eMedicine Specialties > Gastroenterology > Colon

Hereditary Colorectal Cancer

Juan Carlos Munoz, MD, Clinical Assistant Professor of Medicine, Division of Gastroenterology, University of Florida College of Medicine at Jacksonville
Louis R Lambiase, MD, Associate Professor of Medicine, University of Florida College of Medicine; Chief, Division of Gastroenterology, Department of Internal Medicine, University of Florida Health Science Center/Jacksonville

Updated: Feb 25, 2009

Introduction

Background

Hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal-dominant syndrome, accounts for 2-5% of all colorectal carcinomas. Colorectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) presents at an earlier age than in the general population and is characterized by an increased risk of other cancers, such as endometrial cancer and, to a lesser extent, cancers of the ovary, stomach, small intestine, hepatobiliary tract, pancreas, upper urinary tract, prostrate, brain, and skin.

Hereditary nonpolyposis colorectal cancer (HNPCC) is divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (HNPCC associated with other cancers of the gastrointestinal [GI] or reproductive system). The increased cancer risk is due to inherited mutations that degrade the self-repair capability of DNA .

Lynch syndrome was named after Dr. Henry T. Lynch. In 1966, Dr. Lynch and colleagues described familial aggregation of colorectal cancer with stomach and endometrial tumors in 2 extended kindreds and named it cancer family syndrome. Authors later termed this constellation Lynch syndrome, and, more recently, this condition has been called hereditary nonpolyposis colorectal cancer (HNPCC).

Before molecular genetic diagnostics became available in the 1990s, a comprehensive family history was the only basis from which to estimate the familial risk of colorectal cancer.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer Screening, Colon Cancer, and Rectal Cancer.

Pathophysiology

In hereditary nonpolyposis colorectal cancer (HNPCC), an inherited mutation in one of the DNA mismatch repair (MMR) genes appears to be a critical factor. MMR genes normally produce proteins that identify and correct sequence mismatches that may occur during DNA replication. In hereditary nonpolyposis colorectal cancer (HNPCC), a mutation that inactivates an MMR gene leads to the accumulation of cell mutations and greatly increases the likelihood of malignant transformation and cancer.

Researchers have identified 7 distinct MMR genes, including the following:

• hMLH1 on band 3p22
• hMSH2 and hMSH6  on band 2p16
• hPMS1 on band 3p32 and hPMS2 on band 7q22

Other mutations include hMSH3 on band 5q14.1 and EXO1 on band 1q43. Mutations of hMLH1 and hMSH2 account for nearly 70% of MMR mutations in hereditary nonpolyposis colorectal cancer (HNPCC); 10% involve hMSH6. The genes responsible for the remaining 20-25% of cases have not yet been discovered.

Table 1. Seven different genes are known to be associated with HNPCC, and all of them are involved with DNA mismatch repair. How often they have been identified:

Example of an autosomal dominant pedigree.

Despite the absence of polyposis, hereditary nonpolyposis colorectal cancer (HNPCC)-associated colorectal cancers are believed to arise from preexisting discrete proximal colonic adenomas. Affected individuals have a propensity to develop predominantly right-sided, flat adenomas at a young age. Patients with Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) develop adenomas at the same rate as individuals in the general population; however, the adenomas in those with Lynch syndrome or HNPCC are more likely to progress to cancer. Carcinogenesis progresses more rapidly in these patients (in 2-3 y) than in patients with sporadic adenomas (8-10 y).

Synchronous colorectal tumors (primary tumors diagnosed within 6 mo of each other) and metachronous colorectal tumors (primary tumors occurring more than 6 mo apart) are more common in persons with hereditary nonpolyposis colorectal cancer (HNPCC). An individual with an HNPCC mutation who does not undergo a partial or total colectomy after the first mass is diagnosed as malignant has an estimated 30-40% risk of developing a metachronous tumor within 10 years and a 50% risk within 15 years. In the general population, the risk is 3% in 10 years and 5% within 15 years.

Mortality/Morbidity

Although not everyone who inherits the gene for hereditary nonpolyposis colorectal cancer (HNPCC) develops colorectal cancer, individuals with Lynch syndrome have a 70-80% lifetime risk of developing colon cancer. Of these cancers, two thirds occur in the proximal colon (proximal to the splenic flexure). In approximately 45% of affected individuals, multiple synchronous and metachronous colorectal may occur within 10 years of resection.

Other cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC) include the following:

• Endometrial cancer: The lifetime risk is 30-40% by age 70 years. The average age at diagnosis is 46 years. Half of patients with both colon and endometrial cancer present with endometrial cancer first.
• Ovarian cancer: The lifetime risk is 9% by age 70 years. The average age at diagnosis is 42.5 years. Approximately 30% of these tumors present before age 40 years.
• Gastric cancer: The mean age at diagnosis of gastric cancer is 56 years; intestinal-type adenocarcinoma is the most commonly reported pathology, especially in Asian countries such as Japan, Korea, and China.
• Transitional cell carcinoma: This principally affects the upper urinary tract (ureters and renal pelvis).
• Adenocarcinoma of the small bowel cancers: These occur most commonly in the duodenum and jejunum.
• Glioblastoma: Also known as Turcot syndrome, this is a variant of hereditary nonpolyposis colorectal cancer (HNPCC) (see below).
• Malignancies of the larynx, breast, prostate, liver, biliary tree, pancreas, and the hematopoietic system are more common in patients with hereditary nonpolyposis colorectal cancer (HNPCC).

