Background

This rare syndrome is manifested by multiple skin tumors including keratoacanthomas, sebaceous neoplasms including sebaceous carcinoma, and internal visceral malignancies, particularly of the gynecological and gastrointestinal tract. It is an autosomal dominantly inherited disease. Recent work in molecular biology has revealed that this disease is a variant of the cancer syndrome known as . This syndrome is a defect in the DNA mismatch repair genes.

OUTLINE

Disease Associations
Pathogenesis
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

DISEASE ASSOCIATIONS	CHARACTERIZATION
AIDS
The Muir-Torre syndrome in a black patient with AIDS: histopathology and molecular genetic studies. Warschaw KE, Eble JN, Hood AF, Wolverton SE, Halling KC. Department of Dermatology, Indiana University School of Medicine, Indianapolis, USA.	J Cutan Pathol 1997 Sep;24(8):511-8 Abstract quote 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 sero-positive 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.
ALPHA-1 ANTITRYPSIN DEFICIENCY
Muir-Torre syndrome associated with alpha 1-antitrypsin deficiency and cutaneous vasculitis. Report of a case with exacerbation of a cutaneous neoplasm during immunosuppressive therapy. Guitart J, McGillis ST, Bergfeld WF, Tuthill RJ, Bailin PL, Camisa C. Department of Dermatology, Cleveland Clinic Foundation, Ohio.	J Am Acad Dermatol 1991 May;24(5 Pt 2):875-7 Abstract quote We describe a patient with both Muir-Torre syndrome and alpha 1-antitrypsin deficiency. A keratoacanthoma developed after immunosuppressive therapy for necrotizing vasculitis. To our knowledge, this is the first reported case of Muir-Torre syndrome associated with alpha 1-antitrypsin deficiency.
CANCER FAMILY SYNDROME
Muir-Torre syndrome in several members of a family with a variant of the Cancer Family Syndrome. Lynch HT, Fusaro RM, Roberts L, Voorhees GJ, Lynch JF.	Br J Dermatol 1985 Sep;113(3):295-301 Abstract quote Distinguishing cutaneous signs which are associated with hereditary cancer-prone syndromes are known as cancer-associated genodermatoses. Muir-Torre syndrome (M-T) is characterized by the occurrence of sebaceous hyperplasia, adenoma and carcinoma, basal cell carcinoma with sebaceous differentiation, and/or keratoacanthoma in association with visceral cancer (often multiple), and improved survival. Family studies of M-T have been either wholly lacking or too incomplete to elucidate hereditary aetiology. We describe the cutaneous phenotype of M-T in an extended kindred with a possible variant of the Cancer Family Syndrome. We emphasize the need for more thorough documentation of family histories and cancer association in this cancer-associated genodermatosis in order to clarify hereditary syndrome identification, and to improve cancer control through employment of cutaneous signs as a beacon for highly targeted forms of visceral cancer.
Genetic linkage in Muir-Torre syndrome to the same chromosomal region as cancer family syndrome. Hall NR, Murday VA, Chapman P, Williams MA, Burn J, Finan PJ, Bishop DT. Imperial Cancer Research Fund Genetic Epidemiology Laboratory, St. James's University Hospital, Leeds, U.K.	Eur J Cancer 1994;30A(2):180-2 Abstract quote The Muir-Torre syndrome, in which sebaceous gland tumours occur in association with internal malignancy, is inherited as an autosomal dominant disorder. Many features of the syndrome are similar to those of the Lynch II cancer family syndrome, and thus the two disorders might share a common genetic basis. We typed two large families with DNA markers on chromosome 2p around D2S123, a site recently shown to be linked to the Lynch II syndrome. LOD scores at this locus demonstrated significant and tight linkage to D2S123, suggesting that defects in the same gene might give rise to both syndromes.
Muir-Torre syndrome: a variant of the cancer family syndrome. Hall NR, Williams MA, Murday VA, Newton JA, Bishop DT. Imperial Cancer Research Fund Genetic Epidemiology Laboratory, St James's University Hospital, Leeds, UK.	J Med Genet 1994 Aug;31(8):627-31 Abstract quote Muir-Torre syndrome is characterised by the association of sebaceous tumours of the skin with internal malignancy. In many instances there is a strong family history of cancer and the autosomal dominant mode of inheritance, tumour spectrum, and high incidence of synchronous and metachronous tumours show parallels with the cancer family syndrome or Lynch II syndrome. We report a five generation family with at least two persons displaying the Muir-Torre phenotype, while many other family members have had tumours consistent with cancer family syndrome. The majority of tumours are gastrointestinal, gynaecological, and urological, with several persons having multiple primaries. The prognosis appears to be better than would be expected. Sebaceous tumours are a marker for internal malignancy and should prompt a search for occult cancer in the individual person and family members. In documented Muir-Torre families, at risk persons should be entered into screening programmes similar to those used in the Lynch II syndrome.
