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The DNA Mismatch Repair System in Sebaceous Tumors: An Update on the Genetics and Workup of Muir-Torre Syndrome
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Mohammed Dany, MD, PhD

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.1 If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.2

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,3 colorectal adenocarcinomas,4 keratoacanthomas,5 and other visceral malignancies.6 Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.5 These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.7 This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).8 This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.9 Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.10 Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.9

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.11 Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.12 These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.13 Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,14 which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.15 Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.16

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.17 It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.18

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.19 Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.20 Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.21

 

 

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.22 Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.23

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).24 In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).25 These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.26 A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.27

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.28 In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.29

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.30 Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.31 Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.32

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.33 Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.34 The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.34

 

 


These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.



Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.13

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.37 As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.38



It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.19

References
  1. Yamamoto H, Imai K. An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. Semin Oncol. 2019;46:261-270.
  2. Tamura K, Kaneda M, Futagawa M, et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol. 2019;24:999-1011.
  3. Shiki M, Hida T, Sugano K, et al. Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination. Eur J Dermatol. 2017;27:54-58.
  4. Büttner R, Friedrichs N. Hereditary colon cancer in Lynch syndrome/HNPCC syndrome in Germany. Pathologe. 2019;40:584-591.
  5. Kuwabara K, Suzuki O, Chika N, et al. Prevalence and molecular characteristics of DNA mismatch repair protein-deficient sebaceous neoplasms and keratoacanthomas in a Japanese hospital-based population. Jpn J Clin Oncol. 2018;48:514-521.
  6. Burris CKH, Rodriguez ME, Raven ML, et al. Muir-torre syndrome: the importance of a detailed family history. Case Rep Ophthalmol. 2019;10:180-185.
  7. Walsh MD, Jayasekara H, Huang A, et al. Clinico-pathological predictors of mismatch repair deficiency in sebaceous neoplasia: a large case series from a single Australian private pathology service. Australas J Dermatol. 2019;60:126-133.
  8. Georgeson P, Walsh MD, Clendenning M, et al. Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome. Mol Genet Genomic Med. 2019;7:E00781.
  9. Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008;129:391-407.
  10. Li YC, Korol AB, Fahima T, et al. Microsatellites within genes: structure, function, and evolution [published online February 12, 2004]. Mol Biol Evol. 2004;21:991-1007.
  11. Ellegren H. Microsatellites: simple sequences with complex evolution. Nat Rev Genet. 2004;5:435-445.
  12. Everett JN, Raymond VM, Dandapani M, et al. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatol. 2014;150:1315-1321.
  13. Nojadeh JN, Sharif SB, Sakhinia E. Microsatellite instability in colorectal cancer. EXCLI J. 2018;17:159-168.
  14. Yang G, Zheng RY, Jin ZS. Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol. 2019;145:2891-2899.
  15. Garbe Y, Maletzki C, Linnebacher M. An MSI tumor specific frameshift mutation in a coding microsatellite of MSH3 encodes for HLA-A0201-restricted CD8+ cytotoxic T cell epitopes. PLoS One. 2011;6:E26517.
  16. Peng M, Mo Y, Wang Y, et al. Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer. 2019;18:128.
  17. Rubay D, Ohanisian L, Bank MP, et al. Muir-Torre syndrome, a rare phenotype of hereditary nonpolyposis colorectal cancer with cutaneous manifestations. ACG Case Reports J. 2019;6:E00188.
  18. Velter C, Caussade P, Fricker JP, et al. Muir-Torre syndrome and Turcot syndrome [in French]. Ann Dermatol Venereol. 2017;144:525-529.
  19. John AM, Schwartz RA. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74:558-566.
  20. Kibbi N, Worley B, Owen JL, et al. Sebaceous carcinoma: controversies and their evidence for clinical practice. Arch Dermatol Res. 2020;312:25-31.
  21. Marcoval J, Talavera-Belmonte A, Fornons-Servent R, et al. Cutaneous sebaceous tumours and Lynch syndrome: long-term follow-up of 60 patients. Clin Exp Dermatol. 2019;44:506-511.
  22. Roth RM, Haraldsdottir S, Hampel H, et al. Discordant mismatch repair protein immunoreactivity in Lynch syndrome-associated neoplasms: a recommendation for screening synchronous/metachronous neoplasms. Am J Clin Pathol. 2016;146:50-56.
  23. Westwood A, Glover A, Hutchins G, et al. Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation. J Clin Pathol. 2019;72:443-447.
  24. Claes K, Dahan K, Tejpar S, et al. The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP). Acta Gastroenterol Belg. 2011;74:421-426.
  25. Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362:39-41.
  26. Tomonari M, Shimada M, Nakada Y, et al. Muir-Torre syndrome: sebaceous carcinoma concurrent with colon cancer in a kidney transplant recipient; a case report. BMC Nephrol. 2019;20:394
  27. Levi Z, Hazazi R, Kedar-Barnes I, et al. Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir-Torre syndrome. Am J Transplant. 2007;7:476-479.
  28. Mork ME, Rodriguez A, Taggart MW, et al. Identification of MSH2 inversion of exons 1–7 in clinical evaluation of families with suspected Lynch syndrome. Fam Cancer. 2017;16:357-361.
  29. Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol. 1995;33:90-104.
  30. Chen W, Swanson BJ, Frankel WL. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagn Pathol. 2017;12:24.
  31. Bansidhar BJ. Extracolonic manifestations of Lynch syndrome. Clin Colon Rectal Surg. 2012;25:103-110.
  32. Kato A, Sato N, Sugawara T, et al. Isolated loss of PMS2 immunohistochemical expression is frequently caused by heterogenous MLH1 promoter hypermethylation in Lynch syndrome screening for endometrial cancer patients. Am J Surg Pathol. 2016;40:770-776.
  33. Singh RS, Grayson W, Redston M, et al. Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol. 2008;32:936-942.
  34. Roberts ME, Riegert-Johnson DL, Thomas BC, et al. A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome [published online March 6, 2014]. Genet Med. 2014;16:711-716.
  35. Chhibber V, Dresser K, Mahalingam M. MSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir-Torre syndrome. Mod Pathol. 2008;21:159-164.
  36. Orta L, Klimstra DS, Qin J, et al. Towards identification of hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient’s age or other clinical characteristics. Am J Surg Pathol. 2009;33:934-944.
  37. Mathiak M, Rütten A, Mangold E, et al. 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. Am J Surg Pathol. 2002;26:338-343.
  38. Campanella NC, Berardinelli GN, Scapulatempo-Neto C, et al. Optimization of a pentaplex panel for MSI analysis without control DNA in a Brazilian population: correlation with ancestry markers. Eur J Hum Genet. 2014;22:875-880.
  39. Ponti G, Manfredini M, Tomasi A, et al. Muir-Torre Syndrome and founder mismatch repair gene mutations: a long gone historical genetic challenge. Gene. 2016;589:127-132.
  40. Ferreira I, Wiedemeyer K, Demetter P, et al. Update on the pathology, genetics and somatic landscape of sebaceous tumours [published online December 10, 2019]. Histopathology. doi:10.1111/his.14044
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From the Department of Dermatology, University of Pennsylvania, Philadelphia.

