Muir-Torre syndrome is a subtype (phenotypic variant) of Lynch syndrome (hereditary nonpolyposis colorectal cancer). It is characterized by the coexistence of at least one sebaceous skin tumor and at least one visceral malignancy.
It was independently reported by Muir in 1967 and by Torre in 1968, and Lynch et al. characterized the association between sebaceous tumors and colorectal cancer in 198110). The name Muir-Torre syndrome was proposed in 198210).
The cause is germline mutations in DNA mismatch repair genes (MSH2, MLH1, MSH6, PMS2). It is inherited in an autosomal dominant pattern. It is found in 9.2% of patients with Lynch syndrome. The male-to-female ratio is 3:2, with a male predominance3), and the age at onset of malignancy ranges from 23 to 89 years (median 53 years)8).
Two subtypes have been reported7).
Cases have been reported in which latent Muir-Torre syndrome became apparent after solid organ transplantation (especially after kidney transplantation) or under immunosuppression with tacrolimus or cyclosporine8).
It is a rare hereditary tumor syndrome seen in about 9.2% of patients with Lynch syndrome. The male-to-female ratio is 3:2, and the median age at malignancy onset is 53 years. There are Type I (65%) and Type II (35%), with the former being the main type associated with mismatch repair gene mutations7).
The typical initial symptom is painless, slowly enlarging pink or yellow papules and nodules that commonly arise on the eyelids, face, and trunk. They may be accompanied by central umbilication or ulceration.
Sebaceous carcinoma of the eyelid is often mistaken for a chalazion, and it is characteristic for it to present as a masquerade syndrome, with repeated recurrence and enlargement after incision. Unlike sporadic cases (which tend to involve the head and neck), Muir-Torre syndrome tends to show more tumor development on the trunk1).
It may be accompanied by Fordyce granules (ectopic sebaceous glands) in the oral mucosa7).
Skin tumors associated with Muir-Torre syndrome are broadly divided into three types.
Sebaceous adenoma (68%)
Appearance: Fleshy yellow papules/nodules. With or without ulceration/umbilication7)
Pathology: Mainly mature sebaceous cells. Morule-like cells (cells with coarse vacuolated cytoplasm and star-shaped nuclei), epithelial membrane antigen (EMA) positive
Features: The most common MTS-associated skin tumor
Sebaceous carcinoma (30%)
Appearance: Yellowish, irregular-surfaced nodular mass. Has tumor vessels and tends to bleed easily. Common on the upper eyelid
Pathology: Cellular atypia, high mitotic activity, infiltrative growth, pagetoid spread (sheet-like spread of tumor cells into the palpebral conjunctival epithelium)
Prognosis: Local recurrence rate 9–36%, distant metastasis rate 3–25% (parotid gland, liver, lung, bone)3)
Sebaceous epithelioma (27%)
Definition: sebaceoma. A subtype of sebaceous adenoma, composed of more than 50% basaloid epithelial cells
Appearance: Papular to nodular lesion
Significance: Even when found alone, consider surveillance for Muir-Torre syndrome
The incidence of eyelid sebaceous carcinoma is rare at 0.2–0.7% of all eyelid tumors, but it is highly malignant3). The overall incidence of sebaceous carcinoma is 1–2 per 1 million people per year; 80% occur in the head and neck, and half of those are around the eyes9). Risk of local lymph node metastasis increases when the tumor size exceeds 15 mm.
Dermoscopic findings (review of 34 sebaceous carcinoma cases)2):
Pattern of visceral malignancies: 56% had internal cancer before skin lesions, 22% had sebaceous tumors first, and 6% occurred at the same time8). About 50% of patients with Muir-Torre syndrome develop two or more visceral malignancies8).
The main cause of Muir-Torre syndrome is germline mutations in mismatch repair genes.
| Gene | Mutation frequency in Muir-Torre syndrome | Characteristics |
|---|---|---|
| MSH2 | About 90% | Characteristic of Muir-Torre syndrome (evenly distributed in Lynch syndrome overall) |
| MLH1 | approximately 10% | BRAF V600E testing is useful for distinguishing it from sporadic cancer |
| MSH6 | rare | only mononucleotide repeats are involved6) |
| PMS2 | rare | — |
In Muir-Torre syndrome type II, biallelic variants in the MYH (MUTYH) gene are the cause, and it does not show microsatellite instability because the base excision repair pathway is impaired7). Epigenetic silencing of MSH2 due to EPCAM gene deletion can also rarely be a cause6).
Immunosuppression is known to promote the emergence of Muir-Torre syndrome8).
There are reports that use of tacrolimus or cyclosporine after solid organ transplant can unmask latent Muir-Torre syndrome8). There are also cases where switching to an mTOR inhibitor (sirolimus) suppressed new tumor development, so Muir-Torre syndrome should be actively considered when a cutaneous sebaceous tumor is found in a post-transplant patient.
