The Global population is now 6,1 billion people. Every year 133 million people are born and 52 million people die. Average life expectancy is 65 years. 12% (6,3 million) die from Cancers every year which is the 3:rd most common cause of death after 1 Infectious & Parasitic diseases from which 33% (17,3 million) die, and 2Diseases of the Circulatory System from which 29% (15,3 million) die every year. Number 4 is Perinatal & Maternal diseases 8% (4,3 million), 5 Diseases of the Respiratory System 6% (2,9 million), and 6 Other & Unknown causes 12% (5,9 million) .

There are big differences in what people die from in the Developed and Developing world. Infectious & Parasitic diseases account for only 1% of all deaths in the Developed world but account for 43% of all deaths in the Developing world. Cancers account for 21% of all deaths in the Developed world and 9% of all deaths in the Developing world.

Worldwide about 8 million people get cancers every year. About 876 000 people get Colorectal Cancer every year, which makes it the 3:rd most common type of cancer to strike people worldwide every year after 1 Lung Cancer (1 321 000), and 2 Stomach Cancer (1 013 000). Number 4 is Breast Cancer (910 000) , 5Mouth & Pharynx Cancer (576 000), and 6 Cervix Cancer (524 000).

Worldwide about 6,3 million people die from cancers every year. About 525 000 people die from Colorectal Cancer every year, which makes it the 3:rd most common cause of cancer death worldwide after 1 Lung Cancer (1 100 000), and 2 Stomach Cancer (765 000). Number 4 is Liver Cancer (505 000), and 5 Breast cancer (385 000).

As just mentioned there are about 876 000  new cases of Colorectal Cancer worldwide every year out of a population of 6,1 billion people. This means that about 15 people out of every 100 000 people come down with Colorectal Cancer every year. This is called the Incidence Rate. The Incidence Rate differs considerably for Colorectal Cancer between different countries. It's highest in the more Industrialized Countries of North America, Northern and Western Europe and New Zeeland where it's about 50 and lowest in Asia and Africa with Incidence Rates down to 1. The Incidence Rate for Colorectal Cancer is, as with many malignancies, extremely low in childhood but increases dramatically with age. For persons aged 50 in the U.S. the Incidence Rate is about 50 but for persons 75-79 it's about 400.

The United States population is now 283 million people. Every year 3,9 million people are born and 2,3 million people die. Average life expectancy is 76,1 years (Males 73,0 and Females 79.0). 24 % (539 000) die from Cancers every year which is the 2:nd most common cause of death after 1 Heart Disease from which 32% (733 000) die every year. Number 3 is Stroke (160 000), 4 Chronic Pulmonary Disease (106 000), 5 Accidents (95 000), 6 Pneumonia/Influenza (84 000), 7 Diabetes (62 000), 8 HIV/AIDS (31 000), 9 Suicide (31 000), 10 Chronic Liver Disease and Cirrhosis (25 000).

In the U.S. about 1,2 million people get cancers every year. About 132 000 people get Colorectal Cancer (96 000 Colon and 36 000 Rectum) every year, which makes it the 4:th most common cancer to strike people in the U.S. every year after 1 Prostate Cancer (184 000) , 2 Breast Cancer (180 000) and 3 Lung Cancer (171 000). Number 5 is Lymphomas (62 000) and 6 Urinary Bladder Cancer (54 000).

In the U.S. about 539 000 people die from cancers every year. About 56 500 people die from Colorectal Cancer every year (47 700 Colon and 8 800 Rectum) which makes it the 2:nd most common cause of cancer death in the U.S. every year after 1 Lung Cancer (160 000 people). Number 3 is Breast Cancer (44 000), 4Prostate Cancer (39 000), 5 Pancreatic Cancer (29 000), 6 Lymphomas (26 000).

Colorectal cancer represents about 11% of all cancers diagnosed every year and about 10% of all cancer deaths every year in the U.S. The lifetime risk of developing Colorectal Cancer in the U.S. is about 6% and the lifetime risk of dying from Colorectal Cancer about 3%. The mean age at presentation is about 70 for men and 73 for women. The overall incidence rate is 49/100 000 (Colon 36 and Rectum 13). White men (52/100 000), Black men (59/100 000), White women (36/100 000), Black women (46/100 000).

The worldwide incidence of Colorectal Cancer has been slowly rising during the last decades. The rise in incidence does not seem to be an effect of an ageing population as the rise is across the age bands. A sharp rise has been seen in Eastern Europe and Japan. This is compared to virtually no change in the U.S. The dramatic rise in incidence in some countries over a short period of time points to environmental rather than hereditary factors.

The basic unit of life is the Cell. The cell's nucleus contains the Chromosomes which are made up of DNA. The DNA double helixes code for the information stored in the cell. The DNA on the chromosomes are divided into functional units called Genes.  The fertilized egg, the Zygote contains 46 chromosomes and is formed by a unification of the spermatozoo with 23 chromosomes from the male, and the oocyte with 23 chromosomes from the woman. The zygote represents the formation of a new organism and is the one cell we all started our lives as. The Zygote divides into the trillions of cells that our bodies consist of. The cells divide and differentiate into the different tissues and organs that our bodies consist of, and form them at the right place and in the right amount. This is done through a very delicate mechanism that we know very little about. Every time the cell divides the chromosomes are duplicated into to the new cell. When a cancer cell is formed it is generally believed that it starts in one single cell that transforms into a cancer cell by changes in its DNA, or with other words - Mutations - changes  in the genes, the information code. This means that cancer is a Genetic Disorder. Usually mutations (changes) of more than one gene is necessary for the formation of a normal cell into a cancer cell. This may happen by influence of environmental factors or may just be mistakes done by the cell when it divides. It may happen in several different steps over a long time. Mutations may be inherited leading to an inherited susceptibility to form cancers. Mutations are believed to happen all the time but the cell has repair mechanisms  and only certain deletarian gene mutations i.e. mutations - alterations in Oncogens and Tumor Suppressor genes lead to cancer cell formation. This makes the cell lose its normal control and start to divide in an uncontrolled manner. It will also look different in terms of shape, size and its internal components. The transformed properties are transferred upon all of the daughter cells. The cancer cells have properties of endless replication, loss of contact inhibition, invasiveness and the ability to metastasize. When the cancer cell and the daughter cells have divided 30 times, the new growth, the Neoplasia consists of 1 billion cells but weighs only 1 gram and is for the first time possible to detect through examinations like X-Rays or Colonoscopy.