HEREDITARY NON-POLYPOSIS COLORECTAL CANCER SYNDROME
The Muir-Torre syndrome: a rare variant of hereditary nonpolyposis colorectal cancer associated with hMSH2 mutation. Suspiro A, Fidalgo P, Cravo M, Albuquerque C, Ramalho E, Leitao CN, Costa Mira F. Servico de Gastroenterologia and Centro de Patobiologia Molecular, Instituto Portugues de Oncologia Francisco Gentil, Lisboa.	Am J Gastroenterol 1998 Sep;93(9):1572-4 Abstract quote The Muir-Torre syndrome is a rare autosomal dominant disorder characterized by the association of visceral malignancies with typical skin lesions. This syndrome is now considered a subtype of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC). This last condition has been ascribed to mutations in four mismatch repair genes, and similar mutations, mostly located at hMSH2 gene, are now being described in some Muir-Torre patients. We describe the case of a 64-yr-old woman with no family history of colorectal cancer, who developed two visceral malignancies belonging to the usual spectrum of hereditary nonpolyposis colorectal cancer (colon and stomach), beginning at age 41. She additionally developed several skin tumors, including multiple keratoacanthomas, thus fulfilling Muir-Torre diagnostic criteria. Because of her cutaneous phenotype, she was screened for DNA mismatch repair gene mutations by in vitro synthetized protein assay (IVSP) and a truncating mutation was identified at hMSH2. We further discuss the clinical significance of the Muir-Torre phenotype, the association of this syndrome with hMSH2 mutations and the important implications of genetic diagnosis for the patient and her offspring.
Colorectal cancer and the Muir-Torre syndrome in a Gypsy family: a review. Lynch HT, Leibowitz R, Smyrk T, Fusaro RM, Lynch JF, Smith A, Franklin B, Stella A, Liu B. Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.	Am J Gastroenterol 1999 Mar;94(3):575-80 Abstract quote OBJECTIVES: The Muir-Torre syndrome (MTS) is characterized by an autosomal dominant predilection to sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, in concert with the cancer phenotype of hereditary nonpolyposis colorectal cancer (HNPCC). Proof that patients showing a familial aggregation of MTS's cutaneous signs in combination with a specific pattern of visceral cancers which are consonant with an HNPCC diagnosis has been buttressed by the discovery of hMSH2 and hMLH1 germ-line mutations in such families. Our purpose in this investigation was to determine the germ-line mutation in a Gypsy family with MTS in concert with HNPCC cancer features, and to provide genetic counseling. An added objective for this paper is to review the literature on MTS. METHODS: We describe a Gypsy family with MTS in concert with HNPCC cancer features, as well as the molecular genetic and genetic counseling procedures used in the interest of improved compliance with cancer control recommendations. We review the clinical phenotype, natural history, and molecular genetics involved in the MTS variant HNPCC. RESULTS: An hMSH2 germ-line mutation was identified as the culprit germ-line mutation in this family. CONCLUSIONS: The presence of the hMSH2 germ-line mutation in this family provides powerful predictability of colorectal and other HNPCC integral cancers. The gastroenterologist must assume an important role in the diagnosis and management of MTS.
Microsatellite instability in benign skin lesions in hereditary non-polyposis colorectal cancer syndrome. Swale VJ, Quinn AG, Wheeler JM, Beck NE, Dove-Edwin I, Thomas HJ, Bodmer WF, Bataille VA. Academic Department of Dermatology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK.	J Invest Dermatol 1999 Dec;113(6):901-5 Abstract quote The coexistence of cutaneous and extra-cutaneous malignancies within one family could be explained by shared genetic mechanisms such as common tumor suppressor gene mutations or oncogene activation, as well as mutations in DNA repair genes. Hereditary non-polyposis colorectal cancer syndrome (HNPCC) and its variant Muir-Torre syndrome (MTS) are caused by germline DNA mismatch repair gene mutations. Colonic and endometrial tumors from HNPCC patients exhibit microsatellite instability (MSI), as do sebaceous lesions in MTS. We recruited individuals from cancer prone families to determine if MSI is found in benign and malignant skin lesions and to assess whether MSI in the skin is predictive of genomic instability with susceptibility to tumors characteristic of HNPCC. One hundred and fifteen benign, dysplastic, and malignant skin lesions from 39 cancer prone families were analyzed. Thirteen benign skin lesions from three individuals belonging to two HNPCC pedigrees showed MSI. No mutations in hMSH2 and hMLH1 were found in two of the three individuals with RER + skin lesions. We found MSI in non-sebaceous non-dysplastic skin lesions in HNPCC pedigrees. MSI was not found in skin lesions within other family cancer syndromes. These results have important clinical implications as the detection of MSI in prevalent readily accessible skin lesions could form the basis of noninvasive screening for HNPCC families. It may also be a valuable tool in the search for new mismatch repair genes.
HYPERLIPIDEMIA
Muir-Torre syndrome associated with a family history of hyperlipidemia. Rodenas JM, Herranz MT, Tercedor J, Lopez B, Naranjo R, Delgado V. Department of Dermatology, Hospital Universitario, Granada, Spain.	J Am Acad Dermatol 1993 Feb;28(2 Pt 2):285-8 Abstract quote The Muir-Torre syndrome is a rare disorder characterized by sebaceous neoplasms of the skin and multiple visceral malignancies. The syndrome appears to be a familial, autosomal dominant condition. We diagnosed this syndrome in a previously unreported patient and found a personal and family history of malignancies and hyperlipidemia. The association of Muir-Torre syndrome with a family history of hyperlipidemia, another autosomal dominant condition, has not been previously reported. The possible genetic relationship between the two disorders is discussed.
