Hereditary colorectal cancer
Hereditary colorectal cancer is cancer of the colon or rectum that develops chiefly as the result of inherited factors.
The colon, or the large intestine, is a long muscular tube that absorbs water from stool and advances the stool towards the rectum. The rectum works in conjunction with the anus to coordinate the process of defecation. The colon and rectum are jointly referred to as the colorectum.
A neoplasm is a portion of abnormal tissue that grows rapidly and out of control. Cancer is the malignant type of neoplasm. Colorectal cancer is a relatively common and dangerous cancer. Tumors originate in the mucosa, or inner lining of the colorectum, and grow inwardly. Eventually, the tumor spreads outwardly until it reaches lymph nodes or other organs in the abdomen. Ultimately, cancer cells may detach from the original tumor and spread to distant parts of the body (such as the liver, lungs, bone, and brain) in a process called metastasis.
The development of colorectal cancer is not a random event, but rather arises in a sequential fashion. The first easily detected step is the appearance of adenomatous polyps. Polyps are grossly defined as elevations of a surface. An adenomatous polyp is derived from the glandular elements of the mucosa. A person may have any number of colorectal adenomatous polyps. Eventually, one or more of these polyps may transform into a cancer. The risk of colorectal cancer increases with the number of polyps. Larger polyps are also more likely to become cancerous than smaller ones. The factors that initiate this adenoma-cancer sequence are inherited and/or acquired from the environment.
Colorectal cancer occurs in certain families much more often than expected by chance alone. In fact, an important and common risk factor for the development of colorectal cancer is the occurrence of colorectal cancer in the family. About 10% of people have a first-degree relative with colorectal cancer. Having a first-degree relative with colorectal cancer increases the chance of developing colorectal cancer by two- to three-fold. The risk becomes even higher when colorectal cancer occurs in a relative at an early age (before 50 years of age) or when more than one relative has the cancer. This suggests that susceptibility of developing colorectal cancer in affected families is due to inherited factors, although shared exposure to environmental stimuli may play a role. Scientists are investigating the genetic factors that may be responsible for the increased risk of colorectal cancer in these cases of common inheritance.
The vast majority of cases of colorectal cancer are sporadic; that is, they occur in the absence of a hereditary syndrome, although familial risk may be involved. But rarely, colorectal cancer is inherited as part of a well-defined syndrome. These syndromes altogether account for about 2-5% of all cases of colorectal cancer.
Familial adenomatous polpyposis
In the syndrome of familial adenomatous polyposis (FAP), adenomas develop in the colon and rectum
Other types of polyps are also common in patients with FAP. Polyps may develop in the stomach or duodenum. Those in the stomach are benign, while those in the duodenum may become malignant. The cancer risk in these other polyps is much less than the risk associated with the colorectal polyps. Patients with FAP may also have abnormalities outside the gastrointestinal tract, such as osteomas, desmoid tumors, extra teeth, and hypertrophy of the retinal pigment epithelium.
Three variants of FAP have been identified. Gardner syndrome is a rare variant of FAP characterized by colorectal polyps and a marked prominence of extraintestinal growths. Examples of the growths include osteomas, epidermoid cysts, and desmoid tumors. Although these growths usually present only cosmetic problems, desmoid tumors can occasionally compress nearby tissue in a harmful way.
Turcot syndrome is another rare type of FAP. Patients with this syndrome have the typical colorectal polyps, as well as malignant tumors of the central nervous system such as medulloblastoma, astrocytoma, ependymoma, and glioblastoma multiforme.
Patients with the attenuated adenomatous polyposis coli form of FAP have many colonic polyps, but not the hundreds or thousands seen in typical FAP. The chance of developing colon cancer approaches but does not reach 100%, and colon cancer usually appears later than in patients with typical FAP.
Hereditary nonpolyposis colorectal cancer
Patients with hereditary nonpolyposis colorectal cancer (HNPCC) have about an 80% risk of developing colorectal cancer if untreated. They may have more polyps than the general population, but not the hundreds or thousands of polyps associated with FAP. The average age for the development of cancer is 45 years old. Frequently, a patient with HNPCC will have multiple cancers at the same time (synchronous) or may develop cancers at different time periods (metachronous).
Extraintestinal cancers sometimes occur in HNPCC. The most common is uterine cancer, but other examples include cancer of the uterus, stomach, small intestine, pancreas, kidney, and ovary.
