Colorectal cancer

To view the overview of familial adenomatous polyposis (FAP), click here
To view the overview of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D, Faizan Sheraz, M.D. [2]

Colorectal cancer is the third most commonly diagnosed cancer in the world, and accounts for 8% of all cancer-related deaths annually. There are both genetic and environmental factors that can increase the risk of colorectal carcinoma (CRC). The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC. There are both genetic and environmental causes of colorectal carcinoma (CRC). Colorectal cancer may be differentiated from other diseases that cause unexplained weight loss, unexplained loss of appetite, nausea, vomiting, diarrhea, anemia, jaundice, and fatigue, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hemorrhoids, anal fissures, and diverticular disease. Current guidelines recommend that colonoscopy is the optimal screening tool for colon cancer since it detects 98-99% of the cases. The progression from an edematous polyp to colorectal cancer may take 10-15 years. A colorectal cancer may be considered to be early-onset CRC if it occurs in a patient younger than 50 years old. Colorectal cancer staging is an estimate of the amount of penetration of the cancer. Staging is based on the TNM classification system which depends on the extent of local invasion, the degree of lymph node involvement, and whether there is distant metastasis. The history of a patient with colorectal cancer may include a family history of polyps/colorectal cancer or a history of inflammatory bowel disease. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain. Metastatic symptoms include dyspnea, abdominal pain, fractures, and confusion. Generally, the most common signs of colorectal cancer are emaciation, lethargy, and pallor Other signs include low-grade fever, discomfort on palpation, ascites, rectal bleeding, rectal mass, and jaundice. The laboratory findings associated with colorectal carcinoma are the following: Complete Blood Count (CBC), Fecal Occult Blood Tests (FOBT), serum CEA and CA 19-9 concentration, serum iron concentrations, serum vitamin B12 and folate concentrations, liver function tests, and pulmonary function tests. Chest radiography (CXR) is the initial imaging modality used in the detection of suspected pulmonary metastasis. CT scan is used to determine the extent of involvement on colon cancer, most commonly in the abdomen and lungs. Other imaging tests that can be used for colorectal cancer are MRI, ultrasound, endoscopy, PET scan, barium study, and angiography. A biopsy and genetic testing can be performed when a suspected lesion is found on colonoscopy. Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, and slow tumor growth. Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient’s staging and other medical factors. When colorectal cancer metastasizes, there will be a different approach than with a localized tumor. The most common site of metastasis is the liver, and the second most common is the lung.

Colorectal cancer can be dated back to an Egyptian mummy who had lived in the Dakleh Oasis during the Ptolemaic period (200-400 CE). Dr. Aldred Warthin (an American pathologist) studied a family in 1895 and published his first report on it in 1913, documenting a pattern of endometrial, gastric, and colon cancers. In 1971, Lynch and Krush updated the studies of the family which eventually became known as hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch Syndrome. In February 2000, President Bill Clinton officially dedicated March as National Colon Cancer Awareness Month.

The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC. Sporadic instability originates from the epithelial cells that line the colon or rectum. Colitis-associated CRC includes genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas.

The cause of colorectal cancer has not been identified. To review risk factors for the development of colorectal cancer, click here.

Colorectal cancer may be differentiated from other diseases that cause unexplained weight loss, unexplained loss of appetite, nausea, vomiting, diarrhea, anemia, jaundice, and fatigue, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hemorrhoids, anal fissures, and diverticular disease. There are less common conditions that may be confused as colorectal cancer such as infectious colitis and gastrointestinal lymphoma.

Colorectal cancer is the third most commonly diagnosed cancer in the world, and accounts for 8% of all cancer-related deaths annually. In the United States, the prevalence of colorectal cancer is 376.3 per 100,000 persons, and the incidence is 42.9 per 100,000 persons. The incidence of colorectal cancer is higher in males, the elderly, and in the African American race.

There are both genetic and environmental factors that can increase the risk of colorectal carcinoma (CRC). Some of the genetic risk factors are familial adenomatous polyposis and hereditary non-polyposis colorectal cancer. Some environmental risk factors are personal/family history, history of inflammatory bowel disease, diet, alcohol, cigarette smoking, race, and gender.

Early detection of premalignant colorectal masses or early-stage colorectal cancers is essential in treating these patients and possibly preventing cancer or colorectal cancer related death. According to the USPSTF (United States Preventive Services Task Force): Screening for colorectal cancer is recommended among adults older than 50 years of age and do not have an increased risk of developing the disease (average-risk adults).

