Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Etiology

Lynch syndrome results from a germline mutation in 1 of 4 mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. Large deletions in a non-mismatch repair gene called epithelial cellular adhesion molecule (EPCAM), which silences MSH2 expression, have also been found to cause Lynch syndrome. Mismatch repair genes are necessary for correcting incorrect pairing of nucleotide bases during DNA replication. If these mismatches are not resolved, the resulting copy may not function properly, leading to an increased cancer risk. These mutations lead to a high amount of microsatellite instability (MSI). While these heritable defects cause some portion of MSI, most MSI arise from somatic gene inactivation, most commonly by methylation of the MLH1 promotor region. Therefore, once MSI is identified, further testing must be performed to clarify the nature of the mutation.

Individuals with Lynch syndrome are born with 1 functional and 1 non-functional allele (copy) of a specific gene. When a mutation occurs in the functional allele, the risk for cancer occurs. Rarely an individual is not born with Lynch syndrome but develops mutations in both alleles, leading to the somatic loss of the MMR proteins.[5][6][7] Lynch syndrome is inherited in an autosomal dominant manner. First-degree relatives (parents, siblings, and children) have a 50% chance of being affected with Lynch syndrome.

Epidemiology

After colorectal cancer, the most common malignancy associated with Lynch syndrome is endometrial cancer. Lynch syndrome accounts for 2% to 4% of all colorectal cancer cases and approximately 2.5% of endometrial cancer cases. One out of every 35 colorectal cancers and one out of every 50 endometrial cancers are attributable to Lynch syndrome. The mean age at diagnosis of colorectal cancer in affected patients is 44 to 61 and 48 to 62 for endometrial cancer. Around 12,000 individuals per year may be diagnosed with Lynch syndrome in the United States with optimal screening.[8] 

Pathophysiology

Lynch syndrome is due to autosomal dominant germline mutations in genes involved in DNA mismatch repair. Mutations of these genes lead to frameshift alterations and, ultimately, to accumulating these errors within microsatellites. Microsatellites are nucleotide repeats which, when functional, are identical in every cell within 1 person. Mutations in mismatch repair allow for the proliferation of aberrant microsatellites within tumor suppressor genes, resulting in cancerous growth.

MSI occurs frequently in sporadic cancers, commonly due to methylation of mismatch repair gene promoter regions (often, the MLH1 promoter is methylated secondary to a BRAF mutation). These patients tend to be older than the typical patients with Lynch syndrome. The clinical presentation of Lynch syndrome depends on the affected genes and associated molecular changes; colonic and extracolonic manifestations vary. A low rate of polyp formation is common in this population; those diagnosed or at risk benefit from regular surveillance.

Tumors often present in the right colon, in younger persons, and often with synchronous or metachronous tumors. Tumors in Lynch syndrome do proceed through the adenoma phase but tend to be more dysplastic and have an accelerated transition to carcinoma. Patients with Lynch syndrome tend to have fewer than 10 adenomatous polyps cumulatively. Adenomas are commonly seen in patients aged younger than 40 and frequently have a mucinous villous growth pattern with moderate to high-grade dysplasia. Tumors often have histologic features that are not specific but common to Lynch syndrome, including poor differentiated medullary-type carcinoma, mucinous adenocarcinoma, signet-ring cells, and a Crohn-like reaction with infiltrating lymphocytes.[9][10][11][12]

History and Physical

Patients with Lynch syndrome are at an increased risk of colonic and extracolonic tumors, including endometrial, ovarian, upper gastrointestinal tract, urothelial, prostate, pancreatic, and brain cancers.[4] Personal or family history is critical in identifying patients at risk for Lynch syndrome. Persons who meet the criteria should undergo immunohistochemical and/or microsatellite analysis followed by germline DNA analysis for definitive diagnosis.

Screening criteria include the Amsterdam II Criteria and the Revised Bethesda Guidelines, which screen patients with a high likelihood of Lynch syndrome.[13][14] The initial Amsterdam criteria only included colonic tumors, but the criteria were revised to include cancers within the endometrium, small intestine, ureter, and kidney. Due to the low sensitivity of those criteria, the Bethesda Guidelines (subsequently updated) focusing on MSI were added to identify a larger number of affected people. 

