Colon cancer is believed to arise from two types of precursor polyps via two distinct pathways: conventional adenomas by the conventional adenoma-to-carcinoma sequence and serrated adenomas according to the serrated adenoma-to-carcinoma theory. Conventional adenomas arise from mutation of the APC gene; progression to colon cancer is a multistep process. The fundamental genetic defect in serrated adenomas is unknown. Environmental factors can increase the risk for colon cancer. Advanced colon cancer often presents with symptoms, but early colon cancer and premalignant adenomatous polyps commonly are asymptomatic, rendering them difficult to detect and providing the rationale for mass screening of adults over age 50.
Colorectal cancer afflicts approximately 150,000 Americans annually, approximately one third of whom die . It afflicts approximately 250,000 annually in Europe and approximately 1 million people worldwide . A review of the pathophysiology, clinical presentation, and diagnosis of colon cancer is important and timely. This field is changing rapidly because of breakthroughs in the molecular basis of carcinogenesis and in the technology for colon cancer detection and therapy. This article provides an overview of the pathophysiology, clinical presentation, and management of colon cancer, with a focus on recent advances, to help clinicians and gastroenterologists appropriately screen, diagnose, and manage patients to reduce mortality from this cancer. The other articles in this issue focus on individual aspects of colon cancer in detail.
Pathophysiology and Molecular Genetics
Precursor Lesions
Colon cancer is the best understood complex (multistep) cancer in terms of molecular genetics. The first step in carcinogenesis is the development of specific types of neoplastic polyps in colonic mucosa. Polyp histology is critical for determining malignant potential. The two common histologic types are hyperplastic and adenomatous. Histologically, hyperplastic polyps contain an increased number of glandular cells with decreased cytoplasmic mucus but generally lack nuclear hyperchromatism, stratification, or atypia . Adenomatous nuclei usually are hyperchromatic, enlarged, cigar-shaped, and crowded together in a palisade pattern. Adenomas are classified as tubular or villous. Histologically, tubular adenomas are composed of branched tubules, whereas villous adenomas contain digitiform villi arranged in a frond. Tubulovillous adenomas contain both elements.
Most colon cancers arise from adenomas (adenoma-to-carcinoma sequence) as demonstrated by epidemiologic, clinical, pathologic, and molecular genetic findings. First, operative specimens containing colon cancer frequently contain one or more synchronous adenomas. Second, the risk for colon cancer increases markedly with increasing number of adenomatous polyps within the colon . Third, adenomatous tissue frequently is found contiguous to frank carcinoma . Fourth, patients who have familial adenomatous polyposis (FAP), who have hundreds or thousands of adenomatous colonic polyps, inevitably develop colon cancer if colectomy is not performed . Fifth, patients who have adenomatous polyps larger than 1 cm diagnosed by barium enema who do not undergo colonoscopic polypectomy develop colon cancer at a rate of 1% to 1.5% per annum .
Although most hyperplastic polyps seem to have little or no association with colon cancer , some hyperplastic polyps are associated with colon cancer. Risk factors for malignancy in hyperplastic polyps include large polyp size (>1 cm diameter), location in the right colon, a focus of adenoma within the polyp (mixed hyperplastic-adenomatous polyp), more than 20 hyperplastic polyps in the colon, a family history of hyperplastic polyposis, and a family history of colon cancer . Hyperplastic polyps seem to be linked to colon cancer via the recently reclassified (sessile) serrated adenoma, previously classified as a hyperplastic polyp . A serrated adenoma arises within a hyperplastic polyp but differs from an ordinary hyperplastic polyp by abnormal proliferation of crypt epithelium and by nuclear atypia . In one study, approximately 18% of removed polyp specimens originally classified as hyperplastic were reclassified as serrated adenomas using the revised classification .