The progression from an adenomatous polyp to colorectal cancer may take 10-15 years. Complications may arise if the cancer is not eradicated or from the treatment itself. Complications include intestinal obstruction, gastrointestinal bleeding, metastasis, cancer recurrence, radiation therapy adverse effects, chemotherapy adverse effects, post-surgical complications, metachronous colon cancer, and death. The 5 years survival rate depends on the stage of colorectal cancer.

Colorectal cancer staging is an estimate of the amount of penetration of the cancer. It is performed for diagnostic and research purposes and to determine the optimal method of treatment. Staging is based on the TNM classification system which depends on the extent of local invasion, the degree of lymph node involvement, and whether there is distant metastasis. The staging systems are called Duke’s classification, TNM classification, and AJCC stage grouping.

The history of a patient with colorectal cancer may include a family history of polyps/colorectal cancer or a history of inflammatory bowel disease. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain. Metastatic symptoms include dyspnea, abdominal pain, fractures, and confusion.

Generally, the most common signs of colorectal cancer are emaciation, lethargy, and pallor. Other signs include low-grade fever, discomfort on palpation, ascites, rectal bleeding, rectal mass, and jaundice.

The laboratory findings associated with colorectal carcinoma are the following: CBC, FOBT, serum CEA and CA 19-9 concentration, serum iron concentrations, serum vitamin B12 and folate concentrations, liver function tests, and pulmonary function tests.

Chest radiography (CXR) is the initial imaging modality used in the detection of suspected pulmonary metastasis. It normally appears as peripheral, rounded nodules of variable size, scattered throughout both lungs. Atypical features include consolidation, cavitation, calcification, hemorrhage, and secondary pneumothorax.

CT scan is used to determine the extent of involvement of colon cancer, most commonly in the abdomen and lungs.

MRI in colon cancer is used to determine the extent of the spread of the tumor to the liver, lung, brain and lymph nodes. MRI is also used for staging the cancer.

Abdominal ultrasound can be used to look for tumors in the liver, gallbladder, pancreas, or elsewhere in the abdomen, but it is insufficient in identifying colorectal cancer. The two special types of ultrasound exams that can be performed to evaluate colon and rectal cancers are endorectal ultrasound and intraoperative ultrasound.

Other imaging tests that can be used for colorectal cancer are endoscopy, PET scan, barium study, and angiography.

A biopsy and genetic testing can be performed when a suspected lesion is found on colonoscopy.

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, and slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as primary therapy if surgery is not indicated (palliative). Other therapies include radiation and support therapies.

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient’s staging and other medical factors.

When colorectal cancer metastasizes, a different approach is utilized as opposed to a localized tumor. The most common site of metastasis is the liver, and the second most common is the lung.

Most colorectal cancers could be preventable through screening, maintaining an improved and healthy lifestyle.

Secondary prevention of colorectal cancer, as opposed to primary prevention, indicates that a person has already had the disease and there are steps being taken to prevent cancer recurrence, usually as metachronous tumors. This involves annual surveillance with colonoscopy after surgical removal and possibly an adjunct after the initial operation. The timing for secondary prevention is critical to prevent recurrent advanced disease.

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To view the historical perspective of familial adenomatous polyposis (FAP), click here
To view the historical perspective of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D.

Colorectal cancer can be dated back to an Egyptian mummy who had lived in the Dakleh Oasis during the Ptolemaic period (200-400 CE). Dr. Aldred Warthin (an American pathologist) studied a family in 1895 and published his first report on it in 1913, documenting a pattern of endometrial, gastric, and colon cancers. In 1971, Lynch and Krush updated the studies of the family which eventually became known as hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch Syndrome. In February 2000, President Bill Clinton pronounced March as National Colon Cancer Awareness Month.

• The first historical diagnosis of cancer, in particular colorectal cancer, was by Professor Michael Zimmerman on an ancient Egyptian mummy who had lived in the Dakleh Oasis during the Ptolemaic period (200-400 CE).^[1]
• The first account of a hereditary colorectal disease was by Dr. Aldred Warthin, who first suspected the disorder on a female patient.^[2]
• Dr. Aldred Warthin (an American pathologist) began studying her family in 1895 and published his first report on it in 1913 documenting a pattern of endometrial, gastric, and colon cancers.^[2]
• In February 2000, President Bill Clinton pronounced March as National Colon Cancer Awareness Month.

