1. General Background Colorectal cancer (CRC) is a major health problem affecting both developed and undeveloped countries.

Approximately 1 million new cancers occur worldwide and CRC remains in the top three of all cancer deaths(1). By location, two-thirds of the colorectal cancer cases occur in the colon and one-third in the rectum (2). The incidence in Africa is low, but unfortunately so is survival, mostly due to late presentation(3). Prevalence is more difficult to estimate in underdeveloped countries due to lack of a cancer registry in these countries. Some, like Zambia, are trying to establish such a registry at the current time. In both developed and under-developed countries CRC is of public and political concern. The aim of this review is to discuss important issues surrounding rectal cancer, including its surgical and medical management. For a comprehensive review on colon cancer, please see our published review on that topic http://www.ptolemy.ca/members/current/ColonC/ . 2. General Anatomy The rectum is a continuation of the colon preceded by the sigmoid colon and terminating in the anal canal. It has two major curves, one at the proximal end and one at the distal end, bending backward and forward respectively. It extends about 2-3cm below the coccyx before it ends at the anal canal above the dentate line. The total length of the rectum is about 12-15 cm and the diameter is similar to that of the sigmoid. The rectum is not covered by taenia coli, in contrast to the sigmoid colon. There are 3-4 transverse folds, known as the valves of Houston, which consist of circular muscle fibers and have a role in retaining fecal matter in the rectum. Peritoneum covers the upper one third of the rectum, while the remaining portion remains extraperitoneal. The anterior peritoneal space is also called the pouch of Douglas and is a well known area of metastatic disease (Bloomer's shelf). The arteries that supply the rectum include the superior, middle and inferior hemorrhoidal arteries which are branches from the inferior mesenteric, hypogastric and internal pudendal arteries, respectively. The superiorhemorrhoidal artery divides into two branches that run down the lateral aspect before entering the rectum and supply up to the point of the internal sphincter where they anastomose with the middle and inferior hemorrhoidalarteries. The veins start off as the hemorrhoidal plexus and form trunks that run parallel to the arteries. Veins include the superior, middle and inferior hemorrhoidal veins with the anal canal being drained by the middle and inferior veins. The superior hemorrhoidal drains into the inferior mesenteric vein and the middle and inferior vein drain into the hypogastric vein that drains directly into the inferior vena cava. This difference in drainage accounts for differences in metastatic patterns, mainly portal versus systemic, respectively. Lymphatics lie within the mesorectum. Proximal rectum lymphatic drainage is mostly through the Para-aortic nodes, while the distal rectum drains through the Para-aortic and the internal iliac system that ends up in the superficial inguinal region. Innervation is both from sympathetic and parasympathetic nerves. Postganglionic sympathetic fibers come from the pelvic plexus (T12-L3) that is adherent to the pelvic sidewalls and lateral stalks. It receives its branches from the presacral plexus, which condenses into the left and

right hypogastric nerves. Failure to preserve at least one of these nerves during dissection results in ejaculatory retrograde dysfunction in men. The pelvic parasympathetic nerves arise from S2 to S4 and through the pelvic plexus innervate the prostate, urethra and urinary bladder. Disruption of these can result in bladder and sexual erectile dysfunction which have been reported in up to 40% of malignant resection cases. The main function of the rectum is to retain fecal matter. When stool enters the rectum the anorectal inhibitory reflex is triggered resulting in voluntary contraction of the external sphincter. It also triggers the rectocolic reflex allowing relaxation of the rectum and subsequent filling of the rectum. Muscles aiding in continence usually extend just proximal to the dentate line. For anatomy of the anal canal, please see our review on common anorectaldisorders http://www.ptolemy.ca/members/current/anorectal/ . 3. Epidemiology/Etiology Both the epidemiology and etiology of colorectal cancer are discussed in detail in our review on colon cancer. As such only a general overview is given here. In the United States each year about 42,000 individuals are diagnosed with rectal cancer, and 8,500 die of this disease (4). As with colon cancer, Western nations tend to have a higher incidence than Asian and African countries and incidence peaks in the sixth and seventh decades.In spite of the low incidence of cancer in Africa, survival rates are very low, not exceeding 55% at 5 years in Zimbabwe. This has been explained by poor distribution of resources among other reasons (3,5). These figures are expected to worsen in the future due to increased urbanization, adoption of the Western diet and relatively poor funding for cancer-related conditions in Africa. Etiology is again similar to colon cancer and is multifactorial in origin. It includes environmental factors, such as diet, and a large genetic component. In the West about two thirds of cases are sporadic and develop in people with no specific risk factors; while the other one-third occur in people with either a positive family history or a personal history of colorectal cancer or polyps. A smaller percentage occur in people with genetic predispositions, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP). 4. Relevant Pathophysiology As with colon cancer over 70% of rectal cancers, regardless of etiology, arise from adenomatous polyps. The adenoma-carcinoma sequence discussed in the colon review takes place over 7 to 15 years. Since 1932, when Sir Cuthbert Dukes described his staging system, many advances have been made especially in the genetic and molecular fields. Mutations discovered since then include point mutations in the K-ras protooncogene;hypomethylation of DNA, leading to gene activation; loss of tumor-suppressor gene (the adenomatous polyposis coli (APC) gene on 5q21 and colorectal cancer (DCC) gene on 18q) and mutations in the p53 tumor-suppressor gene (6). These alterations then result in mucosal proliferation forming a polyp and finally carcinoma. Distinct mutations associated with familial colorectal cancer-associated syndromes include APC for FAP, MLH1, MSH2, MSH6, and PMS mutations for HNPCC.

