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Year : 2014  |  Volume : 19  |  Issue : 1  |  Page : 31-37

Nonurological malignancies in children

Department of Surgery, Division of Pediatric Surgery, King Fahd Hospital of the University, University of Dammam, Al Khobar, Saudi Arabia

Date of Web Publication28-Jan-2014

Correspondence Address:
Lalit Parida
Department of Surgery, Division of Pediatric Surgery, King Fahd Hospital of the University, University of Dammam, P. O. Box-40176, Al Khobar-31952
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-9261.125960

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Context: Nonurological malignancies in children include a wide variety of tumors. These tumors include primary tumors of the liver, thyroid, lung, gastrointestinal tract (GIT), and adrenals; soft tissue sarcomas (STSs) like rhabdomyosarcoma (RMS) and non-RMS; and finally extragonadal germ cell tumors (GCT). Aims: This article aims at describing the current thinking in the management of these childhood solid tumors. This is critical in view of the recent advances in the elucidation of the molecular, genetic, and biologic behavior of these tumors and how these factors are getting integrated not only in the staging but also in developing a risk-based approach towards the management of these tumors. Materials and Methods: Reference was made to recently published literature from the leading pediatric cancer centers of the world to make a sense of things of the most current thinking in this rapidly expanding field. This will provide surgeons and physicians taking care of these children with a working knowledge in this somewhat challenging field. Conclusions: Treatment results vary from center to center depending on access to resources and following different management protocols. Results have improved for these tumors with the advent of newer chemotherapeutic agents, novel delivery methods of radiation therapy (RT), and improvement in surgical technique. Due to the limited number of patients presenting with these tumors, national and international collaboration of data is critical for all and beneficial to individual treatment centers. This has resulted in better results in the past and will definitely result in still better results in the future.

Keywords: Childhood, nonurological malignancies, hepatoblastoma, rhabdomyosarcoma, extragonadal germ cell tumor, pediatric solid tumor

How to cite this article:
Parida L. Nonurological malignancies in children. J Indian Assoc Pediatr Surg 2014;19:31-7

How to cite this URL:
Parida L. Nonurological malignancies in children. J Indian Assoc Pediatr Surg [serial online] 2014 [cited 2023 Jan 28];19:31-7. Available from: https://www.jiaps.com/text.asp?2014/19/1/31/125960

The most common solid tumors not involving the genitourinary system but encountered by surgeons dealing with children include liver tumors like hepatoblastoma (HB) and hepatocellular carcinoma (HCC), soft tissue sarcomas (STSs) like rhabdomyosarcoma (RMS) and non-RMS, extragonadal germ cell tumors (GCTs), and tumors involving the thyroid, lung, gastrointestinal (GI) system, and adrenals. Great progress has been made in the understanding of these tumors over the years. We are at a stage where we can classify these tumors in a better manner and offer our patients a risk based management incorporating various genetic, biologic, and imaging criteria. The following describes the current thinking of these various tumors.

   Liver Tumors Top

Primary malignant liver tumors like HB and HCC are rare in children and account for around 1-2% of all pediatric malignancies with the former accounting for almost two-thirds of all liver tumors. According to the United States Surveillance, Epidemiology, and End Results (SEER) program data, the incidence of HB is 10.5 cases per million in infants 0-1 year of age and 5.2 cases per million in children who are 1-4-years-old. The incidence of HB in familial adenomatous polyposis is 847 times, while in  Beckwith-Wiedemann syndrome More Details (BWS) it is 2,280 times more common compared to the SEER population. Very low birth weight is strongly associated with HB. [1] The small cell undifferentiated (SCUD) HB is associated a low or normal alpha-fetoprotein (AFP) and confers a poor prognosis. [2] AFP is an excellent tumor marker and is elevated in 90%. AFP less than 100 ng/ml at presentation is associated with poor prognosis. An elevated AFP in the setting of a liver mass should be seen through the prism of the child's age. A baby who is less than 6 months of age with a liver mass and raised AFP should be investigated further to rule out hamartomas, hemangioendothelioma, sarcomas, and yolk sac tumors. HCC should be ruled out if the child is older than 3 years of age. [3] The SIOPEL group of Europe based Society of International Pediatric Oncology (SIOP) advocates the PRETEXT (pretreatment extent of disease) system for staging liver tumors prior to surgery. The United States based Children's Oncology Group (COG) utilizes PRETEXT to decide about tumor resectability [Table 1].
Table 1: PRETEXT staging system

