Review Article| Volume 9, ISSUE 2, P201-214, June 2016

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Lynch Syndrome

Female Genital Tract Cancer Diagnosis and Screening
Published:April 12, 2016DOI:


      Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed.


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        • Aarnio M.
        • Sankila R.
        • Pukkala E.
        • et al.
        Cancer risk in mutation carriers of DNA-mismatch-repair genes.
        Int J Cancer. 1999; 81: 214-218
        • Vasen H.F.
        • Watson P.
        • Mecklin J.P.
        • et al.
        New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.
        Gastroenterology. 1999; 116: 1453-1456
        • Watson P.
        • Lynch H.T.
        Extracolonic cancer in hereditary nonpolyposis colorectal cancer.
        Cancer. 1993; 71: 677-685
        • Lu K.H.
        • Broaddus R.R.
        Gynecologic cancers in Lynch syndrome/HNPCC.
        Fam Cancer. 2005; 4: 249-254
        • Hampel H.
        • Frankel W.
        • Panescu J.
        • et al.
        Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients.
        Cancer Res. 2006; 66: 7810-7817
        • Hampel H.
        • Frankel W.L.
        • Martin E.
        • et al.
        Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
        N Engl J Med. 2005; 352: 1851-1860
        • Ollikainen M.
        • Abdel-Rahman W.M.
        • Moisio A.L.
        • et al.
        Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome?.
        J Clin Oncol. 2005; 23: 4609-4616
        • Ferguson S.E.
        • Aronson M.
        • Pollett A.
        • et al.
        Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing.
        Cancer. 2014; 120: 3932-3939
        • Malander S.
        • Rambech E.
        • Kristoffersson U.
        • et al.
        The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer.
        Gynecol Oncol. 2006; 101: 238-243
        • Bewtra C.
        • Watson P.
        • Conway T.
        • et al.
        Hereditary ovarian cancer: a clinicopathological study.
        Int J Gynecol Pathol. 1992; 11: 180-187
        • Bonadona V.
        • Bonaiti B.
        • Olschwang S.
        • et al.
        Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.
        JAMA. 2011; 305: 2304-2310
        • Domanska K.
        • Malander S.
        • Masback A.
        • et al.
        Ovarian cancer at young age: the contribution of mismatch-repair defects in a population-based series of epithelial ovarian cancer before age 40.
        Int J Gynecol Cancer. 2007; 17: 789-793
        • Grindedal E.M.
        • Renkonen-Sinisalo L.
        • Vasen H.
        • et al.
        Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds.
        J Med Genet. 2010; 47: 99-102
        • Jensen K.C.
        • Mariappan M.R.
        • Putcha G.V.
        • et al.
        Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger.
        Am J Surg Pathol. 2008; 32: 1029-1037
        • Ketabi Z.
        • Bartuma K.
        • Bernstein I.
        • et al.
        Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors.
        Gynecol Oncol. 2011; 121: 462-465
        • Watson P.
        • Butzow R.
        • Lynch H.T.
        • et al.
        The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.
        Gynecol Oncol. 2001; 82: 223-228
        • Buttin B.M.
        • Powell M.A.
        • Mutch D.G.
        • et al.
        Increased risk for hereditary nonpolyposis colorectal cancer-associated synchronous and metachronous malignancies in patients with microsatellite instability-positive endometrial carcinoma lacking MLH1 promoter methylation.
        Clin Cancer Res. 2004; 10: 481-490
        • Peltomaki P.
        • Aaltonen L.A.
        • Sistonen P.
        • et al.
        Genetic mapping of a locus predisposing to human colorectal cancer.
        Science. 1993; 260: 810-812
        • Loeb L.A.
        Microsatellite instability: marker of a mutator phenotype in cancer.
        Cancer Res. 1994; 54: 5059-5063
        • Esteller M.
        • Levine R.
        • Baylin S.B.
        • et al.
        MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas.
