Muir-Torre Syndrome

In 1967, Muir and Torre each reported patients with multiple cutaneous tumors along with visceral malignancies. Muir-Torre syndrome (MTS) is the combination of neoplasms of the skin (usually sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma but also keratoacanthoma) and a visceral malignancy (usually colorectal, endometrial, small intestine, and urothelial).[1]

MTS has an autosomal dominant pattern of inheritance in 59% of cases and has a high degree of penetrance and variable expression.[2, 3, 4, 5]

Muir-Torre syndrome (MTS) is considered to be a subtype of HNPCC.[6, 7] This condition is associated with an inherited defect in one copy of a DNA mismatch repair gene (MMR), which leads to microsatellite instability.[8] The 2 major MMR proteins involved are hMLH1 and hMSH2. Approximately 70% of tumors associated with the MTS have microsatellite instability. While germline disruption of hMLH1 and hMSH2 is evenly distributed in HNPCC, disruption of hMSH2 is seen in greater than 90% of MTS patients.[9] Two other proteins involved in MTS are MSH6 and PMS2.

See Pathophysiology. The main anomaly detected in  Muir-Torre syndrome (MTS) patients is the alteration in the mismatch repair genes, particularly MSH2 on chromosome 2 and MLH1 on chromosome 3.[10] Other genes are MSH-6, MLH-3, and PMS-2.[11] Loss of 2 of the retinoid receptors (RXR-beta and RXR-gamma) seems apparent in sebaceous carcinoma.[12]

Frequency

Muir-Torre syndrome (MTS) is a rare disorder,[13] with approximately 200 patients reported. Families with MTS are probably more common than reported.

Sex

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

Age

The patient's age at presentation of MTS ranges from young adulthood to elderly patients, with a median age of 53 years.[14]

Sebaceous carcinoma is an aggressive neoplasm, which can recur locally after excision and can metastasize. When local recurrences develop, they usually do so within the first five years of excision. Recurrence rates are estimated to be around 30% range.[15]

Relatives of patients should receive genetic counseling.

A positive family history of Muir-Torre syndrome (MTS) can be found in roughly 50% of patients. There is an association with a family history of colon cancer, particularly in patients younger than 50 years.

Cutaneous sebaceous neoplasms can precede or follow a diagnosis of visceral malignancy.[16]

MTS is associated with HNPCC, an autosomal dominant cancer genetic syndrome.[17] The diagnostic criteria (Amsterdam criteria) include the following[18, 19] :

• 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 two 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 histologic examination

Criteria for the diagnosis of Muir-Torre syndrome (MTS) include the presence of at least one sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation; 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 found as well in these patients. In general, sebaceous neoplasms occurring below the neck are more strongly associated with MTS than those lesions arising around the eye or ear.[20] Non–head and neck lesions are more commonly associated with mutations in the epidermal growth factor receptor.[21]

The skin lesions may precede the presentation of internal malignancy, although they often develop later. Cutaneous neplasms 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 a predominance of 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, as shown in the images below. 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.

The distinction of sebaceous carcinoma and adenoma/epithelioma is usually based upon the architecture of the lesion (infiltrative in carcinoma versus circumscribed in adenoma/epithelioma). However, some lesions may have circumscribed borders but do show frank cytologic atypia,[22] while the authors have seen lesions without any degree of cytologic atypia diffusely infiltrating the subcutaneous tissue.

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. Those keratoacanthoma cases with sebaceous differentiation are strongly associated with MTS.

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 chondrosarcomahave also been 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.

In hereditary nonpolyposis colorectal cancer syndrome (HNPCC), 40% of the germline mutations occur in hMSH2 and 35% in hMLH1, while in Muir-Torre syndrome (MTS), a larger majority have mutations in hMSH2. Other markers that may be mutated in a number of cases are MSH-6 and PMS-2.[24, 25]

These mutations in the microsatellite instability enzymes may be detected by genetic studies on peripheral blood or through immunohistochemical analysis of a biopsy specimen. There is a major problem with the latter method in that mutations are seen in sebaceous tumors in patients without the syndrome. The situation is analogous to testing sporadic neurofibromas for mutations in neurofibromin. The mutations are present in the tumor, even though the patient does not have germline mutation or neurofibromatosis. Likewise, a high proportion of sebaceous adenomas demonstrate loss of MSH-2 or MLH-1, but very few of these patients will have MTS. If both PMS-2 and MSH6 are preserved, however, that strongly indicates the patient does not have microsatellite instability.[26]

