Muir-Torre syndrome: case report and review of the literature

Muir-Torre syndrome (MTS), a subtype of Lynch syndrome II, presents as at least one internal malignancy associated with at least one sebaceous skin tumor. This autosomal-dominant genetic disorder is thought to arise from microsatellite instability. Although not all patients with sebaceous tumors have MTS, even a single biopsy-proven sebaceous adenoma may warrant evaluation for MTS. We report the case of a 76-year-old man with a marked family history of colon cancer; a personal history of colon cancer status post-partial resection of the colon; and multiple cutaneous neoplasms including sebaceous adenomas, sebaceous gland hyperplasia, and basal and squamous cell carcinomas. We review the literature describing MTS and highlight the important role of dermatologists and dermatopathologists in the potential early detection and initial diagnosis of this familial or hereditary colon cancer in patients presenting with cutaneous sebaceous adenomas. Correct diagnosis may be lifesaving in patients with MTS and their at-risk relatives who would benefit from earlier colonoscopy, tumor surveillance, and potential early cancer detection. Muir-Torre syndrome represents yet another dermatologic symptom of an internal disease.     

Muir-Torre syndrome: Diagnostic and screening guidelines

A 65-year-old man presented with a history of multiple skin coloured papules on his face that were asymptomatic. He had an adenocarcinoma resected from his proximal colon 12 years prior to presentation as well as a family history of colon cancer on the maternal side. Diagnostic biopsies showed the lesions to be sebaceous adenomas and epitheliomas and the diagnosis of Muir-Torre syndrome was made. The sebaceous tumour tissue showed microsatellite instability and immunohistochemical staining indicated diminished expression in the DNA mismatch-repair protein complex MSH2/MSH6. Genetic analysis showed a germline mutation in the MSH2 gene confirming the diagnosis of Muir-Torre syndrome. The patient and his first-degree relatives have been referred for genetic counselling and screening. We review the diagnostic criteria in this syndrome and review the recommended screening guidelines.     

Muir-Torre-Syndrom

The Muir-Torre syndrome (MTS) is a rare, autosomal-dominant inherited disease characterized by sebaceous gland tumors and at least one internal malignancy. In many cases a genetic defect known as microsatellite instability can be identified. Similar pathogenetic mechanisms are found in patients with the hereditary non-polyposis colon cancer syndrome, so that at least some patients with MTS are considered as having a phenotypic variant of that syndrome. A 66-year-old woman with MTS, developed multiple malignant cutaneous and visceral tumors over 32 years; in addition, she had multiple sebaceous gland adenomas. Microsatellite instability could be proved with 2 out of 5 studied markers. The family history was positive as numerous relatives of the patient's mother were reported to have developed internal malignancies.     

Muir-torre syndrome with intriguing squamous lesions: a case report and review of the literature

Muir-Torre syndrome (MTS) is an autosomal, dominantly inherited disorder characterized by sebaceous neoplasms and visceral malignancies. We report a 56-year-old woman who underwent resections of extraocular sebaceous carcinoma, sebaceous epithelioma, actinic keratosis, and keratoacanthoma (KA)-like squamous cell carcinoma (SCC) with venous invasion metachronously over a 9-year period. Because of the mixed, unusual features of the skin lesions, and her history of endometrial and colorectal cancers that had been resected 12 years and 1 year, respectively, before the present event, a possible diagnosis of Muir-Torre syndrome was suggested. Immunohistochemical studies revealed loss of hMSH2 expression in all the cutaneous lesions including the actinic keratosis, and also in the endometrial and colorectal cancers. This patient presented with intriguing squamous lesions including keratoacanthoma-like squamous cell carcinoma that showed venous invasion and actinic keratosis, and associated loss of hMSH2 expression, in addition to the sebaceous neoplasms typical of Muir-Torre syndrome.     

Muir-Torre syndrome caused by partial duplication of MSH2 gene by Alu-mediated nonhomologous recombination.

