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Hereditary Colon Cancer Syndromes and Genetic Testing

Paul E. Wise, MD, FACS, FASCRS

Associate Professor of Surgery, Washington University School of Medicine

Director, Washington University Inherited Colorectal Cancer and Polyposis Registry

Associate Program Director, Colon and Rectal Surgery Residency

 

 

 

Introduction

 

With a twenty-fold increase in gene discovery over the last two decades, genomic medicine plays an increasingly important role in the care of patients and their families, and the field of Colon and Rectal Surgery is no exception. It has been pointed out “…that clinicians [should] be sufficiently versed in genomics to understand when it should be applied and to communicate the potential limitations and benefits to their patients.”[1] The following will capitalize on prior “Core Subjects” from 1998 (Bleday), 2002 (Church), 2006 (Dietz), and 2008 (Ellis) (http://www.fascrs.org/physicians/education/core_subjects/), with recent updates to reach the goal of better understanding of the genomics of inherited colorectal cancer syndromes.

 

A syndrome is defined as a group of symptoms or signs that occur together and collectively characterize a disease process. Hereditary colorectal cancer syndromes are thought to account for up to 10% of all colorectal cancers, with another 20% having a familial predilection for colorectal cancer without a clear hereditary syndrome being identified.[2] Given the more than 140,000 new colorectal cancer cases expected to be diagnosed in 2012, [3] this would mean that more than 40,000 were related to a hereditary predilection and more than 10,000 might be diagnosed with a hereditary syndrome. Not all of these syndromes have yet to be linked to a clear genotypic abnormality or genetic mutation. Therefore, the hereditary colorectal cancer syndromes are characterized by their phenotypic manifestations (physical, biochemical, or physiologic properties), most easily categorized into those with multiple colonic polyps (polyposis syndromes including familial adenomatous polyposis [FAP], attenuated FAP [aFAP], MutYH-associated polyposis [MAP], serrated polyposis syndrome [SPS, previously known as hyperplastic polyposis syndrome], and hamartomatous polyposes) and those without multiple polyps (hereditary nonpolyposis colorectal cancer [HNPCC] and Lynch syndrome). 

 

Polyposis Syndromes

 

Familial Adenomatous Polyposis: The most common polyposis syndrome is FAP, characterized phenotypically by colonic involvement with 100 or more adenomatous polyps. This is an autosomal dominant syndrome (although 20-30% of cases are diagnosed with a spontaneous gene mutation) associated with a mutation in the APC gene. The more intense the degree of polyposis, the more likely an APC gene mutation will be identified, but not all patients with an intense phenotype are found to have an APC mutation. For example, 80% of patients with >1000 polyps are identified with an APC mutation, while less than 60% of those with between 100 and 1000 polyps will have an APC mutation. [1] The syndrome does have a 100% penetrance (if the patient has a gene mutation, they will develop polyps) with the polyps developing on average around the time of puberty (age 16) and the average colorectal cancer diagnosis being before age 40, with up to 7% of the cancers being diagnosed before age 21. Because of the early polyp onset, colonoscopic or sigmoidoscopic screening (the author prefers the former to rule out right-sided polyps) should begin at age 10-12 in those patients with a confirmed gene mutation or are at-risk for having a mutation but have not yet been tested. Colonic endoscopy (usually sigmoidoscopy is sufficient for subsequent follow-up) should continue yearly until polyps are confirmed, thus confirming the diagnosis, or until gene testing is performed with a negative result in a family with a known APC mutation. Positive endoscopic or genetic test results require continued surveillance and/or surgical intervention for colonic and extracolonic pathology related to FAP.[5,6]

 

The location of the APC gene mutation also impacts the risk of developing extracolonic manifestations associated with FAP (Figure 1).[7] Osteomas, supernumerary teeth, and congenital hypertrophy of the retinal pigment epithelium (CHRPE, seen in 66-100% of FAP patients) are benign signs associated with the syndrome and can be diagnostic in patients at-risk for FAP. Desmoids are “benign” fibromatous tumors that can occur anywhere in the body, are associated with mutations in the 5’ end of the APC gene, are seen in 15-30% of FAP patients, and can lead to significant and life-threatening complications including intestinal fistulas and/or bowel obstruction. Desmoids can require surgical and/or medical therapy when they become too large or symptomatic, and a staging system has been developed and validated that can assist with the care of desmoids in patients with FAP [8,9]. Neoplasias such as duodenal polyps (95% incidence in FAP with 4-12% developing cancer), gastric polyps (usually benign fundic gland polyps in 40%, but adenomas and cancers can occur), thyroid cancer (<2%), pancreatic cancer (<2%), and hepatoblastoma in children can all occur. Surveillance strategies for the more common extracolonic pathologies exist, including surveillance thyroid ultrasounds and upper intestinal endoscopy for duodenal and gastric pathology (frequency being based on the Spigelman criteria, Table 1) [10,11].