TRANSPLANTATION
An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients. Harwood CA, Swale VJ, Bataille VA, Quinn AG, Ghali L, Patel SV, Dove-Edwin I, Cerio R, McGregor JM. Center for Cutaneous Research, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College	J Invest Dermatol 2001 Feb;116(2):246-53 Abstract quote 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.

 

PATHOGENESIS	CHARACTERIZATION
MISMATCH REPAIR GENES
Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Kolodner RD, Hall NR, Lipford J, Kane MF, Rao MR, Morrison P, Wirth L, Finan PJ, Burn J, Chapman P. Division of Cell and Molecular Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.	Genomics 1994 Dec;24(3):516-26 Abstract quote Hereditary nonpolyposis colorectal carcinoma (HNPCC) is a major cancer susceptibility syndrome known to be caused by inheritance of mutations in genes such as hMSH2 and hMLH1, which encode components of a DNA mismatch repair system. The MSH2 genomic locus has been cloned and shown to cover approximately 73 kb of genomic DNA and to contain 16 exons. The sequence of all the intron-exon junctions has been determined and used to develop methods for analyzing each MSH2 exon for mutations. These methods have been used to analyze two large HNPCC kindreds exhibiting features of the Muir-Torre syndrome and demonstrate that cancer susceptibility is due to the inheritance of a frameshift mutation in the MSH2 gene in one family and a nonsense mutation in the MSH2 gene in the other family.
Widespread microsatellite instability in sebaceous tumours of patients with the Muir-Torre syndrome. Peris K, Onorati MT, Keller G, Magrini F, Donati P, Muscardin L, Hofler H, Chimenti S. Department of Dermatology, University of L'Aquila, Italy.	Br J Dermatol 1997 Sep;137(3):356-60 Abstract quote Muir-Torre syndrome (MTS) is an autosomal dominant disorder characterized by the presence of at least one sebaceous gland tumour and a minimum of one visceral malignant tumour. Recently, microsatellite instability (MSI) has been detected in the tumours of patients with MTS and germline mutations of the hMSH2 and hMLH1 mismatch repair genes have been detected in some patients with this syndrome. To determine if the tumours of patients with MTS have widespread genomic instability and whether loss of heterozygosity (LOH) in the chromosomal regions containing hMSH2 and hMLH1 is detectable, MSI and LOH were examined at 10 dinucleotide repeats on chromosomes 2p, 3p, 5q, 9p, 17p and 18q. Data were obtained from six sebaceous gland tumours and two adenocarcinomas of the colon from three patients of two Muir-Torre families. MSI was detected at more than half of the loci tested in all sebaceous tumours examined. In addition, there was LOH at D2S119 in one sebaceoma and one sebaceous carcinoma from one patient. The colon carcinomas from two patients showed MSI at five of the 10 loci analysed. These results show that widespread MSI is a feature of tumours in patients with MTS. In addition, the finding of LOH at D2S119, a marker located in the vicinity of hMSH2, in sebaceous tumours of one patient indicates that this gene may have a pathogenetic role in this patient.
Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Kruse R, Rutten A, Lamberti C, Hosseiny-Malayeri HR, Wang Y, Ruelfs C, Jungck M, Mathiak M, Ruzicka T, Hartschuh W, Bisceglia M, Friedl W, Propping P.	Am J Hum Genet 1998 Jul;63(1):63-70 Abstract quote Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. About half of MTS patients are affected by colorectal cancer. In a subgroup of MTS patients the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlying cause of the MTS phenotype. We ascertained 16 MTS patients with sebaceous skin tumors and colorectal cancer, and we examined their skin and visceral tumors for microsatellite instability. All the patients exhibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS patients revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic search for germ-line mutations in patients ascertained on the basis of sebaceous skin tumors. Our results indicate that (1) MTS patients exhibit significantly more mutations in the hMSH2 gene than in the hMLH1 gene; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical criteria for HNPCC.
Is the mismatch repair deficient type of Muir-Torre syndrome confined to mutations in the hMSH2 gene? Kruse R, Lamberti C, Wang Y, Ruelfs C, Bruns A, Esche C, Lehmann P, Ruzicka T, Rutten A, Friedl W, Propping P. Institute of Human Genetics, University of Bonn, Germany.	Hum Genet 1996 Dec;98(6):747-50 Abstract quote The Muir-Torre syndrome (MTS) is a rare autosomal-dominant condition characterized by the occurrence of sebaceous skin lesions and internal tumours in a patient. It has been demonstrated that at least a subgroup of MTS exhibits clinical and molecular genetic features of hereditary nonpolyposis colorectal cancer, including microsatellite instability in skin and visceral tumours, because of mutations in DNA mismatch repair genes. We have identified germline mutations in the hMSH2 gene in two unrelated MTS patients ascertained because of their skin tumours. Our results, together with published MTS cases, support the hypothesis that MTS with its characteristic skin lesions is confined to mutations in the hMSH2 gene.
Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome. Entius MM, Keller JJ, Drillenburg P, Kuypers KC, Giardiello FM, Offerhaus GJ. Academic Medical Center, Department of Pathology, Amsterdam, The Netherlands.	Clin Cancer Res 2000 May;6(5):1784-9 Abstract quote Sebaceous gland carcinomas (SGCs) are rare malignant skin tumors occurring sporadically or as a phenotypic feature of the Muir-Torre syndrome (MTS). A subset of patients with MTS have a variant of the hereditary nonpolyposis colorectal cancer syndrome caused by mutations in mismatch repair (MMR) genes, which lead to microsatellite instability (MSI). We evaluated the value of MSI and loss of expression of the MMR genes, hMLH-1 and hMSH-2, as a marker to identify and distinguish MTS from sporadic SGC. Using a nationwide pathology report database system, we identified patients with the MTS phenotype. SGCs from 10 MTS patients and the colorectal carcinomas from 3 additional MTS patients were collected. In addition, SGCs from eight patients without a history of visceral neoplasm were collected. MSI was detected in 9 of 13 MTS-associated tumors (69%) versus 0 of 8 sporadic SGCs (P = 0.002). Except for the age of onset of colorectal carcinoma [58 years in the MSI-positive group versus 69.8 years in the MSI-negative group (P = 0.17)], no differences were seen between the MSI-negative and the MSI-positive MTS patients. Loss of expression of hMLH-1 (n = 4) or hMSH-2 (n = 4) was found in MSI-positive patients only. MSI and loss of expression of MMR genes can be used as markers for MTS in patients with SGC. Consequently, MSI and loss of MMR gene expression in a patient presenting with SGC as the initial malignancy have important consequences for the patient and family. There are at least two variants of MTS with different molecular genetic mechanisms because 31% of the patients with the MTS phenotype had no MSI.
Probable involvement of a germ-line mutation of an unknown mismatch repair gene in a Japanese Muir-Torre syndrome phenotype. Kubota T, Dakeishi M, Nozaki J, Manabe M, Koizumi A. Department of Dermatology, Akita University School of Medicine, Akita, Japan.	J Dermatol Sci 2000 Jun;23(2):117-25 Abstract quote A combination of haplotype analysis and direct sequencing were conducted on Japanese Muir-Torre syndrome kindred. In the kindred, two females revealed a hereditary non-polyposis colon cancer (HNPCC) phenotype and one male had a sebaceous tumor in addition to a HNPCC phenotype. Haplotype analysis and direct sequencing failed to show involvement of the known mismatch repair genes, with the exception of MSH5, in this kindred. Analysis of large fragments (from 3.9 to 6. 2 kb) covering the entire 25 kb MSH5 gene in the proband revealed the absence of gross changes in the promoter region and exons. The direct sequencing of the promoter region and all 25 exons failed to demonstrate any mutations in the coding regions except for a CA repeat polymorphism in intron 3 and a C/A polymorphism in intron 15. Taken together present results indicate that a novel and yet unknown mismatch repair gene is likely involved in the HNPCC in this kindred.
"Second hit" in sebaceous tumors from Muir-Torre patients with germline mutations in MSH2: allele loss is not the preferred mode of inactivation. Kruse R, Rutten A, Hosseiny-Malayeri HR, Bisceglia M, Friedl W, Propping P, Ruzicka T, Mangold E.	J Invest Dermatol 2001 Mar;116(3):463-5 Abstract quote Muir-Torre syndrome is an autosomal-dominant inherited disorder predisposing to both sebaceous skin tumors and internal neoplasms. In a significant proportion of Muir-Torre syndrome patients skin tumors exhibit microsatellite instability as a hallmark of hereditary nonpolyposis colorectal cancer. Most individuals predisposed to hereditary nonpolyposis colorectal cancer harbor a germline mutation in the DNA mismatch repair genes MSH2 or MLH1. In Muir-Torre syndrome the vast majority of germline mutations have been identified in MSH2. Microsatellite instability in tumor tissue develops after somatic inactivation of the corresponding second mismatch repair allele ("second hit"). So far, the mechanisms of somatic inactivation of the second allele in microsatellite instability positive tumors from patients with known mismatch repair germline mutations are not well understood. We examined whether allele loss (loss of heterozygosity) is a frequent mechanism for inactivation of the second MSH2 allele in a sample of nine microsatellite instability positive skin tumors from eight unrelated Muir-Torre patients with known MSH2 germline mutations. Loss of heterozygosity was determined using microsatellite markers or heteroduplex analysis, respectively. Only one of the nine skin tumors exhibited loss of heterozygosity at the MSH2 locus. Thus, we could show in a sample of sebaceous tumors from patients with genetically proven Muir-Torre syndrome that loss of heterozygosity most probably is not the preferred mode of somatic inactivation of the second MSH2 allele.
Molecular pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis. Southey MC, Young MA, Whitty J, Mifsud S, Keilar M, Mead L, Trute L, Aittomaki K, McLachlan SA, Debinski H, Venter DJ, Armes JE. Department of Pathology, Victorian Breast Cancer Research Consortium, Peter MacCallum Cancer Institute, and the Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.	Am J Surg Pathol 2001 Jul;25(7):936-41 Abstract quote The Muir-Torre syndrome (MTS) is an autosomal dominantly inherited disorder, characterized by visceral malignancies and sebaceous skin lesions. In a subset of MTS families the disease is due to an underlying DNA mismatch-repair defect. We have identified a MTS family whose spectrum of reported neoplasia included adenocarcinomas of numerous gastrointestinal sites, carcinomas of the endometrium, ovary and breast, papillary transitional cell carcinoma of the ureter, a range of cutaneous tumors, as well as keratoacanthomas. All tumors were tested for microsatellite instability and immunohistochemically stained for expression of MLH1 and MSH2 proteins. All tumors were found to be microsatellite unstable and lacking in MSH2 protein expression. The subsequent mutation detection focused on hMSH2, and a germline mutation was identified (CAA-->TAA, Gln-->STOP, codon 337). This mutation was subsequently found in a family member with a single skin lesion only. We propose that the combination of immunohistologic and microsatellite instability analysis can be exploited to screen individuals with characteristic skin lesions even before development of visceral tumors and to direct the subsequent germline mutation search. The profile of microsatellite instability and the genes rendered dysfunctional differed between tumor samples, suggesting that the molecular pathogenesis varied between lesions, despite a common germline mutation.
Loss of DNA Mismatch Repair Proteins in Skin Tumors From Patients With Muir-Torre Syndrome and MSH2 or MLH1 Germline Mutations: Establishment of Immunohistochemical Analysis as a Screening Test. Mathiak M, Rutten A, Mangold E, Fischer HP, Ruzicka T, Friedl W, Propping P, Kruse R. Institute of Pathology (M.M., H.-P.F.) and Institute of Human Genetics (E.M., W.F., P.P.), University of Bonn, Bonn, the Department of Dermatology (R.K., T.R.), Heinrich-Heine-University, Dusseldorf, and the Laboratory of Dermatohistopathology (A.R.), Friedrichshafen, Germany.	Am J Surg Pathol 2002 Mar;26(3):338-343 Abstract quote Muir-Torre syndrome (MTS) is a rare autosomal-dominant disorder characterized by the predisposition to both sebaceous skin tumors (or multiple keratoacanthomas) and internal malignancies. A subtype of MTS is allelic to hereditary nonpolyposis colorectal cancer and is caused by germline mutations in the DNA mismatch repair genes MSH2 or MLH1. In these cases both internal and skin tumors show characteristic microsatellite instability (MSI). The aim of the present study was to determine whether immunohistochemical examination of MSH2 or MLH1 protein expression in MTS-associated skin tumors can be used as a diagnostic screening tool to identify patients with germline mutations in MSH2 or MLH1. In the present study 28 skin lesions from 17 patients (20 sebaceous gland tumors, 4 sebaceous hyperplasias, 3 keratoacanthomas, and 1 squamous cell carcinoma) were tested immunohistochemically with antibodies against MSH2 and MLH1. Eighteen of these tumors were from eight patients with known MSH2 germline mutations, two tumors were from a patient with a germline mutation in MLH1, and eight microsatellite stable sporadic skin tumors served as controls. One sample had to be excluded because of a lack of immunoreactivity. All eight microsatellite stable tumors expressed both DNA repair proteins. In 15 of the tumors from MSH2 germline mutation carriers, loss of MSH2 expression was observed, one tumor showed reduced MSH2 expression, and one tumor displayed positive immunoreactivity to MSH2. Both tumors of the MLH1 germline mutation carrier showed loss of the MLH1 protein. In conclusion, our findings demonstrate that immunohistochemical testing of MTS-related skin tumors is a reliable screening method with high predictive value for the diagnosis of the DNA mismatch repair-deficient MTS.
Microsatellite instability and immunostaining for MSH-2 and MLH-1 in cutaneous and internal tumors from patients with the Muir-Torre syndrome. Machin P, Catasus L, Pons C, Munoz J, Conde-Zurita JM, Balmana J, Barnadas M, Marti RM, Prat J, Matias-Guiu X. Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona Department of Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Department of Pathology, Hospital de Valme, Seville, Department of Medicine, Dermatology, Hospital Universitari Arnou de Vilanova, Universitat de Lleida, Spain.	J Cutan Pathol 2002 Aug;29(7):415-420 Abstract quote 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.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
The Muir-Torre syndrome: a 25-year retrospect. Schwartz RA, Torre DP. UMD New Jersey Medical School, Newark, NJ 07103-2714, USA.	J Am Acad Dermatol 1995 Jul;33(1):90-104 Abstract quote The Torre or Muir-Torre syndrome consists of certain types of sebaceous neoplasms of the skin, with or without keratoacanthomas, and one or more low-grade visceral malignancies in the absence of other predisposing factors. The sebaceous tumors are relatively uncommon or rare: sebaceous adenoma, sebaceous epithelioma, basal cell epithelioma with sebaceous differentiation, and sebaceous carcinoma. Sebaceous hyperplasia and hamartomas such as nevus sebaceus of Jadassohn, with or without a sebaceous epithelioma within it, are not a defining part of this syndrome. Sebaceous hyperplasia is common in elderly light-complexioned people with or without this syndrome. Nevus sebaceus of Jadassohn is not rare and is predisposed to the development of other neoplasms within it, including occasionally a sebaceous epithelioma. Colonic polyps are frequently present. Muir-Torre syndrome requires recognition because affected patients are at risk of multiple primary malignancies. The skin lesions may be the first sign of this syndrome, although more often its cutaneous signs follow the diagnosis of at least the first visceral malignancy. The Muir-Torre syndrome portends the greater possibility of a favorable prognosis than might be anticipated otherwise because the visceral cancers are usually low-grade malignancies. However, they are often multiple, so identifying such patients will affect their management in a few ways. Because these indolent visceral malignancies tend to permit prolonged survival, even metastatic disease may respond well to aggressive surgical treatment. The sebaceous cancers in this syndrome, like the visceral malignancies, are less aggressive than their counterparts unassociated with this syndrome. Because this syndrome is inherited in an autosomal dominant manner, identifying one patient means delineating an entire family, which should be investigated. This syndrome may be caused by a defective mismatch DNA repair gene.
