Are You Confident of the Diagnosis?

The Muir-Torre syndrome (MTS) is a cancer-associated genodermatosis characterized by multiple cutaneous lesions comprised of solitary or multiple sebaceous proliferations (benign and malignant) and keratoacanthoma(s), in association with variable systemic cancers that are integral to Lynch syndrome (LS or hereditary nonpolyposis colorectal cancer [HNPCC] phenotype. To diagnose MTS within LS, most clinicians consider it necessary to have the characteristic phenotypes of MTS; that is, one or more of its cutaneous phenotypic lesions with one or more visceral systemic cancers and/or a mutation in a mismatch repair (MMR) gene.

Connection of the Muir-Torre syndrome with Lynch syndrome

Muir and associates, in 1967, and Torre in 1968, were the first to describe isolated patients who had cutaneous stigmata of MTS associated with visceral systemic cancers; however, there were no significant family histories of cancers mentioned in these reports, suggesting that a hereditary cancer-associated genodermatosis was involved. In 1980 and 1981, Lynch and colleagues gave the first reports of cutaneous features of MTS as integral components in four highly investigated family pedigrees that were considered to be classic examples of LS.

A review of MTS patients in our Creighton University cancer pedigree resource and members of these patients’ pedigrees showed them to share certain common systemic visceral cancers with what was then called the Cancer Family Syndrome. The MTS patients were subsequently designated to be part of the autosomal dominant mode of inheritance of LS. These classic examples of LS had different patterns of cutaneous expressions of sebaceous proliferations (benign and/or malignant) and keratoacanthomas occurring in certain high-risk cancer -affected family members in association with different phenotypic patterns of expressions of systemic visceral and extracolonic cancers. The clinical findings led us to postulate that the MTS was a manifestation of an apparently unrelated syndrome, namely LS.

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Since that time, we have come to understand more about MTS’s genotypic and phenotypic heterogeneity, which includes mutations in the MMR genes MSH2, MSH6, MLH1, PMS2; however, recently the heterogeneity has been extended to cases with biallelic MYH mutations. Clearly the MTS cutaneous phenotype is of particular concern when evaluating families with cancers as well as non-cancer phenotypic features.

Obtaining/verifying presence or absence of family histories of cancer occurrences

If the cutaneous phenotypic lesions of the MTS are present before the age of 50 years; they are strong indicators of this rare MTS phenotype of LS. The presence of the isolated MTS clinical features should cause the physician to explore an in-depth a verified family history of at least three generations of the patient’s heritage for these relatively rare cutaneous MTS lesions and/or systemic cancers seen in LS. Such family history studies are ideally performed by a genetic counselor or a trained registered nurse who has the time to contact the MTS patient and relatives, to obtain signed consents from each of the relatives, and to verify the presence of critical medical information of all relatives.

This clinical cancer information can then be shared with all members of the pedigree in order to foster cancer control. It is equally important to verify the presence or absence of the occurrence of cancers in each member of the pedigree. Such an investigation of the members of the MTS patient’s pedigree can change a so-called sporadic MTS occurrence into an important preventative cancer program for those members of the pedigree who have the MTS variant of this LS cancer associated genodermatosis.

There has been a recent groundswell of knowledge about hereditary forms of cancer, although its translation into the clinical setting has been problematic as demonstrated in a study reported in 1993. For example, a comprehensive history of cancers in a family is often the critical key investigative tool in this effort, but is too often insufficiently recorded in many MTS patients’ medical records, thereby compromising its clinical significance in preventative medical care. Obstacles are not just a physician problem; they also involve families who must participate actively in the process of becoming aware of their family cancer histories. Once diagnosed as a member of a cancer-causing hereditary syndrome, the members of the pedigree must comply with surveillance and management recommendations, if cancer control is to be achieved.

Cutaneous manifestations and pathology of MTS

The clinical spectrum of sebaceous benign (adenoma) or malignant proliferations varies in number (single or multiple) as flesh- or yellow- colored papules, plaques or nodules. That spectrum also includes the occurrence of sebaceous epitheliomas with sebaceous differentiation (Figure 1, Figure 2).

Figure 1.

Sebaceous adenoma in a patient with Muir-Torre syndrome. (Courtesy of Bryan Anderson, MD)

Figure 2.

