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COLORECTAL CANCER

colon cancer or bowel cancer, is a cancer from uncontrolled cell growth in the colon or rectum (parts of the large intestine), or in the appendix. Symptoms typically include rectal bleeding and anemia which are sometimes associated with weight loss and changes in bowel habits. Most colorectal cancer occurs due to lifestyle and increasing age with only a minority of cases associated with underlying genetic disorders. It typically starts in the lining of the bowel and if left untreated, can grow into the muscle layers underneath, and then through the bowel wall. Screening is effective at decreasing the chance of dying from colorectal cancer and is recommended starting at the age of 50 and continuing until a person is 75 years old. Localized bowel cancer is usually diagnosed through sigmoidoscopy or colonoscopy. Cancers that are confined within the wall of the colon are often curable with surgery while cancer that has spread widely around the body is usually not curable and management then focuses on extending the person's life via chemotherapy and improving quality of life. Colorectal cancer is the third most commonly diagnosed cancer in the world, but it is more common in developed countries. Around 60% of cases were diagnosed in the developed world. It is estimated that worldwide, in 2008, 1.23 million new cases of colorectal cancer were clinically diagnosed, and that it killed 608,000 people.

SIGNS AND SYMPTOMS


The symptoms and signs of colorectal cancer depend on the location of tumor in the bowel, and whether it has spread elsewhere in the body (metastasis). The classic warning signs include: worsening constipation, blood in the stool, weight loss, fever, loss of appetite, and nausea or vomiting in someone over 50 years old. While rectal bleeding or anemia are high-risk features in those over the age of 50, other commonly described symptoms including weight loss and change in bowel habit are typically only concerning if associated with bleeding.

CAUSE


Greater than 75-95% of colon cancer occurs in people with little or no genetic risk. While some risk factors such as older age and male gender cannot be changed, many can. A high fat, alcohol or red meat intake are risk factors for colorectal cancer as is obesity, smoking and a lack of physical exercise. Approximately 10% of cases are linked to insufficient activity. The risk for alcohol appears to increase at greater than one drink per day

INFLAMMATORY BOWEL DISEASE
People with inflammatory bowel disease (ulcerative colitis and Crohn's disease) are at increased risk of colon cancer. The risk is greater the longer a person has had the disease, and the worse the severity of inflammation. In these high risk groups both prevention with aspirin and regular colonoscopies are recommended. People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. In those with Crohn's disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. In those with ulcerative colitis approximately 20% develop tumors within the first 10 years.

GENETICS
Those with a family history in two or more first degree relatives have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer. Other syndromes that are strongly associated include: Gardner syndrome, and familial adenomatous polyposis (FAP) in which cancer nearly always occurs and is the cause of 1% of cases.

PATHOGENESIS


Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that artificially increase signaling activity. The mutations can be inherited or are acquired, and most probably occur in the intestinal crypt stem cell. The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. The APC protein is a "brake" on the accumulation of B-catenin protein; without APC, B-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of genes that are normally important for stem cell renewal and differentiation but when inappropriately expressed at high levels can cause cancer. While APC is mutated in most colon cancers, some cancers have increased B-catenin because of mutations in B-catenin (CTNNB1) that block its degradation, or they have mutation(s) in other genes with function analogous to APC such as AXIN1, AXIN2, TCF7L2, or NKD1. Beyond the defects in the Wnt-APC-beta-catenin signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from an adenoma into an invasive carcinoma. (Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is.) Other apoptotic proteins commonly deactivated in colorectal cancers are TGF-B and DCC (Deleted in Colorectal Cancer). TGF-B has a deactivating mutation in at least half of colorectal cancers. Sometimes TGF-B is not deactivated, but a downstream protein named SMAD is. DCC commonly has deletion of its chromosome segment in colorectal cancer. Some genes are oncogenes - they are overexpressed in colorectal cancer. For example, genes encoding the proteins KRAS, RAF, and PI3K, which normally stimulate the cell to divide in response to growth factors, can acquire mutations that result in over-activation of cell proliferation. The chronological order of mutations is sometimes important, with a primary KRAS mutation generally leading to a self-limiting hyperplastic or borderline lesion, but if occurring after a previous APC mutation it often progresses to cancer. PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated. Comprehensive, genome-scale analysis has revealed that colorectal carcinomas are clearly separable into hypermutated and non-hypermutated tumor types. In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme among these genes, across both tumor types, is their involvement in WNT and TGF-B signaling pathways, which in turn results in increased activity of MYC, a central player in colorectal cancer.

DIAGNOSIS


Diagnosis of colorectal cancer is via tumor biopsy typically done during sigmoidoscopy or colonoscopy. The extent of the disease is then usually determined by a CT scan of the chest, abdomen and pelvis. There are other potential imaging test such as PET and MRI which may be used in certain cases. Colon cancer staging is done next and based on the TNM system which is determined by how much the initial tumor has spread, if and where lymph nodes are involved, and if and how many metastases there are.