The serrated adenoma seems to transform into colon cancer via a different pathway from that of conventional adenomas and to result in a recognizably different form of colon cancer ( Table 1 ). Unlike conventional adenomas, serrated adenomas frequently have BRAF genetic mutations and exhibit extensive DNA methylation but lack adenomatous polyposis coli ( APC ) gene mutations . The serrated adenoma is a precursor lesion of colorectal carcinoma with high microsatellite instability (MSI-H), which constitutes approximately 15% of sporadic colon cancer . Like serrated adenomas, MSI-H colon cancers exhibit BRAF gene mutations and extensive DNA methylation but generally lack mutations of the APC gene or the K-ras oncogene . DNA methylation at the promoter region can terminate and silence gene expression without DNA mutation . For example, DNA methylation can inactivate DNA mismatch repair genes, such as the hMLH1 gene, and thereby lead to microsatellite instability (MSI) . The specific genetic defects responsible for the serrated adenoma are, however, unknown.
| Characteristic | Conventional adenoma to carcinoma sequence | Serrated adenoma to carcinoma theory |
|---|---|---|
| Precursor lesion | Conventional adenoma | Serrated adenoma |
| Location of precursor lesion | Throughout colon | Predilection for right colon |
| Morphology of precursor lesion | Usually pedunculated (tubular adenoma) | Often sessile, may be flat |
| Occasionally sessile (eg, villous adenoma) | ||
| Frequency of dysplasia in a moderate-sized polyp | Uncommon | Common |
| Likelihood of a small precursor adenoma transforming into cancer | Infrequent | Frequent?? |
| Progression from a medium sized polyp to cancer | Slow (7 or more years)? | Moderate (3–5 years)??? |
| Kudo pit pattern of adenoma | Types III or IV | Type II??? |
| Basic genetic defect | APC mutation | ???? |
| Frequently associated genetic mutation | p53 oncogene | BRAF mutation |
| DNA hypermethylation | Uncommon | Common |
| Mismatch repair gene malfunction/inactivation | Uncommon | Common ( hMLH1 inactivation) |
| MSI-H | Rare | Typical |
| Genetic syndrome exhibiting same pathway | Familial polyposis coli | Hyperplastic polyposis??? |
| Estimated relative frequency in sporadic colon cancer | 85% a | 15% a |
| Evidence for pathway | Well established and well documented | Theory supported by significant evidence |
| Pathway first proposed | More than 50 years ago | Last 5–7 years |
a The molecular mechanism of colon cancer in inflammatory bowel disease is unknown and may be distinct from either of these molecular pathways.
Considerable evidence supports that serrated adenomas can transform to cancer . First, serrated adenomas share the same genetic mutations characteristic of sporadic MSI-H cancers (described previously), suggesting a common molecular pathway. Second, serrated adenomas sometimes are found contiguous to areas of severe dysplasia, suggesting that the dysplasia arose from this precursor lesion . Third, patients who have hyperplastic polyposis and who have 30 or more hyperplastic polyps distributed throughout the colon (or at least five hyperplastic polyps proximal to the sigmoid colon, at least two of which are greater than 1 cm in diameter) frequently have serrated adenomas and frequently develop colon cancer. Fourth, in a retrospective pathologic study, 91 MSI-H colorectal cancers developed in the same area of the proximal colon where hyperplastic polyps previously were identified by colonoscopy with pathologic examination of polyp tissue; all the previously removed polyps on re-review were reclassified as serrated adenomas .
With separation of the high-risk serrated adenomas from hyperplastic polyps in the reclassified nomenclature, the remaining conventional hyperplastic polyps are believed to harbor a negligible risk for developing colon cancer.