Recurrent sebaceous carcinoma in Muir-Torre syndrome. Small ulcerated yellow papule along the scar line of a previous surgical excision of a sebaceous carcinoma. (Courtesy of Bryan Anderson, MD)

Histologic mucinous and cystic areas within these sebaceous proliferations are considered a marker for MTS (Figure 3, Figure 4). Sebaceous carcinomas can occur with a significant occurrence of metastatic carcinoma. Keratoacanthomas are usually singular but multiple lesions can occur. The clinical manifestations of the cutaneous MTS features vary from extremely mild, such as a single sebaceous adenoma, sebaceous carcinoma, or keratoacanthoma, to that of severe clinical manifestations as reported by us in a gypsy family, wherein the proband had multiple cutaneous MTS features leading to facial disfigurement as well as cancers of the cecum, ascending colon, rectum, and hairy cell leukemia.

Figure 3.

Histology of sebaceous adenoma. (Courtesy of Bryan Anderson, MD)

Figure 4.

Histology of sebaceous carcinoma. (Courtesy of Bryan Anderson, MD)

The malignant cutaneous lesions seen in MTS are sebaceous epitheliomas with sebaceous differentiation or the more serious sebaceous carcinomas. The latter are yellow-colored papules, plaques or nodules that are most often ulcerated and about 1-4 cm in diameter, usually on the head/neck areas; these striking tumors are often seen in the periocular and extraocular tissues. The tissue histology often has Pagetoid or carcinoma in-situ findings in the overlying epidermis. About one third of the sebaceous carcinomas develop metastases to cervical and preauricular lymph nodes.

The accuracy of the histologic diagnosis is improved if the specimens from these patients are reviewed by dermatopathologists who have extensive experience with cancer-associated genodermatoses and their variable spectrum of systemic cancers. Extensive histologic descriptions have been reported and reviewed with accompanying microscopic photographs.

Diagnostic testing of MTS patients

If a suspected MTS or LS family has fulfilled the Amsterdam Criteria or Bethesda Guidelines for these syndromes, we can verify the diagnosis with relatively inexpensive immunohistochemistery (IHC) testing on histologically fixed tissue that is interpreted as being positive by showing absence of the normal protein. If the IHC is considered positive (ie, the absence of staining), the next testing to be considered is MMR testing. The IHC staining of paraffin-imbedded tissue sections of suspicious cutaneous tumors seen in MTS is a reliable screening method with high predictive value for the diagnosis of DNA MMR deficient MTS patients.

The tests should be done on those potentially suspected patients who only have one or more of the characteristic cutaneous lesions seen in MTS patients even though the proband MTS patient does not have visceral or other systemic cancers. In this situation, the identification of LS patients in the pedigree increases their cancer risks which have the potential for the development of visceral and other systemic cancers that occur in the MTS phenotypic stigmata of the LS cancer associated genodermatosis.

Who is at Risk for Developing this Disease?

Muir-Torre is a rare genetic autosomal dominantly inherited disease.

What is the Cause of the Disease?
Molecular genetics of MLH1, MSH2, MSH6, and PMS2 mutations in MTS

Ponti et al screened a cohort of 538 LS patients from 57 LS families in the interest of detecting sebaceous skin tumors (including keratoacanthomas) considering the importance of MMR genes, namely MLH2, MSH2, and MLH6, and their roles in pathogenesis. Their findings showed that among these 57 HNPCC families, four pedigrees were found. with one suspected MTS patient, wherein sebaceous carcinoma was found in a single mutation carrier who did not show a visceral malignancy. Furthermore, “In four of these families, linked to two MLH1 mutations and to two MSH2 mutations, biomolecular characterization showed concordance among immunohistochemistry testing analysis and gene mutations.” They concluded that MLH1 and MSH2 germline mutations showed an equivalent etiopathological role both for LS and for MTS, which indicated broadened clinical and molecular genetic criteria for definition of LS that includes sebaceous neoplasms and keratoacanthomas.