 

While chemoprevention agents such as sulindac and celecoxib have been used for the treatment of the colonic polyps in FAP (and other agents are being tested currently), they have not been shown to prevent the development of colorectal cancer. Therefore, while chemoprevention may allow for the delay of an operation, operative intervention remains the definitive treatment for FAP. Operative options include total colectomy and ileorectal anastomosis (IRA) versus proctocolectomy with or without restoration through an ileal pouch anal anastomosis (IPAA). If an IRA is performed, the rectal stump requires subsequent endoscopic surveillance due to future rectal cancer risks (ranging from 2-37%) and potential need for future proctectomy being as high as 45%. [12] Desmoids developing after an IRA may also preclude future reconstruction options if a subsequent proctectomy is required. When performing an IPAA, for those who are candidates, controversy remains as to whether a mucosectomy and handsewn anastomosis is preferred over a double-stapled technique to reduce cancer risk in the anal transition zone, which has been reported after both techniques. Just as with the IRA, the IPAA patient requires continued surveillance of the pouch due to the risk of developing pouch polyps or (more rarely) cancer, especially in those patients with more extensive colonic polyposis [13,14,15,16].

 

The choice of the approach for the initial operation depends on multiple factors, including but not limited to the following: rectal polyp numbers (as a surrogate of rectal cancer risk, with <20 rectal polyps, and ideally less than ten, determining whether rectal preservation is appropriate), genotype (a mutation in APC codons 1250-1464 having a more virulent phenotype), the presence of colon or rectal cancer at the time of operation, familial patterns of disease and familial experience with the operative options, the patient’s willingness and ability to be compliant with future surveillance of the IPAA or rectal remnant, the presence or concern for future development of desmoids, the patient’s fertility concerns, and the patient’s functional status, continence, and co-morbidities [6,14,17]. Timing of the operation depends on a number of considerations, including the following: phenotype/extent of polyposis, the age and/or maturity of the patient (usually the operations are performed in the late teens or early twenties for those patients diagnosed early in life, assuming they are capable of understanding the risks and benefits of the procedures), timing of planned child-bearing, familial patterns of polyp and cancer development, the patient’s cancer fears, concerns about desmoids and their potential impact on operative choice and timing, and the presence of cancer or high grade dysplasia. All of the procedures can be performed open or laparoscopically, the approach based on standard risk and candidacy assessments by the surgeon [14].

 

Attenuated Familial Adenomatous Polyposis: The attenuated form of FAP is characterized by between 10 and 100 colonic polyps (median 20-30 polyps). It is autosomal dominant in many cases due to a mutation in APC, but as noted above, fewer patients with the aFAP are actually identified with a gene mutation [4].  As with FAP, some patients with aFAP may be due to sporadic mutations in APC, while other cases may due to a biallelic mutation in MutYH (see below) and may therefore present with an autosomal recessive pattern.

 

The polyps in aFAP are primarily right-sided and often rectal sparing with older patient age at polyp onset (35-45yrs) and older age of first colorectal cancer diagnosis (55-59yrs) when compared to FAP. Because of the polyp locations in aFAP, sigmoidoscopy is not recommended for surveillance. Instead, colonoscopic surveillance is recommended to begin at age 20-30, or ten years sooner than the first polyp diagnosis in the family, whichever is first. While extracolonic manifestations are not as extensive or frequent, aFAP patients do frequently have upper intestinal polyps requiring surveillance as with FAP. Because the colonic polyps in aFAP may be manageable endoscopically, prophylactic colectomy may not be necessary for all patients. Chemoprevention with agents used in FAP may be effective, but larger trials have not been done. The surgical options, indications and considerations are otherwise the same as with FAP.[5,6]

 