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To view the pathophysiology of familial adenomatous polyposis (FAP), click here
To view the pathophysiology of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D., Roukoz A. Karam, M.D.[2], Elliot B. Tapper, M.D.

The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC. Sporadic instability originates from the epithelial cells that line the colon or rectum. Colitis-associated CRC includes genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas.

The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC.

The picture below depicts the molecular pathogenesis of sporadic colon cancer:^[1]

Sporadic colorectal cancer originates from the epithelial cells that line the colon or rectum; it may involve the following:^[2]

• APC gene

• Produces the APC protein, which prevents the accumulation of β-catenin protein (responsible for stem cell renewal)

• Mutation of the APC protein leads to the accumulation of β-catenin protein and causes inappropriately high levels of stem cell renewal.

• TP53 gene

• Produces the p53 protein, which monitors cell division and promotes apoptosis if there are cell defects
• Mutations result in loss of control over cell division or apoptosis

• TGF-β and DCC (Deleted in Colorectal Cancer)

• Usually responsible for apoptosis, but deactivated in colorectal cancer

• Oncogenes

• Stimulate cellular division
• Mutations lead to over-activation of cell proliferation

The picture below depicts the molecular pathogenesis of colitis-associated colon cancer:^[1]

At a microbiological level, the development of colitis-associated colorectal cancers (CRC) can be linked to defects within the cell cycle.^[3]

Although it is poorly understood, the following five factors may be responsible for its neoplastic changes:^[1]

• Genetic instability^[4]
  • Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it occurs with 85% frequency.
  • Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it occurs with 15% frequency.

• Epigenetic alteration
  • Sporadic CRC can develop from dysplasia in 1 or 2 foci of the colon, while colitis-associated CRC can develop from multifocal dysplasia.^[5][6]
  • This indicates a field change effect where large areas of cells within the colon are affected by carcinogenic alterations.
• Chronic inflammation^[7]
  • COX-2 is triggered by inflammatory stimuli such as IL-1, IFN-γ, and TNF-α.
  • COX-2 expression is elevated in approximately 85% of adenocarcinomas.
• Oxidative stress^[8]
  • Oxidative stress results from inflammatory reactions which include inflammatory cells, activated neutrophils, and macrophages.
  • Macrophages produce large amounts of reactive oxygen and nitrogen species.
  • These reactive oxygen and nitrogen species can interact with key genes involved in carcinogenic pathways such as P53 and DNA mismatch repair genes.

• Intestinal microbiota^[9]
  • The Modification of enteric flora by probiotic lactobacilli is a proposed mechanism that may contribute to the development of colitis-associated cancer.

• Early-onset CRC may possess a higher level of microsatellite instability due to germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2).^[10]
• Studies have shown a higher number of somatic genomic alterations involving TP53 and CTNNB1 as well as a lower number of APC, KRAS and BRAF variants in individuals with early-onset CRC.^{[11] [12] [13]}

From a genetic standpoint, colorectal cancer can be divided into three categories:^[14]

• Sporadic (75% of cases)
  • No indication of a hereditary component
• Familial (20% of cases)
  • Resulting from multifactorial hereditary factors and/or environmental exposures to non-genetic risk factors
• Hereditary (10% of cases)

• Hereditary nonpolyposis colon cancer (HNPCC) also known as Lynch Syndrome results from mutations in hMLH1, hMSH2, hMSH6, and PMS2
• Familial adenomatous polyposis (FAP) results from mutations in the APC gene located on chromosome 5p22.2
• MUTYH-associated polyposis (MAP) results from biallelic mutation of the MutY, E. Coli, Homolog gene which functions to remove adenine residues mispaired with 8-hydroxyguanine in DNA

• On gross pathology, a polypoid or fungating exophytic (growing outwards) lesion is characteristic of right-sided colorectal tumors including the ascending colon and cecum.^[15]
• Left-sided tumours tend to be circumferential and annular producing an “apple-core” appearance on barium enema x-ray.^[15]

According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas:^[16]

• Carcinomas
  • Adenocarcinoma
  • Mucinous adenocarcinoma
  • Signet-ring cell carcinoma
  • Small cell carcinoma
  • Adenosquamous carcinoma
  • Squamous cell
  • Medullary carcinoma
  • Undifferentiated carcinoma
• Neuroendocrine neoplasms
• Hamartomas
• Mesenchymas tumors
• Lymphomas

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To view the causes of familial adenomatous polyposis (FAP), click here
To view the causes of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: ; Roukoz A. Karam, M.D.[2] Saarah T. Alkhairy, M.D.