The author reports no conflict of interest.

Correspondence: Mohammed Dany, MD, PhD, 3600 Spruce St, 2 Maloney, Philadelphia, PA 19104 (mohammed.dany@pennmedicine.upenn.edu).

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The author reports no conflict of interest.

Correspondence: Mohammed Dany, MD, PhD, 3600 Spruce St, 2 Maloney, Philadelphia, PA 19104 (mohammed.dany@pennmedicine.upenn.edu).

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From the Department of Dermatology, University of Pennsylvania, Philadelphia.

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It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.1 If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.2

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,3 colorectal adenocarcinomas,4 keratoacanthomas,5 and other visceral malignancies.6 Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.5 These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.7 This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).8 This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.9 Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.10 Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.9

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.11 Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.12 These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.13 Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,14 which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.15 Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.16

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.17 It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.18

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.19 Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.20 Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.21

 

 

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.22 Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.23

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).24 In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).25 These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.26 A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.27

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.28 In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.29

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.30 Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.31 Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.32

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.33 Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.34 The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.34

 

 


These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.



Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.13

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.37 As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.38



It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.19

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.1 If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.2

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,3 colorectal adenocarcinomas,4 keratoacanthomas,5 and other visceral malignancies.6 Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.5 These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.7 This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).8 This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.9 Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.10 Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.9

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.11 Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.12 These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.13 Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,14 which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.15 Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.16

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.17 It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.18

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.19 Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.20 Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.21

 

 

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.22 Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.23

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).24 In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).25 These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.26 A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.27

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.28 In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.29

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.30 Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.31 Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.32

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.33 Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.34 The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.34

 

 


These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.



Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.13

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.37 As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.38



It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.19

References
  1. Yamamoto H, Imai K. An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. Semin Oncol. 2019;46:261-270.
  2. Tamura K, Kaneda M, Futagawa M, et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol. 2019;24:999-1011.
  3. Shiki M, Hida T, Sugano K, et al. Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination. Eur J Dermatol. 2017;27:54-58.
  4. Büttner R, Friedrichs N. Hereditary colon cancer in Lynch syndrome/HNPCC syndrome in Germany. Pathologe. 2019;40:584-591.
  5. Kuwabara K, Suzuki O, Chika N, et al. Prevalence and molecular characteristics of DNA mismatch repair protein-deficient sebaceous neoplasms and keratoacanthomas in a Japanese hospital-based population. Jpn J Clin Oncol. 2018;48:514-521.
  6. Burris CKH, Rodriguez ME, Raven ML, et al. Muir-torre syndrome: the importance of a detailed family history. Case Rep Ophthalmol. 2019;10:180-185.
  7. Walsh MD, Jayasekara H, Huang A, et al. Clinico-pathological predictors of mismatch repair deficiency in sebaceous neoplasia: a large case series from a single Australian private pathology service. Australas J Dermatol. 2019;60:126-133.
  8. Georgeson P, Walsh MD, Clendenning M, et al. Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome. Mol Genet Genomic Med. 2019;7:E00781.
  9. Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008;129:391-407.
  10. Li YC, Korol AB, Fahima T, et al. Microsatellites within genes: structure, function, and evolution [published online February 12, 2004]. Mol Biol Evol. 2004;21:991-1007.
  11. Ellegren H. Microsatellites: simple sequences with complex evolution. Nat Rev Genet. 2004;5:435-445.
  12. Everett JN, Raymond VM, Dandapani M, et al. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatol. 2014;150:1315-1321.
  13. Nojadeh JN, Sharif SB, Sakhinia E. Microsatellite instability in colorectal cancer. EXCLI J. 2018;17:159-168.
  14. Yang G, Zheng RY, Jin ZS. Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol. 2019;145:2891-2899.
  15. Garbe Y, Maletzki C, Linnebacher M. An MSI tumor specific frameshift mutation in a coding microsatellite of MSH3 encodes for HLA-A0201-restricted CD8+ cytotoxic T cell epitopes. PLoS One. 2011;6:E26517.
  16. Peng M, Mo Y, Wang Y, et al. Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer. 2019;18:128.
  17. Rubay D, Ohanisian L, Bank MP, et al. Muir-Torre syndrome, a rare phenotype of hereditary nonpolyposis colorectal cancer with cutaneous manifestations. ACG Case Reports J. 2019;6:E00188.
  18. Velter C, Caussade P, Fricker JP, et al. Muir-Torre syndrome and Turcot syndrome [in French]. Ann Dermatol Venereol. 2017;144:525-529.
  19. John AM, Schwartz RA. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74:558-566.
  20. Kibbi N, Worley B, Owen JL, et al. Sebaceous carcinoma: controversies and their evidence for clinical practice. Arch Dermatol Res. 2020;312:25-31.
  21. Marcoval J, Talavera-Belmonte A, Fornons-Servent R, et al. Cutaneous sebaceous tumours and Lynch syndrome: long-term follow-up of 60 patients. Clin Exp Dermatol. 2019;44:506-511.
  22. Roth RM, Haraldsdottir S, Hampel H, et al. Discordant mismatch repair protein immunoreactivity in Lynch syndrome-associated neoplasms: a recommendation for screening synchronous/metachronous neoplasms. Am J Clin Pathol. 2016;146:50-56.
  23. Westwood A, Glover A, Hutchins G, et al. Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation. J Clin Pathol. 2019;72:443-447.
  24. Claes K, Dahan K, Tejpar S, et al. The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP). Acta Gastroenterol Belg. 2011;74:421-426.
  25. Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362:39-41.
  26. Tomonari M, Shimada M, Nakada Y, et al. Muir-Torre syndrome: sebaceous carcinoma concurrent with colon cancer in a kidney transplant recipient; a case report. BMC Nephrol. 2019;20:394
  27. Levi Z, Hazazi R, Kedar-Barnes I, et al. Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir-Torre syndrome. Am J Transplant. 2007;7:476-479.
  28. Mork ME, Rodriguez A, Taggart MW, et al. Identification of MSH2 inversion of exons 1–7 in clinical evaluation of families with suspected Lynch syndrome. Fam Cancer. 2017;16:357-361.