The word Cancer is a popular term for a Malignant Neoplasm. Cancers arising in Epithelial cells, which are the cells that outline the hollow organs, are called Carcinomas. Cancers arising in the Mesenchymal  tissues, (Non-Epithelial cells) are called Sarcomas. Carcinomas are further divided into Adenocarcinomas when they have a glandular growth pattern and Squamous Cell Carcinomas when they produce recognizable squamous cells. It's further practice to specify the organ of origin when possible e.g. Bronchogenic Squamous Cell Carcinoma or Colorectal Adenocarcinoma. Sometimes the cancer is composed of very primitive undifferentiated cells and must be designated merely as a poorly differentiated or undifferentiated malignant tumor or when possible undifferentiated carcinoma or undifferentiated sarcoma.

Colorectal Cancer arises in the Epithelial cells outlining the lumen of the Colon and Rectum (a Simple Glandular Columnar Epithelium). The cancer is thus called a Colorectal Adenocarcinoma. This is what we mean when we talk about Colorectal Cancer! There are other forms of Colorectal Cancer like Squamous Cell Carcinoma, Sarcoma, Lymphoma and Carcinoid Tumors but they are very rare and altogether constitue less than 2% of all Colorectal Cancer. They are often not treated the same way as Adenocarcinoma.

It's generally believed that the transformation of the normal epithelial cell into a cancer cell is a multistage process that starts with specific genetic alterations (mutations) on specific chromosomes with stepwise accumulation of multiple genetic defects. There may be as many as 20 genes involved in colorectal carcinogenesis. The most well defined genetic mutations include these in the APC gene on chromosome 5, K-ras on chromosome 12, DCC on chromosome 18, p53 on chromosome 17, hMSH2 on chromosome 2, and hMLH1 on chromosome 3. Mutations of the APC tumor suppressor gene has been documented in more than 80% of sporadic Colorectal Cancer and early adenomas, suggesting that an APC gene mutation may be an early or initiating event in the Colorectal Cancer tumorigenesis. In this way first an aberrant crypt foci is formed. Additional genetic events involve the formation of a very small polyp (adenoma) which later turns into a cancer as a result from accumulation of these distinct genetic alterations. The process is one of a progression from an early to an intermediate, then late phase adenoma, and ultimately in situ transformation to an invasive carcinoma. This requires multiple genetic alterations with formation of oncogenes and inactivation of tumor suppressor genes. Each of these subsequent mutational events provide a growth advantage for a single cell over the other tumor cells in the developing tumor resulting in stepwise clonal expansion and tumor progression.

The Colon & Rectum or Large Bowel is a storage and absorptive organ. It starts in the right lower abdominal fossa where the Small Intestine enters through the Ileocecal Valve. This part is called the Cecum. The Appendix is attached to the lower part of the Cecum. The next part is called the Ascending Colon which runs up to the Hepatic Flexure also called the Right Flexure situated just under the Liver in the right upper abdominal quadrant. The Transverse Colon runs transversely across the abdomen to the Splenic Flexure also called the Left Flexure lying just below the Spleen in the left upper abdominal quadrant. Colon then runs downwards and is called the Descending Colon down to the left lower abdominal quadrant where it makes an S-shaped loop which is called the Sigmoid Colon. The Sigmoid Colon then runs down into the Pelvis and is called the Rectum. The junction between the the Sigmoid Colon and the Rectum is called the Rectosigmoid Junction. Rectum is about 5 inches or 13 cm long and its upper limit is where the Sigmoid Colon loses its Mesentery  which usually happens in front of the third Sacral Vertebra. Rectum then goes over into the Anal Canal which ends with the Anus. The Anal Canal is about 1* inches or 4 cm long. The Colon together with Rectum is about 5 feet or 150 cm long.

Adenocarcinoma situated from the Anus and with a lower border at the upper limit of the Rectum is by most standards referred to as Rectal Cancer. Squamous Cell Carcinoma in the Anal Canal is referred to as Anal Cancer. Anal Cancer is not treated the same way as Rectal Cancer. Rectal Cancer is by most standards considered to include tumors from 0 cm from the Anus (The Anal Verge) up to tumors with their lower border within 15 centimeters from the Anal Verge. This may differ from different clinics and there are many examples where tumors even at 25 cm from the anus have been classified as Rectal Cancers. This may have an implication when Rectal Cancer materials from different clinics are compared.

It's also important to know the different layers of the colorectal wall. As in other parts of the Gastrointestinal Tract the wall is made up of four layers - the Mucosa, the Submucosa, the Muscularis Propria and the Serosa. The Mucosa is closest to the lumen and consists of, starting from the lumen - the Epithelium (simple columnar), Lamina Propria and Muscularis Mucosae. Under the Mucosa comes the Submucosa. Then comes the Muscularis propria. Then comes the Serosa which is the external coat consisting of a layer of Mesothelial cells resting on loose connective tissue outside the Muscular layer. The lower part of the Rectum lacks the Serosa as it goes down and leaves the Peritoneal cavity. This happens at about 10 cm from the Anal Verge. At 2 cm from the Anal Verge there is an abrupt transition from the Simple Columnar Epithelium to a Stratified Squamous Epithelium. This is the Transition Zone between mucosa and skin also called the Dentate Line.

The Staging of Colorectal Cancer relates to the degree of penetration of the tumor through the bowel wall. The prognosis of Colorectal Cancer is also clearly related to the degree of penetration of the tumor through the bowel wall. The difference between an adenoma which is a benign polyp and a cancer also relates to the penetration of the wall. The cells may look exactly the same under the microscope but as long as the cells do not penetrate the Muscularis Mucosae down into the Submucosa it's not an invasive cancer and cannot metastasize, but when they penetrate the Muscularis Mucosae the tumor is a cancer.

