Hemant K. Roy, MD and Amir Patel, MD
True/False: A patient whose parents have familial adenomatous polyposis (FAP) has a normal flexible sigmoidoscopy at age 12. He is unlikely to develop FAP.
False. Fifty percent of patients with FAP will develop polyps by age 15. In general, screening is accomplished by flexible sigmoidoscopy starting after puberty. For early diagnosis, gene testing is available if a proband is positive. The upper age for screening is unclear given that most patients will develop full-blown FAP by their 30s. Of note, the discovery of attenuated FAP syndromes, which can present later in life, has complicated this approach. Furthermore, attenuated FAP (mutations in the 5’ or 3’ end of the gene) has a predilection for involving the right side of the colon.
What are recommended screening options for a patient with a family history of FAP? Of hereditary nonpolyposis colorectal cancer (HNPCC)?
FAP: genetic counseling and consider genetic testing. A negative test result rules out FAP only if an affected family member has an identified mutation. Gene carriers or indeterminate cases should be offered flexible sigmoidoscopy every 12 months beginning at puberty and, if polyposis is identified, offered colectomy.
HNPCC: genetic counseling and consider genetic testing. They should undergo a colonoscopic examination every 1 to 2 years starting between the ages of 20 and 30 and yearly after age 40. Female patients should be counseled on their risks for endometrial and ovarian cancer and their screening options.
What is the recommended for surveillance interval in patients with an adenomatous polyp?
According to recent guidelines, patients with large or multiple adenomatous polyps should have repeat colonoscopy 3 years after the initial exam. If this exam is normal or shows only a small tubular adenoma, follow-up colonoscopy can be performed in 5 years. In special circumstances (eg, polyps with invasive cancer, large sessile adenomas, or numerous adenomas), follow-up colonoscopy may be done sooner.
True/False: A 28-year-old woman with no significant family history is found to have thousands of colonic polyps. Based on this, she is given the diagnosis of FAP and undergoes colectomy. Genetic testing is negative. The patient’s 2-year-old son is also tested for the adenomatous polyposis coli (APC) gene mutation and is negative. No further surveillance is necessary for the child.
False. Approximately 20% of patients with APC gene mutations will not have a family history of FAP. The in vitro synthesized protein (IVSP) assay that is commercially available only has 80% sensitivity for APC gene mutations. Therefore, a negative test is not interpretable if no one else in the family is known to be positive for gene mutations by this assay.
True/False: Gastric polyps in patients with FAP occur in the proximal stomach.
True. Gastric polyposis typically occurs in half the patients with FAP. They generally consist of fundic gland polyps and are most common in the proximal stomach. Rarely, adenomatous polyps can be found in the antrum (5%).
True/False: Gastric cancer is the next most common cause of mortality in patients with FAP following colectomy.
False. The next most common cause of mortality is from periampullary duodenal carcinomas (lifetime risk 4%). Periodic screening with a side-viewing endoscope is probably cost-effective and is generally offered starting at the age of 25 to 30 years.
True/False: Retinoblastomas are common in patients with FAP.
False. Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) may occur.
What is the earliest histological abnormality that occurs during colon carcinogenesis?
Aberrant crypt foci (ACF). ACF are clonal lesions present on macroscopically normal mucosa. They are often seen by examining, under magnification, colons stained with methylene blue. Recent studies have shown that these may be detectable by utilization of a magnifying colonoscope. These lesions typically demonstrate K-ras mutations with dysplastic ACF having APC mutations.
True/False: Juvenile polyps have no malignant potential.
False. Juvenile polyps are hamartomas characterized by distended mucus-filled glands. They typically occur in children and usually slough off or regress but occasionally may be found in adults. When single they have no malignant potential; however, when part of familial juvenile polyposis syndrome, they are associated with mixed juvenile-adenomatous polyps and have malignant potential.
What is the inheritance pattern of juvenile polyposis?
