Muir-Torre syndrome (MTS): An update and approach to diagnosis and management Ann M. John, MD,a and Robert A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin)a,b Newark, New Jersey 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. ( J Am Acad Dermatol 2016;74:558-66.) Key words: immunohistochemistry; keratoacanthoma; Lynch syndrome; microsatellite instability; mismatch repair; Muir-Torre; sebaceous adenoma; sebaceous carcinoma; sebaceous epithelioma; sebokeratoacanthoma.


uir-Torre syndrome (MTS) (Online Mendelian Inheritance in Man [OMIM] #158320) is a rare condition characterized by a genetic predisposition to sebaceous neoplasms and visceral malignancies. First described by Muir et al in 19671 and Torre in 1968,2,3 it represents a variant of the autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, also known as Lynch syndrome (OMIM #120435). HNPCC occurs in about 1 of 350 individuals in the general population4; MTS is evident in about 9.2% of individuals and 28% of families with HNPCC.5 The most characteristic cutaneous markers are sebaceous neoplasms.6

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

From the Department of Dermatology, RutgerseNew Jersey Medical School,a and Rutgers University School of Public Affairs and Administration.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication September 28, 2015. Reprint requests: Robert A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin), Professor and Head, Dermatology, RutgerseNew Jersey


Abbreviations used: ERF: HNPCC: IHC: MLH: MMR: MSH: MSI: MTS: OMIM: PMS:

eukaryotic release factor hereditary nonpolyposis colorectal cancer immunohistochemistry Mutator L Homologue mismatch repair Mutator S Homologue microsatellite instability Muir-Torre syndrome Online Mendelian Inheritance in Man Postmeiotic Segregation Increased

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 proteins are responsible for detecting and repairing errors during DNA replication, particularly in microsatellite regions, which are characterized by

Medical School, Medical Science Building H-576, 185 S Orange Ave, Newark, NJ 07103. E-mail: [email protected] 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc.


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repetitive mono- or di-nucleotide repeats. The CLINICAL PRESENTATION most commonly disrupted gene is MSH2, found in Cutaneous tumors over 90% of patients with MTS I.8 To date, 70 Although sebaceous gland hyperplasia is mutations have been found in MSH2. A ‘‘second frequently encountered in the general population, hit’’ of the corresponding MMR allele is necessary sebaceous neoplasmseadenoma, epithelioma, for accumulation of replication errors and increase and carcinomaeare rarely seen, except in patients in microsatellite instability (MSI) and tissue carcinowith MTS. Sebaceous adenoma is the most genesis. MSI causes malfunccommon subtype, with a tioning of tumor suppressor frequency of 68%.19 9 CAPSULE SUMMARY genes. Approximately one quarter It has been estimated that (27%) of sebaceous neoMuir-Torre syndrome is an inherited around 35% of tumors in plasms are sebaceous syndrome characterized by sebaceous patients with MTS do not epitheliomas, and 30% are neoplasms and visceral malignancies. display MSI, comprising the sebaceous carcinomas.18 A newly identified subtype of Muir-Torre second subtype of MTS (MTS Other cutaneous tumors syndrome displays microsatellite stability II).9 In contrast to MTS I, this include keratoacanthoma, and autosomal recessive inheritance. subtype shows microsatellite basal cell carcinoma with Immunohistochemistry for mismatch stability (Table I). In MTS II, sebaceous differentiation, repair gene products may be considered biallelic inactivation of MYH and cystic sebaceous tuas part of the diagnostic criteria. (OMIM #604933), a base mors6,20,21 (Fig 1). excision repair gene, leads Sebaceous neoplasms An approach to diagnosis based on to an autosomal recessive with MMR deficiency may modified criteria and management is inheritance pattern.9-11 occur outside the head and offered to guide dermatologists when Although there are no clear neck region, in contrast to evaluating patients with sebaceous factors that predispose an insporadic sebaceous tumors neoplasms. dividual to developing tumors that tend to arise on earlier in life, ultraviolet radithe nose and eyelid.22 ation, radiotherapy, and immunosuppression have However, sebaceous neoplasms in the head and been implicated in MTS I. One study reported the neck area should still be subject to immunodevelopment of sebaceous tumors in the pelvic histochemical analysis. These neoplasms are first region, to which radiotherapy had been applied evident as painless, slow-growing, pink or yellow 8 years earlier in the treatment of uterine cancer. The papules, plaques, or nodules, often with central radiotherapy likely triggered loss of the corresponding umbilication and ulceration. Although most of MMR allele, allowing for the accumulation of DNA the sebaceous tumors are benign, sebaceous replication errors.12 In addition, certain immunosupcarcinoma can be aggressive, resulting in local pressants have been associated with increased tumor invasion and metastases. It may be first evident as development in MTS I, including tacrolimus and a cystic nodule, often with ulceration. Because of cyclosporine. These agents increase activity of its benign appearance, biopsy is often delayed.23 transforming growth factor beta and interleukin 6, Cystic sebaceous tumors are well circumscribed facilitating tumor invasiveness, progression, and with a thin cyst wall and tend to be larger and metastases.13-15 In contrast, sirolimus has antimore deeply located than their noncystic neoplastic effects and is recommended for patients counterparts.24 15 with MTS I after transplantation. Keratoacanthomas in MTS usually demonstrate sebaceous differentiation. The presence of multiple keratoacanthomas should prompt EPIDEMIOLOGY immunohistochemical analysis. These keratoaOverall, MTS has a male predilection, with a male canthomas are typical morphologically, evident to female ratio of 3:2.16 One study of 205 cases of MTS as bud-, dome-, or berry-shaped nodules with documented sebaceous tumors appearing before central craters filled with keratinized matter. internal malignancy in 22% of cases, concurrently in They often rapidly increase in size, going 6% of cases, and after in 56% of cases; 16% of cases through 3 stages: proliferative, mature, and demonstrated no temporal relationship.17 The resolving. When subject to immunohistoaverage age that sebaceous neoplasms present is chemical analysis, keratoacanthomas associated 53 years, ranging from 21 to 88 years.17 In addition, with MTS I demonstrate a loss of MMR gene cutaneous tumors occur as long as 25 years before or products.20,25,26 37 years after visceral malignancy.18 d