The Amsterdam criteria are clinical criteria for the diagnosis of HNPCC in a family:
- At least three relatives with colorectal cancer, one of whom must be a first-degree relative of the other two.
- Colorectal cancer involving at least two generations.
- One or more cases of colorectal cancer before the age of 50.
It must be understood that all colorectal cancers stem from genetic mutations. Environmental factors may also contribute to the development of cancer. Sometimes colorectal cancer appears in a patient who has neither affected relatives nor an inherited syndrome. Other cases appear in families that seem genetically susceptible to the development of these cancers. The presence of colorectal cancer in relatives, especially young relatives, increases the risk of developing colorectal cancer. In families affected by the rare syndromes of hereditary colorectal cancer (HNPCC, FAP, and their variants), the genetic mutations are inherited in autosomal dominant fashion.
Whether it appears sporadically or is inherited as part of a syndrome, colorectal cancer is generally linked to mutations in certain categories of genes: proto-oncogenes, tumor suppressor genes, DNA mismatch repair genes, or modifier genes. The proto-oncogene category inludes the K-ras, src, and c-myc genes. The tumor suppressor genes are the APC (adenomatous polyposis coli) gene, the DCC (deleted in colon cancer) gene, the MCC (mutated in colon cancer) gene, the DPC4 gene, and p53. The mismatch repair genes are hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6/GTBP. The modifier genes inlude the COX2 (cyclooxygenase 2) gene, the CD44v gene, and the phospholipase A2 gene.
The genetic defect in FAP and its three variants (Gardner syndrome, Turcot syndrome, and attenuated adenomatous polyposis coli) reside on the APC gene, which is on the long arm of chromosome 5. However, there are a wide variety of mutations within the APC gene that can result in those syndromes. Sometimes Turcot's syndrome is associated with the same mutations as those in HNPCC. Mutations of mismatch repair genes, such as hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6/GTBP, are characteristic of the HNPCC syndrome. The transmission of these hereditary colorectal cancer syndromes occurs through mutations of the same genes that are mutated in sporadic cases of colorectal cancer. But it must be emphasized that the hereditary colorectal cancer
Families with the inherited syndromes of colorectal cancer can undergo genetic testing to determine which individuals have inherited the disease. The tests for the defective genes can detect the mutation in approximately 60 to 80% of FAP families and about 50% of HNPCC families. However, if one person is found to have the mutation, the other family members can be tested with nearly 100% accuracy. Although genetic testing can provide useful information to the patients, it may be associated with psychosocial risks. Thus, genetic testing should be performed only in formal programs. Genetic counseling should also be provided.
Colorectal cancer is relatively common with approximately 160,000 new cases diagnosed each year, but the syndromes of inherited colorectal cancer are rare. It is estimated that they comprise only 2-5% of all cases of colorectal cancer. FAP occurs in about one in every 10,000 births. The incidence of all colorectal cancer increases with age.
Signs and symptoms
The clinical manifestations of colorectal cancer depend largely on location and tumor size. Tumors in the proximal colon can grow to large sizes before detection. They may cause weight loss, abdominal pain, or bleeding. The bleeding may be readily noticed by the patient as frank blood in the toilet, or smears of blood in the stool. Less extensive bleeding may be detected by the fecal occult blood test, in which a sample of stool obtained during a rectal exam is tested for microscopic amounts of blood. Anemia, or low red blood cell count, detected by a laboratory test may prompt further examination of the colon to determine if a tumor is the source of bleeding. In the smaller, distal colon, tumors are more likely to cause obstruction. This may cause gas pains and decrease in the caliber of the stool. Additionally, these cancers may cause bleeding or a change in bowel habits. In FAP, the first symptom is usually diarrhea.
The presence of symptoms such as abdominal pain, weight loss, change in bowel habits, or decrease in stool caliber may point to a diagnosis of colorectal cancer. Of course, these symptoms must be interpreted within the context of the patient's age, previous medical history, and family history of colorectal cancer.