Molecular pathology can also help predict the response of a tumor to therapy. The presence of p53 has been associated with an increased likelihood of resistance to radiotherapy, while expression of p21 gene makes it more sensitive (7). Likewise, increased thymidylate synthase activity increases resistance to 5-FU, while microinstability increases sensitivity (8). Invasiveness is a very important indicator of prognosis, defined as extension of malignant cells through the muscularis mucosa. Haggitt and colleagues proposed a classification system according to the depth of invasion forpedunculated polyps: Level 0 (no invasion of muscularis mucosa), Level 1 (invasion through muscularis mucosa limited to head of polyp), Level 2 (invasion through muscularis mucosa limited to neck of polyp), Level 3 (invasion through muscularis mucosa in any part of the stalk), and Level 4 (invasion into the submucosa of the native bowel wall below the polyp). These levels correlate with degree of lymph node metastases with level 0-3 being associated with less than 5% risk and level 4 has a 10-25% risk of associated metastases. Pathologists use the classification systems of Dukes or TNM classification (37). The TMN system is similar to that for colon cancer. (See Tables 1 & 2) With rectal cancer there may be early lymphatic spread into the nodes of the mesorectal fascia or hematogenous spread, mainly to the liver or lungs.

Pathophysiology
The mucosa in the large intestine regenerates approximately every 6 days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation and maturation, and ultimately lose the ability to replicate. The significant portions of colorectal carcinomas are adenocarcinomas. The adenoma-carcinoma sequence is well described in the medical literature.[2, 5]Colonic adenomas precede adenocarcinomas. Approximately 10% of adenomas will eventually develop into adenocarcinomas. This process may take up to 10 years.[2] Three pathways to colon and rectal carcinoma have been described: the adenomatous polyposis coli (APC) gene adenoma-carcinoma pathway the hereditary nonpolyposis colorectal cancer (HNPCC) pathway ulcerative colitis dysplasia. The APC adenoma carcinoma pathway involves several genetic mutations, starting with inactivation of the APC gene, which allows unchecked cellular replication at the crypt surface. With the increase in cell division, further mutations occur, resulting in activation of the K-ras oncogene in the early stages and p53 mutations in later stages. These cumulative losses in tumor suppressor gene function prevent apoptosis and prolong the cell's lifespan indefinitely. If the APC mutation is inherited, it will result in familial adenomatous polyposis syndrome. Histologically, adenomas are classified in three groups: tubular, tubulovillous, and villous adenomas. Kras mutations and microsatellite instability have been identified in hyperplastic polyps. Therefore, hyperplastic polyps may also have malignant potential in varying degrees. [6] The other common carcinogenic pathway involves mutation in DNA mismatch repair genes. Many of these mismatched repair genes have been identified, including hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6. Mutation in mismatched repair genes negatively affects the DNA repair. This replication error is found in approximately 90% of HNPCC and 15% of sporadic colon and rectal cancers.[2, 7]A separate carcinogenic pathway is also described in inflammatory bowel disease (IBD).

Chronic inflammation such as in ulcerative colitis can result in genetic alterations which then lead into dysplasia and carcinoma formation.