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Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis
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Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2016. | This topic last updated: Jan 19, 2016.

INTRODUCTION — Lynch syndrome is the most common cause of inherited colorectal cancer (CRC). It is characterized by a significantly increased risk for CRC and endometrial cancer as well as a risk of several other malignancies. This topic will review the genetic basis, clinical manifestations, and diagnosis of Lynch syndrome. Surveillance strategies for individuals with Lynch syndrome are discussed separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management".)

TERMINOLOGY

Hereditary nonpolyposis colorectal cancer (HNPCC) refers to patients and/or families who fulfill the Amsterdam criteria for Lynch syndrome (table 1). (See 'Amsterdam criteria' below.)

Lynch syndrome refers to patients and families with a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene.

EPIDEMIOLOGY — Approximately 70 to 80 percent of patients with CRC have sporadic disease, but the remaining 20 to 30 percent have a familial or inherited component that might be causative. Lynch syndrome is the most common inherited CRC susceptibility syndrome and accounts for approximately 3 percent of newly diagnosed cases of CRC and 2 percent of endometrial cancer.

GENETICS — Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes or loss of expression of MSH2 due to deletion in the EPCAM gene (previously called TACSTD1). The MMR genes that are associated with Lynch syndrome include:

MLH1 (MutL homolog 1), which is located on chromosome 3p21

MSH2 (MutS homolog 2), which is located on chromosome 2p16

MSH6 (MutS homolog 6), which is located on chromosome 2p16

PMS2 (postmeiotic segregation 2), which are located on chromosome 7p22

Among individuals with identifiable germline mutations in the MMR genes, mutations in MLH1, MSH2, MSH6, and PMS2 are found in approximately 32, 39, 15, and 14 percent, respectively [1].

The role of the DNA MMR system is to maintain genomic integrity by correcting base substitution mismatches and small insertion-deletion mismatches that are generated by errors in base pairing during DNA replication. Normal MMR requires the coordinated function of several different gene products. The MMR system recognizes base-pair mismatches by two heterodimeric protein complexes termed MutS-alpha and MutS-beta. MutS-alpha is a heterodimer of MSH2 and MSH6 proteins and MutS-beta is an MSH2/MSH3 heterodimer. Either the MSH2/6 or the MSH2/3 pair can recognize insertion/deletion loops that contain more than two bases but the MSH2/6 pair preferentially recognizes single base-base mispairs and small (one to two base) insertion-deletion loops [2]. The repair components of the MMR system consist of three other heterodimer pairs termed MutL-alpha, MutL-beta, and MutL-gamma. MutL-alpha is a heterodimer of MLH1 and PMS2, MutL-beta is a MLH1/PMS1 heterodimer, and MutL-gamma is a MLH1/MLH3 heterodimer.

Inactivation of both alleles of one of the MMR genes leads to defective MMR. As a general rule, patients with Lynch syndrome have a germline mutation in one allele of a MMR gene and the second allele is inactivated by mutation, loss of heterozygosity, or epigenetic silencing by promoter hypermethylation. Biallelic inactivation of MMR genes in a cell then causes an increased mutation rate (genomic instability) due to failure to repair the DNA mismatches that occur during normal DNA synthesis (about one in every 106 bases). DNA mismatches commonly occur in regions of repetitive nucleotide sequences called microsatellites. Thus, a characteristic feature of loss of mismatch repair in tumors is the expansion or contraction of these microsatellite regions in the tumor compared with normal tissue. This genetic alteration is termed microsatellite instability (MSI) and is characteristic of Lynch-associated cancers. Microsatellite instability may affect genes that control cell growth (transforming growth factor [TGF] beta and insulin-like growth factor [sIGF] receptors), regulate apoptotic cell death (Caspase 5, Bax), and some of the DNA MMR genes themselves (hMSH3, hMSH6) [3]. Accumulation of mutations in these cancer-related genes is thought to drive the process of carcinogenesis in Lynch syndrome.