The genetics are unknown. It is thought to be an autosomal dominant condition with incomplete penetrance. Research in juvenile polyposis syndrome families has identified two specific gene changes causing disruption of the transforming growth factor beta: SMAD4 and BMPR1A. Recent data suggest that mutations may occur in stromal cells leading to a “landscaper” defect. The gene that has been implicated is PTEN (phosphatase and tensin homologue) on the deleted part of chromosome 10q.
A 27-year-old man with mucocutaneous pigmentation presents with abdominal pain. What malignancies are associated with this syndrome?
Peutz–Jeghers polyps are hamartomas that, not uncommonly, cause intussusception. These patients are at higher risk for carcinomas of the colon, duodenum, jejunum, and ileum. Ovarian sex cord tumors and testicular cancers have also been described. Breast and pancreatic cancers have been known to occur at a young age. Approximately half of the patients with this syndrome will develop cancer. The gene, recently discovered (STK11 also known as LKB1), is a serine-threonine kinase.
True/False: K-ras is responsible for FAP in patients that are APC wild-type.
False. MYH has been noted to cause FAP in a significant proportion of APC-negative FAP. MYH is autosomal recessive. K-ras is believed to initiate most ACF but the relationship to polyps is unclear.
A 56-year-old woman is noted to have a sessile serrated adenoma. What is the most appropriate management strategy?
Currently, sessile serrated adenomas are treated like conventional adenomas. There is some evidence that they may be more aggressive. Molecularly, they are more likely to be microsatellite unstable and frequently have B-raf involvement.
True/False: A 62-year-old woman is found to have a 1.5-cm flat lesion in her cecum on colonoscopy. The malignancy risk is lower in this case than if she had a more raised lesion.
False. Typically flat and depressed lesions have a higher risk of malignancy compared with more raised polypoid lesions and are more difficult to endoscopically visualize. Techniques such as chromoendoscopy and narrowband imaging may improve detection.
In what segment of the colon are colon polyps most likely to remain undetected (ie, missed)?
The emerging data suggests that right-sided lesions are less likely to be detected. There is emerging evidence that colonoscopy is suboptimally protective in the right colon. Procedural characteristics such as withdrawal time and, possibly, use of adjunctive approaches such as high-definition colonoscopes and chromoendoscopy may be involved. Microsatellite stability (three- to fourfold higher incidence in missed lesions), unsuccessful cecal intubation, and poor preparation in the proximal colon may also play a role.
A 50-year-old man presents with diffuse gastrointestinal polyposis, dystrophic changes in the fingernails, alopecia, cutaneous hyperpigmentation, diarrhea, weight loss, abdominal pain, and complications of malnutrition. Do his children need to be screened?
No. Cronkite–Canada syndrome is an acquired, nonfamilial syndrome. The polyps are juvenile-type but may have adenomatous epithelium. Carcinomas are quite rare. The malabsorption syndrome is progressive and portends a poor prognosis.
Which is the best estimate for the risk of colorectal cancer in 1–2 cm tubular adenomatous polyps—3%, 10%, or 25%?
10%. With adenomas < 1 cm, the risk is about 1.3%, while the risk for those > 2 cm is 46%. These rates are higher in villous compared to tubular adenomas. With regard to high-grade dysplasia, it may be found in 1.1% of polyps < 0.5 cm, 4.6% of polyps between 0.5 and 0.9 cm and 20.6% of those > 1.0 cm.
True/False: The earliest mutation in colon carcinogenesis is K-ras.
False. In the multistage colon cancer genetic model, the APC tumor suppressor gene is mutated in > 80% in histologically normal mucosa followed by K-ras at the small adenoma stage, deleted in colon cancer (DCC) at the large adenoma stage and p53 at the malignancy stage. Often, if APC is not mutated, its downstream effector—β-catenin—is altered.
True/False: Microsatellite instability is seen only in patients with HNPCC.
