Research report: Case Report: Metachronous multiple primary neoplasms in a carrier of germline MSH2 c.958dupA Lynch syndrome

A 38-year-old woman in Shenzhen developed four separate neoplastic lesions across four organ systems in eight years, and a new case report assesses each lesion individually, finding that only the endometrial carcinoma could be confidently linked to her inherited MSH2 fault while the others remained of uncertain relationship. The woman carried a germline MSH2 c.958dupA mutation, a frameshift variant that disrupts one of the four genes responsible for correcting replication errors in dividing cells. The report, published in Frontiers in Oncology by clinicians at The University of Hong Kong-Shenzhen Hospital, follows her from an endometrial cancer diagnosis in 2018 through lung surgery, gastric endoscopic resection and, most recently, colonoscopic findings in 2026. What makes the account unusual is not simply the number of lesions but the differing confidence with which each could be tied to her inherited condition.

The story began with abnormal uterine bleeding that persisted from 2016 into early 2018. The woman had been diagnosed with premature ovarian insufficiency in 2015 and was receiving cyclic hormone replacement therapy. Pelvic ultrasound in January 2018 identified an intrauterine lesion measuring 13 by 7 millimetres with ill-defined borders and abundant blood-vessel signals; serial scans showed it enlarging to 34 by 23 millimetres by March. Diagnostic hysteroscopy on March 14, 2018 revealed a broad-based grey-white exophytic tumour, and partial curettage with electrocautery resection of its stalk was performed. Her serum CA125, a tumour marker, measured 35.4 U/mL, a borderline elevation the authors describe as non-specific and not a recognised feature of Lynch syndrome.

Malignancy was suspected, and on April 18, 2018 she underwent comprehensive surgical staging: total hysterectomy, removal of both ovaries and fallopian tubes, and pelvic and para-aortic lymphadenectomy. Pathology confirmed endometrioid endometrial adenocarcinoma, FIGO grade 3, confined to stage IA (pT1a N0 M0), with less than half myometrial invasion. Thirty-seven lymph nodes were examined and none contained tumour; the cervix, parametrial tissues, ovaries and tubes were tumour-free, and all margins were clear. Immunohistochemistry showed the tumour was negative for oestrogen and progesterone receptors and for WT1, with heterogeneous p53 staining consistent with a wild-type pattern, an immunophenotype the authors note is atypical for endometrioid tumours. Focal suspicious lymphovascular invasion was seen on routine staining but was never confirmed with the CD31 and D2-40 markers that current guidelines require.

The decisive molecular clue came from mismatch repair immunohistochemistry on the tumour specimen. A four-antibody panel showed complete loss of MSH2 and MSH6 protein expression with retained MLH1 and PMS2, and non-neoplastic cells stained normally, confirming an adequate internal control. Germline testing on December 11, 2018, using a 21-gene hereditary cancer panel, identified the heterozygous pathogenic frameshift variant MSH2 c.958dupA, predicted to truncate the protein within its ATPase and dimerisation domains. The finding was validated the same day with a separate 14-gene gastrointestinal panel, establishing the diagnosis of Lynch syndrome. No additional pathogenic variants were detected, and no functional studies specifically assessing this variant’s effect on mismatch repair activity are available.

She received adjuvant high-dose-rate vaginal brachytherapy, 30 Gy in five fractions, on an individualised basis, without chemotherapy or external beam radiotherapy. The authors acknowledge that under the 2021 ESGO/ESTRO/ESP guidelines, suspected lymphovascular invasion without confirmatory staining is insufficient to assign her definitively to the high-intermediate risk group. They also caution that her favourable eight-year outcome cannot be extrapolated to other MMR-deficient grade 3 endometrial cancers and should not be read as support for treatment de-escalation. Notably, in 2018 universal MMR screening of endometrial cancers was not standard practice at their institution; germline sequencing was triggered by her young age and adverse pathology, and tumour immunohistochemistry was performed retrospectively on archived tissue. Current NCCN, SGO and ESGO guidance now favours universal mismatch repair screening for every newly diagnosed endometrial carcinoma, regardless of age or family history.