However, MSI is not specific for Lynch syndrome, and approximately 15 percent of sporadic colorectal cancers also demonstrate MSI. Sporadic MSI-high (MSI-H) colorectal cancers typically develop through a methylation pathway called CpG island methylator phenotype (CIMP), which is characterized by aberrant patterns of DNA methylation and frequently by mutations in the BRAF gene. These cancers develop somatic promoter methylation of MLH1, leading to loss of MLH1 function and resultant MSI. (See "Molecular genetics of colorectal cancer", section on 'Hypermethylation phenotype (CIMP+) pathway' and 'Additional evaluation' below.)

Large deletions in the 3' end of the EPCAM gene leads to transcriptional read-through into and subsequent epigenetic silencing of the neighboring MSH2 gene [4]. In EPCAM 3' end deletion carriers, MSH2 inactivation is cell type-specific. MSH2 is only inactivated in cells in which the EPCAM locus is active, therefore showing a mosaic pattern of MSH2 inactivation. This may lead to a tumor spectrum that is different from individuals with a germline MSH2 mutation or a deletion that encompasses EPCAM as well as MSH2 or extending close to the MSH2 promoter [4]. (See 'Genotype phenotype correlation' below.)

CLINICAL FEATURES — Individuals with Lynch syndrome are at an increased risk of colorectal cancer (CRC) (picture 1), endometrial cancer, and several other malignancies.

Colonic manifestations — The majority of patients are asymptomatic until they present with symptoms of colorectal cancer such as gastrointestinal bleeding, abdominal pain, or a change in bowel habits. The lifetime risk of CRC in Lynch syndrome is approximately 70 percent but varies by genotype (table 2) [5,6]. The incidence of CRC is moderately higher in men than in women, and although the age of onset varies by genotype, CRC in Lynch syndrome occurs at a younger age as compared with sporadic CRC (44 to 61 versus 69 years) [7]. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical presentation'.)

Individuals with Lynch syndrome are at increased risk for synchronous and metachronous CRCs. Approximately 7 to 10 percent of individuals with Lynch syndrome have more than one cancer by the time of diagnosis and 20 to 60 percent develop a metachronous CRC after initial resection if a subtotal colectomy is not performed [8,9]. In one study, the cumulative risk of metachronous CRC in patients with Lynch syndrome who had undergone a segmental resection for the first CRC was 16 percent at 10 years, 41 percent at 20 years, and 62 percent at 30 years [9]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management", section on 'Management of colorectal cancer'.)

CRCs in Lynch syndrome differ from sporadic CRCs in that they are predominantly right sided in location. Although Lynch-associated CRCs evolve from adenomas, the adenomas tend to be larger, flatter, are more often proximal, and are more likely to have high-grade dysplasia and/or villous histology as compared with sporadic adenomas. The adenoma-carcinoma sequence also progresses much more rapidly in Lynch syndrome as compared with sporadic CRC (35 months versus 10 to 15 years). However, the overall five-year survival from CRC in Lynch syndrome is higher as compared with sporadic CRC [10,11]. (See 'Pathological features' below and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management".)

Extracolonic manifestations — The most common extracolonic tumor in Lynch syndrome is endometrial cancer. The risk of endometrial cancer varies depending on the mismatch repair (MMR) mutation (table 2) [4,12-15]. Individuals with Lynch syndrome are also at increased risk of cancer of the ovary, stomach, small bowel, hepatobiliary system, transitional cell cancer of the renal pelvis and ureter, brain (glioma), and sebaceous neoplasms. (See "Endometrial and ovarian cancer screening and prevention in women with Lynch syndrome (hereditary nonpolyposis colorectal cancer)", section on 'Endometrial cancer'.)

An increased risk of cancer of the pancreas, prostate, and breast in individuals with Lynch syndrome has not been consistently demonstrated [16-26]. Laryngeal, hematologic malignancies, adrenocortical cancers and sarcomas have been reported in individuals with Lynch syndrome, but it is unclear if these cancers are associated with Lynch syndrome [27].

Muir-Torre and Turcot variants — Muir-Torre syndrome, a variant of Lynch syndrome, is characterized by sebaceous tumors and cutaneous keratoacanthomas, in addition to cancers associated with Lynch syndrome [28,29]. (See "Muir-Torre syndrome".)

