Dig Dis Sci DOI 10.1007/s10620-014-3464-0

REVIEW

Colorectal Cancer in Young Adults Jennifer A. Inra • Sapna Syngal

Received: 14 July 2014 / Accepted: 24 November 2014 Ó Springer Science+Business Media New York 2014

Abstract The incidence and mortality rates of colorectal cancer (CRC) have been decreasing in adults over 50 years of age, however, these rates have been increasing in adults under 50. The majority of CRC in young adults is sporadic, and is likely due to behavioral and environmental causes, however the exact etiology still remains unclear. The minority of CRC in this population is due to inherited CRC syndromes. Young adults with CRC are often symptomatic (abdominal pain, rectal bleeding), and diagnosis is often delayed due to reasons such as under-utilized health care services, and physicians attributing symptoms to diagnoses other than CRC. Young adults with CRC often have more aggressive tumor characteristics, but they tend to have better survival rates when compared with older adults when matched for stage. Treatment is the same for young patients with CRC, however there are issues that arise in this population that do not necessarily affect older adults, such as the negative effect of chemotherapy/radiation on fertility. It is not clear that screening individuals for CRC at ages under 50 is beneficial or costeffective. Further studies are needed regarding this topic. Keywords Colorectal cancer
Young adults
Colorectal cancer screening
Review

J. A. Inra
S. Syngal Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA e-mail: [email protected] J. A. Inra
S. Syngal (&) Harvard Medical School, Boston, MA, USA e-mail: [email protected] S. Syngal Population Sciences Division, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA

Introduction Colorectal cancer (CRC) is the third most common cancer in women and in men. It is the second leading cause of cancer death in the USA and accounts for approximately 9 % of all cancer deaths [1]. CRC is infrequent before 40 years of age in average-risk individuals, and 85 % of CRC cases occur after 55 years old [2]. The likelihood of individuals less than 40 years old developing CRC is 1:1,200, as opposed to 1:25 for individuals over 70 [3]. For these reasons, CRC screening in average-risk adults less than 50 years old is not considered to be cost-effective. Over the past few decades, however, the incidence and mortality rates of CRC, particularly rectal cancer, in adults under 50 years old have been rising [4–6]. This review will address incidence trends, etiology, presentation and management of CRC in adults less than 50 years old.

Guidelines for CRC Screening in Average-Risk Individuals Multiple organizations have issued guidelines for CRC screening in average-risk individuals. A joint statement from the American Cancer Society (ACS), US MultiSociety Task Force (MSTF) on Colorectal Cancer and American College of Radiology (ACR) recommends several options for CRC screening, beginning at age 50 years in average-risk individuals and ending when an individual’s life expectancy is less than 10 years [7]. Their recommendations focus on the prevention of CRC through structural examinations (flexible sigmoidoscopy, colonoscopy, double-contrast barium enema or computed tomographic colonography at varying intervals) that detect and remove premalignant adenomas in addition to CRC. Stool-

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based tests (annual guaiac fecal occult blood test, annual fecal immunohistochemical test or stool DNA at varying intervals), which are used primarily to detect CRC and not polyps, were also recommended if individuals were unwilling or unable to undergo structural exams. A second set of guidelines, published by the US Preventive Services Task Force (USPSTF), recommend CRC screening in individuals ages 50–75 years and do not recommend barium enema, computed tomographic colonography or fecal DNA testing [2]. They also do not express a preference for structural exams over stool-based tests. Incidence and mortality rates of CRC in individuals over 50 years old in the USA have been declining over the past few decades. Specifically, over the last decade, the incidence and mortality rates decreased by 3.4 and 3 % per year, respectively, from 2003 to 2007 [8]. CRC incidence declined significantly in 35 states, and mortality declined in 49 states and Washington DC, with the highest rates of decline observed in the states with the highest screening rates. About 50 % of the decline in incidence has been attributed to increased screening and 50 % to changes in CRC risk factors, while about 50 % of the decline in mortality has been attributed to increased screening, 35 % to improvement in risk factors and 12 % to improved treatment for CRC [9]. In contrast to older individuals, the incidence rates of CRC in young adults have been increasing (Fig. 1); however, the cause of this trend is not well understood. Risk factors for CRC in young adults, which will be discussed in depth below, are also present in older adults. It has been postulated that since routine CRC screening omits young adults, CRC cannot be prevented in this group by removing premalignant polyps, and this may potentially explain a lack in the decrease in incidence [10]. In addition, the discrepancy may partially be due to detection bias, such that symptomatic younger adults may be screened and managed differently than older adults. Regardless, the causes for the increased incidence rates have not been well defined, and further study is warranted.

