Thymoma

Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.

Thymic epithelial tumors (TETs) are a rare and diverse group of neoplasms characterized by distinct molecular signatures. This review delves into the complex molecular networks of TETs, highlighting key aspects such as chromosomal abnormalities, molecular subtypes, aberrant gene mutations and expressions, structural gene rearrangements, and epigenetic changes. Additionally, the influence of the dynamic tumor microenvironment on TET behavior and therapeutic responses is examined. A thorough understanding of these facets elucidates TET pathogenesis, offering avenues for enhancing diagnostic accuracy, refining prognostic assessments, and tailoring targeted therapeutic strategies. Our review underscores the importance of deciphering TETs' unique molecular signatures to advance personalized treatment paradigms and improve patient outcomes. We also discuss future research directions and anticipated challenges in this intriguing field.

BackgroundThymic malignancies represent a heterogeneous group of rare thoracic cancers, which are classified according to the World Health Organization histopathologic classification, that distinguishes thymomas from thymic carcinomas. Data regarding the biology of those tumors are limited in the literature, and the vast majority have been obtained using surgical specimens from early-stage disease. Meanwhile, treatment of advanced, refractory thymic tumors currently relies on chemotherapy, with limited efficacy. Comprehensive genomic profiling (CGP) of advanced, refractory tumors would open some opportunities for innovative treatments.Patients and methodsA total of 90 and 174 consecutive patients with thymoma or thymic carcinoma, respectively, for whom formalin-fixed, paraffin-embedded specimens from recurrent, refractory tumor were sequenced, were included. Sequencing was performed using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >500× for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer.ResultsThymomas featured a low frequency of genomic alterations (average of 1.8/tumor), and low levels of TMB. The genomic alterations identified in more than 10% of cases were in the CDKN2A/B and TP53 genes. Amplification in the NTRK1 gene was found in an unresectable, stage III, type B3 thymoma. Thymic carcinomas featured a significantly higher frequency of alterations at 4.0/tumor (P ConclusionsOur cohort is the largest available so far, reporting on CGP of thymic epithelial tumors in the setting of advanced disease. The identification of clinically relevant genomic alterations in the KIT, PI3K, CDKN2A/B, or NTRK genes provides a strong rationale for potential precision medicine approaches using targeted agents. A subset of thymic carcinomas show high tumor mutation burden, what may be a predictor of efficacy of immune checkpoint inhibitors.

ObjectivesIncreased susceptibility to infections is observed in patients with thymomas. These have been invariably attributed to Good syndrome with hypogammaglobulinemia, but there is noticeable heterogeneity in clinical presentation. We clinically and immunophenotypically characterized the infective susceptibilities encountered in these patients.MethodsOf thymoma patients recruited from Singapore and South Korea, their infection types were correlated against immunological parameters, including IgG, IgM, IgA, CD19+ B cells, and CD4+ T cells, and the presence of neutralizing anti-cytokine autoantibodies using direct ELISA. Lymphocyte subset immunophenotyping was performed. Ascertainment of immune signaling pathway disruption was through serum switch experiments. Respective immune signal outputs were probed using Western blotting.ResultsA total of 15 thymoma patients (median age, 54 years; 13 men [87%]) were clustered into two groups with discernible differences in infective manifestations. In one group, nine patients (60%) had recurrent/severe viral or Pneumocystis jirovecii infections. These patients had low immunoglobulins and CD19+ B cells. The second group of six patients (40%) had difficult-to-treat non-tuberculous mycobacterium (NTM) or invasive bacterial or fungal infections. They had normal immunoglobulins levels and possessed autoantibodies against interleukin (IL-)-12, IL--23, or interferon-alpha (IFN-α), which consisted of anti-IFN-α2 and anti-IFN-ω subtypes. The autoantibodies consisted of a heterogeneous spread across IgG1 to IgG4 subclasses. These anti-IL--12, anti-IL--23, and anti-IFN-α autoantibodies were neutralizing and compromised various phosphorylated-STAT signaling pathways that are critical in host anti-pathogen response.ConclusionsThe dichotomy of infective manifestations (viral/PJP versus NTM/invasive bacteria/fungal) underlies distinct and novel immune susceptibility beyond the classic Good syndrome label in thymoma patients, with implications for different approaches to clinical management.