The cause of colorectal cancer has not been identified. To review risk factors for the development of colorectal cancer, click here.

The cause of colorectal cancer has not been identified. However, there are certain risk factors that predisposes to risk of CRC.

To review risk factors for the development of colorectal cancer, click here.

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To view the differential diagnosis of familial adenomatous polyposis (FAP), click here
To view the differential diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2], Qurrat-ul-ain Abid, M.D.[3]

Colorectal cancer must be differentiated from other diseases that cause unexplained weight loss, unexplained loss of appetite, nausea, vomiting, diarrhea, anemia, jaundice, and fatigue, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hemorrhoids, anal fissures, and diverticular disease. There are less common conditions that may be confused as colorectal cancer such as infectious colitis and gastrointestinal lymphoma.

• Colorectal cancer must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, cystitis, and endometritis.^{[1][2][3][4][5][6]}

Other conditions that can be mistaken for colorectal cancer include the following:

• Benign colon polyps
• Infectious colitis
• Arteriovenous malformation (AVM)
• Carcinoid/neuroendocrine tumors
• Small intestine carcinomas
• Gastrointestinal lymphoma
• Pregnancy
• Appendicitis
• Hernia
• Lactose intolerance
• Flatulence
• Ulcer
• Cholecystitis

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To view the epidemiology and demographics of familial adenomatous polyposis (FAP), click here
To view the epidemiology and demographics of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: ; Roukoz A. Karam, M.D.[2], Saarah T. Alkhairy, M.D.

Colorectal cancer is the third most commonly diagnosed cancer in the world, and accounts for 8% of all cancer-related deaths annually. In the United States, the prevalence of colorectal cancer is 376.3 per 100,000 persons, and the incidence is 42.9 per 100,000 persons. The incidence of colorectal cancer is higher in males, the elderly, and in the African American race.

The epidemiology and demographics of colorectal carcinoma can be explained as follows:

• In 2014, the incidence of colorectal cancer was estimated to be 42.9 cases per 100,000 persons in the United States^[1]
• From 2001-2010, the overall incidence rates of colorectal cancer has decreased by an average of 3.4% per year^[1]
• In 2014, the incidence of colorectal deaths was 5.8 per 100,000 persons in the United States.^[1]

• In 2012, the prevalence of colorectal cancer was estimated to be 376.3 cases per 100,000 individuals in the United States^[1]

• The incidence of colorectal cancer increases with age.^[1]

• Colorectal cancer usually affects individuals of the African American race. Asian Pacific Islander individuals are less likely to develop colorectal cancer.^[1]
• In 2006-2010, the colorectal cancer incidence rates among the African American race were approximately 25% higher than the Caucasian race and 50% higher than the Asian Pacific Islander race.^[1]

• Men are more commonly affected by colorectal cancer than women. The male to female ratio varies with age and is approximately:^[1]
  • 1 to 1 – birth to 49 years
  • 1 to 4 – 50 to 79 years
  • 1 to 2 – 80 years and older

• Worldwide, colorectal cancer is the third most commonly diagnosed cancer when men and women are considered separately, and the second leading cause when both sexes are combined.^[1]

Early-onset colorectal cancer is defined as colorectal cancer diagnosed before the age of 50 years.^[2][3][4]

• Early-onset colorectal cancer accounts for approximately 14% of all colorectal cancer cases in the United States.^[5]
• In 2022, an estimated 20,805 individuals were diagnosed with early-onset colorectal cancer in the United States.^[6][7]

• Worldwide, there were 184,709 new cases of early-onset colorectal cancer in 2022, making it the most common early-onset gastrointestinal malignancy.^[6][7]

• Incidence of early-onset CRC has been increasing at a rate of approximately 2% annually.^[8]
• Highest increase in annual early-onset CRC rates are among patients younger than 40 years old, rising from 4.1 to 5.5 per 100,000 between 2013 and 2022.^[5][9]

• Incidence rates of early-onset colorectal cancer are increasing across all racial and ethnic groups, with particularly rapid rises among non-Hispanic Black and Hispanic individuals.^[5]
• Compared with later-onset colorectal cancer, patients with early-onset disease are more likely to be Black (15% vs 11%) or Hispanic (9% vs 5%).^[10]

• CRC was the leading cause of cancer-related among men and second leading cause of death of women aged 20 to 49 years in the United States.^[11]
• Early-onset colorectal cancer incidence is higher in males than females, with a male-to-female incidence rate ratio of approximately 1.20.^[12]

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To view the risk factors of familial adenomatous polyposis (FAP), click here
To view the risk factors of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D.