Incidence of CRC in Young Adults In contrast to the decreasing incidence of CRC in adults 50 years and older, there is an increasing incidence of CRC in young adults over the past few decades. A study by O’Connell et al. [6] analyzed SEER databases from 1973 to 1999 to determine CRC rates in 20- to 40-years-olds, a group where CRC screening is not recommended for individuals at average-risk. They found a colon cancer rate of 2.1 per 100,000 persons and a rectal cancer rate of 1.4 per 100,000 persons. In addition, there was a 17 and 75 % increase in the incidence of colon and rectal cancer, respectively, over this time period. This analysis, however, omitted individuals aged 40–49 years.

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Two subsequent studies using SEER databases corroborated the findings of O’Connell et al. and expanded their analyses by including the 40- to 49-year-old demographic group. Siegel et al. [5] examined the CRC incidence trends from 1992 to 2005. Incidence rates increased 1.5 % in men and 1.6 % in women per 100,000 individuals per year during this time period. Interestingly, the largest percent increase in CRC incidence was among adults ages 20–29 years, with an increase of 5.2 % in men and 5.6 % in women per year. Subset analysis stratified by location showed that this increase was primarily due to left-sided cancers, especially rectal cancers. In the second study, Austin et al. [4] looked at CRC rates from 1998 to 2005 for adults less than 50 years and again found that the rate of CRC was increased for male and female non-Hispanic whites during this time period, and the largest increase was observed for rectal cancer, followed by distal colon cancer. Most recently, a study by Bailey et al. [11] analyzed the age-related CRC incidence in the USA from 1975 to 2010, starting at age 20 years, again using SEER databases. They found that the overall age-adjusted CRC incidence rate decreased by 0.92 % over the time period examined; however, for patients 20–49 years old, the CRC cancer rate increased, with the most significant increase in patients aged 20–34 years, with an annual percentage change of 2 %. In addition, the annual incidence rate for CRC in this age-group increased for both localized CRCs as well as metastatic CRCs. Based on a predictive model, the authors predict that by the year 2030, CRC incidence will continue to increase for individuals younger than 50 years. They predict 1 in 10 colon cancers, and nearly 1 in 4 rectal cancers will be diagnosed in this age-group.

Behavioral and Environmental Etiologies of CRC The majority of CRC cases in young adults are sporadic in nature, and the etiology remains unclear. Several factors, however, have been proposed to contribute to the increasing rate of CRC in young adults, specifically unhealthy dietary choices and red meat consumption [12], physical inactivity [13] and obesity [14], all of which have become increasingly prevalent in the USA over the past decades. Between the 1970s and 1990s, the consumption of fast food in children (ages 2–17 years) and adults (ages 18 years and older) increased threefold to fivefold, and this fast-food diet generally contains a large amount of red and processed meat [15]. A meta-analysis by Larsson and Wolk [12] evaluated the association between red meat and processed meat consumption and the risk of CRC. They included almost 8,000 cases from 19 prospective studies through March 2006 and found a positive association between consumption of red or processed meat and risk of

Dig Dis Sci Fig. 1 Time trends of CRC incidence in USA. Modified from the website of the National Cancer Institute (http://www. cancer.gov). a Age under 50 years. b Age over 50 years

CRC. Specifically, individuals in the highest consumption category of red meat had a 28 % higher risk of CRC compared with individuals in the lowest category. The increased risk was 20 % for processed meat. In addition, the results were similar for men and women, and for individuals in the USA and Europe. This trend in unhealthy dietary choices in younger adults has been thought to contribute to the rising incidence of CRC. Additionally, a meta-analysis was conducted by Wolin et al. [13] to examine the association between physical activity and the risk of colon cancer. They included 54 case–control or cohort studies with a colon cancer end point through June 2008, and physical activity was defined as activity in a recreational, leisure, occupational or commuting setting. They demonstrated that individuals who have an active lifestyle had a 24 % lower risk of CRC than those who are sedentary. These active individuals had lower insulin resistance, a lower BMI and less adipose tissue, all factors that lead to decreased chronic inflammation and a lower risk of CRC. Declining rates of physical activity in children and young adults could contribute to the increasing CRC rate in this group.

Lastly, obesity, diabetes type 2 (DMT2) and metabolic syndrome (central obesity, hypertension, hyperglycemia, hyperlipidemia) are established risk factors for CRC in both men and women, and the rates of obesity and DMT2 in young adults continue to increase [14, 16]. Larson et al. [16] analyzed a total of 15 case–control and cohort studies to examine the relationship between DMT2 and CRC. They reported that DMT2 was associated with an increased risk of CRC in women and in men as compared to individuals without DMT2. This increased risk did not differ by cancer subsite or by geographic location (USA vs. Europe). In another study evaluating the relationship between obesity and CRC, it was found that the rate of CRC increased about 20 % in both men and women for every 5-unit increase in BMI, with a stronger association in men [14]. Taken together, all of these factors may be partially responsible for the increase in CRC rates in the young adult demographic. Recent studies have proposed that earlier CRC screening may be justified in patients with metabolic syndrome, who are typically considered ‘‘average-risk’’ (no family history of CRC or personal history of high-risk CRC syndromes). A study by Chang et al. [17] found that the overall prevalence of

