Clinical and Immunologic Features of Primary Enteric-Type Thymic Adenocarcinomas: A Rare Variant of a Rare Cancer

Primary thymic adenocarcinomas are a rare subtype of thymic carcinoma, which share morphologic and immunohistochemical features with gastrointestinal cancers. The immunologic features of thymic adenocarcinoma remain poorly understood, and optimal treatment strategies have not been established.

In this single-institution retrospective study, we identified seven patients with enteric-type thymic adenocarcinoma. Clinical characteristics, histopathology, and molecular profiles were analyzed. Comprehensive immune profiling was conducted using peripheral blood mononuclear cells (PBMCs) and archival tumor tissue. The PBMC immune profiles were compared with those of non-adenocarcinoma thymic epithelial tumors and with samples obtained from healthy donors.

Enteric-type thymic adenocarcinomas exhibit aggressive clinical behavior and respond poorly to systemic therapy, including immune checkpoint inhibitors. Genomic analyses revealed frequent TP53 mutations, a marker of poor prognosis for thymic epithelial tumors. Immune analyses in PBMCs revealed higher levels of effector T-cell subsets, including CD4⁺ and CD8⁺ T-cell subsets, and lower levels of immunosuppressive cell populations compared with other thymic epithelial tumors. Higher levels of serum analytes related to angiogenesis, cell proliferation, and growth were detected. Tumor immune profiling revealed features of an immune-desert phenotype.

Enteric-type thymic adenocarcinomas are immunologically cold tumors that are enriched in peripheral immune markers reflective of cell proliferation and angiogenesis. The immunologic profile appears distinct from other thymic epithelial tumors and provides a potential explanation for the aggressive nature of this disease. If validated in other studies, these findings can potentially inform the development of optimal systemic therapies for this rare variant of thymic carcinoma.