Formerly considered a separate disorder from familial adenomatosis polyposis (FAP), Turcot syndrome is clinically characterized by both multiple colorectal adenomas and primary brain tumor. In 1995, Hamilton et al demonstrated that this association may result from at least 2 distinct types of germline defects: a mutation in the APC gene (which represents two thirds of cases and is responsible for FAP) and a mutation in MMR gene PMS2 or MLH1 (which represents one third of cases).¹ Medulloblastoma is most common with APC mutations, whereas glioblastoma is most common with MMR gene mutations.

Muir-Torre syndrome

A mutation in MSH2 and MHL causes Muir-Torre syndrome, which is considered a variant of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Muir-Torre syndrome accounts for much less than 1% of all hereditary colorectal cancer cases and is characterized by the typical features of HNPCC, sebaceous gland tumors, and keratoacanthomas.

Age

Colorectal cancer in persons with hereditary nonpolyposis colorectal cancer (HNPCC) occurs at an earlier age than in the general population. In persons with hereditary nonpolyposis colorectal cancer (HNPCC), the average age of polyp onset is in the late second decade and early third decade of life. The average age of colorectal cancer onset is 44 years in members of families that meet the Amsterdam criteria compared with age 60-65 years in the general population (see History, Guidelines).

Race

Lynch syndrome has no known racial proclivity; however, ethnic-specific mutations have been observed in Finnish and Swedish populations. Colorectal cancer rates in the Ashkenazi Jewish population are disproportionately high, possibly the highest of any ethnic group worldwide. Although neither HNPCC nor classic FAP are more common in Ashkenazim than in the general population, both have a connection to individuals of Ashkenazi Jewish heritage.
 
A specific mutation in the MSH2 gene, G1906K, is found in 2-3% of all colorectal cancers in Ashkenazi Jews younger than 60 years. One third of Ashkenazi Jewish individuals who meet criteria for genetic testing of HNPCC have this mutation. This mutation is rarely found in the general population but is more common in young Ashkenazi Jews with colorectal cancer. In individuals in whom colorectal cancer is diagnosed at age 40 years or younger, 7% have been found to carry this mutation. Conversely, the mutation is found in less than 1% of Ashkenazim persons in whom colorectal cancer is diagnosed after age 60 years.

Contrary to American and European reports, gastric cancer may be more common than endometrial cancer in the Asian (Japanese, Korean, Chinese) population.

Sex

Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly diagnosed in both men and women; however, uterine and ovarian cancer are more common in women with HNPCC.

Frequency

United States

The incidence of hereditary nonpolyposis colorectal cancer (HNPCC) in the United States is 2-5%, or 7500 new occurrences of HNPCC annually.

International

Large geographic differences are observed in the occurrence of hereditary nonpolyposis colorectal cancer (HNPCC).

Clinical

History

Making the diagnosis of Lynch syndrome is usually a 3-stage process, including review of family cancer history, tumor testing, and genetic testing .

A considerable number of patients diagnosed with colorectal cancer have a family history of this disease; however, most patients do not have any of the known colorectal cancer syndromes. When a diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) or other familial colon cancer syndrome is considered, a pedigree should be drawn of each patient.
 
When a pedigree is analyzed, the family's size is an important consideration. For instance, a small family with 2 cases of colorectal cancer among first-degree relatives is more likely to indicate hereditary nonpolyposis colorectal cancer (HNPCC) than a large family with 2 cases of similar diagnosis. Patients must be asked about colorectal cancer or polyps in family members and about other associated neoplasms (see Table 2).

The following history findings should raise suspicion for hereditary nonpolyposis colorectal cancer (HNPCC):

• Multiple cases of colorectal cancer or numerous adenomatous polyps diagnosed in different generations
• People younger than 50 years affected
• The combination of syndrome-related tumors in other organs
• Synchronous or metachronous tumors in one person

Significant suspicion for hereditary nonpolyposis colorectal cancer (HNPCC) should prompt further evaluation of the patient and his or her family.

Guidelines

In 1990, following a conference in Amsterdam, the International Collaborative Group (ICG) first proposed clinical criteria to identify patients at risk of developing hereditary nonpolyposis colorectal cancer (HNPCC). These criteria, now known as the ICG or Amsterdam I criteria are predicated on an accurate family history of colorectal cancer that includes the number of affected relatives, degree of closeness, and age at diagnosis.


Amsterdam Criteria I

• Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first-degree relative (parent, child sibling) of the other two
• Two successive affected generations (one of the patients is a first-degree family member of the other patients) 
• One or more colon cancers diagnosed younger than 50 years 
• FAP has been excluded.

In 1999, the Amsterdam I criteria were revised to include extracolonic cancers, known as Amsterdam II criteria. 

Amsterdam Criteria II

• Three or more family members with HNPCC-related cancers,^* one of whom is a first-degree relative of the other two 
• Two successive affected generations (one of the patients is a first-degree family member of the other patients)
• One or more of the HNPCC-related cancers diagnosed younger than 50 years
• FAP has been excluded.

^* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).

Less stringent guidelines, such as the modified Bethesda criteria were established in 1997. These guidelines, for appropriate microsatellite instability (MSI) testing on colorectal tumor specimens, were used to identify families likely to have an MMR gene mutation.

• Colorectal cancer diagnosed in a patient who is younger than 50 years
• Presence of the synchronous or metachronous colorectal cancer or other HNPCC-associated tumors,* regardless of age
• Colorectal cancer with the MSI-H,^† histology, diagnosed in a patient who is younger than 60 years
• Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor,*with one of the cancers diagnosed in a patient younger than 50 years
• Colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors, regardless of age

^* MSI-H in tumors refers to changes that are equal or greater than 2 of the 5 National Cancer Institute (NCI)-recommended panels.

^† Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).

