Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome)

Etiology

HNPCC is caused by mutations in 1 of 4 MMR genes: MLH1, MSH2, MSH6, and PMS2. These genes are responsible for fixing deoxyribonucleic acid mismatches during replication. Mutations in these genes lead to a high level of MSI. HNPCC is inherited in an autosomal dominant manner, meaning having just 1 copy of the mutated gene increases cancer risk. The specific type of mutation can affect the likelihood and type of cancer, with MLH1 and MSH2 mutations being particularly associated with higher risks of colorectal and endometrial cancers.[7]

The variation in cancer risk and onset is linked to the specific gene affected and the nature of the mutation (eg, frameshift versus missense). In some cases, mutations in these MMR genes can cause Muir-Torre syndrome, a subtype of HNPCC characterized by additional skin and sebaceous gland tumors. Genetic testing and family history are crucial for identifying at-risk individuals and developing appropriate surveillance strategies.

Epidemiology

HNPCC is the most common inherited colorectal cancer susceptibility syndrome, with an estimated worldwide prevalence of 2%. The prevalence of HNPCC is similar across multiple ethnic, geographic, and subject settings.[8] This condition equally affects men and women and accounts for approximately 3% of newly diagnosed colorectal cancer and 2% to 3% of endometrial cancer.[9] HNPCC is responsible for 1 out of every 35 colorectal cancers and 1 out of every 50 endometrial cancers. The mean age at diagnosis of colorectal cancer in affected patients is 44 to 61, and for endometrial cancer, it is 48 to 62. Around 12,000 individuals per year may be diagnosed with HNPCC in the United States with optimal screening.[10]

Pathophysiology

The MMR genes in HNPCC correct deoxyribonucleic acid mismatches during replication. These genes include MLH1, MSH2, MSH6, and PMS2. Mutations in these genes lead to a failure in the repair mechanism, resulting in MSI, a hallmark of HNPCC-associated tumors. Ultimately, the proliferation of aberrant microsatellites within tumor suppressor genes results in cancerous growth.

In HNPCC, the adenoma to carcinoma sequence differs from that in sporadic colorectal cancer, as tumors often arise from nonpolypoid lesions and have an accelerated transition to carcinoma due to MMR deficiency. Tumors often present in the right colon, in younger persons, and often with synchronous or metachronous tumors. Patients with HNPCC tend to have fewer than 10 adenomatous polyps cumulatively. Adenomas are commonly seen in patients 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 HNPCC, including poorly differentiated medullary-type carcinoma, mucinous adenocarcinoma, signet-ring cells, and a Crohn-like reaction with infiltrating lymphocytes.[11][12]

The risk for endometrial cancer is notably higher than in the general population, with lifetime risks varying by genotype and reaching up to 60% to 70% for MLH1 and MSH2 mutations. These cancers occur at younger ages compared to sporadic cases, often before age 50. Endometrial cancers in HNPCC typically present with abnormal uterine bleeding and are most often of endometrioid histology, although nonendometrioid types can also occur.[13][14] Ovarian cancer risk in HNPCC is also elevated, with a higher likelihood of early-stage diagnosis and a predilection for the endometrioid subtype. Both cancers often occur concurrently or metachronously with other HNPCC-associated malignancies.[15][16]

History and Physical

HNPCC is an autosomal dominant genetic disorder caused by germline mutations in deoxyribonucleic acid MMR genes such as MLH1, MSH2, MSH6, PMS2, or EPCAM. This condition predisposes individuals to an increased risk of colorectal cancer and other malignancies, including endometrial, ovarian, gastric, and urinary tract cancers. A thorough history and physical examination are essential for identifying individuals with HNPCC.

Family history often reveals a strong pattern of colorectal or endometrial cancer, particularly colorectal cancer diagnosed before the age of 50, multiple relatives with colorectal cancer or HNPCC-associated cancers across generations, or relatives with multiple primary malignancies. Personal history may include early-onset colorectal cancer (usually before 50), right-sided colorectal tumors, or multiple primary cancers such as colorectal cancer and endometrial cancer. Symptoms of colorectal cancer, including rectal bleeding, changes in bowel habits, abdominal pain, weight loss, and fatigue, are common. Women may present with abnormal uterine bleeding, pelvic pain, or bloating, indicating endometrial or ovarian cancer. A history of other HNPCC-associated cancers, such as gastric, small bowel, hepatobiliary, urinary tract, or brain cancers (glioblastoma), may also be present.

Physical findings in HNPCC are often nonspecific but may include signs of chronic illness, such as pallor from anemia or cachexia and weight loss in advanced cancers. Abdominal examination may reveal a palpable mass or organomegaly, and ascites may indicate advanced disease. A rectal exam might detect a palpable mass or evidence of hematochezia or melena. Skin examination could reveal sebaceous adenomas, sebaceous carcinomas, or keratoacanthomas, particularly in individuals with Muir-Torre syndrome, a variant of HNPCC. Gynecologic examination may identify uterine enlargement or adnexal masses, while neurological examination may show focal deficits in cases of glioblastoma.