Turcot syndrome is a historical term that originally described the association of familial CRC with brain tumors (primarily medulloblastomas and gliomas). As the genetics of the familial CRCs were defined, it became clear that brain tumors were associated with both familial adenomatous polyposis (FAP) and Lynch syndrome. The majority of FAP-associated brain tumors are medulloblastomas, whereas Lynch syndrome is more commonly associated with gliomas. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Turcot syndrome'.)

Genotype phenotype correlation — The cumulative cancer risks vary among the different MMR mutations with MSH6 and PMS2 having an overall lower risk as compared with MLH1 and MSH2 mutations (table 2). The overall cancer risk and the CRC risk is similar in MLH1 and MSH2 families but the risk of endometrial and other extracolonic appears to be higher in MSH2 families [30-32]. Individuals with an EPCAM mutation appear to have a comparable risk of CRC as MSH2 mutation carriers, but the risk for endometrial cancer is lower unless the deletion extends close to the promoter of MSH2 [33,34]. Families with MSH6 and possibly PMS2 mutations appear to have an attenuated cancer phenotype with a later age of cancer diagnosis and a lower penetrance as compared with MLH1 and MSH2 families [4,14,30].

PATHOLOGICAL FEATURES — Colorectal cancers in Lynch syndrome have distinct histologic features. They are more often mucinous, signet ring cell or medullary histologic type, poorly differentiated, and have a brisk lymphocytic infiltrate or are rimmed by a Crohn-like, germinal center-producing lymphoid reaction [35,36]. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Mismatch repair deficiency' and 'Tumor-based strategies' below.)

IDENTIFICATION OF INDIVIDUALS AT RISK FOR LYNCH SYNDROME — Lynch syndrome is largely under-recognized [37]. Traditionally, a family history of colorectal and other cancers was the primary tool to identify Lynch syndrome. Once it was recognized that Lynch-associated colorectal cancers (CRCs) were microsatellite unstable, tumor testing became an additional tool for identification of Lynch syndrome. (See 'Genetics' above.)

Family history based strategies — Several family history based criteria have been used to identify individuals at risk for Lynch syndrome. They have limited sensitivity for identification of patients with Lynch syndrome.

Amsterdam criteria — The Amsterdam I criteria were proposed to identify individuals who were likely to be mutation carriers for Lynch syndrome [38]. These criteria require the presence of young onset CRC in addition to a family history of three CRCs involving two successive generations. The Amsterdam I criteria were subsequently modified to include other Lynch-associated malignancies. According to the Amsterdam II criteria, Lynch syndrome should be suspected in kindreds that meets all of the following criteria:

Three or more relatives with histologically verified Lynch syndrome-associated cancers (CRC, cancer of the endometrium or small bowel, transitional cell carcinoma of the ureter or renal pelvis), one of whom is a first-degree relative of the other two and in whom familial adenomatous polyposis (FAP) has been excluded.

Lynch syndrome-associated cancers involving at least two generations.

One or more cancers were diagnosed before the age of 50 years.

The Amsterdam criteria can be remembered by the "3-2-1 rule" (3 affected members, 2 generations, 1 under age 50) (table 1). The sensitivity and specificity of Amsterdam II criteria for a diagnosis of Lynch syndrome are 22 and 98 percent, respectively.

Bethesda criteria — The Bethesda and the revised Bethesda criteria are clinical criteria that were developed to identify individuals with CRC who should undergo tumor testing for microsatellite instability (MSI) (table 3). The sensitivity and specificity of any one of the revised Bethesda criteria for a diagnosis of Lynch syndrome are 82 and 77 percent, respectively. (See 'Genetics' above and 'Tumor-based strategies' below.)

Prediction models — Several prediction models have been developed to provide quantitative estimates of the likelihood of a mismatch repair (MMR) mutation [39-42]. As these models use different data, they can provide a range of mutation-likelihood estimates in the same patient, thereby assisting patients in their decision to undergo genetic testing. Although the performance characteristics of these models improve on clinical criteria in identifying patients with Lynch syndrome, the models still depend on clinicians to suspect the possibility of a hereditary syndrome and elicit an accurate family history.