The Bethesda criteria may be more sensitive than either form of the Amsterdam criteria in identifying families with hereditary nonpolyposis colorectal cancer (HNPCC), but they are not diagnostic of HNPCC, because MSI also occurs in 15% of sporadic tumors. These patients should undergo a DNA test for confirmation (see Image 2 and below). 

Diagnostic approach for patients with colorectal tumors.

Criteria for referral to genetic counseling have also been developed, as follows. Endoscopic surveillance should be performed if genetic testing is refused, unavailable, or offers no information.

• Adenomatous polyps in patients younger than 40 years
• Greater than 10 or greater than 100 adenomatous polyps in the classic FAP
• Multiple colorectal carcinomas or other HNPCC-related tumors,* in one individual
• Colorectal cancer or endometrial cancer diagnosed in a patient younger than 50 years
• Two first-degree relatives with colorectal carcinoma or HNPCC-related tumor,* independent of age of diagnosis

* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).

Physical

Despite the term hereditary nonpolyposis, people with HNPCC actually do have polyps. However, these individuals tend to have less than 100; the number is usually much higher in other forms of inherited colorectal cancers.

Polyp formation starts in the late second and early third decade of life. Although these cancers are often asymptomatic in their early stages, the following signs and symptoms may develop as the cancer advances: 

• Changes in bowel habits (eg, constipation or diarrhea that persists for longer than several days)
• Visible or no blood in stool (positive fecal occult blood test)
• Black, tarry stool (may represent bleeding above the rectum)
• Iron deficiency without an identifiable cause
• Abdominal pain, cramps, or frequent feeling of distention (or bloating) in the abdominal or  bowel region
• Fatigue or weakness
• Decline in appetite
• Unexplained weight loss 

Causes

See Pathophysiology.

Differential Diagnoses

Other Problems to Be Considered

Attenuated familial adenomatous polyposis
Cowden disease
Cronkite-Canada syndrome
Familial clustering of late onset of colorectal neoplasm
Hyperplastic polyps
Juvenile polyposis syndrome
Lymphomatous polyposis
Muir-Torre syndrome
MYH-associated polyposis
Neurofibromatosis type 1 (NF-1)
Nodular lymphoid hyperplasia
Peutz - Jeghers syndrome
Sporadic colon cancer
Turcot syndrome

Workup

Other Tests

When a family fulfills the Amsterdam or Bethesda Criteria (see History, Guidelines), examination of tumor tissue is indicated (even those removed years before). Tests include immunohistochemistry (IHC) testing, MSI testing (usually used as a prescreening test), and DNA analysis (considered unnecessary, expensive, and time-consuming) (see Genetic Testing, below).

Tumor testing

• IHC^2,3,4,5,6
• Samples of tumor tissue are stained to assess for the MLH1, MSH2, MSH6, and PMS2 proteins associated with colorectal cancer. 
• An IHC pattern with absent staining for MLH1 and PMS2 and positive staining for MSH2 and MSH6 indicates a mutation in MLH1 (see Table 3, below) 
• An IHC pattern with no staining for MSH2 and MSH6 and positive staining for MLH1 and PMS2 indicates a mutation in MSH2 (see Table 3) 
• Of the tumors from carriers of a germline mutation in MSH6, 5% have been detected with an ICH pattern compatible with MSH2 mutation. Thus, if MSH2 mutation screening results are negative, experts recommend DNA analysis of MSH6.
• In the fourth row of Table 3, the IHC pattern matching a mutation in MSH6 is shown as absent staining for MSH6 and positive staining for the remaining 3 MMR proteins. This demonstrates the same principle as MSH2: If no mutation is identified, DNA analysis of MSH2 may be considered. In the fifth row of Table 3, the IHC pattern matching a mutation in PMS2 is shown as absent staining for PMS2, with positive staining for the remaining 3 MMR proteins.
• Compared with MSI analysis, IHC has the additional advantage of indicating the MMR gene that is most eligible for DNA analysis. IHC is especially indicative for MMR mutations that result in truncation of the protein, such as frame shift, splice site mutations, large genomic rearrangements, and mismatch, although IHC is not always diagnostic for mismatch. In this case, the protein may be functionally abnormal but is still detected with IHC.

• MSI analysis
• MSI is the hallmark of the defective DNA MMR gene. First described in 1993, MSI is a phenomenon found in colorectal cancer DNA but not in the adjacent normal colorectal mucosa of individuals with MMR mutations. MSI is characterized by expansion or contraction of short repeated DNA sequences caused by insertion or deletion of repeated units.
• More than 90% of HNPCC tumors (including both adenomas and cancers) and 15% of sporadic colorectal cancers exhibit MSI. This test is used to detect failure of the DNA MMR machinery to repair errors that occur during DNA replication. Such failure leads to increased length in the variation of simple, repetitive sequences distributed throughout the genome.
• A standardized panel of 5 markers is used (D2S123, D5S346, D17S250, BAT25, BAT26 [and possibly BAT40 to increase test sensitivity]). MSI can be subclassified as MSI-high (MSH-H), if 2 or more markers are positive or at least 30% of the markers shows instability, or MSI-low (MSH-L), if only a single marker is positive or less than 30% of the markers show instability. Tumors with no positive markers are referred to as microsatellite stable (MSS).
• Carcinomas in MSH6 carriers, particularly endometrial carcinomas, have been shown to present with an MSS phenotype; therefore, if an MSS phenotype is found, IHC of MSH6 should be obtained. Nearly 90% of hMLH1 and hMSH2 mutations result in the MSH-H phenotype, whereas nearly 10% of hMLH6 mutations may result in the MSI-L or MSS phenotype. Although most microsatellite regions are located in noncoding regions of the genome, some are located in the coding regions of genes involved in growth regulation (eg, transforming growth factor [TGF]-beta receptor type II) and apoptosis (eg, BAX). Alterations in these important regulatory genes are believed to be responsible for the accelerated rate of malignant transformation observed in hereditary nonpolyposis colorectal cancer (HNPCC).^2,3,4,5,6
• MSI analysis has a sensitivity of 93% in detecting MMR deficiency in carriers of MMR mutation. However, this test cannot be used to predict which of the MMR genes harbors a mutation.

Because genetic testing for mutations in DNA MMR genes is expensive and time-consuming, researchers have proposed techniques to identify ideal candidates (patients with cancer who are most likely to be HNPCC carriers). The Amsterdam criteria are useful but do not identify up to 30% of potential Lynch syndrome carriers.

Researchers have combined MSI profiling and IHC testing for DNA MMR gene expression. They identified an additional 32% of Lynch syndrome carriers that MSI profiling alone would have missed. Currently, this combined MSI profiling and IHC testing strategy is the most advanced method of identifying candidates for genetic testing for Lynch syndrome. The next step would be to consider performing a blood test to assess for hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome genetic mutation.

Genetic testing is not necessary to establish a diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome and does not provide a definitive diagnosis. The decision to go forward with genetic testing is complex. Patients should consult a genetic specialist, such as a genetic counselor, to discuss the benefits and risks before undergoing genetic testing.

In 1997, the National Cancer Institute (NCI) Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome suggested 5 markers for evaluation of MSI. The results are classified as MSI-H if 2 or more markers are positive.
 
The American Gastroenterological Association published a literature summary of MSI test results that found that the highest percentage of MSI-H test results were found in families that met the Amsterdam criteria I, followed by patients with colorectal cancer who were diagnosed before age 35 years. Identical results were found for MMR gene testing.
 
In general, genetic testing should be offered when clinical suspicion of hereditary nonpolyposis colorectal cancer (HNPCC) is firmly established—that is, clinical criteria have been met. It is generally accepted that patients who fulfill the Amsterdam criteria or the broader Bethesda criteria are candidates for testing.
 
The new guidelines recommend MSI or IHC analysis of tumors from affected high-risk patients as the preferred initial diagnostic strategy, followed by germline testing for hMLH1 and hMSH2 mutations for those with MSI-H tumors or tumors with a loss of expression of one of the MMR gene products. hMSH6 germline mutation testing should be considered when the tumor tests MSI-H.

Direct germline testing without MSI or IHC analysis remains an option for high-risk individuals if tissue testing is not feasible (eg, affected proband's tumor is unavailable) or if there is a strong suspicion of HNPCC and MSI/IHC testing reveals MSI-L, MSS, or normal expression of hMLH1 and hMSH2.

Benefits of genetic testing include the following^7,8 :

• Genetic test results may allow for a more accurate assessment of cancer risk. If a mutation is identified, genetic testing and early cancer screening can be offered to the patient and other at-risk family members.
• Vigorous surveillance and management can then be recommended for patients with identified mutations.
• Patients with negative test results can avoid these rigorous, expensive, and time-consuming surveillance and management measures and simply follow the American Cancer Society's (ACS) recommendations for the general population.
• Genetic testing involves no physical risk other than that of a routine blood draw.

Difficulties in HNPCC^9,10,11

If the patient's family does not fulfill the Amsterdam criteria, but 2 tumors with an MSS phenotype are encountered, the Lynch syndrome surveillance protocol is currently recommended. The age at which surveillance should be initiated and the surveillance intervals are the same as those recommended in the Netherlands surveillance protocol for carriers of mismatch repair gene mutation (see Table 3, above).

If the patient's family is considered at risk and the specific gene mutation has not yet been identified, a negative genetic test result does not mean that the patient is not at risk for hereditary nonpolyposis colorectal cancer (HNPCC). The patient is still considered at risk if a family history of cancer, tumor testing, or genetic testing indicates HNPCC, even if genetic testing does not identify the gene mutation. Researchers have discovered only 7 mutations known to cause HNPCC but believe that many more remain to be discovered (see Table 1).

One important problem to resolve is compliance with recommended screening procedures because of the patient's fear and denial, as well as socioeconomic and educational barriers.

If a family does not fulfill the Bethesda criteria, no specific analysis for Lynch syndrome is indicated. This does not, however, exclude a hereditary factor in the development of colorectal carcinoma in a family. For that reason the referral criteria for genetic counseling are broader than the Bethesda criteria.
 
Also, it is not always clear, before a family is referred and before the family history and medical records are analyzed, if a family truly fulfills these criteria. Individuals with a first-degree relative with colorectal carcinoma have an increased relative risk of developing colorectal carcinoma compared with the population risk, but the cumulative risk is not higher than 10%. If a first-degree relative was diagnosed before the age 45 years or if an individual has 2 first-degree relatives with colorectal carcinoma, the risk is increased four- to sixfold (cumulative risk higher than 10%).

For these indications, a colonoscopic examination every 5 years from the age of 45 to 50 years has been recommended. However, the American Gastroenterological Association, US Multi-Society Task Force on Colorectal Cancer, and the ACS recommend a colonoscopy every 5 years from age 40 years or 10 years before the earliest diagnosis if an individual has 2 or more first-degree relatives with colon cancer, or a single first-degree relative with colon cancer or adenomatous polyp diagnosed at an age <60 years.

Colon screening tests

The major indications for colon screening tests are as follows:

• Individuals harboring deleterious germline MMR gene mutations
• Individuals whose affected relatives are unavailable for genetic testing
• At-risk relatives who refuse genetic testing
• At-risk asymptomatic individuals for whom genetic testing is inappropriate  (eg, family members of probands with MSI-H tumors and noninformative MMR gene testing)

Published recommendations for colorectal cancer screening in hereditary nonpolyposis colorectal cancer (HNPCC) are based on expert and consensus opinion. The goals of screening and surveillance are the same: to reduce mortality through the detection of presymptomatic, early-stage cancers and to reduce the incidence through the identification and removal of precancerous adenomas.

