Pediatr Blood Cancer
Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes Marie L. Weber,1 Dominik T. Schneider, MD, PhD,2 Sonja Offenmüller,1 Peter Kaatsch, PhD,3 Hagen Graf Einsiedel, MD,4 Martin Benesch, MD, PhD,5 Alexander Claviez, MD, PhD,6 Martin Ebinger, MD, PhD,7 Christof Kramm, MD, PhD,8 Christian Kratz, MD, PhD,9 Jennifer Lawlor,1 Ivo Leuschner, MD, PhD,10 Susanne Merkel, MD, 11 PhD, Markus Metzler, MD, PhD,1 Rainer Nustede, MD, PhD,12 Sabine Petsch, MD,13 Karl-Heinz Seeger, MD, PhD,14 Paul-Gerhardt Schlegel, MD, PhD,15 Meinolf Suttorp, MD, PhD,16 Oliver Zolk, MD, PhD,17 and Ines B. Brecht, MD1∗ Introduction. Colorectal carcinoma (CRC) is the second most common adult cancer in Germany, however, it is extremely rare in children and adolescents. In these patients, previous literature describes aggressive behavior and diagnosis at advanced stage. Method. Thirty-one patients with CRC age ! 18 years and treated between 1990 and 2012 have been identified through the structures and registries of the German Society for Pediatric Oncology and Hematology. Results. The age range was 9–18 years (median 13.5 years); the median follow-up time was 43.9 months (range 1– 124 months). Twenty-six patients (84%) were tested for a genetic tumor syndrome (GTS); of these, 11 patients (35% of all patients) tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, two patients with constitutional mis-
Key words:
match repair deficiency). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) in 68% of carcinoma (n = 21). Overall survival (OS) and event-free survival at 5 years was 52.0% and 65.6%, respectively. Five-year survival according to stage was 100% in stage II (n = 2), 100% in stage III (n = 13), and 12.9% in stage IV (n = 15; P < 0.001). Five-year OS in patients with and without a defined GTS was 100% and 36.5% (P = 0.019), respectively. Conclusion. Children and adolescents with CRC are frequently diagnosed in advanced stages and have an unfavorable prognosis. In this study, a high percentage of pediatric CRC patients presented with a tumor predisposition syndrome and showed an especially favorable OS. Pediatr Blood Cancer ⃝C 2015 Wiley Periodicals, Inc.
cancer predisposition; colorectal carcinoma; familial adenomatous polyposis; Lynch syndrome; mismatch repair deficiency; pediatric rare tumors
INTRODUCTION Abbreviations: AJCC, American Joint Committee on Cancer; CACO4, combination chemotherapy of folinic acid, fluorouracil, interferon α2a; CRC, colorectal carcinoma; EFS, event-free survival; ERCRC, Erlangen Registry for Colorectal Carcinoma; EXPeRT, European Cooperative Study Group for Pediatric Rare Tumors; FOLFOXIRI, combination chemotherapy of folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOX, combination chemotherapy of folinic acid, fluorouracil, and oxaliplatin; GCCR, German Childhood Cancer Registry; GPOH, German Society of Pediatric Hematology and Oncology; GTS, genetic tumor syndrome; HIPEC, hyperthermic intraperitoneal chemotherapy; HNPCC, hereditary nonpolyposis colorectal cancer; OS, overall survival; RTX, radiotherapy; SEER, Surveillance, Epidemiology, and End Results; STEP, German Registry for Rare Pediatric Tumors; T-NHL, T-cell non-Hodgkin Lymphoma; TNM, tumor node metastasis—classification system for malignant tumors; UICC, Union Internationale Contre le Cancer 1
Department of Pediatric Hematology and Oncology, University Children’s Hospital Erlangen, Germany; 2 Clinic of Pediatrics, Dortmund, Germany; 3 German Childhood Cancer Registry (GCCR), Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Germany; 4 Department of Pediatric Oncology and Hematology, University Children’s Hospital Greifswald, Germany; 5 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria; 6 Pediatric Hematology and Oncology, University Children’s Hospital Kiel, Germany; 7 Pediatric Hematology and Oncology, University Children’s Hospital Tuebingen, Germany; 8 Pediatric Hematology and Oncology, University Children’s Hospital Goettingen, Germany; 9 Pediatric Hematology and Oncology, University Children’s Hospital Hannover, Germany; 10 Department of Paidopathology, ⃝ C 2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25839 Published online in Wiley Online Library (wileyonlinelibrary.com).