Together, these criteria include colorectal cancer with associated MSI, additional cancers associated with Lynch syndrome, age on diagnosis, and affected relatives. However, a proportion of patients with Lynch syndrome may not meet the criteria due to the variability in presentation depending on the affected gene. Genes involved in Lynch syndrome have variable penetrance, and a family with a mutation in a lower-penetrance gene may not display a disease pattern that follows criteria. Mutations in individual genes confer varying risks for developing tumors and associated lifetime risk of these cancers.

Evaluation

Several tests may aid in diagnosing Lynch syndrome, including polymerase chain reaction (PCR) to assess for MSI, immunohistochemical staining (IHC) to assess for mismatch repair proteins, and germline sequencing. In addition, the common somatic mutation involving MLH1 promoter methylation is analyzed to help differentiate somatic vs germline etiology. The mismatch repair DNA, defective in Lynch syndrome, generates the MSI that can be identified via PCR. MSI is characterized by variations in the length of repetitive DNA sequences known as microsatellites and occurs due to a deficiency of mismatch repair activity. Diagnosing microsatellite instability involves assessing the length of DNA microsatellites from the tumor sample. Changes in length indicate the presence of microsatellite instability.

Most Lynch syndrome tumors have microsatellite instability, but this feature is common in 15% to 25% of sporadic colorectal cancers, which also exhibit deficiency of at least 1 mismatch repair protein in 10% to 15% of cases. Germline testing for Lynch syndrome is recommended in all tumors with abnormal MSI or IHS. IHC staining, utilizing antibodies against the 4 main repair proteins, can be used to predict the likelihood of MSI. Immunohistochemical staining is performed on a tumor sample to look for mismatch repair proteins. A mismatch repair gene mutation is unlikely if all mismatch repair proteins are present. This is referred to as mismatch repair proficiency. If staining is negative for at least 1 mismatch repair protein, this is referred to as mismatch repair deficient, and germline testing should be offered.

Concordance is high between PCR and IHC, and both are highly sensitive and specific; both have a false negative rate of about 5% to 10%. Many deficiencies of the MLH1 protein are due to sporadic promoter methylation. If immunohistochemical staining for MLH1 (either alone or with PMS2) is abnormal, testing for BRAF V600E mutation or methylation of the promoter should be conducted. Methylation suggests sporadic colorectal cancer rather than Lynch syndrome. If the test is negative, germline mutation testing for Lynch syndrome should follow. For more information, please refer to the National Comprehensive Cancer Network Screening Guidelines for Colorectal Cancer.

Screening guidelines for Lynch syndrome are published by the National Comprehensive Cancer Network (NCCN). NCCN recommends immunohistochemical staining of the mismatch repair proteins in all colorectal cancer tumors in every patient with colorectal cancer aged younger than 70, those older than 70 meeting the Revised Bethesda Guidelines, and endometrial tumors diagnosed in patients aged younger than 50. Germline mutation testing for Lynch syndrome is diagnostic. Testing is accomplished by DNA sequencing and large rearrangement analysis. Due to the complexities of test selection and interpretation and the potential consequences of the results for the family, germline mutation testing should be preceded by genetic counseling. 

Patients with abnormal immunohistochemical staining or microsatellite instability whose germline testing does not reveal a mutation may have double somatic mismatch repair gene mutations in the tumor DNA or may have Lynch syndrome with incomplete penetrance. Management should be based on the patient's personal and family history in such cases.

Clinical Testing Criteria

Assessment for Lynch syndrome begins with a thorough family cancer history, including at least 3 generations made up of first, second, and third-degree relatives. All cancers should be noted, including the age of diagnosis if available. Genetic testing for Lynch syndrome should be considered for patients who meet the following:

• Amsterdam II Criteria (Table 1A) 
• Revised Bethesda Guidelines (Table 1B)
• Endometrial cancer diagnosed before age 50
• Known Lynch syndrome in the family
• Testing should be considered in patients with at least 5% risk of Lynch syndrome on MMRpro, PREMM, or MMRpredict prediction models

Amsterdam II Criteria and Revised Bethesda Guidelines

Amsterdam II criteria

More than 3 relatives with a Lynch syndrome-related cancer (colorectal, endometrial, small bowel, ureter, or renal pelvis) and meet the following additional criteria:

