Although colorectal carcinoma (CRC) is the third most common cancer in adults,1 it is exceptionally rare in children, adolescents, and young adults, with an incidence of only about 1 per million persons below 20 years of age (Fig. 1).2 Because of the extreme rarity of the tumor in this age group, it may be difficult to develop a treatment plan when CRC is diagnosed. Pediatric case series, which are limited by relatively small numbers of patients and by referral bias, cannot serve as the basis of definitive treatment recommendations.3,4 Here we will briefly review what is known about the incidence, epidemiology, and clinical presentation of CRC in children, adolescents, and young adults and summarize the clinical options described in the peer-reviewed literature to provide a basis for management decisions by pediatric oncologists.
In 2010, approximately 142,000 patients in the United States were diagnosed with CRC and approximately 51,000 died of CRC.1 However, fewer than 100 cases are diagnosed each year in children, adolescents, and young adults (Fig. 1).4 CRC accounts for 2.1% of malignancies in the 15- to 29-year-old age group5 and has been reported in children as young as 9 months.2
In adults, CRC is more common in developed countries. Although the cause of this disparity is not well understood, dietary differences have been suggested as a major factor. Other factors reported to be associated with an increased incidence of CRC in adults include obesity,6 a high-calorie diet, high consumption and/or overcooking of red meat, excess alcohol consumption, sedentary lifestyle, and cigarette smoking.7 However, the disparate incidence in developed and undeveloped countries is more likely to reflect complex interactions among multiple factors, including genetics, lifestyle, and environment, as well as diet.2 Most of these factors are unlikely to exert a major effect in children. Although case series offer clues about the biological nature of CRC in patients under 20 years of age,3,8 definitive conclusions cannot be drawn from the small numbers of patients studied.
In adults, most cases of CRC occur sporadically, although approximately 20% to 30% have a possible genetic cause.9 Only about 5% of patients have a well-defined inherited genetic syndrome. The most common of these (3% to 5% of all patients) is hereditary nonpolyposis CRC or Lynch syndrome; the second most common (~1%) is familial adenomatous polyposis (FAP) or Gardner syndrome. The remainder are syndromes involving hamartomatous polyps, such as Peutz-Jeghers syndrome and familial juvenile polyposis.4 The incidence of these well-defined genetic syndromes in children with CRC cannot be clearly determined from available pediatric series.3,4,10–20 Because nearly every patient with FAP will eventually develop CRC if left untreated, the standard of care is prophylactic colectomy. However, the optimal timing of colectomy in children with FAP is unknown.13,21 Colonic polyps appear at a median age of 16 years22 but have been seen in children as young as 5 years.23 The majority of children with FAP who developed CRC had a severe polyposis phenotype (more than 1000 colonic polyps).12 CRC arises from the mucosal surface of the bowel; in adults, it usually arises from preexisting adenomas that are thought to progress to invasive carcinoma in a stepwise manner over a decade or more.5,24 The applicability of this model to children with CRC is unknown. There are several factors that argue for a different pathogenesis in children: (1) CRC has been seen in children as young as 9 months; (2) premalignant adenomas are rarely seen in proximity to sporadic CRC in children; and (3) CRC in children tends to be of mucinous histology.2,4
Most large series suggest that children tend to present with late-stage disease and mucinous histology and that they have a relatively poor outcome.3,4,10–12,14–20,25 However, a recent review of data from the Surveillance, Epidemiology, and End Results (SEER) program suggests that these findings may reflect reporting bias.5 Early signs of CRC are difficult to distinguish from common causes of abdominal complaints. Anemia, vague abdominal pain, bleeding, weight loss, and change in bowel habits have been reported as presenting complaints for children with colon cancer.2–4 In a recent review of 77 children with CRC who presented to St Jude Children’s Research Hospital, patients had experienced symptoms for a median of 3 months and most were anemic.3 All of the presenting complaints are so common in pediatric care that the possible diagnosis of CRC may be overlooked, whereas in an older adult the same complaints would prompt colonoscopy; this factor may be partially responsible for data suggesting later-stage disease at diagnosis in children. As in most other series (summarized in Saab and Furman4), 66 of 77 patients (86%) at St Jude presented with advanced-stage disease, 48 (62%) had mucinous histology, 33 (43%) had >10% signet-ring cells, and the 10-year event-free survival estimate overall was only 17.7%±5.1%.3 All of these parameters are “worse” than those reported in adults with CRC.1,26 However, while vigilance for pediatric CRC remains important, adult-type screening exams (eg, colonoscopy, routine fecal occult blood testing, and sigmoidoscopy) are not likely to be cost-effective and will generally identify many false positives in the absence of known risk factors.
