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Chapter 10 - Detection of Genetic Syndromes

Published online by Cambridge University Press:  17 June 2025

By
Mai P. Hoang
Edited by
Mai P. Hoang
Mai P. Hoang
Affiliation:
Harvard Medical School, Boston
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Summary

Cutaneous tumors including adnexal, melanocytic, and mesenchymal lesions in the setting of multiple tumors can be associated with a hereditary syndrome. Some are of clinical importance due to the association with internal malignancy and they can be screened by immunohistochemical stains performed on the associated tumors. Early diagnosis would allow timely genetic counseling and appropriate cancer surveillance. In this chapter the role of mismatch repair proteins in the screening for Muir-Torre syndromes, BAP1 for BAP1-tumor syndrome, PTEN for Cowden syndrome/PTEN hamartoma syndrome, and 2SC and FH for hereditary leiomyomatosis and renal cell carcinoma will be discussed.

Keywords

Muir-Torre syndromeLynch syndromeCowden syndromehereditary leiomyomatosis
Type
Chapter
Information
Immunohistochemistry and Ancillary Studies in Diagnostic Dermatopathology , pp. 333 - 347
Publisher: Cambridge University Press
Print publication year: 2025

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References

Moreira, L, Balaguer, F, Lindor, N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012; 308: 1555–65.CrossRefGoogle Scholar
Muir, EG, Bell, AJ, Barlow, KA. Multiple primary carcinomata of the colon, duodenum, and larynx associated with keratoacanthomata of the face. Br J Surg 1967; 54: 191–5.CrossRefGoogle ScholarPubMed
Torre, D. Multiple sebaceous tumors. Arch Dermatol 1968; 98: 549–51.Google ScholarPubMed
Lachiewicz, AM, Wilkinson, TM, Groben, P, Ollila, DW, Thomas, NE. Muir-Torre syndrome. Am J Clin Dermatol 2007; 8: 315–19.CrossRefGoogle ScholarPubMed
Aziz, S, O’Sullivan, H, Heelan, K, Alam, A, McVeigh, TP. Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review. Fam Cancer 2023; 22: 167–75.CrossRefGoogle ScholarPubMed
Ponti, G, Losi, L, Di Gregorio, C, et al. Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry. Cancer 2005; 103: 1018–25.CrossRefGoogle ScholarPubMed
Cohen, PR, Kohn, SR, Kurzrock, R. Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med 1991; 90: 606–13.CrossRefGoogle ScholarPubMed
Abbott, JJ, Hernandez-Rios, P, Amirkhan, RH, Hoang, MP. Cystic sebaceous neoplasms in Muir-Torre syndrome. Arch Pathol Lab Med 2013; 127: 614–17.Google Scholar
Rutten, A, Burgdorf, W, Hugel, H, et al. Cystic sebaceous tumors a marker lesions for the Muir-Torre syndrome: a histopathologic and molecular genetic study. Am J Dermatopathol 1999; 21: 405–13.CrossRefGoogle ScholarPubMed
Al-Shobaili, HA, AlGhamdi, KM, Al-Ghamdi, WA. Cystic sebaceous carcinoma: is it a constant pathognomic marker for Muir-Torre syndrome? J Drugs Dermatol 2007; 6: 540–3.Google ScholarPubMed
Maloney, NJ, Zacher, NC, Hirotsu, KE, Rajan, N, Aasi, SZ, Kibbi, N. Comparison of clinicopathologic features, survival, and demographics in sebaceous carcinoma patients with and without Muir-Torre syndrome. J Am Acad Dermatol 2023; 89: 269–73.CrossRefGoogle ScholarPubMed
Schwartz, RA, Torre, DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol 1995; 33: 90–104.CrossRefGoogle ScholarPubMed
