AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1967, Muir and Torre each reported on patients with multiple cutaneous tumors (including sebaceous neoplasms and other tumors) and visceral malignancies (including gastrointestinal and other sites). Muir-Torre syndrome (MTS) is a syndrome that combines at least one sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma) and at least one visceral malignancy (usually gastrointestinal or genitourinary carcinomas). MTS has an autosomal dominant pattern of inheritance in 59% of cases and has a high degree of penetrance and variable expression.

Pathophysiology

MTS is considered a subtype of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC). This condition is associated with an inherited defect in one copy of a DNA mismatch repair gene (MMR), which eventually leads to microsatellite instability (MSI). The 2 major MMR proteins involved are hMLH1 and hMSH2. Approximately 70% of tumors associated with the MTS have MSI. While germline disruption of hMLH1 and hMSH2 is evenly distributed in HNPCC, disruption of hMSH2 is seen in greater than 90% of MTS patients.

Frequency

United States

MTS is a rare disorder, with approximately 200 patients reported. Families with MTS are probably more common than reported.

Mortality/Morbidity

In many patients, the skin cancers tend to have a nonaggressive course. Despite this, approximately 60% of patients reportedly develop metastatic disease, with a 50% survival rate calculated at 12 years. Those lesions outside the head and neck may have a more aggressive behavior.

Sex

The syndrome occurs in both sexes, with a male-to-female ratio of 3:2.

Age

The patient's age at presentation ranges from young adulthood to elderly patients, with a median age of 53 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• A positive family history of MTS can be found in roughly 50% of patients.
• An association with a family history of colon cancer has also been documented.
• Cutaneous sebaceous neoplasms can precede or follow a diagnosis of visceral malignancy.
• MTS is associated with HNPCC, an autosomal dominant cancer genetic syndrome. The diagnostic criteria (Amsterdam criteria) include the following:
• • Three or more relatives with an HNPCC-associated cancer (ie, colorectal, cancer of the endometrium, small bowel, ureter, or renal pelvis)
  • Cancer affecting at least 2 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 examination in a pathology laboratory

Physical

Criteria for the diagnosis of MTS include the presence of at least one sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma (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 included in the cutaneous tumors. The skin lesions may precede the presentation of internal malignancy, although they often develop later. Cutaneous nodules 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 MTS. 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 MTS, 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 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 (see Media Files 1-2). 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.
• Keratoacanthoma, whether solitary or multiple, is frequently seen in MTS. 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.
• The most common visceral neoplasm in MTS 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 chondrosarcoma, are reported. Intestinal polyps occur in at least one quarter of patients. Other benign tumors described in MTS include ovarian granulosa cell tumor, hepatic angioma, benign schwannoma of the small bowel, and uterine leiomyomas.

Causes

See Pathophysiology. The main anomaly detected in these patients is the alteration in the mismatch repair genes (MSH2 on chromosome 2 and MLH1 on chromosome 3).

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Basal cell nevus syndrome
Metastatic renal cell carcinoma (clear cell variant)
Extramammary Paget disease (for those sebaceous carcinoma cases with prominent pagetoid involvement of the overlying epidermis)

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• In HNPCC, 40% of the germline mutations occur in hMSH2 and 35% in hMSH1, while in MTS, a larger majority have mutations in hMSH2. These mutations may be detected by genetic studies on peripheral blood. Because the presence of MSI can now be established more easily with immunostaining of a biopsy specimen, peripheral blood studies are ordered less commonly.
• Stool guaiac may be helpful in detecting colonic carcinomas.

Histologic Findings

Sebaceous adenoma is composed of variably sized, incompletely differentiated sebaceous lobules. Lobules contain basaloid cells at the periphery and mature sebaceous cells, with characteristic cytoplasmic vacuoles toward the center (see Media File 3).

Sebaceous epithelioma (also known as sebaceoma) differs from sebaceous adenoma mainly in regards to the degree of differentiation. Sebaceous epithelioma lacks the lobular architecture and sebaceous maturation of sebaceous adenoma, and contains an obvious preponderance of undifferentiated cells (see Media File 4).

Sebaceous carcinoma is an outright malignant neoplasm with prominent cellular pleomorphism and anaplasia. Sebaceous carcinomas are common on the eyelid and tend to present with pagetoid extension of atypical sebaceous cells in the conjunctiva or in the epidermis. Occasionally, the tumor invades the adipose tissue of the orbit.

Keratoacanthoma in MTS often shows the typical histologic findings of sporadic keratoacanthomas, with marked epithelial proliferation and a crater filled with a large keratin plug (see Media File 5). Sometimes, sebaceous differentiation can be seen, and such cases are more commonly related to MTS.

Sebaceous neoplasms, with the exception of sebaceous hyperplasia and nevus sebaceus of Jadassohn, are rare and should signal the possibility of MTS. Screening for MSI in sebaceous tumors is of value in the detection of inherited DNA mismatch repair defects, which predispose to the various types of internal cancers in persons with MTS.

Kruse et al¹ demonstrated that sebaceous gland tumors frequently have high microsatellite instability in comparison with a variety of other randomly selected tumors and that sebaceous gland hyperplasia rarely exhibits high MSI. Mathiak et al² demonstrated that immunohistochemical testing of MTS-related skin tumors for MLH1 and MSH2 is a reliable screening method with high predictive value for the diagnosis of the DNA mismatch repair-deficient MTS. Ponti et al³ showed concordance of MSI and immunohistochemical analysis in patients with MTS. This indicates that the clinical, biomolecular, and immunohistochemical characterization of skin tumors may be used as screening for the identification of families at risk of MTS.

