colorectal cancer Adenocarcinoma of the colon and rectum is the third most common site of new cancer cases and deaths in men (following prostate and lung or bronchus cancer) and women (following breast and lung or bronchus cancer) in the United States The risk of colorectal cancer increases with age, with more than 90% of new cases being diagnosed in patients older than 50 years Colorectal cancer hereditary sporadic Familial Hereditary colorectal cancer family history young age at onset the presence of other tumors Sporadic colorectal cancer absence of family history affects an older population isolated colon or rectal lesion 1
Genetic mutations associated with the cancer are limited to the tumor itself, unlike in hereditary disease, in which the specific mutation is present in all cells of the affected individual Colorectal Cancer Genetics Tumor Suppressor Genes Tumor suppressor genes produce proteins that inhibit tumor formation by regulating mitotic activity and providing inhibitory cell cycle control Tumor formation occurs when these inhibitory controls are deregulated by mutation Both alleles of the gene must be nonfunctional to initiate tumor formation 2
The APC gene is a tumor suppressor gene located on chromosome 5q21 A germline APC truncation mutation is responsible for the autosomal dominant inherited disease FAP Thirty percent of cases of FAP are de novo germline mutations, presenting without a family history of the disease FAP more than 100 adenomatous polyps present in the colon and rectum. These polyps often number in the thousands and are almost always manifested by the late second or early third decade of life Most patients with FAP die of colon cancer by their fifth decade of life in the absence of surgical intervention APC truncation mutations similar to those found in APC patients occur in 85% of sporadic colorectal cancers 3
extraintestinal manifestations osteomas of the mandible and skull desmoid tumors of the mesentery periampullary neoplasms Mismatch Repair Genes MMR genes are called caretaker genes because of their important role in policing the integrity of the genome and correcting DNA replication errors 3% of colorectal cancers in the United States are caused by HNPCC Mutations in MMR genes produce microsatellite instability Microsatellites are repetitive sequences of DNA that appear to be randomly distributed throughout the genome. Stability of these sequences is a good measure of the general integrity of the genome 4
Oncogenes Proto-oncogenes are genes that produce proteins that promote cellular growth and proliferation. Mutations in proto-oncogenes typically produce a gain of function and can be caused by mutation in only one of the two alleles Adenoma-Carcinoma Sequence The adenoma-carcinoma sequence is the process through which most colorectal carcinomas develop colorectal carcinomas evolve through a progression of benign polyps to invasive carcinoma Colorectal Polyps 5
A colorectal polyp is any mass projecting into the lumen of the bowel above the surface of the intestinal epithelium Polyps gross appearance pedunculated (with a stalk) sessile (flat, without a stalk) histologic appearance (a)tubular adenoma (with branched tubular glands) (b)villous adenoma (with long finger-like projections of the surface epithelium) (c)tubulovillous adenoma (with elements of both cellular patterns) degree of cellular atypia less atypia in tubular adenomas severe atypia or dysplasia (precancerous cellular change) found more often in villous adenomas 6
The incidence of invasive carcinoma being found in a polyp is dependent on the size and histologic type of the polyp there is less than a 5% incidence of carcinoma in an adenomatous polyp smaller than 1 cm in diameter, whereas there is a 50% chance that a villous adenoma larger than 2 cm in diameter will contain a cancer Adenomatous polyps should be considered precursors of cancer The treatment of an adenomatous or villous polyp is removal, usually by colonoscopy sessile (flat) polyps The presence of any polypoid lesion is an indication for a complete colonoscopy and polypectomy present technical problem because of the danger of perforation associated with the snare technique 7
sessile lesions that are large or have a central depression or cannot be "lifted" with saline may be perforation risks and should be surgically excised by segmental colectomy for complete removal and lymph node examination malignant polyp Invasive carcinoma describes the situation in which malignant cells have extended through the muscularis mucosae of the polyp, whether it is on a stalk or a sessile lesion If invasive carcinoma penetrates the muscularis mucosae, the risk for lymph node metastasis and local recurrence must be considered to determine whether a more extensive resection is required complete excision need for surgery no piecemeal lymphovascular invasion differentiation depth 8
There is a high risk for lymph node and distant metastases associated with sessile cancers in the rectum, and these lesions should be treated aggressively Familial Adenomatous Polyposis the gene responsible for the transmission of the disease, the APC gene The gene is expressed in 100% of patients with the mutation. Autosomal dominance results in expression in 50% of offspring There is a negative family history in 10% to 20% of affected individuals, who apparently acquire the syndrome as the result of a spontaneous germline mutation the common expression of the syndrome 9