Eight months after surgery, surveillance chest CT detected a suspicious lesion in the right upper lobe. Video-assisted thoracoscopic wedge resection on January 14, 2019 removed a tumour measuring 0.8 centimetres, staged as minimally invasive adenocarcinoma, pT1mi N0 M0, stage IA1, with negative margins and no visceral pleural invasion. Elastic fibre staining showing focal disruption of alveolar elastic fibres provided morphological support for the diagnosis by demonstrating stromal invasion beyond the lepidic component. Molecular testing by ARMS-PCR found an EGFR exon 19 deletion, a canonical driver alteration in sporadic lung adenocarcinoma, with no mutations in other tested EGFR hotspots. Exploratory immunohistochemistry showed diffuse c-MET and VEGF expression and negative PD-L1 and PD-1 staining, but these markers did not guide management. Because archival lung tissue could not be retrieved, mismatch repair status was never assessed, so a Lynch-associated contribution cannot be definitively excluded, even though the EGFR finding is compatible with an independent sporadic event.

The stomach told a slower story. Annual surveillance endoscopy from 2019 to 2021 documented antral lesions reported as low-grade intraepithelial neoplasia on biopsies taken in each of those three years. Endoscopic submucosal dissection in March 2023 confirmed high-grade intraepithelial neoplasia with negative resection margins, achieving curative resection. The authors are careful about interpretation: because forceps biopsies sample only part of a lesion, the apparent change from low-grade to high-grade disease may reflect diagnostic upgrading due to sampling limitations rather than true biological progression, and that possibility cannot be excluded. Mismatch repair testing was never performed on the gastric tissue, although ESD material remains available, so the lesion is classified only as possibly Lynch-associated. The suggestion that gastric low-grade neoplasia in carriers might warrant six-monthly surveillance is described as hypothesis-generating and not supported by current guidelines.

The colorectal findings remain the least defined. Colonoscopy in April 2026 identified more than ten scattered flat micro-polyps, 0.2 to 0.3 centimetres, in the rectum and sigmoid colon with NICE type 1 endoscopic morphology. All visible polyps were ablated with argon plasma coagulation without histological sampling, so their adenomatous nature was never confirmed; the authors state plainly that histological confirmation would have been preferable and that the decision followed individualised risk discussion. A tubulovillous adenoma removed by polypectomy in 2018 is documented separately as possibly Lynch-associated colorectal neoplasia. The patient’s only notable family history is a mother with triple-negative breast cancer at around age 70, which the report treats as background information rather than evidence of an expanded MSH2 phenotype, and no other first- or second-degree relatives had documented Lynch-associated malignancies.

Across eight years of surveillance from 2018 to 2026 the patient remained asymptomatic, with serial imaging and endoscopies showing no recurrence of the treated endometrial, pulmonary or gastric lesions. The authors frame the central lesson as heterogeneity: a germline MSH2 variant establishes cancer predisposition but does not dictate the molecular origin of every subsequent lesion. Only the endometrial carcinoma can be confidently linked to Lynch syndrome on tumour-based evidence; the lung tumour, gastric lesion and micro-polyps remain uncertain to varying degrees because tissue or testing was unavailable. They emphasise that assessment of any new tumour in a carrier should begin with tumour mismatch repair status, followed where possible by somatic testing, and that each lesion be judged on its own histology, stage and molecular profile. As a single case, the report is explicitly hypothesis-generating and cannot support changes to surveillance guidelines, though it illustrates why systematic multi-organ surveillance and timely intervention matter for people living with mismatch repair deficiency.

Subject of Research: Metachronous multiple primary neoplasms in a carrier of the germline MSH2 c.958dupA Lynch syndrome variant

Article Title: Case Report: Metachronous multiple primary neoplasms in a carrier of germline MSH2 c.958dupA Lynch syndrome

Article References: Wang, L., Li, P., Hu, D., Wang, X., & Xu, Z. (2026). Case Report: Metachronous multiple primary neoplasms in a carrier of germline MSH2 c.958dupA Lynch syndrome. Frontiers in Oncology, 16, 1958351. https://doi.org/10.3389/fonc.2026.1958351

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1958351

Keywords: Lynch syndrome, MSH2, endometrial cancer, mismatch repair deficiency, minimally invasive adenocarcinoma, EGFR exon 19 deletion, gastric intraepithelial neoplasia, colonoscopy surveillance, case report, hereditary cancer, immunohistochemistry, multiple primary neoplasms