Related narrative: Obstructing Colon Cancer
Colorectal cancer (CRC) is a significant public health concern in the United States and worldwide. CRC is the third most common cause of cancer death in the world accounting for 630,000 deaths annually. In the United States, CRC is the third most common cancer in both sexes and the second leading cause of cancer mortality. There are approximately 150,000 new cases diagnosed each year in the US, with nearly 60,000 deaths from the disease. Mortality related to CRC has been steadily declining at a rate of approximately 1.7% per year in the United States for the last 15 years. This decrease in mortality seems to be related to improvements in treatment and screening of CRC.
The average lifetime risk of developing CRC has been estimated at 6%. This risk increases with age; average age of diagnosis is 62-63 years-old. Other risk factors for the development of CRC include a personal history of an adenoma, previous CRC, inflammatory bowel disease, or a family history of colon cancer/polyposis syndrome. Tubular adenomas measuring 1 cm or greater, presence of high-grade dysplasia, or adenomas with greater than 25% villous component are classified as advanced adenomas and have a higher malignant potential.
Approximately 15-20% of CRCs are associated with a positive family history, defined as a first-degree relative with CRC. The most common CRC syndrome is HNPCC (see Hereditary Nonpolyposis Colorectal Cancer Syndrome, Lynch Syndrome II), accounting for approximately 4% of all CRC. Tumors in patients with HNPCC display microsatellite instability (MSI), which is the phenotypic marker of a defective mismatch repair gene. The most commonly affected mismatch repair genes are MLH1, MSH2 and MSH6, which are responsible for 80-90% of HNPCC.
Familial Polyposis Syndrome (FAP) accounts for 1% of CRC. FAP results from a mutation of the APC gene situated on chromosome 5q21. Twenty percent of these mutations occur spontaneously, while the majority are passed in an autosomal dominant fashion. Clinically FAP is characterized by the development of hundreds to thousands of polyps in the colon and rectum with a 100% lifetime risk of CRC if untreated. Polyps begin to develop in adolescence and CRC develops by age 39 in classic FAP.
Inflammatory bowel disease confers a significant risk of CRC. The risk on CRC in IBD is related to the duration, as well as the extent of disease. Previously, it was believed that the risk of CRC was greater in patients with UC rather than chronic Crohn's colitis; however Crohn's colitis carries an equivalent risk of malignancy when compared to UC. Other less common risk factors for CRC include pelvic radiation, certain breast cancers, ureterosigmoidostomy, Peutz-Jeghers syndrome, as well as other rare polyposis syndromes.
In its early stages, CRC is often silent, thus the importance of screening. The most common presenting symptoms, when present, include changes in bowel habits, abdominal pain, rectal bleeding or occult bleeding. When symptoms are present this implies a more advanced stage of disease. CRC is most commonly staged using the TNM system. This system is based on 3 descriptors of the cancer, represented by T (tumor), N (lymph nodes) and M (metastases). Based on the combination of T, N and M, tumors are classified as stage I-IV. The importance of staging the tumor is for treatment planning as well as prognosis.
The primary treatment for CRC is surgery, (see:
sigmoid resection for carcinoma
Treatment for colon cancer differs significantly from rectal cancer (see abdominoperineal resection, anterior resection of rectum.) This difference in treatment is due largely to the rectum's confined location within the pelvis. The pelvis is a relatively small, deep space limited by a bony skeleton. Wide dissections are complicated by the proximity of critical neurovascular structures, the genitourinary system, and the anal sphincter complex. In general, colon cancer resection includes the major lymph-vascular structures to the segment involved. Any adjacent organ or structure involved with the cancer is resected in continuity with the tumor in what is called an en-bloc resection. In general, 5-fluorouracil based chemotherapy is reserved for colon cancer with involved lymph nodes, i.e. stage III disease. Typically this is given post-operatively over a period of six months.
For rectal cancer, the anatomic limitations of the pelvis make oncologic resection challenging, while maintaining fecal continence and genitourinary function. Typically a rectal cancer which is staged as T3 or greater, or N1 or greater will be treated with preoperative (neoadjuvant) chemoradiation therapy followed by definitive resection. Therefore accurate preoperative staging is critical in treatment planning for rectal cancer. The goals of neoadjuvant therapy for rectal cancer are to improve local control of the disease, improve resectability in locally advanced rectal cancer, and to facilitate sphincter-preserving operations in low lying rectal cancers.
Screening can prevent CRC by detecting and removing adenomatous polyps. Also, screening can detect early asymptomatic cancers leading to early treatment and improved mortality. Screening regimens for CRC are based on a patient's risk for developing CRC. Risk stratification begins with an accurate and thorough family history. Average risk individuals, who account for 75% of CRC, should be screened beginning at age 50. There are several different screening modalities, the standard being optical colonoscopy. If an average risk patient has an optical colonoscopy without abnormalities, a repeat exam should be performed in 10 years. If an advanced adenoma or 3 or more adenomas are identified a repeat exam should be performed in 3 years. If less than three adenomas are identified a repeat colonoscopy should be performed in 5 years. For a patient with a first degree relative with an adenoma or CRC, a colonoscopy should be performed at 40 years-old or 10 years earlier than the relative, whichever is earlier.
Future research in CRC is an exciting and dynamic field. Screening methods continue to evolve as virtual colonoscopy, chromoendoscopy, and narrow band imaging become more refined. The American Gastroenterological Association published a position statement in 2006 that virtual colonoscopy is indicated as a diagnostic tool for patients who have undergone incomplete colonoscopies. This position statement is expected to include broader indications in the near future. Chromoendoscopy and narrow band imaging are two methods used to enhance the detection of small, flat, or depressed adenomas. Chromoendoscopy involves the topical application of stains/pigments to the colonic mucosa. Narrow band imagining utilizes interference filters to illuminate colonic mucosa in narrowed red, green, and blue light. Stool DNA testing may eventually negate all other screening exams, reserving colonoscopy to a strictly therapeutic modality. As our knowledge of the genetics behind CRC improves, so does our understanding of the biology. Certain genes have already been identified which may produce CRCs which are less responsive to 5-FU based therapies. This could lead to modified adjuvant therapy based on tumor genetics.
Michael P McNally, MD
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