In Germany 65,000 new cases of colorectal carcinoma (CRC) are diagnosed each year in adults with over 50% of new malignant diseases arising beyond the 70th year of age.[1,2] Over the last decades, insight has been gained in tumor genesis and clinical characteristics of adult CRC resulting in new therapeutic strategies and improved survival. In contrast, pediatric CRC is extremely rare and little is known about its biology and optimal management. The estimated annual incidence is approximately one case per one million individuals.[3] Past reports of small series indicate that University of Kiel, Germany; 11 Clinical Tumor Registry, Department of Surgery, University of Erlangen, Germany; 12 Department of Pediatric Surgery, University Children’s Hospital Hannover, Germany; 13 Tumor Registry, University of Erlangen-Nuernberg, Germany; 14 Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany; 15 Department of Pediatric Hematology and Oncology, University Children’s Hospital Wuerzburg, Germany; 16 Department of Pediatric Hematology and Oncology, University Children’s Hospital Dresden, Germany; 17 Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany Grant sponsor: German Childhood Cancer Foundation. Partly orally presented at the Scientific Meeting of the German Society for Pediatric Oncology and Hematology in Mai 2013, Berlin. Conflict of interest: Nothing to declare. Correspondence to: Ines B. Brecht, Department of Pediatric Oncology and Hematology, University Children‘s Hospital Erlangen, Loschgestrasse 15, 91054 Erlangen, Germany, E-mail:
[email protected] ∗
Received 18 August 2015; Accepted 15 October 2015
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pediatric CRC presents with aggressive histological subtypes and poor differentiation as well as advanced stages of disease and poor survival.[3–12] Unspecific gastrointestinal symptoms and rare occurrence of CRC in childhood often lead to delayed diagnosis. Moreover, due to its rarity, biological research and clinical trials have been virtually impossible. Consequently, evidence-based guidelines for diagnosis and treatment are not available.[12] This retrospective analysis of 31 pediatric and adolescent cases with CRC diagnosed in Germany, Austria and Switzerland between 1990 and 2012 was performed in order to understand clinical features and prognosis of children with this very rare malignant tumor.
PATIENTS AND METHODS Patients Thirty-one pediatric patients with CRC were identified through the German Childhood Cancer Registry (GCCR), Kiel Pediatric Tumor Registry, Erlangen Registry for Colorectal Carcinoma (ERCRC), and German Registry for Rare Pediatric Tumors (STEP). Inclusion criteria were diagnosis of a carcinoma of the colon or rectum (ICD10 code C18.2-C20) between 1990 and 2012 and age ! 18 years at the time of diagnosis. All patients were diagnosed and treated within the network structures of the German Society of Pediatric Hematology and Oncology (GPOH) in Germany, Switzerland, or Austria. All patients or guardians gave their informed consent for using their data in the context of clinical registries of the GPOH. Ethical approval was obtained.
Clinical Data, Pathological Review, Genetic Testing Twenty-eight patients with CRC were identified through the network of the GPOH (GCCR, STEP registry, and Kiel Pediatric Tumor Registry). Records were anonymized by the treating physicians before they were sent to us and subsequently reviewed for symptoms at diagnosis, time interval between start of symptoms and diagnosis of CRC, tumor characteristics, treating modalities, second malignancies, and family history of CRC. Three patients with CRC were identified through the ERCRC, which provided us with an anonymized database including detailed information. Tumor site was categorized in left colon (cecum, ascending colon, splenic flexure), transverse colon, right colon (descending colon, hepatic flexure), sigmoid, and rectum. Pathology reports were assessed for histological subtype, grade of differentiation (well, moderate, poor, and undifferentiated), completeness of resection (complete resection, microscopic residual tumor, macroscopic residual tumor), and tumor node metastasis (TNM) stage. The histological subtype was categorized in adenocarcinoma (favorable histology) and mucinous carcinoma with or without signet ring component as well as signet ring carcinoma (unfavorable histology). All tumors were staged according to the TNM and the joint staging system of the Union Internationale Contre le Cancer (UICC) and American Joint Committee on Cancer (AJCC).[13] Genetic testing within medical reports was reviewed for a genetic tumor syndrome (GTS) such as Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC; MIM 114500) or familial adenomatous polyposis syndrome (MIM 175100). Pediatr Blood Cancer DOI 10.1002/pbc
Statistical Methods Overall survival (OS) was defined as the interval between diagnosis and death of any cause or last follow-up. An event was defined as death of any cause, progression, or recurrence of the tumor. Event-free survival (EFS) was specified as interval between diagnosis and an event. The probability of OS and EFS was estimated by the Kaplan–Meier method; probability distributions were compared using the log-rank test. Fisher’s exact test was performed to examine association between categoric variables.