As just stated the prognosis of Colorectal Cancer is better for smaller tumors. If the tumor is very small the cure rate is virtually 100%. The problem though is that the tumors often don't give any symptoms at all until they are quite large, sometimes not until they have metastasized. There is also often a delay between the start of symptoms and until the cancer is found. The patient doesn't go to a doctor or he goes to a doctor but proper examinations are not performed. It's very common that rectal bleeding is blamed on simple hemorrhoids when the real reason is a rectal cancer. It cannot be overemphasized that all symptoms should be a signal to make a doctor's appointment and proper examinations be installed without delay. The best would of course be to screen and find the tumors before they give any symptoms at all. The most common symptoms are Rectal Bleeding - red blood that you can detect with your eyes (gross or macroscopic), or what is called occult or microscopic that you cannot see, which usually results in Anemia. Change Of Bowel Habits, any change including Constipation or Diarrhea, Abdominal Pain or discomfort, Decreased Stool Diameter, Rectal Urgency, Tenesmus, Weight Loss.

The patient's Medical History is taken including past medical history, family history especially presence of malignant disease, history of present illness, onset, symptoms etc. Then a Physical Examination is performed that for symptoms stated above should include an Abdominal Examination, a Digital Rectal Exam and a Rigid Sigmoidoscopy. The doctor then may want to order examinations like Blood Samples, FOBT (Fecal Occult Blood Test), Colonoscopy, Barium Enema etc. Colonoscopy is a very effective way to visualize the entire Colon and Rectum. It requires the large bowel to be cleansed which usually is done by drinking a special bowel cleansing prep the day before the exam. During the colonoscopy the bowel can be examined, polyps can be removed, tumors that require surgery can be found and biopsies can be taken etc. In the U.S. more than 2 million colonoscopies are performed every year. If a Colorectal Cancer is found a Biopsy is generally taken to reveal the histology. Blood samples and a Chest X-ray is also ordered. An Ultrasound of the liver may also be done. If the cancer is very large, especially if it's a rectal cancer, Magnetic Resonance Imaging, Computer Tomography and or Transrectal Ultrasound may be wanted to see if the tumor invades adjacent structures which may require preop radiotherapy in order to have a possibility to curatively remove the cancer, or if it's a very small cancer that may be possible to remove by local excision.

The stage of the tumor is not finally revealed until after the operation when the removed specimen has been analyzed by the pathologist. The characteristics that form the basis of the staging system is 1: The degree of penetration of the tumor through the bowel wall, 2: Presence or absence of lymph node involvment, 3: Presence or absence of distant metastases. There are three widely used Staging Classifications. TNM is the most modern and should preferably be used today.

Duke's: A: Tumor does not grow beyond muscularis propria, B: Tumor grows beyond muscularis propria, C: Lymph node metastases with the tumor, D: Distant metastases (Added by Turnbull).

Astler-Coller: A: Tumor limited to mucosa -ca in situ, B1: Tumor grows through muscularis mucosae but not through muscularis propria, B2: Tumor grows beyond muscularis propria, C1: Stage B1 with regional lymph node metastases, C2: Stage B2 with regional lymph node metastases, D: Distant metastases.

Stage Groupings: Stage 0: Tis, N0, M0, Stage I: T1 or T2, N0, M0 (Dukes A), Stage II: T3 or T4, N0, M0 (Dukes B), Stage III: Any T, N1, N2 or N3, M0 (Dukes C), Stage IV: Any T, any N, M1 (Dukes D).

Surgery is the primary treatment for Colorectal Cancer and the only treatment that can cure the patient. The involved bowel segment is removed including the regional lymphnodes. Right Hemicolectomy is performed for lesions in the Cecum, Ascending Colon and Hepatic Flexure. Transverse Colectomy or Extended Right Hemicolectomy is performed for lesions in the Transverse Colon. Left Hemicolectomy is performed for lesions in the Splenic Flexure and Descending Colon. Resection of the Sigmoid Colon is performed for lesions in the Sigmoid Colon. For Rectal Cancer the options are a High Anterior Resection for lesions in the very upper part of the Rectum, Low Anterior Resection for most lesions in the Rectum and Abdomino Perineal Resection with a Sigmoidostomy for the very low lesions in the Rectum. Total Colectomy may be performed for multiple lesions. Total Proctocolectomy may be performed for Familial Adenomatous Polyposis. Very small cancer tumors especially those within a pedunculated adenoma may be removed by a Local Excision or even a Polypectomy during a colonoscopy.

About 30% of all Colorectal Cancer is located in the Rectum, 25% in the Sigmoid Colon, 3% in the Descending Colon, 3% in the Left Flexure, 8% in the Transverse Colon, 5% in the Right Flexure, 10% in the Ascending Colon, and 15% in the Cecum.

For Colon cancer the operation is pretty easy and can be performed by most surgeons without any difference in the prognostic outcome, but for operations on Rectal cancer you should be more concerned. Here the operating technique differs between different surgeons with great differences in the prognostic outcome. The best surgeons have Local Recurrence Rates (which means that the tumor recurs at the site of the previous operation) of about 4% while other surgeons have local recurrence rates of even up to 40%. Techniques of Extrafascial Excision also called Total Mesorectal Excision that involves a careful dissection of the pelvic cavity outside the mesorectal fascia sparing the nerve supply to the urinary bladder and genital organs should be used.

Adjuvant Chemotherapy means that you treat with chemotherapy after the operation that has removed all visible tumor tissue to kill single cancer cells or micro metastatic tumor deposits that may have spread from the primary tumor before or at the time of surgery through blood or lymph vessels to diminish the risk of clinically evident distant metastases. The effect of adjuvant chemotherapy after Colorectal Cancer has been debated for many years and many studies have been made, some not showing any benefit, but some showing a benefit. There is an increasing number of recent studies and meta analyses showing a positive effect on Stage III (node positive) Colon cancer and also but not as well documented Stage III Rectal Cancer. This is now being accepted by more and more treating clinics around the world especially for Colon Cancer. The benefit for Stage II is still unclear. The increase in 5-year survival is in the range from 50% up to 65% for Stage III Colorectal Cancer. The drugs being used are 5-FU + Leucovorin or 5-FU + Levamisol. Studies are also being made with adding Oxiplatin and with using Monoclonal Antibodies (Immunotherapy) which may be just as effective.

