10615 Background: LS is a hereditary cancer syndrome that increases risk for gastrointestinal, gynecologic, genitourinary, and other cancers, and is typically characterized by microsatellite instability (MSI-H), mismatch repair-deficiency (MMR-D), and high tumor mutational burden (TMB). TETs, including thymomas and thymic carcinomas, are rare neoplasms not known to be associated with LS and usually show low TMB and microsatellite-stable (MSS) biology. We sought to describe the clinical, pathologic, and molecular characteristics of TETs diagnosed in individuals with LS seen at our institution. Methods: We conducted a retrospective, single-institution study to identify TETs among individuals with LS. We queried all LS patients seen in the DFCI Cancer Genetics and Prevention program from 1990 (n = 1, 386) and identified those with a TET. We also reviewed TET cases that had paired tumor–germline sequencing between July 2023 and September 2025 (n = 12) to identify additional cases with LS pathogenic germline variants (PGVs). Clinical and molecular data, including MMR immunohistochemistry (IHC), and tumor and germline sequencing reports, were abstracted from the medical record. Results: Of the 1, 398 cases reviewed, 4 females were identified with TETs (1 thymoma and 3 thymic carcinomas) diagnosed at a median age of 54. 0 years (range 23-70 years), all with a confirmed PGV in an MMR gene Table 1. All four cases had tumor characteristics consistent with MMR-D. Two TETs were MMR-D by IHC, and one TET had biallelic MLH1 variants on somatic testing, so MMR-D is inferred. Three TET cases were MSI-H by next generation sequencing, and one was MSS, despite being MMR-D by IHC. Three cases had high TMB and one did not have TMB assessment. One patient received neoadjuvant chemotherapy for two cycles, with the addition of pembrolizumab after discovering the tumor’s MSI-H status; this patient had a pathological complete response at surgery. One patient received neoadjuvant chemotherapy, surgery, and adjuvant proton beam radiation; another received neoadjuvant chemoradiotherapy followed by surgery. The fourth underwent resection and plans adjuvant therapy. All four are alive at a median of 34. 8 months post-surgery (range 3. 6-60. 7 months). Conclusions: Our data show that TETs in patients with LS frequently demonstrate molecular biology (MMR-D, MSI-H, TMB-H) like other classic LS-associated cancers, suggesting that these may be rare manifestations of LS. Further clarifying the link between LS and TETs may have important implications for treatments. Age at diagnosis Sex Histologic subgroup TMB (mut/Mb) Microsatellite status MMR status PGV 53 F Thymoma 30. 4 MSI-H MMR-D MLH1 c. 116+2T>G 70 F Thymic squamous cell carcinoma 18. 25 MSI-H NA MSH6 5’UTREX6del 23 F Poorly differentiated carcinoma, favor thymic origin 14. 48 MSI-H MMR-D MSH2 c. 1906G>C 55 F Thymic carcinoma NA MSS MMR-D PMS2 c. 2137C>T
Dwyer et al. (Wed,) studied this question.