GASTROINTESTINAL TUMORS
Obstructive jejunal adenocarcinoma in the Muir-Torre syndrome. Panday SC, Go IH, Mravunac M, de Koning RW. Department of Internal Medicine, Canisius Wilhelmina Hospital, Nijmegen, Netherlands.	Neth J Med 1993 Oct;43(3-4):116-20 Abstract quote A young male patient was referred for endoscopic resection of a recto-sigmoid polyp and abdominal complaints. His medical history revealed a sebaceous adenoma resection from his back and a tubular adenoma excision from his right upper eyelid. After disclosure of a jejunal tumour on a small bowel enema and given the remarkable family history characterized by the frequent occurrence of bowel cancer, the diagnosis of Muir-Torre syndrome was established. This syndrome pertains to the combination of sebaceous gland tumours/adenomas in combination with gastrointestinal or genitourinary tract tumours. Inheritance takes place in an autosomal dominant manner. It usually occurs in males at an early age. Given its low malignancy potential, early detection of the syndrome renders a favourable prognosis. Careful examination and follow-up also involving the small intestine are mandatory for patients and relatives.
Muir-Torre syndrome: case report of a patient with concurrent jejunal and ureteral cancer and a review of the literature. Akhtar S, Oza KK, Khan SA, Wright J. Department of Medicine, University Hospital, State University of New York, Health Science Center at Syracuse, New York, USA.	J Am Acad Dermatol 1999 Nov;41(5 Pt 1):681-6 Abstract quote BACKGROUND: Muir-Torre syndrome is a rare autosomal dominant genodermatosis, first described in 1967, characterized by the presence of sebaceous tumors and an internal malignancy in the absence of other predisposing factors. OBJECTIVE: Our purpose was to review and update published literature on Muir-Torre syndrome. METHODS: We describe a 66-year-old white man with a history of sebaceous tumors and newly diagnosed transitional cell cancer of the right ureter and adenocarcinoma of the jejunum. The literature on Muir-Torre syndrome is reviewed by means of MEDLINE search and available published reports and updated. RESULTS: Only 205 cases of Muir-Torre syndrome with 399 internal malignancies have been reported. The common presentation is the presence of sebaceous tumors along with a low-grade visceral malignancy. Sebaceous tumors appeared before the internal malignancy in 45 cases (22%), concurrently in 12 (6%), and after the internal malignancy in 114 (56%). In 33 (16%) of 205 patients, a temporal relationship was not reported. The total number of sebaceous gland carcinomas reported is 44; 17 of 44 were neoplasms of the meibomian gland. Keratoacanthomas have been noted in 48 (23%) of 205 patients. Gastrointestinal cancers are the most common internal malignancies (61%), followed by genitourinary (22%). CONCLUSION: The presence of sebaceous tumors warrants a search for an internal malignancy. In patients with Muir-Torre syndrome, regular follow-up and search for new malignancy is mandatory. Evaluation and monitoring of the family members of patients are also necessary. Patients and their families should be counseled for genetic testing. Genetic analysis of the primary tumor and skin lesions should be arranged as an added research tool if possible to better understand the disease.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
GENITOURINARY TUMORS
Genitourinary tumors in men with the Muir-Torre syndrome. Davis DA, Cohen PR. Department of Medicine, University of Colorado Medical School, Denver, USA.	J Am Acad Dermatol 1995 Nov;33(5 Pt 2):909-12 Abstract quote The Muir-Torre syndrome is an autosomal dominant genodermatosis characterized by the occurrence of one or more sebaceous gland tumors (either adenoma, epithelioma, or carcinoma) and a single malignant internal neoplasm. To date, 133 cases of Muir-Torre syndrome have been described. Colorectal (49%) and genitourinary (21%) carcinomas are the most common initial neoplasms. The case of a man with a history of recurrent ocular sebaceous carcinoma who subsequently had seminoma is described, and previously published reports of men with Muir-Torre syndrome and genitourinary tumors are discussed. Including this report, an associated genitourinary tumor was the initial malignant internal neoplasm in 11 men with Muir-Torre syndrome. The detection of a genitourinary neoplasm preceded diagnosis of the patient's Muir-Torre syndrome-associated sebaceous gland tumor in five patients (45%). All patients with sebaceous gland tumors of the type associated with Muir-Torre syndrome warrant consideration of Muir-Torre syndrome and appropriate workup to detect asymptomatic malignant visceral neoplasms.
