This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric colorectal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Incidence

Carcinoma of the large bowel is rare in the pediatric age group.[1] It is seen in 1 case per 1 million people younger than 20 years in the United States annually. Fewer than 100 cases are diagnosed in children each year in the United States.[2] From 1973 to 2006, the Surveillance, Epidemiology, and End Results (SEER) Program database recorded 174 cases of colorectal cancer in patients younger than 19 years.[3] Colorectal carcinoma accounts for about 2% of all malignancies in patients aged 15 to 29 years.[4] An analysis of SEER data identified 5,350 adolescents and young adults (AYA) between the ages of 15 and 39 years with colorectal cancer from 2010 to 2015.[5] Right-sided tumors (cecum to transverse colon) were diagnosed in 28.6% of AYA cases. The proportion of right-sided colorectal cancers differed significantly by age group at diagnosis (38.3% of AYA patients aged 15–19 years vs. 27.3% of AYA patients aged 35–39 years). The incidence of mucinous adenocarcinoma and signet ring cell carcinoma histopathological subtypes was higher in younger patients.

A pediatric oncology group in the Netherlands performed a retrospective analysis of adolescents and adults aged 25 years or younger with colorectal cancer.[6] They analyzed clinical data and molecular and genetic features of colorectal tumor tissues from 139 AYA patients (age, ≤25 years; median age, 23 years; 58% male), collected between 2000 and 2017. Mucinous and/or signet ring cell components were observed in 33% of tumor samples. A genetic tumor-risk syndrome was confirmed in 39% of the patients. Factors associated with shorter survival time included younger age at diagnosis, signet ring cell carcinoma histology, the absence of a genetic tumor-risk syndrome, and advanced stage of disease at diagnosis.

Clinical Presentation

Colorectal tumors can occur in any location in the large bowel. Larger series and reviews suggest that ascending and descending colon tumors are each seen in approximately 30% of cases, with rectal tumors occurring in approximately 25% of cases.[1-3]

Signs and symptoms in children with descending colon tumors include the following:

• Abdominal pain (most common).
• Rectal bleeding.
• Change in bowel habits.
• Weight loss.
• Nausea and vomiting.

The median duration of symptoms before diagnosis was about 3 months in one series.[4,5]

Changes in bowel habits may be associated with tumors of the rectum or lower colon.

Tumors of the right colon may cause more subtle symptoms but are often associated with the following:

• Abdominal mass.
• Weight loss.
• Decreased appetite.
• Blood in the stool.
• Iron-deficiency anemia.

Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.

Diagnostic Evaluation

Diagnostic studies include the following:[1,2]

• Examination of the stool for blood.
• Studies of liver and kidney function.
• Measurement of carcinoembryonic antigen (CEA).
• Various medical imaging studies, including direct examination using colonoscopy to detect polyps in the large bowel. Other conventional radiographic studies include barium enema or video-capsule endoscopy followed by computed tomography of the chest and bone scans.[3]

Histology and Molecular Features

There is a higher incidence of mucinous adenocarcinoma in the pediatric and adolescent age group (40%–50%), with many lesions being the signet ring cell type,[1-5] whereas only about 15% of adult lesions are of this histology. The tumors of younger patients with this histologic variant may be less responsive to chemotherapy. In the adolescent and young adult population with the mucinous histology, there is a higher incidence of signet ring cells, microsatellite instability, and mutations in the mismatch repair genes.[5-7] Tumors with mucinous histology arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls.[8]

Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRAS mutations and other cytogenetic anomalies seen in older patients.[9] In a genomic study that used exome and RNA sequencing to identify mutational differences in colorectal carcinomas of adults (n = 30), adolescents and young adults (n = 30), and children (n = 2), five genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR) were identified that were more frequently mutated in adolescents and young adult patients. These genes contained a damaging mutation and were identified through whole-exome sequencing and RNA sequencing. In addition, higher mutational rates in DNA mismatch and DNA repair pathways, such as MSH2, BRCA2, and RAD9B, were more prevalent in adolescent and young adult samples but the results were not validated by RNA sequencing.[10]

Staging

Most reports also suggest that children present with more advanced disease than do adults, with 80% to 90% of patients presenting with Dukes stage C/D or TNM stage III/IV disease (refer to the Stage Information for Colon Cancer section of the PDQ summary on adult Colon Cancer Treatment for more information about staging).[1-16]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child-life professionals.
• Psychologists.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[4] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than 2 cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than 2 cases per 1 million people were also included in the very rare group because there is a lack of knowledge and expertise in the management of these tumors.[7]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]
  Most cancers in subgroup XI are either melanomas or thyroid cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as the PDQ summary on adult Colon Cancer Treatment and adult Rectal Cancer Treatment.

