Muir-Torre Syndrome Workup
- Author: Victor G Prieto, MD, PhD; Chief Editor: Dirk M Elston, MD more...
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.
These mutations in the microsatellite instability enzymes may be detected by genetic studies on peripheral blood or through immunohistochemical analysis of a biopsy specimen. One publication suggests an algorithm that uses first immunohistochemical analysis of tissue samples and then polymerase chain reaction analysis of the genes. Since the four markers come in pairs, it has been suggested that screening with immunohistochemistry only requires examination of PMS-2 and MSH6. If these two markers are preserved, that strongly indicates that the patient does not have MSI.
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.
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.
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 (MTS) patients.
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 the image below. Those cases with cystic degeneration are more likely associated with MTX.
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. 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.[25, 26]
Keratoacanthoma in Muir-Torre syndrome (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 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 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 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, 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. 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.
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