The immunohistochemical demonstration of loss of hMSH2, or rarely hMLH1, is characteristic of MTS and strongly suggests a germline mutation, which may be confirmed by further genetic testing and counseling. The absence of this finding does not exclude MTS, and screening evaluation for internal malignancy should still be considered in patients with sebaceous neoplasms other than sebaceous hyperplasia.

TREATMENT

Section 6 of 11  

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• Differentials
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Oral isotretinoin can possibly prevent some of the neoplasms in persons with MTS. A dosage of as much as 0.8 mg/kg/d may be effective. Graefe et al⁴ note in a case report that the combination of interferon with retinoids may be of promise to prevent cutaneous tumor development in persons with MTS. They used interferon (interferon alfa-2a) SC 3 X 10⁶ U 3 times/wk in combination with 50 mg isotretinoin daily and topical isotretinoin gel.

Surgical Care

Benign sebaceous tumors and keratoacanthomas can be conservatively treated with excision or cryotherapy. Sebaceous carcinoma should be excised completely and followed-up for detection of possible metastases.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Retinoids

These agents regulate cell growth and proliferation. They may prevent some of the neoplasms in MTS.

FOLLOW-UP

Section 8 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

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

Patient Education

• Relatives of patients should receive genetic counseling.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Biopsy specimens that only include the upper portion of the lesion may result in a diagnosis of sebaceous adenoma/epithelioma because the deep infiltrative component of well-differentiated sebaceous carcinomas may be missed.
• Patients with sebaceous neoplasms (other than sebaceous hyperplasia or nevus sebaceus) may have MTS; therefore, the possibility of internal malignancies should be considered.
• Poorly differentiated sebaceous carcinomas may show only focal sebaceous differentiation (scalloped nuclei). Therefore, such lesions may be interpreted to be squamous cell carcinomas.

MULTIMEDIA

Section 10 of 11  

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Sebaceous carcinoma of the upper eyelid. Courtesy of Mark S. Brown, MD, University of South Alabama Medical Center.
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Media file 2:  Sebaceous carcinoma as viewed from the conjunctival side (same patient as in Media File 1). Courtesy of Mark S. Brown, MD, University of South Alabama Medical Center.
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Media file 3:  Histologic section of sebaceous adenoma showing a predominance of sebaceous cells with prominent cytoplasmic vacuoles.
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Media file 4:  Histologic section of sebaceous epithelioma showing a predominance of basaloid cells.
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Media file 5:  Histologic section of keratoacanthoma showing the characteristic central crater with a keratin plug.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Follow-up
• Miscellaneous
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• References

1. Kruse R, Rutten A, Schweiger N, Jakob E, Mathiak M, Propping P, et al. Frequency of microsatellite instability in unselected sebaceous gland neoplasias and hyperplasias. J Invest Dermatol. May 2003;120(5):858-64. [Medline].
2. Mathiak M, Rutten A, Mangold E, Fischer HP, Ruzicka T, Friedl W, et al. 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. Mar 2002;26(3):338-43. [Medline].
3. Ponti G, Losi L, Di Gregorio C, Roncucci L, Pedroni M, Scarselli A, et al. Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry. Cancer. Mar 1 2005;103(5):1018-25. [Medline].
4. Graefe T, Wollina U, Schulz H, Burgdorf W. Muir-Torre syndrome - treatment with isotretinoin and interferon alpha-2a can prevent tumour development. Dermatology. 2000;200(4):331-3. [Medline].
5. Barana D, van der Klift H, Wijnen J, Longa ED, Radice P, Cetto GL, et al. Spectrum of genetic alterations in Muir-Torre syndrome is the same as in HNPCC. Am J Med Genet A. Mar 15 2004;125(3):318-9. [Medline].
6. Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med. May 1991;90(5):606-13. [Medline].
7. Honchel R, Halling KC, Schaid DJ, Pittelkow M, Thibodeau SN. Microsatellite instability in Muir-Torre syndrome. Cancer Res. Mar 1 1994;54(5):1159-63. [Medline].
8. Kruse R, Rutten A, Lamberti C, Hosseiny-Malayeri HR, Wang Y, Ruelfs C, et al. Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Am J Hum Genet. Jul 1998;63(1):63-70. [Medline].
9. Lynch HT, Fusaro RM, Roberts L, Voorhees GJ, Lynch JF. Muir-Torre syndrome in several members of a family with a variant of the Cancer Family Syndrome. Br J Dermatol. Sep 1985;113(3):295-301. [Medline].
10. Ponti G, Losi L, Pedroni M, Lucci-Cordisco E, Di Gregorio C, Pellacani G. Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or keratoacanthomas. J Invest Dermatol. Oct 2006;126(10):2302-7. [Medline].
11. Rao NA, Hidayat AA, McLean IW, Zimmerman LE. Sebaceous carcinomas of the ocular adnexa: A clinicopathologic study of 104 cases, with five-year follow-up data. Hum Pathol. Feb 1982;13(2):113-22. [Medline].
12. Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol. Jul 1995;33(1):90-104. [Medline].
13. Spielvogel RL, DeVillez RL, Roberts LC. Oral isotretinoin therapy for familial Muir-Torre syndrome. J Am Acad Dermatol. Mar 1985;12(3):475-80. [Medline].
14. Wick MR, Goellner JR, Wolfe JT 3rd, Su WP. Adnexal carcinomas of the skin. II. Extraocular sebaceous carcinomas. Cancer. Sep 1 1985;56(5):1163-72. [Medline].

Article Last Updated: Jun 4, 2007