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The Increasing Incidence of Young-Onset Colorectal Cancer: A Call to Action

Published:January 06, 2014DOI:https://doi.org/10.1016/j.mayocp.2013.09.006

      Abstract

      In the United States, colorectal cancer (CRC) is the third most common and second most lethal cancer. More than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) have a young onset (ie, occurring in individuals younger than 50 years). The CRC incidence and mortality rates are decreasing among all age groups older than 50 years, yet increasing in younger individuals for whom screening use is limited and key symptoms may go unrecognized. Familial syndromes account for approximately 20% of young-onset CRCs, and the remainder are typically microsatellite stable cancers, which are more commonly diploid than similar tumors in older individuals. Young-onset CRCs are more likely to occur in the distal colon or rectum, be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Yet, stage-specific survival in patients with young-onset CRC is comparable to that of patients with later-onset cancer. Primary care physicians have an important opportunity to identify high-risk young individuals for screening and to promptly evaluate CRC symptoms. Risk modification, targeted screening, and prophylactic surgery may benefit individuals with a predisposing hereditary syndrome or condition (eg, inflammatory bowel disease) or a family history of CRC or advanced adenomatous polyps. When apparently average-risk young adults present with CRC-like symptoms (eg, unexplained persistent rectal bleeding, anemia, and abdominal pain), endoscopic work-ups can expedite diagnosis. Early screening in high-risk individuals and thorough diagnostic work-ups in symptomatic young adults may improve young-onset CRC trends.

      Abbreviations and Acronyms:

      APC (annual percent change), CRC (colorectal cancer), FAP (familial adenomatous polyposis), FDR (first-degree relative), HR (hazard ratio), MSS (microsatellite stable), PCP (primary care physician), SEER (Surveillance, Epidemiology, and End Results)
      Colorectal cancer (CRC), the third most common and second most lethal cancer in the United States, is also the leading cause of cancer-related deaths among nonsmokers.
      • Richardson L.C.
      • Rim S.H.
      Vital signs: colorectal cancer screening among adults aged 50-75 years—United States, 2008.
      The American Cancer Society estimated that 143,460 new CRC cases and 51,690 CRC deaths occurred in 2012.
      American Cancer Society
      Cancer Facts & Figures 2012.
      • Siegel R.
      • Naishadham D.
      • Jemal A.
      Cancer statistics, 2012.
      Despite these sobering statistics, the Centers for Disease Control and Prevention reported statistically significant decreases in CRC incidence and mortality from 1999 through 2008 for both men and women and in virtually all racial and ethnic groups.
      • Eheman C.
      • Henley S.J.
      • Ballard-Barbash R.
      • et al.
      Annual report to the nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity.
      These decreases are partially attributed to population-based CRC screening, which was first recommended in 1977 and became a Healthcare Effectiveness Data and Information Set performance measure in 2003.
      • Edwards B.K.
      • Ward E.
      • Kohler B.A.
      • et al.
      Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates.
      • Eddy D.
      ACS report on the cancer-related health checkup.
      • Sarfaty M.
      • Myers R.E.
      The effect of HEDIS measurement of colorectal cancer screening on insurance plans in Pennsylvania.
      Although average-risk screening is generally recommended to begin at 50 years of age, more than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) occur in younger individuals, and incidence and mortality are increasing significantly in this age group.
      • Edwards B.K.
      • Ward E.
      • Kohler B.A.
      • et al.
      Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates.

      National Cancer Institute. State Cancer Profiles. http://statecancerprofiles.cancer.gov/recenttrend/recenttrend.html. Accessed November 18, 2012.

      • O’Connell J.B.
      • Maggard M.A.
      • Livingson E.H.
      • et al.
      Colorectal cancer in the young.
      • You Y.N.
      • Xing Y.
      • Feig B.W.
      • et al.
      Young-onset colorectal cancer: is it time to pay attention?.
      • Meyer J.E.
      • Narang T.
      • Schnoll-Sussman F.H.
      • et al.
      Increasing incidence of rectal cancer in patients aged younger than 40 years: an analysis of the Surveillance, Epidemiology, and End Results database.
      • Siegel R.L.
      • Jemal A.
      • Ward E.M.
      Increase in incidence of colorectal cancer among young men and women in the United States.
      • Zbuk K.
      • Sidebotam E.L.
      • Bleyer A.
      • La Quaglia M.P.
      Colorectal cancer in young adults.
      • Dozois E.J.
      • Boardman L.A.
      • Suwanthanma W.
      • et al.
      Young-onset colorectal cancer in patients with no known genetic predisposition: can we increase early recognition and improve outcome?.
      • O’Connell J.B.
      • Maggard M.A.
      • Liu J.H.
      • et al.
      Do young colorectal cancer patients have worse outcomes?.
      • Varma J.R.
      • Sample L.
      Colorectal cancer in patients aged less than 40 years.
      We describe incidence and mortality trends, clinical characteristics, and outcomes of CRC in individuals younger than 50 years (young-onset CRC). We aim to raise awareness of young-onset CRC and to instruct primary care physicians (PCPs) in how to help reduce the burden of young-onset CRC.