Early studies by Love and Morrissey,¹²  Vasen et al,¹³ and Mecklin et al¹⁴  demonstrated that screening of asymptomatic, high-risk individuals detects early-stage cancers and advanced adenomas, thus providing indirect evidence of screening effectiveness. More compelling evidence is derived from a controlled trial by Jarvinen et al that involved 2 cohorts of at-risk individuals from 22 families with hereditary nonpolyposis colorectal cancer (HNPCC). One cohort (n = 133) underwent colonic screening with flexible sigmoidoscopy plus barium enema or colonoscopy every 3 years; the second cohort (n = 119) declined screening and served as the control group. After 15 years of patient observation, 8 screened subjects (6%) developed colorectal cancer compared with 19 unscreened subjects (16%; P = 0.014).

• Colonoscopy
• In 1997, colonoscopy was added to the guidelines as a screening option. Colonoscopy is considered the preferred screening test in patients with hereditary nonpolyposis colorectal cancer (HNPCC). The evidence to support colonoscopy is derived from data that show a decreased mortality rate in patients with colorectal cancer who have undergone colonoscopic adenoma removal. Additionally, colonoscopy screening is cost-effective compared with other screening strategies. 
• According to current ACS guidelines, colonoscopy should be offered to patients with a family history of colorectal cancer at age 20-25 years or 5-10 years before the earliest diagnosis of colorectal cancer in the family (whichever comes first) until age 40 years.⁷ Thus, patients with familial nonpolyposis colorectal cancer syndrome (3 or more family members with colon or related adenocarcinomas [including at least 1 first-degree relative], should undergo colonoscopy at age 25 years and then every 2-3 years thereafter. After age 40 years, colonoscopies should be performed every 1-2 years. This cost-effective strategy reduces both the incidence of and mortality from HNPCC-associated colorectal cancer.
• Barium contrast study: Barium enema has the advantage of allowing visualization of the entire colon. However, there is evidence to suggest this technique is inaccurate in the detection of small polyps and early cancers and is suboptimal for colorectal cancer screening or surveillance in patients with hereditary nonpolyposis colorectal cancer (HNPCC). In a prospective study comparing the use of double-contrast barium enema and colonoscopy, the barium enema missed 52% of polyps smaller than 1 cm. If barium enema is the only option for screening or surveillance, it should be coupled with flexible sigmoidoscopy. The use of flexible sigmoidoscopy allows visualization of the rectosigmoid, which the barium enema may not depict well because of overlapping bowel loops. Lesions detected on barium enema warrant colonoscopic evaluation.
• Flexible sigmoidoscopy: Flexible sigmoidoscopy is not significantly sensitive in individuals with hereditary nonpolyposis colorectal cancer (HNPCC) mutations, because an estimated two thirds of HNPCC tumors develop on the right side of the colon (before the splenic flexure). Thus, flexible sigmoidoscopy should always be combined with at least barium enema when patients with HNPCC are screened.
• Virtual colonoscopy: In virtual colonoscopy, computed tomography (CT) scanning is used to create a 3-dimensional (3-D) image of the air-extended, prepared colon. This procedure has potential as a colorectal cancer screening test in patients with hereditary nonpolyposis colorectal cancer (HNPCC). Virtual colonoscopy does not carry the risks of traditional colonoscopy, such as sedation or perforation. However, if a polyp is detected, a traditional colonoscopy would have to be performed to remove and analyze the polyp. The sensitivity for small polyps has been questioned, and negative virtual colonoscopy results may not be truly negative for the presence of a polyp. This test is not currently recommended as a screening test for patients who carry an MMR gene mutation.

Surveillance for extracolonic malignancies

IHC and MSI testing may be useful in carriers of an MMR gene mutation (see Table 3), as proposed in the Netherlands surveillance protocol.