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colonic neoplasms and advanced adenomas was increased in men ages 40–49 years with metabolic syndrome with or without cigarette smoking, as compared to women in the same age-group and average-risk women ages 50–59 years. The number of colonoscopies needed to detect one advanced adenoma in these younger men with metabolic syndrome and smoking, smoking alone, metabolic syndrome alone and women who are average-risk ages 50–59 years was 14.6, 24.8, 39.8 and 47.8, respectively. Their findings are similar to those of Hong et al. [18], who showed an increased risk of advanced adenomas in men ages 40–49 years with obesity or metabolic syndrome, but not in women. Whether the influence of metabolic syndrome, smoking and male gender status on the development of advanced adenomas and/or CRC in this age demographic warrants earlier CRC screening deserves further study using cost-effectiveness analyses and/or clinical studies. Lastly, young adults who are childhood cancer survivors often develop secondary cancers as a long-term complication of radiation treatment, and CRCs are among the most common secondary cancers. These CRCs tend to develop within the field of prior radiation. Nottage et al. [19] conducted a nested case–control study of patients who developed secondary CRC after treatment for malignancy in childhood and found that the development of CRC was not only dependent on the location of radiation, but was also dependent on both the radiation dose and volume, such that there was a 70 % increase in CRC risk for every 10-Gy increase in radiation dose. Other studies corroborate this association between childhood radiation exposure and development of CRC [20, 21]. Therefore, earlier screening in individuals who have undergone prior abdominal radiation may be justified, but once again has not been thoroughly evaluated from a population-based perspective.

Hereditary Etiologies of CRC When a young adult is diagnosed with CRC, inherited high-risk CRC syndromes, such as familial adenomatous polyposis (FAP), Lynch syndrome (LS), MUTYH-associated polyposis (MAP) and the less common hamartomatous polyposis syndromes (Peutz–Jeghers syndrome and juvenile polyposis syndrome), must be considered. Surprisingly, though, the minority of cases of CRC in young adults are due to these CRC syndromes. It is currently estimated that approximately 10 % of young-onset CRC is attributable to inherited syndromes; however, this has not yet been comprehensively studied. As genomic technologies improve, become more efficient and yield new discoveries, this estimate is likely to be refined (and possibly increase), in upcoming years. FAP is an autosomal dominant syndrome due to mutations in the APC gene. Clinically, classic FAP is

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characterized by hundreds to thousands of colonic adenomas which present in the second and third decades of life, while attenuated FAP (AFAP) typically has more than 10 but less than 100 adenomas with a later age of onset [22]. CRC in classic FAP occurs in nearly 100 % of individuals if prophylactic colectomy is not performed, with an average age of 45 years at cancer diagnosis. The lifetime risk of CRC is lower in AFAP and typically has a later age of onset. Individuals with LS also have a high risk of developing CRC over their lifetime, although the lifetime risk is lower than individuals with FAP [23]. The lifetime risk of CRC in individuals with Lynch syndrome is 50–80 % [23], with the average age of CRC onset of approximately 45 years. LS is thought to account for 1–3 % of all new cases of CRCs [24, 25]. These rates, however, are higher in individuals younger than 50 years. Limberg et al. [26] found that 5.6 % of individuals in a random sample of subjects who were diagnosed with CRC younger than 50 years old had LS, while Giraldez et al. [27] found that 7.8 % of individuals less than 50 years old in their sample of subjects with CRC had LS. In addition, it is not unusual to have multiple synchronous lesions at the time of initial CRC diagnosis, and metachronous lesions are also common [28]. MAP is an autosomal recessive disorder due to biallelic mutations in the MUTYH gene, a base excision repair gene. The clinical presentation of MAP is variable, with some individuals having a polyposis phenotype that resembles attenuated FAP [29] and others having a polyposis phenotype that resembles classic FAP [30]. It is also possible that individuals with MAP develop CRC in the absence of polyposis, or even any polyps [29]. Individuals typically present between the ages of 40 and 60, and the risk of CRC is as high as 80 % for biallelic MUTYH mutation carriers, with an average age of CRC diagnosis of 45 years [31]. The hamartomatous polyposis syndromes include Peutz–Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS). Although very rare, these inherited diseases are also associated with an increased risk of CRC. PJS is an autosomal dominant disorder due to mutations in the STK11 gene, and individuals have a lifetime risk of CRC that approaches 40 % [32]. JPS is another rare autosomal dominant disorder due to a mutation in the SMAD4 or BMPR1A gene. This disorder is characterized by juvenile polyps throughout the GI tract, and individuals often present with GI bleeding, pain or anemia. The risk of CRC approaches 40 %, and individuals also have elevated lifetime risks of gastric and small bowel cancers.