Adjuvant Radiotherapy is generally not used in the treatment of Colon Cancer but plays an important role in the treatment of Rectal Cancer. Radiotherapy either given before or after Rectal Cancer surgery has been shown to lower the local recurrence rate of up to 50% in some studies. Many of these studies though where done in clinics that had high local recurrence rates, so critics have said that maybe radiotherapy only compensates for not so perfect surgery. There are surgeons that have top of the notch results, with very low recurrence rates, without the use of any radiotherapy. Many clinics in the western world use radiotherapy either in a preop or postop setting. Radiotherapy is not harmless and may have both short and long term side effects. The trend may be going towards using radiotherapy for larger tumors but not for smaller tumors.

Treatment of advanced disease. Advanced disease means that the the primary tumor has metastasized to distant organs, and/or that the primary tumor is so large that it's not possible to radically remove. The liver is the most common site of distant spread. After that the lung, and spread into the peritoneal cavity called peritoneal carcinosis. The best treatment of metastases is surgery which virtually is the only chance of cure. Surgery usually requires that the metastases are confined to one liver lobe or to one lung lobe and that there is no disease apart from that. Surgery is only possible in a minority (about 5%) of patients with distant spread disease. If surgery is not possible the patient may be treated with Chemotherapy. Chemotherapy may prolong survival and palliate symptoms but cure is extremely rare. 5-FU + Leucovorin has been the standard treatment for metastatic Colorectal Cancer for many years. By adding Oxiplatin or Irinotecan (CPT-11) to this standard treatment of 5-FU and Leucovorin, progression-free survival and overall survival may be improved. The new Oral Fluorinated Pyrimidines (like UFT and Capecitabine) may have the advantage over 5-FU to be less toxic and have the ease of oral administration while being just as effective. In certain tumors with molecular markers for 5-FU resistance, the nonfluorinated pyrimidine thymidylate synthase inhibitor Tomudex may be effective. Research is also going on with Immunotherapy like different Monoclonal Antibodies, Vaccination therapies,  Radio-Immunotherapy with radioactive iodine bound to anti-CEA monoclonal antibody, Interleucins, Interferon, Angiogenesis inhibitors etc. There are also different locally destructive therapies like Cryotherapy, Alcohol-injection therapy, Precision radiotherapy, Radiofrequency ablation and other Heat therapies, Intraarterial chemotherapy, Chemo-embolization, Whole liver irradiation, Intraperitoneal Chemotherapy etc. that may have an effect. If the primary tumor is very large and grows through the bowel wall into adjacent structures it may not be possible to radically remove. This is sometimes the case especially with Rectal Cancers. These cancers may be treated with radiotherapy and often also chemotherapy before the surgery in order to try to shrink the tumor to make it possible to remove. An extended surgical procedure may then be required like Pelvic Excenteration etc. Intra Operative Radio Therapy (IORT) may also be given.

About 20% of all Colorectal Cancer is estimated to be Hereditary. Non hereditary Colorectal Cancer is called Sporadic and accounts for 80%. Hereditary Colorectal Cancer results from specific genetic alterations. In inherited Colorectal Cancer the first mutational hit has been inherited and is present in all body cells. Familial Colorectal Cancer accounts for about 15% of all Colorectal Cancer, HNPCC (Hereditary Non Polyposis Colorectal Cancer) for about 5% and FAP (Familial Adenomatous Polyposis) for about 1%. There are also other very rare syndromes like Juvenile Polyposis, Gardner's syndrome, Turcot's syndrome, and Peutz-Jeghers syndrome.

Familial Colorectal Cancer accounts for about 15% of all CRC. In familial Colorectal Cancer the causative genes have not been characterized. Individuals have an increased risk of Colorectal Cancer if one or more first degree relatives have developed CRC especially if the CRC was diagnosed at a young age. Epidemiological data (Murday 1990) suggests that the life time risk of getting CRC if an individual has one first degree relative affected by CRC is 1 in 17, one first degree relative diagnosed before age 45 1 in 10, one first degree and one second degree relative 1 in 12, both parents affected 1 in 8, two first degree relatives 1 in 6, and three first degree relatives 1 in 2. Surveillance by Colonoscopy every second year starting 5-10 years earlier than the earliest CRC case in the family has been suggested if the calculated life time risk exceeds 20%.

