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  • Scientifi c American SurgeryDOI 10.2310/7800.2073


    2014 Decker Intellectual Properties Inc

    gastrointestinal tract and abdomen

    A D E N O C A R C I N O M A O F T H E C O L O N A N D R E C T U M

    Martin R. Weiser, MD, and Leonard B. Saltz, MD*

    Colorectal cancer (CRC) is one of the most dynamic fi elds in oncology. The molecular events associated with cellular transformation were reported over 20 years ago, and intense study of the mechanisms of carcinogenesis and tumor progression continues. Molecularly based therapies now in use may be harbingers of more elegant, tumor-specifi c CRC therapy. Clinically, CRC is a diverse disease, requiring individually tailored treatment strategies. This topic review discusses the most current data on the epidemiology, screen-ing, diagnosis, staging, and multimodal treatment of CRC.

    Incidence and Epidemiologic Associations

    Worldwide, over 1 million people are diagnosed with CRC annually, and there are more than 500,000 associated deaths.1 The highest rates of colorectal carcinoma are found in industrialized countries. The rates are signifi cantly lower in eastern Europe, Asia, Africa, and South America.2 However, studies of Japanese migration to the United States, Asiatic Jewish migration to Israel, and eastern European migration to Australia show that migrants acquire the high rates of CRCs prevalent in their adopted countries. There is little question that environmental factors, most likely dietary, account for this.

    Colon cancer is three times more common than rectal cancer. Interestingly, epidemiologic studies indicate a rising proportion of right-sided colonic lesions. The proximal migration of colon cancer may be associated with changing environmental factors; however, there is no doubt that increased screening successfully detects early lesions in an aging population [see Figure 1].3

    CRC ranks as the third most common malignancy in the United States (behind prostate and lung cancer in men and breast and lung cancer in women) and the second leading cause of cancer-related mortality. Approximately 143,000 patients are diagnosed with CRC in the United States each year, and 51,000 die of disease.4,5 The probability of CRC developing during an individuals lifetime is about 6%. In contrast to the three previous decades, however, the overall incidence and mortality of CRC have declined for both men and women. Age-adjusted incidence and mortality are associated with race and ethnicity; however, the relation-ships are complex, infl uenced by social and economic confounding factors more than tumor biology.6

    Genetic Pathways to CRC

    Cancer cells are characterized by an ability to avoid normal aging and death. Cumulative sequential mutations

    in oncogenes, and an associated mutational deactivation of tumor suppressor genes over time, result in the production of abnormal cells that grow uncontrollably, invading local tissues and metastasizing to distant organs. This model of tumorigenesis, the adenoma-carcinoma cascade in CRC, was fi rst described by Fearon and Vogelstein in 1990.7

    Genomic instability is key to tumor development, and several genetic pathways, each characterized by specifi c mutations, lead to the development of CRC. The chromo-somal instability (CIN) pathway is typifi ed by an accumula-tion of deactivated tumor suppressor genes and abnormally active proto-oncogenes. Tumors developing along this path-way demonstrate characteristic mutations of the APC, TP53, and K-ras genes, allelic loss of 18q, and aneuploidy. The APC gene is crucial in tumor development: virtually all (100%) patients with familial adenomatous polyposis (FAP), who carry this mutation, develop CRC in the absence of preven-tive surgery. This progression was recently reevaluated using large-scale genetic comparative lesion sequencing of multiple lesions from a single patient.8 The investigators

    * The authors and editors gratefully acknowledge the contribu-tions of the previous authors, Bruce M. Brenner, MD, FACS, and David M. Ota, MD, FACS, to the development and writing of this topic review.

    Cecum17% (15%)

    Rectum18% (21%)

    Ascending Colon12% (8%)

    DescendingColon4% (6%)

    Sigmoid Colon23% (25%)

    Rectosigmoid Junction10% (10%)

    Transverse Colon13% (13%)

    Figure 1 The relative frequencies of colorectal cancer for various anatomic subsites of the colon in 1996. For comparative purposes, fi gures for 1976 are provided in parentheses.

  • Scientifi c American Surgery


    gastro adenocarcinoma of the colon and rectum 2

    estimated that it takes approximately 17 years for a large adenoma to progress to invasive malignancy but less than 2 additional years to develop the capacity to metastasize. Nearly 80% of tumors develop along the CIN pathway.