Syndromic Colon Cancer
Discoveries in the pathogenesis of the uncommon genetic cancer syndrome of FAP led to breakthroughs in understanding the molecular basis of the transformation of sporadic adenomas to colon cancer. Patients who have FAP develop hundreds or thousands of adenomatous polyps throughout the colon beginning after puberty and inevitably develop colon cancer . This syndrome is inherited as a classic Mendelian single autosomal dominant gene. During the past 2 decades, FAP was shown to be the result of germline mutation of the APC gene located on chromosome 5q. Patients who have FAP carry this germline mutation in one allele in all somatic cells, including colonocytes ( Table 2 ) . This mutation underlies the development of hundreds of adenomatous polyps throughout the colon; colonic adenomas form when the second APC allele is lost or undergoes mutation in an individual colonocyte.
| First author (reference) | Discovery/finding |
|---|---|
| A. APC | |
| Veale | Determined by pedigree analysis that FAP resulting from a single dominant mutation |
| Herrera | Reported a de novo APC mutation associated with a large deletion in chromosome 5 |
| Bodmer | Applied restriction length polymorphism to localize the APC mutation to the long arm of chromosome 5 |
| Kinzler | Identified the APC gene on chromosome 5 by positional cloning |
| B. HNPCC | |
| Peltomaki | Described MSI in HNPCC |
| Fishel | Identified and cloned the first human mismatch repair gene hMSH2 ( hMLH2 ) |
| Bronner and Papadopoulos | Identified the second mismatch repair gene, hMLH1 , and localized it to chromosome 3p |
| Kolodner | Showed patients who have Muir-Torre syndrome (HNPCC associated with sebaceous gland and skin tumors) have hMSH2 mutations or other mutations that cause MSI. |
In hereditary nonpolyposis colon cancer (HNPCC), multiple kindred develop colon cancer. Affected patients typically have only a few colonic polyps. Colon cancer typically occurs in the right colon beginning as sessile polyps in middle age. The Amsterdam II criteria, used to clinically diagnose HNPCC, include all the following: three or more relations with colon cancer, one of whom is a first-degree relative of the other two; colon cancer involving at least two generations in the family; and at least one colon cancer diagnosed before age 50 . During the past 15 years, HNPCC was shown to be the result of mutations of one of the mismatch repair genes, such as hMLH1 , hMSH2 , and hMSH6 (see Table 2 ) . Germline mutations of the hMLH1 or hMSH2 gene account for most cases. Mismatch repair enzymes, encoded by the mismatch repair genes, normally recognize errors in nucleotide matching of complementary chromosome strands and initiate segmental excision of the newly synthesized strand to ensure faithful strand replication . Cells with mismatch repair gene mutations cannot repair spontaneous DNA errors and progressively accumulate mutations with succeeding DNA replications throughout the genome, resulting in genetic hypermutability and chaos. Accumulation of mutations in oncogenes and tumor suppressor genes can result in colon cancer. Mismatch repair gene mutation is detected as MSI, in which errors occur in simple DNA repetitive sequences, such as poly-A (ie, AAAA…) or CA-tandem repeating (ie, CACACACA…) nucleotide sequences . The molecular genetics of variants of FAP and HNPCC are described in Table 3 . The history of molecular genetic discoveries in other intestinal polyposis syndromes is described in Table 4 . Genetic factors in the pathogenesis of syndromic colon cancer are reviewed in the article by Desai and Barkel elsewhere in this issue.
