Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in

the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the fourth most common
form of cancer in the United States and the third leading cause of cancer-related death in the Western
world.[1][2] Colorectal cancers arise from adenomatous polyps in the colon. These mushroom-shaped
growths are usually benign, but some develop into cancer over time. Localized colon cancer is usually
diagnosed through colonoscopy.

Invasive cancers that are confined within the wall of the colon (TNM stages I and II) are curable with
surgery. If untreated, they spread to regional lymph nodes (stage III), where up to 73% are curable by
surgery and chemotherapy. Cancer that metastasizes to distant sites (stage IV) is usually not curable,
although chemotherapy can extend survival, and in rare cases, surgery and chemotherapy together have
seen patients through to a cure.[3] Radiation is used with rectal cancer.

On the cellular and molecular level, colorectal cancer starts with a mutation to the Wnt signaling pathway.
When Wnt binds to a receptor on the cell, that sets in motion a chain of molecular events that ends with β-
catenin moving into the nucleus and activating a gene on DNA. In colorectal cancer, genes along this chain
are damaged. Usually, a gene called APC, which is a "brake" on the Wnt pathway, is damaged. Without a
working APC brake, the Wnt pathway is stuck in the "on" position.[

Signs and symptoms

he symptoms of colorectal cancer depend on the location of tumor in the bowel, and whether it has spread
elsewhere in the body (metastasis). Most of the symptoms may occur in other diseases as well, and hence
none of the symptoms mentioned here is diagnostic of colorectal cancer. Symptoms and signs are divided
into local, constitutional (affecting the whole body) and metastatic (caused by spread to other organs).

Local

Local symptoms are more likely if the tumor is located closer to the anus. There may be a change in bowel
habit (new-onset constipation or diarrhea in the absence of another cause), and a feeling of incomplete
defecation (rectal tenesmus) and reduction in diameter of stool; tenesmus and change in stool shape are
both characteristic of rectal cancer. Lower gastrointestinal bleeding, including the passage of bright red
blood in the stool, may indicate colorectal cancer, as may the increased presence of mucus. Melena, black
stool with a tarry appearance, normally occurs in upper gastrointestinal bleeding (such as from a duodenal
ulcer), but is sometimes encountered in colorectal cancer when the disease is located in the beginning of the
large bowel.

A tumor that is large enough to fill the entire lumen of the bowel may cause bowel obstruction. This
situation is characterized by constipation, abdominal pain, abdominal distension andvomiting. This
occasionally leads to the obstructed and distended bowel perforating and causing peritonitis.
Certain local effects of colorectal cancer occur when the disease has become more advanced. A large tumor
is more likely to be noticed on feeling the abdomen, and it may be noticed by a doctor on physical
examination. The disease may invade other organs, and may cause blood or air in the urine (invasion of
the bladder) or vaginal discharge (invasion of the female reproductive tract).

Constitutional

If a tumor has caused chronic occult bleeding, iron deficiency anemia may occur; this may be experienced
as fatigue, palpitations and noticed as pallor (pale appearance of the skin). Colorectal cancer may also lead
to weight loss, generally due to a decreased appetite.

More unusual constitutional symptoms are an unexplained fever and one of several paraneoplastic
syndromes. The most common paraneoplastic syndrome is thrombosis, usually deep vein thrombosis.

Metastatic

Colorectal cancer most commonly spreads to the liver. This may go unnoticed, but large deposits in the
liver may cause jaundice and abdominal pain (due to stretching of the capsule). If the tumor deposit
obstructs the bile duct, the jaundice may be accompanied by other features of biliary obstruction, such
as pale stools.

the lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a
person's risk of developing the disease.[4] These include:

 Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and
70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.[5]
 Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The
removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.
 History of cancer. Individuals who have previously been diagnosed and treated for colon cancer
are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus,
or breast are at higher risk of developing colorectal cancer.
 Heredity:
 Family history of colon cancer, especially in a close relative before the age of 55 or
multiple relatives.[6]
 Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal
cancer by the age of 40 if untreated
 Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome

 Gardner syndrome
  Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American
Cancer Society study found that "Women who smoked were more than 40% more likely to die from
colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in
risk of dying from the disease compared to men who never had smoked."[7][8]
 Diet. Studies show that a diet high in red meat[9] and low in fresh fruit, vegetables, poultry and fish
increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation
into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in
fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish
showed a decreased risk.[10] However, other studies have cast doubt on the claim that diets high in fiber
decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors,
leading to confounding.[11] The nature of the relationship between dietary fiber and risk of colorectal
cancer remains controversial.
 Physical inactivity. People who are physically active are at lower risk of developing colorectal
cancer.
 Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be
associated with colorectal cancer.
 Primary sclerosing cholangitis offers a risk independent to ulcerative colitis

 Inflammatory bowel disease.[15][16] About one percent of colorectal cancer patients have a history of
chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of
onset of the colitis and directly with the extent of colonic involvement and the duration of active
disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but
less than that of patients with ulcerative colitis.[17]
 Environmental factors.[15] Industrialized countries are at a relatively increased risk compared to
less developed countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations
have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal
cancers.
 Exogenous hormones. The differences in the time trends in colorectal cancer in males and females
could be explained by cohort effects in exposure to some gender-specific risk factor; one possibility
that has been suggested is exposure to estrogens.[18] There is, however, little evidence of an influence of
endogenous hormones on the risk of colorectal cancer. In contrast, there is evidence that exogenous
estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be
associated with colorectal tumors.[19]
 Alcohol. Drinking, especially heavily, may be a risk factor.[20]

