Metastatic mismatch repair deficient oesophageal squamous cell carcinoma leading to diagnosis of Lynch syndrome with a complete response to nivolumab treatment

A 59-year-old woman with two colorectal adenocarcinomas in 2015 and 2022 (both with loss of MSH2 and focal presence of MSH6 protein, thus MMR-deficient profile) had a variant of c.1012G > C p.(Gly338Arg) in the MSH2 gene, classified as Variant of Uncertain Significance (VUS) in 2023. That year, she was also diagnosed with oesophageal squamous cell carcinoma (ESCC), again MMR-deficient. Although uncommon, a proportion of ESCC can be MMR-deficient. The ESCC showed complete response to nivolumab. Genetic studies of the three tumours showed the same germline variant. During follow-up, the tumour board requested a reclassification of the VUS due to suspected Lynch syndrome. This time the genetic variant was classified as likely pathogenic, confirming Lynch syndrome in May 2025. This case highlights the importance of additional MMR profile evaluation in patients with multiple tumours, even if tumour types are unusual. Such evaluation may improve individual treatment and classification of syndrome-associated tumours.