KERATOACANTHOMA
SEBACEOUS TUMORS
Muir-Torre syndrome. Histologic spectrum of sebaceous proliferations. Burgdorf WH, Pitha J, Fahmy A.	Am J Dermatopathol 1986 Jun;8(3):202-8 Abstract quote The sebaceous proliferations seen in patients with Muir-Torre syndrome are unique and difficult to classify. Having reviewed over 50 skin biopsies from five patients with Muir-Torre syndrome, we conclude that the primary proliferation involves the hair follicle and most often resembles either a keratoacanthoma or a sebaceous proliferation, but may have histologic features of both lesions. Unusual patterns seen in the sebaceous components may include solid basaloid sheets, mucinous areas, and convoluted glands.
Sebomatricoma: a unifying term that encompasses all benign neoplasms with sebaceous differentiation. Sachez Yus E, Requena L, Simon P, del Rio E. Department of Dermatology (Hospital Universitario San Carlos, Madrid, Spain.	Am J Dermatopathol 1995 Jun;17(3):213-21 Abstract quote Literature regarding neoplasms with sebaceous differentiation is confusing, particularly concerning the concept of sebaceous epithelioma, accepted by some observers as a specific neoplasm but defined by others as basal cell carcinoma with sebaceous differentiation and still others as sebaceous adenoma in which undifferentiated basaloid cells predominate. From our study of 19 benign sebaceous neoplasms within this spectrum and a critical review of the literature, we conclude that (a) "sebaceous epithelioma" is a nonuseful term; (b) the term "basal cell carcinoma with sebaceous differentiation" should be used only for an otherwise conventional basal cell carcinoma with histological evidence of sebaceous differentiation; (c) "sebaceous adenoma," as described by Troy and Ackerman, represent polar ends of the spectrum of a benign neoplasm with varying degrees of sebaceous differentiation, for which we propose the term "sebomatricoma"; and (d) sebomatricoma, so defined, embraces such diverse benign neoplasms with sebaceous differentiation as superficial epithelioma with sebaceous differentiation and previously "unclassifiable" sebaceous neoplasms, often found in patients with Muir-Torre syndrome or within nevus sebaceus of Jadassohn.
Cystic sebaceous tumors as marker lesions for the Muir-Torre syndrome: a histopathologic and molecular genetic study. Rutten A, Burgdorf W, Hugel H, Kutzner H, Hosseiny-Malayeri HR, Friedl W, Propping P, Kruse R. Laboratory of Dermatohistopathology, University of Bonn, Germany.	Am J Dermatopathol 1999 Oct;21(5):405-13 Abstract quote Cystic sebaceous tumors (CST) are well-circumscribed, large, deeply located dermal sebaceous proliferations with a cystic growth pattern. We identified 12 CST in 8 of 19 patients with Muir-Torre syndrome (MTS). We interpret CST as a tumor spectrum with clearly benign cystic sebaceous adenomas at one end and proliferative atypical cystic sebaceous tumors at the other. When examining these proliferative atypical tumors on morphologic criteria alone, the possibility of an evolving cystic sebaceous carcinoma cannot be excluded. We have not observed recurrences or metastases, indicating that these lesions are not highly malignant carcinomas. In 10 of 12 cases of CST, we examined microsatellite instability (MSI). All 10 examined examples of CST from patients with MTS showed MSI characteristic for hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by autosomal dominant inherited DNA mismatch repair (MMR) defects. Mutational analysis of the MMR genes hMSH2 and hMLH1 had revealed different germline mutations in the hMSH2 gene in three of six examined patients with MTS with CST. We then found four more CST in patients without a history of internal malignancy. All four CST exhibited MSI. By mutational analysis in one of these patients we identified a truncating germline mutation in the MMR gene hMLH1. We conclude that CST is a marker for the mismatch repair-deficient subtype of MTS with a high risk for later internal malignancies. By recognizing CST, the histopathologist can suggest the great likelihood of MTS to the clinician.
Sebaceous neoplasms in Muir-Torre syndrome. Misago N, Narisawa Y. Department of Internal Medicine, Saga Medical School, Japan.	Am J Dermatopathol 2000 Apr;22(2):155-61 Abstract quote 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.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
SEBACEOUS TUMORS

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
GENERAL
Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Cohen PR, Kohn SR, Kurzrock R. Department of Dermatology, University of Texas Medical School, Houston 77030.	Am J Med 1991 May;90(5):606-13 Abstract quote The Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by: (1) at least a single sebaceous gland tumor (either an adenoma, an epithelioma, or a carcinoma) and (2) a minimum of one internal malignancy. To date, 120 patients with MTS have been reported. The most commonly associated neoplasms were colorectal (51%) and genitourinary (25%). Unlike colorectal neoplasms in the general population, the majority (58%) of these tumors in MTS patients occurred proximal to or at the splenic flexure. Nearly half of the MTS patients had more than one primary malignancy. Cutaneous lesions occurred before or concurrent with the diagnosis of the initial cancer in 41% of these patients. The median age for the appearance of the skin lesions was 53 years (range, 23 to 89 years); the median age for the detection of the initial visceral neoplasm was 50 years (range, 23 to 81 years). The cancers appear to have an indolent course in many of the MTS patients; the median survival has not been reached and the median follow-up is 10+ years. Patients with an MTS-associated cutaneous lesion should have a complete evaluation for gastrointestinal or genitourinary cancers. Although the penetrance of this disease is variable, its autosomal dominant inheritance suggests that relatives should be examined for sebaceous gland tumors and internal malignancy.
