A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions

Kattapuram, Meera; Shabet, Christina; Austin, Sarah; Jacobs, Michelle F.; Koeppe, Erika; Smith, Emily H.; Lowe, Lori; Else, Tobias; Kelly, B.

doi:10.1007/s10689-022-00322-z

Cited by 2 publications

(7 citation statements)

References 25 publications

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“…Discordant results for immunohistochemistry analysis (preserved expression of MLH1) and germline testing (MLH1 alteration) results were observed for our 59-year-old man in this report with an established germline mutation-confirmed MLH1-associated Lynch syndrome whose sebaceous adenoma has preservation of MLH1 staining (Table 1 ). In addition, researchers have assessed the predictive value of immunohistochemistry screening results of skin sebaceous neoplasm with regard to identifying Lynch syndrome patients; they have compared immunohistochemistry analysis with Lynch syndrome-confirmed diagnosis by germline mutation evaluation (Table 2 ) [ 10 , 12 , 13 , 18 , 19 ]. However, each of these studies has documented several patients with preserved expression of mismatch repair genes and germline documentation of mismatch repair gene mutation; if only immunohistochemistry analysis had been performed, the diagnosis of a mutation in the mismatch repair genes would not have been detected, and these individuals and their families would not have been evaluated for cancer and the possible diagnosis of Muir-Torre syndrome or Lynch syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…Also, of the 63 patients seen by genetics, 45 patients underwent genetic testing. The germline testing identified a mismatch repair gene mutation in eight (18%) of the 45 patients: six patients with abnormal immunohistochemistry analysis, one patient with no loss of staining on immunohistochemistry testing, and one patient who had not had immunohistochemistry studies [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…There is a consensus that immunohistochemistry is a good screening test. However, all the investigators have observed negative immunohistochemistry results in patients who had a mismatch repair gene germline mutation (Table 2 ) [ 10 , 12 , 13 , 18 , 19 ]. Most of the researchers suggested genetics referral and additional evaluation when the immunohistochemistry analysis demonstrates loss of gene expression based on staining absence [ 12 , 13 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, all the investigators have observed negative immunohistochemistry results in patients who had a mismatch repair gene germline mutation (Table 2 ) [ 10 , 12 , 13 , 18 , 19 ]. Most of the researchers suggested genetics referral and additional evaluation when the immunohistochemistry analysis demonstrates loss of gene expression based on staining absence [ 12 , 13 , 18 ]. Indeed, one of the group of investigators commented that the standard for diagnosing Muir-Torre syndrome is germline genetic testing [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…They utilize immunohistochemistry staining, microsatellite instability testing, and next-generation sequencing of the paraffin-embedded tumor. In addition, blood, saliva, or normal skin can be used for germline evaluation [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series

Cohen¹,

Kurzrock²

2023

Cureus

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Muir-Torre syndrome, a subtype of Lynch syndrome, is characterized by a germline mutation of one or more mismatch repair genes such as MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2, mismatch repair system component (PMS2) resulting in microsatellite instability and at least one malignancy and a minimum of one syndrome-associated sebaceous neoplasm such as a sebaceous adenoma, epithelioma, or carcinoma. The syndrome has an autosomal dominant mode of inheritance detectable with germline sequencing of normal body elements such as blood, saliva, or normal skin for a mismatch repair gene mutation. Sebaceous neoplasms can occur before, concurrent with, or following Muir-Torre syndrome-related cancer. Immunohistochemistry, microsatellite instability testing, and next-generation sequencing of tumor tissue can evaluate malignancies such as colorectal and endometrial cancer and sebaceous neoplasms for somatic mismatch repair gene defects. However, these tests cannot differentiate somatic (acquired) versus germline alterations, and immunohistochemistry and microsatellite stability assessment can produce false negatives. Finally, the Mayo Muir-Torre syndrome risk score algorithm cannot always reliably determine which patient with a new sebaceous neoplasm should have germline testing.We report three men who presented with a Muir-Torre syndrome-associated sebaceous neoplasm: a 67-yearold male with no personal or family history of cancer who presented with a chest sebaceous carcinoma with MSH2 and MSH6 gene expression loss on immunohistochemistry and a Mayo Muir-Torre syndrome risk score of 0 who declined germline testing; a 74-year-old male with Janus kinase 2 (JAK2)-related myelodysplastic syndrome, yet no history of a Lynch syndrome-associated cancer, who developed a sebaceous epithelioma on his leg with PMS2 gene expression loss by immunohistochemistry and, although Mayo Muir-Torre syndrome risk score was only 1 (suggests no likelihood of a Lynch syndrome germline mismatch repair gene mutation), germline testing demonstrated a PMS2 alteration; and a 59-year-old male with a germlineconfirmed MLH1-associated Lynch syndrome and a prior colon carcinoma, who developed a sebaceous adenoma on his nostril that unexpectedly demonstrated preservation of normal MLH1 staining (reflecting a false negative) by immunohistochemistry. In summary, these cases are consistent with the literature suggesting that tumor immunohistochemistry and microsatellite stability testing can miss germline alterations. Hence, we recommend that the initial evaluation of a patient with even a single new Muir-Torre syndrome-associated sebaceous neoplasm should include germline mismatch repair gene mutation testing. Finding a mismatch repair gene germline mutation should prompt genetic counseling, initial and future cancer screening recommendations, and germline testing of family members.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series

Cohen¹,

Kurzrock²

2023

Cureus

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Muir–Torre syndrome and recent updates on screening guidelines: The link between colorectal tumors and sebaceous adenomas in unusual locations

Shaker,

Abid

et al. 2023

Journal of Surgical Oncology

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BackgroundMuir–Torre syndrome (MTS) is a rare genetic disorder that is caused by mismatch repair (MMR) protein mutations. MTS increases the risk of developing skin and gastrointestinal tumors such as sebaceous adenomas (SAs), sebaceous carcinomas, colorectal cancer, endometrial cancer, and ovarian cancer. The risk of developing these types of tumors varies depending on the involved mutation and the individual's family history risk.Case PresentationA 47‐year‐old male presented with multiple skin lesions on the scalp, face, flank, and back. The examination revealed well‐circumscribed, dome‐shaped papules with a yellowish appearance with white oily material in the center. Histopathologic examination showed a well‐circumscribed sebaceous neoplasm consistent with a mixture of basaloid cells and lobules of bland‐appearing mature adipocytes that communicate directly to the surface epithelium. Focal cystic changes and peritumoral lymphocytic infiltrate were noted. Increased mitotic figures were seen in the basaloid cell component. The overall findings were consistent with the diagnosis of SAs. MMR staining showed preserved expression in MLH1 and PMS2 proteins, while MSH2 and MSH6 staining showed loss of protein expression. A screening colonoscopy showed numerous colon and rectal tumors, prompting concerns about the likelihood of MTS. Surgical intervention was pursued for complete resection. Histology revealed a diagnosis of mucinous adenocarcinoma/adenocarcinoma with mucinous features of the colon. The diagnosis of MTS was supported by molecular testing that revealed MSH2 germline mutation. The increased likelihood of MTS was attributed to the occurrence of SAs in unusual locations of the head and neck regions, unlike typical cases.ConclusionMTS is a rare clinical condition that necessitates prompt thorough evaluation and periodic surveillance. When SA is encountered in atypical locations, it is important to consider additional testing supported by immunohistochemical staining, molecular testing, and regular screening to exclude the likelihood of MTS.

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A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions

Cited by 2 publications

References 25 publications

Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series

Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series

Muir–Torre syndrome and recent updates on screening guidelines: The link between colorectal tumors and sebaceous adenomas in unusual locations

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