      Young-Onset CRC Incidence and Mortality

      In Americans younger than 50 years, CRC incidence per 100,000 individuals ranges from 0.85 (ages 20-24 years) to 28.8 (ages 45-49 years).

      Surveillance Epidemiology and End Results. Fast Stats. http://seer.cancer.gov/faststats/selections.php?#Output. Accessed October 1, 2012.

      Although these rates are substantially lower than those in older age groups, the incidence has increased significantly in younger individuals and decreased in older individuals (Figure 1). The national 1987-2006 Surveillance, Epidemiology, and End Results (SEER) data (Figure 2, A-C) reveal increased colon and rectal cancer incidence in all 5-year age groups between 20 and 49 years, with the sharpest increases among individuals 40 to 44 years old (10.7 per 100,000 population in 1988 and 17.9 per 100,000 population in 2006).
      • Davis D.M.
      • Marcet J.E.
      • Frattini J.C.
      • et al.
      Is it time to lower the recommended screening age for colorectal cancer?.
      Figure thumbnail gr1
      Figure 1Surveillance, Epidemiology, and End Results age-adjusted colorectal cancer incidence per 100,000 individuals in those younger than 50 years (A) and those 50 years or older (B).
      Figure thumbnail gr2
      Figure 2Surveillance, Epidemiology, and End Results age-adjusted incidence per 100,000 individuals by age and year for colorectal cancer (A), colon cancer (B), and rectal cancer (C).
      In the National Cancer Database, a hospital-based cancer registry capturing 70% of all incident cancers in the United States, young-onset CRC incidence increased from 1998 to 2007 (annual percent change [APC], 2.1%; 95% CI, 1.1%-3.1%), whereas later-onset incidence decreased (APC, −2.5%; 95% CI, −3.0% to −2.0%).
      • You Y.N.
      • Xing Y.
      • Feig B.W.
      • et al.
      Young-onset colorectal cancer: is it time to pay attention?.
      As in SEER, young-onset rectal cancer incidence (APC, 3.9%; 95% CI, 3.1%-4.7%) increased more rapidly than young-onset colon cancer (APC, 2.7%; 95% CI, 2.0%-3.3%). Compared with later-onset disease, young-onset CRC was more common among nonwhite individuals and among those who were either uninsured or Medicaid insured.
      The CRC mortality trends mirror incidence trends. Age-adjusted young-onset CRC mortality rates in 2005-2009 ranged from 0.2 per 100,000 population (ages 20-24 years) to 7.7 per 100,000 population (ages 45-49 years).

      Surveillance Epidemiology and End Results. Fast Stats. http://seer.cancer.gov/faststats. Accessed November 18, 2012.

      The mortality rate for those with young-onset CRC remained stable between 1975 and 2004, then increased by approximately 2% annually through 2009. By contrast, the age-adjusted mortality rate in older individuals decreased by 2% to 3% annually between 1992 and 2009.

      Why is Young-Onset CRC Increasing?

      Drivers of increasing young-onset CRC incidence are not well understood. In the absence of rigorous epidemiologic studies, it is noteworthy that young-onset CRC incidence increased, whereas CRC risk factors, such as sedentary lifestyle, obesity, and diabetes mellitus, were common or increasing.
      Centers for Disease Control and Prevention
      Trends in leisure-time physical inactivity by age, sex, and race/ethnicity—United States, 1994-2004.
      • Flegal K.M.
      • Carroll M.D.
      • Ogden C.L.
      • Johnson C.L.
      Prevalence and trends in obesity among US adults 1999-2000.

      Centers for Disease Control and Prevention. Percentage of civilian, noninstitutionalized population with diagnosed diabetes, by age, United States, 1980-2010. http://www.cdc.gov/diabetes/statistics/prev/national/figbyage.htm. Accessed September 13, 2012.