We describe a 54-year-old man with a pedicled tumour on the neck. The surgical specimen revealed a sebaceous carcinoma. He belonged to a cancer-prone family susceptible to gastrointestinal cancer. Systemic evaluation for latent malignancies revealed early-stage colonic adenocarcinoma. These findings were compatible with Muir-Torre syndrome (MTS). Microsatellite instability was detected in the sebaceous carcinoma, suggesting a DNA mismatch repair gene mutation. Moreover, duplication of exon 7 generated a nonsense codon at codon 427 of the MSH2 gene causing truncation of MSH2 protein. Immunohistochemical analysis showed diminished MSH2 protein levels in the sebaceous carcinoma and colonic adenocarcinoma. To date, there have been no reports showing duplication of exon 7 of the MSH2 gene in MTS or hereditary nonpolyposis colorectal cancer kindreds. Furthermore, the present case indicates that the dermatologist plays an important role in the diagnosis of MTS and evaluation for latent malignancies.     

The Muir-Torre syndrome in a black patient with AIDS: histopathology and molecular genetic studies

In 1981, a black man had adenocarcinoma of the colon. In 1986, he had a sebaceous adenoma and the diagnosis of the Muir-Torre syndrome was established. The patient was found to be HIV seropositive in 1986, and 8 years later fulfilled the CDC criteria for AIDS. During 1989 to 1993 the CD4 count was >200 cells/ml and the patient had 2 sebaceous tumors, 1 basal cell carcinoma and 1 keratoacanthoma. In 1994 to 1996, the CD4 count was <200 cells/ml and the patient developed 18 sebaceous tumors and a poorly differentiated adenocarcinoma of the finger which metastasized to axillary lymph nodes. Microsatellite analysis of tumor DNA from a sebaceous adenoma and adenocarcinoma of the finger revealed widespread microsatellite instability. The interaction of AIDS with the behavior of the tumors in the Muir-Torre syndrome has not previously been reported. Although our patient had an increase in the number of new sebaceous tumors at the same time he experienced deterioration of the immune system, he is doing well 15 years after resection of adenocarcinoma of the colon and 16 months after metastatic poorly differentiated adenocarcinoma of the skin. This follows the previously observed tendency for cancers of the Muir-Torre syndrome, especially those displaying widespread microsatellite instability, to be less lethal than their histologically similar counterparts in people without Muir-Torre syndrome.     

Different phenotypes in Muir-Torre syndrome: clinical and biomolecular characterization in two Italian families

The Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the presence of sebaceous gland tumours, with or without keratoacanthomas, associated with visceral malignancies. We describe and characterize two families in which the ample phenotypic variability of MTS was evident. After clinical evaluation, the skin and visceral tumours of one member of a family with 'classic' MTS and one member of a family with a 'peculiar' MTS phenotype without sebaceous lesions, but with only multiple keratoacanthomas, were analysed for microsatellite instability (MSI) and by immunohistochemistry. Tumours of both individuals showed MSI, with a concomitant lack of MSH2 immunostaining in all evaluated skin and visceral lesions; moreover, in the proband of family 2 a constitutional mutation (C-->T substitution leading to a stop codon) in the MSH2 gene was identified. We conclude that the diagnosis of MTS, which is mainly clinical, should take into account an ample phenotypic variability, which includes both cases with typical cancer aggregation in families and cases characterized by the association of visceral malignancies with multiple keratoacanthomas (without sebaceous lesions), without an apparent family history of cancer.     

Considerations on the performance of immunohistochemistry for mismatch repair gene proteins in cases of sebaceous neoplasms and keratoacanthomas with reference to Muir-Torre syndrome

Cutaneous sebaceous tumors, as well as keratoacanthomas, are associated with Muir-Torre syndrome (MTS). Visceral neoplasias are a feature of this syndrome; thus, early detection using a cutaneous biopsy is very important in dermatopathology. A dermatopathologist can apply different techniques in such cases, including immunohistochemistry for several mismatch repair proteins or molecular studies for microsatellites instability. However, in a world where economic resources play an increasing role, how discriminative the dermatopathologist should be in investigating cutaneous lesions that may indicate MTS is not a trivial matter. Although previous reports have presented algorithms on MTS focusing on a multidisciplinary approach, our report emphasizes the role of the dermatopathologist and tries to answer several questions that could arise when facing a cutaneous tumor that may indicate MTS.     

