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Colorectal Carcinoma in Childhood and Adolescence: A Clinicopathologic Review

D. Ashley Hill, Wayne L. Furman, Catherine A. Billups, Shannon E. Riedley, Alvida M. Cain, Bhaskar N. Rao, Charles B. Pratt, Sheri L. Spunt

From the Departments of Pathology, Hematology-Oncology, Biostatistics, and Surgery, St Jude Children's Research Hospital; and the Department of Pediatrics, The University of Tennessee College of Medicine, Memphis, TN
Deceased

Address reprint requests to D. Ashley Hill, MD, Lauren V. Ackerman Division of Surgical Pathology, Washington University Medical Center, Box 8118, 660 S Euclid Ave, St Louis, MO 63110; e-mail: hill{at}path.wustl.edu

	ABSTRACT

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Purpose Pediatric colorectal carcinoma (CRC) is rare, but the available data suggest that it is more likely than adult CRC to be advanced at presentation and to have a poor outcome. We sought to better characterize pediatric CRC.

Patients and Methods We reviewed the clinical and pathologic features, prognostic factors, and outcome of CRC in 77 children and adolescents (ages 7 to 19 years) referred to St Jude Children's Research Hospital between 1964 and 2003.

Results At presentation, 76 patients had one or more signs or symptoms of CRC (abdominal pain, altered bowel habits, weight loss, anemia). Tumors were evenly distributed between the right and left colon; 62% were mucinous adenocarcinoma. At presentation, 86% of patients had advanced-stage disease; more than half had distant metastases. Overall outcome was poor. Advanced stage and mucinous histology were significant predictors of adverse outcome. Stage-specific survival at 10 years was 67% ± 27% (stage 1), 38% ± 15% (stage 2), 28% ± 11% (stage III), and 7% ± 4% (stage 4). Although no patient had a diagnosis of polyposis syndrome before diagnosis of CRC, 17 (22%) had colon polyps and eight (including two who previously underwent pelvic radiotherapy) had multiple polyps.

Conclusion Initial signs and symptoms of CRC are similar in pediatric and adult patients. The strikingly higher frequency of mucinous histology suggests that the biology of CRC differs in pediatric and adult patients and may contribute to poor outcomes. Children should be included in prospective clinical trials for CRC.

	INTRODUCTION

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Colorectal carcinoma (CRC) is a tumor of older adults; its frequency peaks at age 65 years. Because CRC is rare in children and adolescents, it is frequently overlooked in the differential diagnosis of abdominal pain, weight loss, and anemia. Data from the Surveillance, Epidemiology, and End Results (SEER) program¹ suggest that CRC has a similar natural history in patients age 15 to 29 years as in older patients. However, many small series suggest that children are more likely than adults to have advanced-stage disease at presentation, unfavorable (mucinous) tumor histology, and a poor outcome.^2-12 Delayed diagnosis and treatment have been speculated to play a role. Further, the pathobiology of pediatric and adult CRC may differ. We analyzed the clinical and pathologic features and outcome of childhood CRC in 77 patients referred to St Jude Children's Research Hospital between 1964 and 2003.

	PATIENTS AND METHODS

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Patients
Of 10,968 patients evaluated for malignancy at St Jude between February 1964 and September 2003, 97 (0.9%) had epithelial neoplasia or neoplastic polyps of the GI tract. CRC was diagnosed in 81 patients. Four were excluded because of limited clinical data and follow-up; therefore, 77 patients were analyzed. A subset of these cases, described in 1985,² were reevaluated for this report. This retrospective analysis was approved by the St Jude Institutional Review Board.

Clinical Data
Patient records were reviewed for presenting symptoms (presence or absence of abdominal pain, weight loss, or change in bowel habits). Symptoms not documented were tabulated as "record not informative." We also recorded the interval between presentation and diagnosis; abnormal physical or laboratory findings; relevant medical history; presence or absence and number of polyps; presence or absence of a polyposis syndrome or family history of cancer; initial diagnostic impression or differential diagnosis; diagnostic procedures; type of treatment (surgery, radiotherapy, chemotherapy); site and timing of recurrence; and current disease status or cause of death.