      Each 5-unit increase in body mass index is associated with an estimated 13% to 18% increase in CRC risk.
      • Siegel R.
      • Naishadham D.
      • Jemal A.
      Cancer statistics, 2012.
      • Pan S.Y.
      • DesMeules M.
      Energy intake, physical activity, energy balance, and cancer: epidemiologic evidence.
      Diabetes mellitus has been associated with up to a 38% (summary relative risk 95% CI, 1.26-1.51) increase in colon cancer risk and a 20% increase in rectal cancer risk (95% CI, 1.09-1.31).
      • Yuhara H.
      • Steinmaus C.
      • Cohen S.E.
      • et al.
      Is diabetes mellitus an independent risk factor for colon cancer and rectal cancer?.
      Similarly, regular physical activity is associated with a 24% to 31% reduction in CRC risk.
      • Wolin K.Y.
      • Yan Y.
      • Colditz G.A.
      • Lee I.M.
      Physical activity and colon cancer prevention: a meta-analysis.
      These risk factors alone do not explain the observed trends in young-onset CRC because they are common or increasing in older age groups in which CRC incidence decreased.
      Screening for CRC in average-risk individuals is credited as the largest single driver of decreasing CRC incidence and mortality overall. From 1990 to 2010, screening adherence increased to approximately 65% for individuals 50 to 70 years old, with concurrent decreases in CRC incidence.
      • Edwards B.K.
      • Ward E.
      • Kohler B.A.
      • et al.
      Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates.
      • Joseph D.A.
      • King J.B.
      • Miller J.W.
      • et al.
      Prevalence of colorectal cancer screening among adults—Behavioral Risk Factor Surveillance System, United States, 2010.
      Average-risk screening is generally only recommended for individuals after 50 years of age. The fact that routine screening is largely confined to those older individuals might partially explain age-related disparities in CRC incidence and mortality trends. Additional epidemiologic research is needed, however, to better understand these trends.

      Distinctive Biology and Genetics of Young-Onset CRC

      Single-institution and population-based studies have found distinctive tumor location, stage at presentation, and histologic features in young-onset CRC.
      • You Y.N.
      • Xing Y.
      • Feig B.W.
      • et al.
      Young-onset colorectal cancer: is it time to pay attention?.
      • Lee P.Y.
      • Fletcher W.S.
      • Sullivan E.S.
      • Vetto J.T.
      Colorectal cancer in young patients: characteristics and outcomes.
      • Domergue J.
      • Ismail M.
      • Astre C.
      • et al.
      Colorectal carcinoma in patients younger than 40 years of age: Montpellier Cancer Institute experience with 78 patients.
      • Fairley T.L.
      • Cardinez C.J.
      • Martin J.
      • et al.
      Colorectal cancer in U.S. adults younger than 50 years of age 1998-2001.

      Mitchell EP, Topham A, Anne PR, et al. Colorectal cancer characteristics and outcomes in patients less than age 50: a comparison of an urban university hospital with the NCI SEER database [abstract]. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=101590. Accessed October 7, 2012.

