MTE11.01 The Clinical Impact of the 2015 WHO Classification of Lung Tumors

Abstract

There are many important changes in the 2015 WHO classification of lung tumors, reflecting the numerous advances in tumor genetics and therapy over the past decade.1 Many have been in the field of adenocarcinoma, with discontinuation of the term bronchioloalveolar carcinoma and the concept of stepwise progression accepted for adenocarcinoma.1 Adenocarcinoma in situ (AIS) is a small (less than 3 cm in diameter), pure lepidic adenocarcinoma; minimally invasive adenocarcinoma (MIA) is also a small lepidic adenocarcinoma but has small invasive areas less than 5 mm across. As both entities have a very favorable outcome, with an expected 5-year survival rate of 100%, AIS and MIA are targets for reduction surgery, and are frequently detected by low-dose CT screening. High-resolution (HR)-CT demonstrates these tumors as a pure ground glass nodule (GGN) or a part-solid nodule (PSN), being closely correlated with their pathological features.2 Therefore, AIS and MIA can be assessed by HR-CT. However, the size of the solid component in HR-CT images does not necessarily correspond to the extent of histological invasion, since features such as alveolar collapse and fibrosis are also included in the solid part demonstrated by HR-CT.1 Although the new WHO classification defines the histological criteria for MIA invasion, the degree of inter-observer agreement regarding the histological definition of invasion in MIA has still not been fully studied, and a consensus trial will be needed in the near future. More advanced adenocarcinoma is subdivided into five categories: lepidic, papillary, acinar, solid and micropapillary. These subtypes are diagnosed according to the predominant component and the group comprising lepidic, papillary and acinar adenocarcinomas shows a better prognosis than those with solid and micropapillary patterns. Therefore the presence of solid and/or micropapillary adenocarcinoma should be reported, even if the predominant component is lepidic, papillary or acinar adenocarcinoma. These patterns also predict response to adjuvant chemotherapy,3 and the above changes overall have also led new proposals for both clinical and pathologic staging in the 8th TNM revision in terms of multiple primary tumors and measurement of tumor invasive size.4,5 For the other three major tumor types (large cell carcinoma (LCC), squamous cell carcinoma (SQCC) and neuroendocrine (NE) tumors), the classification has evolved from mainly morphological to a more biologically based system, which allows more appropriate decisions in relation to adjuvant therapy and better defined subgroups for studies into molecular characterization and the search for potentially treatable targets. LCC is now restricted to resected tumors that lack clear morphologic and immunohistochemical differentiation, with reclassification of those that do to solid adenocarcinoma (TTF-1 positive) and non-keratinizing SQCC (P40 and/or CK5/6 positive). This has already been shown to correlate with molecular data.6 For SQCC, classification is simplified to keratinizing, nonkeratinizing and basaloid subtypes, with the non-keratinizing tumors ideally requiring immunohistochemical confirmation. Criteria for diagnosing NE tumors remain essentially unchanged but these tumors are now grouped in one category, with further subdivision into carcinoids, and large cell neuroendocrine carcinoma and small cell carcinoma. Molecular studies based on these definitions are already identifying interesting subgroups.7 In relation to rarer entities, the definition of pleomorphic carcinomas is also being shown to have clinical relevance in terms of correlating with potential therapies, both in relation to specific molecular abnormalities (exon 14 skipping mutations)8 and immunomodulatory therapy with high levels of PD-L1 expression.9 Molecular characterization is also increasingly important in the accurate diagnosis and potential treatment of other rare tumors, such as NUT-carcinoma and inflammatory myofibroblastic tumors (ALK and ROS1/RET gene rearrangements).10 A classification system for small biopsies and cytology is provided for the first time, with emphasis on integration of molecular testing and usage of a limited panel of immunohistochemistry when needed (table 1). The presence of such a system for the first time provides a system for consistent classification of the majority (unresectable) of lung cancer cases, both in terms of clinical management, assignment to pathways for molecular and immunomodulatory characterizations, and for assessment of the results of clinical trials that have sometimes been confounded by inaccurate subgrouping. The book also emphasizes how to obtain the greatest value from small sample via efficient usage and avoidance of inappropriate testing.1Table 1Classification of non-small cell lung carcinoma in small biopsies and cytology specimens when there is no morphologic evidence of differentiation2015 WHO Small Biopsy/Cytology TerminologyMorphology/Stains2015 WHO Classification in resection specimensNon-small cell carcinoma, favor adenocarcinoma using IHCMorphologic adenocarcinoma patterns (lepidic, acinar, papillary, micropapillary) not present, but supported by special stains (+TTF-1)Adenocarcinoma, solid pattern (may only be a component)Non-small cell carcinoma, favor squamous cell carcinoma using IHCMorphologic squamoid features (keratinization and/or clear intercellular bridging) not present, but supported by stains ( +p40)Squamous cell carcinoma, (non-keratinizing pattern may be just one component)Non-small cell carcinoma, not otherwise specified NSCLC-NOS using IHCNo clear adenocarcinoma, squamous or neuroendocrine morphology or staining pattern (IHC or mucin stains).Large cell carcinoma Open table in a new tab 1. WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart. Lyons, France.: International Agency for Research on Cancer (IARC); 2015. 2. Kakinuma R, Noguchi M, Ashizawa K, et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol. Jul 2016;11(7):1012-1028. 3. Tsao MS, Marguet S, Le Teuff G, et al. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol. Oct 20 2015;33(30):3439-3446. 4. Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. Feb 29 2016. 5. Travis WD, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. Aug 2016;11(8):1204-1223. 6. Clinical Lung Cancer Genome P, Network Genomic M. A genomics-based classification of human lung tumors. Sci Transl Med. Oct 30 2013;5(209):209ra153. 7. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clin Cancer Res. Jul 15 2016;22(14):3618-3629. 8. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations. J Thorac Oncol. Sep 2016;11(9):1493-1502. 9. Chang YL, Yang CY, Lin MW, Wu CT, Yang PC. High co-expression of PD-L1 and HIF-1alpha correlates with tumor necrosis in pulmonary pleomorphic carcinoma. Eur J Cancer. Jun 2016;60:125-135. 10. Antonescu CR, Suurmeijer AJ, Zhang L, et al. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. Jul 2015;39(7):957-967. lung cancer, classification, WHO, Adenocarcinoma