| Gene mutations | Clinical syndromes | Manifestations |
|---|---|---|
| APC | FAP | Development of hundreds of colonic adenomas and inevitably of colon cancer, without colon resection |
| Attenuated FAP | Mutations at specific sites (both terminals or exon 9) of APC gene can cause attenuated polyposis syndrome with development of dozens of colonic adenomas | |
| Gardner’s syndrome | Variant of FAP with prominent extracolonic growths, such as osteomas | |
| Turcot syndrome | Variant of FAP with typical colonic manifestations and medulloblastomas or other tumors of the central nervous systerm, often the result of mutations of the APC gene | |
| MYH | Mutation of the MYH gene causes an attenuated adenomatous polyposis syndrome phenotypically resembling attenuated adenomatous polyposis from APC mutation. It is characterized by the presence of 10 or more adenomatous polyps in the colon and a high risk for developing colon cancer. | |
| Mismatch repair | HNPCC | Develop several adenomatous colonic neoplasms, primarily in the right colon, with rapid malignant transformation |
| Turcot syndrome | Variant of HNPCC with typical colonic findings of few colonic neoplasms and glioblastoma multiforme tumors of the central nervous system, sometimes due to mutations of mismatch repair genes |
| First author (reference) | Discovery/finding |
|---|---|
| Zigman | Showed the Ruvalcaba-Myhre-Smith syndrome (hamartomatous, lipomatous hemangiomatous, and lymphangiomatous gastrointestinal polyps) results from an autosomal dominant mutation of the PTEN gene on chromosome 10q |
| Nelen | Showed Cowden’s disease (gastric and colonic hamartomatous polyps) results from an autosomal dominant mutation of the PTEN gene on chromosome 10q |
| Howe | Showed familial juvenile polyposis (more than 10 juvenile intestinal polyps) results from an autosomal dominant mutation in the SMAD4 ( DRC4 ) gene on chromosome 10q |
| Jenne | Showed Peutz-Jeghers syndrome (small number of intestinal polyps associated with mucocutaneous pigmentation) results from an autosomal dominant mutation in the STK11 gene on chromosome 19p |
Sporadic Cancer
These breakthroughs not only provided the molecular basis of syndromic hereditary colon cancer but also contributed to understanding sporadic colon cancer. Colon cancer is believed the result of a cascade of genetic mutations leading to progressively disordered local DNA replication and accelerated colonocyte mitosis. Progressive accumulation of multiple genetic mutations results in the transition from normal mucosa to benign adenoma to severe dysplasia to frank carcinoma ( Table 5 ). Malfunction of the mismatch repair genes may account for approximately 15% of sporadic colon cancers . In the HNPCC syndrome, the mismatch repair genes malfunction because of genetic mutation. In sporadic serrated adenomas, the mismatch repair gene hMLH1 often malfunctions because of DNA hypermethylation. APC mutation is believed to account for approximately 80% to 85% of sporadic colon cancers . Colon cancer may arise in inflammatory bowel disease from a different but so far uncharacterized pathway. Spontaneous somatic APC mutation in colonocytes is believed to underlie the development of sporadic adenomatous polyps. APC gene mutations occur early in adenoma development and often are found in aberrant crypt foci, the earliest identifiable dysplastic crypts . APC mutations are found in approximately 50% of sporadic adenomas . Adenomas usually remain benign. Malignant transformation requires further genetic alterations.
| Gene | Chromosome location | Normal physiologic function of encoded protein | Clinical manifestations of mutation |
|---|---|---|---|
| APC gene | 5q | Regulates cell growth and apoptosis | Homozygous somatic mutation associated with colonic adenomas. |
| K-ras gene family | Various chromosomes | Encodes a small guanosine triphosphate binding protein on cell membrane involved in transduction of mitogenic signals across cell membrane | Mutated in approximately 50% of colon cancers. May act in an intermediate stage of carcinogenesis. Mutation common in hyperplastic polyps. |
| P53 gene | 17p | Regulates G1 cell cycle and apoptosis | Critical in transition from late adenoma to early cancer. |
| DCC gene | 18q | Encodes a neural cell adhesion molecule; facilitates apoptosis, tumor suppressor | Believed to promote progression to frank carcinoma. |
| Mismatch repair genes | Located on several chromosomes | Recognize errors in nucleotide matching on complementary chromosome strand and initiate excision of erroneous strand | Progressive accumulation of mutations throughout the genome in affected cells leading to hypermutability and genetic chaos. Mutations of oncogenes or tumor suppressor genes can lead to colon cancer. |
The k-ras gene encodes for a protein involved in signal transduction from the cell membrane to the nucleus. Specific mutations of this gene activate this signal pathway and promote colonocyte replication. These mutations are associated with exophytic growth of adenomas in the transition to carcinoma . Approximately 50% of colon cancers have k-ras mutations .