      These tumors occur more often than later-onset tumors in the distal colon and the rectum (69.0% vs 57.7%, P<.001).
      • You Y.N.
      • Xing Y.
      • Feig B.W.
      • et al.
      Young-onset colorectal cancer: is it time to pay attention?.
      In individuals 35 to 39 years of age, 32% of CRC tumors occurred in the rectum. The percentages decreased in subsequent age groups to a low of 15.1% in the 85 years and older group.
      • Davis D.M.
      • Marcet J.E.
      • Frattini J.C.
      • et al.
      Is it time to lower the recommended screening age for colorectal cancer?.
      The proportion of rectal cancers occurring in young individuals recently reached 18%.
      Poorly differentiated histologic features and mucinous and signet ring features, which are common in young-onset disease, are typically associated with worse outcomes in CRC. In the National Cancer Database, mucinous and signet ring histologic subtype occurred more commonly in patients with young-onset CRC than in patients with older-onset CRC, although the differences were relatively small (12.6% vs 10.8%, P<.001).
      • You Y.N.
      • Xing Y.
      • Feig B.W.
      • et al.
      Young-onset colorectal cancer: is it time to pay attention?.
      Similarly, in SEER data (1991-1999) young patients (ages 20-40 years) were more likely than older patients (ages 60-80 years) to have mucinous CRC tumors (15.7% vs 11.5%, P<.001); the corresponding rates for signet ring cell tumors were 3.8% and 0.8% (P<.001).
      • O’Connell J.B.
      • Maggard M.A.
      • Liu J.H.
      • et al.
      Do young colorectal cancer patients have worse outcomes?.
      Tumors were also poorly differentiated in 27.3% of patients 20 to 40 years old vs 17.2% in patients 60 to 80 years old (P<.001) and anaplastic in 1.6% of the younger cohort vs 0.7% of the older cohort (P<.001). The reasons for these histologic differences are not yet known, but differences in the molecular biology of these tumors is one possible explanation.
      Young age of CRC onset is one of the hallmarks of hereditary CRC syndromes, and these syndromes contribute disproportionately to young-onset CRCs.
      • Gryfe R.
      • Kim H.
      • Hsieh E.T.
      • et al.
      Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.
      • Giraldez M.D.
      • Balaguer F.
      • Bujanda L.
      • et al.
      MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer.
      • Chang D.T.
      • Pai R.K.
      • Rybicki L.A.
      • et al.
      Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features.
      From a consecutive series of more than 1100 CRCs, Chang et al
      • Chang D.T.
      • Pai R.K.
      • Rybicki L.A.
      • et al.
      Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features.
      characterized 75 CRCs in patients younger than 40 years and found that 22% of these tumors were likely due to hereditary syndromes (17% due to abnormalities in DNA mismatch repair and 5% due to other genetic syndromes). Several studies have reported that the nonhereditary young-onset CRCs may have a unique molecular profile in that they are typically microsatellite stable (MSS) and have a lower frequency of aneuploidy and BRAF sequence variation, a lower frequency of the CpG island methylator phenotype, and a greater frequency of hypomethylation of LINE than older-onset MSS CRCs.
      • Chang D.T.
      • Pai R.K.
      • Rybicki L.A.
      • et al.
      Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features.
      • Antelo M.
      • Balaguer F.
      • Shia J.
      A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer.
      • Boardman L.A.
      • Johnson R.A.
      • Petersen G.M.
      • et al.
      Higher frequency of diploidy in young-onset microsatellite-stable colorectal cancer.
      • Chan T.L.
      • Curtis L.C.
      • Leung S.Y.
      • et al.
      Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes.
      • Goel A.
      • Nagasaka T.
      • Spiegel J.
      • et al.
      Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer.
      Young-onset CRC is more likely to be detected at an advanced stage. One large-scale study found that patients with young-onset CRC were significantly more likely to present with stage III/IV disease compared with patients with older-onset disease (colon cancer: 63.4% vs 49.0%, P<.01; rectal cancer: 57.3% vs 46.2%, P<.01).
      • You Y.N.
      • Xing Y.
      • Feig B.W.
      • et al.
      Young-onset colorectal cancer: is it time to pay attention?.
      Among patients with young-onset disease, advanced stage at diagnosis was more common in the youngest ages (ages 18-29 years: hazard ratio [HR], 1.4; 95% CI, 1.2-1.6; ages 30-39 years: HR, 1.2; 95% CI, 1.1-1.4; vs ages 40-49 years). Patients with young-onset CRC who were African American (HR, 1.2; 95% CI, 1.1-1.3; vs white race) and Medicaid insured or uninsured (uninsured: HR, 1.2; 95% CI, 1.1-1.3; Medicaid: HR, 1.6; 95% CI, 1.5-1.8; vs insured) were also more likely to present with stage III/IV disease.
      Later stage at diagnosis, possibly related to lower screening rates and/or failure to recognize and evaluate colonic symptoms in younger individuals, is concerning because it likely leads to worse prognosis. SEER data (1991-1999) confirm that young (ages 20-40 years) patients with colon cancer have a poorer overall 5-year survival compared with their 60- to 80-year-old counterparts (61.5% vs 64.9%; P=.02); stage-specific survival rates in patients with young-onset CRC, however, equal or exceed those of their counterparts with later-onset CRC, which may in part reflect a lower comorbidity burden and a tendency toward a higher treatment completion rate in younger patients (Table 1).
      • O’Connell J.B.
      • Maggard M.A.
      • Liu J.H.
      • et al.
      Do young colorectal cancer patients have worse outcomes?.
      • Chagpar R.
      • Xing Y.
      • Chiang Y.J.
      • et al.
      Adherence to stage-specific treatment guidelines for patients with colon cancer.
      The combination of a disproportionate share of Lynch syndrome and a poorly understood group of MSS diploid CRCs to young-onset CRCs may contribute to the higher frequency of poorly differentiated mucinous and signet ring cell CRCs without the worse prognosis usually associated with this histologic type. Ultimately, our knowledge regarding the molecular basis of most young-onset CRC remains limited, and more research in this area is needed.
      Table 1Five-Year Overall Survival Rates in Younger and Older Individuals Diagnosed as Having Colon Cancer
      AJCC = American Joint Committee on Cancer; NS = nonsignificant.
      ,
      Data from World J Surg.15
      AJCC stageSurvival rate (%)P value
      Younger (20-40 y) (n=1196)Older (60-80 y) (n=35,837)
      All61.564.9.02
      I93.394.9NS
      II88.682.7.01
      III58.957.2NS
      IV18.16.2<.001
      a AJCC = American Joint Committee on Cancer; NS = nonsignificant.
      b Data from World J Surg.
      • O’Connell J.B.
      • Maggard M.A.
      • Liu J.H.
      • et al.
      Do young colorectal cancer patients have worse outcomes?.

      High-Risk Individuals: Early Screening for Young Adults With Family History, Predisposing Conditions, or Hereditary Syndromes

      A family history of CRC or advanced adenomatous polyps in a first-degree relative (FDR), particularly if the CRC occurred before 60 years of age, can increase an individual’s CRC risk up to 4-fold.

