One Colon Lumen but Two Organs

The colon is a remarkable organ in that it manages the final products of digestion after nutrient assimilation, and packages it as waste to expel. The colon has the highest bacterial load of any organ, with commensal bacteria occupying a niche that prevents noncommensal organisms from expanding, and some bacteria producing vitamins that can be utilized. It is the colon, with its local environmental influences on intrinsic stem cells and an individual's genetic background, that makes this organ the third most common site for cancer in men or women and the site with the second highest cause for cancer deaths overall.1Jemal A. Siegel R. Xu J. et al.Cancer statistics, 2010.CA Cancer J Clin. 2010; 60: 277-300Google Scholar Because of the risk for cancer, early detection is key, and men and women are screened according to the latest guidelines to detect cancers and its precursor lesion, the adenoma, in hopes of reducing the cancer incidence and to intervene early to save lives.2Levin B. Lieberman D.A. McFarland B. et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology. 2008; 134: 1570-1595Google Scholar The relatively high risk for colon cancer in the population has led to the development of multiple tests that can either detect adenomas and/or cancer, with each having variable sensitivities and specificities.2Levin B. Lieberman D.A. McFarland B. et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology. 2008; 134: 1570-1595Google Scholar Colonoscopy in particular has been advocated because of its relative high sensitivity, and its diagnostic and therapeutic capabilities for both adenomas and cancer. Although it is the gold standard for colonic neoplasia detection, colonoscopy can miss lesions that may be related to the endoscopist's expertise or thoroughness,3Chen S.C. Rex D.K. Endoscopist can be more powerful than age and male gender in predicting adenoma detection at colonoscopy.Am J Gastroenterol. 2007; 102: 856-861Google Scholar although other factors may be related to the biology and growth characteristics of neoplasia that occur within the colon. Fundamentally, the colon is 1 organ, but develops from 2 different embryonic areas of the primitive gut: the midgut, which gives rise to the small intestine through to the proximal two thirds of transverse colon, and the hindgut, which gives rise to the distal third of the transverse colon through the upper anal canal.4Jacobs E.T. Thompson P.A. Martínez M.E. Diet, gender, and colorectal neoplasia.J Clin Gastroenterol. 2007; 41: 731-746Google Scholar Functionally, the proximal colon absorbs most of the remaining water from the incoming digestive contents utilizing effective haustral shuttling, whereas the remainder of the colon utilizes peristalsis as its primary motility characteristic, and lubricates the remaining waste as it becomes more solid while progressing toward the rectum. The right colon “sees” bile acids and other metabolites that have escaped the small intestine's reuptake or detoxifying mechanisms, and in a form before colonic bacterial action on the metabolites. Genetic profiling of normal right and left colon confirm major differences between sites of this endodermally derived organ: There are >165 genes showing >2-fold and 49 genes showing >3-fold differences in gene expression between the adult human right and left colon.5Glebov O.K. Rodriguez L.M. Nakahara K. et al.Distinguishing right from left colon by the pattern of gene expression.Cancer Epidemiol Biomarkers Prev. 2003; 12: 755-762Google Scholar The development of neoplasia likewise differs by site within the colon. As we age, a left-to-right colon cancer shift ensues between the seventh and eighth decades of life.6Takada H. Ohsawa T. Iwamoto S. et al.Changing site distribution of colorectal cancer in Japan.Dis Colon Rectum. 2002; 45: 1249-1254Google Scholar Females are more likely to develop proximal cancers whereas males develop more distal cancers,4Jacobs E.T. Thompson P.A. Martínez M.E. Diet, gender, and colorectal neoplasia.J Clin Gastroenterol. 2007; 41: 731-746Google Scholar suggesting the possibility of hormonal influences on incidence. African Americans have higher prevalence of adenomas >9 mm proximally compared with Caucasians, and have a higher prevalence of proximal cancers.7Lieberman D.A. Holub J.L. Moravec M.D. et al.Prevalence of colon polyps detected by colonoscopy screening in asymptomatic black and white patients.JAMA. 2008; 300: 1417-1422Google Scholar, 8Carethers J.M. Should African Americans be screened for colorectal cancer earlier?.Nat Clin Pract Gastroenterol Hepatol. 2005; 2: 352-353Google Scholar Adjuvant and neoadjuvant treatment of colon cancer is different based on site, with rectal cancers being treated at earlier stages (stage II) with addition of radiation treatment to chemotherapy, compared with more proximal stage III cancers and no radiation.9Carethers J.M. Systemic treatment of advanced colorectal cancer: tailoring therapy to the tumor.Ther Adv Gastroenterol. 2008; 1: 33-42Google Scholar Treatment responses indicate biological behavior differences for site-specific colon cancers.10Grady W.M. Carethers J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis.Gastroenterology. 