The normal p53 gene product arrests the cell cycle after DNA injury to permit DNA repair, if the damage is mild and correctable, or apoptosis, if the damage is severe and irreversible. The wild-type p53 protein product is upregulated after cell stress from radiation exposure, or other noxious events, to prevent new DNA synthesis and halt cell division. Loss of p53 function can promote genomic instability as genetic errors are replicated without check, resulting in loss of heterozygosity (LOH). Mutation of the p53 gene is believed important in the transition from advanced adenoma to frank carcinoma. Approximately 50% of colonic lesions with high-grade dysplasia and approximately 75% of frank cancers exhibit p53 mutations .
Accumulation of genetic mutations leads to genetic instability, manifested by LOH . LOH accelerates carcinogenesis. Cells with LOH have one, instead of the normal two, alleles of some genes because of choromosomal loss. A tumor suppressor gene is more likely to lose normal function when only one allele is present after LOH. Only one, rather than two, allelic mutations then are required for loss of its function.
This molecular mechanism is important in loss of function of the deleted in colon cancer ( DCC ) gene. The DCC gene encodes for a neural cell adhesion molecule receptor that normally promotes apoptosis and suppresses tumors. Loss of the normal DCC gene is believed important in the transition from an intermediate to an advanced adenoma .
DNA methylation can inactivate suppressor genes, thereby promoting cancer (described previously for hMLH1 ) . Approximately 25% of colon cancers are associated with methylation and inactivation of p14, normally an upstream inducer of the p53 tumor suppressor pathway . The inactivation produces the same cancer phenotype as p53 mutation . Methylation of the tumor suppressor gene p16, designated CDKN2A , occurs in approximately 35% of colon cancers .
Pathology of Colon Cancer
Histology
Colon cancers are classified as well differentiated, moderately well differentiated, or poorly differentiated based on the degree of preservation of normal glandular architecture and cytologic features. Poor differentiation presumably is a histologic marker of severe underlying genetic mutations, but the mutations associated with poor differentiation currently are unknown. Approximately 20% of colon cancers are poorly differentiated. They have a poor prognosis . Approximately 15% of colon cancers are classified as mucinous, or colloid, because of prominent intracellular accumulation of mucin. In the signet-ring variety of mucinous colon cancer, cancerous cells contain so much mucin that the nuclei are displaced peripherally. This cancer variant is very aggressive and has a poor prognosis . This biologic behavior may be the result of extracellular mucin dissecting beyond the tumor wall, thereby promoting local extension .
Colon cancer associated with HNPCC has unusual histopathologic features, such as mucinous differentiation, prominent lymphocytic reaction, and a medullary growth pattern . The medullary form of colon cancer, previously classified as an undifferentiated carcinoma, is characterized by sheets of eosinophilic and polygonal cells heavily infiltrated with small lymphocytes and devoid of glandular elements. This form of cancer also is associated with high MSI .
Other cancers of the colon are rare. Kaposi’s sarcoma can involve the colon as part of disseminated disease with the acquired immunodeficiency syndrome . Lymphoma of the colon is rare. It is a non-Hodgkin’s lymphoma. It may be associated with the acquired immunodeficiency syndrome . Carcinoid usually occurs in the lower gastrointestinal tract in the rectum or appendix but rarely can present in the rest of the colon.
Gross Pathology
Colon cancer can occur in a pedunculated polyp, sessile polyp, mass, or stricture. Small polyps rarely contain cancer. Only approximately 1% of diminutive polyps contain cancer . Cancer in a sessile polyp may metastasize earlier than cancer in a pedunculated polyp because of closer proximity to the lymphatic drainage . Also, a flat lesion may be biologically more aggressive than a pedunculated polyp because of cellular growth into the colonic wall rather than the colonic lumen. The relative frequency of right-sided colon cancer has increased gradually during the past several decades, and now approximately one half of colon cancers are right sided . This effect is attributed to a decreased frequency of left-sided cancer resulting from polypectomy of premalignant left-sided polyps at flexible sigmoidoscopy . Flexible sigmoidoscopy results in substantial reduction of the incidence of left-sided colon cancer but negligibly reduces the incidence of right-sided colon cancer .