While the predominant mutations in MTS are MLH1 and MSH2, nevertheless, germline mutations other than MMR genes may be important in MTS’s etiology. Specifically, Guillen-Ponce et al described a male who manifested multiple adenomatous colonic polyps, gastric cancer, multiple colorectal cancers (CRC’s) and cutaneous features consonant with MTS. The etiology of this case resulted from the finding of the biallelic mutations in the MYH gene.

In an earlier paper, Ponti et al had described a female with multiple sebaceous gland tumors who manifested early onset colon and thyroid cancers in addition to attenuated polyposis coli and whose family history was positive for multiple colonic adenomas. Her daughter had yellow papules on her forehead region that developed in late infancy. The proband’s colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. In addition, “Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. “

Compound heterozygosity due to biallelic mutations in MYH, R168H, adn 379delC was identified in the proband. The proband’s 11-year-old daughter was a carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in her sister, the R168H MYH gene mutation was detected.” This report is of interest with respect to the association between MYH-associated polyposis and sebaceous gland tumors, findings which suggest that patients with MTS phenotype and multiple colonic polyps should be screened for MYH gene mutations.

Systemic Implications and Complications

From the discussion and the literature, we have summarized the cardinal features of the Lynch syndrome (Table I).

Table I.
Autosomal dominant inheritance pattern seen for LS cancers in the family pedigreeEarlier average age of colorectal cancer (CRC) onset than the general population:  average age of 45 years in LS versus 63 years in the general populationProximal (right -ided) colonic cancer predilection:  70-85% of CRC’s in LS pedigrees are proximal to the splenic flexureAccelerated carcinogenesis (tiny colonic adenomas can develop into carcinomas more quickly): within 2-3 years in LS versus 8-10 years in the general populationHigh risk of additional CRCs:  25-30% of patients having surgery for LS-associated CRC will have a second primary CRC within 10 years of surgical resection if the surgery was less than a subtotal colectomyIncreased risk for malignancy at certain extracolonic sites:–endometrium (40-60% lifetime risk for female mutation carriers)–ovary (12-15% lifetime risk for female mutation carriers)–stomach (higher risk in indigenous Orient families, reasons unknown)–small bowel–hepatobiliary tract–pancreas–upper uro-epithelial tract (transitional cell carcinoma of the ureter and renal pelvis)–brain (Turcot’s syndrome variant of the Lynch Syndrome)                         Sebaceous adenomas, sebaceous malignancies (epitheliomas and carcinomas), and keratoacanthomas in the Muir-Torre syndrome variant of Lynch syndrome.
Pathology of CRC’s is more often poorly diffferentiated, with an excess of mucoid and signet-cell features, a Crohn’s-like reaction, and a significant excess of infiltrating lymphoctes within the tumor
Increased survival from CRC can occur in patients with LS in comparison to patients with sporadic CRC in the general population
The sine qua none for diagnosis is the identification of a germline mutation in a mismatch repair gene (most commonly MLH1, MSH2, or MSH6) that segregates in the family: i.e., members who carry the mutation show a much higher rate of syndrome-related cancers than those who do not carry the mutation

The cardinal features of the Muir-Torre syndrome are summarized in Table II.

Table II.
 Autosomal dominant inheritance patternSebaceous adenomas and or sebaceous malignancies (epitheliomas and carcinomas)Visceral malignancy (Colonic and or urogential)Other findings:–Keratoacanthomas–Basal cell carcinomas with sebaceous differntiationDiagnosis requires at least one sebaceous tumor and 1 visceral carcinomaMutation of the DNA mismatch repair genes hMLH1 and hMSH2

Treatment Options

Treatment options are summarized in Table III.

Table III.
Medical Surgical Physical Modalities
 Sunprotection and routine skin examinations Surgical excision of benign and malignant skin tumors with margin control. At least 5 mm for malignant tumors.  Consider Mohs surgical removal.  
 Routine GI and GU examinations  Routine colonoscopies  

GI, gastrointestinal; GU, genitourinary.

Optimal Therapeutic Approach for this Disease

The benign lesions are removed with simple excision, but the carcinomas will need wider margins of excision of about 5 mm. Mohs surgery has been done in some cases. There have not been adequate numbers of these MTS patients to determine the best choices of chemotherapeutic agents for metastatic sebaceous carcinomas.