      Sarfaty M. How to increase colorectal cancer screening rates in practice: a primary care clinician’s evidence-based toolbox and guide 2008. National Colorectal Cancer Roundtable, revised 2008. http://www.cancer.org/acs/groups/content/documents/document/acspc-024588.pdf. Accessed November 18, 2012.

      Approximately 10% to 15% of American adults have at least 1 FDR with CRC and are therefore at increased risk for this disease (Table 2).

      Sarfaty M. How to increase colorectal cancer screening rates in practice: a primary care clinician’s evidence-based toolbox and guide 2008. National Colorectal Cancer Roundtable, revised 2008. http://www.cancer.org/acs/groups/content/documents/document/acspc-024588.pdf. Accessed November 18, 2012.

      Individuals with an FDR younger than 60 years diagnosed as having CRC should begin screening either at 40 years of age or 10 years earlier than the youngest age at CRC diagnosis for any affected FDR.
      • Byers T.
      • Levin B.
      • Rothenberger D.
      • Dodd G.D.
      • Smith R.A.
      American Cancer Society Detection and Treatment Advisory Group on Colorectal Cancer
      American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997.
      • Austin G.L.
      • Goldstein J.I.
      • Peters S.L.
      • Ahnen D.J.
      Are colorectal cancer screening recommendations for first-degree relatives of patients with adenomas too aggressive?.
      • Lieberman D.A.
      • Rex D.K.
      • Winawer S.J.
      • et al.
      Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.
      • Qaseem A.
      • Denberg T.D.
      • Hopkins R.H.
      • et al.
      Screening for colorectal cancer: a guidance statement from the American College of Physicians.
      Adherence to these guidelines requires PCPs to discuss CRC-related family history with patients before 40 years of age, an approach also consistent with the American College of Physicians’ recommendation to complete CRC risk assessments for all adult patients.
      • Qaseem A.
      • Denberg T.D.
      • Hopkins R.H.
      • et al.
      Screening for colorectal cancer: a guidance statement from the American College of Physicians.
      • Levin 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.
      Table 2Family History and Individual Risk for Colorectal Cancer (CRC)
      Adapted from National Colorectal Cancer Roundtable,

      Sarfaty M. How to increase colorectal cancer screening rates in practice: a primary care clinician’s evidence-based toolbox and guide 2008. National Colorectal Cancer Roundtable, revised 2008. http://www.cancer.org/acs/groups/content/documents/document/acspc-024588.pdf. Accessed November 18, 2012.

      with permission.
      Family historyApproximate lifetime risk
      No history of CRC or adenoma (%)6
      One second-degree
      Second-degree relatives include grandparents, grandchildren, aunts, and uncles.
      or third-degree
      Third-degree relatives include great-grandparents and cousins.
      relative with CRC
      1.5-Fold increase
      One first-degree
      First-degree relatives include parents, siblings, and children.
      relative with an advanced adenomatous polyp
      2-Fold increase
      One first-degree relative with colon cancer2- to 3-Fold increase
      Two second-degree relatives with colon cancer2- to 3-Fold increase
      Two first-degree relatives with colon cancer3- to 4-Fold increase
      First-degree relative with CRC diagnosed at <50 y3- to 4-Fold increase
      a Second-degree relatives include grandparents, grandchildren, aunts, and uncles.
      b Third-degree relatives include great-grandparents and cousins.
      c First-degree relatives include parents, siblings, and children.
      Tools are available to help PCPs obtain a cancer-related family history and improve risk-based CRC screening. For example, the Office of the Surgeon General has developed a family history initiative portal to enhance the accuracy of the personal and family medical history.

      US Department of Health and Human Services. Surgeon General’s Family Health History Initiative. http://www.hhs.gov/familyhistory. Accessed September 13, 2012.

      Similarly, the National Colorectal Cancer Roundtable’s PCP toolkit also provides clinical information, lists common errors physicians may make in risk assessment and screening recommendations, and notes that an office-specific CRC screening policy, reminder system, and communication strategy can improve screening adherence and outcomes.

      Sarfaty M. How to increase colorectal cancer screening rates in practice: a primary care clinician’s evidence-based toolbox and guide 2008. National Colorectal Cancer Roundtable, revised 2008. http://www.cancer.org/acs/groups/content/documents/document/acspc-024588.pdf. Accessed November 18, 2012.