MutYH-associated polyposis is an autosomal recessive syndrome caused by a biallelic mutation in MutYH, a DNA base repair gene. In MAP, the patient usually presents as aFAP (<100 polyps), but 7.5-17% of those patients presenting with more classic FAP actually are due to a biallelic mutation in MutYH. The condition usually presents when patients are in their 40s or 50s, and approximately 50% of those diagnosed with MAP will initially present with colorectal cancer. The colonic polyps found in MAP may be manageable endoscopically, and colonoscopic surveillance is recommended to start by age 20-30 (or ten years earlier than the first family diagnosis, whichever is earlier) and continue yearly if necessary. While not as common as with FAP and aFAP, duodenal polyps may be present, so at least an initial screening upper endoscopy is also recommended. Monoallelic MutYH mutations (mutation carriers) do show some increase in colorectal cancer risk in some studies [6,18].

 

Serrated Polyposis syndrome is defined by ≥20 colonic serrated polyps (sessile serrated polyps/adenomas, hyperplastic polyps, etc.) anywhere in the colon, ≥5 proximal colonic serrated polyps with two or more being equal to or larger than 1cm, or any number of hyperplastic polyps or sessile serrated polyps in a patient with a primary relative with SPS. The genotype for the syndrome is unknown to date, but the syndrome is often associated with BRAF mutations; and the phenotype in terms of type and distribution of polyps, and therefore cancer risk, is variable. The colorectal cancer risk is elevated and estimated to be between 7-40%, especially in those patients with a mixed phenotype of serrated and adenomatous polyps. Screening and surveillance is performed on a case by case basis depending on the phenotype but is thought best to start by age 40 (or ten years earlier than the youngest relative was diagnosed, whichever is earlier) and continuing every 5 years until polyps are found, at which time the frequency should increase. There are no formal colectomy recommendations and, as with the other conditions, colectomy is recommended when the disease cannot be controlled endoscopically or the polyps become symptomatic or show high grade dysplasia or cancer. Resecting the area of the colon with the pathology is recommended, but a more extended colectomy may be indicated for some patients. There are no known effective chemoprevention agents at this time.[19,20,21]

 

Hamartomatous polyposis syndromes are rare, with an incidence of 1 in 50,000-200,000 live births (but with high penetrance), and are characterized with involvement of the gastrointestinal tract in varying degrees with hamartomas or benign tumor overgrowths of normal but disorganized tissues. Peutz-Jeghers syndrome (PJS) is diagnosed with the presence of two or more hamartomatous gastrointestinal polyps and cutaneous (and/or buccal) hyperpigmentation, especially with a family history of PJS. It is an autosomal dominant syndrome due to a mutation in the STK11/LKB1 gene. The colorectal cancer risk associated with PJS is 10-39%. Juvenile polyposis syndrome (JPS) is characterized by hamartomatous juvenile polyps (three to five) in the colon, multiple polyps (five or more) throughout the GI tract, or any number of hamartomatous polyps in the setting of a family history of JPS. It is also an autosomal dominant syndrome due to mutations in the SMAD4 or BMPR1A genes. JPS has an associated colorectal cancer risk of 10-50%. PTEN syndromes (including Cowden and Bannayan-Riley-Ruvalcaba syndromes) are hamartoma syndromes associated with a mutation in the PTEN gene and have at least a 9% risk of colorectal cancer. All of these syndromes are associated with a variety of extracolonic malignancies and benign signs that will not be outlined here, but are summarized in the references for this section.

 

Colonic surveillance in the hamartomatous polyposis syndromes includes a colonoscopy every 2-3 years, starting in the teens. There are no formal colectomy recommendations for these syndromes, so operations are performed if the patient is symptomatic from the polyps (obstruction or bleeding), there is cancer or high grade dysplasia, or the polyps cannot be controlled endoscopically. Enterotomy and polypectomy may be sufficient for small bowel polyps in these syndromes, unless cancer is identified in the polyp necessitating a formal small bowel resection. The familial pattern of polyp and/or cancer formation may necessitate the consideration of a prophylactic colectomy.[22,23,24,25,26]

 

Nonpolyposis Colorectal Cancer Syndromes

 