A preventive therapy has been used in a few cases of MTS to inhibit the future occurrence of cutaneous lesions with some success; however, the results need to be replicated in larger studies. This therapy consists of inteferon (IFN-alpha-2a) three times a week, oral isotretinoin 50mg daily, with the addition of topical isotretinoin gel. As earlier report in 1985 used low-dose maintenance oral isotretinoin in two patients with keratoacanthoms that stabilized the cutaneous manifestations with inhibition of new lesions.

Patients should have full skin examinations every 6 months.

All patients should see a genetic counselor.

All patients need routine gastroenterology follow-up.

All patients shoud be screened by a urologist or nephrologist.

Patient Management

Recommend follow-up and recommendations for follow-up colonoscopy; urology testing should be determined by the consulting gastroenterologist and urologist/nephrologist. Routine screening annual is typically performed.

Patients should be evaluated by a dermatologist at least 2-3 times yearly. They need to practice sun protection, with monthly self-skin examinations.

Refereral to a physician specializing in genetics is important to screen children and to give patients advice.

Unusual Clinical Scenarios to Consider in Patient Management

Familial adenomatous polyposis (FAP) is quite closely related. It has an initial sign of congenital hypertrophy of the retinal pigment epithelium. FAP’s key characterization of pathology is early development of hundreds to thousands of tubular adenomas in the large intestine, and associated features include upper gastrointestinal polyps, extracolonic malignancies, and desmoid tumors.

Turcot Syndrome is characterized by multiple colorectal adenomatous polyps along with tumors in the brain (glioblastoma multiforme, medulloblastoma). In Turcot’s there are usually fewer than 100 intestinal polyps, and in addition, cafe-au-lait spots and basal cell carcinomas can be seen on the skin

Attenuated FAP is characterized by fewer than 100 adenomatous polyps in the colon. Patients may present with extracolonic features such as gastric polyps or mandibular osteomas. In attenuated FAP, the diagnosis is usually later in life (mean age of 44 years), the right side of the colon tends to be more involved, and the rectum is usually spared.

What is the Evidence?

Burgdorf, W, Pitha, J, Fahmy, A. “Muir-Torre syndrome”. Am J Dermatopathol. vol. 8. 1986. pp. 202-8. (Review of 50 sebaceous tumors in patients with Muir-Torre syndrome. The authors suggest that any sebaceous tumor that is difficult to fully classify may be an indicator of Muir-Torre.)

Weedon, D, Weedon, D. “Tumors of the cutaneous appendages”. Skin pathology. 2010. pp. 775-8. (One of the best texts on dermatopathology. Review of all sebaceous tumors.)

Lynch, HT, Lynch, PM, Lanspa, SJ. “Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis and medicolegal ramifications”. Clin Genet. vol. 76. 2009. pp. 1-18. (Approximately 3% of the 1 million individuals diagnosed with colorectal cancer each year will have the Lynch syndrome. Recommendations for genetic screening and colonoscopy intervals are discussed.)

Muir, EG, Bell, AJ, Barlow, KA. “Multiple primary carcinomata of the colon, duodenum and larynx associated with kerato-acanthomata of the face”. Br J Surg. vol. 54. 1967. pp. 191-5. (Original description by Dr Muir of the constellations of Muir-Torre syndrome.)

Torre, D. “Multiple sebaceous tumors”. Arch Dermatol. vol. 98. 1968. pp. 549-51. (Torre’s landmark article discussing sebaceous tumors.)

Fusaro, RM, Lynch, HT, Pester, J. “Torre’s syndrome as phenotypic expression of cancer family syndrome”. Arch Dermatol. vol. 116. 1980. pp. 986-7. (Discussion of the Torre (Muir-Torre) syndrome in association with familial cancer syndromes.)

Lynch, HT, Lynch, PM, Pester, J. “The cancer family syndrome: rare cutaneous phenotypic linkage of Torre’s syndrome”. Arch Intern Med. vol. 141. 1981. pp. 607-11. (Discussion linking Torre’s syndrome with cancer family syndrome.)

Lynch, HT, Fusaro, RM, Roberts, L. “Muir-Torre syndrome in several members of a family with a variant of the cancer family syndrome”. Br J Dermatol. vol. 113. 1985. pp. 295-301. (Discussion of a family with Muir-torre syndrome and thier underlying cancer family syndrome.)