Pathology Review
All original pathology reports (n = 77) and available tumor slides (n = 62) were reviewed by the study pathologist (D.A.H.), who determined the degree of differentiation (well differentiated, > 95% gland-forming; moderately differentiated, 50% to 95%; poorly differentiated, < 50%); presence or absence of a mucinous component, a signet ring component, neuroendocrine differentiation, and adenomatous changes in adjacent mucosa; and type and number of polyps. When mucin lakes comprised more than 50% of their area, tumors were classified as mucinous adenocarcinomas.¹³ All tumors were staged using the tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer.¹⁴

Treatment Plan
Before 1975, patients with newly diagnosed CRC underwent upfront tumor resection if feasible. When administered, subsequent chemotherapy comprised cyclophosphamide and vincristine or fluorouracil. Beginning in 1975, all eligible patients with newly diagnosed CRC were offered enrollment onto one of a series of five prospective clinical trials (Table 1). All enrolled patients or their parent(s) or guardian(s) provided informed consent. Each trial was approved by the St Jude Institutional Review Board. The principles governing treatment remained unchanged throughout the study period. Surgical resection of the primary tumor with lymph node sampling was recommended at the time of diagnosis for all patients with resectable, nonmetastatic disease. No adjuvant therapy was recommended for stage 1 or 2 tumors. Patients with stage 3 or 4 disease who had undergone upfront tumor resection received postoperative chemotherapy; all others were treated with neoadjuvant chemotherapy and delayed surgery. Patients with rectal primary tumors underwent pelvic radiotherapy. Local management of metastatic disease was individualized.

	RESULTS

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Clinical Features
Of the 77 patients, 46 (60%) were male and 48 (62%) were white. Median age at diagnosis was 15.5 years (range, 7.5 to 19.9 years). Seventy-six patients presented with pain, altered bowel habits, and/or weight loss. One patient was diagnosed incidentally during exploratory laparotomy after an accident. Sixty-four (85%) of 75 patients with informative records reported pain. Fourteen had localized pain in the abdomen (n = 12) or rectum (n = 2); 12 of these had pT3 or pT4 tumors in corresponding sites. Eighty percent (61 of 76) of patients with informative records reported vomiting (n = 35), constipation (n = 20), diarrhea (n = 17), hematochezia or rectal bleeding (n = 16), or nausea (n = 12). Sixty-five percent (47 of 72) of patients with informative records reported weight loss (median, 20 pounds [9.07 kg]; range, 5 to 81 pounds [2.27 to 36.74 kg]). Available data for 59 patients showed a 3-month median duration of symptoms before presentation (range, 1 day to 18 months). Four patients had a relevant medical history: ulcerative colitis (n = 1), neurofibromatosis type 1 (n = 1), or abdominal/pelvic radiation for bladder rhabdomyosarcoma (RMS) 10.3 and 10.7 years before CRC (n = 2). Documentation of family history was poor. Twenty-three charts had no information, 14 reported an "unremarkable" family history, and 40 noted cancer (often "unknown type") in family member(s). Eleven charts indicated family members with colon cancer (none a parent), and five listed family members with uterine cancer.

The charts of 32 patients described physical findings before surgical intervention. Twenty-one had palpable masses or fullness in the abdomen (n = 14), rectum (n = 6), or cul de sac (n = 1). One additional patient had only tenderness in the right lower quadrant. The 10 remaining charts contained no notable findings. Fecal occult blood test results were positive in 10 of 12 patients, three of whom had gross hematochezia. Thirty-four (77%) of the 44 patients with hemoglobin records were anemic at presentation: less than 6.5 g/dL (n = 4), 6.5 to 10 g/dL (n = 14), and between 10.1 g/dL and the lower limit of normal for age and sex (n = 16).

Initial Clinical Impression and Diagnostic Evaluation
The initial impressions varied greatly (Table A1, online only), as did the diagnostic approaches. For the 65 patients whose records provided sufficient detail, the initial diagnostic procedure was exploratory laparotomy (n = 19), endoscopy (n = 19), enteric contrast-enhanced imaging (n = 16), or other (n = 12).