• Women with Lynch syndrome are recommended to have an annual pelvic examination, ultrasonographic examination, and small biopsies of the uterus starting at around age 30 or 35 years to screen for uterine cancer.¹⁵
• In at-risk women, an annual screening test for endometrial cancer is recommended, beginning at age 20-30 years. No consensus has been reached on the optimal method of screening: endometrial aspiration (for cytology or histology) or biopsy and transvaginal ultrasonography should be performed annually (see Treatment, Surgical Care, Prophylactic hysterectomy and salpingo-oophorectomy).
• An annual screening test for ovarian cancer is also recommended.¹⁵ Transvaginal ultrasonography and the ovarian cancer blood test (CA-125) are occasionally used for screening beginning at age 25-30 years, but these techniques are not sensitive and often reveal only cancerous tumors at a later stage. An alternative is to have surgery to remove at-risk body parts before cancer develops. Thus, in addition to recommending endometrial cancer surveillance, it is prudent to recommend to women in families with hereditary nonpolyposis colorectal cancer (HNPCC) to seek prompt evaluation of abnormal menstrual bleeding, regardless of their last surveillance exam results.
• Based on the results of current data, routine upper endoscopic surveillance is of no benefit in Lynch syndrome. However, selective use of upper endoscopy may be justifiable in high-risk kindred. Although there are authors who do not support routine upper endoscopy evaluation in patients with HNPCC,¹⁶ most authorities, including the International Collaborative Group on hereditary nonpolyposis colorectal cancer (HNPCC), recommend an upper endoscopic procedure every 1-2 years beginning at age 30 years for at-risk relatives with HNPCC-associated gastric cancer.^{13,15,17,18,19,20,21}
• For example, in the Asian population (eg, Japanese, Koreans, and Chinese), gastric cancer is the second most common cause of cancer-related death; therefore these individuals are probably in a higher risk than other people.
• As we know most of these studies have been done in Japan and China, where the rates of stomach cancer are much higher. To date, the data have been inconclusive as to whether these screening tools affect the stomach cancer prognosis. Therefore, routine stomach cancer screening for the general population is not recommended. However, stomach cancer screening may be recommended for some people who are at greater risk of developing the disease. People who are considered at risk include:
• Elderly people with atrophic gastritis or pernicious anemia
• Patients with partial gastrectomy
• Patients with the diagnosis of sporadic adenomas
• Those with FAP
• Those with hereditary nonpolyposis colon cancer
• Immigrant ethnic populations from countries with high rates of gastric carcinoma
• Even in these groups of people, the impact of screening on death from stomach cancer is not known.
• A similar argument can be made for selective surveillance of Lynch syndrome kindred who exhibit small bowel adenocarcinomas. Despite the lack of supporting data, endoscopic surveillance with enteroscopy or capsule endoscopy every 1-2 years may be justifiable in high-risk individuals (Asian population).
• For families with a history of urinary tract tumors, upper urinary tract screening tests may be beneficial. These families should undergo urinary tract ultrasonography, cytoscopy, and urinary cytology every 1-2 years beginning  at age 30-35 years.
• At this time, no specific screening recommendations for hepatobiliary tract cancers exist, and, in general, liver and biliary tract screening tests are not recommended. However, hepatocellular carcinoma is known to be associated with polyposis coli, and children with maternal ancestors who were affected with the syndrome have developed hepatoblastoma. For families with a history of this type of cancer, transabdominal ultrasonography of the biliary tree and liver function tests have been suggested.^22,23,24,25

Histologic Findings

Adenomas are often villous with components of high-grade dysplasia and exhibit an accelerated rate of malignant transformation. Colorectal cancers in hereditary nonpolyposis colorectal cancer (HNPCC) have a more aggressive histology (increased frequency of poorly differentiated, mucinous, and signet cells).

Treatment

Surgical Care

Removal of the entire colon is the only way to completely prevent the development of colon cancer or to treat an existing cancer. Several different operations are currently available for treatment of hereditary nonpolyposis colorectal cancer (HNPCC).
 
The 3 most commonly performed operations are as follows:

• Subtotal colectomy with ileorectal anastomosis
• Total colectomy ileoanal pull-through (pouch procedure)
• Total colectomy with ileostomy

Subtotal colectomy with ileorectal anastomosis and postsurgical rectal surveillance are recommended when colorectal cancer develops in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This operation may be considered for prophylaxis in selected MMR gene mutation carriers (see Prophylactic subtotal colectomy, below).

Subtotal colectomy with ileorectal anastomosis is preferred over segmental resection or hemicolectomy for HNPCC-associated cancers that arise proximal to the peritoneal reflection. Although total proctocolectomy with ileoanal anastomosis and total proctocolectomy with ileostomy eliminate the need for endoscopic surveillance, these procedures are generally reserved for patients with hereditary nonpolyposis colorectal cancer (HNPCC) who present with rectal cancers, primarily because of concerns about postoperative morbidity and quality of life.  
 
Postoperative surveillance
 
Postoperative surveillance is indicated following curative resection in patients with hereditary nonpolyposis colorectal cancer (HNPCC) because of the high rates of metachronous cancers (estimated as high as 40% at 10 y and 72% at 40 y, depending on the length of colon remaining after surgery). Surveillance sigmoidoscopy is recommended every 1-2 years following subtotal colectomy or surveillance colonoscopy is recommended every 1-2 years following subtotal partial colectomy.

Evidence supporting this recommendation is derived from the aforementioned studies demonstrating an accelerated rate of malignant transformation in hereditary nonpolyposis colorectal cancer (HNPCC) and 2 postresection surveillance studies demonstrating a high rate of metachronous cancers within 2-5 years. In 1994, Lanspa et al identified 17 patients (8%) (among a cohort of 225 patients with HNPCC) who developed metachronous cancers within 5 years of resection (mean, 26.7 mo; range, 4-58.5 mo).²⁶  In a Danish study of 110 patients with HNPCC, 8 Dukes A or B cancers and 1 Dukes C cancer were detected within 2 years of negative examination findings.²⁷  

Prophylactic subtotal colectomy^{28,29,30,31,32}

Because of the excessive occurrence of both incident and metachronous cancers, prophylactic subtotal colectomy may be an alternative to surveillance colonoscopy for individuals with confirmed mutations. Opponents argue that, because of incomplete penetrance, 15-20% of these colectomies may be unnecessary and that patients undergoing prophylactic subtotal colectomy remain at risk of developing metachronous rectal cancers and extracolonic malignancies.

Syngal et al used a decision-analysis model to evaluate life expectancy and quality-adjusted life expectancy derived from surveillance colonoscopy compared with prophylactic surgery in patients aged 25 years who had a confirmed mutation.²⁸ The analysis showed that, although both approaches offer a modest survival benefit over no intervention, immediate proctocolectomy or subtotal colectomy was superior to surveillance, with an expected gain in life expectancy of 15.6 post immediate proctocolectomy and 15.3 years post subtotal colectomy, as compared with 13.5 years for surveillance.²⁸ However, the incremental benefit of surgery compared with surveillance diminished with increasing age. Moreover, quality-of-life adjustments favored surveillance over surgery.²⁸  

Because no evidence-based data support one approach over another, aggressive surveillance is generally preferred, except in select situations in which surveillance is not technically feasible or in patients with mutations who refuse colonoscopic surveillance but agree to sigmoidoscopic surveillance of the rectal remnant. Regardless, patients should be informed about the advantages and disadvantages of each approach and should be encouraged to participate in the decision-making process. In such cases, because of the high rate of metachronous cancers, the colonic remnant should be examined by sigmoidoscopy every 1-2 years.