DIAGNOSIS AND STAGING
Histopathologic examination of tissue is required for diagnosis. The procedure used to obtain tissue is best determined in consultation with surgical colleagues and depends on the patient’s clinical situation. Decisions about how tissue is to be obtained should take into account that surgery is the most important component of effective therapy. Complete evaluation of a patient with suspected CRC should include a chest x-ray, CT of the chest, abdomen, and pelvis, and a bone scan. Barium enema is sometimes used to help identify areas of concern before the diagnosis is made. At this point, the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) scans is unclear. This method appears to be less useful in detecting lesions of mucinous histology.27 Because mucinous lesions appear to predominate in children, FDG-PET scans may be less helpful in these patients. Other tests to consider include a total colonoscopy to identify other lesions or polyps, complete blood count, blood chemistry panel with liver enzymes, and typically a carcinoembryonic antigen (CEA) assay. Although this antigen is useful in adults28 to monitor disease and predict recurrence or progression, it is less likely to be useful in most pediatric cases. In a study by Rao et al,29 CEA levels in 9 of 23 pediatric patients did not correspond with either residual disease or disease progression. In a follow-up study, the same group concluded that CEA is not an effective marker for monitoring most children with CRC.30
Staging guidelines for adult patients should be applied to children with CRC. Currently the American Joint Commission on Cancer guidelines (http://www.cancerstaging.org/staging/posters/colon8.5x11.pdf)31 provide the most widely used staging system.
Only 1 small prospective clinical trial has been reported for CRC in pediatric patients,25 and therefore treatment recommendations must be adapted from experience in adults. Surgery is the mainstay of treatment, and patients whose tumors cannot be completely surgically resected are rarely cured. Resection should follow guidelines established in adults. The basic surgical principles are removal of the major vascular pedicle supplying the tumor along with its lymphatics, and en bloc resection of any organs or structures attached to the tumor. At least a 5 cm margin of normal bowel should be obtained on either side of the tumor to minimize the possibility of an anastomotic recurrence.32 Adequate lymph node resection is imperative, as some patients with stage III tumors can be cured by surgery alone. In particular, primary and secondary draining lymph node echelons should be removed. The number of lymph nodes examined by the pathologist is prognostic of survival,33 and therefore a minimum of 12 negative lymph nodes should be examined to define node-negative disease.34 The surgeon must also remember that the pattern of spread of mucinous CRC may be intraperitoneal. Therefore, extensive exploration of the peritoneal surface, including that overlying Gerota fascia and the diaphragm, should be undertaken during laparotomy. All peritoneal nodules should be removed if feasible. If the diagnosis was not made preoperatively and CRC is found in a patient being urgently explored for an acute abdomen, the surgeon should convert the procedure to a standard colon cancer resection with excision of draining lymphatics, which may necessitate closing the original wound (eg, an appendectomy incision) and using a midline approach. Cases of localized recurrence may benefit from reexcision. Hyperthermic perfusion of the peritoneal cavity after colon resection and peritonectomy has been applied in only a few cases, and there are insufficient data to recommend this approach for all patients.