MMRpredict model – The MMRpredict model includes sex, age at diagnosis of CRC, location of the tumor (proximal versus distal), multiple CRCs (synchronous or metachronous), occurrence of endometrial cancer in any first-degree relatives and age at diagnosis of CRC in first-degree relatives to calculate the risk of a patient having a Lynch syndrome gene mutation [39]. In a validation study involving 725 consecutive patients with CRC whose DNA mismatch repair status was available, the sensitivity and specificity of the MMRpredict model were 94 and 91 percent, respectively [43]. A calculator for this model is available online.

MMRpro model – The MMRpro model uses the personal history and family history of CRC and endometrial cancer, age of diagnosis (or current age in unaffected family members) and the results of tumor testing for mismatch repair and previous germline testing results (when it is available) to determine the probability of a person having a deleterious germline mutation in the MLH1, MSH2, or MSH6 genes. The model also provides an estimate of future cancer risk in unaffected persons, including mutation carriers, untested persons, and those in whom no mutation is found. It takes into account CRC, endometrial cancer, and MSI status, but it does not include other Lynch syndrome associated cancers. Validation studies have found that it has better discriminatory ability as compared with the Bethesda guidelines [44]. The MMRpro model can be accessed online.

PREMM model – The PREMM1,2,6 model provides risk estimates of the likelihood of a MMR mutation and the probability of finding a mutation in MLH1, MSH2, and MSH6 genes [45]. Variables included in the model include proband sex, and personal and/or family history (including age at diagnosis) of CRC, endometrial cancer, or other Lynch syndrome associated cancers. As compared with other models, the PREMM1,2,6 model has the highest sensitivity but lowest specificity (90 and 67 percent, respectively) [46]. Risk assessment of individuals between the ages of 25 and 35 years, followed by genetic testing for those whose estimated risk of carrying a MMR mutation exceeds 5 percent, may be cost-effective [47]. In addition, combining tumor immunohistochemistry (IHC) results with risk prediction estimates using the PREMM1,2,6 model may further improve the identification of individuals at risk for Lynch syndrome [48]. The PREMM1,2,6 model is available online.

Few studies have directly compared the prediction models [39,43,49,50]. One such study compared the predictive performance and clinical usefulness of MMRpredict, MMRpro, and PREMM1,2,6 models in 5706 individuals included from clinic and population-based cohorts with CRC [42]. MMR mutations were detected in 539 (23 percent) of individuals from clinic-based cohorts and 150 (4 percent) individuals from the population-based cohorts. Both MMRPro and PREMM1,2,6 better discriminated MMR gene mutation carriers from noncarriers as compared with MMRpredict in both clinic and population-based cohorts (observed/expected mutation carriers 0.38 and 0.31; 0.62 and 0.36; and 1.0 and 0.70, respectively). MMRpro and PREMM1,2,6 models were clinically useful in identifying mutation carriers at risk thresholds of ≥5 percent and, in particular, at greater than 15 percent. (See 'Candidates for genetic evaluation' below.)

Tumor-based strategies — Testing tumors for evidence of defective DNA mismatch repair has been used to identify individuals at risk for Lynch syndrome. While many experts recommend "universal testing" of all CRCs, others employ a more "selective strategy" of testing tumors of high-risk individuals identified by their personal and family cancer history [46,51-55]. Universal testing has slightly greater sensitivity for identification of Lynch syndrome as compared with other strategies, including Bethesda criteria, or a selective tumor testing strategy and may be cost-effective [56-58]. (See 'Tumor evaluation' below.)

Microsatellite instability testing — Tumors in Lynch syndrome demonstrate MSI due to a loss of DNA MMR. MSI testing is performed using polymerase chain reaction (PCR) to amplify a standard panel of DNA sequences containing nucleotide repeats. In the most commonly used panel, if 30 percent or more of the markers show expansion or contraction of the repetitive sequences in the tumor compared with the normal mucosa from the same patient, the tumor is reported to have a high level of MSI (MSI-H). (See 'Genetics' above.)

Immunohistochemistry — The mutations in the MMR genes that cause Lynch syndrome typically result in a truncated or lost MMR protein that can be detected as loss of staining of the protein on tumor IHC testing [59,60]. The likelihood to find a germline mutation in one of the MMR genes based on IHC results varies depending on the protein that is absent (table 4) [61].