Muir-Torre syndrome: clinical features and molecular genetic analysis

We report a 62-year-old man with rectal cancer, two keratoacanthomas and multiple sebaceous adenomas, epitheliomas and sebaceous hyperplasia. His brother and father died from colorectal cancer. A subgroup of patients with the Muir-Torre syndrome (MTS) is allelic to the cancer family syndrome. This genetic disorder is caused by an autosomal dominant inherited germline mutation in one of the DNA mismatch repair genes. It is thought that a somatic mutation of the other allele leads to a genomic instability responsible for tumorigenesis. In the patient presented here the instability was detected in two characteristic skin lesions; sebaceous adenoma and epithelioma. The search for a causal germline mutation revealed a frameshift mutation in the mismatch repair gene hMSH2 leading to a truncated protein. A presymptomatic molecular diagnosis can be offered to the children of the patient.     

An illustrative case of Muir-Torre syndrome: contribution of immunohistochemical analysis in identifying indicator sebaceous lesions

BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the association of at least 1 cutaneous sebaceous tumor and 1 internal malignancy, often arising in the gastrointestinal tract. It is secondary to germline mutations in DNA mismatch repair genes, mainly MLH-1 and MSH-2. OBSERVATIONS: We report the case of a 54-year-old man with a 2-year history of skin-colored papules clinically reminiscent of large sebaceous hyperplasias on the nose and back, but histologically diagnosed as sebaceous adenomas and epitheliomas. His family history was positive for colon cancer in the mother and 2 brothers. A colonoscopy done during the hospitalization revealed 2 sessile polyps in the left colon, both showing a low-grade dysplasia on the biopsy specimen. Immunohistochemical staining performed on the cutaneous and colic biopsy specimens revealed a lack of expression of MSH-2 and MSH-6. Genetic testing revealed microsatellite instability in the colon and cutaneous tumors. CONCLUSION: The immunohistochemical testing for MSH-2, MSH-6, and MLH-1 is useful for rapid identification of an underlying mismatch repair defect and early diagnosis of MTS.     

A case of multiple sebaceous epithelioma: analysis of microsatellite instability

Sebaceous gland tumor is a rare disease that is a sign of Muir-Torre syndrome, an autosomal, dominantly inherited genodermatosis characterized by the presence of at least one sebaceous gland tumor and a minimum of one internal malignancy. Recent studies have indicated that defective DNA mismatch repair occurs in Muir-Torre syndrome. Cutaneous lesions may occur before diagnosis of the internal cancer. We describe a 64-year-old male patient with multiple sebaceous epitheliomas with no evident internal malignancy. Microsatellite instability, determined by examining dinucleotide CA repeats at the microsatellite loci, was observed in DNA from one sebaceous epithelioma but not from the other two sebaceous epitheliomas or from one basal cell epithelioma with sebaceous differentiation, suggesting that this condition is unlikely to be due to germ-line mutation of mismatch repair genes.     

Muir-Torre syndrome.

Muir-Torre syndrome is characterized by multiple sebaceous tumors, various internal malignancies and an autosomal dominant inheritance. We herein report a typical case. The patient was a 69-year-old man with sebaceous adenomas, a keratoacanthoma, and actinic keratosis in addition to carcinomas of the prostate, colon, duodenum, and larynx. His family members also suffered from multiple cancers.     

Muir-Torre syndrome

A 65-year-old man with a history of multiple neoplastic and pre-neoplastic gastrointestinal lesions as well as urogenital carcinoma presented for evaluation of two asymptomatic skin-colored papules in the head and neck region. Biopsy revealed sebaceous neoplasms and immunohistochemical staining was negative for the presence of hMSH-2 protein in both specimens. These findings were consistent with a diagnosis of Muir-Torre syndrome in the setting of a prior history of visceral malignancies. Muir-Torre Syndrome is a rare autosomal dominant genodermatosis associated with mutations in mismatch repair proteins, hMSH-2 and hMLH-1, which predispose affected patients to visceral malignancies as well as sebaceous gland neoplasms.     

