Colorectal Cancer in Young Adults Kevin Zbuk, a Emma L. Sidebotham, b Archie Bleyer, c and Michael P. La Quaglia b Colorectal cancer (CRC) is rare in young adults. It presents more frequently with stage 3 or 4 disease, underscoring its relevance in this population. Prognosis, matched for stage of disease at presentation, is likely similar to that in older adults, although survival is clearly lower for the youngest subgroups within this population. This article reviews the literature on the etiology, presentation, treatment, and outcome of CRC in young adults. New chemotherapeutic regimens have demonstrated survival benefits and the introduction of new biological agents has offered ways to control metastatic disease that may eventually show promise in the treatment of earlier-stage CRC. The benefit of these newer agents in young adults is assumed but currently unproven. Molecular genetic studies are increasing the understanding of the pathobiology of CRC and may ultimately allow at-risk patients to be identified at an earlier stage. Semin Oncol 36:439-450 © 2009 Elsevier Inc. All rights reserved. A pproximately 150,000 new cases of colorectal cancer (CRC) were diagnosed in the United States in 2008 and approximately 6% of these cases oc- curred in the first four decades of life, while 3% were diagnosed between the ages of 20 and 40 years. 1 The incidence of CRC rises exponentially up to the age of 40 years (Figure 1). Estimates from the Surveillance, Epide- miology and End Results (SEER) database are that 113 new diagnoses of CRC would occur yearly in the United States in the 20- to 25-year age group, but this number increases to greater than 1,400 in the 35- to 40-year age group. Additionally, the incidence of CRC in young adults has been increasing over the last 25 years, with the in- crease much more pronounced for rectal cancer than colonic cancer, while the incidence has remained rela- tively stable for older adults. 2 Equal proportions of males and females are affected, 1,3 but the proportion of cases occurring in African Americans may be somewhat higher in young adults compared with older patients. 3,4 PREDISPOSING SYNDROMES It is felt that most CRC in young adults is sporadic or due to predisposing factors that are currently unclear. A review suggests that only 16% of patients have a documented predisposing factor and 22% have a family history of CRC. 1 However, two well-characterized fa- milial syndromes, hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) and familial ad- enomatous polyposis (FAP), are more common in young adults with CRC. These autosomal dominantly inherited disorders are rare in adults, accounting for approximately 2% and 0.1%–1% of all adult cases of CRC, respectively. 5 HNPCC is characterized by an increased risk of CRC in the absence of polyposis, occurring at a relatively young age (median, 42– 45 years), 6 with 35%– 40% di- agnosed under 40 years of age. 7 In HNPCC, tumors are predominantly right-sided. In addition to CRC there is also an increased risk of extracolonic malignancies, including endometrium, ovary, stomach, small bowel, pancreas and biliary tract, ureter and renal pelvis, and brain (usually glial tumors, and when present in an individual with HNPCC, referred to as Turcot syn- drome). 8,9 The association of sebaceous gland adeno- mas and keratoacanthomas in HNPCC is referred to as Muir-Torre syndrome. 8,9 A clinical diagnosis of HNPCC is made by the fulfillment of the Amsterdam criteria (Table 1). 8,10 However, the stringency of the Amster- dam criteria makes it likely that a number of individuals or families, in whom genetic testing for HNPCC is warranted, may not be identified, especially among young adults without a strong family history. Durno et al identified 16 patients less than 24 years of age in their Toronto Cancer Registry from 1960 –2003; only 50% of patients satisfied the Amsterdam criteria, and three of five individuals (60%) not meeting Amsterdam criteria carried a mutation in a mismatch repair (MMR) gene (see below). 11 Therefore, more inclusive criteria such a Juravinski Cancer Center and McMaster University, Hamilton, Ontario, Canada. b Department of Surgery, Pediatric Surgical Service, Memorial Sloan- Kettering Cancer Center, New York, NY. c St. Charles Medical Center, Bend, OR. Supported in part by the Aflac Foundation. Address correspondence to Kevin Zbuk, MD, Department of Medical Oncology, Juravinksi Cancer Centre, Hamilton, Ontario, Canada L8V- 5C2. E-mail: Kevin.Zbuk@jcc.hhsc.ca 0270-9295/09/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2009.07.008 Seminars in Oncology, Vol 36, No 5, October 2009, pp 439-450 439