Characteristics of Genomic Mutations and Signaling Pathway Alterations in Thymic Epithelial Tumors

Purpose: To elucidate mechanisms of thymic epithelial tumor (TET) canceration through characterization of genomic mutations and signal pathway alterations.Methods: Primary tumor and blood samples were collected from 21 patients diagnosed with TETs (thymoma and thymic cancer), 15 of whom were screened by nucleic acid extraction and total exon sequencing. Bioinformatics was used to comprehensively analyze sequencing data for these samples, including differences in tumor mutation burden (TMB) and signaling pathways.Results: We found that the gene with the highest mutation frequency in thymic carcinoma was ZNF429 (36%). In addition, mutations in BAP1 (14%), ABI1 (7%), BCL9L (7%), CHEK2 (7%) were only detected in thymic carcinoma, whereas ZNF721 mutations (7%) were found only in thymoma. Mean TMB values for thymic carcinoma and thymoma groups were 0.722 and 0.663 mutations per megabase (Mb), respectively, differences that were not statistically significant. There were significant differences in enriched pathways for cellular components between tumor metastasis and non-metastatic samples. The ErbB signaling pathway was enriched in both the thymoma group and the intersection group, whereas “pathways in cancer” was found in both the thymoma group and thymic cancer group. In contrast, enrichment of longevity-regulating and MAPK signaling pathways was found only in the thymoma group.Conclusions: We identified multiple differences in somatic genes and pathways, providing insights into differences between thymoma and thymic carcinoma that could aid in designing personalized clinical therapy.

Clinical Utility of Striational Antibodies in Paraneoplastic and Myasthenia Gravis Paraneoplastic Panels

Objective:To critically assess the clinical utility of striational antibodies (StrAbs) within paraneoplastic and myasthenia gravis serological evaluations.Methods:All Mayo Clinic patients tested for StrAbs from January 1st 2012-December 31st 2018 utilizing Mayo’s Unified Data Platform (UDP) were reviewed for neurological diagnosis and cancer.Results:38,502 unique paraneoplastic and 1,899 MG patients were tested. In paraneoplastic evaluations, the StrAbs positivity rate was higher in cancer vs without cancer (5% [321/6775] vs 4% [1154/31727]; p<0.0001; OR 1.35; CI=1.19-1.53) but ROC analysis indicated no diagnostic accuracy in cancer (AUC=0.505). No neurological phenotype was significantly associated with StrAbs in the paraneoplastic group. Positivity was more common in all MG cancers compared to paraneoplastic cancers (p<0.0001). In MG evaluations, the StrAbs positivity rate was higher in those with cancer vs without (46% [217/474] vs 26% [372/1425]; p<0.0001; OR 2.39, CI 1.9-2.96) with ROC analysis indicating poor diagnostic accuracy for thymic cancer (AUC 0.634, recommended cutoff=1:60, sensitivity=56%, specificity=71%), with worse accuracy for extrathymic cancers (AUC 0.543). In paraneoplastic or MG evaluations, the value of antibody positivity did not improve cancer predictions. Paraneoplastic evaluated patients were more likely with positive StrAbs to obtain computed tomography (CT) (p=0.0001) with 3% (12/468) cancer found.Conclusion:Despite a statistically significant association with cancer, an expansive review of performance in clinical service demonstrates that StrAbs are neither specific nor sensitive in predicting malignancy or neurological phenotypes. CT imaging is over utilized with positive StrAbs results. Removal of StrAbs from paraneoplastic or MG evaluations will improve the diagnostic characteristics of the current MG test.Classification of Evidence:This study provides Class II evidence that the presence of StrAbs do not accurately identify patients with malignancy or neurological phenotypes.

Asymptomatic brainstem lesions and pachymeningeal enhancement after anti-PD-1 therapy

Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint inhibitor therapy. We propose that patients with thymic malignancies and graft-versus-host disease (GVHD) are predisposed to irAEs. We present two asymptomatic patients, one with thymoma and another with GVHD, who developed abnormal brain MRIs after treatment with programmed cell death protein 1 inhibitors. The first patient, with thymic cancer and thymoma, developed pontine enhancing MRI lesions following treatment with pembrolizumab. The second patient, with prior GVHD, developed pachymeningeal enhancement following treatment with nivolumab. IrAEs with abnormal MRI studies, despite asymptomatology, have significant impact on the treatment strategy for these patients.