The semantics of the nonpolyposis syndromes have changed over the last few decades since Dr. Henry Lynch initially described the “family cancer syndrome” in the early 1970s. Most authors now currently accept that the term “HNPCC” or hereditary nonpolyposis colorectal cancer describes patients who fit current accepted clinical criteria (see below) but their genotype is unclear or not yet tested. The clinical criteria for HNPCC were developed to identify patients for research studies (Amsterdam I and II criteria) or to better identify those patients who should be considered for genetic testing for Lynch syndrome (Bethesda and revised-Bethesda criteria). These criteria are outlined in Table 2. Unfortunately, 40% of those patients that fit the HNPCC clinical criteria will not have a mismatch repair (MMR) gene mutation when tested.[7,27]  For those patients and families that do have a MMR gene mutation identified, the term “Lynch syndrome” applies, regardless of their familial history or clinical phenotype. “Familial Colorectal Cancer Type X” is a term that has been used to describe those patients who fit clinical criteria for HNPCC but are negative for any of the known genetic mutations leading to Lynch syndrome. These patients have a lower cancer risk versus those with Lynch syndrome [28].

 

Lynch syndrome and HNPCC show an autosomal dominant inheritance pattern with a variable 30-72% penetrance in terms of lifetime colorectal cancer risk, depending on the gene mutation involved and the population studied. On average, patients are diagnosed with colorectal cancer in their early to mid 40s with some studies showing colorectal cancer risks increasing instead in the early 60s, again depending on the MMR gene mutation and population. The colorectal cancers in HNPCC/Lynch syndrome are usually (60-70%) proximal in the colon and have high rates of synchronous and metachronous lesions (5-20% and 10-50%, respectively). There is also a high association with extracolonic cancers including those of the uterus (20-60%), stomach (13-19%), and ovary (9-12%), as well as less frequently involving the small bowel, biliary tree, central nervous system, and urinary tract (all <4%). As more data is gathered, genotype-phenotype correlations of the various associated cancers have become apparent, as noted above, depending on which of the MMR genes is mutated.[29]

 

The MMR genes linked to Lynch syndrome include MLH1, MSH2, MSH6, and PMS2. Their role is to recognize and repair errors in DNA replication that normally occur in every 1 in 103 or 104 base pairings. When a patient has a mutated allele, the normal allele from the other parent is able to produce the proteins needed for appropriate repair function, but when a “second hit” occurs knocking out the normal allele, the proteins from these genes fail to form or function correctly. If MMR errors then occur in the replication of an oncogene or tumor suppressor gene, neoplasia may result. The lack of a functional protein leads to the development of variability in the length of short, tandemly repeated sequences of nucleotides that normally exist in the DNA, called microsatellites. This variability is known as microsatellite instability (MSI), and can be assessed as a molecular pathology screening test by assessing the difference between normal and tumor tissue. If there is a high level of microsatellite instability (MSI-H) in a patient’s tumor tissue, regardless of their family history, there is a 60% chance of identifying a MMR gene mutation in that patient. In addition, another screening test for Lynch syndrome is to use immunohistochemistry (IHC) to assess tumor tissue for the presence of normal or abnormal MMR protein staining. This type of testing can also guide which MMR genes to test for a mutation based on the protein staining pattern, thus avoiding testing for all four of the MMR genes and lowering costs. Testing tumor tissue for both MSI and IHC significantly increases the likelihood of identifying patients with Lynch syndrome, but can lead to increased costs. Because of the equivalence of many of the testing strategies available for Lynch syndrome, there has not been universal consensus as to the best approach, so testing is therefore based on institutional preference and resource availability.[29] Based on the high prevalence of the syndrome, the EGAPP Working Group “…found sufficient evidence to recommend offering genetic testing for Lynch syndrome to [all] individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives.” [30] See below for further discussion of genetic testing for Lynch syndrome.

 

Screening and treatment for the extracolonic malignancies in HNPCC will not be addressed in this report, but can be found in the references. In terms of colorectal cancer screening and treatment for those patients with HNPCC or Lynch syndrome (therefore, regardless of whether the patient’s diagnosis is based on clinical or genetic criteria), colonoscopic screening should start at age 20-25 years (or 10 years before the earliest colorectal cancer diagnosis in the family), performed every 1-2 years and then yearly after age 40. This has been shown to improve survival in patients with HNPCC. If a colon cancer is diagnosed, there should be consideration of a total or subtotal colectomy, as opposed to a segmental resection, because of the high rate of metachronous colorectal cancer development. Modeling data support a more extended resection, and recent retrospective studies have confirmed higher rates of metachronous cancers after segmental resections, but survival differences have not been shown (Table 3).[31,32,33]  In addition, QOL data show that the increase in bowel frequency after a more extended resection is well-tolerated. Regardless of whether a segmental or extended resection is performed, continued surveillance of the remaining colon and rectum is needed.[34,35,36,37]

