Chapter 087. Gastrointestinal Tract Cancer (Part 6) ppsx

Chapter 087. Gastrointestinal Tract Cancer (Part 6) Gastric (Nonlymphoid) Sarcoma Leiomyosarcomas and GISTs make up 1–3% of gastric neoplasms. They most frequently involve the anterior and posterior walls of the gastric fundus and often ulcerate and bleed. Even those lesions that appear benign on histologic examination may behave in a malignant fashion. These tumors rarely invade adjacent viscera and characteristically do not metastasize to lymph nodes, but they may spread to the liver and lungs. The treatment of choice is surgical resection. Combination chemotherapy should be reserved for patients with metastatic disease. All such tumors should be analyzed for a mutation in the c-kit receptor. GISTs are unresponsive to conventional chemotherapy; ~50% of patients experience objective response and prolonged survival when treated with imatinib mesylate (Gleevec) (400–800 mg PO daily), a selective inhibitor of the c-kit tyrosine kinase. Many patients with GIST whose tumors have become refractory to imatinib subsequently benefit from sunitinib (Sutent), another inhibitor of the c- kit tyrosine kinase. Colorectal Cancer Incidence Cancer of the large bowel is second only to lung cancer as a cause of cancer death in the United States: 153,760 new cases occurred in 2007, and 52,180 deaths were due to colorectal cancer. The incidence rate has remained relatively unchanged during the past 30 years, while the mortality rate has decreased, particularly in females. Colorectal cancer generally occurs in persons ≥50 years. Polyps and Molecular Pathogenesis Most colorectal cancers, regardless of etiology, arise from adenomatous polyps. A polyp is a grossly visible protrusion from the mucosal surface and may be classified pathologically as a nonneoplastic hamartoma (juvenile polyp), a hyperplastic mucosal proliferation (hyperplastic polyp), or an adenomatous polyp. Only adenomas are clearly premalignant, and only a minority of such lesions becomes cancer. Adenomatous polyps may be found in the colons of ~30% of middle-aged and ~50% of elderly people; however, <1% of polyps ever become malignant. Most polyps produce no symptoms and remain clinically undetected. Occult blood in the stool is found in <5% of patients with polyps. A number of molecular changes are noted in adenomatous polyps, dysplastic lesions, and polyps containing microscopic foci of tumor cells (carcinoma in situ), which are thought to reflect a multistep process in the evolution of normal colonic mucosa to life-threatening invasive carcinoma. These developmental steps toward carcinogenesis include, but are not restricted to, point mutations in the K-ras protooncogene; hypomethylation of DNA, leading to gene activation; loss of DNA (allelic loss) at the site of a tumor-suppressor gene [the adenomatous polyposis coli (APC) gene] on the long arm of chromosome 5 (5q21); allelic loss at the site of a tumor-suppressor gene located on chromosome 18q [the deleted in colorectal cancer (DCC) gene]; and allelic loss at chromosome 17p, associated with mutations in the p53 tumor-suppressor gene (see Fig. 79-2). Thus, the altered proliferative pattern of the colonic mucosa, which results in progression to a polyp and then to carcinoma, may involve the mutational activation of an oncogene followed by and coupled with the loss of genes that normally suppress tumorigenesis. It remains uncertain whether the genetic aberrations always occur in a defined order. Based on this model, however, cancer is believed to develop only in those polyps in which most (if not all) of these mutational events take place. Clinically, the probability of an adenomatous polyp becoming a cancer depends on the gross appearance of the lesion, its histologic features, and its size. Adenomatous polyps may be pedunculated (stalked) or sessile (flat-based). Cancers develop more frequently in sessile polyps. Histologically, adenomatous polyps may be tubular, villous (i.e., papillary), or tubulovillous. Villous adenomas, most of which are sessile, become malignant more than three times as often as tubular adenomas. The likelihood that any polypoid lesion in the large bowel contains invasive cancer is related to the size of the polyp, being negligible (<2%) in lesions <1.5 cm, intermediate (2–10%) in lesions 1.5–2.5 cm in size, and substantial (10%) in lesions >2.5 cm. Following the detection of an adenomatous polyp, the entire large bowel should be visualized endoscopically or radiographically, since synchronous lesions are noted in about one-third of cases. Colonoscopy should then be repeated periodically, even in the absence of a previously documented malignancy, since such patients have a 30–50% probability of developing another adenoma and are at a higher-than-average risk for developing a colorectal carcinoma. Adenomatous polyps are thought to require >5 years of growth before becoming clinically significant; colonoscopy need not be carried out more frequently than every 3 years. . Chapter 087. Gastrointestinal Tract Cancer (Part 6) Gastric (Nonlymphoid) Sarcoma Leiomyosarcomas and GISTs make up. inhibitor of the c- kit tyrosine kinase. Colorectal Cancer Incidence Cancer of the large bowel is second only to lung cancer as a cause of cancer death in the United States: 153,760 new cases. to colorectal cancer. The incidence rate has remained relatively unchanged during the past 30 years, while the mortality rate has decreased, particularly in females. Colorectal cancer generally