HNPCC accounts for about 5% of all CRC. It's an autosomal dominant disease which means that the children have a 50% risk of inheriting the genetic trait if only one of the parents have the trait and he or she is heterozygotic, but this is usually the case. It's caused by defects of mismatch repair genes (MMR) which identify and repair naturally occurring somatic mutations (replication errors) in DNA during cell division. Thus the repair system doesn't work. A number of MMR genes carrying mutations have been identified and named hMSH2 on chromosome 2, hMSH6 on chromosome 2, hMLH1 on chromosome 3, hPMS1 on chromosome 2, hPMS2 on chromosome 7, and TGF-beta on chromosome 18. Mutations on hMSH2 account for 60% of the inherited forms of HNPCC and together hMSH2 and hMLH1 account for 90%. Today blood tests are available to detect mutations in hMSH2 and hMLH1 only. The genetic test is positive in about 50% of kindreds with HNPCC. These mutations have about 80% penetrance, which means that Colorectal Cancer will develop in 80% of patients who inherit the mutations, but 20% will not develop cancer. Some HNPCC individuals (Lynch II) not only have an increased risk of CRC but also for endometrial carcinoma (cancer of the uterus), ovaries, small bowel, stomach, pancreas, bileducts and transitional cell carcinoma of the ureter and renal pelvis. Unlike FAP there is no pathognomonic phenotype (obvious signs) to recognize HNPCC cases or separate it from sporadic cases of Colorectal Cancer. To suspect HNPCC the patient should have a family history of CRC in multiple close relatives, across generations and occur at a young age. A pattern of dominant inheritance, diagnosis before the age of 50 years, proximal colon cancers, metachronous and synchronous colorectal neoplasms and strongly associated cancers (endometrial, ovarian, gastric, small bowel, hepatobiliary, and ureteric) offer diagnostic clues. The patient should preferably fulfill the "Amsterdamcriteria" 1: at least three family members affected by CRC, 2: at least one first degree relative of another, 3: at least two successive generations affected, 4: at least one affected before the age of 50. FAP should of course be excluded also (see below). Small families might have too few members to be able to fulfill these criteria even in the case of HNPCC. The Colorectal Cancers are usually right sided (60-70%) and the site is usually specific for each kindred. The mean age of onset is 45. The risk of a new CRC if one was removed from the Colon is high - about 40% over a 10 year time. Indications for genetic testing include: Any patient with colon or rectal cancer who meets the Amsterdam criteria; First degree relatives of patients with CRC who carry a germline mutation; Young patients with colon cancer proximal to the splenic flexure. Colonoscopic surveillance is currently recommended over prophylactic colectomy for the management of HNPCC. Factors to be assessed include compliance with colonoscopy surveillance, absence of Colorectal Cancer in up to 20% of gene positive carriers, and a 12% risk of rectal cancer subsequent to colectomy. Genecarriers who develop Colon Cancer require total colectomy with IRA and follow up with annual sigmoidoscopy. If a patient presents with a Colon Cancer and fulfills the Amsterdamcriteria it may be wise to consider doing a colectomy and an ileorectal anastomosis. If HNPCC is suspected in a healthy individual screening is recommended with colonoscopy every second year from age 20-25 and every year from age 40. Colonoscopy should be started at least 5 years earlier than the youngest case of CRC in the family. Screening for other cancers has also been recommended like for uterine endometrial cancer and ovarian cancer with gynecological examination, transvaginal sonography and tumormarker CA-125 every 1-2 years starting at 30-35, and if there is a history of stomach or urinary tract cancer in the family, gastroscopy every 1-2 years starting at 30-35, or sonography of the urinary tract and urine analysis every 1-2 years starting at 30-35 years of age. If the disease causing germ line mutation in an index person that already has developed the disease can be detected, genetic testing can be performed to distinguish asymptomatic mutation carriers from non-mutation carriers, thus distinguishing relatives that need regular surveillance from those that can be discharged. Another special feature in HNPCC tumors is MSI - micro satellite instabilities which is replication errors in short repetitive DNA sequences (microsatellites). MSI positive tumors reflect a defect in the mismatch genes and together with a positive family history supports HNPCC.

FAP is rare and constitutes only about 0.5-1% of all CRC. It's important because affected individuals carry an almost 100% lifetime risk of getting CRC which can be avoided. It's an autosomal dominantly inherited disease. It's caused by mutations in the APC (adenomatous polyposis coli) gene on chromosome 5. APC is a tumor suppressor gene and inactivation of the APC gene leads to neoplastic growth. Multiple adenomatous polyps, more than 100, develop in the Colon and Rectum during the teenage or early adulthood and if not discovered and treated Colorectal Cancer develops in almost 100% most often before the age of 40. The condition is usually suspected because of a family history of adenomatous polyposis. The APC gene mutation can be detected by bloodsamples, a PTT test. The current commercially available genetic test is positive in about 80% of kindreds with FAP. A negative test rules out FAP only if affected family members are APC gene mutation positive. If an APC gene mutation is identified in an affected family, gene testing for first degree relatives is considered 100% accurate. 10-25% of FAP patients are new cases due to spontaneous mutations at the time of conception. These patients have no previous family history of polyposis but all the next generations are at risk of inheriting the newly mutated gene. Specific genotype-phenotype correlations exist for the number and location of colorectal adenomas. If a patient with FAP tests positive for an APC mutation, unaffected family members can then be tested for the same mutation. If a family member of a patient with FAP and a detectable APC mutation undergoes APC testing and is found to be negative for the germline mutation one can be confident  that FAP will not develop in the relative, and colonoscopy screening is not necessary. If a patient with FAP does not have an APC mutation there is no need for family members to undergo genetic screening. Instead these relatives should undergo annual surveillance flexible sigmoidoscopy starting at the age of 12. If polyps are detected total colectomy is necessary. Unless polyps exhibit unfavorable histologic features total colectomy can be delayed until the late teenage years. If relatives have inherited a germline mutation, they should undergo prophylactic total colectomy between the ages of 10-19 years. In patients compliant with follow up, total colectomy, and ileorectal anastomosis and biannual proctoscopy can be performed and the risk of developing cancer in the rectal remnant is 4-10%. Total proctocolectomy, ileal pouch with ileoanal anastomosis is recommended if there is a family history of rapid progression of rectal disease to cancer.  Even if no adenomas are identified initially regular screening colonoscopy should be carried out until the age of 40. Thereafter in the absence of adenomas the surveillance interval can be increased to every 3-5 years. There is also an increased risk for polyps in the upper gastrointestinal tract, particularly adenomas developing into adenocarcinomas in the periampullary region of the duodenum, which is the most common cause of death in FAP patients once Colorectal Cancer has been excluded, and although its efficacy is yet to be established, a surveillance program is advisable. ASGE recommends upper endoscopy starting around the time the patient is considered for colectomy, or in the early 20's. If no adenomas are detected another exam should be performed in three to five years. There is also an attenuated variant of FAP (AAPC attenuated APC) clinically diagnosed on the basis of fewer than 100 adenomas present at endoscopy with a predilection for right sided lesions with rectal sparing clinically diagnosed at a later age often after 40 years of age. For AAPC colectomy with an ileorectal anastomosis sparing the rectum may be the best choice.

