Lynch syndrome, also called hereditary nonpolyposis colorectal cancer, is among the most common hereditary cancer syndromes, accounting for roughly 1 to 3 percent of all colorectal cancers, according to background cited in the report. The carrier frequency of pathogenic Lynch syndrome variants in the general population is estimated at about 1 in 300. The syndrome arises from germline mutations in DNA mismatch repair genes, which trigger genomic instability and raise the risk of malignancies across multiple organs. Among the core mismatch repair proteins, MLH1 carries the highest mutation frequency, while pathogenic variants in MSH2 are associated with the heaviest tumor burden and the broadest tumor spectrum. Tumors arising in Lynch syndrome are typically characterized by high microsatellite instability and loss of mismatch repair protein expression.

The patient’s medical history began in June 2015, when she underwent surgical resection for colon cancer. Postoperative pathology revealed moderately differentiated adenocarcinoma with mucinous components arising from the transverse colon, invading the serosal layer of the intestinal wall. Metastatic carcinoma was found in 2 of 21 pericolonic lymph nodes, and the disease was staged as stage III (T3N1M0). She received eight cycles of adjuvant FOLFOX chemotherapy. In December 2015, malignant transformation of endometrial polyps was detected, and hysteroscopic resection was performed. Pathological examination combined with immunohistochemistry suggested poorly differentiated adenocarcinoma. Because the tissue fragments lacked identifiable adjacent anatomical structures, repeat hysteroscopy, pelvic ultrasound, and external pathological consultation were recommended to clarify the primary lesion.

On December 21, 2015, the patient underwent total hysterectomy with bilateral adnexectomy, and no residual carcinoma was found on final postoperative pathology. The diagnosis of primary endometrial carcinoma, estimated at stage IA, rested on the metachronous clinical timeline, an immunohistochemical profile distinct from her colorectal tumor, and external pathological consultation. The authors note that retrospective mismatch repair immunohistochemistry and microsatellite instability testing of the two earlier tumors could not be performed, because the archival pathological specimens were unavailable. This gap means the molecular features of the colon and endometrial cancers remain undocumented, a limitation the authors acknowledge explicitly.

Between the second and third malignancies, the patient developed several non-cancerous conditions. She was diagnosed with hypertension in 2021, with a maximum recorded systolic blood pressure of 150 mmHg, controlled by regular oral amlodipine besylate 2.5 mg once daily. Cerebral thrombosis was detected in 2023, from which she recovered after symptomatic treatment without obvious sequelae, and hyperuricemia was identified during a physical examination the same year. In April 2026, an elevated CA19-9 tumor marker was detected during a routine physical examination following her earlier colectomy, prompting the imaging work-up that would uncover the third malignancy.

Abdominal computed tomography and magnetic resonance imaging revealed a mass in the distal common bile duct and suspected malignant transformation of an intraductal papillary mucinous neoplasm in the pancreatic uncinate process, together with biliary dilatation; hepatic metastasis could not be excluded on initial imaging. Positron emission tomography-computed tomography identified hypermetabolic malignant lesions involving the distal common bile duct and the duodenal papilla, without definite distant metastatic foci. Endoscopic biopsy of the duodenal papilla demonstrated high-grade intraepithelial neoplasia with focal adenocarcinoma. The multidisciplinary team evaluated an equivocal hepatic lesion as benign, and the ampullary carcinoma was staged clinically as T2N1M0. The authors note that an ampullary origin was favored over distal bile duct carcinoma or pancreatic carcinoma, but minor diagnostic uncertainty remained because of the anatomical adjacency of these structures.

Molecular profiling of the ampullary tumor produced a striking and uncommon discrepancy. Mismatch repair immunohistochemistry showed heterogeneous protein expression, with MLH1 and PMS2 positive and MSH2 and MSH6 only partially weakly positive; because none of the four proteins showed complete loss of expression in tumor nuclei, the result was interpreted as proficient mismatch repair. Yet next-generation sequencing covering multiple microsatellite loci, with 30 percent or more unstable loci defined as high microsatellite instability, confirmed MSI-H status in a specimen with tumor cellularity above 60 percent. The authors propose several possible explanations: spatial tumor heterogeneity leading to sampling differences, a somatic MSH2 c.1759+1G>A splice-site variant that may cause abnormal splicing and functional inactivation while retaining partial antibody epitopes, and inherent technical differences between protein-level and genomic-level assays. The coexistence of a germline frameshift variant and a somatic splice-site variant strongly suggests biallelic inactivation of MSH2, although the authors state this cannot be definitively confirmed by genetic data alone. Their conclusion is practical: microsatellite instability testing should be recommended for patients with clinically suspected Lynch syndrome even when mismatch repair immunohistochemistry appears proficient.