False. Microsatellite instability is seen in 15% of all colorectal cancers. Fewer than 20% will have germline mutations in the mismatch repair enzymes. Recently, the analysis of BRAF mutations has been shown to be helpful in discriminating between sporadic and HNPCC-related colorectal cancers.
HNPCC is associated with what genes?
Lynch syndrome is a hereditary cancer syndrome that is inherited in an autosomal dominant manner. It is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. MLH1 and MSH2 mutations account for the majority of mutations (approximately 30% are due to MLH1 and 40% due to MSH2).
For Lynch syndrome (ie, HNPCC), does the gene involved result in any clinical significant difference in outcome?
Yes. Typically the colorectal cancer risk is highest for MLH1 and lowest for MSH6. In contrast, MSH6 has a high risk for endometrial cancer.
True/False: Tumors with microsatellite instability have a worse prognosis than standard colon cancers.
False. While tumors with microsatellite instability are typically less differentiated and mucinous, they tend to have a significantly better prognosis than standard tumors. These tumors, whether sporadic or part of HNPCC, tend to be flat, right-sided and have lymphocyte infiltration. The general recommendations for screening for microsatellite instability in colon cancer (Bethesda criteria) include young patients, right-sided mucinous tumors, and family history of colon cancer.
What genetic marker has prognostic implications for Dukes B2 colon cancer?
DCC status. Adjuvant chemotherapy has not been shown to have a survival advantage for Dukes B2 colon cancer; however, recent evidence suggests that if this tumor suppressor gene is mutated, B2 tumors “behave” more like a C1 tumor. Adjuvant chemotherapy has been shown to provide a survival advantage for Dukes C tumors.
True/False: Nonsteroidal anti-inflammatory drugs (NSAIDs) are helpful in preventing polyp formation in FAP but not sporadic colon cancer.
False. Epidemiological and experimental studies have demonstrated responsiveness to NSAIDs in both of these conditions. Both conditions are characterized by upregulation of cyclooxygenase-2 early in carcinogenesis.
What types of gastrointestinal polyps are associated with the basal cell nevus syndrome?
Multiple gastric hamartomatous polyps.
True/False: Colon cancer is common in Cowden’s syndrome.
False. The hallmark of Cowden’s syndrome is facial trichilemmomas. It is characterized by multiple oral and dermatological hamartomas, breast disease (both fibrocystic and cancer), thyroid disease (nontoxic goiter and cancer), as well as hamartomatous polyps of the stomach, small bowel, and colon. The colorectal polyps have disorganization and proliferation of the muscularis mucosa with normal overlying colonic epithelium. These rarely cause symptoms or degenerate into colon cancer.
What are the major extracolonic manifestations of Gardner’s syndrome?
Gardner’s syndrome is a variant of FAP with a germline mutation in the APC gene. It is characterized by bone disease, especially osteomas of the long bones, skull, and mandible. Dental abnormalities including supernumerary teeth, impacted teeth, and mandibular cysts have been seen. CHRPE is commonly seen. Soft tissue tumors including fibromas, lipomas, and epidermoid cysts can be seen. Extracolonic malignancies are similar to classic FAP (peri-ampullary and gastric); however, papillary carcinoma of the thyroid and adrenals and tumors of the liver and biliary tree have also been reported.
What tumors are commonly associated with HNPCC?
Endometrial, ovarian, gastric, pancreatic, hepatobiliary, small intestinal and transitional cell carcinomas of the ureter, and renal pelvis.
True/False: Bone cancer is the second leading cause of death in patients with Gardner’s syndrome.
False. Desmoid tumors have been reported in 8%–13% of patients and are second only to metastatic colon cancer as a cause of death. This diffuse mesenteric fibromatosis is often a reaction to a laparotomy but may appear spontaneously. The progressive growth of mesenteric fibroblasts can cause gastrointestinal obstruction, vascular compromise, and ureteral obstruction. While responsive to radiation therapy, this is often impractical because of concerns over mesenteric injury. NSAIDs and anti-estrogens may have some effect.