RESULTS Clinical Features The male/female ratio was 2.1 (68% males). The age at the time of diagnosis ranged from 9 to 18 years with a median age of 13.5 years. All patients, with one exception, showed typical symptoms of CRC including abdominal pain, change in bowel habits, nausea, vomiting, and weight loss. The patient without typical symptoms was identified by a screening endoscopy due to a positive family history with HNPCC; the other patients did not receive tumor screening because of a known or suspected cancer predisposition. The most common presenting symptom was abdominal pain in 22 cases (71%), followed by nausea and vomiting (35%), and diarrhea (29%). Visible fecal blood was documented in five cases (16%) with three of them showing a carcinoma of the rectum. The time from presenting symptoms to definite diagnosis of CRC ranged from 1 day to 6 months. Twenty-two patients (76%) were diagnosed within 2 months and 7 patients (22%) following a longer duration of symptoms (up to 6 months).
Family History, Tumor Predisposition and Second Malignancy A positive family history of CRC was reported in 10 cases and excluded in 13 cases. For eight patients, information on familial CRC was not available. Among the 10 cases with a positive family history of CRC, 70% (n = 7) tested positive for a GTS after the diagnosis of CRC. Only one patient had a known predisposition syndrome prior to the diagnosis. Collectively, 26 patients (84% of all patients) were tested for a genetic tumor predisposition syndrome and 11 patients (35% of all patients) were positive (Table II). Extracolic neoplasm appeared in 19% of all patients (n = 6), in three cases of T-cell non-Hodgkin lymphoma (T-NHL), the colon carcinoma appeared as a secondary malignancy (treated according to NHL-BFM 95 without local radiotherapy [RTX]), while three patients developed a glioblastoma multiforme (WHO grade IV). Two patients with T-NHL, in addition to the three patients with glioblastoma multiforme, were diagnosed with a mismatch repair deficiency syndrome. One patient with a T-NHL as a secondary malignancy was not tested for HNPCC. None of all 31 cases had any other predisposing factor for CRC, neither radiation of the pelvic/abdomen nor a chronic bowel disease such as Crohn’s disease or ulcerative colitis.
