What is Muir Torre syndrome

Muir-Torre syndrome is a rare inherited condition, a form of Lynch syndrome (hereditary non-polyposis colorectal cancer), in which there are sebaceous (oil gland) skin tumors  (usually sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma but also keratoacanthoma) in association with internal cancers ¹. The most common internal site involved is the gastrointestinal tract with almost half of affected people having colorectal cancer. The second most common site is cancer of the genitourinary tract. Skin lesions may develop before or after the diagnosis of the internal cancer ². Muir-Torre syndrome is caused by changes (mutations) in the MLH1 or MSH2 genes and is inherited in an autosomal dominant manner ¹. A mutation in either of these genes gives a person an increased lifetime risk of developing the skin changes and types of cancer associated with Muir-Torre syndrome.

Muir-Torre syndrome is also known as Torre-Muir syndrome and ‘sebaceous neoplasia/visceral carcinoma’ ². Muir-Torre syndrome was first described by Muir et al. in 1967 and independently, by Torre et al. one year later in 1968 ³.

Muir Torre syndrome has an autosomal dominant pattern of inheritance in 59% of cases and has a high degree of penetrance and variable expression.

Muir-Torre syndrome is now considered a phenotypic variant of the Lynch syndrome.

Lynch syndrome is also known as hereditary non-polyposis colorectal cancer (HNPCC). Lynch syndrome inheritance is also autosomal dominant. It is the most common genetic syndrome that gives a predisposition to cancer of the lower gastrointestinal tract (colorectal), uterus (endometrium) and ovary. Lynch syndrome is due to an inability to repair damaged DNA.

Research has shown that some families with Lynch syndrome share the same genetic fault as families with Muir-Torre syndrome ⁴.

Most documented cases of Muir-Torre syndrome have occurred in Caucasian patients from developed countries while data is lacking in many other parts of the world. There is a slight predilection in males with the male-to-female ratio of 3:2. The median age of onset for malignancy is 53 years with the earliest reported case at 23 years and the latest at 89 years. Muir-Torre syndrome is observed in 9.2% of patients with Lynch syndrome ³.

Once the diagnosis has been established. The association of mismatch repair gene mutations and visceral malignancies warrants an earlier and more frequent evaluation for cancer in patients with Muir-Torre syndrome ⁵. Muir-Torre syndrome patients should undergo annual surveillance for visceral and cutaneous malignancy. Upper and lower gastrointestinal endoscopy should be performed. Colonoscopy may begin as early as 18 years while upper endoscopy is recommended around 25 to 30 years. Men should undergo annual testicular and prostate exams, and women should have annual breast and pelvic exams along with transvaginal ultrasound and endometrial sampling for suspicious findings. Other potentially beneficial tests would include chest x-ray, cervical and urine cytology, carcinoembryonic antigen levels, fecal occult blood testing, liver function tests, and complete blood counts.

The cutaneous manifestations of Muir-Torre syndrome can be difficult to treat due to the potential number and disfigurement that numerous sebaceous neoplasms can cause. Reassurance should be offered for benign lesions. Local excision and cryotherapy may be performed for patients desiring removal of benign lesions. Keratoacanthomas should also be managed conservatively with local excision. Sebaceous carcinomas have the potential for local and distant metastasis and should be managed more aggressively with wide local excision with 5 to 6 millimeter margins or Mohs micrographic surgery. Radiation may also be employed but only as adjuvant therapy after excision of a recurrent sebaceous carcinoma, or regional metastasis. Radiation as monotherapy for primary cutaneous sebaceous carcinoma has been associated with higher rates of mortality and recurrence. Additionally, interferon-alpha in conjunction with oral isotretinoin has been reported to decrease the development of cutaneous and visceral malignancies.

Figure 1. Muir Torre syndrome 

Footnote: Multiple skin-coloured to yellow–pink papules (arrows) on the face of a 64-year-old woman with a history of colon and cervical cancer. A skin biopsy confirmed a diagnosis of sebaceous adenoma resulting from Muir–Torre syndrome, which was confirmed with genetic testing.

[Source ⁶ ]

What is the cause of Muir Torre syndrome?

Muir-Torre syndrome is considered to be a subtype of Lynch syndrome (hereditary non-polyposis colorectal cancer) ⁷. Muir-Torre syndrome is associated with an inherited defect in one copy of a DNA mismatch repair (MMR) gene, which leads to microsatellite instability ⁸. The genes most commonly mutated in Muir-Torre syndrome include MLH1, MSH2, MSH6, and PMS2. The 2 major mismatch repair (MMR) proteins involved are MLH1 and MSH2. Approximately 70% of tumors associated with the Muir Torre syndrome have microsatellite instability. While germline disruption of MLH1 and MSH2 is evenly distributed in Lynch syndrome (hereditary non-polyposis colorectal cancer), disruption of MSH2 is seen in greater than 90% of Muir Torre syndrome patients ⁹. Two other proteins involved in Muir Torre syndrome are MSH6 and PMS2.