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The COG recommends a lobectomy or segmentectomy at diagnosis for PRETEXT I and II and a lobectomy or trisegmentectomy after neoadjuvant chemotherapy for POST-TEXT II or III which do not have macroscopic venous involvement. It recommends a complex hepatic resection or liver transplant after neoadjuvant chemotherapy for POSTTEXT III with macroscopic venous involvement or POST-TEXT IV. The COG has shown that a completely resected tumor with a pure fetal histology and low mitotic activity does not need adjuvant chemotherapy. [4] It further comments that positive microscopic surgical margins does not always mean a poor prognosis and excision of metastatic pulmonary nodules may provide a long-term cure in some patients. Diagnosis of small pulmonary nodules less than 1 cm can be difficult and thoracoscopic resection of these nodules localized preoperatively by computed tomography (CT) is helpful in the diagnosis. [5] The tumor, if it has to shrink, will shrink maximally within the first three to four cycles of neoadjuvant chemotherapy. The COG recommends a liver resection or orthotopic liver transplantation prior to or at the latest following the fourth cycle of chemotherapy. Cisplatin is usually given in a dosage of 80-100 mg/m 2 over 4-24 h every 2, 3, or 4 weeks for 4-8 cycles. A 5-day cisplatin regimen with a dosage of 20-40 mg/m 2 /day has also been utilized. Doxorubicin is usually given in a dosage of 30 mg/m 2 /dose for 2-4 days for 4-8 cycles. Rapamycin (mammalian target of rapamycin (mTOR) inhibitor) may help in preventing tumor recurrence. [6]

An increased risk of HCC is observed with liver cirrhosis due to biliary atresia, chronic carrier of hepatitis B virus, total parenteral nutrition, Fanconi's syndrome, hereditary tyrosinemia, and in liver metastases due to HB and Wilms' tumor treated with hepatic radiation. AFP is elevated in 50% and a positive hepatitis B serology can be observed in some cases. The PRETEXT staging system is also recommended by some groups as the staging system for HCC in children. The fibrolamellar variant of HCC constituting around 30% of HCC is commonly seen in patients younger than 20 years of age and has the same survival rate as HCC. Neoadjuvant chemotherapy is not effective in reducing the tumor to a resectable size and complete resection rates range within 18-36%. [3] Surgical options include hepatic resection in non-cirrhotic children with HCC; whereas, transplantation in cirrhotic children with unresectable HCC. Newer chemotherapeutic agents like sorafenib have been utilized in HCC treatment.

   Rhabdomyosarcoma Top

The incidence of RMS is 4.3 per million per year in children less than 20 years of age. Eighty percent of the prognostically more favorable embryonal RMS (ERMS) has a loss of heterozygosity at the 11p15 locus, while 80% of the less favorable alveolar RMS (ARMS) has a PAX/FKHR translocation. Recent studies have demonstrated that fusion gene negative ARMS and ERMS have similar clinical outcomes. [7]

The primary tumor in RMS and its adjacent structures are better evaluated by magnetic resonance imaging (MRI); whereas, abdominal lymphadenopathy and erosion of bony structures are better delineated by CT. 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in assessing regional lymphadenopathy along with its additional role in detecting occult metastasis, tumor recurrence in operative site, and persistent viable disease. [7]

Imaging and physical examination prior to start of any treatment allows us to define tumor (T) characteristics (site, size, and tumor invasion) along with lymph node (N) involvement and metastasis (M) and subsequently determine a TNM stage [Table 2]. A postsurgical staging system based on the extent of residual tumor after surgery places the patient into clinical groups [Table 3]. The STS Committee of the COG has developed a risk stratification based on the extent of disease (TNM status) and extent of resection (clinical groups) and patients are assigned a low, intermediate, or high risk status [Table 4].
Table 2: Pretreatment TNM staging system

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Table 3: Postsurgical clinical grouping for RMS

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Table 4: Risk-based stratification of RMS patients

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The ideal surgical treatment for RMS lesions should include a wide local excision of the tumor along with a rim of normal surrounding tissue. Though a rim of 0.5 cm is considered adequate, it is sometimes difficult to obtain in head and neck lesions. Sentinel lymph node biopsy is a safe and effective means to evaluate the regional lymph node basins especially for extremity and truncal lesions. [8] Regional lymph node basins need to be evaluated for their involvement in children with extremity lesions and in children with paratesticular lesions who are older than 10 years of age.