Hayani, KM, Zelger, BG, Kind, P, Zelger, B. Seborrheic keratosis with sebaceous differentiation, a series of 8 cases and critical review of the literature. Am J Dermatopathol 2021; 43: 801–10.CrossRefGoogle ScholarPubMed
Kruse, R, Ruzicka, T. DNA mismatch repair and the significance of a sebaceous skin tumor for visceral cancer prevention. Trends Mol Med 2004; 10: 136–41.CrossRefGoogle ScholarPubMed
Toon, CW, Walsh, MD, Chou, A, et al. BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am J Surg Pathol 2013; 37: 1592–602.CrossRefGoogle ScholarPubMed
Kalloger, SE, Allo, G, Mulligan, AM, et al. Use of mismatch repair immunohistochemistry and microsatellite instability testing: exploring Canadian practices. Am J Surg Pathol 2012; 36: 560–9.CrossRefGoogle ScholarPubMed
Shia, J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. J Mol Diagn 2008; 10: 293–300.CrossRefGoogle ScholarPubMed
Cook, S, Pethick, J, Kibbi, N, et al. Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018. J Am Acad Dermatol 2023: 89: 1129–35.CrossRefGoogle ScholarPubMed
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. Genet Med 2014: 16: 711–16.CrossRefGoogle ScholarPubMed
Sinson, H, Karayan-Tapon, L, Godet, J, Rivet, P, et al. Immunohistochemistry, molecular biology and clinical scoring for the detection of Muir-Torre syndrome in cutaneous sebaceous tumors: which strategy? Dermatology 2023; 239: 889–97.CrossRefGoogle ScholarPubMed
Cornejo, KM, Hutchinson, L, Deng, A, et al. BRAF/KRAS gene sequencing of sebaceous neoplasms after mismatch repair protein analysis. Hum Pathol 2014; 45: 1213–20.CrossRefGoogle ScholarPubMed
Musulén, E, Sanz, C, Muñoz-Mármol, AM, Aurelio Ariza, A. Mismatch repair protein immunohistochemistry: a useful population screening strategy for Lynch syndrome. Hum Pathol 2014; 45: 1388–96.CrossRefGoogle ScholarPubMed
Jessup, CJ, Redston, M, Tilton, E, Reimann, JD. Importance of universal mismatch repair protein immunohistochemistry in patients with sebaceous neoplasia as an initial screening tool for Muir-Torre syndrome. Hum Pathol 2016; 49: 1–9.CrossRefGoogle Scholar
Everett, JN, Raymond, VM, Dandapani, M, et al. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatol 2014; 150: 1315–21.CrossRefGoogle ScholarPubMed
Ponti, G, Ponz de Leon, M, Maffei, S, et al. Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations. Clin Genet 2005; 68: 442–7.CrossRefGoogle ScholarPubMed
O’Shea, AM, Cleary, SP, Croitoru, MA, et al. Pathological features of colorectal carcinomas in MYH-associated polyposis. Histopathology 2008; 53: 184–94.CrossRefGoogle ScholarPubMed
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: 936–42.CrossRefGoogle ScholarPubMed
Abdel-Rahman, MH, Pilarski, R, Cebulla, CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 2011; 48: 856–9.CrossRefGoogle ScholarPubMed
Carbone, M, Ferris, LK, Baumann, F, et al. BAP1 cancer syndrome: malignant mesotheliomas, uveal and cutaneous melanoma, and MBAITs. J Transl Med 2012; 10: 179. doi: 10.1186/1479-5876-10-179.CrossRefGoogle ScholarPubMed
Wadt, K, Choi, J, Chung, JY, et al. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res 2012; 25: 815–18.CrossRefGoogle Scholar
Wiesner, T, Obenauf, AC, Murali, R, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 2011; 43: 1018–21.CrossRefGoogle ScholarPubMed
Popova, T, Hebert, L, Jacquemin, V, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 2013; 92: 974–80.CrossRefGoogle ScholarPubMed