More recently, some autosomal recessive cases of Muir-Torre syndrome have been described which do not display microsatellite instability and are due to defects in the base excision repair gene known as MYH ³. It is estimated that these cases account for roughly 35% of Muir-Torre syndrome cases and have been named Muir Torre syndrome 2.

Sporadic Muir Torre syndrome cases also have been described, and these are usually seen in the setting of immunosuppression with tacrolimus and cyclosporine being the main offenders ¹⁰.

The MLH1 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein called PMS2 (produced from the PMS2 gene), to form a protein complex. This complex coordinates the activities of other proteins that repair errors made during DNA replication. The repairs are made by removing a section of DNA that contains errors and replacing the section with a corrected DNA sequence.

The MSH2 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other proteins, MSH6 or MSH3 (each produced from a different gene), to form a protein complex. This complex identifies locations on the DNA where errors have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors.

The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes. The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA where errors have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors.

Muir Torre syndrome and Lynch syndrome are autosomal dominant conditions due to genetic mutations, meaning half of an affected person’s children also have the syndrome.

A positive family history of Muir-Torre syndrome can be found in roughly 50% of patients. There is an association with a family history of colon cancer, particularly in patients younger than 50 years.

Cutaneous sebaceous cancers can precede or follow a diagnosis of visceral malignancy ¹¹.

Muir Torre syndrome symptoms

The hallmark features of Muir-Torre syndrome are sebaceous neoplasms of the skin and visceral malignancies with colonic carcinoma being the most common.  Skin lesions may occur before or after the diagnosis of the internal cancer. Sebaceous tumors are generally otherwise rare and their development should arouse suspicion of Muir-Torre syndrome or Lynch syndrome and the need for more investigative tests. Sebaceous hyperplasia and sebaceous nevus are not usually related to Muir-Torre syndrome.

Muir Torre synThe clinical presentation can differ due to the variable expression of defects in the mismatch repair genes, and the number of sebaceous neoplasms can range from a solitary lesion to hundreds. Sebaceous lesions often present as slow-growing, painless, yellowish-colored papules or nodules which may or may not have ulceration. The most common location is the face, but any part of the skin with a sebaceous gland can develop a tumor. The majority of sporadic sebaceous tumors in patients without Muir-Torre syndrome are seen on the nose and eyelid, and any sebaceous tumor below the neck should raise suspicion of Muir-Torre syndrome. The clinical presentation of keratoacanthomas is similar to the sporadic counterpart, and they may be seen as solitary lesions or multiple.drome

The sebaceous neoplasms associated with Muir-Torre syndrome and Lynch syndrome include:

• Sebaceous adenomas
• Sebaceous epitheliomas
• Sebaceous carcinomas.

Not all instances of these tumors are due to Muir-Torre syndrome.

Other skin lesions that may arise in affected family members include:

• Keratoacanthoma usually displaying some sebaceous differentiation
• Squamous cell carcinoma
• Multiple follicular cysts.

Sebaceous adenoma and sebaceous epithelioma

Sebaceous adenoma and sebaceous epithelioma are the most characteristic cutaneous markers of Muir-Torre syndrome/Lynch syndrome.

• They are benign tumors that present as yellow papules or nodules.
• They can grow on any part the body but are mostly located on the head, particularly on the face, scalp and eyelids.

Sebaceous carcinoma

Sebaceous carcinoma is a malignant tumour that occurs most commonly on the eyelids.

• On eyelids, the tumor appears as a firm, yellow nodule with a tendency to ulcerate
• Carcinomas on the eyelid can frequently metastasize and cause death
• May also occur anywhere on the skin, including ears, feet, penis and labia

Keratoacanthoma

Solitary or multiple keratoacanthomas are commonly seen in Muir-Torre syndrome.

A keratoacanthoma starts as a red papule that rapidly grows to become a skin-colored, shiny nodule with telangiectasis (red spider-like markings caused by dilated blood vessels) and a horny central plug covered by a crust.

Muir Torre syndrome diagnosis

Muir Torre syndrome is usually suspected because of the clinical features. However, if a sebaceous adenoma, a sebaceous carcinoma or colonic polyp is removed surgically, the pathologist may examine the cells to see whether the MSH gene products have microsatellite instability, a characteristic of the syndrome. Immunohistochemistry testing shows loss of mismatch repair (MMR) protein expression, indicating a mutation in MSH2 or another associated gene.

