lunes, 8 de abril de 2019

Unusual Cancers of Childhood Treatment (PDQ®) 4/5 —Health Professional Version - National Cancer Institute

Unusual Cancers of Childhood Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version


Cardiac Tumors

Histology

Cardiac tumors are rare, with an autopsy frequency of 0.001% to 0.30%;[91] in one report, the percentage of cardiac surgeries performed as a result of cardiac tumors was 0.093%.[92]
The most common primary tumors of the heart are benign and include the following:[93-95]
  • Rhabdomyoma.
  • Myxoma.
  • Teratoma.
  • Fibroma.
Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[93,96-99]
Myxomas are the most common noncutaneous finding in Carney complex, a rare syndrome characterized by lentigines, cardiac myxomas or other myxoid fibromas, and endocrine abnormalities.[100-102] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[100,103]
Primary malignant pediatric heart tumors are rare and include the following:[93,104,105]
  • Malignant teratoma.
  • Lymphoma.
  • Various sarcomas, including rhabdomyosarcoma, angiosarcoma, chondrosarcoma, synovial sarcoma, and infantile fibrosarcoma.
Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, other sarcomas, melanoma, leukemia, thymoma, and carcinomas of various sites.[91,93]

Risk Factors

The distribution of cardiac tumors in the fetal and neonatal period is different from that in older patients, with two-thirds of teratomas occurring during this period of life.[96] Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[96,106] A retrospective review of 94 patients with cardiac tumors detected by prenatal or neonatal echocardiography showed that 68% of the patients exhibited features of tuberous sclerosis.[107] In another study, 79% of patients (15 of 19) with rhabdomyomas discovered prenatally had tuberous sclerosis, while 96% of those diagnosed postnatally had tuberous sclerosis. Most rhabdomyomas, whether diagnosed prenatally or postnatally, will spontaneously regress.[108]

Clinical Presentation and Diagnostic Evaluation

Patients may be asymptomatic and present with sudden death,[109][Level of evidence: 3iiiA] but about two-thirds of patients have symptoms that may include the following:
  • Abnormalities of heart rhythm.
  • Enlargement of the heart.
  • Fluid in the pericardial sac.
  • Congestive heart failure.
  • Syncope.
  • Stroke.
  • Respiratory distress.[95]
The utilization of new cardiac MRI techniques can identify the likely tumor type in most children.[110] However, histologic diagnosis remains the standard for diagnosing cardiac tumors.

Treatment

Successful treatment may require surgery, debulking for progressive symptoms, cardiac transplantation, and chemotherapy that is appropriate for the type of cancer that is present.[111-113]; [114][Level of evidence: 3iiA]
Treatment options for cardiac tumors, according to tumor types, are as follows:
  1. Rhabdomyoma. Although some lesions such as rhabdomyomas can regress spontaneously, some practitioners recommend prophylactic resection to prevent mass-related complications.[92,95,106]; [115][Level of evidence: 3iiDiii] Treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus has been reported to be associated with a decrease in the size of rhabdomyomas in patients with tuberous sclerosis.[106,116,117]
  2. Sarcoma. Cardiac sarcomas have a poor outcome and can be treated with multimodal therapy; the use of preoperative chemotherapy may be of value in reducing tumor volume before surgery.
  3. Other tumor types. Complete surgical excision of other lesions offers the best chance for cure, with postoperative complications seen in about one-third of patients and postoperative mortality rates in less than 10% of patients.[92,95]
In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.[95]

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Mesothelioma

Incidence, Risk Factors, and Clinical Presentation

Mesothelioma is extremely rare in childhood, with only 2% to 5% of patients presenting during the first two decades of life.[118] Fewer than 300 cases in children have been reported.[119]
Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.[120,121] The amount of exposure required to develop cancer is unknown. In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.[122] There is no information about the risk for children exposed to asbestos.
This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.[123-125] These tumors can spread over the surface of organs, without invading far into the underlying tissue, and may spread to regional or distant lymph nodes.

Prognosis

Benign and malignant mesotheliomas cannot be differentiated using histologic criteria. A poor prognosis is associated with lesions that are diffuse and invasive and with those that recur. In general, the course of the disease is slow, and long-term survival is common.