The diagnosis is made when both of the following two conditions are met:
Note that sebaceous hyperplasia alone does not meet the first criterion.
Mismatch repair gene testing is recommended for scores of 2 or higher1)4).
| Item | Points |
|---|---|
| Age under 60 at diagnosis | 1 point |
| Two or more sebaceous tumors | 2 points |
| Personal history of Lynch-associated cancer | 1 point |
| Family history of Lynch-associated cancer | 1 point |
Reference data: with a score of 3 or higher, 28/29 were confirmed to have Muir-Torre syndrome; with a score of 2, 12/20 were confirmed; and with a score of 0–1, 0/39 were confirmed1).
The diagnostic algorithm proceeds in this order: immunohistochemistry → microsatellite instability testing → next-generation sequencing → germline testing7).
Differential diagnosis: MUTYH-associated polyposis, familial adenomatous polyposis/Gardner syndrome, Cowden syndrome, tuberous sclerosis, Ferguson-Smith syndrome, Brooke-Spiegler syndrome, basal cell nevus syndrome
Calculate the Mayo Muir-Torre syndrome score; if it is 2 points or higher, germline testing of mismatch repair genes is recommended1)4). First, evaluate the four mismatch repair proteins by immunohistochemistry, then perform microsatellite instability testing, and if needed, next-generation sequencing and germline testing. Because immunohistochemistry can give false-negative results, if the clinical suspicion is strong, it is preferable to perform germline testing from the start10).
Complete excision or cryotherapy (freezing treatment) is chosen7).
Wide local excision or Mohs micrographic surgery is the standard5)7).
Eyelid reconstruction (choose the procedure according to the extent of excision):
Management of Paget-like spread (limited to in situ): Mitomycin C 0.04% eye drops (4 times a day, 1 week on/1 week off for 2 to 3 cycles) may be an option (not covered by insurance).
Radiation therapy: used as an adjuvant therapy, or in elderly patients or those in poor general condition who cannot tolerate curative resection. Used alone, the recurrence rate is high7).
Skin and eyes
Full-body skin examination: once a year1)4)
Ophthalmologic evaluation: including follow-up of sebaceous tumors
Gastrointestinal tract
Colonoscopy: starting at age 20–25 (or 5 years before the youngest age of onset in the family), every 1–2 years1)4)
Upper gastrointestinal endoscopy: starting at age 30–35, every 2–3 years (if there is a family history of gastric cancer)1)4)
Genitourinary
Pelvic examination, transvaginal ultrasound, and endometrial biopsy: once a year for women starting at age 30–354)
Urinalysis and urine cytology: once a year starting at age 30–351)4)
Prostate examination (men): once a year
If neurological symptoms appear, perform head imaging with a low threshold.
Genetic counseling: after the person’s definitive diagnosis, genetic testing is recommended for first-degree relatives7).
There are limited reports that combining low-dose isotretinoin with interferon α-2a suppressed the new development of skin and internal organ tumors7)4). In immunosuppressed patients, there are cases where switching from tacrolimus to an mTOR inhibitor (sirolimus) helped suppress tumor formation8).
Excision with a safety margin of at least 3 mm is the basic approach. In cosmetically and functionally important areas, Mohs micrographic surgery is recommended to minimize the risk of recurrence5). Reconstruction is performed according to the amount of tarsal defect (from simple closure to the Cutler-Beard procedure), and for intraepithelial lesions (pagetoid spread), 0.04% mitomycin C eye drops are also an option.
Mismatch repair genes (MLH1, MSH2, MSH6, PMS2) recognize and repair base mismatches during DNA replication7). When these genes are inactivated, errors accumulate in microsatellite regions (short repeated base sequences in the genome), leading to microsatellite instability7)10). When microsatellite instability affects oncogenes and tumor suppressor genes, cancer develops10).
The MSH6 gene is located near MSH2 on the short arm of chromosome 2. It is involved only in the repair of mononucleotide repeats and does not repair dinucleotide repeats, so it is difficult to detect with standard microsatellite instability panels6). For searching for MSH6 mutations, a panel of five mononucleotide markers (NR21, BAT25, BAT26, NR24, NR22) is recommended6).
Deletion of the EPCAM gene leads to epigenetic silencing of the MSH2 promoter, causing loss of MSH2 protein and high-frequency microsatellite instability6).
In sebaceous carcinoma, loss of two retinoid receptors, RXR-β and RXR-γ, may occur3). This is considered one of the theoretical bases for preventive intervention with isotretinoin (a retinoid).
Calcineurin inhibitors (tacrolimus and cyclosporine) impair immune surveillance and promote tumor progression in patients with Muir-Torre syndrome8). mTOR inhibitors (sirolimus) are thought to reduce tumor formation by suppressing the mTOR pathway8).
Several studies have pointed out the limitations of the current algorithm that relies on immunohistochemistry alone as the basis for diagnosis.
