ED07.02 The 2015 WHO Classification of Neuroendocrine Tumors

Abstract

France Neuroendocrine lung tumors were considered as separate entities in the previous WHO classification 2004: the carcinoid tumors, small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) were grouped separately. However, in the current WHO 2015 classification, they are grouped together.1 They are listed in the order of their frequency with SCLC first as it is the most common. SCLC (15% of lung tumors) is a malignant epithelial tumor which consist of densely packed small cells with scant cytoplasm, finely dispersed granular chromatin and absent or inconspicuous nucleoli. In contrast LCNEC is made of large cells and should show both neuroendocrine morphology (rosettes, palisades) and immunohistochemical neuroendocrine markers (at least one). Both SCLC and LCNEC can be pure or combined with NSCLC components but keep their diagnostic priority (SCLC-or LCNEC- combined). Carcinoid tumors are neuroendocrine malignancies accounting for <1% of all lung cancer, divided in two categories with highly different frequencies, the typical and atypical carcinoid, the last being extremely rare. Typical carcinoids are carcinoid tumors with <2mm2 and lacking necrosis. They measure ≥0.5 cm in size. Atypical carcinoids are carcinoid tumors with 2-10 mitoses per 2mm2 and/or foci of necrosis. Despite the grouping of these tumors together, it is clear that the carcinoids have major clinical, epidemiologic, histologic and genetic differences compared to the high grade SCLC and LCNEC. Carcinoid patients are significantly younger, have a better prognosis and lack the strong association with smoking that applies for SCLC and LCNEC. Also compared to carcinoid tumors, SCLC and LCNEC have much higher mitotic rates (more than 11 per 2mm2), more necrosis and can show combinations with other lung cancer types including adenocarcinoma or squamous cell carcinoma, which testify of a common progenitor cell derivation, not shared by carcinoid which is never mixed with a non-neuroendocrine (NE) tumor type. Carcinoid tumors also have very few genetic abnormalities compared to SCLC and LCNEC which show the highest rate of mutations per megabase among all cancer.3,4,5 While in many cases, SCLC and carcinoid tumors can be diagnosed on good quality tumor material with a high quality H&E stained section and in well preserved cytological samples, immunohistochemistry (IH)/neuroendocrine markers can be very helpful in diagnosing pulmonary NE tumors especially in small biopsies with crushed artefact. Endocrine morphology and neuroendocrine IH markers are both required for the diagnosis of LCNEC. The cases with one missing (endocrine morphology or NE markers) are considered as large cell carcinoma in the absence of other differentiation marker on resection specimens, and as non-small cell lung carcinoma on small samples (cytology or biopsy) Mitotic counts are still retained to differentiate typical carcinoids (less than 2 mitoses per mm2) from atypical carcinoids (2 to 10 per 2mm2) and from high grade NE tumors SCLC and LCNEC (more than 11 mitoses per 2 mm2 for being more reproducible than KI-67 evaluation. The role of Ki-67 is mainly to separate the high grade SCLC (more than 50%) and LCNEC (more than 40%) from the carcinoid tumors (from 1 to 15%) especially in small biopsies with crushed and/or necrotic tumor cells. It is recommended to avoid the diagnosis of SCLC or LCNEC for tumors with less than 50% and 40% MIB1/KI67 index respectively. Data are conflicting regarding the use of KI-67 in separating typical from atypical carcinoid tumors, so it is not recommended in this setting. Careful counting of mitoses is essential as it is the most important histologic criteria for separating typical from atypical carcinoid and the carcinoids from the high grade SCLC and LCNEC. Due to recognition of the potential overlap in the morphology of LCNEC and basaloid squamous cell carcinoma, it can be helpful to confirm negative squamous markers (i.e. p40) in TTF-1 negative tumors that otherwise meet criteria for LCNEC. Many recent progress have been made on the comprehensive genomic profiles of SCLC3,4 LCNEC5 and carcinoids.6 Although sharing NE features, these 3 tumors group show substantial and significant differences. Recent comprehensive genomic analyses have established the genomic profile of SCLC.3,6 Their unique and remarkable characteristic is the universal bi-allelic alteration of both TP53 and RB1 gene (100% for P53 and 93% for RB1) by different alterations of each of the 4 alleles: non synonymous mutations, damaging mutations by complex genomic rearrangements. Locally clustered mutations, indicative of functional selection, occurred on CREBBP (15%) and EP300 (13%) genes, inactivating their histone acetylase functions. Notch family genes inactivating their protein functions occurred in 25% of SCLC.4 Notch is considered as a master regulator of NE differentiation. LCNEC genomics share characteristic features with SCLC for a part of LCNEC (SCLC-like LCNEC) or with AD /SQC for another part (about 25%). Mutations pattern and frequency of combined cases imply a considerable plasticity of theses tumors which might represent an evolutionary trunk branching SCLC to NSCLC. Carcinoid is a unique example of a tumor driven entirely by chromatin modifiers and remodeling genes, which are not mutant in SCLC. In summary, 51% of carcinoid carried mutations in chromatin remodeling genes. In addition, the eukaryotic translation initiation factor (EIF1AX) was mutated in 9% of cases, genes of the E3 ubiquitin ligases system were mutated or rearranged in 18%. Altogether 73% of carcinoids have driver genes that are candidates for targeted therapy.6 New evidence is provided that carcinoid is not an early progenitor of high grade NE tumors SCLC and LCNEC. 1. Travis WD, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of the Tumors of the Lung, Pleura, Thymus and Heart. 4th Edition. Lyon: IARC Press; 2015. 2. Clinical Lung Cancer Genome Project (CLCGP), Network Genomic Medicine (NGM). A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. http://dx.doi.org/10.1126/scitranslmed.3006802. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44(10):1104-1110. http://dx.doi.org/10.1038/ng.2396. 4. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53. http://dx.doi.org/10.1038/nature14664. 5. Fernandez-Cuesta L, Peifer M, George J, et al. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors. J Thorac Oncol. 2015;10(9 - WCLC 2015 Abstracts: PDF Only):S185. http://dx.doi.org/10.1097/01.JTO.0000473439.77589.a7. 6. Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518. http://dx.doi.org/10.1038/ncomms4518. Neuroendocrine tumors, lung cancer, Pathology, genetic