MTS refers to the independent descriptions made more than four decades ago by Drs Muir and Torre of sebaceous neoplasms occurring coincident with internal malignancy. We now understand this syndrome to represent a subset of the hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome. HNPCC is an autosomal dominant cancer predisposition syndrome due to inheritance of a defective gene encoding a DNA mismatch repair protein. Loss of wild-type allele leads to genomic microsatellite instability (MSI).62, 63
Although initially reported having a predisposition solely to colorectal cancer, these patients actually show an increased risk of various malignancies, including endometrial, ovarian, genitourinary, and small bowel cancers. Multiple primary tumours are common, and patients typically present at earlier age with malignancy.62
Many of these patients demonstrate germ-line mutations in genes encoding DNA mismatch repair proteins MLH1 or MSH2 and, less commonly, MSH6, MSH3, MLH3, PMS1 and PMS2. These proteins function to detect and repair errors in base pairing occurring during DNA replication, especially in regions of DNA (microsatellites) characterized by repetitive mono- or dinucleotide repeats. Consistent with the Knudson hypothesis, mismatch repair protein mutation, when paired with a second somatic mutational “hit” of the remaining functional allele, leads to susceptibility to tumour formation through the accumulation of base pair mismatches and increasing genomic instability.64
The “second hit” may be through somatic mutation or methylation suppression,65
although a small report has suggested that loss of heterozygosity by complete allele loss is unlikely to be a common mechanism.66
Conceptually, mismatch repair genes can be considered tumour suppressor genes.
MTS comprises a small subset (1–3%) of HNPCC families and is characterized by sebaceous tumours or perhaps keratoacanthomas preceding or existing coincidently with visceral malignancies.67
Because the sebaceous lesions may be the presenting feature of a patient with MTS, increasing reports are being published regarding recommendations for patient screening following the diagnosis of a sebaceous tumour.17, 68–72
The diagnosis of a sebaceous neoplasm should prompt additional clinical and/or laboratory screening, and a currently accepted method to evaluate for the functional status of mismatch repair proteins within the sebaceous tumour is the use of immunohistochemistry with antibodies against the commonly encountered lost mismatch repair proteins, MSH2 and MLH1, sometimes with MSH6 as well17, 68–72
(). A lack of nuclear imunoreactivity within tumour cells is supportive of a mutation in the gene and has been shown to correlate well with high levels of MSI, as assessed by the gold standard of polymerase chain reaction-based amplification and chromatographic or electrophoretic assessment of multiple, defined microsatellite regions of DNA73–76
The sebaceous tumour (a) from this Muir–Torre patient shows nuclear expression of MLH1 (b) with loss of MSH2 (c) on immunohistochemistry. The overlying epidermis serves as an internal positive control.
Figure 8 The BAT26 microsatellite shows increased variability in a sebaceous tumour from a Muir–Torre patient (lower panel) compared with normal tissue from the same patient (upper panel). This DNA-based test uses polymerase chain reaction amplification (more ...)
Although all types of sebaceous neoplasms (with the exception of strictly defined sebaceous hyperplasia) have been the subject of reports linking them to MTS,77–80
more recent literature has attempted to better define a genotype–phenotype correlation of the syndrome by confirming the presence of mutations in mismatch repair gene or loss of the encoded proteins within sebaceous neoplasms. Interestingly, in contrast to the colorectal carcinomas of HNPCC, the sebaceous neoplasms implicated in MTS more often display loss of MSH2 much more commonly than MLH1.17, 71, 81, 82
Isolated mutations in MSH6 are noted exceptionally,82
but MTS has not yet been linked to isolated loss of MSH3 or PMS1. Only a subset of sebaceous neoplasms demonstrate evidence of mismatch repair deficiency determined by various tests, ranging from 26 to 59% overall with obvious referral bias in the published series.17, 71, 72
Interestingly, benign sebaceous lesions (sebaceous adenomas and sebaceomas) have been shown to have significantly higher rates of mutations than carcinomas—either extraocular or periocular.17, 18, 82
Moreover, several reports have now documented that loss of mismatch repair proteins is more common in sebaceous tumours occurring outside of the head and neck region and may more strongly suggest MTS.17, 18, 71
Strong indicators of MTS include multiple sebaceous neoplasms, but only a single cutaneous tumour can herald the syndrome. Alternative mechanisms of pathogenesis within the spectrum of MTS may exist, since not all patients with sebaceous neoplasia and a characteristic internal malignancy display MSI.
Additional morphological properties have been suggested to correlate with syndrome-associated sebaceous lesions. Keratoacanthoma-like and cystic change had both been proposed as occurring more frequently in MTS-associated sebaceous lesions83, 84
(). However, a recent report did not find cystic change to be statistically associated with sebaceous tumours demonstrating loss of mismatch repair protein expression, but additional study is needed.17
More recently, the presence of increased intratumoral lymphocytes has been shown to correlate with MSI, similar to the feature commonly seen in colorectal carcinomas associated with MSI.71, 85
a, Sebaceous adenoma with cystic features. b, Sebaceous adenoma with keratoacanthoma-like architecture. Both of these features are thought to more specifically suggest the Muir–Torre syndrome, but more study is needed.
Interestingly, mutations in the genes for mismatch repair proteins may not be the only mechanism by which to obtain an MTS phenotype. Mutations in the gene MYH
, inherited in an autosomal recessive manner, result in an attenuated gastrointestinal polyposis phenotype, with patients showing an increased risk of colorectal carcinoma and other cancers.86
The protein product of MYH
is involved in DNA base excision repair following DNA oxidative damage. Several case reports have now noted the presence of sebaceous neoplasms in patients with MYH-associated polyposis syndrome, and one paper established that these sebaceous lesions did not exhibit MSI.87–89