Diagnostic Evaluation

Diagnostic thoracoscopy should be considered in suspicious cases to confirm diagnosis.[118]

Treatment

Treatment options for malignant mesothelioma include the following:
  1. Surgery.
  2. Radiation therapy.
  3. Chemotherapy.
Radical surgical resection has been attempted with mixed results.[126] In adults, a multimodal therapy including extrapleural pneumonectomy and radiation therapy after combination chemotherapy with pemetrexed-cisplatin may achieve durable responses.[127][Level of evidence: 2A] However, this approach remains highly controversial.[128] In children, treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[125,129-131]
Hyperthermic chemotherapy has been used to treat adults with pleural mesothelioma.[132,133]
Pain is an infrequent symptom; however, if pain occurs, radiation therapy may be used for palliation.
Papillary serous carcinoma of the peritoneum may be mistaken for mesothelioma.[134] This tumor generally involves all surfaces lining the abdominal organs, including the surfaces of the ovary. Treatment includes surgical resection whenever possible and use of chemotherapy with agents such as cisplatin, carboplatin, and paclitaxel.

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
(Refer to the PDQ summary on adult Malignant Mesothelioma Treatment for more information.)
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  103. Boikos SA, Stratakis CA: Carney complex: pathology and molecular genetics. Neuroendocrinology 83 (3-4): 189-99, 2006. [PUBMED Abstract]
  104. Kogon B, Shehata B, Katzenstein H, et al.: Primary congenital infantile fibrosarcoma of the heart: the first confirmed case. Ann Thorac Surg 91 (4): 1276-80, 2011. [PUBMED Abstract]
  105. Wang JG, Li NN: Primary cardiac synovial sarcoma. Ann Thorac Surg 95 (6): 2202-9, 2013. [PUBMED Abstract]
  106. Kocabaş A, Ekici F, Cetin Iİ, et al.: Cardiac rhabdomyomas associated with tuberous sclerosis complex in 11 children: presentation to outcome. Pediatr Hematol Oncol 30 (2): 71-9, 2013. [PUBMED Abstract]
  107. Tworetzky W, McElhinney DB, Margossian R, et al.: Association between cardiac tumors and tuberous sclerosis in the fetus and neonate. Am J Cardiol 92 (4): 487-9, 2003. [PUBMED Abstract]
  108. Bader RS, Chitayat D, Kelly E, et al.: Fetal rhabdomyoma: prenatal diagnosis, clinical outcome, and incidence of associated tuberous sclerosis complex. J Pediatr 143 (5): 620-4, 2003. [PUBMED Abstract]
  109. Neri M, Di Donato S, Maglietta R, et al.: Sudden death as presenting symptom caused by cardiac primary multicentric left ventricle rhabdomyoma, in an 11-month-old baby. An immunohistochemical study. Diagn Pathol 7: 169, 2012. [PUBMED Abstract]
  110. Beroukhim RS, Prakash A, Buechel ER, et al.: Characterization of cardiac tumors in children by cardiovascular magnetic resonance imaging: a multicenter experience. J Am Coll Cardiol 58 (10): 1044-54, 2011. [PUBMED Abstract]
  111. Michler RE, Goldstein DJ: Treatment of cardiac tumors by orthotopic cardiac transplantation. Semin Oncol 24 (5): 534-9, 1997. [PUBMED Abstract]
  112. Stiller B, Hetzer R, Meyer R, et al.: Primary cardiac tumours: when is surgery necessary? Eur J Cardiothorac Surg 20 (5): 1002-6, 2001. [PUBMED Abstract]
  113. Günther T, Schreiber C, Noebauer C, et al.: Treatment strategies for pediatric patients with primary cardiac and pericardial tumors: a 30-year review. Pediatr Cardiol 29 (6): 1071-6, 2008. [PUBMED Abstract]