Pathogenesis
Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of
the gastrointestinal tract, as a result of mutations along the 'Wnt signaling pathway. Some of the mutations
are inherited, and others are acquired.[34][35] The most commonly mutated gene in all colorectal cancer is
the APC gene, which produces the APC protein. The APC protein is the "brake" on the β-catenin protein.
Without APC, β-catinin moves into the nucleus, binds to DNA, and activates more proteins. (If APC is not
mutated in colorectal cancer, then β-catinin itself is.)[3]

Beyond the defects in the Wnt-APC-beta-catinin signaling pathway, other mutations must occur for the cell
to become cancerous. The TP53 protein, produced by the p53 gene, normally monitors cell division
and kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the p53 gene
and transforms the tissue from an adenoma into an invasive carcinoma. (Sometimes p53 is not mutated, but
another protective protein named BAX is.)[3]

Other apoptotic proteins commonly deactivated in colorectal cancers are TGF-β and DCC (Deleted in
Colorectal Cancer). TGF-β has a deactivating mutation in at least half of colorectal cancers. Sometimes
TGF-β is not deactivated, but a downstream protein named SMAD is.[3] DCC commonly has deletion of its
chromosome segment in colorectal cancer.[36]

Some genes are oncogenes -- they are overexpressed in colorectal cancer. For example, RAS, RAF,
and PI3K, which normally encourage the cell to divide in response to growth factors, can become mutated
with mutations that make them oversignal the cell. PTEN normally inhibits PI3K, but sometimes PTEN
gets mutated.[3]

Diagnosis

Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves
the chances of a cure. The National Cancer Policy Board of the Institute of Medicine estimated in 2003 that
even modest efforts to implement colorectal cancer screening methods would result in a 29 percent drop in
cancer deaths in 20 years. Despite this, colorectal cancer screening rates remain low.[37]Therefore, screening
for the disease is recommended in individuals who are at increased risk. There are several different tests
available for this purpose.

 Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel
for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is
useful as an initial screening test.
 Fecal occult blood test (FOBT): a test for blood in the stool. Two types of tests can be used for
detecting occult blood in stools i.e. guaiac based (chemical test) and immunochemical. The sensitivity
of immunochemical testing is superior to that of chemical testing without an unacceptable reduction in
specifity.[38]
 Endoscopy:
  Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and lower
colon to check for polyps and other abnormalities.
 Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the
entire colon to look for polyps and other abnormalities that may be caused by cancer. A
colonoscopy has the advantage that if polyps are found during the procedure they can be removed
immediately. Tissue can also be taken for biopsy.

In the United States, colonoscopy or FOBT plus sigmoidoscopy are the preferred screening options.

Staging

Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is performed for
diagnostic and research purposes, and to determine the best method of treatment. The systems for staging
colorectal cancers depend on the extent of local invasion, the degree of lymph node involvement and
whether there is distant metastasis.

Definitive staging can only be done after surgery has been performed and pathology reports reviewed. An
exception to this principle would be after a colonoscopic polypectomy of a malignant pedunculated polyp
with minimal invasion. Preoperative staging of rectal cancers may be done with endoscopic ultrasound.
Adjunct staging of metastasis include Abdominal Ultrasound, CT, PET Scanning, and other imaging
studies.

The most common staging system is the TNM (for tumors/nodes/metastases) system, from the American
Joint Committee on Cancer(AJCC). The TNM system assigns a number based on three categories. "T"
denotes the degree of invasion of the intestinal wall, "N" the degree of lymphatic node involvement, and
"M" the degree of metastasis. The broader stage of a cancer is usually quoted as a number I, II, III, IV
derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and
likely a worse outcome. Details of this system are in the graph below:

AJCC stage TNM stage TNM stage criteria for colorectal cancer[42]

Stage 0 Tis N0 M0 Tis: Tumor confined to mucosa; cancer-in-situ

Stage I T1 N0 M0 T1: Tumor invades submucosa

Stage I T2 N0 M0 T2: Tumor invades muscularis propria

Stage II-A T3 N0 M0 T3: Tumor invades subserosa or beyond (without other organs involved)
Stage II-B T4 N0 M0 T4: Tumor invades adjacent organs or perforates the visceral peritoneum

Stage III-A T1-2 N1 M0 N1: Metastasis to 1 to 3 regional lymph nodes. T1 or T2.

Stage III-B T3-4 N1 M0 N1: Metastasis to 1 to 3 regional lymph nodes. T3 or T4.

Stage III-C any T, N2 M0 N2: Metastasis to 4 or more regional lymph nodes. Any T.

Stage IV any T, any N, M1 M1: Distant metastases present. Any T, any N.

Dukes system

Dukes classification is an older and less complicated staging system, that predates the TNM system, and
was first proposed by Dr. Cuthbert Dukes in 1932; it identifies the stages as:[43]

 A - Tumour confined to the intestinal wall

 B - Tumour invading through the intestinal wall

A few cancer centers still use this staging system.

Astler-Coller

A: Tumor limited to mucosa; carcinoma 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.