        Oncogene. 1998; 17: 2413-2417
        • Mills A.M.
        • Liou S.
        • Ford J.M.
        • et al.
        Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer.
        Am J Surg Pathol. 2014; 38: 1501-1509
        • Westin S.N.
        • Lacour R.A.
        • Urbauer D.L.
        • et al.
        Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome.
        J Clin Oncol. 2008; 26: 5965-5971
        • Broaddus R.R.
        • Lynch H.T.
        • Chen L.M.
        • et al.
        Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma.
        Cancer. 2006; 106: 87-94
        • Carcangiu M.L.
        • Radice P.
        • Casalini P.
        • et al.
        Lynch syndrome–related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types.
        Int J Surg Pathol. 2010; 18: 21-26
        • Garg K.
        • Leitao Jr., M.M.
        • Kauff N.D.
        • et al.
        Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities.
        Am J Surg Pathol. 2009; 33: 925-933
        • Honore L.H.
        • Hanson J.
        • Andrew S.E.
        Microsatellite instability in endometrioid endometrial carcinoma: correlation with clinically relevant pathologic variables.
        Int J Gynecol Cancer. 2006; 16: 1386-1392
        • Ryan P.
        • Mulligan A.M.
        • Aronson M.
        • et al.
        Comparison of clinical schemas and morphologic features in predicting Lynch syndrome in mutation-positive patients with endometrial cancer encountered in the context of familial gastrointestinal cancer registries.
        Cancer. 2012; 118: 681-688
        • Shia J.
        • Black D.
        • Hummer A.J.
        • et al.
        Routinely assessed morphological features correlate with microsatellite instability status in endometrial cancer.
        Hum Pathol. 2008; 39: 116-125
        • Kwon J.S.
        • Scott J.L.
        • Gilks C.B.
        • et al.
        Testing women with endometrial cancer to detect Lynch syndrome.
        J Clin Oncol. 2011; 29: 2247-2252
        • Altrabulsi B.
        • Malpica A.
        • Deavers M.T.
        • et al.
        Undifferentiated carcinoma of the endometrium.
        Am J Surg Pathol. 2005; 29: 1316-1321
        • Silva E.G.
        • Deavers M.T.
        • Bodurka D.C.
        • et al.
        Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma?.
        Int J Gynecol Pathol. 2006; 25: 52-58
        • Tafe L.J.
        • Garg K.
        • Chew I.
        • et al.
        Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms.
        Mod Pathol. 2010; 23: 781-789
        • Garg K.
        • Soslow R.A.
        Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma.
        J Clin Pathol. 2009; 62: 679-684
        • Mills A.M.
        • Liou S.
        • Kong C.S.
        • et al.
        Are women with endocervical adenocarcinoma at risk for Lynch syndrome? Evaluation of 101 cases including unusual subtypes and lower uterine segment tumors.
        Int J Gynecol Pathol. 2012; 31: 463-469
        • ten Broeke S.W.
        • Brohet R.M.
        • Tops C.M.
        • et al.
        Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.
        J Clin Oncol. 2015; 33: 319-325
        • Umar A.
        • Boland C.R.
        • Terdiman J.P.
        • et al.
        Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.
        J Natl Cancer Inst. 2004; 96: 261-268
        • Vasen H.F.
        • Mecklin J.P.
        • Khan P.M.
        • et al.
        The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).
        Dis Colon Rectum. 1991; 34: 424-425
        • Lancaster J.M.
        • Powell C.B.
        • Chen L.M.
        • et al.
        Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions.
        Gynecol Oncol. 2015; 136: 3-7
        • Leenen C.H.
        • van Lier M.G.
        • van Doorn H.C.
        • et al.
        Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer </= 70 years.
        Gynecol Oncol. 2012; 125: 414-420
        • Mvundura M.
        • Grosse S.D.
        • Hampel H.
        • et al.
        The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer.
        Genet Med. 2010; 12: 93-104
        • Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group
        Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives.