Germline testing on genomic DNA from peripheral blood leukocytes identified the pathogenic MSH2 c.687delA, p.A230Lfs*16 variant, confirming the Lynch syndrome diagnosis. The frameshift arises from deletion of a gene fragment that shifts the reading frame and introduces a premature stop codon, truncating the protein. The tumor also carried multiple somatic variants, including KRAS p.V14I, KRAS p.A59T, GNAS and TP53 alterations, alongside high microsatellite instability and a high tumor mutational burden of 59.75 mutations per megabase, ranking in the top 2 percent among cholangiocarcinoma cases. PD-L1 expression was negative, with a tumor proportion score below 1 and a combined positive score below 1. According to the patient’s own report, her nephew has also been diagnosed with Lynch syndrome by genetic testing, but the authors stress that this diagnosis and his exact genotype could not be verified from available medical records, so the information cannot be used to confirm familial transmission of this specific variant.

Treatment planning for the ampullary carcinoma reflected both the molecular profile and the patient’s overall condition. After multidisciplinary discussion, dual immunotherapy with nivolumab plus ipilimumab at 1 mg/kg was planned as proposed first-line systemic treatment for unresectable advanced disease. The stated rationale included the molecular basis provided by MSI-H status and high tumor mutational burden, reported superior response rates of dual over single-agent checkpoint inhibition in MSI-H gastrointestinal malignancies, and the limited activity of conventional chemotherapy in MSI-H tumors. However, the patient’s bilirubin and transaminase levels rose markedly, attributed to obstructive jaundice secondary to tumor progression. Percutaneous transhepatic biliary drainage was performed, draining approximately 500 mL of bile daily. As of the data cutoff date of June 11, 2026, dual immunotherapy had not been initiated; bilirubin levels had decreased after drainage but had not yet normalized, and re-evaluation of treatment eligibility was planned after liver function recovery. The authors state that no conclusion on preferential use of dual immune checkpoint inhibition can be drawn from this single case.

The report closes with recommendations grounded in the clinical evidence and the patient-reported family history, while acknowledging its limits as a single-case study with short follow-up, no immunotherapy efficacy data, unavailable archival specimens, and minor diagnostic uncertainty about the ampullary lesion’s exact origin. The authors recommend routine germline mismatch repair gene testing for patients presenting with multiple metachronous gastrointestinal and gynecological cancers, and lifelong regular multi-organ tumor surveillance once Lynch syndrome is confirmed. Carriers of pathogenic MSH2 variants, they note, should begin regular colonoscopic surveillance before age 40, and female carriers require annual gynecologic ultrasonography and endometrial biopsy. Clinicians are advised to remain vigilant for rare Lynch-associated gastrointestinal malignancies, including ampullary carcinoma, cholangiocarcinoma, and small bowel carcinoma, and to offer genetic counseling and germline testing to individuals with a family history of cancer. Future research, the authors write, should further explore the tumor penetrance of MSH2 p.A230Lfs*16 and the long-term efficacy of combined immunotherapy for Lynch syndrome-related ampullary carcinoma, work that will require large cohorts rather than isolated case reports.

Subject of Research: A case report of sequential colorectal, endometrial, and ampullary cancers in a carrier of the pathogenic germline MSH2 p.A230Lfs*16 Lynch syndrome variant.

Article Title: Lynch syndrome associated with the pathogenic MSH2 p.A230Lfs*16 variant presenting with sequential colorectal, endometrial, and ampullary cancers: a case report

Article References: Hei, Y., Ji, Z., Jiao, L., & Su, R. (2026). Lynch syndrome associated with the pathogenic MSH2 p.A230Lfs*16 variant presenting with sequential colorectal, endometrial, and ampullary cancers: a case report. Frontiers in Oncology, 16, Article 1972190. https://doi.org/10.3389/fonc.2026.1972190

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1972190

Keywords: Lynch syndrome, MSH2, ampullary carcinoma, colorectal cancer, endometrial cancer, germline variant, microsatellite instability, mismatch repair, immunotherapy, case report, genetic testing, cancer surveillance