Surveillance in High-Risk Individuals Early-onset CRC due to prior childhood radiation, FAP, LS, MAP and the hamartomatous polyposis syndromes can

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be prevented by screening affected individuals, given that CRCs still arise from adenomas, as they do in average-risk individuals. In the inherited etiologies, a number of specific additional factors need to be taken into account, however. The adenoma to carcinoma sequence is significantly accelerated in Lynch syndrome, necessitating more frequent surveillance than those individuals who are at increased risk of sporadic tumors. In the polyposis syndromes, the sheer multitude of polyps may make effective surveillance problematic, due to the inability to remove or polyps and/or distinguish adenomas from hamartomas or hyperplastic polyps. Expert consensus guidelines for screening childhood cancer survivors who have previously received radiation therapy have been published due to the well-described risk of developing secondary CRC [33]. For survivors who are determined to be high-risk (abdominal, pelvic or spinal radiation of C30 Gy), CRC screening should begin at age 35 years, or 10 years post-radiation, whichever occurs last [33]. Colonoscopy should be repeated every 5 years, or more frequently based on results. For individuals with FAP, it is recommended that CRC screening begin at age 10–15 with an annual flexible sigmoidoscopy [32]. Once adenomas are detected, annual colonoscopy is recommended. For individuals with AFAP, it is recommended that screening start at age 20–25 years, and surveillance includes a colonoscopy every 1–3 years, depending on the number of polyps. For LS, colonoscopy is recommended at age 20–25 years, or 2–5 years prior to the earliest CRC diagnosis if diagnosed before age 25, with repeated colonoscopy every 1–2 years given the high cancer risk, the subtle endoscopic appearance of tumors and accelerated growth sequence from adenoma to carcinoma [32]. For MAP, CRC screening begins with colonoscopy at age 25–30 years and is repeated every 2–3 years if negative [32]. Once adenomas are found, colonoscopy is repeated every 1–2 years. In regard to PJS, no screening or surveillance recommendations have been validated by clinical trials, and the recommendations vary somewhat by expert group. Generally, individuals with PJS should have a baseline colonoscopy as early as age 8, but no later than 18, and have a repeat colonoscopy every 2–3 until age 50 years [32, 34]. After 50 years, colonoscopy should be repeated every 1–2 years [34]. Similarly, individuals with JPS should start CRC screening at age 15 years [32]. A repeat colonoscopy should be performed every 2–3 years if no polyps are found and annually if polyps are found. In addition, genetic testing for at-risk family members of affected individuals is recommended given the autosomal dominant inheritance of these syndromes (with the exception of MAP, which is an autosomal recessive syndrome).

It is recommended that individuals with ten or more cumulative adenomas without any other family history be considered for genetic evaluation and testing [32]. Recent evidence shows that increasing number of adenomas and young age of adenoma onset are strong predictors of carrying a mutation, specifically an APC mutation [35].

Presentation and Diagnosis O’Connell et al. [36] published a detailed systematic review of 55 articles pertaining to CRC in adults less than 40 years old in 2004. They found that CRC affects both young adult males and females in a similar proportion. Of the 5,051 individuals with CRC in their analysis, 51.4 % were men and 48.6 % were women. The location of CRC was predominately left-sided: 54 % of individuals had CRC in the rectum and sigmoid colon, while 22 % had tumors the ascending colon (cecum, ascending colon, hepatic flexure), 11 % in the transverse and 13 % in the descending colon (splenic flexure, descending colon). Not surprisingly, the majority of individuals present with symptoms at the time of diagnosis and few were detected by screening. Siegel et al. [5] also reported that 86 % of young adults were symptomatic at the time of diagnosis. Symptoms are often general and include abdominal pain (55 %), weight loss (35 %) and fatigue; however, younger patients also tended to have a predominance of ‘‘left-sided symptoms,’’ such as rectal bleeding (46 %) and change in bowel habits (32 %) [36]. Unfortunately, there is often a delay in CRC diagnosis in young adults, either due to patient-based factors or physician-based factors. One explanation is that young adults under-utilize healthcare services, partially due to the lack of health insurance [37]. The lack of health insurance and lack of medical evaluation clearly leads to a delay in time to cancer diagnosis. In addition, a delay in diagnosis may be due to the fact that physicians, as well as patients, do not attribute symptoms such as abdominal pain and rectal bleeding to cancer in young individuals and therefore do not pursue aggressive diagnostic testing. In the study by Siegel et al. [36], the average length of delay, when due to patient-related factors, was 6.2 months (range of days to 9 years) and the delay related to physician-related factors was 3–6 months. A common cause of medical malpractice litigation is the attribution of rectal bleeding in a young person to hemorrhoids without a proper evaluation. In addition, young adults with CRC tend to present with later stage tumors compared to older adults. This may be in part due to the delay in diagnosis. O’Connell’s review found that a greater percentage of patients less than 40 years old presented with Dukes’ C or D lesions (average of 66 %), as contrasted to patients over 40 years old (32 and 49.2 % for Dukes’ C and D lesions, respectively) [36].

