Review
Muir-Torre syndrome (MTS): An update and approach to diagnosis and management

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Muir-Torre syndrome (MTS) is a rare genetic condition that predisposes individuals to skin tumors and visceral malignancies. Because of the potentially aggressive nature of internal malignancies and sebaceous carcinoma, and the tendency to have multiple low-grade visceral cancers, close cancer surveillance is required in individuals and their families with this usually autosomal dominant disorder. Although the majority of MTS is caused by mutations in DNA mismatch repair genes resulting in microsatellite instability, a newly described subtype of MTS does not demonstrate microsatellite instability and may be inherited in an autosomal recessive pattern. In addition, MTS may be unmasked in transplant recipients taking specific immunosuppressant drugs or other immunosuppressed patients. Neoplasms may be subject to immunohistochemistry or both immunohistochemistry and genetic testing to confirm the diagnosis of MTS. Here, we offer an update and an approach to the diagnosis and management of MTS with a particular emphasis on the role of immunohistochemistry and genetic testing.

Section snippets

Pathogenesis

The majority of cases of MTS (MTS I) demonstrate autosomal dominant inheritance with high penetrance and variable expression. It may also occur sporadically, most commonly documented in transplant recipients.7

In the majority of cases of MTS (MTS I), germline mutations have been detected in mismatch repair (MMR) genes: Mutator S Homologue (MSH)2 (OMIM #609309), Mutator L Homologue (MLH)1 (OMIM #120436), MSH6 (OMIM #600678), and Postmeiotic Segregation Increased (PMS)2 (OMIM #600259). The MMR

Epidemiology

Overall, MTS has a male predilection, with a male to female ratio of 3:2.16 One study of 205 cases of MTS documented sebaceous tumors appearing before internal malignancy in 22% of cases, concurrently in 6% of cases, and after in 56% of cases; 16% of cases demonstrated no temporal relationship.17 The average age that sebaceous neoplasms present is 53 years, ranging from 21 to 88 years.17 In addition, cutaneous tumors occur as long as 25 years before or 37 years after visceral malignancy.18

Cutaneous tumors

Although sebaceous gland hyperplasia is frequently encountered in the general population, sebaceous neoplasms–adenoma, epithelioma, and carcinoma–are rarely seen, except in patients with MTS. Sebaceous adenoma is the most common subtype, with a frequency of 68%.19 Approximately one quarter (27%) of sebaceous neoplasms are sebaceous epitheliomas, and 30% are sebaceous carcinomas.18 Other cutaneous tumors include keratoacanthoma, basal cell carcinoma with sebaceous differentiation, and cystic

Histology

Sebaceous tumors often demonstrate “mulberry cells”, with vacuolated cytoplasm and starry nuclei (Table II and Fig 2). Lipid granules in the cytoplasm of the cells result in a characteristic “frothy” appearance. Sebaceous carcinomas tend to have overexpression of p53 and ki67 compared with other sebaceous neoplasms.37, 38, 39, 40 Keratoacanthomas may be histologically typical or may show sebaceous elements, designated as sebokeratoacanthomas41 (Fig 3). These tumors have a central crater with

Importance of solitary sebaceous adenoma

If an individual has a solitary sebaceous adenoma, the sebaceous neoplasm most closely linked with MTS, immunohistochemistry (IHC) testing should be performed on the tumor. Loss of staining of combinations of certain gene products appears to give 100% positive predictive value that the patient has MTS I. These include MLH1 and MSH2; and MLH1, MSH2, and MSH642 (Table III). In addition, the tumor should be subject to MSI gene analysis.

Diagnosis

Diagnosis of MTS is largely determined with existing diagnostic criteria that consist of at least 1 sebaceous neoplasm and at least 1 internal organ cancer at some point in the patient's life without other contributory factors, such as radiotherapy or AIDS.3 In addition, a family history of MTS with a personal history of multiple keratoacanthomas or keratoacanthomas in areas not exposed to sunlight also suggest the diagnosis (Table IV).

Dermoscopy and reflectance confocal microscopy have been

Differential diagnosis

Several other genetic disorders may be considered in patients with cutaneous nodules. These disorders include Gardner syndrome (OMIM #175100), Cowden syndrome (OMIM #158350), Brooke-Spiegler syndrome (OMIM #605041), basal cell nevus syndrome (OMIM #109400), Ferguson-Smith syndrome (OMIM #132800), and tuberous sclerosis (OMIM #191100).

Treatment

Most cutaneous cancers in MTS are treated with complete excision. Sebaceous carcinomas have the potential for angioinvasion and metastases, and therefore require wide local excision with 5- to 6-mm margins; frozen section control may be used to confirm sufficient margins.54 Recurrence rates range from 4% to 28%.37 Mohs micrographic surgery is also appropriate for sebaceous carcinoma. Radiation therapy is often used as an adjuvant to excision after recurrence. However, if used as a sole

Approach to diagnosis and management

We provide an approach to diagnosing MTS and treating patients, using modified diagnostic criteria based on the Schwartz and Torre3 criteria (Fig 4). The appearance of a sebaceous gland neoplasm or multiple keratoacanthomas should prompt a thorough discussion about family (first- and second-degree relatives) and personal history of internal malignancies. Before subjecting lesions to further testing, patient consent should be obtained.70 In addition, as per the United Nations International

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    Funding sources: None.

    Conflicts of interest: None declared.

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