Pediatric Colorectal Carcinoma
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TABLE I. Patient Characteristics and Prognostic Factors of 31 Patients !18 years With Colorectal Carcinoma Factor Sex Male Female Genetic tumor syndrome HNPCC FAP Other No Not tested Genetic tumor syndrome Yes No Not tested Tumor site Right colon Transverse colon Left colon Sigmoid Rectum Multiple sites Peritonealcarcinomatosis Yes No Histology Unfavorablea Favorable Differentiation Poor Moderate Good Unknown T 1 2 3 4 Unknown N 0 1 2 Unknown M 0 1 Stage I II III IV Unknown Extent of resection R0 R1 R2 HIPEC Yes No
N
5-Year OS Estimate ± 1 SE
5-Year OS Estimate ± 1 SE
21 10
72.8 ± 11.7 51.9 ± 17.6
0.089
8 1 2 15 5
100 100 100 36.5 ± 16.5 50.0 ± 25.0
11 15 5
100 36.5 ± 16.5 50.0 ± 25.0
11 4 8 1 4 3
51.4 ± 20.4 25.0 ± 21.7 83.3 ± 15.2 100 75.0 ± 21.7 100
13 18
14.7 ± 13.4 92.9 ± 6.9
0.000
13.3 ± 12.2 73.4 ± 11.5
0.001
17 14
57.4 ± 14.8 73.3 ± 13.2
0.997
47.9 ± 13.8 57.5 ± 14.7
0.794
21 7 1 2
58.0 ± 13.6 83.3 ± 15.2 100 50.0 ± 35.4
0 2 12 15 2
– 100 70.0 ± 14.5 58.6 ± 16.3 50.0 ± 35.4
4 9 17 1
100 71.4 ± 17.1 60.2 ± 14.1 0.00
16 15
100 12.9 ± 11.9
0 2 13 15 1
– 100 100 12.9 ± 11.9 100
18 3 10
92.9 ± 6.9 0.00 17.9 ± 16.0
6 25
40.0 ± 29.7 69.8 ± 10.4
0.064
0.019
0.326
0.080
0.756
0.004
0.000
0.000 0.000 0.186
62.5 ± 12.4 33.8 ± 15.8 83.3 ± 15.2 100 100 20.6 ± 12.7 53.3 ± 24.8 88.9 ± 10.5 20.6 ± 12.7 53.3 ± 24.8 31.2 ± 18.0 25.0 ± 21.7 83.3 ± 15.2 0.00 75.0 ± 21.7 66.7 ± 27.2
34.4 ± 12.8 83.3 ± 15.2 100 50.0 ± 35.4 – 50.0 ± 35.4 70.7 ± 14.3 33.0 ± 15.3 50.0 ± 35.4 100 59.3 ± 18.5 46.0 ± 13.3 0.00 83.9 ± 10.4 10.9 ± 10.1 – 100 80.8 ± 12.2 10.9 ± 10.1 100 73.4 ± 11.5 0.00 21.0 ± 18.1 40.0 ± 29.7 53.4 ± 10.9
0.109
0.067
0.016
0.185
0.097
0.915
0.087
0.000
0.000 0.001 0.560
(Continued) Pediatr Blood Cancer DOI 10.1002/pbc
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TABLE I. Continued Factor
N
Patients with peritoneal-carcinomatosis, HIPEC performed Yes 6 No 7 Chemotherapy regime FOLFOX 13 FOLFOXIRI 7 Other (oxaliplatin, CACO4, 5FU + 6 RTX) No chemotherapy 4 Unknown 1 Radiotherapy Yes 2 No 28 Unknown 1 Targeted therapy Cetuximab 5 Bevacizumab 2 No 23 Unknown 1
5-Year OS Estimate ± 1 SE 40.0 ± 29.7 0.00 77.9 ± 14.1 20.8 ± 18.4 80.0 ± 17.9
5-Year OS Estimate ± 1 SE 0.160
0.132
66.7 ± 27.2 100 100 60.2 ± 11.1 100 25.0 ± 21.7 50.0 ± 35.4 76.4 ± 10.5 100
40.0 ± 29.7 0.00 51.9 ± 15.7 22.9 ± 19.7 62.5 ± 21.3
0.050
0.463
66.7 ± 27.2 100 0.531
0.111
50.0 ± 35.4 50.6 ± 10.9 100 0.00 50.0 ± 35.4 62.6 ± 11.4 100
0.482
0.186
a
Mucinous ± signet ring component; EFS, event-free survival; OS, overall survival; HIPEC, hyperthermic intraperitoneal chemoperfusion; FOLFOX, combination chemotherapy of folinic acid, fluorouracil, and oxaliplatin; FOLFOXIRI, combination chemotherapy of folinic acid, fluorouracil, oxaliplatin, and irinotecan; CACO4, combination chemotherapy of folinic acid, fluorouracil, interferon α2a; RTX, radiotherapy.