Lynch, HT, de la Chapelle, A. “Genomic medicine: hereditary colorectal cancer”. N Eng J Med. vol. 348. 2003. pp. 919-32. (Discussion of the overall clinical approach to hereditary colorectal colon cancer.)

Abel-Rahman, WM, Peltomaki, P. “Lynch syndrome and related familial colorectal cancers”. Crit Rev Oncogen. vol. 14. 2008. pp. 1-22. (Review of the Lynch syndrome and findings.)

Ponti, G, Losi, L, Pedroni, M. “Value of MLH1 and MSH2 mutations inthe appearance of the Muir-Torre syndrome phenotype in HNPCC patients presenting with sebaceous gland tumors and keratoacanthomas”. J Invest Dermatol. vol. 126. 2006. pp. 2302-7.

Guillen-Ponce, C, Castillejo, A, Barbera, VM. “Biallelic MYH germline mutations as cause of Muir-Torre syndrome”. Fam Cancer. vol. 9. 2010. pp. 151-4.

Ponti, G, Ponz de Leon, M, Maffei, S. “Attenuated familial adenomatous polyposis and Muir-torre syndrome linked to compound bialleic constitutional MYH gene mutations”. Clin Genet. vol. 68. 2005. pp. 442-7.

Fusaro, RM, Lemon, SJ, Lynch, HT. “The Muir-Torre Syndrome: a variant of hereditary nonpolyposis colorectal cancer syndrome”. J Tumor Marker Oncol. vol. 11. 1996. pp. 19-31.

Watson, P, Lynch, HT. “The tumor spectrum in HNPCC”. Anticancer Res. vol. 14. 1994. pp. 1635-40.

Lynch, HT, Lynch, PM, Pester, JA, Lynch, HT, Fusaro, RM. “Sebaceous neoplasia and visceral cancer (Torre’s syndrome) and its relationship to the cancer family syndrome”. Cancer-associated genodermatoses. 1982. pp. 366-93.

Lynch, HT, Fusaro, RM. “Muir-Torre syndrome: heterogeneity, natural history, diagnosis and management”. Prob Gen Surg. vol. 10. 1993. pp. 1-14.

Lynch, HT, Leibowitz, R, Smyrk, T. “Colorectal cancer and the Muir-Torre syndrome in a Gypsy family: a review”. Am J Gastroenterol. vol. 94. 1999. pp. 575-80.

Fusaro, RM, Hoden, RH, Johnson, LR. “The clinical use of genealogical techniques in cancer investigations: a questionnaire survey”. J Cancer Edu. vol. 8. 1993. pp. 217-25.

Guttmacher, AE, Collins, FS, Carmona, RH. “The family history – more important than ever”. N Engl J Med. vol. 351. 2004. pp. 2333-6.

Rutten, A, Burgdorf, W, Hugel, H. “Cystic sebaceous tumors as marker lesions for the Muir-Torre syndrome: a histopathological and molecular genetic study”. Am J Dermatopathol. vol. 21. 1999. pp. 405-13.

Mathiak, M, Rutten, A, Mangold, E. “Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations”. Establishment of immunohistochemical analysis as a screening test. Am J Surg Pathol. vol. 26. 2002. pp. 338-43.

Machin, P, Catasus, L, Pons, C. “Microsatellite instability and immunostaining for MSH-2 and MLH-1 in cutaneous and internal tumors from patients with Muir-Torre syndrome”. J Cutan Pathol. vol. 29. 2002. pp. 415-20.

Hasain, A, Blumenscchein, G, Esmaeli, B. “Treatment and outcomes of metastatic sebaceous carcinoma of the eyelid”. Int J Dermatol. vol. 47. 2008. pp. 276-9.

Graefe, T, Wollina, U, Schulz, H. “Muir-Torre syndrome – treatment with isotretinoin and interferon alpha-2a can prevent tumor development”. Dermatology. vol. 200. 2000. pp. 331-3.

Spievogel, R, DeVillez, R, Roberts, L. “Oral isotretinoin therapy for familial Muir-Torre syndrome”. J Am Acad Dermatol. vol. 12. 1985. pp. 475-80.