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Table I. Comparison of Muir-Torre syndrome I and II MTS I d Represents 65% of tumors in MTS patients d Genetic analysis shows microsatellite instability d MSH2, MSH6, MLH1, PMS2 implicated d Autosomal dominant inheritance d Earlier-onset tumors d High penetrance

MTS II Represents 35% of tumors in MTS patients d Genetic analysis does not show microsatellite instability d MYH1 implicated d Autosomal recessive inheritance d Later-onset tumors d Moderate to low penetrance d Gastrointestinal polyposis d

MLH, MutL Homolog; MSH, MutS Homolog; MTS, Muir-Torre syndrome.

because of an overlap with Turcot syndrome, a variant of HNPCC marked by colorectal cancer and gliomas. One study reported that brain tumors occurred in approximately 14% of 288 analyzed families, with higher risk of development in patients with MSH2 mutations versus MLH1 or MSH6 mutations. Glioblastomas were most commonly diagnosed, followed by astrocytomas and oligodendrogliomas.36


Fig 1. Muir-Torre syndrome. Multiple sebaceous tumors on the nose (A) and forehead (B) (arrows). Used with permission; by Schwartz and Torre.3

Visceral malignancies The most common visceral malignancy is colorectal adenocarcinoma, which tends to occur proximal to the splenic flexure rather than distal to it, as in sporadic cancers. An association between gastrointestinal polyposis and MTS was first documented by Schwartz et al,27 in 1980. MTS II may predispose individuals to developing between dozens and a few hundred adenomatous polyps.28 Other reported cancers include those of the endometrium, ovary, small bowel, pancreas, hepatobiliary tract, brain, upper uroepithelial tract, breast, and lung.29,30 Less commonly noted are neuroendocrine small cell carcinoma of the cervix,31 acute myeloid leukemia,32 primary bone sarcoma, chondrosarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, and rhabdomyosarcoma.33 B-cell lymphoma has also been rarely linked to patients with MTS.34,35 Central nervous system malignancies have an increased incidence in patients with MTS, perhaps

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.37-40 Keratoacanthomas may be histologically typical or may show sebaceous elements, designated as sebokeratoacanthomas41 (Fig 3). These tumors have a central crater with keratinized material and extensive keratinization and sebaceous gland differentiation.26 Colorectal adenocarcinomas in this syndrome have distinct histologic characteristics of infiltrating lymphocytes, mucinous/signet-ring differentiation, and medullary growth pattern. These tumors tend to have a better prognosis than sporadic colorectal carcinoma.19

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.


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Table II. Histologic characteristics of sebaceous neoplasms Sebaceous adenoma Sebaceous epithelioma Sebaceous carcinoma

Cystic sebaceous neoplasm

Lobules of sebaceous cells with peripheral basaloid cells that progress to more mature sebocytes centrally Higher proportion of basaloid epithelial cells than adenoma with rare mature sebocytes and ductal elements Basaloid cells arranged in sheets with cytologic atypia, increased mitotic activity, and central areas of comedo-type necrosis; pagetoid intraepidermal spread of tumor cells is commonly seen Thin walls lined with basaloid cells and central progression to sebocytes; more advanced cystic sebaceous tumors demonstrate cytologic atypia, high mitotic activity, and lobules of basaloid cells (Fig 2)

