Overview

Muir-Torre syndrome (MTS) is an autosomal dominant disorder and is a subtype of Lynch syndrome, a condition also known as hereditary nonpolyposis colorectal cancer (HNPCC). It was discovered by Sir Edward Grainger Muir in 1967, and independently by Dr. Douglas Torre the following year.¹ 

MTS results from an impairment in DNA mismatch repair genes, leading to microsatellite instability and the accumulation of mutated DNA. Muir-Torre syndrome is characterised by features including sebaceous skin tumours and internal cancers, with colon cancer being the most common. Since mutations in the mismatch repair gene increase the likelihood of internal cancers, earlier and more frequent testing for these cancers is required.

Symptoms of MTS mostly occur late in middle age, and may include cancers of the skin, abdominal pain, rectal bleeding, anaemia, loss of appetite, and vomiting. Once MTS is diagnosed, monitoring and treatment may be required throughout an individual’s life. The prognosis for Muir-Torre Syndrome is based on the stage of diagnosis and the speed at which medical intervention is initiated. It has been reported that a mutation in the MSH2 gene (in over 90% of cases) is responsible for Muir-Torre syndrome.^2,4

What is Muir-Torre syndrome?

MTS is a very rare inherited disorder. It forms tumours within the oil-secreting glands of the skin and at least one internal organ. Skin tumours may be benign (noncancerous) or malignant (cancerous) and tend to occur on the face, scalp, and eyelids. Visceral tumours are malignant and occur most frequently in the gastrointestinal tract (especially the colon and rectum) or genitourinary tract (endometrium and bladder). MTS is associated with mutations (changes) in the MLH1, MSH2, or MSH6 gene. MTS is a form of Lynch syndrome.³

Causes

It has been reported that MTS results from mutations of the genes mentioned earlier. Genetic mutations involve changes to the DNA sequence and occur during cell division and replication. When an abnormal cell replicates in the body, it could lead to disorders like cancer.⁴

There are two types of MTS. Type 1 MTS results from a mutation of one of the mismatch repair genes responsible for correcting errors in the DNA sequence. Such genes, when incapable of repairing errors, cause abnormal cells to build up in tissues. In the majority of cases (90%), this involves the MSH2 gene, although a few others may also be implicated, including MLH1, MSH6, and PMS2.⁵

Type 2 MTS is linked to a mutation of the MUTYH gene, which is responsible for repairing DNA from oxidative damage. Oxidation alters DNA molecules in a way that can lead to uncontrolled cellular production (cancer). When the mutated gene is unable to correct the damage, it gets replicated.^6,7,11

Signs and symptoms

MTS symptoms include skin lesions, as well as symptoms associated with site-specific cancerous tumours. Skin lesions may appear years before, alongside, or even after the development of internal cancer. Regardless of when they develop, skin lesions are usually the first noticeable symptom. Other kinds of cancers associated with MTS may not present their symptoms as clearly.⁸ 

Skin lesions specific to Muir-Torre syndrome

Sebaceous Adenomas are the most common cutaneous lesions associated with Muir-Torre syndrome, occurring in 80-99% of cases. Sebaceous adenomas are harmless tumours that occur in sebaceous glands, the oil-producing glands found in hair follicles. Sebaceous adenomas typically develop on the head or neck; however, in Muir-Torre syndrome, they are more commonly found on the chest, abdomen, pelvis, or back. They appear as small, firm, yellowish, or skin-coloured bumps.⁹

Sebaceous carcinomas are a malignant form of the sebaceous gland tumour. They develop similarly to sebaceous adenomas; however, they spread quickly and generally occur on the eyelids. Sebaceous carcinoma may bleed or discharge a crusty secretion.⁹

Keratoacanthomas are a type of skin tumour arising in the hair follicle on the head, neck, trunk, or arms. They may be benign or malignant and appear as small, dome-shaped elevations with visible blood vessels and a knobby keratin core. They can grow over a period of weeks and can reach widths of up to 3 centimetres, then diminish in a few months or years. They may present as a singular growth or in clusters.⁹

Fordyce spots are dilated and mildly elevated sebaceous glands that occur ectopically (in abnormal places). They are usually found on hairless places, particularly around the mouth. Some reports suggest that fordyce spots may be more common in MTS, and many clinicians would consider their presence a symptom.¹⁰

Other cancers that are linked to Muir-Torre syndrome

The following are the most common cancers linked to MTS and their symptoms:

Colorectal cancer is the most common type of cancer associated with MTS, occurring in approximately half of cases. In MTS, colorectal cancer develops in the proximal (central) area of the colon. Colorectal cancer in MTS may appear 15 to 20 years earlier than usual. The average age of onset for this particular kind of cancer is around 50, and it may also develop more quickly than usual. Symptoms include abdominal pain and bloating, altered bowel movements, and bleeding in the anus.^11,12,13

Other common cancers in MTS include stomach cancer, which can cause stomach pain, indigestion, nausea, loss of appetite, bloating, and blood in your stool.