Busam, KJ, Sung, J, Wiesner, T, von Deimling, A, Jungbluth, A. Combined BRAFV600E-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. Am J Surg Pathol 2013; 37: 193–9.CrossRefGoogle Scholar
de la Fouchardiere, A, Cabaret, O, Savin, L, et al. Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin Genet 2015; 88: 273–7.CrossRefGoogle ScholarPubMed
Mochel, MC, Piris, A, Nose, V, Hoang, MP. Loss of BAP1 expression in basal cell carcinomas in patients with germline BAP1 mutations. Am J Clin Pathol 2015; 143: 901–4.CrossRefGoogle ScholarPubMed
Piris, A, Mihm, MC Jr, Hoang, MP. BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations. Hum Pathol 2015; 46: 239–45.CrossRefGoogle ScholarPubMed
Pena-Llopis, S, Vega-Rubin-de-Celis, S, Liao, A, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2011; 44: 1018–21.Google Scholar
Ladanyi, M, Zauderer, MG, Krug, LM, et al. New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin Cancer Res 2012; 18: 4485–90.CrossRefGoogle ScholarPubMed
Aung, P, Nagarajan, P, Tetzlaff, M, et al. Melanoma with loss of BAP1 expression in patients with no family history of BAP1-associated cancer susceptibility syndrome: a case series. Am J Dermatopathol 2019; 41: 167–79.CrossRefGoogle ScholarPubMed
Murali, R, Wilmott, JS, Jakrot, V, et al. BAP1 expression cutaneous melanoma: a pilot study. Pathology 2013; 45: 606–9.CrossRefGoogle ScholarPubMed
Costa, S, Byrne, M, Pissaloux, D, et al. Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp. Am J Surg Pathol 2016; 40: 368–77.CrossRefGoogle ScholarPubMed
Pilarski, R. PTEN hamartoma tumor syndrome: a clinical overview. Cancers 2019; 11. doi:10.3390/cancers11060844.CrossRefGoogle ScholarPubMed
Yehia, L, Keel, E, Eng, C. The clinical spectrum of PTEN mutations. Annu Rev Med 2020; 71: 103–16.CrossRefGoogle ScholarPubMed
Nelen, MR, Padberg, GW, Peeters, EA, et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 1996; 13: 114–16.CrossRefGoogle ScholarPubMed
Pilarski, R, Burt, R, Kohlman, W, Pho, L, Shannon, KM, Swisher, E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013; 105: 1607–16.CrossRefGoogle ScholarPubMed
Tan, MH, Mester, JL, Ngeow, J, Rybicki, LA, Orloff, MS, Eng, C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012; 18: 400–7.Google ScholarPubMed
Jin, M, Hampel, H, Pilarski, R, et al. Phosphatase and tensin homolog immunohistochemical staining and clinical criteria for Cowden syndrome in patients with trichilemmoma or associated lesions. Am J Dermatopathol 2013; 35: 637–40.CrossRefGoogle ScholarPubMed
Hartsough, E, DeSimone, MS, Lorenzo, ME, et al. Utilizing PTEN immunohistochemistry as a screening test for Cowden syndrome. Am J Clin Pathol 2024; 161: 490–500.CrossRefGoogle ScholarPubMed
Shon, W, Wolz, MM, Sukov, WR, Wieland, CN, Gibson, LE, Peters, MS. Phosphatase and tensin homologue status in sporadic and Cowden syndrome-associated trichilemmomas: evaluation of immunohistochemistry and fluorescence in situ hybridization. Br J Dermatol 2014; 170: 1201–4.CrossRefGoogle ScholarPubMed
Zabetian, S, Mehregan, D. Cowden syndrome: report of two cases with immunohistochemical analysis for PTEN expression. Am J Dermatopathol 2012; 34: 632–4.CrossRefGoogle ScholarPubMed
Peiro, G, Adrover, E, Guijarro, J, et al. Synchronous bilateral breast carcinoma in a patient with Cowden syndrome: a case report with morphologic, immunohistochemical and genetic analysis. Breast J 2010; 16: 77–81.CrossRefGoogle Scholar