Performance characteristics

Colorectal cancer – The sensitivity and specificity of MSI testing for Lynch syndrome are approximately 85 and 90 percent, respectively. Loss of the MLH1 protein expression on IHC can be seen in about 15 percent of sporadic CRCs due to hypermethylation of MLH1 [35]. In addition, MSH6-associated cancers may be missed on MSI testing because MSH6 is preferentially involved in the repair of mononucleotide repeats and mononucleotide markers are not included in all MSI panels. PMS2-associated cancers may have a lower rate of MSI-H than MLH1- or MSH2-associated cancers and can be missed on MSI testing [33]. (See 'Genetics' above and 'Additional evaluation' below.)

IHC testing of tumor tissue for lack of expression of MMR proteins has sensitivity and specificity of 83 and 89 percent, respectively. IHC is easily available, inexpensive and has the added value of detecting loss of expression of PMS2 and MSH6 proteins, which may be missed by PCR testing for MSI. IHC is more easily set up by pathology laboratories and it helps identify which genes may be involved (table 4). However, careful quality control is required to limit variability in IHC results.

Extracolonic cancer – IHC of MMR proteins in endometrial cancer has also shown efficacy for identification of Lynch syndrome. IHC in other Lynch syndrome tumors has been studied less rigorously and, while abnormal tumor studies may be indicative of Lynch syndrome, normal tumor studies do not necessarily rule out Lynch syndrome. IHC results in these tumors should be evaluated in light of the family and personal history of tumors [59].

Colorectal adenomas – MSI or IHC testing of large (>1 cm) adenomas can be a useful tool if no CRCs are available in the family. However, the finding of microsatellite stability does not rule out Lynch syndrome. In one study of polyps in 34 individuals with known Lynch syndrome, MSI-H was seen in 15 of 37 adenomatous polyps (41 percent) and absence of MMR protein expression was seen in 18 of 36 adenomatous polyps (50 percent). All six large (>1 cm) adenomas were MSI-H and had loss of MMR protein expression on IHC [62]. Another study of 109 polyps from 69 individuals with Lynch syndrome found loss of MMR proteins in 60 of 74 (79 percent) adenomas and in all 12 adenomas with high-grade dysplasia [63].

DIAGNOSIS — Lynch syndrome should be suspected in patients with synchronous or metachronous colorectal cancer (CRC), CRC prior to 50 years of age, multiple Lynch syndrome associated cancers (eg, CRC and endometrial, ovarian, stomach, small intestine, or renal pelvis/ureter), and in cases of familial clustering of Lynch syndrome associated cancers. A pathogenic germline mutation in the mismatch repair (MMR) or EPCAM gene is required for a definitive diagnosis of Lynch syndrome.

Diagnostic evaluation — As germline testing on all patients suspected of having Lynch syndrome is prohibitively expensive, sequential genetic evaluation beginning with tumor testing is recommended [27,64].

Candidates for genetic evaluation — We suggest genetic evaluation of the following individuals for Lynch syndrome:

All newly diagnosed patients with CRC

Endometrial cancer prior to age 50 years

First-degree relative of those with known MMR/EPCAM gene mutation

Individuals with >5 percent chance of a MMR gene mutation by prediction models

Family cancer history meeting Amsterdam I or II criteria or revised Bethesda guidelines

Tumor evaluation — We begin genetic evaluation for Lynch syndrome by initially performing tumor microsatellite instability (MSI) and/or immunohistochemistry (IHC) testing. The absence of MSI and intact expression of all four MMR proteins on IHC rules out Lynch syndrome. In individuals with evidence of high MSI (MSI-H) or loss of expression of a MMR protein, further evaluation is based on the MSI/IHC results and is outlined in the suggested algorithm (algorithm 1). (See 'Tumor-based strategies' above.)

