EZH2 and POU2F3 Can Aid in the Distinction of Thymic Carcinoma from Thymoma

Abstract

Thymic carcinoma is an aggressive malignancy that can be challenging to distinguish from thymoma using histomorphology. We assessed two emerging markers for these entities, EZH2 and POU2F3, and compared them with conventional immunostains. Whole slide sections of 37 thymic carcinomas, 23 type A thymomas, 13 type B3 thymomas, and 8 micronodular thymomas with lymphoid stroma (MNTLS) were immunostained for EZH2, POU2F3, CD117, CD5, TdT, BAP1, and MTAP. POU2F3 (≥10% hotspot staining), CD117, and CD5 showed 100% specificity for thymic carcinoma versus thymoma with 51%, 86%, and 35% sensitivity, respectively, for thymic carcinoma. All POU2F3 positive cases were also positive for CD117. All thymic carcinomas showed >10% EZH2 staining. EZH2 (≥80% staining) had a sensitivity of 81% for thymic carcinoma and a specificity of 100% for thymic carcinoma versus type A thymoma and MNTLS but had poor specificity (46%) for thymic carcinoma versus B3 thymoma. Adding EZH2 to a panel of CD117, TdT, BAP1, and MTAP increased cases with informative results from 67/81 (83%) to 77/81 (95%). Overall, absent EZH2 staining may be useful for excluding thymic carcinoma, diffuse EZH2 staining may help to exclude type A thymoma and MNTLS, and ≥10% POU2F3 staining has excellent specificity for thymic carcinoma versus thymoma.

Histogenetic and disease‐relevant phenotypes in thymic epithelial tumors (TETs): The potential significance for future TET classification

“…In addition, it is hypothesized that thymic SQCC might be divided into tuft cell‐like (or POU2F3(+) or medullary‐type) and non‐tuft‐cell‐like (or POU2F3(−) or non‐medullary‐type) 60 . A recent study has confirmed our result of POU2F3 expression in the majority of thymic SQCC 131 . As a next step, retrospective studies with a large cohort to determine the clinical differences between the two groups are warranted to consider incorporating tuft cell‐like phenotype into the TET classification.…”

Thymic Carcinoma: Unraveling Neuroendocrine Differentiation and Epithelial Cell Identity Loss

“…The most classical and reliable markers for thymic SQCC are KIT and CD5 [ 10 , 25 , 26 , 27 , 45 ]. The strong correlation between KIT expression and the tuft cell lineage [ 19 , 20 , 29 ], along with the observation that CD5 expression was relatively confined to the neuroendocrine group [as previously described [ 7 ] and confirmed even in adult TECs alone (shown later)], suggested that CD5 expression might be associated with specific transcription factors related to neuroendocrine lineages.…”

Pathological snapshots of thymic epithelial tumors with invasion into neighboring structures: preparing for the forthcoming revision of the TNM classification

“…As a part of these studies, our group has demonstrated that, compared to thymomas, thymic carcinomas significantly highly express genes/proteins related to tuft cells, which are unique epithelial cells involving type 2 immunity and that were recently found to exist in the thymus as a subset of mTECs ( 23 , 24 ). Immunohistochemically, POU2F3, the master regulator of tuft cells ( 25 ), is significantly more expressed in thymic carcinoma ( Figure 4A ) than in thymomas, including epithelial rich, type B3 thymoma ( 16 , 17 , 21 ). POU2F3 expression is highly correlated with that of KIT proto-oncogene, receptor tyrosine kinase (KIT) ( Figure 4B ), a representative marker of thymic carcinomas ( 6 , 16 ).…”

“…These findings could represent a paradigm shift in the histogenesis of thymic carcinomas, considering that they were historically regarded as tumors lacking the physiological properties of TECs. We applaud the renewed trend toward focusing on the histogenesis of TETs ( 26 , 27 ), and it may have value for diagnostic purposes as well ( 21 ). However, careful interpretations will be needed when inconsistent results are obtained among different studies.…”