Stage
Colon cancer spreads by local invasion to contiguous organs or by lymphatic or hematogenous invasion. Carcinoma in situ, or high-grade dysplasia, denotes cancer that is confined to the mucosa without penetration of the muscularis mucosa. This cancer is highly unlikely to produce metastases because the lymphatic and vascular channels are below the muscularis mucosa. Invasive colon cancer most commonly is staged from A through D according to the Dukes’ classification, with stage A penetrating beyond the muscularis mucosa into the submucosa. Stage B1 extends beyond the submucosa into the muscularis propria; stage B2 extends through the muscularis propria into the serosa; stage C has regional lymph node metastases; and stage D has distant metastases.
Colon cancer recently is staged according to the tumor, node, metastases (TNM) classification by mural depth of the primary tumor (T), by presence of local lymph node metastases (N), and by presence of distant metastases (M). This classification is helpful particularly in endosonographic staging of colon cancer (described later) . In the TNM classification, invasive colon cancer is classified from stage I to IV. Stage I in the TNM classification corresponds to Dukes’ A or B1 lesions, stage II corresponds to Dukes’ B2 lesion, stage III corresponds to Dukes’ C lesion, and stage IV corresponds to Dukes’ D lesion. Pathologic stage, as classified by either scheme, correlates highly with cancer prognosis .
Approximately 20% of patients initially present with Dukes’ D colon cancer, with identified metastases . Perhaps another 30% of patients have no metastases detected preoperatively or intraoperatively but eventually succumb to colon cancer after apparently curative surgery because of gross cancer recurrence presumably from initially undetected micrometastases. The most common sites of gross metastases are the regional lymph nodes and liver. Colon cancer metastasizes early to the liver because of venous drainage of the colon via the portal system. Other sites, including the lungs, peritoneum, pelvis, and adrenals, typically become involved only after hepatic or lymphatic metastases occur. Rectal cancers, which are below the peritoneal reflection, lack a serosa and, therefore, penetrate early into adjacent pelvic structures.
Pathology of Colon Cancer
Histology
Colon cancers are classified as well differentiated, moderately well differentiated, or poorly differentiated based on the degree of preservation of normal glandular architecture and cytologic features. Poor differentiation presumably is a histologic marker of severe underlying genetic mutations, but the mutations associated with poor differentiation currently are unknown. Approximately 20% of colon cancers are poorly differentiated. They have a poor prognosis . Approximately 15% of colon cancers are classified as mucinous, or colloid, because of prominent intracellular accumulation of mucin. In the signet-ring variety of mucinous colon cancer, cancerous cells contain so much mucin that the nuclei are displaced peripherally. This cancer variant is very aggressive and has a poor prognosis . This biologic behavior may be the result of extracellular mucin dissecting beyond the tumor wall, thereby promoting local extension .
Colon cancer associated with HNPCC has unusual histopathologic features, such as mucinous differentiation, prominent lymphocytic reaction, and a medullary growth pattern . The medullary form of colon cancer, previously classified as an undifferentiated carcinoma, is characterized by sheets of eosinophilic and polygonal cells heavily infiltrated with small lymphocytes and devoid of glandular elements. This form of cancer also is associated with high MSI .
Other cancers of the colon are rare. Kaposi’s sarcoma can involve the colon as part of disseminated disease with the acquired immunodeficiency syndrome . Lymphoma of the colon is rare. It is a non-Hodgkin’s lymphoma. It may be associated with the acquired immunodeficiency syndrome . Carcinoid usually occurs in the lower gastrointestinal tract in the rectum or appendix but rarely can present in the rest of the colon.
Gross Pathology
Colon cancer can occur in a pedunculated polyp, sessile polyp, mass, or stricture. Small polyps rarely contain cancer. Only approximately 1% of diminutive polyps contain cancer . Cancer in a sessile polyp may metastasize earlier than cancer in a pedunculated polyp because of closer proximity to the lymphatic drainage . Also, a flat lesion may be biologically more aggressive than a pedunculated polyp because of cellular growth into the colonic wall rather than the colonic lumen. The relative frequency of right-sided colon cancer has increased gradually during the past several decades, and now approximately one half of colon cancers are right sided . This effect is attributed to a decreased frequency of left-sided cancer resulting from polypectomy of premalignant left-sided polyps at flexible sigmoidoscopy . Flexible sigmoidoscopy results in substantial reduction of the incidence of left-sided colon cancer but negligibly reduces the incidence of right-sided colon cancer .
