Deciphering the biology of thymic epithelial tumors

Abstract

Thymic cancers arise from epithelial cells of the thymus and have a predilection for intrathoracic spread. Clinical behavior varies from relatively indolent to highly aggressive with a capacity to metastasize widely and adversely affect survival. Paraneoplastic autoimmune disorders are frequently observed in association with thymoma and have a significant impact on quality of life. Underlying immune deficits associated with thymic epithelial tumors (TETs) increase the risk for development of opportunistic infections and emergence of extrathymic malignancies. Advances in the molecular characterization of thymic tumors have revealed the lowest tumor mutation burden among all adult cancers and the occurrence of distinct molecular subtypes of these diseases. Mutations in general transcription factor IIi (GTF2I) are unique to TETs and are rarely observed in other malignancies. The infrequency of actionable mutations has created obstacles for the development of biologic therapies and has spurred research to uncover druggable genomic targets. Persistence of autoreactive T cells due to altered thymic function increases the risk for development of severe immune-related toxicity and limits opportunities for use of immune-based therapies, especially in patients with thymoma. In this paper we review emerging data on the molecular characterization and immunobiology of thymic tumors and highlight clinical implications of these discoveries.

Molecular pathology of thymomas: implications for diagnosis and therapy

“…The results of the TCGA study of thymic epithelial tumors (Table 1) confirmed previous studies that revealed absence of targetable mutations as tissue-based biomarkers in thymomas (reviewed in [1,2]) and presence of only rare clinically meaningful mutations (e.g., of the KIT gene) in TCs [64]. In line with this, "targeted" approaches that took transcriptomic or immunohistochemical findings (e.g., overexpression of supposedly unmutated genes coding for tyrosine kinases or TETs, thymic epithelial tumors; (-), 0%; n.k., not known; n.t., not tested angiogenic factors) into account achieved rather limited success (Table 2).…”

“…Since thymomas are the cancers with the highest prevalence of abundant and strongly PDL1-expressing tumor cells [19], thymoma patients appear as ideal candidates for immunotherapies. Unfortunately, immune checkpoint inhibitors (ICIs) elicit severe autoimmune phenomena in most thymoma patients even if such phenomena are missing before therapy [2,20]. Echoing the focus of thymoma-associated autoimmunity on striated muscle, the most life-threatening side effects of ICIs in thymoma patients are myositis, myocarditis, and MG [21][22][23].…”

“…Echoing the focus of thymoma-associated autoimmunity on striated muscle, the most life-threatening side effects of ICIs in thymoma patients are myositis, myocarditis, and MG [21][22][23]. In patients with TCs that are not "naturally" prone to autoimmunity, such side effects are less common [2,24,25].…”

“…Another large cluster on chromosome 14 (C14MC), supposedly with tumor suppressor function, is transcriptionally silenced in many TCs [56]. In addition, various non-clustered single miRNAs are differentially expressed between thymomas and TCs [56,57] and thought to contribute to the tumorigenesis of TCs (reviewed in [2]). So far, miRNAs do not play a role as diagnostic or therapeutic targets, and, unlike in renal cancers [58], have not been evaluated as predictive biomarkers (e.g., for sunitinib resistance).…”

“…Thymomas constitute the largest subgroup (75-80%) among thymic epithelial tumors (TETs) and are the focus of this review. Thymic carcinomas (TCs) and thymic neuroendocrine tumors that constitute 10-20% and 1-2% of TETs, respectively, are reviewed elsewhere (Ströbel et al, this volume and in [1,2]). Taking the content of immature thymocytes and the morphology of tumor cells into account, TCs are distinguished from thymomas which, in turn, are separated into WHO type A, AB, B1, B2, B3,and metaplastic thymomas as well as "micronodular thymoma with lymphoid stroma" (MNT) [3].…”