Clinicopathological relevance of the association between gastrointestinal and sebaceous neoplasms: the Muir-Torre syndrome. Paraf F, Sasseville D, Watters AK, Narod S, Ginsburg O, Shibata H, Jothy S. Department of Pathology, Royal Victoria Hospital, Montreal, Canada.	Hum Pathol 1995 Apr;26(4):422-7 Abstract quote The association between sebaceous neoplasms of the skin and visceral cancers, known as Muir-Torre syndrome, is described in three patients, including one with an extensive history of cancer in his family. The first patient, a 54-year-old man, developed multiple sebaceous adenomas, epitheliomas, and carcinomas in association with a colonic carcinoma 6 years after cardiac transplantation. Family history in this patient disclosed colon cancer in 17 relatives. The second patient was a 51-year-old man who had recurrent adenocarcinoma of the sigmoid colon, adenocarcinoma arising in Barrett's esophagus, and sebaceous epithelioma during a period of 15 years. The third patient was a 90-year-old man with a sebaceous adenoma followed 5 months later by adenocarcinoma of the sigmoid colon with liver metastases. Muir-Torre syndrome in 129 other patients published in the literature is reviewed. Although it is a rare disease, Muir-Torre syndrome requires recognition because skin lesions may be the first sign of the syndrome and this may lead to early diagnosis of associated visceral cancers. Moreover, because this syndrome appears to be inherited, family members should be screened for visceral cancer, especially colorectal adenocarcinoma.
The Muir-Torre syndrome: a 25-year retrospect. Schwartz RA, Torre DP. UMD New Jersey Medical School, Newark, NJ 07103-2714, USA.	J Am Acad Dermatol 1995 Jul;33(1):90-104 Abstract quote The Torre or Muir-Torre syndrome consists of certain types of sebaceous neoplasms of the skin, with or without keratoacanthomas, and one or more low-grade visceral malignancies in the absence of other predisposing factors. The sebaceous tumors are relatively uncommon or rare: sebaceous adenoma, sebaceous epithelioma, basal cell epithelioma with sebaceous differentiation, and sebaceous carcinoma. Sebaceous hyperplasia and hamartomas such as nevus sebaceus of Jadassohn, with or without a sebaceous epithelioma within it, are not a defining part of this syndrome. Sebaceous hyperplasia is common in elderly light-complexioned people with or without this syndrome. Nevus sebaceus of Jadassohn is not rare and is predisposed to the development of other neoplasms within it, including occasionally a sebaceous epithelioma. Colonic polyps are frequently present. Muir-Torre syndrome requires recognition because affected patients are at risk of multiple primary malignancies. The skin lesions may be the first sign of this syndrome, although more often its cutaneous signs follow the diagnosis of at least the first visceral malignancy. The Muir-Torre syndrome portends the greater possibility of a favorable prognosis than might be anticipated otherwise because the visceral cancers are usually low-grade malignancies. However, they are often multiple, so identifying such patients will affect their management in a few ways. Because these indolent visceral malignancies tend to permit prolonged survival, even metastatic disease may respond well to aggressive surgical treatment. The sebaceous cancers in this syndrome, like the visceral malignancies, are less aggressive than their counterparts unassociated with this syndrome. Because this syndrome is inherited in an autosomal dominant manner, identifying one patient means delineating an entire family, which should be investigated. This syndrome may be caused by a defective mismatch DNA repair gene.
TREATMENT
ISOTRETINOIN
Oral isotretinoin therapy for familial Muir-Torre syndrome. Spielvogel RL, DeVillez RL, Roberts LC.	J Am Acad Dermatol 1985 Mar;12(3):475-80 Abstract quote Two representative cases of familial Muir-Torre syndrome are presented. Multiple benign sebaceous neoplasms in both cases and a solitary keratoacanthoma in one were successfully treated with oral isotretinoin. Low-dose maintenance therapy has stabilized the cutaneous manifestations in the two patients, and no new epithelial neoplasms have appeared. This report emphasizes (1) the rationale for the use of isotretinoin in the Muir-Torre syndrome and (2) the potential for a familial pattern of inheritance and a possible association with the cancer family syndrome. It speculates on the prevention of future internal malignancies in Muir-Torre syndrome patients by maintenance oral isotretinoin treatment.
Muir-Torre syndrome - treatment with isotretinoin and interferon alpha-2a can prevent tumour development. Graefe T, Wollina U, Schulz H, Burgdorf W. Department of Dermatology and Allergology, Friedrich Schiller University of Jena, Germany.	Dermatology 2000;200(4):331-3 Abstract quote 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.

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Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Hereditary Non-Polyposis Colorectal Cancer Syndrome

Keratoacanthoma

Sebaceous Tumors of the Skin

Skin Syndromes

Last Updated 8/23/2002