Prophylactic hysterectomy and bilateral salpingo-oophorectomy

Women should consider undergoing an annual gynecologic examination, including endometrial screening with biopsy (vacuum curettage or Pipel biopsy should be considered). To help reduce the risk of endometrial and ovarian cancer, some experts recommend discussing prophylactic hysterectomy and bilateral salpingo-oophorectomy with women older than 50 years who have hereditary nonpolyposis colorectal cancer (HNPCC). Counseling should include a discussion of the psychosocial effects of prophylactic surgery and the long-term effects of prolonged estrogen replacement therapy.

Currently, the evidence is insufficient to recommend prophylactic hysterectomy and salpingo–oophorectomy to help reduce cancer risk in women who carry the MMR gene (except in women who carry the hMSH6 mutation) (see Table 3).

Chemoprevention

Observational studies of persons at average risk have suggested that the use of some medications and supplements (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin, estrogens, folic acid, calcium), as well as antioxidants (eg, beta carotene, vitamin C, vitamin E), may prevent the development of colorectal cancer. However, randomized controlled trials of the use of chemopreventive agents are limited, and only a few studies have specifically enrolled people with an inherited predisposition for colorectal cancer; therefore, the evidence has not convinced experts to recommend these medications and supplements specifically to prevent colorectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC).

• NSAIDs^33,34,35,36
  • Randomized controlled trials have shown that NSAIDs (sulindac and celecoxib) induce regression of adenomas in patients with FAP. A considerable volume of preclinical data support the safety and efficacy of cyclooxygenase-2 (COX-2) inhibitors in patients with FAP; therefore, the US Food and Drug Administration (FDA) has approved the use of celecoxib as an adjunct for the management of colorectal adenomas in patients with FAP. The value of COX-2 inhibitors in the sporadic adenoma population is not known.
  • Studies have shown that COX-2 expression occurs in patients with colorectal adenomas and cancers. However, the expression may not be as pronounced in colorectal adenomas and cancers in hereditary nonpolyposis colorectal cancer (HNPCC) as it is in FAP sporadic colorectal cancer.
  • Polymorphisms in drug-metabolizing genes may contribute to varied responses to NSAIDs. For example, flavin monooxygenase 3 (FMO₃) may reduce the catabolism of sulindac, resulting in an increased efficacy in the prevention of polyps in persons with FAP. NSAIDs carry a small risk of bleeding complications, such as stroke and upper GI ulceration and bleeding, which weighs against possible benefits.
• Aspirin³⁷
  • Prospective studies have demonstrated a significant reduction in colorectal cancers in healthcare workers who regularly used aspirin. A randomized, double-blind, placebo-controlled trial in patients with a personal history of colon adenomas demonstrated a modest but statistically significant reduction in the incidence of colonic adenomas with daily aspirin use. In a double-blind placebo study, daily aspirin use was also associated with reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer.
• Folic acid^38,39
  • In one observational study, the use of folic acid supplements for more than 15 years was associated with a 75% lower rate of colorectal cancer (relative risk [RR] of 0.25; 95% confidence interval [CI], 0.13–0.51). This study was performed in women with a family history of colon cancer. One hypothesis holds that, because folate is required for DNA synthesis, suboptimal amounts may cause abnormalities in DNA synthesis or repair.
• Calcium^40,41,42
  • Researchers have suggested that calcium binds bile acids in the bowel lumen, inhibiting their carcinogenic effects. A randomized controlled trial of calcium supplementation, with a daily intake of 1200 mg of elemental calcium for 4 years, reduced the risk of recurrent adenomas in presumably average-risk people with adenomas by 19% (adjusted risk ratio of 0.81; 95% CI, 0.67–0.99). This finding may not apply to people with a genetically increased risk of colorectal cancer.
• Estrogens
  • Studies have demonstrated that estrogens are associated with a lower incidence of colorectal cancer; however, this information does not address those with a genetically increased risk of colorectal cancer.⁴³

Modifying behavioral risk factors^44,45,46

Several components of diet and behavior have been suggested as risk factors for colorectal cancer, with various levels of consistency. Modifying these lifestyle factors may work toward prevention of hereditary nonpolyposis colorectal cancer (HNPCC). Experts differ on the interpretation of the evidence for some of these components. Little is known about whether these same factors are protective in people with a genetically increased risk of colorectal cancer.

In one case-control study, lack of physical activity, low intake of high-energy foods, and low intake of vegetables contributed significantly to an increased cancer risk in people with no family history of colorectal cancer; however, in those with a family history of colorectal cancer, activity level and diet were not related to cancer risk, despite adequate statistical power.

Follow-up

Patient Education

Support groups for individuals and families

Intestinal Multiple Polyposis and Colorectal Cancer (IMPACC)

A national network founded in 1986. Support network to help patients and families dealing with familial polyposis and hereditary colon cancer. Provides information and referrals, encourages research, and educates professionals and public. Phone support network, correspondence, and literature.

IMPACC
c/o Ann Fagan
PO Box 11
Conyngham, PA18219
Phone: 570-788-1818 (day);570-788-3712 (eve)
Fax: 570-788-4046
E-mail: impacc@epix.net or pjfagan@epix.net
(verified as of 2/25/2009)

The American Cancer Society

The ACS provides assistance to those with cancer. Check the telephone directory for your local chapter.

