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While most elaborate some amount of intra- and extracellular mucin, occasional tumors produce abundant pools of extravasated mucin, meriting the separate designation of mucinous carcinomas.The remaining 5% of tumors include tumors arising from the colorectal neuroendocrine cells (carcinoids and small cell carcinomas), stromal tumors and malignant lymphomas. In light of better screening programs, earlier detection rates and improved treatment protocols, the rate of CRC-related deaths has progressively declined over the last 20 years.
Approximately 10% of CRCs have an associated familial or genetic predispostion, and these "hereditary CRCs" arise by one of two major pathways: the polyposis and the non-polyposis syndromes. The polyposis syndromes, the best-studied example of which is familial adenomatous polyposis, are characterized by germline mutations in tumor suppressor genes (such as APC) that result in the development of precancerous outgrowths of the colorectal mucosa known as adenomatous polyps. On the fertile soil of these adenomatous polyps, additional mutations and genetic aberrations accumulate in a multistep process, culminating in the development of CRCs. Patients with familial polyposis syndromes will virtually inevitably develop CRCs, and are candidates for prophylactic colectomy. The second pathway, epitomized by hereditary non-polyposis colorectal carcinoma (HNPCC or Lynch sydrome), results from mutations in genes involved in DNA damage repair (hMSH2, hMLH1); errors acquired during DNA replication accumulate (microsatellite instability), causing abnormal cell growth and tumor development. As the name suggests, HNPCC is characterized by the absence of adenomatous polyps that predate polyposis-associated CRCs.
Studies have convincingly shown that the vast majority of sporadic CRCs also arise on a background of adenomatous polyps, by progressive accumulation of genetic abnormalities. These molecular changes are non-random, and usually follow a sequence, such that inactivation of the APC gene and activating mutations of the K-ras oncogene are two of the earliest changes, while inactivation of the p53 tumor suppressor gene is a late event. The risk of neoplastic transformation is also related to certain pathologic features of the polyp itself, such that polyps greater than 2 cm have a significant chance (~10%) of harboring an occult carcinoma; similarly villous (papillary) adenomas have a three times greater risk of neoplastic transformation compared with tubular adenomas.
The single most important factor influencing prognosis in colon cancer is stage, determined by tumor size, regional lymph node status and distant metastasis. The 5-year relative survival for patients with localized CRCs is 90%, but this drops to 65% for patients whose malignancies have spread beyond the confines of the colon to loco-regional nodes and to a dismal 8% for patients with distant metastases such as to the liver or lungs. Additionally, several adjunct prognostic factors have been identified in CRCs, including: aneuploid DNA content, loss of DCC protein expression, loss of cyclin dependent kinase inhibitors p21WAF1 and p27KIP1 expression, nuclear accumulation of abnormal p53 protein, amplification of c-erbB-2 oncogene, and presence of various metalloproteinases, which have been shown to be associated with more aggressive disease, presence of metastases and shorter survival. High intensity expression of thymidylate sythase ia associated with a poor prognosis and is a marker of resistance to 5-FU related cytotoxic agents. |