2008; 135: 1079-1099Abstract Full Text Full Text PDF Scopus (662) Google Scholar Morphologic and genetic differences of colonic neoplasia are observed based on site within the colon. Laterally spreading tumors, a type of superficial “flat” spreading neoplasm, are commonly found in the right colon, and can be difficult to detect without enhanced endoscopic methods.11Kaku E. Oda Y. Murakami Y. et al.Proportion of flat- and depressed-type and laterally spreading tumor among advanced colorectal neoplasia.Clin Gastroenterol Hepatol. 2011; 9: 503-508Google Scholar These lesions are much more likely to contain cancer than their polypoid counterparts,11Kaku E. Oda Y. Murakami Y. et al.Proportion of flat- and depressed-type and laterally spreading tumor among advanced colorectal neoplasia.Clin Gastroenterol Hepatol. 2011; 9: 503-508Google Scholar and their lack of exophytic growth has been attributed to lack of KRAS mutation.12Yashiro M. Carethers J.M. Laghi L. et al.Genetic pathways in the evolution of morphologically distinct colorectal neoplasms.Cancer Res. 2001; 60: 2676-2683Google Scholar Microsatellite instability (MSI), seen in up to 20% of sporadic cancers and prevalent in proximal cancers, is caused by hypermethylation of the DNA mismatch repair gene hMLH1 (through the CpG island methylator phenotype [CIMP] pathway), and these tumors lack mutated KRAS but contain the V600E BRAF mutation.10Grady W.M. Carethers J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis.Gastroenterology. 2008; 135: 1079-1099Abstract Full Text Full Text PDF Scopus (662) Google Scholar, 13Leggett B. Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis.Gastroenterology. 2010; 138: 2088-2100Google Scholar Sessile serrated adenomas are associated with and progress to right-sided colon cancers, have BRAF mutation, and often manifest MSI from methylation of hMLH1, strongly suggesting that these mutations drive the development of these morphologically low profile and proximally located MSI tumors.13Leggett B. Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis.Gastroenterology. 2010; 138: 2088-2100Google Scholar All of these morphogenetic findings are likely unified in defining a pathogenic pathway in the right colon. One ascertained clinical consequence is that either the presence of CIMP or MSI in a patient's colon cancer predicts a lack of improved survival response with 5-fluorouracil–based chemotherapy.14Ribic C.M. Sargent D.J. Moore M.J. et al.Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.N Engl J Med. 2003; 349: 247-257Google Scholar, 15Carethers J.M. Smith E.J. Behling C.A. et al.Use of 5-fluorouracil and survival in patients with microsatellite unstable colorectal cancer.Gastroenterology. 2004; 126: 394-401Google Scholar, 16Jover R. Nguyen T.P. Pérez-Carbonell L. et al.5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer.Gastroenterology. 2011; 140: 1174-1181Abstract Full Text Full Text PDF Scopus (161) Google Scholar Detection of proximal serrated polyps appears to be endoscopist dependent,17Kahi C.J. Hewett D.G. Norton D.L. et al.Prevalence and variable detection of proximal colon serrated polyps during screening colonoscopy.Clin Gastroenterol Hepatol. 2011; 9: 42-46Google Scholar and their presence at screening increases interval neoplasia during surveillance.18Schreiner M.A. Weiss D.G. Lieberman D.A. Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia.Gastroenterology. 2010; 139: 1497-1502Abstract Full Text Full Text PDF Scopus (201) Google Scholar Are there screening differences for mortality based on colonic site? The best evidence suggests that there is.19Baxter N.N. Goldwasser M.A. Paszat L.F. et al.Association of colonoscopy and death from colorectal cancer.Ann Intern Med. 2009; 150: 1-8Google Scholar, 20Brenner H. Chang-Claude J. Seiler C.M. et al.Protection from colorectal cancer after colonoscopy: a population-based, case-control study.Ann Intern Med. 2011; 154: 22-30Google Scholar At worst, colonoscopy does not improve mortality from proximal cancers,19Baxter N.N. Goldwasser M.A. Paszat L.F. et al.Association of colonoscopy and death from colorectal cancer.Ann Intern Med. 2009; 150: 1-8Google Scholar and at best, it improves it markedly but to a lesser extent than from distal cancers.20Brenner H. Chang-Claude J. Seiler C.M. et al.Protection from colorectal cancer after colonoscopy: a population-based, case-control study.Ann Intern Med. 2011; 154: 22-30Google Scholar Perhaps the colon should be considered 2 organs matching its embryonic origin, with varying approaches for site-specific screening based on the observed morphologic, genetic, racial, gender, age, detection, and mortality differences of proximal colonic neoplasia compared with distal lesions. Akin to unseen moisture on the road after it freezes, right-sided lesions progressing through neoplastic development may be the “black ice” of the colon. Strategies to better recognize and detect right-sided lesions (eg, optical, dye based, genetic, etc) may need to be pursued in a broader fashion for these apparently more difficult to identify lesions, in order to make the impact on par with the beneficial effect observed with screening for left-sided lesions.