W orld Health Organization (WHO) Classifications of Tumors have historically provided a global standard for tumor diagnosis. Familiarity with these classifications is essential for clinicians because they provide the foundation for accurate patient diagnosis and optimal medical management. In addition, the diagnostic terminology and criteria recommended by the WHO should be incorporated into study design of clinical trials and molecular studies such as The Cancer Genome Atlas (TCGA). WHO Classifications are periodically updated to incorporate important advances to make them relevant to current knowledge and clinical practice. The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published 1 and the Journal of Thoracic Oncology will be publishing a series of articles summarizing key points about the new classification outlining the major changes from the 2004 classification. 2-4 † The International Association for Research on Cancer (IARC) under the leadership of Dr. Hiroko Ohgaki coordinated this project and was the publisher of this book. IARC hosted a consensus meeting in Lyon, France, April 24-26, 2014, where all major changes in the classification from the 2004 book were discussed and approved (Figure).The 2015 WHO Classification features the incorporation of many exciting new advances in thoracic tumor diagnosis and classification. It was formulated by a multidisciplinary group of international experts with broad international representation.The primary changes in the lung classification, which are highlighted in the first paper in this series, 3 relate to lung cancer where over the past decade remarkable progress in genetics and therapy has had a major impact on tumor classification. These most significant changes are consequent to the 2011 IASLC/ATS/ERS Classification 5 including recommendations for routine molecular testing and use of immunohistochemistry, a new approach to small biopsies and cytology and a novel way of subtyping of surgically resected lung adenocarcinomas that has provided a powerful new tool for identifying prognostic and molecular correlations. Large scale genomic studies from the TCGA 6,7 and Clinical Lung Cancer Genome Project 8 provided a strong genetic foundation for reclassification of squamous cell carcinoma, adenocarcinoma and large cell carcinoma. These changes have major clinical relevance as histologic type and genetics are now driving personalized medicine for lung cancer patients. New concepts in adenocarcinoma classification with lepidic versus invasive patterns are also having an impact on the approach to tumor size measurement for TNM staging of small tumors ≤3cm and therefore the surgical management of patients. Support from the IASLC, through their Pathology Committee and by providing multidisciplinary input, contributed greatly to the development of this classification. 5,9

Introduction Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. Methods An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive o...

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.