Barletta, JA, Bellizzi, AM, Hornick, JL. Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome. Am J Surg Pathol 2011; 35: 1505–11.CrossRefGoogle ScholarPubMed
Al-Zaid, T, Ditelberg, JS, Prieto, VG, et al. Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors. J Cutan Pathol 2012; 39: 493–9.CrossRefGoogle ScholarPubMed
Reed, WB, Walker, R, Horowitz, R. Cutaneous leiomyomata with uterine leiomyomata. Acta Dermatologica Venerologica 1973; 53: 406–16.Google ScholarPubMed
Tomlinson, IP, Alam, NA, Rowan, AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30: 406–10.Google ScholarPubMed
Bayley, JP, Launonen, V, Tomlinson, IP. The fumarate hydratase mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 2008; 9: 20. doi: 10.1186/1471-2350-9-20.CrossRefGoogle ScholarPubMed
Chan, I, Wong, T, Martinez-Mir, A, Christiano, AM, McGrath, JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol 2005; 30: 75–8.CrossRefGoogle ScholarPubMed
Merino, MJ, Torres-Cabala, C, Pinto, P, et al. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 2007; 31: 1578–85.CrossRefGoogle ScholarPubMed
Sanz-Ortega, J, Vocke, C, Stratton, P, Linehan, WM, Merino, MJ. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol 2013; 37: 74–80.CrossRefGoogle ScholarPubMed
Alam, NA, Barclay, E, Rowan, AJ, et al. Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 2005; 141: 199–206.CrossRefGoogle ScholarPubMed
Joseph, NM, Solomon, DA, Frizzell, N, Rabban, JT, Zaloudek, C, Garg, K. Morphology and immunohistochemistry for 2SC and FH aid in detection of fumarate hydratase gene aberrations in uterine leiomyomas from young patients. Am J Surg Pathol 2015; 39: 1529–39.CrossRefGoogle ScholarPubMed
Ahvenainen, T, Kaukomaa, J, Kämpjärvi, K, et al. Comparison of 2SC, AKR1B10, and FH antibodies as potential biomarkers for FH-deficient uterine leiomyomas. Am J Surg Pathol 2022; 46: 537–46.CrossRefGoogle ScholarPubMed
Llamas-Velasco, M, Requena, L, Kutzner, H, et al. Fumarate hydratase immunohistochemical staining may help to identify patients with multiple cutaneous and uterine leiomyomatosis (MCUL) and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. J Cutan Pathol 2014; 41: 859–65.CrossRefGoogle ScholarPubMed
Bueow, B, Cohen, J, Zoltan, N, et al. Immunohistochemistry for 2-succinocysteine (2SC) and fumarate hydratase (FH) in cutaneous leiomyomas may aid in identification of patients with HLRCC (hereditary leiomyomatosis and renal cell carcinoma syndrome). Am J Surg Pathol 2016; 40: 982–988.CrossRefGoogle Scholar
Jin, M, Hampel, H, Zhou, X, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Clin Pathol 2013; 140: 177–83.CrossRefGoogle ScholarPubMed
Weary, PE, Gorlin, RJ, Gentry, WC, Comer, JE, Greer, KE. Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol 1972; 106: 682–90.CrossRefGoogle ScholarPubMed
Requena, L, Gutiérrez, J, Sánchez Yus, E. Multiple sclerotic fibromas of the skin: a cutaneous marker of Cowden’s disease. J Cutan Pathol 1992; 19: 346–51.CrossRefGoogle ScholarPubMed
Al-Daraji, WI, Ramsay, HM, Ali, RBM. Storiform collagenoma as a clue for Cowden disease or PTEN hamartoma tumour syndrome. J Clin Pathol 2007; 60: 840–2.CrossRefGoogle ScholarPubMed
Kieselova, K, Santiago, F, Henrique, M, Cunha, MF. Multiple sclerotic fibromas of the skin: an important clue for the diagnosis of Cowden syndrome. BMJ Case Rep 2017; 2017. doi:10.1136/bcr-2017-221695.CrossRefGoogle ScholarPubMed

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