology

Handout (pdf 108 p)

Handout (pdf 27 p)

Abstract:

The 2015 WHO classification of lung cancer incorporates a number of changes, some subtle, some major and embeds immunohistochemistry (IHC) within the classification to a much greater extent than previously seen. Whilst the classification is still primarily a description of the pathology of resected tumours, much greater emphasis is given to small sample diagnosis and molecular characterisation of tumours.

A new major category of Neuroendocrine tumours now incorporates small cell carcinoma, large cell neuroendocrine carcinoma and the carcinoid tumours under one heading. Previously these tumours were dispersed in three different sections. Immunohistochemistry still plays an important role in the diagnosis of these tumours, although it remains a de facto requirement, only for a diagnosis of large cell neuroendocrine carcinoma.

The most significant change is in the approach to undifferentiated tumours which would, under 2004 WHO rules, have been classified as Large Cell Carcinoma. Because some of these cases share a molecular mutation profile similar to differentiated tumours, the IHC profile of resected undifferentiated carcinoma is now allowed to define such a case as non-keratinizing squamous cell or solid-pattern adenocarcinoma. These IHC profiles concern the expression of p63, p40 and cytokeratin 5/6 as an indication of squamous differentiation and TTF1 or napsin A as an indication of adenocarcinoma differentiation. As a consequence, the Large Cell category will account for a much smaller proportion of cases, where IHC is inconclusive or cannot be performed.

The squamous cell carcinoma category now includes tumours diagnosed as basaloid carcinoma, given their strong expression of a squamous immunophenotype. Rare undifferentiated carcinomas, showing translocation involving the NUTM1 gene and expressing NUT protein by IHC, share morphological features with basaloid carcinomas but their clinical profile is different and this new category of NUT carcinoma is kept separate from squamous cell carcinoma.

The strong emphasis of IHC as a tool to facilitate the subtyping of undifferentiated non-small cell carcinomas on small samples (biopsy and cytology), as well as the molecular characterisation of such samples, is driven by the emergence of selective and targeted therapies for molecularly-defined groups of tumours. The predictive value of IHC in subtyping such diagnostic samples is recognised by a limited range of recommended diagnoses to be rendered in this context – the full WHO classification is inappropriate.

CV

Keith Kerr has been a Consultant Pathologist in Aberdeen since 1989, after under and post-graduate training in Edinburgh. He was awarded an Honorary Chair in Pulmonary Pathology at the University of Aberdeen in 2006. His research interests include pre-neoplasia and carcinogenesis, lung tumour diagnosis and classification, and the identification of predictors of therapy response. He is a member of numerous national and international lung cancer clinical advisory and research groups (BTOG steering group, the Pulmonary Pathology Society Council, the ETOP Foundation Council, ESMO Educational Faculty for thoracic tumours and the Board of the IASLC). He is Pathology Chair to the EORTC lung group, and Pathology lead for the ETOP Lungscape project. He is a member of the IASLC Pathology committee and the WHO panel for lung cancer classification. He is involved in a number of UK, European and North American initiatives looking at the introduction, operation and quality assurance of guidelines for management of, and molecular pathology testing in, lung cancer.

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KONXION A/S