Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline genetic mutations that impair DNA mismatch repair. It is most commonly associated with colorectal and endometrial malignancies. Less often, gastric, urothelial, small bowel, ovarian, brain, and hepatobiliary cancers occur. Reports of sarcoma in LS are rare. Tracheal chondrosarcoma is an extremely rare head and neck cancer (~35 cases reported) with no known association to LS.

Case Presentation: A 63-year-old male presented to the emergency room with new onset dysphonia and a slowly growing neck mass. Imaging revealed a 7 cm left tracheal mass invading the left hemithyroid, bilateral cervical lymphadenopathy, and no distant metastasis. Biopsy of the primary mass showed a low grade chondroid neoplasm. He underwent hemithyroidectomy and resection of tracheal rings 2-5. Intraoperative frozen pathology evaluation of the lateral neck lymph nodes showed low grade chondroid neoplasm, so bilateral neck dissection was performed and the remaining thyroid lobe was left in vivo. The patient was placed in an extension limiting brace and he recovered well from surgery. Pathology confirmed grade 2/3 chondrosarcoma involving 8/44 lymph nodes in the right, central, and left neck spaces. Given the intermediate grade of the tumor, the recommendation was to proceed with postoperative radiation. Immunohistochemical staining showed loss of nuclear MSH2 and MSH6 expression. Molecular profiling confirmed somatic MSH6 frameshift and likely pathogenic germline MSH2 mutations consistent with LS. There were no other known cases of sarcoma in his family pedigree upon further questioning. His father had colon cancer (around age 50), sister had uterine cancer (age 66), paternal aunt had breast cancer (age 70), and his sister and maternal aunt also had cancer (primary unknown).

Conclusion: Tracheal chondrosarcoma has never been reported in conjunction with LS (or MSH2 mutation) in the literature, though osteosarcomas and soft tissue sarcomas occur at a slightly higher incidence in pathogenic MSH2 carriers. We report the first case of LS-associated tracheal chondrosarcoma, associated with a double hit of somatic MSH6 and germline MSH2 mutations. Implications include potential benefit from immunotherapy, need for specialized cancer screening, and genetic counseling for family members. Mismatch repair testing can be an important part of a complete workup in cancers not typically associated with LS, especially in patients with a family history of LS associated cancers.