Muir-Torre Syndrome Workup

Updated: Oct 01, 2020
  • Author: Victor G Prieto, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Laboratory Studies

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]


Imaging Studies

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]


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. [31]

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

Histologic section of sebaceous adenoma showing a Histologic section of sebaceous adenoma showing a predominance of sebaceous cells with prominent cytoplasmic vacuoles.

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.

Histologic section of sebaceous epithelioma showin Histologic section of sebaceous epithelioma showing a predominance of basaloid cells.

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.

Well-differentiated sebocytes in small nests, deep Well-differentiated sebocytes in small nests, deeply infiltrating the subcutaneous tissue, thus consistent with sebaceous carcinoma.

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.

Low-power view of a keratoacanthomalike sebaceous Low-power view of a keratoacanthomalike sebaceous adenoma. Well-circumscribed, symmetrical lesion with overlying papillomatosis and prominent hyperkeratosis and showing focal sebaceous differentiation (arrows).

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 carcinoma typically infiltrates the over Sebaceous carcinoma typically infiltrates the overlying epithelium in a manner similar to Paget disease. Note in this case how the atypical cells have mostly replaced the normal follicular cells and involve the overlying epidermis.

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.

Normal pattern of expression of MSH-2 (nuclear pos Normal pattern of expression of MSH-2 (nuclear positivity) in a sebaceous carcinoma from a patient with Muir-Torre syndrome (see also MSH-6).
Significant loss of MSH-6 expression in this sebac Significant loss of MSH-6 expression in this sebaceous carcinoma in a patient with Muir-Torre syndrome.

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]



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