  114. Wu KH, Mo XM, Liu YL: Clinical analysis and surgical results of cardiac myxoma in pediatric patients. J Surg Oncol 99 (1): 48-50, 2009. [PUBMED Abstract]
  115. Kutluk T, Demir HA, Büyükpamukçu M, et al.: Cardiac rhabdomyomas in childhood: six cases from a single institution. Turk J Pediatr 55 (1): 69-73, 2013 Jan-Feb. [PUBMED Abstract]
  116. Choudhry S, Nguyen HH, Anwar S: Rapid resolution of cardiac rhabdomyomas following everolimus therapy. BMJ Case Rep 2015: , 2015. [PUBMED Abstract]
  117. Barnes BT, Procaccini D, Crino J, et al.: Maternal Sirolimus Therapy for Fetal Cardiac Rhabdomyomas. N Engl J Med 378 (19): 1844-1845, 2018. [PUBMED Abstract]
  118. Nagata S, Nakanishi R: Malignant pleural mesothelioma with cavity formation in a 16-year-old boy. Chest 127 (2): 655-7, 2005. [PUBMED Abstract]
  119. Rosas-Salazar C, Gunawardena SW, Spahr JE: Malignant pleural mesothelioma in a child with ataxia-telangiectasia. Pediatr Pulmonol 48 (1): 94-7, 2013. [PUBMED Abstract]
  120. Hofmann J, Mintzer D, Warhol MJ: Malignant mesothelioma following radiation therapy. Am J Med 97 (4): 379-82, 1994. [PUBMED Abstract]
  121. Pappo AS, Santana VM, Furman WL, et al.: Post-irradiation malignant mesothelioma. Cancer 79 (1): 192-3, 1997. [PUBMED Abstract]
  122. Hyers TM, Ohar JM, Crim C: Clinical controversies in asbestos-induced lung diseases. Semin Diagn Pathol 9 (2): 97-101, 1992. [PUBMED Abstract]
  123. Kelsey A: Mesothelioma in childhood. Pediatr Hematol Oncol 11 (5): 461-2, 1994 Sep-Oct. [PUBMED Abstract]
  124. Moran CA, Albores-Saavedra J, Suster S: Primary peritoneal mesotheliomas in children: a clinicopathological and immunohistochemical study of eight cases. Histopathology 52 (7): 824-30, 2008. [PUBMED Abstract]
  125. Cioffredi LA, Jänne PA, Jackman DM: Treatment of peritoneal mesothelioma in pediatric patients. Pediatr Blood Cancer 52 (1): 127-9, 2009. [PUBMED Abstract]
  126. Maziak DE, Gagliardi A, Haynes AE, et al.: Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary. Lung Cancer 48 (2): 157-69, 2005. [PUBMED Abstract]
  127. Krug LM, Pass HI, Rusch VW, et al.: Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 27 (18): 3007-13, 2009. [PUBMED Abstract]
  128. Treasure T: What is the best approach for surgery of malignant pleural mesothelioma? It is to put our efforts into obtaining trustworthy evidence for practice. J Thorac Cardiovasc Surg 151 (2): 307-9, 2016. [PUBMED Abstract]
  129. Milano E, Pourroy B, Rome A, et al.: Efficacy of a combination of pemetrexed and multiple redo-surgery in an 11-year-old girl with a recurrent multifocal abdominal mesothelioma. Anticancer Drugs 17 (10): 1231-4, 2006. [PUBMED Abstract]
  130. Sugalski A, Davis M, Prasannan L, et al.: Clinical, histologic, and genetic features of mesothelioma in a 7-year-old child. Pediatr Blood Cancer 60 (1): 146-8, 2013. [PUBMED Abstract]
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  132. Nguyen D, Sugarbaker DJ, Burt BM: Therapeutic R2 resection for pleural mesothelioma. J Thorac Cardiovasc Surg 155 (6): 2734-2735, 2018. [PUBMED Abstract]
  133. Wald O, Sugarbaker DJ: New Concepts in the Treatment of Malignant Pleural Mesothelioma. Annu Rev Med 69: 365-377, 2018. [PUBMED Abstract]
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Abdominal Cancers

Unusual pediatric abdominal cancers include the following:
The prognosis, diagnosis, classification, and treatment of these abdominal cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series. (Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors for information about kidney tumors.)

Adrenocortical Carcinoma

Adrenocortical tumors encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior.

Incidence

The incidence of adrenocortical tumors in children is extremely low (only 0.2% of pediatric cancers).[1] Adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[2,3] Childhood adrenocortical tumors typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence.[4-6]
In children, 25 new cases are expected to occur annually in the United States, for an estimated annual incidence of 0.2 to 0.3 cases per 1 million individuals.[7] Internationally, however, the incidence of adrenocortical tumors appears to vary substantially. It is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[8-11]
Female sex is consistently predominant in most studies, with a female to male ratio of 1.6:1.0.[3,5,6]

Risk Factors

Germline TP53 mutations are almost always the predisposing factor. The likelihood of a TP53 germline mutation is highest in the first years of life and diminishes with age. Predisposing genetic factors have been implicated in more than 50% of the cases in North America and Europe and in 95% of the Brazilian cases. [12]
  • In the non-Brazilian cases, relatives of children with adrenocortical tumors often, although not invariably, have a high incidence of other nonadrenal cancers (Li-Fraumeni syndrome). Germline mutations usually occur within the region coding for the TP53 DNA-binding domain (exons 5 to 8, primarily at highly conserved amino acid residues).[10,12]
  • In the Brazilian cases, the patients’ families do not exhibit a high incidence of cancer, and a single, unique mutation at codon 337 in exon 10 of the TP53 gene is consistently observed.[11,13] In a Brazilian study, neonatal screening for the TP53 R337H mutation, which is prevalent in the region, identified 461 (0.27%) carriers among 171,649 of the newborns who were screened.[14] Carriers and relatives younger than 15 years were offered clinical screening. Adrenocortical tumors identified in the screening participants were smaller and more curable than the tumors found in carriers who did not elect to participate in screening.
Patients with Beckwith-Wiedemann and hemihyperplasia syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors.[15] Hypomethylation of the KCNQ1OT1 gene has also been associated with the development of adrenocortical tumors in patients without the phenotypic features of Beckwith-Wiedemann syndrome.[16] However, less than 1% of children with adrenocortical tumors have these syndromes.[17]
The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.[18]

Histology

Unlike adult adrenocortical tumors, histologic differentiation of pediatric adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[2,4] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenomas and carcinomas appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.[19]
Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[20-22]
Morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.[23] IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[24,25] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from tumor characteristics, such as tumor necrosis, mitotic rate, the presence of atypical mitoses, and venous, capsular, or adjacent organ invasion.[11,22,23]

Molecular Features

A study performed on 71 pediatric adrenocortical tumors (37 in a discovery cohort and 34 in an independent cohort) provided a description of the genomic landscape of pediatric adrenocortical carcinoma.[26]
  • IGF2 overexpression. The most common genomic alteration, present in approximately 90% of cases, was copy number loss of heterozygosity for 11p15 with retention of the paternal allele resulting in IGF2 overexpression.
  • TP53 mutations. TP53 mutations were commonly observed. Twelve of 71 cases had the Brazilian founder R337H TP53 germline mutation. Excluding the Brazilian founder mutation cases, TP53 germline mutations were observed in approximately one-third of cases, with somatic TP53 mutations observed in approximately 10% of the remaining cases, such that approximately 40% of non-Brazilian cases had TP53 mutations. Among cases with TP53 mutations, chromosome 17 loss of heterozygosity with selection against wild-type TP53 was present in virtually all cases.
  • ATRX mutations. ATRX genomic alterations (primarily structural variants) were present in approximately 20% of cases. All ATRX alterations occurred in the presence of TP53alterations. The co-occurrence of TP53 and ATRX mutations correlated with advanced stage, large tumor size, increased telomere length, and poor prognosis.
  • CTNNB1 mutations. Activating CTNNB1 mutations were found in approximately 20% of cases and were mutually exclusive with TP53 germline alterations.

Clinical Presentation

Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[3,4]
  • Virilization. Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) caused by an excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients.[11,27]
  • Hyperestrogenism. Hyperestrogenism can also occur.[28]
  • Cushing syndrome. Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[3-5,11,29]
Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.[11]
Nonfunctional tumors are rare (<10%) and tend to occur in older children.[3]

Prognostic Factors

Overall, adverse prognostic factors for adrenocortical carcinoma include the following:
  • Large tumor size. Tumor weight higher than 200 g or tumor volume greater than 200 cm3 have been associated with a worse outcome.[30,31] Patients with small tumors have an excellent outcome when treated with surgery alone, regardless of histologic features.[6,32,33]
  • Metastatic disease.[6,30,31,33]
  • Age. Age older than 4 or 5 years.[3,6,30,31,33]
  • Microscopic tumor necrosis.[33]
  • Para-aortic lymph node involvement.[33]
  • Incomplete resection or spillage during surgery.[6,30,31]
  • Low HLA class II antigen expression. A low expression of the HLA class II antigens HLA-DRA, HLA-DPA1, and HLA-DPB1 has been associated with older age, larger tumor size, presence of metastatic disease, and worse outcome.[34] In pediatric patients, increased expression of MHC class II genes, especially HLA-DPA1, is associated with a better prognosis.[35]
Stage I disease appears to be associated with a better prognosis.[33]
The overall probability of 5-year survival for children with adrenocortical tumors depends on stage and ranges from greater than 80% for patients with resectable disease to less than 20% for patients with metastases.[3-5,29-32,36]
A portion of patients with adrenocortical carcinoma do not have a germline TP53 mutation. A retrospective review of children with adrenocortical carcinoma identified 60 patients without germline TP53 mutations.[37] There was a strong female predominance (female to male ratio, 42:18) in this group of patients. Three-year progression-free survival (PFS) was 71.4%, and overall survival (OS) was 80.5%. Prognostic factors for this group were the same as the factors identified in previous analyses that did not segregate for TP53 germline status. Unfavorable prognostic features included older age, higher disease stage, heavier tumor weight, presence of somatic TP53 mutations, and higher Ki-67 labeling index. Ki-67 labeling index and age remained significantly associated with PFS after adjusting for stage and tumor weight.

Treatment

At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors can be completely resected), and the remaining patients have either unresectable or metastatic disease.[3]
Treatment of childhood adrenocortical tumors has evolved from the data derived from the adult studies, and the same guidelines are used. Surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens, usually incorporating doxorubicin and etoposide, are recommended for patients with advanced disease.[10,11,38,39]; [5][Level of evidence: 3iiiA]
Treatment options for childhood adrenocortical tumors include the following:
  1. Surgery: An aggressive surgical approach toward the primary tumor and all metastatic sites is recommended when feasible.[40,41] Because of tumor friability, rupture of the capsule with resultant tumor spillage is frequent (approximately 20% of initial resections and 43% of resections after recurrence).[3] When the diagnosis of adrenocortical tumor is suspected, laparotomy and a curative procedure are recommended rather than fine-needle aspiration, to avoid the risk of tumor rupture.[41,42] Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.[43]
  2. Mitotane and cisplatin-based regimens: In adults, mitotane is commonly used as a single agent in the adjuvant setting after complete resection.[38] Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[1,38]
    • A retrospective analysis in Italy and Germany identified 177 adult patients with completely resected adrenocortical carcinoma. Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane. Benefit was present with 1 g to 3 g per day of mitotane and was associated with fewer toxic side effects than doses of 3 g to 5 g per day.[44] (Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)
    • In a review of 11 children with advanced adrenocortical tumors treated with mitotane and a cisplatin-based chemotherapeutic regimen, measurable responses were seen in seven patients. The mitotane daily dose required for therapeutic levels was approximately 4 g/m2, and therapeutic levels were achieved after 4 to 6 months of therapy.[38]
    • In the GPOH-MET 97 trial, mitotane levels greater than 14 mg/L correlated with better survival.[5,11]
The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Adrenocortical tumors are generally considered to be radioresistant. Furthermore, because many children with adrenocortical tumors carry germline TP53 mutations that predispose to cancer, radiation may increase the incidence of secondary tumors. One study reported that three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcoma that arose within the radiation field.[11,45]
(Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Gastric (Stomach) Cancer