  29. Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol. 1995;33:90-104.
  30. Chen W, Swanson BJ, Frankel WL. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagn Pathol. 2017;12:24.
  31. Bansidhar BJ. Extracolonic manifestations of Lynch syndrome. Clin Colon Rectal Surg. 2012;25:103-110.
  32. Kato A, Sato N, Sugawara T, et al. Isolated loss of PMS2 immunohistochemical expression is frequently caused by heterogenous MLH1 promoter hypermethylation in Lynch syndrome screening for endometrial cancer patients. Am J Surg Pathol. 2016;40:770-776.
  33. Singh RS, Grayson W, Redston M, et al. Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol. 2008;32:936-942.
  34. Roberts ME, Riegert-Johnson DL, Thomas BC, et al. A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome [published online March 6, 2014]. Genet Med. 2014;16:711-716.
  35. Chhibber V, Dresser K, Mahalingam M. MSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir-Torre syndrome. Mod Pathol. 2008;21:159-164.
  36. Orta L, Klimstra DS, Qin J, et al. Towards identification of hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient’s age or other clinical characteristics. Am J Surg Pathol. 2009;33:934-944.
  37. Mathiak M, Rütten A, Mangold E, et al. 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. Am J Surg Pathol. 2002;26:338-343.
  38. Campanella NC, Berardinelli GN, Scapulatempo-Neto C, et al. Optimization of a pentaplex panel for MSI analysis without control DNA in a Brazilian population: correlation with ancestry markers. Eur J Hum Genet. 2014;22:875-880.
  39. Ponti G, Manfredini M, Tomasi A, et al. Muir-Torre Syndrome and founder mismatch repair gene mutations: a long gone historical genetic challenge. Gene. 2016;589:127-132.
  40. Ferreira I, Wiedemeyer K, Demetter P, et al. Update on the pathology, genetics and somatic landscape of sebaceous tumours [published online December 10, 2019]. Histopathology. doi:10.1111/his.14044
References
  1. Yamamoto H, Imai K. An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. Semin Oncol. 2019;46:261-270.
  2. Tamura K, Kaneda M, Futagawa M, et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol. 2019;24:999-1011.
  3. Shiki M, Hida T, Sugano K, et al. Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination. Eur J Dermatol. 2017;27:54-58.
  4. Büttner R, Friedrichs N. Hereditary colon cancer in Lynch syndrome/HNPCC syndrome in Germany. Pathologe. 2019;40:584-591.
  5. Kuwabara K, Suzuki O, Chika N, et al. Prevalence and molecular characteristics of DNA mismatch repair protein-deficient sebaceous neoplasms and keratoacanthomas in a Japanese hospital-based population. Jpn J Clin Oncol. 2018;48:514-521.
  6. Burris CKH, Rodriguez ME, Raven ML, et al. Muir-torre syndrome: the importance of a detailed family history. Case Rep Ophthalmol. 2019;10:180-185.
  7. Walsh MD, Jayasekara H, Huang A, et al. Clinico-pathological predictors of mismatch repair deficiency in sebaceous neoplasia: a large case series from a single Australian private pathology service. Australas J Dermatol. 2019;60:126-133.
  8. Georgeson P, Walsh MD, Clendenning M, et al. Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome. Mol Genet Genomic Med. 2019;7:E00781.
  9. Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008;129:391-407.
  10. Li YC, Korol AB, Fahima T, et al. Microsatellites within genes: structure, function, and evolution [published online February 12, 2004]. Mol Biol Evol. 2004;21:991-1007.
  11. Ellegren H. Microsatellites: simple sequences with complex evolution. Nat Rev Genet. 2004;5:435-445.
  12. Everett JN, Raymond VM, Dandapani M, et al. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatol. 2014;150:1315-1321.
  13. Nojadeh JN, Sharif SB, Sakhinia E. Microsatellite instability in colorectal cancer. EXCLI J. 2018;17:159-168.
  14. Yang G, Zheng RY, Jin ZS. Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol. 2019;145:2891-2899.
  15. Garbe Y, Maletzki C, Linnebacher M. An MSI tumor specific frameshift mutation in a coding microsatellite of MSH3 encodes for HLA-A0201-restricted CD8+ cytotoxic T cell epitopes. PLoS One. 2011;6:E26517.
  16. Peng M, Mo Y, Wang Y, et al. Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer. 2019;18:128.
