Molecular Classification of Neuroendocrine Tumors of the Thymus

Abstract

Introduction:The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems.Methods: One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features.Results: Whole-genome sequencing data fell into three clusters: CNI low , CNI int , and CNI high . CNI low and CNI int comprised not only TC and AC, but also six LCNECs. CNI high contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2).Conclusions: TNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a

Thymic Epithelial Tumors as a Model of Networking: Development of a Synergistic Strategy for Clinical and Translational Research Purposes

“…Subsequently, in a pilot study carried out on the egfr microsatellite CA-SSR-1 performed by the first genetic analyzer available in pathology, Thermo Fisher's 3130 genetic analyzer, we were able to show that CA-SSR-1 allelic imbalance with short allele relative prevalence significantly correlated with EGFR 3+ immunohistochemical scores, increased egfr gene copy numbers, and advanced stage with relapsing/metastatic behavior in thymomas (44). More recently, we have established further collaborations with other in-house research units (43) and national (19,42,54) and international institutes (55,56). Thanks to frequent participation in meetings and interfacing with members of the scientific community at major conferences on thymic tumors, as well as holding structured workgroups supported by the scientific society ITMIG, our boundaries have changed and widened.…”

Multidisciplinary treatment of thymic neuroendocrine tumors: surgery remains a key component

“…Additionally, while this disease may display a relatively aggressive tumor biology in comparison to benign thymoma, optimal classification of these tumors has been challenging, resulting in several unique staging systems, and recent investigations to identify biomarkers which may further describe the disease and guide management (16). Given these unique criteria, staging and treatment should be evaluated in the context of all proposed staging models and any available molecular biomarkers which may aid in treatment optimization.…”

Recent advances and conceptual changes in the classification of neuroendocrine tumors of the thymus

“…In stark contrast to thymomas, TNET have a high propensity for regional lymph node metastases and > 50% of patients show involvement of regional lymph nodes at diagnosis [38]. The histological subtype is prognostically relevant: 5-year survival rates decrease from 50-70% in TC and AC [8,22,30,32] to 30-66% in LCNEC [3-5, 9, 20, 24, 25, 29, 32, 36] and to 0% (median survival 13-26 months) in SCC [17,23,32,36,39]. The significant variation of published survival data in LCNEC is remarkable and points to a marked heterogeneity of the tumors analyzed.…”

“…There are few published data on genomic features of TNET [8,21,27,32] and virtually no data on the mutational spectrum of these tumors. One of the largest studies to date [32] using comparative whole-genome hybridization (CGH) found an incremental increase of genomic alterations from TC to AC and LCNEC/SCC that correlated with survival.…”