      Young age at onset is a hallmark of hereditary cancer syndromes. In addition to the general familial risk factors listed in Table 3, PCPs should be aware of the 2 most common hereditary CRC syndromes: Lynch syndrome (also termed hereditary nonpolyposis colorectal cancer) and familial adenomatous polyposis (FAP). The median age at CRC diagnosis among individuals with Lynch syndrome is 42 to 45 years, and 35% to 40% of individuals with this syndrome are diagnosed as having CRC before the age of 40 years.
      • Kastrinos F.
      • Stoffel E.M.
      • Balmana J.
      • Steyerberg E.W.
      • Mercado R.
      • Syngal S.
      Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States.
      • Goecke T.
      • Schulmann K.
      • Engel C.
      • et al.
      Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium.
      Many patients with hereditary nonpolyposis colorectal cancer will report a personal or family history that fulfills either the Amsterdam criteria or the Revised Bethesda Guidelines.
      • Evans D.G.
      • Walsh S.
      • Hill J.
      • McMahon R.T.
      Strategies for identifying hereditary nonpolyposis colon cancer.
      • Vasen H.F.
      • Mecklin J.P.
      • Khan P.M.
      • Lynch H.T.
      The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).
      • Umar A.
      • Boland C.R.
      • Terdiman J.P.
      • et al.
      Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.
      Any patient who meets either criteria should be referred to a genetic counselor, who will typically conduct more detailed assessment of familial risk and, when appropriate, initiate tumor microsatellite testing, immunohistochemical analysis of the mismatch repair genes or proteins, and confirmatory germline testing.
      Table 3Risk Classification
      Adapted from National Colorectal Cancer Roundtable,

      Sarfaty M. How to increase colorectal cancer screening rates in practice: a primary care clinician’s evidence-based toolbox and guide 2008. National Colorectal Cancer Roundtable, revised 2008. http://www.cancer.org/acs/groups/content/documents/document/acspc-024588.pdf. Accessed November 18, 2012.

      with permission.
      Risk levelDescription
      Average riskNo first-degree relatives with a history of either CRC or advanced adenomatous polyp and no personal history of colonic neoplasia or inflammatory bowel disease
      Increased riskPersonal or family history of CRC or adenomatous polyps but does not meet clinical criteria for one of the high-risk familial syndromes
      High-risk familial syndromesEvidence of a potential hereditary CRC syndrome (HNPCC, FAP, or others)
      CRC = colorectal cancer; FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer.
      Characterized by numerous (at least 100) adenomatous polyps in the large intestine, FAP affects approximately 1 in 15,000 to 1 in 8000 individuals, virtually all of whom will develop CRC by 50 years of age if left untreated. The median age for CRC development in this group of individuals is approximately 39 years; 7% have CRC by 20 years of age and 15% by 25 years of age.
      • Al-Sukhni W.
      • Aronson M.
      • Gallinger S.
      Hereditary colorectal cancer with DNA microsatellite instability.
      The median age for development of polyps in individuals with FAP is 16 years, and colonoscopy screenings are recommended to begin in these individuals either at 10 to 12 years of age or 10 years earlier than the earliest CRC diagnosis in the family, whichever comes first.
      • Winawer S.
      • Fletcher R.
      • Rex D.
      • et al.
      Colorectal cancer screening and surveillance: clinical guidelines and rationale—update based on new evidence.
      • Leddin D.
      • Hunt R.
      • Champion M.
      • et al.
      Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: guidelines for colon cancer screening.
      • Zauber A.G.
      • Lansdorp-Vogelaar I.
      • Knudsen A.B.
      • Wilschut J.
      • van Ballegooijen M.
      • Kuntz K.M.
      Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force.
      Assessing CRC risk in younger adults may not only result in earlier screening among high-risk young individuals but may also increase screening rates of average-risk individuals when they reach 50 years of age by introducing the concept of CRC screening earlier. Proactively identifying individuals with a family history or other predisposing factor, such as inflammatory bowel disease or a relevant hereditary syndrome (accounting for 6% of CRC cases), may also lead to recommending risk modification (eg, weight reduction, increased exercise, smoking cessation, and correction of vitamin D deficiency) or considering prophylactic surgery in certain cases.
      • Bleyer A.
      CAUTION! Consider cancer: common symptoms and signs for early detection of cancer in young adults.