Germline testing — Germline testing for a deleterious mutation in the MMR (MLH1, MSH2, MSH6, and PMS2) or EPCAM gene is required to establish the diagnosis of Lynch syndrome. Germline testing should be offered to the following individuals:

Patients with microsatellite unstable tumors by MSI/IHC testing

If tumor testing is not feasible and if the clinical suspicion of Lynch syndrome is strong (eg, individual meets revised Bethesda criteria) (table 3)

If a patient meets the Amsterdam criteria, some experts recommend germline testing without prior tumor testing

A known deleterious (pathogenic) MMR/EPCAM mutation in an affected individual establishes the diagnosis of Lynch syndrome. In such cases, at-risk relatives should be referred for genetic counseling and site-specific testing for the mutation that causes Lynch syndrome in the pedigree. Testing in children should be initiated 10 years before the earliest age of cancer onset in the family. The presence of the same mutation establishes a diagnosis of Lynch syndrome, and a negative test result for the pedigree mutation indicates that the individual does not have Lynch syndrome (algorithm 2).

However, in the absence of a known pathogenic mutation in an affected family member and tumor tissue for MSI testing, the finding of no mutation or a variant of unknown significance in an at-risk individual is an inconclusive finding and does not rule out Lynch syndrome. Such individuals should be managed as individuals with Lynch syndrome.

Prior to germline testing, practitioners must ensure that the patient or guardian has received appropriate counseling that includes the limitations of genetic testing and has provided written informed consent. Comprehensive germline mutation testing involves gene sequencing and deletion/duplication analyses. Sequencing and deletion/duplication analysis will not detect rare cases of Lynch syndrome that are due to constitutional inactivation of MLH1 by hypermethylation, along with somatic loss of heterozygosity of the functional allele. Germline testing may be uninformative in individuals found to have variants of unknown significance. Due to the high level of homology between PMS2 and pseudogenes, identification of deletions/duplications in the PMS2 gene and the interpretation of detected alterations is often difficult. Important practical issues related to genetic testing, including counseling, psychosocial, and ethical issues, are discussed in detail, separately. (See "Genetic counseling and testing", section on 'Practical issues in genetic testing' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management".)

Additional evaluation — In patients with loss of MLH1 staining on IHC, we perform testing for acquired BRAF mutations and MLH1 promoter hypermethylation to distinguish between CRCs that have loss of MLH1 that arise from Lynch syndrome (no MLH1 hypermethylation) and sporadic CRC caused by epigenetic methylation of MLH1 [65,66]. BRAF mutations are found in 40 to 87 percent of sporadic MSI-H CRCs but are rare in Lynch cancers. The identification of a BRAF mutation in an MSI-H CRC essentially rules out Lynch syndrome [67]. Methylation of MLH1 can cause epigenetic MSI-H endometrial tumors in a manner similar to that described for CRCs except that BRAF mutations are not a common occurrence in endometrial tumors.

DIFFERENTIAL DIAGNOSIS

Attenuated familial adenomatous polyposis (AFAP) and MUTYH associated polyposis (MAP) – Individuals with AFAP and MAP and a few colorectal adenomas may be difficult to distinguish clinically from Lynch syndrome [68]. Only genetic testing can definitively distinguish between AFAP, MAP, and Lynch syndrome, although an autosomal dominant pattern of colorectal cancer (CRC) inheritance makes MAP unlikely. AFAP is characterized by germline mutations in the APC gene and individuals with MAP have biallelic mutations in the MUTYH genes. (See 'Genetics' above and "MUTYH-associated polyposis" and "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Clinical manifestations'.)

Constitutional mismatch repair deficiency syndrome – Constitutional mismatch repair (MMR) deficiency syndrome refers to patients and/or families with biallelic mutations of the DNA MMR genes. In contrast with Lynch syndrome in which cancers occur in the fifth or sixth decade of life, homozygous or compound heterozygous mutation carriers of MLH1, MSH2, MSH6, or PMS2 mutations often develop hematologic and brain malignancies during childhood [69-78]. Many of these individuals have a family history of Lynch syndrome on both the maternal and paternal sides of their families. In addition to the cancer risk in the first two decades of life, individuals with constitutional MMR deficiency may have a neurofibromatosis type-1-like phenotype, presenting with café au lait spots, neurofibromas, Lisch nodules, and axillary freckling.

Familial colorectal cancer type X – Familial colorectal cancer type X (FCCTX) refers to patients and/or families that meet Amsterdam I criteria but when tumors are tested, lack microsatellite instability (MSI) that is characteristic of Lynch syndrome. Patients with FCCTX also do not appear to have an increased risk of endometrial or other Lynch-associated cancers [79]. (See 'Amsterdam criteria' above and "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes'.)