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Tumor Characteristics and Molecular Biology Physician and patient-based factors are likely not the only causes of a later stage at presentation in young adults. Young adults often have more aggressive CRC tumor characteristics than older patients. Chiang et al. [38] found that older age favorably influenced the histopathologic characteristics of CRC (poor histopathologic findings include mucin-production, signet-ring histology and poorly differentiated tumors). Specifically, as age increased, there was a significant decrease in the proportion of mucinproducing tumors (including signet-ring cell and mucinous adenocarcinoma) in older adults compared to younger adults. In addition, the proportion of poorly differentiated CRC decreased as age increased. O’Connell et al. [36] also reported that, on average, mucinous tumors were found in 21 %, signet-ring tumors were found in 3 % and poorly differentiated tumors were found in 27 % of young adults. The molecular biology of CRCs in young adults appears to be different from older adults, such that CRCs in younger patients tend to have higher rates of microsatellite instability (MSI-H) [39–41]. Although one study by Gryfe et al. [39] that examined the frequency of MSI-H tumors in CRC samples from 607 individuals younger than 50 years old found that 17 % of CRCs were MSI-H, a proportion similar to older individuals, two additional case–control studies reported that MSI-H tumors were present in 58 % of CRCs in individuals 35 years or younger [40] and 47 % of CRCs in individuals 40 years or younger [41]. Chan et al. [42] showed that the rate of MSI-H tumors varied significantly with age, such that 60 % of individuals younger than 31 years had MSI-H tumors, while fewer than 15 % of individuals older than 46 years had MSI-H tumors. MSI-H tumors tend to have a better prognosis, and this may explain why young adults have improved survival rates than older adults when matched for stage at presentation [36, 39]. Gryfe et al. [39] found that young adults with MSI-H tumors had improved survival and were less likely to have metastatic disease to lymph nodes or distal organs, regardless of depth of tumor invasion, compared to microsatellite stable tumors. They also noted that 85 % of the patients with MSI-H tumors did not have a family history suggestive of LS.

Surgical Management of CRC and Surveillance after CRC The treatment of CRC in young adults is the same as it is for older adults. After diagnosis, CRC staging is performed with a CT scan of the chest, abdomen and pelvis to evaluate for metastatic disease, as recommended by the

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National Comprehensive Cancer Network [43]. Serum CEA levels are also obtained, specifically to help guide post-treatment follow-up. In addition, young adults with CRC should have MSI testing of their tumor to evaluate for the possibility of LS. For CRC in patients without a known genetic predisposition, regardless of age, segmental colectomy is the standard of care [32, 44]. For most patients who undergo an uncomplicated segmental colectomy, primary anastomosis can be accomplished. A temporary proximal diverting colostomy or ileostomy may be necessary in situations where perforation or peritonitis is present, in medically unstable patients, or in rectal cancer [45]. After resection, a surveillance colonoscopy is performed in 1 year, or in 3–6 months after surgery if a preoperative colonoscopy was incomplete or not performed [46, 47]. These recommendations do not vary based on age. If adenomas or sessile serrated adenomas are found, a colonoscopy is repeated in 1–3 years. If no adenomas are found, the colonoscopy is then repeated in 3 years. Intervals change based on findings of adenomas or in the presence of LS [31, 47]. For rectal cancers, rectal ultrasound or flexible sigmoidoscopy is performed every 3–6 months during the first 2 years after resection, due to the high rates of local recurrence as opposed to colon cancer. For other rarer syndromes, such as MAP, PJS and JPS, therapy can be individualized. Please see Table 1 for medical and surgical management of these syndromes.

Adjuvant Chemotherapy for CRC Similar to older adults, younger adults with stage II or III CRC, who have undergone potentially curative surgery, may undergo adjuvant chemotherapy in order to eradicate micrometastases [43]. Adjuvant chemotherapy reduces the likelihood of CRC recurrence and increases the cure rate. Adjuvant chemotherapy regimens for patients with CRC with positive nodes includes 6 months of an oxaliplatincontaining regimen (FOLFOX: 5-FU, leucovorin, oxaliplatin; CAPOX or XELOX: capecitabine, oxaliplatin) [48, 49]. For patients with low-risk stage II CRC (disease characterized by the absence of T4 tumor, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion or \10 lymph nodes examined), adjuvant chemotherapy is not beneficial. A meta-analysis of five trials which evaluated patients with stage II or III colon cancer who were randomly assigned to receive surgery alone or surgery followed by adjuvant 5-FU/leucovorin showed that the majority of benefit from adjuvant chemotherapy was seen in patients with stage III disease [50]. Similarly, a study by Schrag et al. [51] using SEER databases showed no significant difference in overall 5-year survival between

Genetic mutation and inheritance

APC mutation; autosomal dominant; 1/3 of mutations are de novo

MMR gene mutation (MLH1, MSH2, MSH6, PMS2) and EPCAM; autosomal dominant

FAP

LS

50–80 %

45 years (usually CRC)