      Evaluation of Colorectal Symptoms in Young Individuals

      Screening is relevant only for asymptomatic individuals. Once CRC symptoms arise, however, an expeditious work-up is essential for all patients. Unfortunately, lack of awareness of the increasing incidence of young-onset CRC and, consequently, a low suspicion of cancer may delay the thorough symptom evaluation needed to effectively establish or rule out young-onset CRC.
      Patients with young-onset CRC and their physicians both appear to contribute to delayed diagnosis. On average, symptomatic young patients may wait approximately 6 months before seeking medical care.
      • O’Connell J.B.
      • Maggard M.A.
      • Livingson E.H.
      • et al.
      Colorectal cancer in the young.
      The decision to seek care is a complex one, and lack of knowledge about the disease, lack of recognition of the potential seriousness of symptoms, embarrassment about and denial of symptoms, and limited social networks or support may all contribute to patient-mediated delays in symptom evaluation for all age groups.
      • Mitchell E.
      • Macdonald S.
      • Campbell N.C.
      • Weller D.
      • Macleod U.
      Influences on pre-hospital delay in the diagnosis of colorectal cancer: a systemic review.
      In adolescents and young adults, psychological factors (eg, sense of invincibility) and lack of insurance may also delay seeking care.
      • Bleyer A.
      CAUTION! Consider cancer: common symptoms and signs for early detection of cancer in young adults.
      • Bleyer A.
      • Barr R.
      • Hayes-Lattin B.
      • et al.
      The distinctive biology of cancer in adolescents and young adults.
      Once young patients present with colorectal symptoms, they may also encounter physician-related delays (eg, missed symptoms and initial misdiagnosis), which occur in 15% to 50% of young-onset CRC cases.
      • O’Connell J.B.
      • Maggard M.A.
      • Livingson E.H.
      • et al.
      Colorectal cancer in the young.
      By discussing CRC risk factors and symptoms, the importance of screening, and the value of early detection during routine visits, PCPs may help young patients be alert to symptoms and seek care earlier. Given the limited time for PCP-patient interactions, a team approach drawing on the expertise of physician assistants, nursing staff, and health educators may provide an effective way to educate young patients about CRC.
      In addition, PCPs can further reduce the risk of delayed or missed diagnoses by considering CRC as a real possibility in young patients who present with a suggestive family history and/or any of the common CRC symptoms (ie, rectal bleeding, abdominal pain, change in bowel habits, and anemia).
      • Liang J.
      • Church J.
      How to manage the patient with early-age-of-onset (<50 years) colorectal cancer?.
      Often the work-up of these symptoms involves endoscopy, and thus a prompt referral may be needed.
      The rate of CRC among men and women with rectal bleeding is approximately 25 times that of the general population.
      • Lawrenson R.
      • Logie J.
      • Marks C.
      Risk of colorectal cancer in general practice patients presenting with rectal bleeding, change in bowel habit or anaemia.
      A change in bowel habits is somewhat more indicative of CRC in men than in women. Anemia is also more predictive of CRC in men than in women because a number of other conditions may cause anemia in women. Although the rate ratios vary by symptom and for men and women, these data clearly underscore the importance of careful and timely symptom evaluation. The presence of a second symptom doubles the absolute risk of CRC in individuals for all age groups combined.
      • Liang J.
      • Church J.
      How to manage the patient with early-age-of-onset (<50 years) colorectal cancer?.
      Rectal bleeding is a common symptom, especially in combination with anemia, and should be thoroughly investigated. Bright red blood on the surface of brown stool or on toilet tissue along with brown stool or blood dripping or squirting into the bowl, for example, may suggest a distal lesion that can often be evaluated with sigmoidoscopy alone.
      Not all patients with CRC present with clear-cut colorectal symptoms. In a recent study, 86% of 1025 patients with young-onset CRC (mean age, 42.6 years for colon cancer patients and 42.2 years for rectal cancer patients) were symptomatic at diagnosis.
      • Dozois E.J.
      • Boardman L.A.
      • Suwanthanma W.
      • et al.
      Young-onset colorectal cancer in patients with no known genetic predisposition: can we increase early recognition and improve outcome?.
      Patients with rectal cancer were more likely to present with symptoms than those with colon cancer (90% vs 83%; P<.001). Clinical work-ups of the apparently asymptomatic patients revealed anemia (14%), positive fecal occult blood test result (7%), abdominal mass (2%), and mass on digital rectal examination (2%).
      Because most young-onset CRCs occur in the rectum, rectosigmoid colon, and distal colon, sigmoidoscopy may be particularly useful in establishing or ruling out young-onset CRC and can provide initial evaluation of outlet-type rectal bleeding (eg, bright red blood appearing during or after a bowel movement). However, in individuals younger than 55 years, 30% of lesions can occur proximal to the splenic flexure and would be missed by sigmoidoscopy.
      • Davis D.M.
      • Marcet J.E.
      • Frattini J.C.
      • et al.
      Is it time to lower the recommended screening age for colorectal cancer?.
      Colonoscopy is recommended if no anorectal cause is apparent for outlet bleeding and if bleeding persists, regardless of the patient’s age.
      • Bleyer A.
      CAUTION! Consider cancer: common symptoms and signs for early detection of cancer in young adults.
      Cost-effectiveness data are limited, but at least one study has reported colonoscopy to be cost-effective in evaluating individuals 25 to 45 years of age with rectal bleeding and no other symptoms.
      • Lewis J.D.
      • Brown A.
      • Localio A.R.
      • Schwartz J.S.
      Initial evaluation of rectal bleeding in young persons: a cost-effectiveness analysis.

      Should Average-Risk CRC Screening be Initiated Earlier?