Thirty-two charts (42%) indicated the time between initial presentation and pathologic diagnosis. CRC was diagnosed within 2 months in 20 patients and after 2 months in 12 (range, 2 to 6 months); seven of the 12 had unexplained weight loss and six had anemia that was evaluated incompletely or not evaluated. The group with a longer time to diagnosis had lower-stage disease (P = .062) and a higher probability of EFS (P < .001) and survival (P = .014). Nodal or distant disease was observed in seven (58%) of these 12 patients compared with 16 (80%) of the 20 with the shorter time to diagnosis.

Pathology and Staging
Primary tumors were similarly distributed between the left and right colon (Table 2); 22 (29%) were in the sigmoid colon or rectum. Most (48 of 77; 62%) were mucinous adenocarcinoma (Fig A1, online only); 34 of these contained some signet-ring cells, including one comprising exclusively signet-ring cells. Mucinous tumors were equally likely to be in the right and left colon. None of the 34 tumors distal to the splenic flexure, but nine (21%) of the 42 that were proximal were poorly differentiated (P = .003). Preexisting dysplastic lesions found adjacent to CRC in 22% of cases were associated with nonmucinous tumor histology (P < .001).

Thirty-nine patients (51%) presented with distant metastatic disease of the peritoneal surface (n = 32), liver parenchyma (n = 7), ovarian parenchyma (n = 6), bone (n = 5), lung (n = 2), bone marrow (n = 2), skin (n = 1), bladder (n = 1), and uterus (n = 1). Of the 11 patients with stage 1 or 2 CRC, eight (72%) had fewer than 17 lymph nodes sampled.

Treatment
Treatment data were available for 73 patients; the remaining four were seen in consultation, and treatment information was incomplete. Five of the 73 patients underwent definitive surgery alone for stage 1 (n = 2) or 2 (n = 3) disease, 59 received protocol therapy, seven received nonprotocol chemotherapy (fluorouracil, n = 5), and two declined treatment. Ten of the 12 patients whose primary tumors involved the rectum received pelvic radiotherapy (median dose, 45 Gy; range, 24 to 50.4 Gy).

Treatment Failure
Fifty-one of the 77 patients experienced tumor progression or recurrence, a median of 8.7 months (range, 1.0 to 40.5 months) after diagnosis. Recurrence was local (n = 6), regional (lymph nodes; n = 16), distant (n = 14), or locoregional and distant (n = 15). Five additional patients died as a result of CRC, but the dates and sites of relapse were unavailable. The cumulative 10-year incidence of locoregional and distant recurrence was 48.2% ± 5.8% and 37.8% ± 5.6%, respectively. The single patient surviving after recurrence at study conclusion had active disease 22 months after regional recurrence.

Survival
Sixty-three (82%) of the 77 patients experienced adverse events. First events included tumor recurrence (n = 51), second malignant neoplasm (n = 3), and death before recurrence or second malignancy (n = 4). Five additional patients died as a result of CRC; because the dates and sites of relapse or progression were unavailable, we considered their deaths to be their first events in the analyses of EFS and local and distant failure. The 10-year EFS estimate of the cohort was 17.7% ± 5.1% (Fig 1). Three patients had second malignant neoplasms (high-grade glioma, n = 2; osteosarcoma; n = 1) 1.5 to 3.7 years (median, 2.3 years) after the diagnosis of CRC. All patients with second malignancies had juvenile polyps (two had one polyp; one had three).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Distributions of survival and event-free survival (EFS) estimates for 77 pediatric patients with colorectal cancer. Estimated 10-year survival and EFS were 20.1% ± 5.4% and 17.7% ± 5.1%, respectively.

Prognostic Factors
Factors that predicted survival and EFS were similar (Table 3). Disease stage was a significant predictor of survival (P < .001; Table 3; Fig 2). One patient with stage 1 and one with stage 2 CRC died of complications of previous treatment of RMS. The eight patients with stage 2 disease fared more poorly than expected. None of the three patients who had more than 17 lymph nodes sampled died as a result of disease (one died as a result of toxicity), whereas four of the five who had fewer than 17 lymph nodes sampled died as a result of disease. Patients with nonmucinous tumors had a significant survival advantage (P = .020; Fig 3). Mucinous histology was significantly predictive of survival for patients with stage 3 (P = .015), but not stage 4 (P = .40), disease. Ten-year survival estimates were 12.6% ± 6.8% for patients with stage 3 mucinous tumors, but 62.5% ± 22.1% for patients with stage 3 nonmucinous tumors. Tumors with a proportion of signet ring cells more than 10% were also significantly associated with poor outcomes (P = .040). The presence of other polyps did not appear to alter survival (P = .96), nor did tumor site or degree of differentiation. There was no evidence of a survival advantage in more recent clinical trials, but the small groups of patients may have obscured any difference.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival estimates according to disease stage for 77 pediatric patients with colorectal cancer. Survival distributions differed significantly among the four stages (P < .001).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Overall survival estimates according to tumor type (mucinous versus nonmucinous) for 77 pediatric patients with colorectal cancer. Ten-year survival estimates were 37.9% ± 10.6% for patients with nonmucinous tumors and 8.1% ± 3.9% for patients with mucinous tumors (P = .020).

	DISCUSSION

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This is the largest cohort of children and adolescents with CRC described to date to our knowledge. The previous largest study, in 1985, described 30 patients included herein.² We found that the presenting features of pediatric and adult CRC are similar. All but one of our patients presented with abdominal or rectal pain, altered bowel habits, and/or weight loss. Patients had experienced symptoms for a median of 3 months, and most were anemic. In adults, these findings would likely prompt early colonoscopy. Malignancy was considered initially for only four children. Twelve patients received a diagnosis 2 or more months after presentation, despite unexplained weight loss and anemia. However, patients whose diagnosis was delayed fared better than others, those with advanced disease being more likely to present acutely.

None of the carcinomas described herein were identified through screening, although five children were found to have FAP or juvenile polyposis. This observation may reflect a referral bias: Patients who undergo regular screening are less likely to have advanced disease and to be referred to our institution. Remarkably, 25% of patients had one or more polyps identified during diagnostic evaluation. This figure may underestimate the actual frequency because not all patients underwent preoperative colonoscopy, and results of postoperative colonoscopies were not available. One patient had NF-1. Two developed high-grade glioma after CRC. Two others who had received chemotherapy and pelvic radiotherapy for RMS during early childhood had multiple adenomatous polyps in the radiation field, but their p53 status and detailed family history are unknown. The Children's Oncology Group screening guidelines recommend that children and adolescents who receive 30 Gy or more of pelvic radiotherapy be screened for CRC after 10 years or at 35 years of age, whichever is later.¹⁷ Our findings suggest a reduction of this interval, at least for a subset of patients. Future studies of colon carcinoma that arises after pediatric cancer can better assess the period of risk and any underlying genetic predisposition.

The lack of systematic family history and archived tissue prevented our analysis of genetic predisposition. In another series of pediatric patients with CRC, six of 13 studied had microsatellite instability.¹⁸ Therefore, a modest proportion of pediatric CRC may represent early hereditary nonpolyposis colon carcinoma (HNPCC) syndrome. Future prospective studies should include a systematic family history and testing for potentially relevant genetic conditions if indicated. They should also address the risk of CRC in family members and promote sensible family screening guidelines.

The outcome of patients in our study was poor despite the similarity of their treatment to standard therapy for adult CRC. Previous reports have suggested that CRC has a less favorable outcome in children and adolescents. In part, our findings reflect the preponderance of advanced-stage disease (86% stage 3 or 4), a result of referral bias. However, pediatric patients with stage 2 or 3 disease had outcomes inferior to those of comparable adults. Five of our eight patients who had stage 2 CRC had fewer than 17 lymph nodes sampled during diagnostic laparotomy, and only one of them survived. We speculate that inadequate nodal sampling may have led to understaging and inadequate treatment. Awareness of the importance of adequate nodal sampling in children and adolescents with CRC may improve the outcome for those with resectable tumors.^19-24

The only predictors of inferior outcome besides disease stage were incomplete resection, mucinous histology, proportion of signet ring cells more than 10%, and the absence of an in situ component—these latter three features were highly correlated. Mucinous histology was considerably more frequent in our patients (62%) than in adults (11% to 13%),^25-29 as previously reported, and is likely to reflect a difference in biology between pediatric and adult CRC. Many studies have documented an association between mucinous histology, high stage at presentation, and poor outcome in adults,^25,27,28 but there are conflicting data about the independent prognostic value of mucinous histology.^27-29 In our study, mucinous histology was an independent negative predictor of survival for stage 3 disease but not for stage 4 disease.