There are both genetic and environmental factors that can increase the risk of colorectal carcinoma (CRC). Some of the genetic risk factors are familial adenomatous polyposis and hereditary non-polyposis colorectal cancer. Some environmental risk factors are personal/family history, history of inflammatory bowel disease, diet, alcohol, cigarette smoking, race, and gender.

The causes and the risk factors for colorectal carcinoma are the similar. There are both genetic and environmental factors that can increase the risk of colorectal carcinoma.^[1] FAP and HNPCC are the most common risk factors of CRC, but together these two conditions account for only about 5 percent of CRC.^[2]

The table below lists the genetic risk factors for colorectal carcinoma:^[3][4]

Genetic Risk Factor	Description
Familial Adenomatous Polyposis (FAP)	Autosomal dominant inheritance Other variants include Gardner’s syndrome, Turcot’s syndrome, and attenuated adenomatous polyposis coli Caused by germlines mutations in the APC gene Colonic cancer occurs in 90% of untreated individuals around 45 years To view Gardner’s syndrome, Turcot’s syndrome, and attenuated adenomatous polyposis coli , click here
MUTYH-associated Polyposis (MAP)	Autosomal resistant inheritance Caused by bi-allelic germline mutations in the base excision repair gene mutY homolog (MYH or MUTYH)
Lynch Syndrome AKA Hereditary Non-polyposis Colorectal Cancer (HNPCC)	Autosomal dominant inheritance Caused by a defect in one of the mismatch repair genes, most commonly hMLH1, hMSH2, hMSH6, or PMS2 Mean age at initial cancer diagnosis is around 48 years

The table below lists the environmental risk factors for colorectal carcinoma:^{[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]}

Environmental Risk Factor	Description
Family History	Risk increases with number of family members affected and the age of diagnosis If there is a single affected first-degree relative with CRC; the risk further increases if two first-degree relatives have CRC diagnosis If age of diagnosis is less than 50-60 years, the risk significantly increases especially if the family member has an adenomatous colonic polyp
Personal History	Risk increases if there is a personal history of CRC or adenomatous polyps, particularly: If they are multiple polyps >1 cm, or If the polyps are villous or tubulovillous
Ulcerative Colitis	The increase in risk begins about 8 to 10 years after the initial diagnosis of pancolitis and at 15 to 20 years If the colitis is limited to the left colon By the fourth decade of disease it reaches as high as 30% in patients with pancolitis; pseudopolyps and strictures may increase the risk
Crohn’s Disease	There is an increased risk: If 1/3rd or more of the colonic mucosa is involved
Age	The risk of developing CRC increases with age; Majority of cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present Cancer in African American individuals tends to occur earlier
Abdominal Radiation	Adult survivors of childhood malignancy who received abdominal radiation are at significant risk
Race	The African American race has the highest CRC race of all the ethnic groups The mortality is 20% higher in the African American race compared to the Caucasian race
Gender	CRC mortality is about 20-40 percent higher in men than in women
Acromegaly	Patients with acromegaly are more likely to have multiple adenomatous polyps
Immunosuppression	Immunosuppression increases the risk of developing CRC, for example in renal transplantation
Diabetes Mellitus and Insulin Resistance	Although it is not clear why but one possible explanation linking diabetes to CRC is hyperinsulinemia Insulin is an important growth factor for colonic mucosal cells and stimulates colonic tumor cells
Alcohol	The elevated risk may be related to interference of folate absorption by alcohol and decreased folate intake
Obesity	Every 5 kg/m2 increase in BMI was associated with: Twenty four percent increased incidence of both colon and rectal cancer in men Nine percent higher incidence of colon cancer in women
Cigarette Smoking	Risk of developing CRC was increased among cigarette smokers compared to those who never smoked; For both incidence and mortality, the association was stronger for cancer of the rectum than the colon
Uretercolic Anastomoses	There is increased risk of neoplasia in close proximity to the ureteric stoma
Diet	Diets associated with an increased risk of CRC include: Long-term consumption of red meat or processed meats Diets low in vegetables and high in fats
Coronary Heart Disease	The presence of coronary heart disease has been associated with an increased risk of CRC
Sedentary Lifestyle	Regular exercise stimulates peristalsis, thereby decreasing transit time for carcinogenic substances in the colon
Other cancers	The following cancers have been associated with an CRC especially if the first diagnosis was made at an early age: Ovarian Endometrial Breast cancer