True/False: Duodenal polyposis is rare in FAP.
False. Sixty to ninety percent of patients have duodenal polyposis and 50%–85% have adenomatous changes of the papilla of Vater. Four to 12% of these patients develop duodenal/periampullary malignancies.
True/False: Turcot’s syndrome is associated with HNPCC and FAP.
True, partially. The brain tumors that occur in FAP with Turcot’s syndrome are generally medulloblastomas while gliomas are generally found with the HNPCC variant.
True/False: Neurofibromatosis predisposes to colon cancer.
False. Neurofibromas may be seen throughout the gut. Malignant tumors can be seen, often from degeneration of neurofibromas; however, colorectal adenocarcinomas are rare.
True/False: Liver metastases from colorectal cancer are best treated with intra-arterial 5-FU or floxuridine (FUDR).
False. This therapy remains investigational and is complicated by the development of a sclerosing cholangitis-like picture. If there is no evidence of extrahepatic disease and the tumor(s) involve either one lobe of the liver or are focal and surgically accessible in both lobes, surgical resection should be contemplated. After successful surgery, the 5-year survival rate is 20%–34%. Unfortunately, only 5%–6% of patients are considered surgical candidates. Recent data suggest that intra-arterial chemotherapy in combination with surgery is superior to surgery alone.
True/False: Adjuvant chemotherapy has not been shown to have a survival benefit for Dukes B2 rectal cancer.
False. Dukes B2 rectal cancer should be treated with either preoperative or postoperative chemotherapy accompanied by radiation therapy in order to enhance local therapy. This differs for colon cancer per se.
True/False: The use of the carcinoembryonic antigen (CEA) level, abdominal CT scan, and chest x-ray in addition to colonoscopy as surveillance methods after curative resection for colon cancer has been shown to improve survival.
False. Neither routine CT scanning nor chest x-rays have been shown to improve survival. Obtaining CEA levels annually may have a role, although its cost-effectiveness has been controversial.
True/False: Patients with a family history of adenomatous polyps are at a higher risk for colorectal cancer.
True. If diagnosed under age 55, there is a markedly increased risk of colorectal cancer.
True/False: Most patients with a positive fecal occult blood test (FOBT) will have a colon cancer or polyp.
False. While the sensitivity of FOBT is approximately 80%, the positive predictive value is only about 10%–20%.
True/False: The risk of colon cancer in patients with inflammatory bowel disease may be affected by certain extraintestinal manifestations.
True. While the predominant risk factors include the amount of bowel involved and duration of the disease, coexisting sclerosing cholangitis is also a significant risk factor.
What endocrine disorder carries a higher risk of colonic neoplasia?
Acromegaly. Although the studies are retrospective, the estimates of the prevalence of adenomatous polyps and colon cancer range from 6.3% to 25% and 14% to 35%, respectively. The risk may be higher in younger patients, those with a family history of colon cancer, and those with multiple skin tags (acrochordons). While the mechanism is unclear, it is not simply growth hormone-related since the risk of neoplasia may be greater in cured acromegalics than those with active disease.
What organisms responsible for bacteremia are associated with the presence of colorectal neoplasia?
Streptococcus bovis bacteremia has been associated with the presence of colorectal adenomas and carcinomas. Clostridium septicum bacteremia has also been associated with the colonic neoplasia. Finally, endocarditis associated with Streptococcus agalactiae has been reported in several patients with rectal villous adenomas containing small foci of carcinoma.
True/False: Patients with breast cancer have an increased risk of colon cancer.
False. There is no evidence in case-control studies that having a personal history of breast cancer is a risk factor for colon cancer. However, patients with familial breast cancer associated with mutations in BRCA 1 or 2 have a 3- to 6-fold increased incidence of colon cancer.
What are potential mechanisms in colonic neoplasm-induced diarrhea?
A syndrome of large-volume secretory diarrhea has been observed with large villous adenomas in the rectum and rectosigmoid colon and is associated with dehydration and electrolyte abnormalities, especially hypokalemia. The mechanisms are unclear. Some data suggest that prostaglandins are involved.