PATHOLOGY
The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma. Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring. Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated. Most colorectal cancer tumors are thought to be cyclooxygenase-2 (COX-2) positive. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.


PREVENTION


Most colorectal cancers should be preventable, through increased surveillance, improved lifestyle, and, probably, the use of dietary chemopreventative agents.

LIFESTYLE
Current dietary recommendations to prevent colorectal cancer include increasing the consumption of whole grains, fruits and vegetables, and reducing the intake of red meat. The evidence for fiber and fruits and vegetables however is poor. Physical activity can moderately reduce the risk of colorectal cancer.

MEDICATION
Aspirin and celecoxib appear to decrease the risk of colorectal cancer in those at high risk. However it is not recommended in those at average risk. There is tentative evidence for calcium supplementation but it is not sufficient to make a recommendation. Vitamin D intake and blood levels are associated with a lower risk of colon cancer.

SCREENING
More than 80% colorectal cancers arise from adenomatous polyps making this cancer amenable to screening. The three main screening tests are fecal occult blood testing, flexible sigmoidoscopy and colonoscopy. Fecal occult blood testing of the stool is typically recommended every two years and can be either guaiac based or immunochemical. In the United States screening is recommended between the age of 50 and 75 years with sigmoidoscopy every 5 years and colonoscopy every 10 years. For those at high risk, screenings usually begin at around 40. Virtual colonoscopy via a CT scan appears as good as standard colonoscopy but is expensive and associated with radiation exposure. It is believed that screening has the potential to reduce colorectal cancer deaths by 60%. For people over 75 or those with a life expectancy of less than 10 years screening is not recommended.

MANAGEMENT


The treatment of colorectal cancer depends on how advanced it is. When colorectal cancer is caught early surgery can be curative. However, when it is detected at later stages (metastases are present), this is less likely and treatment is often directed more at extending life and keeping people comfortable.

SURGERY
For people with localized cancer the preferred treatment is complete surgical removal with the attempt of achieving a cure. This can either be done by an open laparotomy or sometimes laparoscopically. If there are only a few metastases in the liver or lungs they may also be removed. Sometimes chemotherapy is used before surgery to shrink the cancer before attempting to remove it. The two most common sites of recurrence if it occurs is in the liver and lungs.

CHEMOTHERAPY
Chemotherapy may be used in addition to surgery in certain cases as adjuvant therapy. If cancer has entered the lymph nodes adding the chemotherapy agents fluorouracil, or capecitabine increases life expectancy. If the lymph nodes do not contain cancer the benefits of chemotherapy are controversial. If the cancer is widely metastatic or unresectable, treatment is then palliative. Typically in this case a couple of different chemotherapy medications are used. Chemotherapy drugs may include combinations of agents including fluorouracil, capecitabine, UFT, leucovorin, irinotecan, or oxaliplatin.

RADIATION
While a combination of radiation and chemotherapy may be useful for rectal cancer, its use in colon cancer is not routine due to the sensitivity of the bowels to radiation.

PALLIATIVE CARE
In people with incurable colorectal cancer, palliative care can be considered for improving quality of life. Surgical options may include non-curative surgical removal of some of the cancer tissue, bypassing part of the intestines, or stent placement. These procedures can be considered to improve symptoms and reduce complications such as bleeding from the tumor, abdominal pain and intestinal obstruction. Non-operative methods of symptomatic treatment include radiation therapy to decrease tumor size as well as pain medications.

PROGNOSIS


In Europe the 5 year survival for colorectal cancer is less than 60%. In the developed world about a third of people who get the disease die from it. Survival is directly related to detection and the type of cancer involved, but overall is poor for symptomatic cancers, as they are typically quite advanced. Survival rates for early stage detection is about 5 times that of late stage cancers. For example, patients with a tumor that has not breached the muscularis mucosa (TNM stage Tis, N0, M0) have an average 5-year survival of 100%, while those with an invasive cancer, i.e. T1 (within the submucosal layer) or T2 (within the muscular layer) cancer have an average 5-year survival of approximately 90%. Those with a more invasive tumor, yet without node involvement (T3-4, N0, M0) have an average 5-year survival of approximately 70%. Patients with positive regional lymph nodes (any T, N1-3, M0) have an average 5-year survival of approximately 40%, while those with distant metastases (any T, any N, M1) have an average 5-year survival of approximately 5%. According to the American Cancer Society statistics in 2006, over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.

FOLLOW-UP
The aims of follow-up are to diagnose, in the earliest possible stage, any metastasis or tumors that develop later, but did not originate from the original cancer (metachronous lesions). The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, a polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year. Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. These guidelines are based on recent meta-analyses showing intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.

EPIDEMIOLOGY


Globally greater than 1 million people get colorectal cancer yearly resulting in about 0.5 million deaths. As of 2008 it is the second most common cause of cancer in women and the third most common in men with it being the fourth most common cause of cancer death after lung, stomach, and liver cancer. It is more common in developed than developing countries.



 

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