Few adenomas, multiple cancers may be present at diagnosis (CRC and extraintestinal), CRCs are often right-sided, synchronous CRCs common

100s–1,000s of adenomas presenting at age 20s to 30s ± CRC

Cancers of the uterus, stomach, urinary tract, pancreas, biliary system, small intestine, skin

Duodenal/ampullary adenomas, thyroid cancer, desmoid tumors, fundic gland polyps, childhood hepatoblastomas, CNS tumors

None

Generally present with symptoms

Reported up to 36-fold increased risk compared to general population 100 %

None

Extraintestinal manifestations

Generally present with symptoms (rectal bleeding, change in bowel habits, abdominal pain); left-sided tumors [ right-sided tumors

Gastrointestinal presentation

1:1,200 for individuals less than 40 years

Lifetime risk of CRCa

45 years (polyps ± CRC)

Varied (but typically risk does not increase until 10 years after treatment)

None

Prior childhood radiation treatment

Genetic

Varied

None

Age of presentation

Sporadic

Behavioral and environmental

Etiology

Table 1 Etiologies of CRC in young adults

Segmental colectomy may also be performed

Subtotal colectomy with ileorectal anastomosis preferred

Prophylactic IPAA preferred when adenomas too numerous or CRC present; ileorectal anastomosis may also be performed

Initial endoscopic management of adenomas

Same as sporadic

Segmental colectomy ± chemotherapy/ radiation based on stage

Treatment of CRC

If segmental colectomy, colonoscopy every 1–2 years

If subtotal colectomy, surveillance of rectum with flexible sigmoidoscopy annually

Post-CRC:

Pre-CRC: begin at age 20–25 years, or 2–5 years prior to earliest LS CRC if before age 25 years. Repeat colonoscopy every 1–2 years

If IPAA or ileostomy, endoscopic evaluation of ileal pouch every 1–3 years depending on polyp burden

If ileorectal anastomosis, annual endoscopic surveillance of the rectum is required

Post-CRC:

Pre-CRC: begin at age 10–15 years with annual sigmoidoscopy. Annual colonoscopy once adenomas detected

Post-CRC: same as general population guidelines

Pre-CRC: Begin at age 35 years or 10 years post-radiation, whichever occurs last. Repeat every 5 years if normal

If rectal cancer, include rectal ultrasound or flexible sigmoidoscopy every 3–6 months for first 2 years

If colon cancer, colonoscopy in 1 year (or 3–6 months if not done preoperatively) followed by 3–5 years depending on findings

Post-CRC:

CRC surveillance recommendations

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Biallelic mutations in MUTYH gene; autosomal recessive

STK11 mutation; autosomal dominant

SMAD4 or BMPR1A mutation; autosomal dominant

MAP

PJS

JPS

May resemble classic FAP, attenuated FAP or earlyonset CRC in the absence of polyps

Multiple hamartomatous polyps of the gastrointestinal tract (most often in small bowel)

Multiple juvenile polyps in the gastrointestinal tract (can be few or close to 100 s)

Up to 80 %

Up to 40 %

40–50 %

45 years (polyps ± CRC)

Childhood or young adulthood (abdominal pain or bleeding from intussusception/ obstruction of small bowel by large polyps)

Childhood or young teens (bleeding, anemia most common; abdominal pain or obstruction)

Gastrointestinal presentation

Lifetime risk of CRCa

Age of presentation

Endoscopic polypectomy when able; referral to a surgeon when CRC diagnosed

Endoscopic polypectomy when able; referral to a surgeon when polyp burden too numerous, family history of CRC or CRC diagnosed

Mucocutaneous pigmentation (lips and buccal mucosa); breast, stomach, small intestine, sex cord, pancreatic cancers

Gastric and small bowel juvenile polyps, stomach cancer, hemorrhagic telangiectasias possible

a

In the absence of routine surveillance

Post-CRC: Same as general population guidelines

Pre-CRC: begin at age 15 years, repeat colonoscopy every 2–3 years if negative. Repeat annually once polyps detected

Post-CRC: Same as general population guidelines

Pre-CRC: begin between ages 8 and 18, repeat colonoscopy every 2–3 years until age 50 if negative. Once 50, repeat every 1–2 years. Repeat annually once polyps detected

Post-CRC: same as FAP

Pre-CRC: begin at age 20–25 years and repeat every 2–3 years if negative. Repeat every 1–2 years once adenomas detected

Subtotal colectomy with ileorectal anastomosis preferred

Gastric and duodenal polyps, duodenal cancer, osteomas, sebaceous gland tumors (all less common than FAP) IPAA if significant rectal polyposis that is not amenable to endoscopic management

CRC surveillance recommendations

Treatment of CRC

Extraintestinal manifestations

CRC colorectal cancer, FAP familial adenomatous polyposis, LS Lynch syndrome, MAP MUTYH-associated polyposis, IPAA ileal pouch anal anastomosis