invariable presence of multiple colonic polyps; frequent occurrence of gastric, duodenal, and periampullary polyps; and occasional association of extraintestinal manifestations, including epidermoid cysts, desmoid tumors in the abdomen, osteomas, and brain tumors gastric and duodenal polyps occur in approximately 50% of affected individuals duodenal polyps are adenomatous gastric polyps represent fundic gland hyperplasia, rather than adenomatous polyps, and have limited malignant potential in nature and should be considered premalignant. Patients with FAP have an increased risk for ampullary cancer all patients with the defective gene will develop cancer of the colon if left untreated age when things happen 10
The average age at discovery of a new patient with FAP is 29 years. The average age of a patient who is newly discovered to have colorectal cancer related to FAP is 39 years. Osteomas visible and palpable prominences in the skull, mandible, and tibia of individuals with FAP. They are almost always benign Radiographs of the maxilla and mandible may reveal bone cysts, supernumerary and impacted molars, or congenitally absent teeth Desmoid tumors can present in the retroperitoneum and abdominal wall of affected patients, usually after surgery these tumors seldom metastasize but are often locally invasive; direct invasion of the mesenteric vessels, ureters, or walls of the small intestine can result in death 11
surgical treatment Surgical treatment of patients with FAP is directed at removal of all affected colonic and rectal mucosa Restorative proctocolectomy with IPAA has become the most commonly recommended operation the IPAA is fashioned between the ileal pouch and dentate line of the anal canal IPAA is done for two diseases FAP UC Patients who undergo this procedure for FAP have a better functional result than patients similarly treated for ulcerative colitis 12
The incidence of inflammation in the ileal pouch (pouchitis) is much lower in patients with FAP than in patients with ulcerative colitis an alternative approach total abdominal colectomy with ileorectal anastomosis, If an FAP patient has relatively few polyps in the rectum, consideration may be given to this option certain advantages It is technically a simpler operation to perform, and the pelvic dissection is avoided This eliminates the potential complication of injury to the autonomic nerves that could result in impotence 13
sulindac and celecoxib have caused the regression of adenomatous polyps in some the disadvantages patients with FAP the rectum remains at high risk for the formation of new precancerous polyps proctoscopic examination is required every 6 to 12 months to detect and to destroy any new polyps, and there is a definite increased risk for cancer arising in the rectum with the passage of time genetic testing may help make the decision between restorative proctocolectomy with IPAA and abdominal colectomy with ileorectal anastomosis the risk for rectal cancer is almost three times higher in FAP patients with a mutation after codon 1250 than in patients with mutations before this codon. This may influence the decision to offer abdominal colectomy with ileorectal anastomosis to those whose mutation occurs proximal to codon 1250 if proctoscopic examination reveals no or few polyps in the rectum 14
what should you tell the patient who chooses total coloectomy Patients who choos abdominal colectomy with ileorectal anastomosis should Realize that the risk for development of rectal cancer is real (25% at 20 years after the operation) approximately one third of patients treated by abdominal colectomy and ileorectal anastomosis develop florid polyposis of the rectum that will require proctectomy (and ileostomy or IPAA) within 20 years Polyps of the stomach and duodenum The gastric polyps are usually hyperplastic and do not require surgical removal the duodenal and ampullary polyps are generally neoplastic and require attention 15
surveillance program is for upper GI surveillance every 2 years after the age of 30 years and endoscopic polypectomy, if possible, to remove all large adenomas from the duodenum If an ampullary cancer is discovered at an early stage, pancreatoduodenectomy is indicated The abdominal desmoid tumor an especially vexing and difficult extraintestinal manifestation of FAP After surgical procedures, dense fibrous tissue forms in the mesentery of the small intestine or within the abdominal wall in some patients with FAP If the mesentery is involved, the intestine can be tethered or invaded directly by the tumor 16
The locally invasive tumor can also encroach on the vascular supply to the intestine Small desmoid tumors confined to the abdominal wall are appropriately treated by resection the surgical treatment of mesenteric desmoids is dangerous and generally futile sporadic reports of regression of desmoid tumors after treatment with sulindac, tamoxifen, low-dose methotrexate, radiation, chemotherapy The initial treatment is usually with sulindac or tamoxifen 17