• At least 2 successive generations affected
• One is a first-degree relative of the other 2
• At least 1 relative was diagnosed before age 50
• No evidence of familial adenomatous polyposis (FAP) 
• Tumors are verified by pathological examination [13][15]

Revised Bethesda guidelines 

• Colorectal cancer diagnosed in a patient younger than 50
• Presence of synchronous or metachronous, colorectal, or other Lynch syndrome-related tumors, regardless of age
• Colorectal cancer with microsatellite instability (tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous or signet-ring differentiation, or medullary growth pattern)
• Colorectal cancer diagnosed in a patient with 1 or more first-degree relatives with a Lynch syndrome-related cancer, with one of the cancers diagnosed before age 50
• Colorectal cancer is diagnosed in a patient with 2 or more first- or second-degree relatives with Lynch syndrome-related cancers regardless of age [14]

Lynch syndrome-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, bladder, prostate, biliary tract, brain (usually glioblastoma as seen in Turcot syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas (as seen in Muir-Torre syndrome).[4] Using the Amsterdam II Criteria and the Revised Bethesda Guidelines to identify patients at risk for Lynch syndrome misses approximately 50% of those affected or carriers. In contrast, about 50% of patients meeting the criteria do not have Lynch syndrome. Overall sensitivity and specificity are 82% and 77%, respectively.

Patients identified by testing with immunohistochemical staining and/or microsatellite instability or meeting testing criteria are recommended for genetic testing. Testing of affected family members is encouraged, but when no affected member is available, testing of unaffected individuals should be considered.

Familial Adenomatous Polyposis 

Familial adenomatous polyposis (FAP) is also an autosomal dominant hereditary type of colorectal cancer that has several key differences from Lynch syndrome:

• FAP is caused by a germline alteration of the adenomatous polyposis coli gene, a tumor suppressor gene.
• Genetic testing is not as critical to making the diagnosis as the enormous number of colonic polyps (100s to 1000s) on colonoscopy suggests FAP.
• The finding of 10 or more colonic polyps at a single colonoscopy is highly suggestive of FAP, especially in younger patients.
• The colorectal cancer risk is higher and occurs at much younger ages in FAP. 
• In FAP, the risk of colorectal cancer approaches 100% by 40.
• Rectal cancer is common in FAP; about 30% of patients with FAP will develop rectal cancer by 50 if the rectum is not previously surgically removed.
• Treatment for FAP is usually early total colectomy, often including removal of the rectum.
• If less aggressive surgery is done, then endoscopic surveillance every 6 months is recommended.
• Surgery is necessary when polyps are not amenable to endoscopic treatment.[15][16]

Treatment / Management

Lynch Syndrome Management   

Patients found to have a mutation associated with Lynch syndrome are at increased cancer risk, with the greatest risk being early colorectal and endometrial cancers, followed by gastric and ovarian malignancies. The risk for Lynch syndrome-related colorectal cancer and other malignancies is reported to be lower in MSH6 and PMS2 carriers (lower endometrial and ovarian cancer risk in PMS2 variants).

Guidelines for MLH1, MSH2, MSH6, PMS2 and EPCAM Mutation Carriers:

Colon

• Colonoscopy begins at age 20 to 25 and repeats every 1 to 2 years, or 5 years younger than the youngest person diagnosed (although the risk may vary depending on germline variant).
• Colectomy if colon cancer is diagnosed or if an advanced adenoma is found that cannot be otherwise removed. The preferred treatment remains colectomy with ileorectal anastomosis. Segmental colectomy may be considered in older or select patients. Follow-up surveillance with colonoscopic examination is suggested every 1 to 2 years postoperatively.
• Colectomy can be considered if surveillance measures cannot be followed.

Endometrium, uterus, and ovaries           

• A pelvic exam, transvaginal ultrasound, endometrial sampling, and CA-125 yearly from age 30.
• Abnormal uterine or vaginal bleeding warrants immediate evaluation.
• Hysterectomy with bilateral salpingo-oophorectomy following completion of childbearing (this recommendation may be variant-dependent).