Genetic mutation and inheritance

Etiology

Table 1 continued

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patients with stage II CRC treated and not treated with adjuvant chemotherapy (78 vs. 75 %). The use of adjuvant chemotherapy for high-risk stage II disease is controversial. These patients are generally treated with adjuvant chemotherapy due to their high-risk features [52], but there are no prospective randomizedcontrolled trials proving its benefit. O’Connor et al. [53] evaluated 43,032 Medicare beneficiaries with stage II and III primary CRC diagnosed from 1992 to 2005. They found a 5-year survival benefit from chemotherapy in patients with stage III CRC, but not in patients with stage II CRC, with or without high-risk features. Taking all of this information into account, NCCN guidelines do not routinely recommend adjuvant chemotherapy for stage II CRC given the unproven benefit [43]. However, they do recommend that the decision should be individualized and ultimately based on patient preference. If chemotherapy is desired, non-oxaliplatin-based regimens should be considered based on the significant side effect profile of oxaliplatin-based regimens (specifically peripheral neuropathy, which may be irreversible). On the other hand, as previously mentioned, patients with high-risk stage III CRC (T4 tumor, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion or \10 lymph nodes examined) benefit from adjuvant chemotherapy with or without oxaliplatin [54]. There is no role for adjuvant chemotherapy in stage I disease. These adjuvant chemotherapy regimens are more often used in younger patients. A study by Quah et al. [55] examined 1,327 patients with stage I, II and III CRC who underwent surgical resection at a single-center between 1990 and 2001; 5 % of patients were under 40 years of age. There were no differences in grade, stage or tumor features (lymphovascular invasion, mucinous tumor or perineural invasion) between the older and younger patients. They found that younger patients were more likely to receive adjuvant chemotherapy, even for node negative disease, than older patients, despite similar clinicopathologic features. This difference was most pronounced for the stage II CRC (39 vs. 14 %). The authors speculate that adjuvant chemotherapy is given to younger patients more often than their older counterparts because oncologists perceive that (1) younger patients have fewer comorbidities and therefore are better able to tolerate chemotherapy, and (2) younger patients have a worse prognosis due to their age.

bevacizumab, cetuximab and panitumumab (human monoclonal antibodies), aflibercept, regorafenib and fluoropyrimidines. Chemotherapy tries to prolong survival while maintaining a reasonable quality of life. This focus on palliation, and not cure, however, is sometimes not well understood by patients, especially with CRC [56]. In addition, some individuals with metastatic disease benefit from palliative surgery for symptoms of obstruction or bleeding.

Implications of Treatment One of the main concerns regarding chemotherapy for any cancer in the young adult population, as opposed to their older counterparts, is the negative effect on fertility. There are limited data, however, regarding infertility and chemotherapy. Very often, younger patients are being treated with chemotherapy during their prime reproductive years [57]. Preserving fertility is very important to cancer patients, and the thought of infertility as a result of cancer treatment may be associated with significant psychosocial distress. When considering CRC chemotherapy regimens specifically, 5-FU is associated with a temporary reduction in sperm count and a low risk of amenorrhea in women [57]. Currently, the long-term effects of oxaliplatin and the newer monoclonal antibodies on male and female reproductive systems are unknown. Radiation therapy does have a well-documented negative effect on fertility, causing ovarian damage and possible permanent infertility in women and decreased sperm count, motility or morphology in men, if the radiation field includes the ovaries or testes, respectively [39, 57]. Age at the time of radiation exposure, dose and location of radiation therapy are all related to the degree of infertility. Additionally, the uterus is extremely susceptible to radiation. Women who have received prior radiation therapy in this area often suffer complications of early pregnancy loss, premature labor and low birth weight due to alteration of the anatomy and vascular supply to the uterus [39, 58]. Clinicians treating this patient population should be prepared to discuss fertility preservation options or refer patients to specialists for consideration of sperm/embryo cryopreservation or other reproductive options.

Survival and Prognosis Management of Metastatic CRC For individuals with metastatic CRC, treatment with chemotherapy focuses on palliation and not cure. Chemotherapy options include 5-FU, irinotecan, oxaliplatin,

As previously stated, it is often assumed that younger patients with CRC have a less favorable prognosis than older patients due to their age [59]. In addition, older literature has reported poor outcomes (recurrence rates, 5-year survival) for young patients with CRC; however,

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these studies are limited by the fact that sample sizes are small and are reported from single centers only. Quah et al. [55] reported that survival and outcome were the same, if not better, in patients less than 40 years with CRC stages I–III as compared to their older counterparts, when matched for stage. Specifically, the local and distant recurrence rates were similar in older and younger patients (17 vs. 18 %), and after 55 months of follow-up, 5 year recurrence-free survival was similar in the older and younger patients (80 vs. 79 %). Lastly, the overall 5-year survival rate was significantly higher in the younger group, as compared to the older group (84 vs. 73 %). O’Connell et al. [59] also looked at this topic using a SEER database from 1991 to 1999, which included 1,334 young adults (ages 20–40 years) and 46,457 older adults (ages 60–80 years) with CRC. They found that younger patients had significantly more stage III and IV disease, had significantly worse histologic grades (more often poorly differentiated or anaplastic tumors) and had significantly more mucinous and signet-ring tumors than the older adults. Regarding treatment, younger patients and older patients were equally likely to undergo surgery (91.4 vs.