        Genet Med. 2009; 11: 35-41
        • Mojtahed A.
        • Schrijver I.
        • Ford J.M.
        • et al.
        A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas.
        Mod Pathol. 2011; 24: 1004-1014
        • Shia J.
        • Tang L.H.
        • Vakiani E.
        • et al.
        Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel.
        Am J Surg Pathol. 2009; 33: 1639-1645
        • Modica I.
        • Soslow R.A.
        • Black D.
        • et al.
        Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma.
        Am J Surg Pathol. 2007; 31: 744-751
        • Geurts-Giele W.R.
        • Leenen C.H.
        • Dubbink H.J.
        • et al.
        Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers.
        J Pathol. 2014; 234: 548-559
        • Haraldsdottir S.
        • Hampel H.
        • Tomsic J.
        • et al.
        Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.
        Gastroenterology. 2014; 147: 1308-1316.e1
        • Mills A.
        • Sloan E.
        • Thomas M.
        • et al.
        Clinicopathologic comparison of Lynch syndrome-associated and Lynch-like endometrial carcinomas identified on universal screening.
        Am J Surg Pathol. 2015; 40: 155-165
        • Hagen C.E.
        • Lefferts J.
        • Hornick J.L.
        • et al.
        “Null pattern” of immunoreactivity in a Lynch syndrome-associated colon cancer due to germline MSH2 mutation and somatic MLH1 hypermethylation.
        Am J Surg Pathol. 2011; 35: 1902-1905
        • Resnick K.
        • Straughn Jr., J.M.
        • Backes F.
        • et al.
        Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients.
        Obstet Gynecol. 2009; 114: 530-536
        • Boland C.R.
        • Thibodeau S.N.
        • Hamilton S.R.
        • et al.
        A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.
        Cancer Res. 1998; 58: 5248-5257
        • Suraweera N.
        • Duval A.
        • Reperant M.
        • et al.
        Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR.
        Gastroenterology. 2002; 123: 1804-1811
        • McConechy M.K.
        • Talhouk A.
        • Li-Chang H.H.
        • et al.
        Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas.
        Gynecol Oncol. 2015; 137: 306-310
        • Bessa X.
        • Balleste B.
        • Andreu M.
        • et al.
        A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening.
        Clin Gastroenterol Hepatol. 2008; 6: 206-214
        • Kawaguchi M.
        • Yanokura M.
        • Banno K.
        • et al.
        Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer.
        Int J Oncol. 2009; 34: 1541-1547
        • Buchanan D.D.
        • Rosty C.
        • Clendenning M.
        • et al.
        Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).
        Appl Clin Genet. 2014; 7: 183-193
        • Fiumicino S.
        • Ercoli A.
        • Ferrandina G.
        • et al.
        Microsatellite instability is an independent indicator of recurrence in sporadic stage I-II endometrial adenocarcinoma.
        J Clin Oncol. 2001; 19: 1008-1014
        • Zighelboim I.
        • Goodfellow P.J.
        • Gao F.
        • et al.
        Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type.
        J Clin Oncol. 2007; 25: 2042-2048
        • Xiao X.
        • Melton D.W.
        • Gourley C.
        Mismatch repair deficiency in ovarian cancer–molecular characteristics and clinical implications.
        Gynecol Oncol. 2014; 132: 506-512
        • Kandoth C.
        • Schultz N.
        • Cherniack A.D.
        • et al.
        Integrated genomic characterization of endometrial carcinoma.
        Nature. 2013; 497: 67-73
        • Schmeler K.M.
        • Lynch H.T.
        • Chen L.M.
        • et al.
        Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome.
        N Engl J Med. 2006; 354: 261-269
        • Frolova A.I.
        • Babb S.A.
        • Zantow E.
        • et al.
        Impact of an immunohistochemistry-based universal screening protocol for Lynch syndrome in endometrial cancer on genetic counseling and testing.
        Gynecol Oncol. 2015; 137: 7-13