  17. Rubay D, Ohanisian L, Bank MP, et al. Muir-Torre syndrome, a rare phenotype of hereditary nonpolyposis colorectal cancer with cutaneous manifestations. ACG Case Reports J. 2019;6:E00188.
  18. Velter C, Caussade P, Fricker JP, et al. Muir-Torre syndrome and Turcot syndrome [in French]. Ann Dermatol Venereol. 2017;144:525-529.
  19. John AM, Schwartz RA. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74:558-566.
  20. Kibbi N, Worley B, Owen JL, et al. Sebaceous carcinoma: controversies and their evidence for clinical practice. Arch Dermatol Res. 2020;312:25-31.
  21. Marcoval J, Talavera-Belmonte A, Fornons-Servent R, et al. Cutaneous sebaceous tumours and Lynch syndrome: long-term follow-up of 60 patients. Clin Exp Dermatol. 2019;44:506-511.
  22. Roth RM, Haraldsdottir S, Hampel H, et al. Discordant mismatch repair protein immunoreactivity in Lynch syndrome-associated neoplasms: a recommendation for screening synchronous/metachronous neoplasms. Am J Clin Pathol. 2016;146:50-56.
  23. Westwood A, Glover A, Hutchins G, et al. Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation. J Clin Pathol. 2019;72:443-447.
  24. Claes K, Dahan K, Tejpar S, et al. The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP). Acta Gastroenterol Belg. 2011;74:421-426.
  25. Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362:39-41.
  26. Tomonari M, Shimada M, Nakada Y, et al. Muir-Torre syndrome: sebaceous carcinoma concurrent with colon cancer in a kidney transplant recipient; a case report. BMC Nephrol. 2019;20:394
  27. Levi Z, Hazazi R, Kedar-Barnes I, et al. Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir-Torre syndrome. Am J Transplant. 2007;7:476-479.
  28. Mork ME, Rodriguez A, Taggart MW, et al. Identification of MSH2 inversion of exons 1–7 in clinical evaluation of families with suspected Lynch syndrome. Fam Cancer. 2017;16:357-361.
  29. Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol. 1995;33:90-104.
  30. Chen W, Swanson BJ, Frankel WL. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagn Pathol. 2017;12:24.
  31. Bansidhar BJ. Extracolonic manifestations of Lynch syndrome. Clin Colon Rectal Surg. 2012;25:103-110.
  32. Kato A, Sato N, Sugawara T, et al. Isolated loss of PMS2 immunohistochemical expression is frequently caused by heterogenous MLH1 promoter hypermethylation in Lynch syndrome screening for endometrial cancer patients. Am J Surg Pathol. 2016;40:770-776.
  33. Singh RS, Grayson W, Redston M, et al. Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol. 2008;32:936-942.
  34. Roberts ME, Riegert-Johnson DL, Thomas BC, et al. A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome [published online March 6, 2014]. Genet Med. 2014;16:711-716.
  35. Chhibber V, Dresser K, Mahalingam M. MSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir-Torre syndrome. Mod Pathol. 2008;21:159-164.
  36. Orta L, Klimstra DS, Qin J, et al. Towards identification of hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient’s age or other clinical characteristics. Am J Surg Pathol. 2009;33:934-944.
  37. Mathiak M, Rütten A, Mangold E, et al. 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. Am J Surg Pathol. 2002;26:338-343.
  38. Campanella NC, Berardinelli GN, Scapulatempo-Neto C, et al. Optimization of a pentaplex panel for MSI analysis without control DNA in a Brazilian population: correlation with ancestry markers. Eur J Hum Genet. 2014;22:875-880.
  39. Ponti G, Manfredini M, Tomasi A, et al. Muir-Torre Syndrome and founder mismatch repair gene mutations: a long gone historical genetic challenge. Gene. 2016;589:127-132.
  40. Ferreira I, Wiedemeyer K, Demetter P, et al. Update on the pathology, genetics and somatic landscape of sebaceous tumours [published online December 10, 2019]. Histopathology. doi:10.1111/his.14044
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  • When patients present with a solitary sebaceous tumor, there is a high likelihood they have Muir-Torre syndrome (MTS) and thus are at a high risk to develop visceral malignancies.
  • It is important to perform further testing using immunohistochemistry for DNA mismatch repair proteins and microsatellite instability gene analysis in some cases to confirm the diagnosis of MTS and to perform the appropriate cancer screening tests.
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