How common are adenomatous polyps in the general population?
Clinical studies indicate that adenomatous polyps occur in 25% of patients 50 years old and increase with age. By the late 70s, 50% of people have polyps. Autopsy studies suggest an even higher rate with approximately 60% of men and 40% of women having adenomatous polyps at age 50. They are found more commonly in men than in women. While data on large polyps (> 1 cm) is limited, one autopsy series suggested that 4.6% of the population at age 54 and 15.6% at age 75 had large polyps.
True/False: The risk of colon cancer is lower in patients with Crohn’s disease compared to those with ulcerative colitis.
False. Crohn’s colitis has the same risk as ulcerative colitis when matched for extent, duration, and age of onset of the disease. The cumulative risk for developing colorectal cancer with pancolitis is 30% after 35 years. Surveillance colonoscopy every 1–2 years is recommended after 8 years in those with pancolitis and after 15 years in those with left-sided colitis.
A 63-year-old man had a 2-cm pedunculated polyp, which contained a focus of malignancy, removed from the sigmoid colon. What surveillance is recommended?
If invasive carcinoma is found and poor prognostic features exist (eg, malignancy incompletely excised, less than a 2-mm margin from polypectomy, a relatively undifferentiated tumor or lymphatic or venous invasion), then hemicolectomy is recommended. Sessile polyps are also considered to have a worse prognosis. If no poor prognostic features exist, as in this patient, it would be reasonable to consider that the polypectomy is the definitive therapy. Colonoscopy is often recommended within 3 months of polypectomy and then 1 year later to ensure that there is no residual malignant tissue.
A 10-year-old girl presents with hematochezia and is found to have two juvenile colonic polyps. Her family history is unremarkable. What is the recommended follow-up?
This patient does not meet the criteria for juvenile polyposis which includes the presence of 10 or more juvenile polyps, juvenile polyps throughout the gastrointestinal tract, or juvenile polyps in a patient with a family history of polyposis. These nonneoplastic hamartomatous colonic polyps are extremely common occurring in 1%–2% of all children, usually between the ages of 4 and 14. A solitary polyp is seen in 70% of patients but 30% will have 2 or 3. If a polyposis syndrome is not identified, no other evaluation is necessary.
A 28-year-old patient with Gardner’s syndrome is noted to have nodular lymphoid hyperplasia of the terminal ileum. What therapy is necessary?
Nodular lymphoid hyperplasia is a rare lymphoproliferative disorder associated with a variety of disorders including Gardner’s. It is also present in 20% of patients with common variable immunodeficiency and is rarely associated with intestinal lymphoma. Of note, it has also been seen in otherwise healthy children. These hyperplastic lymphoid nodules are often found in the small bowel but may be seen in the stomach and colon. These nodules range in size from 3 to 6 mm. No therapy is required for nodular lymphoid hyperplasia.
What agents are FDA-approved for preventing colon neoplasia?
While NSAIDs as a class protect against colon cancer, only celecoxib has been approved for this indication in patients with FAP. However, given the cardiotoxicity, this needs to be utilized with caution.
What agents have been shown to inhibit colon cancer?
Epidemiological studies in humans have demonstrated that NSAIDs, estrogens, calcium, and folate inhibit colon cancer. The effect of dietary fiber is controversial. Animal studies suggest that ursodeoxycholic acid, vitamin D analogues, polyethylene glycol, and fish oil may also be protective.
What are the screening recommendations for a patient with a 53-year-old brother who just had an adenomatous polyp removed?
According to current guidelines, any person with a first-degree relative with either colon cancer or an adenomatous polyp should be offered the same screening options as average-risk patients, except starting at age 40 or 10 years prior to diagnosis of the affected relative, whichever comes first. The guideline states that if the patient had colorectal cancer before 55 or adenomatous polyp before age 60, special efforts should be made to ensure that screening takes place.