Tumor Characteristics and Staging The primary tumor was predominantly located in the right colon (n = 11; 36%), followed by the left colon (n = 8; 26%), and the rectum (n = 4; 13%); three patients developed CRC at multiple sites (10%; Table I). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) was noted in 68% of carcinoma (n = 21). Although 73% (n = 11) of the patients without a GTS had an unfavorable histological type, only 36% (n = 4) of the patients affected by a genetic syndrome showed these pathological features. An initial colonoscopy was performed in 17 cases. Preexisting polyps were detected in 15 patients (48%); nine of which had a GTS. All but two of the patients presenting with metastatic disease showed peritoneal spreading of the tumor at the time of diagnosis, and 73% (n = 11) of all patients with stage IV tumors were recorded to have an unfavorable histology. Patients with a GTS did not present with distant disease. For further details on tumor characteristics and staging, refer to Tables I and II.
Treatment In most patients, a multimodal treatment regime was applied. Primary resection with nodal sampling was performed in all cases of colon carcinoma. Two patients with rectal carcinoma received neoadjuvant chemo-RTX followed by surgery. Complete resection (R0) was achieved in 58% of the patients (n = 18), three had microscopic residuals (R1) and 10 had macroscopic residuals (R2) after resection (all of them with peritoneal spreading). HIPEC (hyperthermic intraperitoneal chemotherapy) was performed in six of 13 cases with peritoneal carcinomatosis. Patients with peritoneal spreading that did not receive HIPEC, did not survive. One of the patients receiving HIPEC is alive Pediatr Blood Cancer DOI 10.1002/pbc
15 months after diagnosis and one patient is alive 2 months after diagnosis, four patients died after a median survival time of 35 months. In all patients with genetic predisposition the tumor could be resected without residuals, therefore all of them achieved complete remission after primary surgery. Data on chemotherapy were available in 30 cases. Twentyfour patients with colon carcinoma received adjuvant chemotherapy as described in Table I, two patients with rectal carcinoma received neoadjuvant radiochemotherapy with fluorouracil. Four patients did not receive any chemotherapy, two of them had a short follow-up, and resection was considered adequate treatment for the other two cases, both diagnosed with HNPCC.
Outcome The median follow-up time was 43.9 months (range 1– 124 months). OS was 65.6%, EFS was 52.0% at 5 years. Fiveyear survival according to stage is shown in Fig. 1. At the time of analysis 19 patients were alive, 13 patients (42%) without disease (69%, n = 9 carrier of a GTS) and 6 patients (19%) with disease. Seventy-eight percent (n = 14) of all cases with R0 resection was still alive. A total of 12 patients (39%) did not survive; 10 patients (32%) died of CRC and two patients (6%) died of an extracolic malignancy.
Prognostic Factors Factors influencing survival are shown in Table I. In our analysis, the presence of a GTS (P = 0.019), absence of peritoneal spreading (P < 0.001), tumor stages I–III (P < 0.001), and complete resection (R0; P < 0.001) proved to be significant positive predictors of survival.
Pediatric Colorectal Carcinoma
Fig. 1. Distribution of overall survival at 5-year estimates for 31 patients with colorectal carcinoma according to tumor stage (stage II 100%, stage III 100%, stage IV 12.9%; P < 0.0001).
DISCUSSION We present a large well-defined hospital-based series on recently diagnosed pediatric colorectal cancers. Although CRC is well studied in adults, little is known about its pathogenesis and clinical features in children and young adolescents. Its rarity makes clinical and biological studies difficult to perform. Nevertheless, evidence suggests there are different tumorigenic mechanisms and a diverse biology in pediatric CRC compared to adult cases.[6,14] Distinct clinical features of CRC in children compared to adults were observed in our study. This is in agreement with previous reports [5,15,16], most notably a report of 159 children and adolescents registered with the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute by Sultan et al. and a large retrospective series by Hill et al.[3,6] However, data were lacking for genetic testing or modern therapies in these reports. Previous pediatric CRC reports document that young patients are diagnosed with advanced stages, presumably because of an aggressive behavior of the tumor and/or late diagnosis as concluded by other authors.[3,8,17] They present with an unfavorable tumor histology and poor differentiation in approximately 50–80% of cases [3,5,6,8,16,17] while in adults, only 5– 15% show CRC with mucinous and signet ring components.[10, 12,17,18] It is well known that early lymph node involvement, metastases, and rapid tumor progression is correlated with unfavorable histology and poor differentiation.[3,10,12,16] In accordance with these observations, over 50% of our cases showed an unfavorable histology, a poor differentiation (grade III), and presented with stage III or IV (see Table I). Therefore, our data support the hypothesis that colorectal cancer in pediatric patients may behave more aggressively. Of note, advanced stages at diagnosis were not due to an unreasonable long time from the Pediatr Blood Cancer DOI 10.1002/pbc
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Fig. 2. Distribution of overall survival at 5-year estimates for 11 patients with the presence of a genetic tumor syndrome (100%) and 15 patients with a negative testing for a genetic predisposition (36.5%; P < 0.001).