Ideally, the diagnosis of colorectal cancer should be made before symptoms develop. A number of screening tests are useful for detecting colorectal cancer. The fecal occult blood test that was discussed earlier is a simple test performed in the office. The normal result is the absence of blood in the stool. If blood is found in the stool, the suspicion for colorectal cancer becomes higher. Standard screening also includes an endoscopic exam—either sigmoidoscopy or colonoscopy. In these exams, a thin, specially lighted tube is inserted directly into the anus and advanced into the colon. The physician can view the inside of the colon and check for polyps or tumors. Sigmoidoscopy allows examination of the lower part of the colon while colonoscopy allows a more extensive view. Sometimes a barium enema is added to the screening procedure. In this test, a dye is injected into the anus and up into the colon. The dye coats the inside of the colon so that tumors can be detected by plain x ray.
New screening tests are currently under investigation. In wireless endoscopy, a tiny pill-sized camera is swallowed. As the camera traverses the gastrointestinal tract, it transmits video footage that can be examined for suspicious abnormalities. Eventually the camera is passed out of the anus with the stool. Virtual colonoscopy generates a three-dimensional image of the colon by applying advanced computer graphics technology to images obtained by computed tomography (CT) scanning. These processes can spare the patient the usual discomfort of traditional endoscopy. However, they are not yet fully developed nor approved for colorectal cancer screening.
If any of the above screening tests identifies an abnormality that appears to be a tumor, the diagnosis must be confirmed by biopsy. This is performed during colonoscopy. A small piece of tissue is removed and examined in the laboratory for cancerous cells.
Most medical organizations recommend that screening should begin in the general population at age 40 to 50. The fecal occult blood test is performed annually and sigmoidoscopy every three to five years. If a first degree relative has colorectal cancer, then screening should begin at 35 to 40 years of age. Alternatively, screening can begin five years earlier than the age of a young relative who has colorectal cancer.
Individuals in families affected by hereditary colorectal cancer syndromes are at high risk for developing cancer early in life. Therefore, screening is initiated at a young age. Screening can be reserved for those family members who have been proven to carry the abnormal gene by genetic testing, or it can be applied to all family members if the specific mutation cannot be identified. Some experts propose that in families with a history of FAP, screening should begin at 10 to 12 years of age and be repeated every one to two years. In families with HNPCC, colorectal screening should begin at 20 to 30 years of age and also be repeated every one to two years.
Since FAP and HNPCC are also associated with other cancers, affected patients should undergo appropriate screening for these malignancies as well. Those with FAP require regular upper endoscopy to detect tumors of the stomach and duodenum. Women with HNPCC should undergo screening for uterine cancer by way of random biopsies of the inner lining of the uterus.
Treatment and management
The treatment of sporadic colorectal cancer requires surgical removal of the tumor and surrounding tissue. Chemotherapy or radiation therapy may also be necessary. But the treatment of colorectal cancer in the hereditary syndromes is more aggressive. In these cases, the entire colon must be removed, since cancer will almost certainly develop in any remaining colon. Sometimes the rectum is also removed; alternatively, the patient may undergo frequent examination of the rectum for polyps or cancers. Experts strongly recommend that individuals with known FAP should consider surgical removal of the colon and/or rectum early in life as a prophylactic measure, before cancer is diagnosed. Although the role of prophylactic surgery in patients with HNPCC is less well-defined, many experts favor it. The patient faces a choice between prophylactic surgery and frequent, lifelong screening.
Some studies have shown that the drug sulindac may reduce the number of adenomatous polyps that develop in FAP and its variants. In addition, certain nonsteroidal antiflammatory drugs such as aspirin may also reduce the incidence of colorectal cancer in general.
Patients with a hereditary colorectal cancer syndrome such as FAP, HNPCC, or its variants, have a much higher likelihood of developing colon cancer than the general population. In the extreme case of typical FAP, essentially 100% of patients will develop colon cancer without surgery. If colon cancer does develop, survival depends on the extent to which the cancer has spread. Cancer that is isolated to the colon is associated with much better survival than cancer that has spread to distant organs such as the liver or lungs.
"Colon and Rectum." In Sabiston Textbook of Surgery. Edited by Courtney Townsend Jr., et al. 16th ed. Philadelphia: W.B. Saunders Company, 2001.
"Familial Colon Cancer" and "Predisposition to Colorectal Cancer." In Sleisenger & Fordtran's Gastrointestinal and Liver Disease. Edited by Mark Feldman, et al. Sixth ed. Philadelphia: W.B. Saunders Company, 1998.
Lynch, Henry and Trudy Shaw. "The Genetics of Colorectal Cancer." Primary Care & Cancer (June 1999).
Kevin Osbert Hwang, MD