This retrospective analysis had several important limitations. It covered nearly a 40-year period, during which the diagnosis and treatment of CRC advanced. Our study population was shaped by the referral to our institution of patients with predominantly high-stage disease. Because of the small number of patients with stage 1 or 2 CRC, there is little we can report about these patients. Further, inconsistent documentation and the lack of archived tissue precluded analysis of the proportion of cases likely to reflect genetic predisposition.

Despite its limitations, we believe this is the most comprehensive analysis of pediatric CRC to date. Our findings suggest that CRC differs biologically in pediatric and adult patients and that these differences may have clinical implications. We believe that much can be done for younger patients with this disease, which is increasingly curable in adults. Pediatricians and family practitioners must be made aware of pediatric CRC and its signs and symptoms. Pediatric surgeons and pathologists must recognize the importance of adequate lymph node sampling. Although the relatively small number of children in our study and the extended period over which they were enrolled preclude definitive treatment recommendations, the poor outcome observed suggests that aggressive therapy is warranted. We favor the inclusion of children in adult CRC treatment protocols or alternatively, the continued development of pediatric CRC trials to refine treatment recommendations for these children.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: D. Ashley Hill, Wayne L. Furman, Bhaskar N. Rao, Charles B. Pratt, Sheri L. Spunt

Administrative support: D. Ashley Hill

Provision of study materials or patients: D. Ashley Hill, Wayne L. Furman, Bhaskar N. Rao, Charles B. Pratt, Sheri L. Spunt

Collection and assembly of data: D. Ashley Hill, Shannon E. Riedley, Alvida M. Cain, Charles B. Pratt, Sheri L. Spunt

Data analysis and interpretation: D. Ashley Hill, Wayne L. Furman, Catherine A. Billups, Charles B. Pratt, Sheri L. Spunt

Manuscript writing: D. Ashley Hill, Sheri L. Spunt

Final approval of manuscript: D. Ashley Hill, Wayne L. Furman, Catherine A. Billups, Shannon E. Riedley, Alvida M. Cain, Bhaskar N. Rao, Sheri L. Spunt

	Appendix

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View larger version (146K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Histologic types of childhood colorectal cancer. (A) The mucinous subtype is characterized by malignant glands floating in abundant mucin. (B) Many of the mucinous tumors contained areas with signet-ring cells. (C) The majority of other cases were moderately differentiated adenocarcinoma. (D) In two patients previously treated with abdominal/pelvic radiation for bladder rhabdomyosarcoma, the distal colorectum contained multifocal areas of dysplasia that involved small groups of glands; this finding was consistent with a "field effect."

	ACKNOWLEDGMENTS

 
We dedicate this work to the memory of Charles B. Pratt, MD, whose commitment to the study of rare pediatric tumors inspires us to continue the search for better treatment. We thank Sharon Naron at St Jude Children's Research Hospital for editorial support.

	NOTES

 
Supported in part by Grants No. CA21765 and CA23099 from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC).

Presented in part at the Society for Pediatric Pathology companion meeting at the United States and Canadian Academy of Pathology Spring Meeting, March 25-26, 2000, New Orleans, LA, and at the 36th Annual Meeting of the American Society of Clinical Oncology, May 20-23, 2000, New Orleans, LA. A subset of these cases was described in 1985.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted May 14, 2007; accepted September 20, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hill, D. A. Articles by Spunt, S. L. Search for Related Content PubMed PubMed Citation Articles by Hill, D. A. Articles by Spunt, S. L. Social Bookmarking                            What's this?