Muir-Torre Syndrome

In this case report of Muir-Torre syndrome (MTS), we describe a 47-year-old man with a personal and family history of colon cancer and a personal history of keratoacanthoma who presented with a sebaceous carcinoma and, subsequently, had a cystic sebaceous tumor. Immunohistochemical examination of the patient's colonic tumor, located proximal to the splenic flexure, revealed absence of MutL homolog (MLH)-1 protein. MTS is a rare genodermatosis defined clinically by the occurrence of a sebaceous neoplasm and an internal malignancy in the absence of other predisposing factors. Most patients present with sebaceous adenomas, but cystic sebaceous neoplasms have been reported as specific markers of MTS. Gastrointestinal and genitourinary cancers are the most common internal malignancies, with colorectal cancers often occurring at or proximal to the splenic flexure, contrary to most sporadic colorectal cancers. MTS is most frequently found as a variant of the autosomal dominant disorder hereditary non-polyposis colorectal cancer (HNPCC), with tumors demonstrating microsatellite instability and germline mutations in the DNA mismatch repair genes MutS homolog (MSH)-2 and MLH1. However, the distribution of gene mutations of patients with MTS is slightly different from that seen in all HNPCC families, and some cases of MTS arise spontaneously. Physicians should consider MTS in patients presenting with a sebaceous neoplasm, and immunohistochemical examination of tumors for MSH2 and MLH1 protein can be used as a screening test to identify patients with MTS. While the sebaceous and internal neoplasms of MTS are thought to follow a more indolent course than sporadic malignancies, patients with this disorder should be treated with standard therapies and carefully followed. Evidence indicates that for individuals with or at risk of MTS or HNPCC, colonoscopy every 1-2 years beginning at age 20-25 or 10 years younger than the youngest age at diagnosis in the family can be strongly recommended. Additionally, most experts believe that an annual history and physical examination, including a complete skin examination and urinalysis, as well as periodic endometrial sampling and/or transvaginal ultrasound for women, are worthwhile screening tests for these high-risk patients.     

An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients

Sebaceous carcinomas are rare cutaneous appendageal tumors that may occur sporadically or in association with an internal malignancy in Muir-Torre syndrome. In Muir-Torre syndrome microsatellite instability can often be demonstrated in tumor DNA as a result of an inherited mutation in one of several known mismatch repair genes; however, the role of microsatellite instability in sporadic sebaceous carcinomas has not been previously studied. In this report we describe the clinicopathologic characteristics of a series of unselected sebaceous carcinomas and examine them for the presence of microsatellite instability. Of 10 consecutive tumors identified over a 10 y period, only one was from a patient known to have Muir-Torre syndrome. Of the nine presumed sporadic cases, five were from four renal transplant recipients and four from otherwise healthy individuals. Microsatellite instability was demonstrable in three cases: in the Muir-Torre syndrome-associated tumor and in two tumors from transplant patients. Microsatellite instability was subsequently also found in a sebaceous carcinoma from a further transplant patient prospectively sought from another institution. The presence of microsatellite instability in post-transplant sebaceous carcinomas was associated with loss of expression of the mismatch repair protein hMSH2. In summary, sebaceous gland carcinomas, while characteristic of Muir-Torre syndrome, are commonly found outside this context. Among presumed sporadic cases, our data suggest they may be over-represented in immunosuppressed renal transplant recipients. The presence of microsatellite instability in transplant-associated lesions, together with loss of hMSH2 expression suggests that immunosuppression might unmask a previously silent Muir-Torre syndrome phenotype in some cases. Alternatively, there is experimental evidence to suggest that immunosuppressive drugs, most plausibly azathioprine, could select for the emergence of a mutator phenotype and thus predispose to the development of sebaceous carcinomas. The role of mismatch repair defects in other post-transplant skin malignancies remains to be established.     

Muir-Torre syndrome - treatment with isotretinoin and interferon alpha-2a can prevent tumour development

Muir-Torre syndrome is a genodermatosis in which multiple internal malignancies are associated with cutaneous sebaceous tumours and kerato-acanthomas. A 57-year-old man presented with multiple sebaceous tumours, kerato-acanthomas, verrucous carcinoma of the nose, renal cell and transitional cell carcinomas of the left kidney, adenoma of the colon and a positive family history of colon carcinoma. He was treated with interferon (IFN-alpha2a) s.c. 3 x 10(6) U three times a week along with 50 mg isotretinoin daily as well as topical isotretinoin gel. During a follow-up of 29 months, only 1 sebaceous skin tumour developed and was removed, whereas more than 30 such skin tumours had been surgically removed during the last 3 years. No evidence of internal tumour development or recurrence was found. The combination of IFN with retinoids seems to be of promise to prevent tumour development in Muir-Torre syndrome.     