American Cancer Society
National Home Office
250 Williams St NW
Atlanta, GA 30303-1002
Phone: 404-320-3333
Website: http://www.cancer.org/

Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC)

Established in 1995 "to improve understanding of the basic science of inherited colorectal cancer and the clinical management of affected families." The CGA-ICC's focus is to provides education to professionals and patients, access to clinical and chemoprevention trials, resources for developing new genetic registers, and a forum for collaborative research.

Collaborative Group of the Americas
Dr. James Church
Cleveland Clinic
Department of Colorectal Surgery
Digestive Disease Institute
9500 Euclid Avenue, Desk A30
ClevelandOH44195, USA
Phone: 216-444-9052
Website: http://www.cgaicc.com/

Johns Hopkins Hereditary Colorectal Cancer Website

The intent of this Website is to provide education and information about hereditary colorectal cancer.

Johns Hopkins Hereditary Colorectal Cancer Website
E-mail: hopkinsgi@jhmi.edu
Website: http://hopkins-gi.nts.jhu.edu/

Prognosis

The 5-year survival rate among patients with hereditary nonpolyposis colorectal cancer (HNPCC) is estimated to be approximately 60%, compared with 40-50% for sporadic cases. Investigators have found that MSI-positive tumors are associated with improved survival rates.^17,47,48

When compared based on stage, patients with colorectal cancer from families with a history of hereditary nonpolyposis colorectal cancer (HNPCC) have a better prognosis than patients with colorectal cancer in the general population, which may be explained by immunologic factors. Immunologic studies in mice with colon cancer have demonstrated that tumors influence host immune response by altering host T-cell receptors.⁴⁹ However, the defective T-cell response was observed only in animals with long-standing tumors, implying that rapid tumor growth, as seen in hereditary nonpolyposis colorectal cancer (HNPCC), may preserve immune response.⁴⁹ This hypothesis merits further investigation.

The best evidence that colonoscopic screening is beneficial for preventing colon cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) has come from observational studies of 22 HNPCC families that were followed for 15 years.^50,51 One hundred and thirty-three family members were voluntarily screened every 3 years, and 119 declined colonoscopic surveillance during the study period.

Colorectal cancer was reduced by 62% in the screened group versus the unscreened group. The reduction was ascribed to polypectomies in the intervention group. No colorectal cancer-related deaths occurred in the group that underwent regular colonoscopic screening compared with a 36% colorectal cancer-related mortality rate in the unscreened group.
 
Colon cancers that occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC)are believed to arise from adenomas; however, these adenomatous polyps likely have a shortened adenoma-carcinoma progression sequence compared with the general population. Thus, for a known MLH1 or MSH2 germline mutation carrier, full colonoscopy every 1-2 years beginning at ages 20-25 years or 5 years before the first diagnosed colorectal cancer in the family is recommended. After the age of 35-40 years, colonoscopy should be performed annually.

Miscellaneous

Special Concerns

Concerns related to genetic testing include the following:

• Genetic testing can be emotionally difficult regardless of the results. For example, an otherwise healthy adolescent may become troubled from the knowledge that he or she is a gene carrier with a strong likelihood of developing cancer. This information may compromise interpersonal relationships and educational plans, as well as career goals.
• Once the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has been established, cancer surveillance and management recommendations within the context of genetic counseling should be extended to all available first-degree and second-degree relatives. 
• For people with mutations, the costs associated with cancer screening and prevention may not be covered by their health insurance provider.
• Employer discrimination or insurance provider discrimination based on genetic test results is a possibility. As a result, in New YorkState, a person's genetic test results cannot be given to anyone else without the written permission of the person who was tested.  

Multimedia

Media file 1: Example of an autosomal dominant pedigree.

Media file 2: Diagnostic approach for patients with colorectal tumors.

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Keywords

hereditary colorectal cancer, hereditary nonpolyposis colorectal cancer, HNPCC, hereditary colorectal neoplasms, cancer familial syndrome, Lynch syndrome, Lynch criteria type I, Lynch criteria type II, Amsterdam criteria I, Amsterdam criteria II, Bethesda criteria, international collaborative group, ICG, colonic neoplasia, colorectal cancer, rectal bleeding, Turcot syndrome, HNPCC variant, Muir-Torre syndrome, metachronous, synchronous, germline,

microsatellite instability, MSI, MSI testing, immunohistochemistry, IHC, mismatch repair gene, MMR, endoscopic polypectomy, colectomy, rectal resection, subtotal colectomy with ileoanal anastomosis, total colectomy with ileorectal anastomosis, total proctocolectomy with ileostomy, cancer family syndrome, familial adenomatosis polyposis, FAP, endometrial cancer, glioblastoma, ovarian cancer, adenoma, prophylactic subtotal colectomy, prophylactic hysterectomy and bilateral salpingo-oophorectomy, chemoprevention

Contributor Information and Disclosures

Author

Juan Carlos Munoz, MD, Clinical Assistant Professor of Medicine, Division of Gastroenterology, University of Florida College of Medicine at Jacksonville
Juan Carlos Munoz, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Coauthor(s)

Louis R Lambiase, MD, Associate Professor of Medicine, University of Florida College of Medicine; Chief, Division of Gastroenterology, Department of Internal Medicine, University of Florida Health Science Center/Jacksonville
Louis R Lambiase, MD is a member of the following medical societies: American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Simmy Bank, MD, Chair, Professor, Department of Internal Medicine, Division of Gastroenterology, Long Island Jewish Hospital, Albert Einstein College of Medicine
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

Related eMedicine Topics

• Colon, Adenocarcinoma [in the Radiology section]
• Colorectal Tumors [in the Pediatrics: General Medicine section]
• Rectal Cancer [in the Oncology section]

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