early symptoms to the confirmatory diagnosis: most of the patients (76%, 22 patients) were diagnosed within 2 months after onset of symptoms. These patients presented with typical symptoms of CRC, such as abdominal pain, change in bowel habits, nausea, vomiting, and weight loss. While in adults the abovementioned symptoms generally lead to CRC diagnostics, in children, initial colonoscopy is rare and even in many cases appendectomy is performed before CRC is diagnosed.[6,12,19] Interestingly, despite advanced disease and unfavorable histotype, the overall 5-year survival rate was 65.6%, whereas previous pediatric case series reported much lower 5-year survival rates between 23% and 40%.[3,5,6] OS was especially favorable in patients who were diagnosed with a tumor predisposition syndrome (n = 11, OS at 5 years 100%) compared to those with exclusion of a hereditary colorectal cancer syndrome (n = 15, OS at 5 years 36.5%, P = 0.019; refer to Table I and Fig. 2). As the underlying genetic predisposition was not known before in these patients, the favorable outcome is not a result of early detection because of screening for CRC. Previous studies have shown that microsatellite instability is an independent prognostic marker associated with improved OS and specific clinical characteristics such as less lymph node involvement and less systemic metastases in adult patients with CRC.[20,21] Our data support the findings of adult studies that CRC in patients with tumor syndrome (mainly HNPCC) shows a less aggressive behavior than sporadic pediatric cases of CRC (Table II). In fact, while 73% of the patients without a GTS had an unfavorable histological type, only 36% of the patients affected by a genetic syndrome showed these pathological features. Patients with a GTS did not present with distant disease, and complete resection was possible for all cases. Etiology of CRC in children and adolescents is still largely unknown. In adulthood, CRC occurs as a result of genetic
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TABLE II. Five-Year Overall Survival (OS) and Event-Free Survival (EFS) in 11 Patients With the Presence of a Genetic Tumor Syndrome (GTS) Compared to 15 Patients With a Negative Testing for a Genetic Predisposition According to Prognostic Variables (5 Patients Without any Genetic Testing Were Excluded) 5-Year OS
Factor
n = 11 Presence of a genetic tumor syndromea
Preexisting polyps Yes 9, 82% No 2, 18% Unfavorable histologyb Yes 4, 36% No 7, 64% Stage II 2, 18% III 8, 73% IV 0 Unknown 1 9% Extent of resection R0 11, 100% R1 0 R2 0 Peritoneal carcinomatosis Yes 0 No 11, 100% Grading G2 4, 36% G3 6, 55% G4 1, 9% a
n = 15 Absence of a genetic tumor syndromea
Presence of GTSa
Absence of GTSa
4, 27% 11, 73%
100 100
66.7 ± 27.2 19.7 ± 17.4
11, 73% 4, 27%
100 100
19.7 ± 17.4 66.7 ± 27.2
0 4, 73% 11, 27% 0
100 100 – 100
– 100 0.00 –
6 40% 3 20% 6 40%
100 – –
75.0 ± 21.7 0.00 0.00
9 60% 6 40%
0.00 100
0.00 75.0 ± 21.7
3, 20% 12, 80% 0
100 100 100
50.0 ± 35.4 33.0 ± 18.6 –
5-Year EFS
Estimate ± 1 SE
Estimate ± 1 SE Presence of GTSa
Absence of GTSa
0.019
87.5 ± 11.7 100
25.0 ± 21.7 16.9 ± 15.1
0.023
0.014
100 80.0 ± 17.9
14.1 ± 12.9 37.5 ± 28.6
0.003
100 85.7 ± 13.2 – 100
– 66.7 ± 27.2 0.00 –
88.9 ± 10.5 – –
44.4 ± 22.2 0.00 0.00
0.000
0.00 88.9 ± 10.5
0.00 44.4 ± 22.2
0.001
0.096
100 75.0 ± 21.7 100
50.0 ± 35.4 12.8 ± 11.8 –
0.020
P
0.000
0.001
P
0.000
0.001
HNPCC, FAP, or other b Mucinous type ± signet ring component, signet ring type.