Table III. Positive predictive value of lack of mismatch repair genes in diagnosing Muir-Torre syndrome Gene that is lacking

Positive predictive value

MSH2 MLH1 MSH6 MLH1 and MSH6 MSH2, MLH1, and MSH6 Fig 2. Muir-Torre syndrome. Subcutaneous cyst filled with vacuolated matter, sebaceous cells (arrows), and extracellular lipid matter. (Hematoxylin-eosin stain; original magnification: 340.) Used with permission; by Schwartz and Torre.3

Fig 3. Muir-Torre syndrome. Sebokeratoacanthoma. Histology of a keratoacanthoma with well-differentiated sebaceous lobules (arrows) of sebaceous adenoma. (Hematoxylin-eosin stain; original magnification: 3150.) Used with permission; by Schwartz and Torre.3

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

55% 88% 67% 100% 100%

MLH, MutL Homolog; MSH, MutS Homolog.

keratoacanthomas in areas not exposed to sunlight also suggest the diagnosis (Table IV). Dermoscopy and reflectance confocal microscopy have been used to characterize cutaneous neoplasms. On dermoscopy, sebaceous tumors have 2 main patterns. In tumors with a central crater, dermoscopy demonstrates radial telengiectasis surrounding an ovular, opaque white-yellow center. In tumors without a central crater, dermoscopy shows branching, arborizing vessels overlying a white to yellow background with sporadic yellow comedo-like globules that represent enlarged sebaceous glands. Reflectance confocal microscopy reveals well-circumscribed lesions with lobules of ovoid cells. Basaloid cells surround the lesions and dark tubular structures represent blood vessels.43 More recently, a link between the presence of Fordyce granules and MTS I has been identified. Fordyce granules are intra-oral ectopic sebaceous glands, evident as yellow macules or papules found at the upper lip vermilion, retromolar area, and buccal mucosa. They are extremely rare in the population, and therefore, their presence may be a specific indicator of MTS I.44 Testing with IHC should be performed on lesions to confirm the diagnosis of MTS. IHC showing loss of staining for MMR gene products has an 81% sensitivity for MTS I.45,46 In cases of loss


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Table IV. Modified diagnostic criteria* for Muir-Torre syndrome Group A

Sebaceous adenoma Sebaceous epithelioma d Sebaceous carcinoma d Sebokeratoacanthoma d Immunohistochemistry of tumor, demonstrating negative staining for MLH1 and MSH6 or MSH2, MLH1, and MSH6 d Microsatellite instability in tumor cells d Visceral malignancy d Colorectal tumor with microsatellite instability d Multiple keratoacanthomas d Multiple visceral malignancies d Family history of MTS 1. Positive: detection of a pathogenic mutation 2. Negative: none identified, which does not rule out a mutation not tested; strongly consider personal and family history of malignancy 3. Inconclusive: variant of uncertain significance d d

Group B Group C

Results of genetic testing

MLH, MutL Homolog; MSH, MutS Homolog; MTS, Muir-Torre syndrome. *Either 1 characteristic from Group A and B or all 3 characteristics from Group C to diagnose MTS.

of IHC staining not associated with MTS, inactivation of MMR genes may be caused by gene hypermethylation. Mutations of the BRAF gene (OMIM #164757) or IHC demonstrating loss of p16 are associated with inactivation of MMR genes caused by hypermethylation of DNA. Therefore, the presence of a BRAF mutation or loss of p16 does not suggest the diagnosis of MTS, even with loss of MMR staining.25,47 In contrast, mutations in the KRAS gene (OMIM #190070) may further suggest a diagnosis of MTS.48 In addition, IHC testing of colorectal tumors may be more sensitive and specific for MTS than that of sebaceous neoplasms.49,50 Antibodies against MLH1 and MSH2 may be more valuable than those against PMS2 and MSH6. This is because MLH1 forms a dimer with PMS2, and MSH2 forms a dimer with MSH6. Defective PMS2 and MSH6 are often compensated for by MSH2 and MLH1.51 Negative immunostaining for gene products of MSH2 and MLH1 should prompt surveillance for other cancers. With patients who have a convincing family history and presence of other malignancies, IHC and genetic testing can be used as confirmatory rather than diagnostic tests. Lesions demonstrating a loss of immunohistochemical staining for MMR gene products should be subject to testing with MSI gene locus assays. MSI is assessed using Bethesda markers, which consist of 3 dinucleotide repeats and 2 mononucleotide tracts.52 MSI in 2 of the 5 markers indicates a high probability of MTS. Because microsatellite stability is found in MTS II, patients with a strong family history of malignancy should be referred to a geneticist for further workup and surveillance, even without MSI.