Stage
Colon cancer spreads by local invasion to contiguous organs or by lymphatic or hematogenous invasion. Carcinoma in situ, or high-grade dysplasia, denotes cancer that is confined to the mucosa without penetration of the muscularis mucosa. This cancer is highly unlikely to produce metastases because the lymphatic and vascular channels are below the muscularis mucosa. Invasive colon cancer most commonly is staged from A through D according to the Dukes’ classification, with stage A penetrating beyond the muscularis mucosa into the submucosa. Stage B1 extends beyond the submucosa into the muscularis propria; stage B2 extends through the muscularis propria into the serosa; stage C has regional lymph node metastases; and stage D has distant metastases.
Colon cancer recently is staged according to the tumor, node, metastases (TNM) classification by mural depth of the primary tumor (T), by presence of local lymph node metastases (N), and by presence of distant metastases (M). This classification is helpful particularly in endosonographic staging of colon cancer (described later) . In the TNM classification, invasive colon cancer is classified from stage I to IV. Stage I in the TNM classification corresponds to Dukes’ A or B1 lesions, stage II corresponds to Dukes’ B2 lesion, stage III corresponds to Dukes’ C lesion, and stage IV corresponds to Dukes’ D lesion. Pathologic stage, as classified by either scheme, correlates highly with cancer prognosis .
Approximately 20% of patients initially present with Dukes’ D colon cancer, with identified metastases . Perhaps another 30% of patients have no metastases detected preoperatively or intraoperatively but eventually succumb to colon cancer after apparently curative surgery because of gross cancer recurrence presumably from initially undetected micrometastases. The most common sites of gross metastases are the regional lymph nodes and liver. Colon cancer metastasizes early to the liver because of venous drainage of the colon via the portal system. Other sites, including the lungs, peritoneum, pelvis, and adrenals, typically become involved only after hepatic or lymphatic metastases occur. Rectal cancers, which are below the peritoneal reflection, lack a serosa and, therefore, penetrate early into adjacent pelvic structures.
Epidemiology
The incidence of colon cancer exhibits a striking geographic variation: the age-adjusted incidence varies by up to 12-fold among different countries . Industrialized nations have the highest incidence, whereas South American countries and China have a low incidence. The wide international variation is attributed largely to national differences in diet and other environmental factors . The rate in Japan used to be much lower than that in America but recently has increased with industrialization and adaptation of a Western diet. Moreover, descendants of Japanese immigrants to America, like other Americans, have a high incidence of colon cancer attributed to dietary and other environmental adaptations .
The lifetime risk for colon cancer in America is approximately 1 in 17 . It is responsible for approximately 10% of all cancer mortality in the United States . The incidence of colon cancer has decreased by approximately 20% in the United States, whereas the mortality has decreased by approximately 30% in the past 25 years . American blacks have a small increased risk for colon cancer compared with whites . American Indians have a significantly lower risk . The incidence is slightly higher in American men than women . The incidence of colon cancer rises sharply with age, beginning at age 50, attributed to accumulation of random somatic mutations with age. Ninety percent of cases occur after age 50, and only 4% of cases occur before age 40 .
Related posts:
Prevention of Colorectal Cancer: Diet, Chemoprevention, and Lifestyle
Implementation of Colon Cancer Screening: Techniques, Costs, and Barriers
Implementation of Colonoscopy for Mass Screening for Colon Cancer and Colonic Polyps: Efficiency with High Quality of Care
Surveillance of Patients at Increased Risk of Colon Cancer: Inflammatory Bowel Disease and Other Conditions
Surgical Therapy for Colorectal Adenocarcinoma
Colonoscopic Polypectomy
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