Chemotherapy regimens for RMS have commonly included a combination of vincristine (V), actinomycin-D (A), and cyclophosphamide (C) - the VAC regimen. COG protocols have included irinotecan and V in patients with progressive disease or recurrence; and doxorubicin and irinotecan for advanced stages of RMS. The STS COG has used a chemotherapy regimen consisting of VAC for 45 weeks for intermediate-risk RMS. The European studies have utilized ifosfamide as the alkylating agent in combination with V and A. The STS COG has traditionally based the dose of radiation on the amount of tumor that remains after initial surgery but before the beginning of chemotherapy. This is in contrast to SIOP which bases its radiation dose on the amount of tumor that remains after the start of chemotherapy with or without delayed primary resection. Radiation therapy (RT) is important for local control of tumor. Patients with group II disease receive 40 Grays (Gy) of radiation at 1.5-1.8 Gy/fraction; whereas, patients with group III disease receive around 50 Gy of radiation. RT has its toxic effects and more so in children less than 2 years of age. [7],[9]

   Nonrhabdomyosarocma Top

STS account for 8% of all childhood malignancies and non-RMS STS (NRSTS) make up half of it. The 10 year overall survival is around 73%. These tumors usually present as a painless mass in extremities or abdominal wall with very few intra-abdominal lesions. A tumor size of more than 5 cm has been considered as significant and this is the defining size as per TNM staging. But a tumor of the same size has a different prognosis in infants and younger children compared to older children and adolescents. [10] Regional lymph node evaluation in synovial sarcoma, epithelioid sarcoma, and clear-cell sarcoma can be done with sentinel lymph node biopsy. [8] The common NRSTS include synovial sarcoma, infantile fibrosarcoma, [11] malignant peripheral nerve sheath tumor, dermatofibrosarcoma protuberans, and desmoplastic small round cell tumor.

   Extragonadal Germ Cell Tumours Top

Compared to adults, malignant GCTs (MGCT) in children have a more common extragonadal location, yolk sac tumor is the dominant pathology, and sarcomatous components are less common. Yolk sac tumor or endodermal sinus tumor is the most common pathology seen in tumors arising in the retroperitoneal, sacrococcygeal, and mediastinal locations. An elevated AFP is seen at diagnosis and persistent elevation suggests tumor persistence or recurrence. Tumor markers are incorporated into the COG staging for extragonadal tumors [Table 5]. Stages 1 and 2 are classified as intermediate risk as per COG and receive three cycles of cisplatin, etoposide, and bleomycin (PEB) chemotherapy besides surgery; whereas, stages 3 and 4 are high risk tumors and receive three to four cycles of chemotherapy besides surgery. [12]
Table 5: COG staging of extragonadal germ cell tumors

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Sacrococcygeal tumors present either as huge tumors during the perinatal period and are usually benign, or present later in infancy and childhood and these tumors are usually malignant. Tumors can become symptomatic during the intrauterine phase as polyhydramnios or high output cardiac failure. Proponents of fetal surgery have advocated fetal resection for high-output cardiac failure at less than 28 weeks' gestation. Surgical resection should include excision of the coccyx as this lowers the recurrence rate. Highly vascular tumors can benefit from laparoscopic or open ligation of the middle sacral artery.

Fifteen percent of all pediatric mediastinal GCT are malignant and have the worst prognosis for all GCTs. An initial biopsy should be done to diagnose malignancy considering the fact that most of the tumors in this location are unresectable at diagnosis. This should be followed by neoadjuvant chemotherapy. The 4-year overall survival is around 70%.

Retroperitoneal tumors account for around 4% of all GCTs. Majority of these tumors are benign, but 15% are malignant. The ideal treatment will be a primary resection if no significant contiguous structures are involved. The 6-year-old overall survival is around 87%.

   Thyroid Cancer Top

Thyroid carcinoma accounts for around 3% of all childhood malignancies. Well-differentiated thyroid carcinoma (WDTC) which includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) account for 90-95% of all pediatric thyroid cancers. Medullary thyroid carcinoma (MTC) originates from calcitonin-producing cells and is usually a part of the multiple endocrine neoplasia (MEN) syndromes, MEN2A and MEN2B. MEN2A patients usually have RET-oncogene mutations; whereas, MEN2B have codon 918 mutations. [13] Thyroid cancer patients younger than 45 years of age (and therefore all children) are classified by American Joint Commission on Cancer (AJCC) as stage I (any T, any N, M0) or II (any T, any N, M1). Lymph node and lung metastasis in WDTC is more common in children than adults. MTC usually metastasizes to mediastinal lymph nodes, liver, lung, and bone. Ultrasound (US) is useful as an initial imaging study to differentiate between a solid and cystic thyroid lesion. Three percent of cystic thyroid lesions on US can be malignant. Though fine needle aspiration (FNA) is very accurate in detecting malignancy, it has a positive predictive value of 53% and any doubt should be followed-up by a biopsy. Diagnostic evaluation includes thyroid function tests, thyroid-associated autoantibodies, and iodine 123 scanning and the treating surgeon should be aware that hyperfunctioning nodules are rarely malignant. Serum thyroglobulin is of prognostic value after thyroidectomy for WDTC. MTC evaluation includes calcitonin, calcium, and carcinoembryonic antigen (CEA) levels along with RET mutation testing. A total or near total thyroidectomy should be the primary treatment for WDTC. A central neck dissection is indicated considering the fact that 30% of WDTC patients have a locally invasive tumor and 60% have regional lymph node metastases. Radioactive iodine ablation (RIA) may be useful to treat residual disease. Chemotherapy and RT do not have a major role in WDTC treatment. MTC patients should undergo prophylactic total thyroidectomy with or without central/lateral neck dissection early in life before the occurrence of metastasis. RT is useful for bone and brain metastasis in MTC, but RIA has no role in MTC treatment. The RET kinase inhibitor, vandetanib, is being used for locally advanced or metastatic MTC.

   Lung Tumors Top

Metastatic tumors to the lung are five times more common than primary tumors in children. The more common primary malignant lung lesions include carcinoid, salivary gland tumor, inflammatory myofibroblastic tumor (IMT), and pleuropulmonary blastoma (PPB). The presenting symptoms include lung infection, cough, hemoptysis, and shortness of breath. Helical CT with intravenous contrast is the diagnostic imaging of choice. Bronchoscopy is indicated for central lesions, while a thoracoscopic or image-guided biopsy is useful in the diagnosis of peripheral lesions.

Pulmonary carcinoids account for 20% of all primary lung tumors. Carcinoid syndrome needs symptomatic control, but no adjuvant therapy is indicated for the primary lung lesion. Salivary gland tumors account for 10% of primary lung tumors. It carries a favorable prognosis compared to a poor prognosis in adults. IMT is currently recognized as a low-grade mesenchymal malignancy. Many of these tumors have ALK1 gene mutation and resection is the treatment of choice. PPB is classified into three subtypes depending on its solid and cystic components. Treatment includes aggressive surgery, chemotherapy, and RT. [14]

Malignant chest wall tumors in children include Ewing sarcoma (primitive neuroectodermal tumor), RMS, fibrosarcoma, lymphoma, osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma, and synovial sarcoma. [11],[15]

   Gastrointestinal (GI) Tumors Top

GI stromal tumors (GIST) are rare tumors in children most commonly seen in adolescent females. [16] Metastasis is present in 20% of patients at diagnosis and is usually seen in liver, lymph nodes, and peritoneum; while lung metastasis is uncommon. The frequency of the KIT mutation is less compared to adults. Complete resection with negative margins is the primary goal of treatment. Lymph node sampling is important as its involvement is more common in children compared to adults. Children with KIT mutation may receive adjuvant imatinib after surgical resection and sunitinib can be used in children without this mutation.

Colorectal carcinoma (CRC) is usually diagnosed at a late stage and has an aggressive histology such as mucinous adenocarcinoma, >10% signet-ring cells, and the 10-year event-free survival rate is only 20%. [17] FDG-PET scans are less useful in detecting mucinous histology and are, hence, less beneficial in childhood CRC. CEA is not an effective tumor marker in majority of children with CRC. The surgical guidelines to be followed include obtaining a 5 cm margin of normal bowel on either side of the tumor to reduce the chance of anastomotic recurrence, examining a minimum number of 12 negative lymph nodes prior to defining node-negative disease and excision of any clinically apparent peritoneal nodules. The FOLFOX chemotherapy regimen can benefit children with advanced disease.

GIT lymphoma: Primary GIT lymphomas have a strong male predominance and occur more commonly in the distal ileum and cecum in children compared to adults in whom the stomach is a more common site. [18] Operative intervention is indicated in case of a surgical emergency like mechanical intestinal obstruction or perforation. An elective surgical resection which should include regional lymph node excision is sometimes indicated in localized ileocecal disease and mesenteric involvement. This localized resection can result in 80% survival at 2 years.

Carcinoid has a female predominance and these tumors are most commonly observed in the appendix followed by the small intestine. [19] It usually comes to notice as an incidental finding in appendectomy pathological specimens. Most of these tumors are benign and carcinoid syndrome is very rarely observed. Serum 5-hydroxyindolacetic acid (5-HIAA) is utilized as a serologic marker. Tumors less than 2 cm detected incidentally and without evidence of any metastasis do not need any further treatment beyond an appendectomy. Tumors more than 2 cm need to have a metastatic workup and will need a right hemicolectomy.

Pancreatic tumors in children include solid pseudopapillary tumor (SPT), neuroendocrine tumors (NETs) and pancreatoblastoma. [20] SPT or Frantz's tumor is more commonly seen in young females and the treatment of choice is surgical resection. These tumors are slow growing and metastasis is present in only 10-15% at diagnosis resulting in an overall good prognosis with 5-year survival rate of more than 90%. NET is rare in children and is usually seen in association with genetic syndromes like MEN. These tumors can be functional or nonfunctional and metastasis is present in around 10-20% at diagnosis. Treatment includes surgical resection. Novel chemotherapeutic agents like peptide receptor radionuclide therapy (PRRNT) are being used due to their poor response to conventional agents. Pancreatoblastoma presents in the 1 st decade of life and metastasis is observed in 35% at diagnosis. Prognosis is favorable if the tumor is completely resected, but unresectable tumors will need RT and chemotherapy in form of cisplatin and doxorubicin.

   Adrenal Tumors Top

Pheochromocytoma in children is more commonly familial, bilateral, extra-adrenal, and multifocal compared to adults. [21] Sustained hypertension is observed in the majority of patients. Malignant pheochromocytoma is rare in children and usually manifests with tumor-related pain. Malignancy in children is usually determined by clinical behavior in form of local tumor invasion and distant metastasis to bone, liver, and lung rather than by histology. Tumor localization is done after diagnostic biochemical tests. Preoperative considerations include α-blockade prior to β-blockade, preoperative volume expansion and potassium correction, and perioperative glucose monitoring. Surgical resection in form of adrenalectomy is the mainstay of treatment, but cortical sparing adrenalectomy should be considered for bilateral tumors.

Adrenocortical carcinoma is a very rare tumor in children with an annual incidence of around 0.3 cases per million, but a certain region in southern Brazil has an incidence that is almost 15 times of this rate. [22] The median age at diagnosis is around 3 years with a female predominance. Patients usually present with virilization and precocious puberty as most of these tumors are functional. Nonfunctional tumors account for less than 5% of all adrenocortical tumors and manifest with abdominal symptoms or with an abdominal swelling. An age less than or equal to 4 years is associated with a better outcome. The treatment of choice is an aggressive resection consisting of adrenalectomy, lymph node dissection, and en bloc removal of any involved adjacent structures to achieve negative surgical margins. Mitotane has been utilized as it has demonstrated objective tumor regression and control of hormone excess.

   Conclusion Top

Treatment results vary from center to center depending upon access to resources and following different management protocols. Results have improved for these tumors with the advent of newer chemotherapeutic agents, novel delivery methods of RT, and improvement in surgical technique. Due to the limited number of children presenting with these tumors, national and international collaboration of data is critical for all, and beneficial to individual treatment centers. This has yielded good results in the past and will provide better results in the future.

   References Top

1.Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr Blood Cancer 2012;59:776-9.  Back to cited text no. 1
2.López-Terrada D, Zimmermann A. Current issues and controversies in the classification of pediatric hepatocellular tumors. Pediatr Blood Cancer 2012;59:780-4.  Back to cited text no. 2
3.Emre S, Umman V, Rodriguez-Davalos M. Current concepts in pediatric liver tumors. Pediatr Transplant 2012;16:549-63.  Back to cited text no. 3
4.Meyers RL, Czauderna P, Otte JB. Surgical treatment of hepatoblastoma. Pediatr Blood Cancer 2012;59:800-8.  Back to cited text no. 4
5.Parida L, Fernandez-Pineda I, Uffman J, Davidoff AM, Gold R, Rao BN. Thoracoscopic resection of computed tomography-localized lung nodules in children. J Pediatr Surg 2013;48:750-6.  Back to cited text no. 5
6.Trobaugh-Lotrario AD, Katzenstein HM. Chemotherapeutic approaches for newly diagnosed hepatoblastoma: Past, present, and future strategies. Pediatr Blood Cancer 2012;59:809-12.  Back to cited text no. 6
7.Dasgupta R, Rodeberg DA. Update on rhabdomyosarcoma. Semin Pediatr Surg 2012;21:68-78.  Back to cited text no. 7
8.Parida L, Morrisson GT, Shammas A, Hossain AK, McCarville MB, Gerstle JT, et al. Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 2012;28:571-8.  Back to cited text no. 8
9.Gosiengfiao Y, Reichek J, Walterhouse D. What is new in rhabdomyosarcoma management in children? Paediatr Drugs 2012;14:389-400.  Back to cited text no. 9
10.Hayes-Jordan A. Recent advances in non-rhabdomyosarcoma soft-tissue sarcomas. Semin Pediatr Surg 2012;21:61-7.  Back to cited text no. 10
11.Parida L, Fernandez-Pineda I, Uffman JK, Davidoff AM, Krasin MJ, Pappo A, et al. Clinical management of infantile fibrosarcoma: A retrospective single-institution review. Pediatr Surg Int 2013;29:703-8.  Back to cited text no. 11
12.Rescorla FJ. Pediatric germ cell tumors. Semin Pediatr Surg 2012;21:51-60.  Back to cited text no. 12
13.Rapkin L, Pashankar FD. Management of thyroid carcinoma in children and young adults. J Pediatr Hematol Oncol 2012;34:S39-46.  Back to cited text no. 13
14.Yu DC, Grabowski MJ, Kozakewich HP, Perez-Atayde AR, Voss SD, Shamberger RC, et al. Primary lung tumors in children and adolescents: A 90-year experience. J Pediatr Surg 2010;45:1090-5.  Back to cited text no. 14
15.van den Berg H, van Rijn RR, Merks JH. Management of tumors of the chest wall in childhood: A review. J Pediatr Hematol Oncol 2008;30:214-21.  Back to cited text no. 15
16.Janeway KA, Weldon CB. Pediatric gastrointestinal stromal tumor. Semin Pediatr Surg 2012;21:31-43.  Back to cited text no. 16
17.Saab R, Furman WL. Epidemiology and management options for colorectal cancer in children. Paediatr Drugs 2008;10:177-92.  Back to cited text no. 17
18.Kassira N, Pedroso FE, Cheung MC, Koniaris LG, Sola JE. Primary gastrointestinal tract lymphoma in the pediatric patient: Review of 265 patients from the SEER registry. J Pediatr Surg 2011;46:1956-64.  Back to cited text no. 18
19.Ladd AP, Grosfeld JL. Gastrointestinal tumors in children and adolescents. Semin Pediatr Surg 2006;15:37-47.  Back to cited text no. 19
20.Rojas Y, Warneke CL, Dhamne CA, Tsao K, Nuchtern JG, Lally KP, et al. Primary malignant pancreatic neoplasms in children and adolescents: A 20 year experience. J Pediatr Surg 2012;47:2199-204.  Back to cited text no. 20
21.Havekes B, Romijn JA, Eisenhofer G, Adams K, Pacak K. Update on pediatric pheochromocytoma. Pediatr Nephrol 2009;24:943-50.  Back to cited text no. 21
22.Klein JD, Turner CG, Gray FL, Yu DC, Kozakewich HP, Perez-Atayde AR, et al. Adrenal cortical tumors in children: Factors associated with poor outcome. J Pediatr Surg 2011;46:1201-7.  Back to cited text no. 22


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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