Juvenile Polyposis is a rare autosomal dominantly inherited disease. Molecular genetic testing is not available. It commonly presents from age 20-30 with rectal bleeding and is distinct from Juvenile Polyposis occurring in infancy which is generally accompanied by severe symptoms including rectal prolapse, hemorrhage, intussusception, or protein losing enteropathy. The cumulative lifetime risk of Colorectal Cancer in Juvenile Polyposis is 50%. It is characterized by hamartomatous polyps which typically possess abundant lamina propria overlying normal epithelium and may develop anywhere in the gastrointestinal tract although primarily in the colorectum. A minimum of 3-10 juvenile polyps has been suggested along with a family history to emphasize the familial component and to distinguish it from the more common isolated juvenile polyps in children. Both familial and sporadic cases of Juvenile Polyposis has been identified. Some authors believe that colonoscopic polypectomy and surveillance offer a reasonable alternative if polyp clearance is achieved and patient compliance is high. Prophylactic colectomy has been advised by the age of 20 years, but opinions are divided on the use of IRA (colectomy with ileorectal anastomosis) and IPAA (restorative proctocolectomy with ileal pouch anal anastomosis). For cases presenting with fewer than 20 juvenile polyps, endocopic polypectomy is suggested while prophylactic colectomy is suggested for patients with intractable rectal bleeding, severe dysplasisa, or more than 20 juvenile polyps.

Gardner's syndrome is an autosomal dominant rare disease. Multiple adenomatous colorectal polyps occur with extrabowel tumors, especially osteomas and rather characteristic retinal lesions. This syndrome is believed to be a phenotypic variant of FAP.

Turcot's syndrome. Autosomal recessive rare disease. GI-tract adenomas. CNS tumors. Possible variant of Gardner's syndrome.

Peutz-Jegher's syndrome. Autosomal dominant extremely rare disease affecting approximately 1 in 120 000 individuals due to a mutation on chromosome 19 in the LKB1 or STK11 gene. Predominant features are gastrointestinal tract hamartomatous polyps, mainly in the small bowel, and mucocutaneous melanin spots of the lips, mouth, fingers and toes. Patients have a relative risk from 9-18% for gastrointestinal and extraintestinal cancer. Surveillance include small bowel follow through with upper and lower endoscopy every 2 years where the age to start depends on the family history and symptoms that are present, mammography from the age of 25 years, yearly hemoglobin, and yearly gynecological/testicular examination. Management is symptomatic and patients typically undergo laparatomies for small bowel obstruction or intussusception. Hamartomatous polyps larger than 1 cm should be excised endoscopically or surgically. There is, however, no current evidence to recommend prophylactic colectomy in this patient population. Molecular genetic testing is not widely available.
 
 

Colorectal polyps are benign neoplastic lesions. They are very common. About 30% of people living in western countries are believed to have colorectal polyps. There are two kinds of colorectal polyps: Hyperplastic Polyps and Adenomas. Hyperplastic polyps are small broad-based mucosal elevations that are harmless and will never grow to become a cancerous lesion. Adenomas on the other hand grow, and even though most adenomas never become cancerous some will eventually become cancerous. The majority of Colorectal Cancers are believed to arise from colorectal adenomas and detection and removal of colorectal adenomas has been shown to significantly decrease the subsequent prevalence of Colorectal Cancer. Colorectal Cancers not developed from an adenoma are called de novo cancers. About 70% of colorectal polyps are adenomas and 30% are hyperplastic polyps. Up to 40% of Americans older than 50 have been found to have adenomas in colonoscopy studies. Adenomas may be pedunculated or sessile (broad-based). They may be small when found or quite large, several centimeters or inches. The cells in the adenoma are not normal and always contain a certain degree of atypia = dysplasia which is graded as mild, moderate or severe. The adenomas are divided into Tubular, Villous or Tubulovillous depending on the how they grow - if they grow in a tubular, villous or tubulovillous manner. The larger the size, increased atypia and villous histology increase the likelihood that a specific adenoma may have a cancer already within it or will develop cancer over time. The definition of when the neoplastic growth (tumor) is a cancer and when it's an adenoma is (as was stated above) whether it penetrates the lamina muscularis mucosa or not. A special case is the term Intramucosal cancer (a term that many pathologists think shouldn't be used) which would be when the cells in the tumor deserves to be called cancer cells but they don't grow beyond the lamina muscularis mucosa into the submucosa and therefore is not a real cancer and cannot metastasize and therefore rather should be called adenoma with severe dysplasia. Another special case is the Malignant polyp which is an invasive cancer in an adenoma - the cancer cells grow through the lamina muscularis mucosa into the submucosa but only into the submucosa of the polyp not into the submucosa of the bowel wall, i.e. it's a small cancer confined to the polyp.

All polyps found shall be removed because of the risk of malignant transformation of adenomas. It's not possible to macroscopically discriminate between adenomas and hyperplastic polyps. Most polyps can be removed during colonscopy. The follow up after endoscopic polypectomy have been discussed in different articles for many years and different approaches exist. The duration of follow-up colonoscopy should be individualized. As a general guideline assuming that the colon lining has been well seen and all polyps have been completely removed, most patients (excluding those with genetic syndromes) can have their first subsequent examination in three years. If a subsequent colonoscopy is negative further examinations can be performed at an interval of five years. Patients with only 1 or 2 small tubular adenomas are at particularly low risk. Here follows a more detailed guideline that adheres to the recommendations by ACG (American College of Gastroenterology), AGA (American Gastroenterlogy Association), ASGE (American Society for Gastrointestinal Endoscopy) and SAGES (Society of American Gastrointestinal Endoscopic Surgeons).

Hyperplastic polyps: Have no malignant potential. Do not predict an increased prevalence of adenomas. No follow up is required.

Adenomas: If an adenoma is found on a proctosigmoidoscopy a total colonoscopy should be performed because the risk of synchronous adenomas is 40-50%. Low risk adenomas are small (<1cm) tubular adenomas with no severe dysplasia. Patients with single low risk adenomas that are completely excised at colonoscopy and no other lesions are found and with no family history of colorectal neoplasia do not have an increased risk of cancer and follow up surveillance may not be needed. High risk adenomas are large (>1cm) tubular adenomas, multiple adenomas, adenomas containing villous tissue and adenomas with severe dysplasia. Most of these patients after having such adenomas completely excised should have their first surveillance colonoscopy after 3 years. After one negative 3 year follow-up colonoscopy subsequent intervals can be increased to 5 years. These recommendations for follow up surveillance colonoscopy assume that the initial clearing colonoscopy was complete with complete visualization of the entire colon from the anus to the cecum and that the that all adenomas were completely removed. If not, clearance should be verified  at one year or sooner. The duration of follow-up colonoscopy should be individualized. Large sessile adenomas have a high tendency to recur locally after colonoscopic resection and are at high risk of developing cancer. They may not be possible to safely excise endoscopically and should in these cases undergo surgical resection. If possible to excise endoscopically follow-up endoscopy to confirm that the resection was complete should be performed in 3-6 months. If residual tissue then is encountered it should be resected if possible and the completeness of treatment should be documented within another 3-6 months follow-up interval. If residual tissue is encountered after 2-3 examinations the patient should be referred for surgical resection. If no residual tissue is found subsequent surveillance strategy needs to be individualized to the assessed risk of recurrence.

