Molecular pathology of thymomas: implications for diagnosis and therapy

Abstract

Thymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I gene in WHO type A and AB thymomas (and rarely others); almost unique KMT2A-MAML2 translocations in rare WHO type B2 and B3 thymomas; a unique YAP1-MAML2 translocation in almost all metaplastic thymomas; and unique miRNA profiles in relation to GTF2I mutational status and WHO histotypes. While most thymomas can be diagnosed solely on the basis of morphological features, mutational analyses can solve challenging differential diagnostic problems. No molecular biomarkers have been identified that predict the response of unresectable thymomas to chemotherapy or agents with known molecular targets. Despite the common and strong expression of PDL1 in thymomas, immune checkpoint inhibitors are rarely applicable due to the poor predictability of common, life-threatening autoimmune side effects that are related to the unrivaled propensity of thymomas towards autoimmunity.

Keywords: AIRE; Immune checkpoint inhibitors; MicroRNA; Microsatellite instability; Myasthenia gravis; SMARCA4.

Fig. 1

Microsatellite instability in thymoma. a Type B3 thymoma with anaplasia; b Presence of TdT expressing immature T cells; c Absence of CD117 expression; d Defective expression of MLH1 in tumor cells but not in accompanying lymphocytes. HE stain in (a); immunoperoxidase in b–d. (×200)

Fig. 2

Metaplastic thymoma with recently described YAP1-MAML2 translocation. a Biphasic, epithelioid and spindle cell tumor; b Characteristic expression of p40 in the epithelioid but not the metaplastic/spindle cell component; c FISH analysis showing the split of the MAML2 break-apart probe (a HE stain, × 200; b immunoperoxidase, ×200; c immunofluorescence, ×400)

Fig. 3

SMARCA4-deficient thoracic tumor; core needle biopsy of a mediastinal mass involving the lung (or vice versa). a Partially necrotic, undifferentiated tumor composed of large, poorly cohesive round and polygonal cells with large nuclei and prominent nucleoli; b Absence of SMARCA4 expression in the tumor cells, strong expression of SMARCA4 in endothelial cells. An identical staining pattern was seen with an antibody to SMARCA2 (not shown) (a HE stain, ×350; b immunoperoxidase)

Fig. 4

Integrated genomic landscape of thymomas and thymic carcinomas according to The Cancer Genome Atlas analysis (modified from Radovich et al. [10]). Cohorts comprise samples that are placed in the map according to similarities in their genomic profiles using all molecular platforms. The substantial overlap between the A-like and AB-like cohort indicates that quite some WHO type A and AB thymomas occur in either cohort, suggesting a molecular continuum. Little overlap between the B-like and the AB-like cohorts; of ten thymic carcinomas, one case with unique molecular features (including lack of the typical loss of 16q) was “misplaced” in the AB-like cluster. A selection of key differentially expressed molecular features is listed with each cluster. C19MC denotes a large micro-RNA cluster on chromosome 19q13.42