changes following many years of exposure to carcinogens, but in young patients cancer cannot be due to long-term exposure.[4,12,16,18,22] We postulate that a combination of a genetic predisposition, immunological features, and early exposure to environmental factors promote CRC in children, which might be different from typical carcinogens of adulthood. Although our patients were not systematically screened for a GTS within the frame of a prospective clinical study, a GTS was confirmed in 35% of all cases. This is an unusual high number if compared with the existing literature, where a predisposing tumor syndrome in adult cases of CRC is only reported in about 1–5% of cases.[23,24] However, it is difficult to determine the exact prevalence of HNPCC in children and adolescents with CRC, since many published series have not focused on the underlying genetic aspects of the tumor.[25] Of all 31 cases presented here, there were neither predisposing factors for CRC indicated, nor radiation of the pelvic/abdomen or a chronic bowel disease such as Crohn’s disease or ulcerative colitis. Consequently, the occurrence of this extremely rare tumor type remains unresolved for a considerable number of our patients showing an especially aggressive behavior of CRC. Biological studies are especially needed for this subgroup in order to investigate further genetic alterations. Diagnosis of CRC in a child should lead to a careful examination of family history and intensified genetic screening of the family.[14,26] The life-time risk to develop CRC increases Pediatr Blood Cancer DOI 10.1002/pbc
up to eightfold in case of a first degree relative with CRC, and increases even more if the relative is very young and/or more than one relative is affected.[14] Modified Amsterdam criteria and Bethesda criteria should be applied in case of pediatric CRC.[23,27] Information on the underlying genetic lesions also can impact the treatment strategy. Adult CRC patients with microsatellite instable tumors have a more favorable prognosis, and microsatellite instability might be associated with a poor response to specific chemotherapy regimens including 5fluorouracil and irinotecan.[20] Due to the rarity of pediatric CRC, treatment strategies have to be adopted from adult guidelines initially.[28] Surgical complete resection is the mainstay of treatment. Lymph node examination of at least 12 lymph nodes should be performed to prevent understaging.[6,12] In addition, an exact exploration of the omentum and ovaries should be performed as tumor recurrences often occur in these locations.[17] In adults, it is considered standard practice to apply adjuvant chemotherapy for patients with stage III/IV and high-risk stage II colon cancer. Regimes as combination chemotherapy of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and combination chemotherapy of folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) are applied.[28] In our study, 23 patients received adjuvant chemotherapy; the regimes were mainly FOLFOX, FOLFOXIRI, and combination chemotherapy of folinic acid, fluorouracil, interferon α2a (CACO4). A
Pediatric Colorectal Carcinoma difference in OS or EFS could not be observed between the main treatment regimens. Data on the role of HIPEC are limited in children.[12] However, in case of peritoneal spread, which is generally considered to be a palliative situation, radical peritonectomy in combination with HIPEC provides a chance of cure.[29] Our data suggest that HIPEC might be effective in pediatric CRC patients with carcinomatosis, prolonging their OS. Neoadjuvant radiochemotherapy with fluorouracil is routinely applied in rectal cancer.[30] To support future research, cases of CRC in childhood should be recorded in the existing national registries for rare pediatric tumors. Prospective data and tissue collection including a systematic family history and testing for potentially relevant genetic conditions should be performed. Promoting awareness of the potential risk for colorectal cancer and screening guidelines to family members should be implemented. Furthermore, interdisciplinary and international cooperation—for example, within the frame of the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT)— is needed in order to enable biological studies leading to a better understanding of the etiology and biology of this very rare pediatric cancer.
ACKNOWLEDGMENT This work was performed as part of the doctoral thesis of Marie L. Weber. The work was funded by the German Childhood Cancer Foundation. Ines B. Brecht receives a scholarship from the Madeleine Schickedanz-Foundation.
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