Muir-Torre syndrome
Muir-Torre syndrome (MTS) is an autosomal dominant variant of Lynch syndrome (HNPCC) characterised by the combination of sebaceous neoplasms (sebaceous adenoma, sebaceoma, sebaceous carcinoma) and at least one Lynch-associated visceral malignancy (commonly colorectal, endometrial, urothelial). Caused by germline mutations in mismatch repair (MMR) genes — predominantly MSH2 (~85–90% of MTS), with smaller contributions from MSH6, MLH1 and PMS2, plus rare EPCAM 3' deletions causing epigenetic silencing of MSH2. Note that MMR deficiency demonstrated on sebaceous-tumour immunohistochemistry does not equate to Lynch syndrome on its own — sun-exposed sebaceous tumours frequently show somatic MSH6 (or less commonly MSH2) loss without a germline cause, and MLH1 / PMS2 loss requires a second-tier triage step (see Work-up).
When to suspect
- Two or more sebaceous neoplasms, especially if any are sebaceous carcinoma.
- Sebaceous neoplasm at age <60.
- Sebaceous neoplasm with personal or family history of Lynch-associated cancer (colorectal, endometrial, ovarian, gastric, small bowel, urothelial, pancreatic, hepatobiliary, brain).
- Multiple keratoacanthomas in some series.
Work-up — tiered MMR triage
Tier 1: skin biopsy + MMR IHC
Histology of the sebaceous lesion, with mismatch repair immunohistochemistry (MLH1, PMS2, MSH2, MSH6, plus consideration of EPCAM). Loss of nuclear staining of any of the four MMR proteins indicates MMR deficiency in the tumour. Note: sun-exposed sebaceous tumours frequently show isolated somatic MSH6 loss without a germline cause.
Tier 2: methylation / BRAF triage for MLH1 / PMS2 loss
Where MLH1 (and consequently PMS2) is lost on IHC, the next step is MLH1-promoter methylation analysis on the tumour to distinguish the much commoner sporadic cause from Lynch-syndrome-related germline disease. BRAF V600E testing is the established triage step in colorectal Lynch screening but is less well validated as a triage step in sebaceous tumours; results should be interpreted with caution at the sebaceous level. Methylation analysis is the preferred sebaceous-tumour triage.
Microsatellite instability (MSI)
MSI testing in sebaceous tumours is technically difficult (small specimens, normal-tissue contamination) and is not the principal UK workhorse; MMR IHC is the first-line test. MSI is reserved for equivocal cases.
Tier 3: genetic counselling and germline testing
Refer to clinical genetics for germline testing where IHC + methylation triage suggests a true Lynch-syndrome aetiology, where there is a personal or family Lynch-cancer history, or where the patient is young (typically <60 with a sebaceous neoplasm). The MMR IHC pattern on the index tumour informs which gene to target first (e.g. isolated MSH6 loss → start with MSH6; combined MSH2/MSH6 loss → start with MSH2, then consider EPCAM). Use the Mayo MTS risk score (Roberts 2014) to support pre-test probability where uncertain.
Surveillance (UK / Mallorca Group 2021)
Patients with confirmed MTS / Lynch syndrome require lifelong gene-stratified surveillance per the Mallorca Group 2021 consensus and NICE NG151. Cadence and start age depend on the involved gene:
- Colonoscopy — every 2 years; start age 25 for MLH1 or MSH2 carriers, age 35 for MSH6 or PMS2 carriers.
- Endometrial / ovarian surveillance for women — symptom-led education from menarche; consider annual transvaginal ultrasound ± endometrial biopsy from age 35–40 in higher-risk genes; risk-reducing hysterectomy ± bilateral salpingo-oophorectomy after childbearing for higher-risk carriers (MLH1, MSH2, EPCAM).
- Urothelial surveillance — consider annual urinalysis from age 30–35, particularly for MSH2 and EPCAM carriers; cystoscopy for symptoms.
- Skin surveillance — annual total skin examination.
- Patient education on red-flag symptoms (rectal bleeding, change in bowel habit, post-menopausal bleeding, haematuria).
Management of skin lesions
- Excise any sebaceous neoplasm with clear margin.
- Sebaceous carcinoma per dedicated monograph — usually Mohs.
- Family screening through clinical genetics.
References
- Roberts ME et al. Muir-Torre syndrome: identification and management. Curr Opin Pediatr; 2018.
- Roberts ME et al. MisInterpreting MMR deficiency: identifying Muir-Torre syndrome. J Clin Oncol; 2018.
- South CD et al. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst; 2008.
- Seppälä TT et al.; European Hereditary Tumour Group and European Society of Coloproctology. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. 2021;108(5):484-498.
- NICE NG151. Colorectal cancer. London: NICE; 2020 (last updated 15 December 2021), recommendation 1.1 on Lynch syndrome.
Spot a correction?
If any clinical statement, citation or link on this page needs updating, please email admin@skinoncology.net with the page name, the proposed correction and the supporting source.