Malignant polyps: If macro and microscopically complete resection with at least 2-3 mm's marginal and the cancer cells in the polyp are not poorly differentiated and there is no histological evidence of vascular or lymphatic involvement the endoscopic polypectomy is adequate, but if the resection is not complete or the cancer cells are poorly differentiated or there is vascular or lymphatic involvement the patient should be referred for surgical resection. If the endoscopic polypectomy is judged adequate the patient should be endoscopically checked in 3 months to check for residual polyp tissue at the polypectomy site and if this early follow-up examination is negative subsequent surveillance strategy needs to be individualized to the assessed risk.

Surveillance should always be individualized according to the assessed risk, age and comorbidity of each patient and should be discontinued when it appears unlikely that continued follow-up would prolong life expectancy. In general, depending on the specifics of each case, surveillance can be discontinued after age 75-80 years, especially in patients who already have undergone one or two follow-ups with negative result.

The prognosis and risk of recurrence is clearly related to the stage of the disease. Studies have been made of the 5-year survival for cancer related deaths in large groups of patients having the same stage of disease. If a patient is curatively operated on most recurrences come within 2 years and recurrences after 5 years are very uncommon. The overall 5-year survival rate for Colorectal Cancer in the US is about 60%. Studies have shown the 5-year survival for different Duke's Stages to be: Stage A about 90%, Stage B about 75%, Stage C about 50% and Stage D about 5%. Factors that carry a poor prognosis are: advanced stage, ulceration or perforation of the primary lesion, obstructing lesion, invasion of contiguous structures including nerves and vessels, less differentiated lesions. Adjuvant chemotherapy has been shown to improve the 5 year survival rate for Dukes C patients from about 50% up to about 65%. Duke's C patients with a smaller primary tumor and fewer involved lymph nodes have a better prognosis. In about 5% of all patients with distant metastases (Dukes D) it is possible to perform radical surgery to remove the metastases by liver or pulmonary resection and these patients then have an about 30% 5-year survival. At the time of the operation about 20% of all Colorectal Cancers are Duke's A cancers, about 35% are Duke's B, about 30% are Duke's C and about 15% are Duke's D. About 15% have distant metastases at the time of the operation and another 15% will develop distant metastases postoperatively usually within 2 years. About 85% of all distant metastases are liver metastases, 10% are lung metastases and 5% are other locations. Of all cancers about 15% are well differentiated, about 65% moderately well differentiated and about 20% poorly differentiated.

The possible benefit from detecting asymptomatic recurrences and metachronous cancers (new cancers) after curative Colorectal Cancer is probably small, but more recurrences and metachronous Colorectal Cancers may be removed and a minor part of these patients may actually be cured. The goal of a surveillance program should be a reduced mortality from Colorectal Cancer and prolonged cancer free survival. Trials have been made comparing intensive follow up versus less intensive follow up and most of these trials have not shown any difference in survival between the two groups. The increased chance of new curative surgery did not improve survival significantly. Some trials though have come to the conclusion that systematic postoperative surveillance increase both the rate of tumor recurrence amenable to curative intent-surgery and survival, at least in patients with Rectal Cancer. We are far from reaching a definitive agreement about the usefulness of postoperative follow-up, and surveillance policies vary widely between centers. The best surveillance program with regard to tests, frequency and intensity remains unknown, awaiting performance of prospective, randomized trials comparing different follow up strategies. Follow up may include a number of the following: Clinical History and Physical Examination (including Digital Rectal Exam, Proctoscopy and Rigid Sigmoidoscopy), Blood Screens including CEA, Fecal Occult Blood Tests, Colonoscopy, Barium Enema, Liver Ultrasound or CT, Chest X-ray.

Follow-up should preferably be individualized according to the assessed risk, age and comorbidity of each patient.

The American Society of Clinical Oncology (ASCO) Colorectal Cancer Surveillance Expert Panel has recently published their guidelines for follow-up based on a thorough analysis of the literature of what tests have an impact on the outcome for the patient including overall and disease free survival, quality of life, toxicity reduction, and cost-effectiveness. They recommend Clinical follow-up with history and pertinent physical examination every 3-6 months for the first 3 years, then annually. After that, medical follow-up should be driven by symptoms or the need for age-related periodic health maintenance. CEA testing (Carcinoembryonic Antigen tumor marker - a blood sample) if resection of liver metastases would be clinically indicated every 2 to 3 months in patients with stage II or III disease for > 2 years after diagnosis. An elevated CEA level, if confirmed by retesting, warrants further evaluation for metastatic disease. Colonoscopy every 3 to 5 years to detect new cancers and polyps. All patients should have visualization of the entire large bowel at the time of the initial Colorectal Cancer diagnosis. If this was not, or could not be performed before resection, a postoperative colonoscopy is warranted. Proctosigmoidoscopy at periodic intervals for stage II and III Rectal Cancer patients who have not received pelvic radiation.

The routine use in the follow-up of asymptomatic patients with abdominal CT-scan or Ultrasonography, Chest X-Ray, Pelvic CT, Fecal Occult Blood Tests, Liver Function Tests, and Complete Blood Cell Counts has not been shown to have an impact on the outcome according to ASCO.

Various screening tests have been shown to achieve accurate detection of early stage Colorectal Cancer. Removing adenomatous polyps has been shown to reduce the incidence of Colorectal Cancer. Detecting early stage cancers has been shown to reduce the mortality from Colorectal Cancer. Screening benefits has been shown to outweigh its harms. 3 large controlled clinical trials using annual or biannual Fecal Occult Blood Testing have shown a mortality reduction from Colorectal Cancer by 15-30%.