Extracolonic Lynch-syndrome-associated cancers 

NCCN has no screening guidelines for Lynch syndrome-associated malignancies. Recommendations rely on a family history of a specific cancer and can include the following:

• Upper endoscopy (esophagogastroduodenoscopy) with extended duodenoscopy every 1 to 3 years beginning at age 30 to 35 years in select individuals or families or those of Asian descent. Consider testing and treating for H. Pylori. CT enterography or capsule endoscopy every 2 to 3 years to assess for small bowel cancer.
• Urinalyses at 30 to 35. (The optimal age to begin screening for urinary tract cancers has not been determined, but the risk of developing such types of cancer before age 30 years is quite low). Smoking increases the risk.
• Consider endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound, or other diagnostics concerning pancreatic malignancy.
• Screening for prostate cancer in MSH2 and MSH6 variants.
• Screening for urothelial cancer in men, those with a family history of transitional cell urinary tract malignancies, and those with an MSH2 variant.
• Screening for breast cancer based on personal and family history and general recommendations.[4][17][18] 
(A1)

Medical Management

The efficacy of nonsteroidal anti-inflammatory drugs in patients with Lynch syndrome is under investigation. Data suggest aspirin use may decrease the risk of colon cancer in Lynch syndrome, but the optimal dose and duration remain uncertain. Suggested dosing includes 325 mg to 650 mg daily if tolerated, but 81 mg may be of some benefit.[19](A1)

MSI generates a significant immune response, as noted in the lymphocytic infiltration of many Lynch tumors. The milieu offers therapeutic potential for all persons affected by frequent frameshift mutations; peptides are produced, which cause a resulting lymphocytic reaction. This reaction can be upregulated in a targeted effort to treat these cancers via monoclonal antibodies (eg, pembrolizumab) targeted against immune checkpoints (to magnify the immune response). Studies seek to expand this response as part of a prophylactic regimen. A diagnosis of Lynch syndrome in a patient can also be of significance for at-risk family members. Patients should be advised to discuss with family members regarding possible cancer risk and their opportunities for testing, screening, and surveillance. 

Differential Diagnosis

Significant overlap is recognized in the presentation of Lynch syndrome–associated cancers with cancers caused by somatic mutations. MSI often results from spontaneous mutations of mismatch repair proteins, and some unspecified portions of Lynch syndrome families exhibit incomplete penetrance, making identification more difficult. The mutations inherent to Lynch syndrome can predispose patients to a spectrum of malignancies, and discriminating between Lynch syndrome and other causative etiologies as therapeutic options and prognosis may differ.

A list of differential diagnoses during the workup of malignancies associated with Lynch Syndrome include:

• Attenuated familial adenomatous polyposis
• Cowden disease
• Cronkite-Canada syndrome
• Familial adenomatous polyposis
• Familial clustering of late-onset colorectal neoplasms
• Hyperplastic polyps
• Juvenile polyposis syndrome
• Lymphomatous polyposis
• Muir-Torre syndrome
• Nodular lymphoid hyperplasia
• Sporadic colon cancer
• Turcot syndrome
• Urothelial cancer (smoking-related)

Medical Oncology

Recent interest is in the utility of monoclonal antibodies and immune modulators to upregulate the immune response, taking advantage of the innate immune proliferation noted with frameshift mutations using agents such as pembrolizumab and nivolumab.[20]

Prognosis

The overall reduction in life expectancy in patients with Lynch syndrome is primarily due to the increased incidence of cancer, especially colon cancer, and its appearance at an earlier age.[21] The 10-year overall survival from colorectal cancer in patients with Lynch syndrome remains high at 70% for recto-sigmoid malignancies and 88% for colon cancer.[4][22] Improved colorectal cancer surveillance increases survival further.[23][24]

A more aggressive surgical approach to colonic resection (total colectomy vs hemicolectomy) is also associated with improved cancer-free survival. The estimated risk of a second colorectal cancer after a segmental colonic resection in patients with Lynch syndrome has been estimated at 16% over 10 years, 41% by 20 years, and 62% at 30 years.[25][26][27]

Complications

No specific complications are related to Lynch syndrome other than the increased frequency and earlier presentation of the malignancies associated with the condition. Increased prevalence of synchronous and metachronous tumors is anticipated.