    The microsatellite instability (MSI) pathway is also impli-cated in the development of CRC. It is typifi ed by defi cient DNA mismatch repair (MMR), a near-diploid karyotype; lower levels of p53, SMAD4, and K-ras mutations; and higher levels of BAX, TGF-BIIR, and BRAF mutations. These tumors, which usually develop proximal to the splenic fl exure, have a better prognosis than tumors arising along the CIN pathway. Patients with Lynch syndrome develop tumors along the MSI pathway, with mutation in DNA-MMR genes. The MSI pathway (also referred to as the replication error [RER] pathway), is responsible for approx-imately 20% of carcinomas. Tumors characterized by MSI appear less responsive to 5-fl uorouracil (5-FU)-based chemotherapy.9,10 Therefore, it is important to identify these tumors correctly so that patients can receive optimal treatment.

    Malignancies characterized by excessive gene methylation (CpG island methylator phenotype, or CIMP) are distinct from other colon cancers.11 However, the existence of CIMP as a discrete entity is controversial. CIMP may simply mark one end of a tumor continuum typifi ed by genetic hyper-methylation, or it may comprise a subgroup of CRCs that have a unique molecular etiology. Many precursor lesions associated with CIMP tumors are serrated polyps demon-strating extreme hypermethylation and V600E BRAF muta-tions. This suggests that CIMP colorectal malignancies arise from serrated polyps, which may originate from a stemlike cell different from that of CRCs associated with tubular adenomas. DNA hypermethylation in CRC is currently a prominent topic for investigation.

    Some tumors do not fall into any currently known categor y, suggesting that other genetic pathways exist.12 Additional investigations will give us a better understand-ing of the various stages involved in carcinogenesis, offering opportunities for more specifi c molecular staging and, ulti-mately, tumor-specifi c therapy. Genetic pathways of CRC and the potential therapeutic role of chemopreventive agents are demonstrated here [see Figure 2].

    CRC Risk Factors

    Clearly, CRC is associated with genetic and environmen-tal infl uences. Overt risk factors include a personal or family

    history of CRC or colorectal adenoma(s), a personal history of colorectal polyps, infl ammatory bowel disease (IBD), and age greater than 50. Age is the most common risk factor. The risk of CRC increases after the fourth decade of life.13 Most individuals present with disease after the age of 60, and only 10% of CRCs are diagnosed in individuals younger than 40.

    Nonhereditary CRCs are referred to as sporadic and comprise 75 to 80% of all CRCs. Genetic etiology may be identifi ed in the remaining 20 to 25% of patients, including family history (15 to 20%), Lynch syndrome (5%), and FAP (< 1%). Cancer can arise within a polyp or at another site in the colon or rectum. The likelihood of invasive disease aris-ing in a colorectal polyp is associated with the morphology, histology, and size of the lesion. Polyps can be classifi ed as tubular, villous, or tubulovillous. Large villous polyps are most suspicious for malignancy; about 50% of villous lesions larger than 2 cm harbor cancer. Approximately 40% of patients present with multiple adenomatous polyps and are at high risk for having or developing CRC.14 Patients previ-ously diagnosed with colon or rectal cancer are at risk for metachronous disease; approximately 40% of those treated for sporadic CRC develop metachronous polyps, and about 6% develop a second CRC while under surveillance.15,16

    Patients with IBD are at high risk for developing CRC, proportional to the extent and duration of disease. In indi-viduals with ulcerative colitis, the risk of cancer seems to begin after 8 to 10 years, increasing at a rate of 0.5 to 1.0% each year. Some studies report the absolute risk as 2 to 5% at 10 years, 8 to 10% at 20 years, and 20 to 30% at 30 years.17 Patients with disease extending proximal to the splenic fl exure (pancolitis), patients with IBD diagnosed at a young age,18 and those with colitis-associated sclerosing cholangitis are at highest risk.

    In patients with ulcerative colitis, cancers may develop in any portion of the large bowel. These tumors are usually diagnosed in the fourth decade of life and apparently carry the same prognosis as colon cancer in general.19 However, accurate diagnostic endoscopy in the setting of active colitis is diffi cult, and for this reason, patients with IBD often pres-ent with late-stage disease. Because all of the screening tests commonly used (including repetitive biopsies) are problem-atic,20 most patients with long-standing colitis will eventu-ally benefi t from prophylactic surgery (proctocolectomy). The risk of CRC is also greater in individuals with Crohn colitis. The cancer risk in patients with Crohn colitis appears


    APC/-catenin K-ras/BRAF DCC/SMAD4/SMAD2 p53 Other Changes?