 

Rectal cancer is also common in HNPCC/Lynch syndrome, occurring as the index colorectal cancer in 15% of patients. If a proctectomy alone is performed in this setting (abdominoperineal resection or low anterior resection), there is a 10-20% incidence of metachronous colon cancer within a median of 6 years after the proctectomy (30% will develop other neoplasia as well, such as polyps). Because of this high risk, a number of authors recommend consideration of proctocolectomy (with or without IPAA) at the time of resection for rectal cancer in HNPCC/Lynch syndrome. Again, surveillance is required if any rectum remains.[38,39]        

 

Considerations have also been made for prophylactic colectomy in Lynch syndrome. This is usually based on aggressive colorectal cancer penetrance in the family. This may also be considered in circumstances of excessive cancer fears in the patient or surveillance difficulties or compliance issues. Timing and extent of the resection is unclear, but colorectal surveillance will still be required unless a total proctocolectomy and end ileostomy is performed.[40,41] Promising results of chemoprevention studies with aspirin may impact the need for prophylactic colectomies, however, and these studies may also impact the recommendation for more extended resections for patients with Lynch syndrome and HNPCC.[42]

 

Genetic Testing

 

The American Society of Clinical Oncology “Guidelines for Genetic Testing” recommend genetic testing for a hereditary cancer syndrome when a patient has a personal or familial history suggestive of a genetic cancer susceptibility, the genetic test can be interpreted, and the test results will aid in the patient’s diagnosis or influence management of the patient and/or their family. In addition, there should be the ability to offer follow-up care based on the genetic test results.[43] If these criteria cannot be met to a reasonable degree, genetic testing should not be offered.

 

These criteria underscore the need for genetic counseling (defined as the “…process of helping people understand and adapt to the medical, psychological and familial implications of genetic conditions to disease”[44]) whenever genetic testing is being considered. This is especially true when considering genetic testing for hereditary colorectal cancer syndromes, for which testing and test interpretation can be harder than other genetic syndromes due to the number of potential syndromes in the differential (due to frequent phenotypic overlap), the number of genes that may need to be tested, and the other tests possibly needing interpretation in addition to gene testing (e.g., IHC or MSI tissue testing in Lynch syndrome).[18] The genetic counseling process should include many of the following: discussion of the purpose of the genetic test as well as information about the genes and who in the family to test, any alternatives to genetic testing, possible test results and their accuracy, the likelihood of a positive result, any risks of genetic discrimination, psychosocial aspects and confidentiality issues, use of test results to determine future surveillance and (if available) preventative measures, and details of the storage and potential reuse of genetic materials.[45]

 

Genetic testing is often covered by insurance providers (± the Centers for Medicare and Medicaid Services), but the stringency of the criteria to determine who is eligible for reimbursement for testing varies extensively. On average, the out-of-pocket expenses for patients are between $300-$400 depending on the genes being tested, and there are options for the uninsured to get “free” testing by contacting the testing companies/institutions directly. Each company handles billing differently with some charging the patients or providers directly and others billing the payers, so this should be clarified before testing is ordered. The companies and institutions that provide gene testing can be found at www.genetests.org (which also provides thorough reviews of the genes and syndromes themselves). Contacting the testing organizations will allow for clarification of how they perform the tests/type of testing done (sequencing, large gene rearrangements, etc.), what type of sample is needed (e.g., saliva, blood, etc.), how the results are reported, do they offer access to genetic counselors to assist in interpreting results, will they follow-up for future alterations in the classification of initially “uncertain” results (see below), and will they contact providers when additional tests become available for patients that might have benefited from the tests in the past (e.g., new genes have been identified as linked to the patient’s syndrome).

 

Gene test results are reported in one of three ways. “Deleterious mutation” confirms a gene mutation is present causing the syndrome phenotype, and this result can allow for point testing of the particular mutation for other at-risk family members (at lower cost than full gene testing). “No mutation detected” is informative if a familial gene mutation is already known (and thus the patient being tested does not have the gene mutation/syndrome). Otherwise, this result is uninformative for a patient who has a hereditary colorectal cancer syndrome phenotype (as well as being uninformative for the patient’s at-risk family members), and these patients and family members need to continue high risk screening for their syndrome. A “variant of uncertain significance” (VUS) result is an ambiguous result that may become informative in the future as more patients are diagnosed with the mutation and their phenotypes are assessed. There are a number of sites which may help clarify a VUS as well as maintain data to try to definitively classify them as a deleterious mutation versus a benign polymorphism, including the following examples: www.mappmmr.blueankh.com (for MLH1 and MSH2), www.insight-group.org/mutations (Leiden Open Variation Database), www.med.mun.ca/mmrvariants/ (MMR Genes Variant Database).

