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Comparative Morphologic and Molecular Classification of Neuroendocrine Tumors of the Thymus in Humans

Helen Dinter
Doctoral thesis
Date of Examination: 2021-04-28
Date of issue: 2021-04-30
Advisor: Ströbel, Philipp Prof. Dr.
Referee: Ströbel, Philipp Prof. Dr.
Referee: Ellenrieder, Volker Prof. Dr.
Referee: Schön, Margarete Prof. Dr.
Referee: Schön, Margarete Prof. Dr.

Persistent Address: http://hdl.handle.net/21.11130/00-1735-0000-0008-580B-A

 

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Abstract

English

Neuroendocrine tumors (NET) of the thymus are rare neoplasms that share many similarities with their pulmonary counterpart. The WHO 2015 classification of thymic and pulmonary NET divides tumors into typical and atypical carcinoids (TC, AC) and large cell and small cell neuroendocrine carcinoma (LCNEC, SCC). The classification is based on histomorphology: mitotic rate and necrosis. In comparison, the ENETS classification of gastro-intestinal and pancreatic NET includes a fifth subgroup NET G3 and is additionally based on the ki67 labeling index. Little is known about prognostic markers and the molecular background of TNET. With low coverage whole genome sequencing and immunohistochemistry, our goal was to achieve a better understanding of subgroup specific characteristics and their prognostic importance. The study revealed that TNET fall into three molecular clusters and that there is evidence of NET G3 in the thymus. Low- and intermediate-grade molecular categories are comprised of TC, AC and even LCNEC. High-grade molecular categories contain AC, LCNEC and SCC. Morphology alone is not sufficient in recreating these categories.  EZH2 and chromogranin A immunohistochemistry can help differentiate not only NET G3 from the classic LCNEC, but also function as a marker for genomic instability for all subgroups. Additionally, this study found that morphologic and molecular progression in TNET is possible. Further investigations will be crucial to discover if there is evidence of NET G3 in the pulmonary NET and use these findings for treatment planning and risk stratification. 
Keywords: neuroendocrine tumors of the thymus, TNET, pathology, EZH2, chromogranin A
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