Mismatch repair (MMR)-deficiency is present in 30–45% of sebaceous lesions but not all of these result from the syndrome. If the patient’s personal or family history or clinical features are suggestive of Muir Torre syndrome or Lynch syndrome, the patient may undergo further genetic testing by whole gene or whole exome sequencing.

Immunohistochemistry can be performed on sebaceous neoplasms to identify defects in the mismatch repair (MMR) genes commonly implicated in Muir-Torre syndrome, and current recommendations advocate this test. This method, however, is not diagnostic of Muir-Torre syndrome as there have been reports of mismatch repair gene mutations in sebaceous neoplasms in patients who did not have the defect in other cells elsewhere in the body. This finding suggests that the gene defects were somatic rather than germline mutations. In these patients, the higher risk of visceral malignancy is not seen. Due to the diagnostic limitations of immunohistochemistry for Muir-Torre syndrome, several authors advocate immunohistochemistry testing on sebaceous neoplasms for mismatch repair genes in conjunction with obtaining thorough personal and family histories. If the immunohistochemistry result reveals mismatch repair gene mutations, genetic testing is then warranted before further work-up such as screening tests for malignancy are performed. Once the diagnosis of Muir-Torre syndrome is confirmed with genetic testing, annual evaluations for malignancy should be performed. A lower threshold for biopsy of clinically apparent sebaceous tumors should be adopted in patients with Muir-Torre syndrome because sebaceous carcinomas often initially present similarly to the benign counterparts, and this often leads to a delay in diagnosis. A lower threshold is particularly relevant for periocular lesions as this is the most common location for sebaceous carcinoma; however, sebaceous carcinomas can arise from any sebaceous gland.

Stool guaiac may be helpful in detecting colonic carcinomas but colonoscopy will be performed in possible Muir Torre syndrome. The tumors may be present at the time of diagnosis, or delayed ¹².

Imaging studies

Dermoscopy and confocal microscopy may be helpful in the clinical diagnosis of sebaceous lesions. A review of 20 sebaceous tumors revealed dermoscopic features of radially arranged, elongated crown vessels surrounding opaque structureless yellow areas or yellow comedolike globules and branching arborizing vessels. Confocal microscopy revealed sebaceous lobules composed by clusters of ovoid cells with dark nuclei and bright, highly refractile glistening cytoplasm. These cellular clusters were delimited by a rim of epithelial cells, corresponding to basaloid cells ¹³.

Various central nervous system neoplasms have been associated with familial nonpolyposis gut carcinoma, and appropriate imaging should be performed in the presence of suggestive signs or symptoms ¹⁴.

Muir Torre syndrome diagnostic criteria

The criteria to obtain a diagnosis of Muir-Torre syndrome include at least one sebaceous neoplasm and at least one internal malignancy at some point in the patient’s life, without other causative factors such as radiotherapy or immunosuppression. The diagnosis also can be made in the combined setting of multiple keratoacanthomas, visceral malignancy, and family history of Muir Torre syndrome. Of note, sebaceous hyperplasia and nevus sebaceous of Jadassohn are not considered features of Muir-Torre syndrome ³.

Muir Torre syndrome is associated with Lynch syndrome, an autosomal dominant cancer genetic syndrome ¹⁵. The diagnostic criteria (Amsterdam criteria) include the following ¹⁶:

• Three or more relatives with an Lynch syndrome-associated cancer (ie, colorectal, cancer of the endometrium, small bowel, ureter, or renal pelvis)
• Cancer affecting at least two successive generations
• One person with cancer is a first-degree relative of the other 2, at least 1 case of colorectal cancer younger than age 50 years, a diagnosis of familial adenomatous polyposis has been excluded, tumors are verified by histologic examination

Criteria for the diagnosis of Muir-Torre syndrome include the presence of at least one sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation); sebaceous hyperplasia and nevus sebaceus of Jadassohn are generally excluded, and at least one visceral cancer. Keratoacanthoma, squamous cell carcinoma, and multiple follicular cysts are sometimes found as well in these patients. In general, sebaceous neoplasms occurring below the neck are more strongly associated with Muir Torre syndrome than those lesions arising around the eye or ear ¹⁷. Non–head and neck lesions are more commonly associated with mutations in the epidermal growth factor receptor ¹⁸.

The skin lesions may precede the presentation of internal malignancy, although they often develop later. Cutaneous neplasms occurring on the face, the trunk, and the extremities are found in various other disorders, including Gardner syndrome, Cowden syndrome, multiple trichoepitheliomas, basal cell nevus syndrome, eruptive keratoacanthomas, and tuberous sclerosis. Many of these syndromes are also associated with visceral tumors.

Sebaceous adenoma is the most characteristic marker of Muir Torre syndrome. These fairly rare, benign tumors usually appear as yellow papules or nodules in adult patients. In the sporadic cases, most tumors are located on the head (particularly on the face, the scalp, and the eyelids), with the remaining minority scattered over the rest of the body. In Muir Torre syndrome, lesions on the trunk may be more common. The clinical features of sebaceous epithelioma are similar. The nomenclature for sebaceous neoplasms is controversial. Some authors use the term “sebaceoma” for indolent tumors composed of mature sebocytes and a predominance of undifferentiated basaloid germinative cells. This subset of tumors corresponds to lesions traditionally classified as sebaceous epithelioma.

Sebaceous carcinomas most commonly occur on the eyelids, where they generally arise from the meibomian glands and the glands of Zeiss. They may also occur almost anywhere on the skin, including the ears, the feet, the penis, and the labia. On the eyelids, the tumor appears as a firm, yellow nodule with a tendency to ulcerate, as shown in the images below. Clinically, these lesions are often mistaken for chalazia, chronic blepharoconjunctivitis, or carbuncles. Sebaceous carcinoma of the eyelid can invade the orbit and can frequently metastasize and cause death. Extraocular tumors can also metastasize but are less likely to cause death.

The distinction of sebaceous carcinoma and adenoma/epithelioma is usually based upon the architecture of the lesion (infiltrative in carcinoma versus circumscribed in adenoma/epithelioma). However, some lesions may have circumscribed borders but do show frank cytologic atypia ¹⁹, while the authors have seen lesions without any degree of cytologic atypia diffusely infiltrating the subcutaneous tissue.

Keratoacanthoma, whether solitary or multiple, is frequently seen in Muir Torre syndrome. Keratoacanthoma usually starts as a red papule that rapidly grows to become a skin-colored, shiny nodule with telangiectases and a central horny plug covered by a crust. Common sites of involvement include the face and the dorsum of the hands, but they can occur anywhere on the body. The tumors have a tendency to regress, ultimately leaving a scar. Those keratoacanthoma cases with sebaceous differentiation are strongly associated with Muir Torre syndrome.

The most common visceral neoplasm in Muir Torre syndrome is colorectal cancer, occurring in almost one half of patients. The tumors are usually proximal to the splenic flexure. The second most common site is the genitourinary tract, representing approximately one quarter of visceral cancers. A wide variety of other cancers, including breast cancer, lymphoma and rarely leukemia, salivary gland tumors, lower and upper respiratory tract tumors, and chondrosarcomahave also been reported. Intestinal polyps occur in at least one quarter of patients. Other benign tumors described in Muir Torre syndrome include ovarian granulosa cell tumor, hepatic angioma, benign schwannoma of the small bowel, and uterine leiomyomas.

Muir Torre syndrome treatment

Patients with Muir Torre syndrome and Lynch syndrome need to undergo medical and physical examinations and appropriate laboratory and radiographic tests regularly to check for internal malignancies, particularly of the gastrointestinal and genitourinary tracts. Patients need a regular colonoscopy for early detection of colorectal tumors. Cancers should be managed with appropriate anti-cancer therapies.

In some families, a genetic diagnosis can identify asymptomatic carriers of the mutation. All first-degree relatives, especially mutation carriers, should be referred from the age of 20 years for routine follow-up and early treatment

Treatment of the skin lesions includes:

• Benign tumors and keratoacanthomas may be treated surgically with excision or cryotherapy
• Sebaceous carcinomas should be excised completely and followed-up for detection of possible metastases.
• Oral retinoids, e.g. acitretin or isotretinoin, may prevent some lesions
• Interferon injections are sometimes combined with retinoid treatment

Improvement of Muir Torre syndrome has been noted in patients treated with sirolimus.

Oral isotretinoin can possibly prevent some of the neoplasms in persons with Muir-Torre syndrome ²⁰. A dosage of as much as 0.8 mg/kg body weight per day may be effective. Graefe et al ²¹ note in a case report that the combination of interferon with retinoids may be of promise to prevent cutaneous tumor development in persons with Muir Torre syndrome. They used interferon (interferon alfa-2a) subcutaneously 3 X 106 U 3 times/week in combination with 50 mg isotretinoin daily and topical isotretinoin gel.

Long-Term monitoring

Patients with Muir-Torre syndrome should have regular complete examinations, particularly of the gastrointestinal and genitourinary tracts ²². An annual colonoscopy beginning at age 25 years is desirable because of the high frequency of proximal colorectal cancer. Follow-up care for recurrence or metastasis is mandatory.

Muir Torre syndrome prognosis

Sebaceous carcinoma is an aggressive cancer, which can recur locally after excision and can metastasize. When local recurrences develop, they usually do so within the first five years of excision. Recurrence rates are estimated to be around 30% range ²³.

References

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