91.2 %, respectively), except for stage IV tumors, where older patients had surgery significantly less often than younger patients (74.6 vs. 83.2 %). In addition, the 5-year survival stratified by stage for younger patients versus older patients was similar for stage I and III disease (93.3 vs. 94.9 %; 58.9 vs. 57.2 %, respectively) and significantly better for younger patients with stage II and IV disease (88.6 vs. 82.7 %; 18.1 vs. 6.2 %).

Summary and Implications In summary, the rates of CRC in young adults less than 50 years have been increasing, while the rates in older adults have been decreasing, partially due to screening and modification of risk factors. Despite the rising incidence of CRC in young adults, national guidelines still recommend that CRC screening begins at age 50 years in average-risk individuals. The similarities and differences between CRC in younger and older individuals are summarized in Table 2. However, should CRC screening begin earlier than age 50, given the rising incidence of CRC in this younger age-

Table 2 Comparison of CRC by age Younger adults (\50 years)

Older adults (C50 years)

Incidence

1:1,200 for individuals less than 40 years

1:25 for individuals over 70 years

Presentation

Majority are symptomatic (abdominal pain, rectal bleeding, weight loss, change in bowel habits) and left-sided tumors predominate

May be symptomatic (abdominal pain, bleeding, weight loss, anemia) or asymptomatic (diagnosis is due to routine CRC screening); gradual increase in right-sided tumors

Tumor characteristics

More often unfavorable histopathologic characteristics (poorly differentiated, mucin-production, signet-ring cell histology)

More favorable histopathologic characteristic

Molecular Biology

High rates of microsatellite instability; rate increases with decreasing age (17–58 %)

Lower rates of microsatellite instability (10-mid 20 %)

Management

Sporadic: segmental colectomy ± chemotherapy/radiation (for high risk stage II or III CRC) if not widely metastatic; palliative chemotherapy/surgery if metastatic FAP: IPAA if polyps cannot be managed endoscopically

Sporadic: same

LS: subtotal/total colectomy

FAP: IPAA often favored over subtotal colectomy LS: subtotal colectomy often favored over total colectomy MAP: same

MAP: subtotal colectomy; IPAA if rectal polyp burden is significant Prognosis

Other implications

Similar local/distant recurrence rates as older patients

Similar local/distant recurrence rates as younger patients

Similar 5 year recurrence-free survival as older patients

Similar 5 year recurrence-free survival as younger patients

Higher overall 5 year survival than older patients, especially for stage II and IV disease

Lower overall 5 year survival than younger patients, especially for stage II and IV disease

CRC often treated during prime reproductive years, and possible negative effects of chemotherapy/radiation on ovary/uterus/testes

Due to advanced age and comorbidities, individuals with a 5 year recurrence-free survival may have a lower quality of life than younger patients

Treatment (specifically radiation therapy for rectal cancer) may also cause sexual dysfunction, including decreased libido, erectile dysfunction, dyspareunia CRC colorectal cancer, FAP familial adenomatous polyposis, LS Lynch syndrome, MAP MUTYH-associated polyposis, IPAA ileal pouch anal anastomosis

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group? Traditionally, the justification to start screening at age 50 years stems from the fact that 80 % of diagnosed cases of CRC occur in patients older than 55 years [2]. For all methods of CRC screening, starting at age 50 years resulted in a favorable balance between life-years gained and colonoscopy risks avoided. All recommended structural CRC screening modalities are invasive procedures that can cause serious morbidity, anxiety, inconvenience, discomfort and significant medical expenses. Starting earlier than 50 years, however, tips the balance so that the risks associated with screening outweigh the benefit of lifeyears gained. Further studies are needed to test the feasibility and cost-effectiveness of early CRC screening. For now, physicians should be attuned to younger patients who present with symptoms of CRC like rectal bleeding, especially in those with risk factors such as metabolic syndrome, obesity, DMT2, prior radiation for a childhood cancer, as well as a family history of CRC or malignancies that may increase the risk of CRC in family members (for example, Lynch-associated cancers such as endometrial cancer or sebaceous tumors). In addition, patients should be educated regarding symptoms of CRC that should cause them to seek medical attention. Lastly, further investigation is needed regarding additional environmental, behavioral and genetic risk factors for early-onset CRC. Acknowledgments The authors would like to thank Matthew Yurgelun, M.D. for thoughtful review and suggestions. Supported by NCI Grant K24 113433. Conflict of interest

None.

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