The presence of sebaceous carcinoma warrants lymph node evaluation.23 Reported rates of regional lymph node metastasis range between 3% and 28%.37 However, extraorbital sebaceous carcinoma that usually occurs in MTS has a rate of regional metastasis of 1.4%; therefore, sentinel lymph node biopsy is not routinely recommended.53 Patients with sebaceous tumors should be thoroughly investigated for visceral and neurologic malignancies. This includes performing upper and lower gastrointestinal endoscopy and genitourinary surveillance in patients with sebaceous tumors. In MTS II, colonoscopy should start as early as 18 and 20 years and gastroduodenoscopy at ages 25-30 years. Other indicated tests include chest radiography, gastrointestinal radiography, carcinoembryonic antigen levels, cervical and urine cytology, fecal occult blood testing, and serial measurements of the blood hemoglobin level and liver function tests.

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), FergusonSmith 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


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Fig 4. Algorithm illustration of diagnostic approach and evaluation of a sebaceous neoplasm. Immunohistochemistry, microsatellite instability, and genetic counseling should only be performed after informing the patient of the potential implications of Muir-Torre syndrome, and patient consent should be obtained to perform these tests and inform family members. MLH, MutL Homolog; MSH, MutS Homolog; RCM, reflectance confocal microscopy.

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 treatment, it is associated with higher rates of recurrence and mortality. Therefore, it is reserved for recurrence, regional metastases, and palliative therapy. Chemotherapy relies on DNA damage to induce cytotoxicity and MMR to mediate tumor response. In patients with poor MMR function, tumor cells may become refractory to chemotherapy.35 Lack of MLH1 gene products has been associated with in vitro resistance to doxorubicin and platinum-based chemotherapies.55 Studies in humans demonstrated an increase in mortality in stage 2 and stage 3 cancers with the use of chemotherapy.56 However, other reports have cited appropriate response to 5-fluorouracil in conjunction with platinum-based agents and imiquimod.57-61 Using antibiotics to target genetic abnormalities has been proposed. Typically, eukaryotic release factor (ERF) 1 recognizes a stop codon and initiates protein truncation.62 If transfer RNA successfully competes with ERF 1, the incorporation of an amino acid can occur at a stop codon and translation can continue until the next stop codon. This process is referred to as ‘‘termination suppression.’’63 The use

of aminoglycosides reduces the accuracy of codon recognition by ERF 1, thus allowing transfer RNA to recognize the stop codon, incorporate an amino acid, and prolong translation to produce a potentially functional protein. Although aminoglycosides usually target prokaryotic ribosomal RNA, they also show robust activity at nucleotide regions with nonsense mutations.64 Because the use of aminoglycosides has shown success in genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy, it has potential use in MTS and Lynch syndrome.65,66 However, aminoglycoside use is limited by potential ototoxicity and renal toxicity.67 Other compounds with similar activity include negamycin, a dipeptide antibiotic, and PTC124.68,69

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 Declaration on Human Genetic Data, the physician’s primary responsibility is to protect the privacy of the

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patient.71 Therefore, the patient should decide whether to inform family members. After patient consent is obtained, lesions should be subject to IHC for MMR gene products. Negative staining, indicating lack of MMR gene products, should prompt gene analysis for MSI, genetic counseling, and annual surveillance for internal malignancy.72 Commercial World Wide Web sites, such as and, advertise genetic testing for up to 49 genes related to hereditary cancers. In patients with subsequent negative gene analysis, genetic counseling should still be offered because of the possibility that the patient has MTS II. Detection of BRAF mutations or loss of p16 may allow avoidance of the expensive genetic analysis for MSI, as this suggests a sporadic loss of MMR gene products rather than loss associated with MTS I. We suggest that results of such genetic testing be classified into 3 categories (Table IV). Patients and family members should be reassured that as per the Genetic Information Nondiscrimination Act of 2008, the results of personal or familial genetic tests and genetic counseling cannot be used to deny health insurance or employment. Patients with MTS I who underwent organ transplantation should not be given calcineurin inhibitors, but instead sirolimus as an immunosuppressant.15 In addition, areas of radiation may be subject to more cutaneous neoplasms and should be examined closely. In patients with MTS, cancer surveillance should annually include examination of the breast and pelvis in women, examination of the testicles and prostate in men, colonoscopy starting as early as age 18 years based on genetic subtype of MTS, complete blood cell count, measurement of tumor markers, fecal occult blood, and urinalysis. Colorectal polyps and tumors should also be subject to MSI analysis because of their higher sensitivity and specificity for MTS I.49,50 We recommend adding a thorough central nervous system evaluation, as brain tumors have an increased incidence in patients with MTS. Women with the proven genetic mutation should also undergo annual transvaginal ultrasonography and endometrial biopsy. The authors thank Dr. W. Clark Lambert for his assistance.

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

Muir-Torre syndrome (MTS) is a rare genetic condition that predisposes individuals to skin tumors and visceral malignancies. Because of the potentiall...
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