Lynch-like syndrome – Lynch-like syndrome (LLS) describes patients in which molecular testing demonstrates the presence of MSI and/or abnormalities in the expression of MMR gene proteins on immunohistochemistry testing of tumor tissue expression, but no pathogenic germline mutation can be found in the patient. In one study, approximately half of LLS patients had biallelic somatic mutations of MLH1 or MSH2 to explain the MMR deficient tumors without having causal germline or promoter mutations in the MMR genes [80].

SUMMARY AND RECOMMENDATIONS

Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or loss of expression of MSH2 due to deletion in the EPCAM gene. Lynch syndrome is the most common inherited colorectal cancer (CRC) susceptibility syndrome and accounts for approximately 3 percent of newly diagnosed cases of CRCs and 2 percent of endometrial cancers. (See 'Epidemiology' above and 'Genetics' above.)

The lifetime risk of CRC in Lynch syndrome is approximately 70 percent but varies by genotype (table 2). Individuals with Lynch syndrome are also at an increased risk for endometrial cancer, and several other malignancies including cancers of the ovary, renal pelvis, ureter, stomach, small bowel, bile duct, skin (sebaceous neoplasms), and brain (gliomas). (See 'Clinical features' above.)

CRCs in Lynch syndrome differ from sporadic CRCs in that they are predominantly right sided in location. Although the CRCs appear to evolve from adenomas, the adenomas tend to be larger, flatter, are more often proximal, and more commonly have high-grade dysplasia and/or villous histology as compared with sporadic adenomas. The adenoma-carcinoma sequence also progresses much more rapidly in Lynch syndrome as compared with sporadic CRC. Individuals with Lynch syndrome are at increased risk for both synchronous and metachronous CRCs. (See 'Colonic manifestations' above.)

Tumors in Lynch syndrome typically demonstrate microsatellite instability (MSI) and loss of staining of MMR proteins on immunohistochemistry (IHC) testing. As compared with sporadic CRCs, they are more often mucinous, signet ring cell or medullary histologic type, poorly differentiated, and have a brisk lymphocytic infiltrate or are rimmed by a Crohn-like, germinal center-producing lymphoid reaction. (See 'Pathological features' above.)

Several clinicopathologic criteria (eg, Amsterdam criteria, revised Bethesda guidelines) have been used to identify individuals at risk for Lynch syndrome (table 1 and table 3). However, they are limited in their sensitivity. Although the performance characteristics of clinical prediction models (eg, MMRpro, MMRpredict, PREMM1,2,6) improve on clinical criteria in identifying patients with Lynch syndrome, the models still depend on clinicians to suspect the possibility of a hereditary syndrome and elicit an accurate family history. (See 'Identification of individuals at risk for Lynch syndrome' above.)

Lynch syndrome should be suspected in patients with synchronous or metachronous CRC, CRC prior to 50 years of age, multiple Lynch syndrome associated cancers, and in cases of familial clustering of Lynch syndrome associated cancers. (See 'Diagnosis' above.)

Given the limitations in clinicopathologic criteria and prediction models in identifying individuals at risk for Lynch syndrome, we suggest genetic evaluation for mismatch repair deficiency of all newly diagnosed CRCs ("universal testing") for Lynch syndrome. Other indications for genetic evaluation for Lynch syndrome include:

Family cancer history meeting Amsterdam I or II criteria or revised Bethesda guidelines

Endometrial cancer prior to age 50 years

First-degree relative of those with known MMR/EPCAM gene mutation

Individuals with >5 percent chance of a MMR gene mutation by prediction models

We begin genetic evaluation for Lynch syndrome by performing tumor MSI and/or IHC testing and perform additional testing in MSI-high tumors or those with loss of expression of a MMR protein on IHC (algorithm 1). A pathogenic germline mutation in the MMR or EPCAM genes is required for a definitive diagnosis of Lynch syndrome. (See 'Diagnostic evaluation' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Dennis Ahnen, MD, and Lisen Axell, MS, who contributed to an earlier version of this topic review.

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