• Majority of early-onset colorectal cancers are sporadic rather than heriditary.^[24]
• Approximately 15%–30% of early-onset colorectal cancers have an identifiable hereditary syndrome such as Lynch syndrome.^[25]

• Risk factors for early-onset CRC are mainly the same as later-onset CRC. These include:
  • Alcohol^[26]
  • Cigarette smoke^[27]
  • Inflammatory bowel disease
    • Inflammatory bowel disease is more common among individuals with early-onset CRC compared with later-onset CRC^[28]
  • Obesity^[29]
  • Processed meat
  • Sedentary behavior^[30]
  • Sugar-sweetened beverages^[31]
• Antibiotic exposure, altered gut microbiome, and early-life environmental factors have also been proposed as contributors.^[32]

Template:WikiDoc Sources

To view the screening of familial adenomatous polyposis (FAP), click here
To view the screening of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: ; Roukoz A. Karam, M.D.[2] Elliot B. Tapper, M.D.; Saarah T. Alkhairy, M.D.

Early detection of premalignant colorectal masses or early-stage colorectal cancers is essential in treating these patients and possibly preventing cancer or colorectal cancer related death. According to the USPSTF (United States Preventive Services Task Force): Screening for colorectal cancer is recommended among adults starting at 45 years of age and do not have an increased risk of developing the disease (average-risk adults).^[1] This screening age can vary depending on other conditions such as presence of disease first-degree relatives and heriditary disorders.

According to the USPSTF (United States Preventive Services Task Force):^[2]

• Screening for colorectal cancer is recommended among adults starting at 45 years of age and do not have an increased risk of developing the disease (average-risk adults).
• Decision to screen for colorectal cancer among adults aged 76 to 85 years is an individual one, decided through a discussion between the clinician and patient.
  • Screening would be more beneficial for healthier individuals that are able to undergo possible treatment.
• Screening for colorectal cancer among adults aged 86 years and older is not recommended.
• No preference is given to one screening modality over the other
  • Decision should be shared and according to the patient’s preferences when it comes to choosing an option.
• Screening options:^[2]
  1. Colonoscopy
  2. FIT
     • Fecal immunochemical testing for occult blood
  3. Flexible sigmoidoscopy
  4. Flexible sigmoidoscopy + FIT
  5. CT colonography
  6. FIT-DNA
     • multitargeted stool DNA testing
  7. gFOBT
     • Guaiac-based fecal occult blood testing

Screening for colorectal cancer in individuals that are at increased risk of developing the disease is different and depends on several factors:^[3][2]

• Family history of colorectal cancer before age 50
  • Begin screening 10 years before the diagnosis of disease in family member, or at the age of 40, whichever is earlier
• Risk of rapid disease progression
  • Perform screening more frequently
• Family history of HNPCC or FAP
  • Use most sensitive screening modality: colonoscopy

Protocols have been summarized according to USPSTF guidelines.^[2]

• A fecal occult blood test is a test for blood in the stool.
• There are two types of tests that can be used for detecting occult blood in stools:^[2][4]
  1. FIT
     • Fecal immunochemical testing for occult blood
  2. gFOBT
     • Guaiac-based fecal occult blood testing
• Use of low-sensitivity guaiac fecal tests is not recommended due to its of low sensitivity.^[2]

• A sigmoidoscopy is a lighted probe (sigmoidoscope) that is inserted into the rectum and lower colon to check for polyps and other abnormalities.^[5]
• A colonoscopy is a lighted probe (colonoscope) that 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 immediately removed, and the tissue can also be taken for biopsy. The American Society for Gastrointestinal Endoscopy has released quality indicators for screening colonoscopy, which include:^[5]

• Documentation of prep quality
• Photo documentation of cecal intubation
• Withdrawal time of 6 minutes or more
• Adenoma detection rate of greater than 25% in males and 15% in females greater than 50 years old

• Also known as Virtual Colonoscopy
• Requires special workstation software in order for the radiologist to interpret
• This technique is approaching colonoscopy in sensitivity for polyps
• Any polyps found must still be removed by standard colonoscopy^[6]

• Multitargeted stool DNA testing
• Ability to detect mutations from DNA shed by colorectal cancer^[7]

Advanced adenomas are defined as being ≥10 mm, having villous histology, or having high grade dysplasia. Advanced neoplasia is defined as cancer or advanced adenoma^[8].