      Population-based CRC screening for asymptomatic, average-risk individuals starting at 50 years of age is supported by the US Preventive Services Task Force, the Agency for Healthcare Policy and Research, the US Multi-Society Task Force, and various specialty organizations.
      • Qaseem A.
      • Denberg T.D.
      • Hopkins R.H.
      • et al.
      Screening for colorectal cancer: a guidance statement from the American College of Physicians.
      • Levin B.
      • Lieberman D.A.
      • McFarland B.
      • et al.
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      US Preventive Services Task Force
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      • Winawer S.J.
      • Fletcher R.H.
      • Miller L.
      • et al.
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      • Rex D.K.
      • Johnson D.A.
      • Lieberman D.A.
      • et al.
      Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology.
      From 1975 to 2000, screening has been credited with approximately half of the 22% decrease in CRC incidence and the 26% reduction in CRC mortality, with treatment and risk factor reductions accounting for the remaining gains.
      • Edwards B.K.
      • Ward E.
      • Kohler B.A.
      • et al.
      Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates.
      Because CRC risk varies somewhat by race and sex, subgroups of the average-risk population may benefit from different screening schedules. Research estimating that 10.9% of African Americans had CRC diagnosed before 50 years of age informed the American College of Gastroenterology and the American Society of Gastrointestinal Endoscopy recommendations for African Americans to begin screening at 45 years of age.

      American College of Gastroenterology. Colorectal Cancer Screening. http://gi.org/guideline/colorectal-cancer-screening. Accessed February 2, 2013.

      American Society of Gastrointestinal Endoscopy. Colorectal Cancer Screening. http://www.asge.org/press/press.aspx?id=552. Accessed September 12, 2012.

      However, evidence is currently insufficient to justify initiation of population-wide CRC screening among asymptomatic, average-risk patients who are younger than 50 years. Some researchers have suggested that average-risk screening might begin at the age of 40 years because the CRC incidence rate at the age of 40 years is similar to the cervical cancer rate that prompted the adoption of routine screening with Papanicolaou smears.
      • Davis D.M.
      • Marcet J.E.
      • Frattini J.C.
      • et al.
      Is it time to lower the recommended screening age for colorectal cancer?.
      The presumed benefits that earlier screening offers to these younger individuals would include better outcomes stemming from early detection and even cancer prevention through the detection and removal of polyps at the precancerous stage. On the other hand, decision analysis models have not identified substantial life-year gains for initiation of average-risk screening at the age of 40 years, in part because the overall adenoma prevalence at the age of 40 years is low, and there is not yet robust evidence of a more rapid adenoma-carcinoma sequence in younger individuals.
      • Zauber A.G.
      • Lansdorp-Vogelaar I.
      • Knudsen A.B.
      • Wilschut J.
      • van Ballegooijen M.
      • Kuntz K.M.
      Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force.
      Therefore, currently, the US Preventive Services Task Force and the US Multi-Society Task Force have deemed the current scientific evidence insufficient to justify this large-scale policy change.
      • Levin 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.

      US Preventive Services Task Force. Screening for Colorectal Cancer. http://www.uspreventiveservicestaskforce.org/uspstf/uspscolo.htm. Accessed September 12, 2012.

      There is also concern that making CRC screening recommendations more complex could be a barrier to increasing overall screening rates.
      • Lieberman D.A.
      • Rex D.K.
      • Winawer S.J.
      • et al.
      Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.
      US Preventive Services Task Force
      Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force.

      Conclusion

      In the United States, CRC incidence and mortality are increasing at a significant rate each year in men and women younger than 50 years and steadily decreasing in all other age groups. Primary care physicians can play a critical role in decreasing the incidence and mortality of young-onset CRCs by changing their approach to evaluating and educating their younger patients. Primary care physicians can use readily available tools to obtain a detailed family history, taken well before the age of 50 years, to assess each patient’s CRC risk and then recommend earlier screening to those who meet high-risk family or personal history criteria. Through referrals, genetic counselors can assess patients with suspected high-risk hereditary syndromes, and patients with a confirmed hereditary syndrome can be directed to appropriate screening protocols, prophylactic operations, and/or other risk modification strategies. In addition, PCPs have an important and immediate opportunity to improve detection of CRC in younger patients by maintaining awareness that CRC most often occurs in individuals with no family history or apparent risk factors and is increasingly occurring in individuals younger than 50 years. Young-onset CRC often presents at advanced stages in part due to patient-mediated delays and missed symptoms and misdiagnosis or delays in diagnosis by the physician. Referrals for sigmoidoscopy and colonoscopy should be used as appropriate for patients who present with unexplained persistent rectal bleeding, iron deficiency anemia, or recent and persistent alterations in bowel habits. Clinical studies are needed to estimate the potential decreases in young-onset CRC incidence and mortality from improved screening use in high-risk individuals and more effective diagnostic work-ups in younger symptomatic individuals. In the meantime, discussions of lowering the CRC screening age for some segments of the average-risk population are under way.

      Supplemental Online Material

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