Urothelial carcinoma, also referred to as transitional carcinoma, is a type of bladder cancer that can affect individuals with MTS. It involves the urothelium, the lining tissue of the urinary system, and makes up 90% of bladder cancer cases.^11,14

Endometrial cancer is a type of cancer that grows in the womb, which is the innermost lining of the uterus. Symptoms include pain in the lower abdomen or pelvic region, along with abnormal vaginal discharge that may be bloody or watery. ^11,15

Other cancers that can develop with MTS include other reproductive cancers (ovarian cancer, prostate cancer),  and in rarer cases, kidney and breast cancer.¹¹

Diagnosis

Muir-Torre Syndrome is diagnosed using clinical examination, family history, genetic testing, and immunohistochemical studies of sebaceous tumours of the skin.^1,2 Various diagnostic tools that may be employed include:

• Detailed family history and physical examination
• Laboratory tests, such as a complete blood count and carcinoembryonic antigen testing, and faecal occult tests (a test to check for blood in your stool)
• Imaging tests, such as MRI and CT scans, are used to monitor structural changes of organs
• Endoscopic test, including colonoscopies to screen for cancer and polyps

Specialist tests may be performed and can include:

• MSI (microsatellite assay) is a type of lab test (immunohistochemistry) used to detect microsatellite instability in tumour samples
• Genetic follow-up testing is performed when the results of IHC tests indicate Muir-Torre Syndrome due to positive microsatellite instability

For individuals assigned female at birth (AFAB), additional tests may include:

• Regular PAP smear
• Routine mammogram
• Routine pelvic exam with an endometrial biopsy, if clinically indicated

Treatment

Once a diagnosis has been made, Muir-Torre syndrome patients should undergo annual monitoring for internal and skin malignancies. Both upper and lower gastrointestinal endoscopy are to be performed. Colonoscopy may be started as early as 18 years, while upper endoscopy is recommended around 25 to 30 years of age.^1,11,16

Annual testicular and prostate examinations should be conducted in men; annual breast and pelvic examinations, with the addition of transvaginal ultrasound, should be carried out in women; and, when suspicion arises, additional endometrial sampling should be performed.¹

Other useful tests include radiographs of the chest, cervical and urine cytology studies, carcinoembryonic antigen levels, faecal occult blood testing, liver function tests, and complete blood counts.¹

Cutaneous manifestations of Muir-Torre syndrome can be challenging to treat due to the number and disfigurement that multiple sebaceous neoplasms can cause. For benign lesions, reassurance should be provided. Additionally, for patients who wish to have the benign lesions removed, including keratocanthomas, local excision and cryotherapy can be performed.¹

Sebaceous carcinomas can spread to local and distant areas of the body, and, therefore, require special attention. Sebaceous carcinomas should be treated more aggressively using a wide local excision with 5 to 6-millimetre margins or Mohs micrographic surgery.^1,11

Radiotherapy may be considered, but only as adjuvant therapy after the removal of recurrent sebaceous carcinoma or regional metastasis. Radiation as monotherapy has been associated with higher mortality and recurrences of sebaceous carcinomas.¹¹

Furthermore, the combination of interferon-alpha and oral isotretinoin can reduce the formation of skin and internal organ cancers.¹ Other cancer treatments include:

• Chemotherapy
• Hormone therapy
• Immunotherapy
• Targeted therapy
• Bone marrow transplant

Prognosis

The prognosis for MTS depends on the extent and type of tumours that develop. Regular medical check-ups help in the early detection of cancers, which, if appropriately treated, can increase life expectancy.²

Prevention

Currently, there are no specific methods or guidelines to prevent Muir-Torre Syndrome, as it is a genetically caused condition. Genetic testing for expectant parents and related family members, along with prenatal molecular testing of the fetus during the pregnancy, may help highlight the risks better during pregnancy. Genetic counselling would identify the risks involved if there is a family history of MTS, before planning to start a family.²

Active research is ongoing to explore the possibilities of treating and preventing inherited and acquired genetic disorders. A predisposed family member who has not yet undergone genetic testing should have the following screening:

• Annual colonoscopy
• Annual gynecologic examinations
• Endometrial biopsy: Screening Serum CA 125 test

Summary

Muir-Torre syndrome, or MTS, is a rare hereditary disorder characterised by a predisposition to the formation of tumours in sebaceous glands, both in the skin and in the body. It results from mutations in DNA sequence error repair genes, leading to abnormal cell proliferation. Characteristic hallmarks of this disease are sebaceous tumours of the skin and internal organ malignancies, especially colorectal cancer. Symptoms include skin lesions, abdominal pain, rectal bleeding, and anaemia. Diagnosis involves genetic testing, a review of family history, and immunohistochemical studies. Management often involves regular malignancy surveillance, multiple endoscopies, and numerous tests for the early detection of malignancies. Prognosis is based on tumour types and stages; therefore, it is very important to have regular medical evaluations to achieve proper early detection. Currently, there is no prevention for MTS, but genetic counselling and testing help estimate the risks to family members through pregnancy. Meanwhile, active research is trying to find ways to either treat or prevent genetic disorders like MTS.