Accuracy of screening tests to detect colorectal cancer and advanced adenomas^[9].

Method	Sensitivity	Specificity
Colorectal cancer
Colonoscopy	NA	NA
Fecal Immunochemical Test (FIT)	74	94
Cologuard (sDNA + FIT)	93	85
Advanced adenoma
Colonoscopy (for adenoma > 10 mm)	89 to 95	NA
Fecal Immunochemical Test (FIT)	23	96
Cologuard (sDNA + FIT)	43	89

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To view the natural history of familial adenomatous polyposis (FAP), click here
To view the natural history of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D.; Elliot B. Tapper, M.D.; Roukoz A. Karam, M.D.[2]

The progression from an adenomatous polyp to colorectal cancer may take 10-15 years. Complications may arise if the cancer is not eradicated or from the treatment itself. Complications include intestinal obstruction, gastrointestinal bleeding, metastasis, cancer recurrence, radiation therapy adverse effects, chemotherapy adverse effects, post-surgical complications, metachronous colon cancer, and death. The 5 year survival rates depend upon the stage of colorectal cancer.

• Colorectal cancer usually arises from a precursor lesion, the adenomatous polyp.
• The progression from an adenomatous polyp to colorectal cancer may take 10-15 years.
• The symptoms of colorectal cancer usually develop in the 6th decade of life, and start with symptoms such as change in bowel habits, hematochezia or bleeding per rectum, abdominal cramps or discomfort, rectal pain, tenesmus, and/or diminished caliber of stools.
• Constitutional symptoms such as nausea/vomiting, unexplained weight loss, unexplained loss of appetite, weakness, fatigue, dizziness may develop to suggest colorectal cancer.
• If the disease advances and spreads to other organs, the patient may present with dyspnea, cough with blood-stained sputum, persistent pain or discomfort in the chest, swelling in hands/feet, itchiness, jaundice, and/or dark-colored urine.^[1]
• Patients with early-onset colorectal cancer more commonly present with rectal bleeding, abdominal pain, and change in bowel habits and are more frequently diagnosed at an advanced stage compared with older patients.^[2]

Common complications of colorectal cancer include:^[3]

• Intestinal obstruction
• Intestinal perforation
• Fistula formation
• Gastrointestinal bleeding
• Metastasis
  • Usually in the liver and lungs but may occur in other sites
• Cancer recurrence
  • Local: site of the original tumor
  • Regional: in lymph nodes near the primary tumor
  • Distal: in another part of the body
• radiation therapy adverse effects including skin discoloration, skin burns, headache, fatigue, hair loss, nausea, vomiting, and/or confusion
• chemotherapy adverse effects including hair loss, fatigue, weakness, nausea, vomiting, risk of infection, and/or diarrhea
• Death

Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor.

The 5 year survival rate at diagnosis of colon cancer:^[4]

Stage	5-year Relative Survival Rate
I	74.0%
IIA	66.5%
IIB	58.6%
IIC	37.3%
IIIA	73.1%
IIIB	46.3%
IIIC	28.0%
IV	5.7%

The 5 year survival rate at diagnosis of rectal cancer:^[4]

Stage	5-year Relative Survival Rate
I	74.1%
IIA	64.5%
IIB	51.6%
IIC	32.3%
IIIA	74.0%
IIIB	45.0%
IIIC	33.4%
IV	6.0%

CEA level may also be directly related to the prognosis of disease, since its concentration correlates with the bulk of tumor tissue.

Poor prognostic factors of patients with hepatic metastasis include the following:

• Synchronous (diagnosed simultaneously) liver and primary colorectal tumors
• A short time between detecting the primary cancer and subsequent development of liver metastasis
• Multiple metastatic lesions
• Large-sized metastatic lesions, which can be measured by a high concentration of carcino-embryonic antigen (CEA)

Early-onset colorectal cancer patients often have distinct tumor biology and psychosocial challenges compared with later-onset disease despite similar treatment approaches.^[5]

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