 

Identifying those upon whom to perform gene testing should include the above-described clinical criteria and family histories (not just asking about familial colorectal cancer and/or polyps). If patients present with multiple adenomatous polyps, testing should focus on APC and MutYH testing, depending on the inheritance patterns and clinical manifestations (with consideration of MMR gene testing in some circumstances). Hamartomatous polyps should lead to testing for genes as described above: STK11/LKB1, SMAD4, BMPR1A, and/or PTEN. A mixed polyposis assessment could include any of the genes mentioned above in a case by case basis, starting with the most common polyposis genes.[18] Because at least 25% of individuals with Lynch syndrome are not going to meet Amsterdam or Bethesda criteria, ideally all colorectal cancers would undergo screening tests with MSI and/or IHC as described above.[46] While revised Bethesda Criteria can be effective for determining who to test for Lynch syndrome, other prediction models also exist, including MMRPredict, Leiden, MMRpro, and PREMM [1,2,6] Other adjuncts to clarifying the need for MMR gene testing in high-risk patients (after MSI and/or IHC screening tests shown certain results suggestive of Lynch syndrome) include BRAF or MLH1 promoter hypermethylation testing, both of which can potentially avoid the need to perform costly MMR gene testing. Details of these tests as well as a number of other testing strategies and algorithms for Lynch syndrome are available in the references.[29,47,48,49,50,51]

 

Figures and Tables

 

 

 

 

 

 

 

Figure 1: Schematic representation of the APC gene to show genotype-phenotype correlations in FAP. (From Church J. “Hereditary colorectal cancer”. Chapter in The ASCRS Textbook of Colon and Rectal Surgery, Second Edition. Eds. Beck DE, Roberts PL, Saclarides TJ, et al. Springer, 2011:643-68.)

 

 

Table 1A: Spigelman Staging for Duodenal Polyposis in FAP

 

Number of points*

 

 

 

1

2

3

Number of polyps

1-4

5-20

>20

Polyp size (mm)

1-4

5-10

>10

Histology

Tubular

Tubulovillous

Villous

Dysplasia

Mild

Moderate

Severe

*points used to determine score, see Table 1B

 

Table 1B: Surveillance and Treatment for Duodenal Polyposis in FAP Based on Spigelman Score

Spigelman Stage (score in points from Table 1A)

Management Recommendation

Stage 0 (0 pts)/Stage I (1-4 pts)

Upper endoscopy q5years

Stage II (5-6 pts)

Upper endoscopy q3years, endoscopic therapy, and consider chemoprevention

Stage III (7-8 pts)

Upper endoscopy q1-2years, endoscopic therapy, consider chemoprevention

Stage IV (9-12 pts)

Consider resection

 

Tables adapted from Groves CJ, Saunders BP, Spigelman AD, Phillips RKS. Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut 2002;50:636–641.

 

Table 2A. Amsterdam II Criteria for HNPCC

  1. ≥3 relatives with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis), one should be a first-degree relative of the other two
  2. ≥2 successive generations affected
  3. ≥1 relative diagnosed before age 50 years
  4. FAP has been ruled out

 

Table 2B: Revised Bethesda Criteria for Testing Colorectal Cancer for Microsatellite Instability (MSI)

  1. Patients who meet Amsterdam criteria (above, Table 2A).
  2. Colorectal cancer diagnosed in a patient below age 50 years.
  3. Presence of synchronous and/or metachronous colorectal or other HNPCC-associated tumors (endometrial, stomach, small bowel, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma) tumors, sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel), regardless of patient age.
  4. Colorectal cancer with “MSI histology” (tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) diagnosed in a patient who is less than 60 years of age.

 

Table 3: Studies Comparing Metachronous Cancer Rates in Patients with HNPCC/Lynch Syndrome after Segmental vs. Extended Colectomies*[31,32,33]

 


*of note, none of the studies reported survival comparisons

 

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