Screening  identifies people (without any symptoms of disease) who are more likely to have Colorectal Cancer or adenomatous polyps. Diagnosis classifies people who are suspected of having Colorectal Cancer or adenomatous polyps (in this case because of a positive screening test) into those with or without the disease. Surveillance or Follow-up monitors people with previously diagnosed colorectal disease (for example patients who have had polyps, Colorectal Cancer or Inflammatory Bowel Disease).

Based on an extensive evidence-based review, guidelines have been formulated by representatives from a consortium of medical societies for screening and surveillance of those at average risk and those at increased risk for Colorectal Cancer because of a family history of Colorectal Cancer or genetic syndromes or a personal history of adenomatous polyps, inflammatory bowel disease or curative-intent resection of Colorectal Cancer. These recommendations have been endorsed by organizations like ACS, ACGE, AGA, ASCRS, ASGE, SAGES.

This includes all people 50 years or older without any symptoms of colorectal disease and no other risk factors for Colorectal Cancer.

Recommendation: Fecal Occult Blood Testing (FOBT) each year, or Flexible Sigmoidoscopy every 5 year, or FOBT each year plus flexible sigmoidoscopy every 5 year, or Double-Contrast Barium Enema (DCBE) every 5-10 years, or Total Colonoscopy every 10 year.

Total Colonoscopy as a diagnostic workup should be done if positive FOBT or if an adenoma is found on a Flex Sigmoidoscopy or if DCBE reveals some pathology.

People with a first degree relative (sibling, parent or child) who have had Colorectal Cancer or Adenomatous Polyps:  Same options as average risk persons but beginning at the age of 40. If the familial risk appears to be higher because for example a cancer occurred in a first degree relative at a young age (before 60) or occurred in more than one relative then colonoscopy every 5 years beginning at age 40 (or 10 years earlier than the youngest affected relative, whichever is earlier) may be recommended.

People with a history of Hereditary Nonpolyposis Colorectal Cancer (HNPCC): People with 3 or more relatives with Colorectal Cancer, at least 1 first degree relative of another, at least 2 succesive generations affected, at least 1 cancer diagnosed before 50 (FAP should be excluded). Should be screened with colonoscopy every 2 years starting at age 25 (or 5 years earlier than the youngest diagnosis in the family, whichever is earlier), and every year after the age of 40. once a cancer has been diagnosed, subtotal colectomy is the preferred surgical approach.

People with a family history of Familial Adenomatous Polyposis (FAP): People with a family history of FAP should be genetically tested to see if they are gene carriers. A negative genetic test rules out FAP only if an affected family member has an identified mutation. Gene carriers and indeterminate cases should be screened with flexible sigmoidoscopy every year starting at age 10-12. If polyposis is present a colectomy is indicated.

People with a history of adenomatous polyps: If a large (>1 cm) or multiple adenomatous polyps are found and completely removed at colonoscopy most patients should have a follow-up colonoscopy after 3 years. If the follow up exam is normal or only a single small tubular adenoma is found the next examination can be in 5 years. In special circumstances (e.g. large sessile adenomas, incomplete removal, numerous adenomas, polyps with invasive cancer) shorter intervals may be necessary.

People with a history of Colorectal Cancer: Patients curatively resected should be offered a follow up colonoscopy after 3 years. If normal subsequent follow up colonoscopy every 5 years. A colonoscopy should also be done at the time of the operation.

People with Inflammatory Bowel Disease: In patients with long standing extensive inflammatory bowel disease, surveillance colonoscopy looking for dysplasia as a marker for Colorectal Cancer risk should be considered along with the extent and duration of the disease as a guide to when or if a colectomy should be considered. Surveillance colonoscopy every 1-2 years should begin after 8 years of pancolitis and after 15 years in left colon colitis.

Diet: Different investigations suggest that diets high in total fat, protein, calories, alcohol and meat (both red and white), and low in fiber, dietary vegetables and fruits, calcium, folate and other micronutrients are associated with an increased incidence of Colorectal Cancer. When meat and fish is cooked at high temperatures mutagenic and carcinogenic heterocyclic amines are formed that may contribute to an increased risk of Colorectal Cancer. Fat in particular saturated and monosaturated fats lead to an increased bile acid concentration in the intestinal tract which may be involved in colorectal carcinogenesis. Most studies show a protective effect of dietary fiber, vegetables and fruits on colon carcinogenesis. The term fiber is used to describe a complex mixture of compounds including insoluble fiber (typified by wheat bran and cellulose) and soluble fiber (usually dried beans). The protective effect may be mediated through a number of  potential mechanisms like binding to bile acids and carcinogenic substances, production of anticarcinogenic substances like butyrate, adding naturally occuring anticarcinogens found in vegetables, fruits, legumes, nuts and grains etc. Orally ingested Calcium like in dairy products or dietary supplements may lower the Colon Cancer risk by binding bile acids and fatty acids and thereby reducing exposure to toxic intraluminal compounds.

Other factors: NSAIDs like aspirin, sulindac and piroxicam have in some studies in low doses been shown to reduce the Colon Cancer incidence and polyp formation. NSAIDs increase the risk of gastrointestinal ulcers and bleeding which may outweigh its potential beneficial effect for the average risk individual. Physical Activity has in some studies been associated with a decreased risk of Colorectal Cancer, and a sedentary life style with an increased risk. Alcoholic beverage consumption has in some studies been shown to be a risk factor for Colorectal Cancer. It is hypothesized that alcohol may stimulate mucosal cell proliferation, to activate intestinal procarcinogens and possibly provide a source of unabsorbed carcinogens. Vitamin E, D and Folate has in some studies been associated with a lower risk of Colon Cancer. Smoking has in some studies been shown to increase the risk of Colorectal Cancer and adenomas. The increased male-to-female mortality ratio from Colorectal Cancer over latter half of this century in the United States may have been a result of tobacco use by men earlier in the century. Polyp removal - the National Polyp Study showed a greater than 75% reduction in the subsequent incidence of Colorectal Cancer after colonoscopic polypectomy compared with three non-concurrent external control groups.