Grade 3 Endometrioid Cancer With Mismatch-Repair Loss in a Woman With a Suspicious Family History
A 57-year-old woman undergoes total hysterectomy and bilateral salpingo-oophorectomy for a 4 cm polypoid endometrial tumor. Final pathology shows grade 3 endometrioid adenocarcinoma with 40% myometrial invasion, no lymphovascular invasion, and no cervical or adnexal involvement; no nodes were sampled. Immunohistochemistry shows loss of MLH1 and PMS2 with retained MSH2/MSH6, and a wild-type p53 pattern. Staging CT of chest, abdomen, and pelvis is negative. Her brother had colorectal cancer at 48, and a maternal aunt had endometrial cancer at 52. She asks whether her cancer is 'genetic' and whether her daughter needs testing.
1. Place this tumor in a molecular classification and describe the additional testing needed to distinguish sporadic from hereditary mismatch-repair deficiency.
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This is a mismatch-repair-deficient (MMRd) endometrioid carcinoma on the ProMisE/TCGA framework, with p53 wild-type pattern excluding the p53-abnormal group. The isolated loss of MLH1 with PMS2 is the classic pattern of MLH1 deficiency.
The differential is somatic MLH1 promoter hypermethylation, which accounts for the large majority of MLH1-deficient endometrial cancers, versus a germline MLH1 Lynch syndrome variant. Unlike colorectal cancer, BRAF V600E testing is not useful in endometrial cancer because BRAF mutations are rare; the correct reflex test is MLH1 promoter methylation analysis.
- Methylation present: Lynch syndrome unlikely, but her family history still warrants genetic counselling; methylation is not a perfect exclusion.
- Methylation absent: refer for germline testing of MLH1 and the other mismatch-repair genes.
Her family history - colorectal cancer at 48 in a brother and endometrial cancer at 52 in an aunt - should prompt genetic counselling regardless of the methylation result, because the pretest probability is high and the result changes surveillance for her and her daughter. If Lynch is confirmed: colonoscopy every 1-2 years from age 20-25, aspirin chemoprevention discussion, and consideration of risk-reducing hysterectomy and salpingo-oophorectomy after childbearing.
2. Given stage IA, grade 3, 40% invasion, no lymphovascular invasion, and no nodal sampling, what adjuvant therapy do you recommend, and how does the molecular result influence it?
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She is stage IA grade 3 without lymphovascular invasion - a group where adjuvant treatment is genuinely discretionary and where molecular class should inform the discussion.
- Staging adequacy: no nodes were sampled. CT is negative, which is reassuring but not equivalent to pathological staging. Tumors in the MMRd and POLE classes have low nodal risk, which supports omitting a completion nodal procedure.
- Adjuvant options: observation with close surveillance, or vaginal brachytherapy to reduce vaginal cuff recurrence. Pelvic external beam radiotherapy is not required for stage IA grade 3 without lymphovascular invasion; the randomized trial that established chemoradiation for high-risk disease did not enroll this profile (it required grade 3 with lymphovascular invasion, stage II or III, or serous/clear cell histology).
- Molecular influence: a p53-abnormal tumor would push toward chemoradiation; a POLE-ultramutated tumor would support de-escalation because prognosis is excellent. This tumor is MMRd with p53 wild-type, an intermediate but relatively favorable group, supporting brachytherapy alone or observation rather than combined chemoradiation.
- Counsel: her main recurrence risk is vaginal; brachytherapy is well tolerated and effective. If she prefers to avoid treatment, surveillance with vaginal examination and imaging as indicated is defensible.
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3. Two years later she develops a vaginal cuff recurrence with a 2 cm nodule and no distant disease. She has already had pelvic radiotherapy. What are her options, and how does her molecular profile matter?
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This is an isolated vaginal recurrence after prior brachytherapy, so local control and systemic control both need addressing.
- Local therapy: if she has not received external beam pelvis radiotherapy, she may still be a candidate for pelvic radiotherapy with a boost, depending on prior dose and organ-at-risk constraints; otherwise, surgical excision of the cuff nodule (with reconstruction) is reasonable for an isolated lesion. Re-irradiation is feasible only in highly selected patients at experienced centers.
- Systemic therapy: platinum-based chemotherapy is the standard for recurrent endometrial cancer. Her MMRd status is now directly actionable: pembrolizumab is approved on a tumor-agnostic basis for mismatch-repair-deficient solid tumors, and dostarlimab has activity in MMRd recurrent endometrial cancer, including in combination with carboplatin/paclitaxel in the first-line advanced setting. Immunotherapy responses in MMRd disease can be durable, so this should be raised early rather than after chemotherapy failure.
- Toxicity: immune-related adverse events require monitoring; her autoimmune history must be reviewed.
- Genetics: recurrence reinforces the need to complete germline testing and to ensure her daughter receives counselling.
- Goals: with an isolated vaginal recurrence, long-term control is possible; treat with curative intent and reserve palliative framing unless distant disease emerges.