What are the screening recommendations for patients at an average-risk for colon cancer?
Starting at age 50, colonoscopy every 10 years, CT colonography or double-contrast barium enema every 5 years, annual FOBT, flexible sigmoidoscopy every 5 years, or a combination of FOBT and flexible sigmoidoscopy.
True/False: Lack of exercise and obesity are associated with colonic neoplasia.
True. Epidemiological studies have demonstrated that these are independent risk factors for colon cancer.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of vascular dysplasia (epistaxis, telangiectasia, and arteriovenous malformations) that is associated with what familial cancer syndrome?
Juvenile polyposis syndrome. Identification of SMAD4 mutations in HHT patients without a prior diagnosis of juvenile polyposis syndrome has been demonstrated in a subset of patients. These patients are at risk of having JP-HHT and an increased risk of gastrointestinal cancer.
A 37-year-old male seeks your advice after his 62-year-old mother was recently diagnosed with colon cancer. His maternal uncle was also diagnosed with colon cancer and his maternal grandmother had a history of endometrial cancer. What would be the best way to manage this patient?
This patient’s history is suspicious for HNPCC. He should be referred to a genetic counselor. The best approach to test for HNPCC in this case would be to obtain tumor tissue from the patient’s mother to test for microsatellite instability. If the test is positive, a blood test can be done to identify a germline mutation in the mismatch repair genes. A negative blood test does not exclude the diagnosis and aggressive screening should still be pursued.
On screening colonoscopy, a 50-year-old man is found to have multiple adenomas (3 total) with the largest measuring 2 cm. There is no family history of colorectal cancer. When should the patient have a repeat colonoscopy to check for metachronous adenomas?
Three years. Patients at high risk of developing advanced adenomas should have a repeat colonoscopy 3 years after the primary finding. High-risk patients include patients with multiple adenomas (> 2 adenomas), large adenomas (> 1 cm), adenomas of villous histology or high-grade dysplasia, and/or patients with a family history of colorectal cancer. Patients at low risk of developing advanced adenomas can have repeat colonoscopy 5 years after.
A 63-year-old woman is found to have a malignant polyp on colonoscopy. It is completely excised. On pathology, the cancer is not poorly differentiated and the margins of excision are not involved. There is no vascular or lymphatic involvement. What is the next step in managing this patient?
No further treatment is indicated. The patient has favorable prognostic criteria and should have a follow-up colonoscopy in 3 months to check for residual abnormal tissue at the polypetctomy site. The risk of local recurrence or local lymph node metastasis from invasive carcinoma in a colonoscopically resected polyp is less than the risk for death from colonic surgery. Therefore, the American College of Gastroenterology (ACG) recommends no further treatment if the following criteria are fulfilled: The polyp is completely excised; the cancer is not poorly differentiated; there is no vascular or lymphatic involvement; and the pathology laboratory can confirm the depth of invasion, grade of differentiation, and completeness of excision.
A 65-year-old woman is evaluated after undergoing left hemicolectomy for colon cancer 3 months previously. She was found to have stage IIA disease and has been doing well. She did not undergo full colonoscopy prior to surgical resection. What is the most appropriate endoscopic management for this patient?
An immediate colonoscopy and then again in 1 year. Patients diagnosed with colon cancer require a complete survey of the colon. If it has not been done preoperatively, it should be done postoperatively to check for other lesions. Surveillance colonoscopy should then be performed at 1, 3, and 5 years.
• • • SUGGESTED READINGS • • •
Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010 Jun;138(6): 2044-2058.
Smith KD, Rodriguez-Bigas MA. Role of surgery in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (Lynch syndrome). Surg Oncol Clin N Am. 2009 Oct;18(4):705-715.
Tops CM, Wijnen JT, Hes FJ. Introduction to molecular and clinical genetics of colorectal cancer syndromes. Best Pract Res Clin Gastroenterol. 2009;23(2):127-146.
Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008;134:1570-1595.