Stool guaiac may be helpful in detecting colonic carcinomas but colonoscopy will be performed in possible MTS. The tumors may be present at the time of diagnosis, or delayed.[27]

Dermoscopy and confocal microscopy may be helpful in the clinical diagnosis of sebaceous lesions. A review of 20 sebaceous tumors revealed dermoscopic features of radially arranged, elongated crown vessels surrounding opaque structureless yellow areas or yellow comedolike globules and branching arborizing vessels. Confocal microscopy revealed sebaceous lobules composed by clusters of ovoid cells with dark nuclei and bright, highly refractile glistening cytoplasm. These cellular clusters were delimited by a rim of epithelial cells, corresponding to basaloid cells.[28]

Various central nervous system neoplasms have been associated with familial nonpolyposis gut carcinoma, and appropriate imaging should be performed in the presence of suggestive signs or symptoms.[29]

Some studies have indicated that examination of the sentinel lymph node may help in detecting early metastasis and therefore may help staging Muir-Torre syndrome patients.[30]

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.[31]

See the image below. Those cases with cystic degeneration are more likely associated with Muir-Torre syndrome (MTS).

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 the image below.

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. A finding of invasion of the subcutaneous tissue favors a diagnosis of carcinoma over that of adenoma/epithelioma. See the image below.

Immunohistochemistry may be helpful in the differential diagnosis between benign and malignant sebaceous lesions. Carcinomas tend to show strong expression of p53. Interestingly, such lesions appear to show normal nuclear mismatch repair protein expression, thus suggesting a different neoplastic pathway.[32] Also helpful may be demonstration of lipid contents in the vacuoles of the sebaceous cells in less differentiated carcinomas. Adipophilin and periplipin are two such antigens associated with sebaceous differentiation.[33, 34]

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. Sometimes, sebaceous differentiation can be seen, and such cases are more commonly related to MTS. See the image below.

Particularly helpful in the diagnosis of sebaceous carcinoma is the detection of involvement of the overlying epithelium (either conjunctiva or epidermis) similar to Paget disease. See the image below.

Sebaceous neoplasms, with the exception of sebaceous hyperplasia and nevus sebaceus of Jadassohn, are rare and should signal the possibility of MTS. Screening for microsatellite instability 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 al[35] 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 microsatellite instability. Mathiak et al[36] 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 al[37] showed concordance of microsatellite instability 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, hMSH6, or rarely hMLH1, or PM2S, is characteristic of MTS and strongly suggests a germline mutation, which may be confirmed by further genetic testing and counseling.[38]

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. See the images below.

To illustrate the relative frequency of internal malignancy, in a recent study, 19 out of 85 patients with sebaceous neoplasm had visceral malignancies, of which, 41% were genitourinary. Thirty patients had colonic adenomas and polyps. Ten of the 17 patients with internal malignancy and tissue available (59%) had immunohistochemical loss of MMR expression in their sebaceous neoplasms or somatic MMR mutation.[39]

See Procedures.

Oral isotretinoin can possibly prevent some of the neoplasms in persons with Muir-Torre syndrome (MTS).[40] A dosage of as much as 0.8 mg/kg/d may be effective. Graefe et al[41] 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. Targeted immunotherapy is evolving.[42]

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.

Patients with Muir-Torre syndrome should have regular complete examinations, particularly of the gastrointestinal and genitourinary tracts.[43] An annual colonoscopy beginning at age 25 years is desirable because of the high frequency of proximal colorectal cancer. Follow-up care for recurrence or metastasis is mandatory.

The goals of pharmacotherapy for Muir-Torre syndrome (MTS) are to prevent development of neoplasms, reduce morbidity, and prevent complications.

Class Summary

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

Isotretinoin (Amnesteem, Claravis, Myorisan, Absorica)

Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of naturally occurring tretinoin (trans- retinoic acid). Both agents are structurally related to vitamin A.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.