If HNPCC is suspected based on history and physical findings, diagnostic tools such as family history assessment using Amsterdam II criteria or Bethesda guidelines, genetic testing for MMR mutations, and tumor testing via immunohistochemistry (IHC) or MSI can confirm the diagnosis. Early recognition through careful evaluation and appropriate genetic counseling is critical to managing HNPCC, as it allows for enhanced cancer screening and preventive measures to improve patient outcomes.

Evaluation

Diagnosing HNPCC involves several tests, including polymerase chain reaction (PCR) to check for MSI, IHC staining to assess for MMR proteins and germline sequencing. The common somatic mutation involving MLH1 promoter methylation is also analyzed to differentiate between somatic and germline causes. The MMR deoxyribonucleic acid (DNA), defective in HNPCC, produces 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 MMR activity. Diagnosing MSI involves assessing the length of DNA microsatellites from the tumor sample; changes in length indicate the presence of MSI.[17]

Most HNPCC tumors have MSI, but this feature is also common in 15% to 25% of sporadic colorectal cancers, which also exhibit a deficiency of at least 1 MMR protein in 10% to 15% of cases. Germline testing for HNPCC is recommended in all tumors with abnormal MSI or IHC. IHC staining, utilizing antibodies against the 4 main repair proteins, can be used to predict the likelihood of MSI. IHC staining is performed on a tumor sample to look for MMR proteins. An MMR gene mutation is unlikely if all MMR proteins are present. This is referred to as MMR proficiency. If staining is negative for at least 1 MMR protein, this is referred to as MMR deficient, and germline testing should be offered.[18]

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 IHC staining for MLH1 (either alone or with PMS2) is abnormal, testing for BRAF mutation or methylation of the promoter should be conducted. Methylation suggests sporadic colorectal cancer rather than HNPCC. If the test is negative, germline mutation testing for HNPCC should follow. For more information, please refer to the National Comprehensive Cancer Network (NCCN) screening guidelines for colorectal cancer.

The NCCN publishes screening guidelines for HNPCC. NCCN recommends IHC staining of the MMR 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 HNPCC 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.[19]

People who meet the criteria should undergo IHC or microsatellite analysis and germline DNA analysis for definitive diagnosis.[20] Screening criteria include the Amsterdam II criteria and the revised Bethesda guidelines, which screen patients with a high likelihood of HNPCC. 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.[21] Together, these criteria include colorectal cancer with associated MSI, additional cancers associated with HNPCC, age on diagnosis, and affected relatives. However, a proportion of patients with HNPCC may not meet the criteria due to the variability in presentation depending on the affected gene.

Because genes involved in HNPCC have variable penetrance, a family with a lower-penetrance mutation may not display a disease pattern that follows the criteria. Mutations in individual genes confer varying risks for developing tumors and associated lifetime risk of these cancers.[22] Patients with abnormal IHC staining or MSI whose germline testing does not reveal a mutation may have double somatic MMR gene mutations in the tumor DNA or have HNPCC with incomplete penetrance. In such cases, management should be based on the patient's personal and family history.

Clinical Testing Criteria

Assessment for HNPCC 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 HNPCC should be considered for patients who meet the following:

• Amsterdam II criteria  
  • More than 3 relatives with an HNPCC-related cancer (colorectal, endometrial, small bowel, ureter, or renal pelvis) and meet the following additional criteria:
    • At least 2 successive generations were 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  
    • Tumors are verified by pathological examination [23][24] 
• Revised Bethesda guidelines 
  • Colorectal cancer diagnosed in a patient younger than 50
  • Presence of synchronous or metachronous, colorectal, or other HNPCC-related tumors, regardless of age
  • Colorectal cancer with MSI (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 HNPCC-related cancer, with 1 of the cancers diagnosed before age 50
  • Colorectal cancer is diagnosed in a patient with 2 or more first- or second-degree relatives with HNPCC-related cancers, regardless of age [21] 
• Endometrial cancer diagnosed before age 50
• Known HNPCC in the family
• Testing should be considered in patients with at least a 5% risk of HNPCC on MMRpro, PREMM, or MMR prediction models.

HNPCC-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).[6] Using the Amsterdam II Criteria and the revised Bethesda guidelines to identify patients at risk for HNPCC misses approximately 50% of those affected or carriers. In contrast, about 50% of patients meeting the criteria do not have HNPCC. Overall sensitivity and specificity are 82% and 77%, respectively. Genetic testing is recommended for patients identified by testing with IHC staining and/or MSI or meeting testing criteria. Testing of affected family members is encouraged, but when no affected member is available, testing of unaffected individuals should be considered.

Treatment / Management

Patients identified with a mutation linked to HNPCC are at an elevated risk for developing malignancies. The highest risk is for early-onset colorectal and endometrial carcinomas, followed by gastric and ovarian cancers. The risk associated with HNPCC varies based on the specific MMR gene mutation. Individuals carrying mutations in MSH6 and PMS2 generally have a lower risk of HNPCC-related colorectal cancer and other malignancies. Specifically, PMS2 variants are associated with a reduced risk of endometrial and ovarian cancer. In contrast, mutations in MLH1 confer a significantly higher risk for these cancers.

MLH1, MSH2, MSH6, PMS2 and EPCAM Mutation Carriers

The following are treatment guidelines for patients with the mutations above:

• Colon
  • Colonoscopy begins at age 20 to 25 and repeats every 1 to 2 years or at 5 years younger than the youngest person diagnosed (although the risk may vary depending on germline variant).
  • A colectomy is performed if colon cancer is diagnosed or if an advanced adenoma is found that cannot be otherwise removed. The preferred treatment remains total abdominal 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 cancer antigen 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).[20]
• Extracolonic HNPCC-associated cancers 
  • NCCN has no screening guidelines for HNPCC-associated malignancies. Recommendations rely on a family history of a specific cancer and can include the following:
    • Upper endoscopy (esophagogastroduodenoscopy) with extended duodenoscopy should be done every 1 to 3 years from age 30 to 35 in select individuals or families or those of Asian descent. Consider testing and treating for Heliobacter pylori. Computed tomography (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, endoscopic ultrasound, or other diagnostics concerning pancreatic malignancy.
    • Screening for prostate cancer in patients with MSH2 and MSH6 should be done. 
    • Screening for urothelial cancer in men, those with a family history of transitional cell urinary tract malignancies, and those with an MSH2 should be done. 
    • Screening for breast cancer based on personal and family history and general recommendations should be done.[6][25][26]  
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Medical Management

The efficacy of nonsteroidal anti-inflammatory drugs in patients with HNPCC  is under investigation. Data suggest aspirin use may decrease the risk of colon cancer in HNPCC, 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.[26]

MSI generates a significant immune response, as noted in the lymphocytic infiltration of many HNPCC 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) that are targeted against immune checkpoints (to magnify the immune response). Studies seek to expand this response as part of a prophylactic regimen. 

Genetic Testing

Genetic testing for HNPCC is important for diagnosing at-risk individuals and informing cancer prevention strategies. Germline testing should be offered to patients diagnosed with colorectal cancer or endometrial cancer before age 50 or to those diagnosed at a later age who have a family history suggesting HNPCC. Additionally, genetic testing should be considered if a pathogenic MMR variant is identified through somatic tumor testing or in cases where familial risk is high but testing is not feasible (eg, due to adoption).

The current standard for genetic evaluation often involves multigene panel testing, which simultaneously assesses a wide range of hereditary cancer syndromes, including HNPCC-related genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). A diagnosis of HNPCC 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. Testing is particularly recommended for individuals with a family history of colorectal or endometrial cancers, especially when these cancers occur at a younger age or in multiple family members. The Amsterdam criteria are often used to identify families at risk for HNPCC. However, more advanced genetic testing, such as testing for mutations in the MMR genes (MLH1, MSH2, MSH6, PMS2, and EPCAM), is necessary to confirm the diagnosis.[27][28]

Differential Diagnosis

There is considerable overlap between cancers associated with HNPCC and those caused by somatic mutations. MSI, often resulting from spontaneous mutations in MMR proteins, is commonly observed in these cancers. Some families with HNPCC exhibit incomplete penetrance, making it more difficult to identify affected individuals. The mutations underlying HNPCC can predispose patients to a broad spectrum of malignancies. Distinguishing hereditary colorectal cancers, such as familial adenomatous polyposis, MUTYH-associated polyposis, and Cowden syndrome, from sporadic colorectal cancer is necessary for determining the most effective management and treatment strategies.

Prognosis

The overall reduction in life expectancy in patients with HNPCC is primarily due to the increased incidence of cancer, especially colon cancer, and its appearance at an earlier age.[29] The 10-year overall survival from colorectal cancer in patients with HNPCC remains high at 70% for rectosigmoid malignancies and 88% for colon cancer.[6][30] 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 HNPCC has been estimated at 16% over 10 years, 41% by 20 years, and 62% at 30 years.[23][31][32]

Complications

No specific complications are related to HNPCC other than the increased frequency and earlier presentation of the malignancies associated with the condition. Individuals with HNPCC are at increased risk for synchronous and metachronous colorectal cancers. The most common extracolonic manifestation in HNPCC is endometrial cancer. Individuals with HNPCC are also at increased risk of cancer of the ovary, stomach, small bowel, hepatobiliary system, renal pelvis and ureter, brain (glioma), and sebaceous neoplasms. There is also an increased risk of cancer of the pancreas, prostate, breast, and cervix in individuals with HNPCC. A few cases of laryngeal cancer, hematologic malignancies, adrenocortical cancers, and sarcomas have also been reported in individuals with HNPCC.[33]