Treatment and Outcome of Childhood Colorectal Cancer

Most patients present with evidence of metastatic disease,[1] either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[2,3] Of almost 160,000 patients with colorectal cancer included in the National Cancer Database, 918 pediatric patients were identified. Age younger than 21 years was a significant predictor of increased mortality.[4]

Treatment options for childhood colorectal cancer include the following:

1. Surgery. Complete surgical excision is the most important prognostic factor and is the primary goal of surgery, but in most instances, this is impossible. Removal of large portions of tumor provides little benefit for those with extensive metastatic disease.[5] Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.
2. Radiation therapy and chemotherapy. Current therapy includes the use of radiation for rectal and lower colon tumors, in conjunction with chemotherapy using fluorouracil (5-FU) with leucovorin.[6] Other agents, including irinotecan, may be of value.[1][Level of evidence C1] No significant benefit has been determined for interferon-alfa given in conjunction with 5-FU/leucovorin.[7]
   A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved progression-free survival and overall survival (OS) in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[8][Level of evidence B4]
   Ipilimumab and nivolumab demonstrated high response rates in pediatric patients aged 12 years and older with microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer who had disease progression after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.[9]
   Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[10- 13]

Survival is consistent with the advanced stage of disease observed in most children with colorectal cancer, with an overall mortality rate of approximately 70%. For patients with a complete surgical resection or for those with low-stage/localized disease, survival is significantly prolonged, with the potential for cure.[14]

Treatment Options Under Clinical Evaluation for Childhood Colorectal Cancer

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Genetic Syndromes Associated With Colorectal Cancer

About 20% to 30% of adult patients with colorectal cancer have a significant history of familial cancer; of these, about 5% have a well-defined genetic syndrome.[1] Hereditary colorectal cancer has two well-described forms:[2,3]

• Polyposis (including familial adenomatous polyposis [FAP] and attenuated FAP, which are caused by pathogenic variants in the APC gene; and MUTYH-associated polyposis, which is caused by pathogenic variants in the MUTYH gene).
• Lynch syndrome (often referred to as hereditary nonpolyposis colorectal cancer), which is caused by germline pathogenic variants in DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM.

Other colorectal cancer syndromes and their associated genes include oligopolyposis (POLE, POLD1),[3] NTHL1,[4] juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).[2] (Refer to the PDQ summary on Genetics of Colorectal Cancer for more information related to these syndromes.)

The incidence of these genetic syndromes in children has not been well defined, as follows:

• In one review, 16% of patients younger than 40 years had a predisposing factor for the development of colorectal cancer.[5]
• A later study documented immunohistochemical evidence of mismatch repair deficiency in 31% of colorectal carcinoma samples in patients aged 30 years or younger.[6]
• A retrospective review of patients younger than 18 years in Germany identified 31 patients with colorectal carcinoma.[7] Eleven of the 26 patients who were tested for a genetic predisposition syndrome tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, and two patients with constitutional mismatch repair deficiency). When compared with the patients without a genetic predisposition syndrome, the 11 patients with a genetic predisposition syndrome presented with more localized disease, allowing complete surgical resection and improved outcome (100% survival).

Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminates the risk of developing carcinomas of the large bowel.[8,9] Some colorectal carcinomas in young people, however, may be associated with a mutation of the APC gene, which also is associated with an increased risk of brain tumors and hepatoblastoma.[10] FAP syndrome is caused by mutation of a gene on chromosome 5q, which normally suppresses proliferation of cells lining the intestine and later development of polyps.[11] A double-blind, placebo-controlled, randomized phase I trial in children aged 10 to 14 years with FAP reported that celecoxib at a dose of 16 mg/kg per day is safe for administration for up to 3 months. At this dose, there was a significant decrease in the number of polyps detected on colonoscopy.[12][Level of evidence B3] The role of celecoxib in the management of FAP in children is not clear.

Another tumor suppressor gene on chromosome 18 is associated with progression of polyps to malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I and several other rare syndromes.[13]

Despite the increased risk of multiple malignancies in families with Lynch syndrome, the risk of malignant neoplasms during childhood in those families does not seem to be increased when compared with the risk in children from non-Lynch syndrome colorectal carcinoma families.[14]

Changes to This Summary (02/23/2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary