Muir-Torre Syndrome

Etiology

Muir-Torre syndrome is caused by a genetic defect in mismatch repair genes and is most often inherited in an autosomal dominant manner. The genes most commonly mutated in Muir-Torre syndrome include MLH1, MSH2, 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. It is estimated that these cases account for roughly 35% of Muir-Torre syndrome cases and have been named MTS II. Sporadic cases also have been described, and these are usually seen in the setting of immunosuppression with tacrolimus and cyclosporine being the main offenders.[5][6][7][8]

Epidemiology

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 HNPCC.

Pathophysiology

As their name implies, the mismatch repair genes produce proteins that are responsible for correcting mistakes that are made during base-pair matching of DNA replication. Defects in these genes result in an increased number of unrepaired mistakes which cause an increased probability of tumorigenesis. Biallelic defects in the MYH gene cause the autosomal recessive form of Muir-Torre syndrome (MTS II). The function of the protein expressed by this gene is base excision repair. Microsatellite instability is not seen in this subset of Muir-Torre syndrome.[9][10][11]

Histopathology

Sebaceous adenomas are well-demarcated proliferations displaying numerous lobules comprised of sebaceous cells surrounded by basaloid cells. The proliferation often is incorporated into the epidermis. The number of differentiated (sebaceous) and undifferentiated (basaloid) cells is approximately equal. Three histologic variants have been described including solid, cystic, and keratoacanthoma-like. Sebaceous epitheliomas share the same architectural features as sebaceous adenomas; however, the number of undifferentiated cells accounts for more than half of the cells seen in the proliferation. Sebaceous carcinomas display a proliferation of basaloid cells and sebaceous cells arranged in sheets and with features of malignancy such as mitotic figures, hyperchromatism, necrosis, cellular pleomorphism, and occasional pagetoid spread.

Keratoacanthomas observed in Muir-Torre syndrome not only appear clinically like the sporadic variant, but the histologic appearance is similar as well. Occasionally some sebaceous differentiation can be observed within a keratoacanthoma. When these features are seen, it should be considered a marker for Muir-Torre syndrome, and appropriate testing for mismatch repair genes should be performed.

History and Physical

The cutaneous neoplasms that have been reported in Muir-Torre syndrome include sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, cystic sebaceous tumors, basal cell carcinomas with sebaceous differentiation, and keratoacanthomas usually displaying some sebaceous differentiation. Sebaceous adenomas are the most common among these tumors. 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 MTS. Of note, sebaceous hyperplasia and nevus sebaceus of Jadassohn are not considered features of Muir-Torre syndrome.

The 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.

A thorough history should be performed in the evaluation of any patient suspected of having Muir-Torre syndrome. While the most common malignancy is colon carcinoma, numerous other cancers have been described in association with Muir-Torre syndrome including malignancies involving the endometrium, cervix, ovaries, breast, small bowel, bone, hepatobiliary tract, brain, pancreas, upper uroepithelial tract, blood (lymphoma and leukemia), and lung.

Evaluation

Immunohistochemistry (IHC) can be performed on sebaceous neoplasms to identify defects in the mismatch repair 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, a higher risk of visceral malignancy is not seen. Due to the diagnostic limitations of IHC for Muir-Torre syndrome, several authors advocate IHC testing on sebaceous neoplasms for mismatch repair genes in conjunction with obtaining thorough personal and family histories. If the IHC result reveals mismatch repair gene mutations, genetic testing is then warranted before further workup 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 their 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.

Treatment / Management

Once the diagnosis has been established, 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.

Differential Diagnosis

The differential diagnosis of Muir-Torre syndrome would include other syndromes in which multiple cutaneous papules and nodules appear on the face and/or body, such as Cowden syndrome, Birt-Hogg-Dube syndrome, Tuberous Sclerosis, Brooke-Spiegler syndrome, and Gorlin syndrome. Syndromes such as the Grzybowski-type generalized eruptive keratoacanthomas and the Ferguson-Smith-type multiple eruptive keratoacanthomas should be considered in patients with numerous keratoacanthomas. The sporadic versions of sebaceous tumors and keratoacanthomas also should also be considered although the former is not common in the general population. As noted previously, sporadic sebaceous neoplasms occur most often on the head while they are rarely seen below the neck. Sebaceous neoplasms found below the neck should raise suspicion of Muir-Torre syndrome.