The case series by Cohen and Kurzrock (2023) reported a case in which all four proteins showed normal expression on immunohistochemistry despite a confirmed germline MLH1 mutation10). Roberts et al. reported normal immunohistochemistry (false negative) in 15% of patients with Muir-Torre syndrome, Everett et al. reported false-negative immunohistochemistry in 44% of patients with confirmed germline mutations, and Nguyen et al. reported false-negative immunohistochemistry in 1 of 11 cases (9%)10). In addition, Aziz et al. confirmed false-negative immunohistochemistry in 14 of 253 skin lesion specimens (5.5%) from patients with confirmed Lynch syndrome10).
These findings suggest that germline genetic testing should be performed in parallel with immunohistochemistry, microsatellite instability testing, and next-generation sequencing from the initial evaluation of sebaceous tumors10).
In microsatellite instability testing, false negatives have also been reported at 28% with the pentaplex PCR method and 10% with an improved seven-marker method10). Development of more sensitive microsatellite instability panels is ongoing.
Tetzlaff et al. reported finding clinically actionable genetic mutations (mutations that may be eligible for targeted therapy) in 52% of sebaceous carcinomas10). NOTCH1/NOTCH2 mutations have also been newly identified in Muir-Torre syndrome–associated sebaceous tumors (Simic et al.)10).
Renal cell carcinoma is rare in patients with Lynch syndrome/Muir-Torre syndrome, and only 26 cases have been reported in the literature6). Clear cell type is the most common, but papillary types (Type 1/2) have also been reported.
Yang et al. (2021) reported a case of synchronous papillary renal cell carcinoma and colon adenocarcinoma in an 85-year-old man with Muir-Torre syndrome and a germline pathogenic variant in MSH66). They emphasized that MSH6 mutations are prone to false negatives on the usual five-marker microsatellite instability panel and that a panel dedicated to mononucleotide markers is needed.
Savoia et al. (2024) reviewed dermoscopy in 34 cases of extraocular sebaceous carcinoma and proposed “milky red areas” as a new diagnostic feature, found in 47%2). Adding this to the traditional diagnostic features (yellow areas and polymorphous vessels) may improve early detection by dermatologists and ophthalmologists.
Bagga E, Innes D, Leung E, Leung E.. Looking beyond the surface: Muir Torre syndrome. Arch Clin Cases. 2023;10(3):119-122. doi:10.22551/2023.40.1003.10255. PMID:37736596; PMCID:PMC10510334.
Savoia F, Medri M, Melandri D, Domeniconi L, Crisanti E, Sechi A, Stanganelli I.. Extraocular cutaneous sebaceous carcinoma in a patient with Muir-Torre syndrome: special emphasis on histologic and dermoscopic features. Dermatol Reports. 2024;16(3):9832. doi:10.4081/dr.2023.9832. PMID:39539987; PMCID:PMC11558309.
Karla Ranđelović. Sebaceous Carcinoma of the Eyelid and Muir-Torre Syndrome. ACC. 2023. doi:10.20471/acc.2023.62.04.21.
Saurborn E, Adeshina B, Stuart IG, Cook S.. Sebaceous Carcinoma as a Presentation of Muir-Torre Syndrome. Cureus. 2025;17(1):e77386. doi:10.7759/cureus.77386. PMID:39949456; PMCID:PMC11821365.
Dhamale SS, Baghel A, Kanak K, Sardesai V.. Extraocular Sebaceous Carcinoma in Lynch Syndrome: A Sentinel Cutaneous Clue to Muir-Torre Syndrome. Cureus. 2025;17(7):e88267. doi:10.7759/cureus.88267. PMID:40831808; PMCID:PMC12358640.
Yang Y, Dhar S, Taylor J, Krishnan B. Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis: Report of a Case and Review of the Literature. Journal of kidney cancer and VHL. 2021;8(2):8-19. doi:10.15586/jkcvhl.v8i2.175. PMID:33977078; PMCID:PMC8064920.
Sheth R, Menon P, Malik D.. A Case of Muir-Torre Syndrome. Cureus. 2021;13(4):e14582. doi:10.7759/cureus.14582. PMID:34036002; PMCID:PMC8136295.
Qudaih AT, Al Ashour BH, Naim AK, Joudeh AA. Kidney Transplant Recipient With Multiple Contemporaneous Malignancies Secondary to Muir-Torre Syndrome. Cureus. 2021;13(7):e16642. doi:10.7759/cureus.16642. PMID:34466316; PMCID:PMC8396404.
Bui A, Shah S, Winston N, Mahmoud A.. Muir-Torre Syndrome: Abdominal Sebaceous Carcinoma. Cureus. 2022;14(12):e33103. doi:10.7759/cureus.33103. PMID:36733789; PMCID:PMC9888597.
Cohen PR, Kurzrock R.. Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series. Cureus. 2023;15(1):e33975. doi:10.7759/cureus.33975. PMID:36824550; PMCID:PMC9941027.