Muir-Torre syndrome. An interdisciplinary challenge

Muir-Torre syndrome (MTS) is a rare autosomal dominant tumor syndrome characterized by the occurrence of tumors of the sebaceous glands and/or multiple keratoacanthomas in addition to internal neoplasia. Skin tumors include not only sebaceous adenomas and sebaceomas but also sebaceous carcinomas which are associated with colorectal carcinomas in over 50%, less commonly with carcinomas of the remaining gastrointestinal, urinary or genital tract. The underlying pathogenesis is a defect of the DNA mismatch repair system introducing microsatellite instability in tumor tissue.     

p53 staining correlates with tumor type and location in sebaceous neoplasms

Sebaceous neoplasms are commonly considered in their relationship to the Muir-Torre syndrome and the now well-documented loss of DNA mismatch repair proteins leading to microsatellite instability. However, sebaceous neoplasms showing microsatellite instability comprise only a subset of this group of tumors, and thus, alternative tumorigenic mechanisms must exist. This article explores the relationship of p53, a tumor suppressor implicated in other cutaneous malignancies, and sebaceous neoplasia. We examined 94 sebaceous tumors from 92 patients. Tumors with strong nuclear p53 staining were significantly associated with the diagnosis of sebaceous carcinoma compared with benign sebaceous lesions, most notably for periocular carcinomas. Importantly, nuclear mismatch repair protein expression was intact in all lesions showing p53 alterations, suggesting that p53 dysfunction may represent a divergent pathway in the molecular pathogenesis of these tumors.     

Microsatellite instability and immunostaining for MSH-2 and MLH-1 in cutaneous and internal tumors from patients with the Muir-Torre syndrome

BACKGROUND: Muir-Torre syndrome (MTS) is characterized by the co-existence of sebaceous gland tumors of the skin and internal malignancies. Currently, MTS is regarded as a variant of the hereditary non-polyposis colon cancer syndrome (HNPCC). Both MTS and HNPCC are secondary to germline mutations in DNA mismatch repair genes (mainly MSH-2 and MLH-1). METHODS: Cutaneous (eight sebaceous adenomas, one sebaceous carcinoma and one keratoacanthoma) and internal tumors (four colonic adenocarcinomas, two endometrial carcinomas, two transitional cell carcinomas of renal pelvis and ureter, one adenocarcinoma of the small bowel, one ovarian carcinoma and one colonic tubular adenoma) were obtained from six patients with MTS and were subjected to microsatellite instability (MI) analysis, and to immunostaining for MLH-1 and MSH-2. MI was assessed by evaluating three (CA)n dinucleotide repeats (D2S123, D5S346, D17S250) and the mononucleotide tracts BAT 26 and BAT 25. RESULTS: All cutaneous and internal tumors exhibited MI. An immunohistochemical concordance between all tumors within each single patient was obtained in five cases. In these five patients all tumors exhibited a lack of MSH-2 staining, consistent with a germline abnormality in this gene. In the one remaining case, the immunohistochemical staining in the sebaceous adenoma was negative for MLH-1 and positive for MSH-2, consistent with a germline alteration in MLH-1. However, the colonic adenocarcinoma in that patient showed positivity for MSH-2 and an equivocal positivity for MLH-1. CONCLUSIONS: The results confirm that tumors from patients with MTS exhibit MI. Moreover, immunostaining for MLH-1 and MSH-2 may be useful to identify the most probable gene responsible for the disease in each family.     

Sebaceous neoplasms in Muir-Torre syndrome

A 59-year-old Japanese woman presented with two sebaceous neoplasms on the chest wall and on the left cheek. The patient had a history of ascending colon cancer, and her mother had died of gastric cancer. The histopathologic features of both sebaceous neoplasms were vaguely in accordance with those of sebaceous adenoma and sebaceoma. Based on these findings, we diagnosed the patient as having Muir-Torre syndrome. The sebaceous neoplasm on the chest wall exhibited features of a sebaceous adenoma with a unique cystic appearance, namely cystic sebaceous adenoma, which has been reported as a specific marker for Muir-Torre syndrome (MTS). However, histopathologically, both the sebaceous adenoma and sebaceoma had relatively large, vesicular or heterochromous and crowded nuclei with some pleomorphism and distinct nucleoli associated with some mitotic figures, casting doubt on their benignancy. We show that some or most benign sebaceous neoplasms in MTS might have a high potential for malignant transformation or may be well-differentiated sebaceous carcinomas with low-grade malignancy, mimicking sebaceous adenoma/sebaceoma. This results in difficulties in classification regarding sebaceous neoplasms in MTS.