Unfortunately for many children, adolescents, and young adults, CRC is rarely considered in the initial differential diagnosis, and therefore the initial surgical approach is often inadequate. In those cases, reexploration of the abdomen, with the goals of bowel resection with adequate margins and adequate lymph node sampling, should be performed at a center experienced in this type of surgery.
Because of the rarity of CRC in children, few pediatric oncologists will have any substantial experience with this disease. Consultation with medical oncologists experienced in evaluating adults with CRC is essential. The treatment for children should be adapted from current adult treatment recommendations. For stage II disease, in general the benefit of adjuvant chemotherapy is still being studied. Currently, adjuvant chemotherapy does not appear to improve survival by more than 5%.34–36 Careful observation is a reasonable recommendation for most adults who have no evidence of disease after resection; however, adjuvant therapy may be recommended for those with any poor prognostic features, such as poorly differentiated histology, perforation, T4 lesion, peritumoral lymphovascular involvement, or inadequate lymph node sampling.34,35
As noted above, most pediatric patients with CRC present with 1 or more of the poor prognostic features. For example, in the largest available pediatric series, the 8 children with stage II disease had only a 37.5%±15% 10-year event-free survival estimate,3 although 5-year disease-free survival is 60% to 80+% in most adult studies.35 The best option for children with CRC is participation in a clinical trial, although this opportunity is rarely available for pediatric patients with CRC. The relative prevalence of 1 or more negative prognostic factors at diagnosis and young age by definition suggest that adjuvant chemotherapy be strongly considered (and carefully discussed by the oncologist with the family) for many children, adolescents, and young adults with stage II disease. Chemotherapy has demonstrated a clear survival benefit for adults with stage III or IV disease,34,37 and children should be treated in a similar fashion. Although the FOLFOX regimen38,39 or one of its derivatives, such as modified FOLFOX-6,40 is the current regimen of choice,37 chemotherapy for advanced-stage disease is under active investigation and changing rapidly. Addition of the targeted agents bevacizumab,41,42 cetuximab,43 and panitumumab44–46 to standard chemotherapy regimens has shown benefit in selected patient groups. There is accumulating evidence that some patients who present with stage IV disease can be cured, if complete surgical resection can eventually be attained.47 In considering options for a pediatric patient with advanced-stage disease, one should carefully review the current medical literature and consult with an adult oncologist experienced in treating CRC before recommending a specific regimen.
Careful observation is recommended for the child with sporadic CRC who completes all planned treatment. However, few data are available to predict the risk of recurrence in such children or the risk of second malignancies later in life. Because CRC is both rare in children and extremely difficult to cure, the number of survivors is small. Although to date no large-scale randomized trials have documented the efficacy of a standard postoperative monitoring program in adults, young patients have a long period of latency for relapse and should undergo posttreatment screening with regular colonoscopy and radiologic evaluations at least as frequently as recommended for adults.34,48 Screening with CEA at reasonable intervals could be considered for children who had high CEA levels at presentation. Although the 5-year survival estimate for early-stage colon cancer is excellent at about 90%, patients with metastatic disease have less than a 10% likelihood of 5-year survival. It is not clear how long relapse surveillance should be continued for patients who survive metastatic pediatric CRC. The child should be followed in a clinic specializing in the long-term sequelae of treatment for childhood cancer, regardless of other follow-up plans.
CRC in children, adolescents, and young adults is rare. Although presenting symptoms are similar to those in adults, CRC is often not considered in the initial evaluation of a young patient. Because of its rarity in children, few pediatric oncologists have any substantial experience with CRC, and clinical trials are rarely available. The majority of reported cases present with advanced-stage disease and have mucinous or signet-ring cell carcinomas,4 whereas only 5% to 15% of adults present with these histologic subtypes.49 Treatment of young patients should be adapted from adult guidelines. Surgery is the mainstay of treatment, and patients who cannot be rendered surgically free of disease are rarely cured. The treatment of CRC in adults is evolving rapidly,50 and consultation with medical oncologists experienced in treating adults with CRC is essential.
The authors thank Sharon Naron for editorial assistance.
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