Incidence

Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual.[46] In one series, gastric cancer in children younger than 18 years accounted for 0.11% of all gastric cancer cases seen over an 18-year period.[47] The frequency and death rate from stomach cancer has declined worldwide for the past 50 years with the introduction of food preservation practices such as refrigeration.[48] Rare cases of familial diffuse gastric cancer associated with CDH1 germline mutations have been reported in adolescents.[49]

Clinical Presentation and Diagnostic Evaluation

The tumor must be distinguished from other conditions such as non-Hodgkin lymphoma, malignant carcinoid, leiomyosarcoma, and various benign conditions or tumors of the stomach.[46] Symptoms of carcinoma of the stomach include the following:
  • Vague upper abdominal pain, which can be associated with poor appetite and weight loss.
  • Nausea and vomiting.
  • Change in bowel habits.
  • Poor appetite.
  • Weakness.
  • Helicobacter pylori infection.[47,50]
  • Anemia. Many individuals become anemic but otherwise show no symptoms before the development of metastatic spread.
Fiberoptic endoscopy can be used to visualize the tumor or to take a biopsy sample to confirm the diagnosis. Confirmation can also involve an x-ray examination of the upper gastrointestinal tract.

Treatment and Outcome

Treatment options for gastric carcinoma include the following:
  1. Surgery.
  2. Radiation therapy and chemotherapy.
Treatment includes surgical excision with wide margins. For individuals who cannot have a complete surgical resection, radiation therapy may be used along with chemotherapeutic agents such as fluorouracil (5-FU) and irinotecan.[51] Other agents that may be of value are the nitrosoureas with or without cisplatin, etoposide, doxorubicin, or mitomycin C.
Prognosis depends on the extent of the disease at the time of diagnosis and the success of treatment that is appropriate for the clinical situation.[47] Because of the rarity of stomach cancer in the pediatric age group, little information exists regarding the treatment outcomes of children.
(Refer to the Gastrointestinal Stromal Tumors [GIST] section of this summary for information about the treatment of GIST.)

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Cancer of the Pancreas

Malignant pancreatic tumors are rare in children and adolescents, with an incidence of 0.46 cases per 1 million individuals younger than 30 years.[52-55]
The primary pancreatic tumors of childhood can be classified into the following four categories:

Solid Pseudopapillary Tumor of the Pancreas

Incidence
Solid pseudopapillary tumor of the pancreas, also known as Frantz tumor, is the most common pediatric pancreatic tumor, accounting for up to 70% of cases in most institutional series.[54,56] This tumor has low malignant potential and most commonly affects females of reproductive age (median age, 21 years), with a predilection for blacks and East Asians.[52,54,57] There is no known genetic or hormonal factor to explain the strong female predilection, although it has been noted that all tumors express progesterone receptors.[58]
Histology
Histologically, the tumors are characterized by a combination of solid, pseudopapillary, and cystic changes. The fragility of the vascular supply leads to secondary degenerative changes and cystic areas of hemorrhage and necrosis. The cells surrounding the hyalinized fibrovascular stalks form the pseudopapillae.[52] A highly specific paranuclear dot-like immunoreactivity pattern for CD99 has been described.[59]
Clinical Presentation
Solid pseudopapillary tumor of the pancreas is a very friable tumor, and tumor rupture and hemoperitoneum have been reported.[52,54,57] Tumors can occur throughout the pancreas and are often exophytic. On imaging, the mass shows typical cystic and solid components, with intratumoral hemorrhage and a fibrous capsule.[52]
Outcome
The outcome of solid pseudopapillary tumors of the pancreas is excellent, with 10-year survival rates exceeding 95%.[58]
Treatment
Treatment options for solid pseudopapillary tumor of the pancreas include the following:
  1. Surgery.
  2. Chemotherapy.
Treatment of solid pseudopapillary tumor of the pancreas is surgical; however, preoperative and operative spillage is not unusual.[60] Whipple procedures (pancreaticoduodenectomy) are often necessary, but non-Whipple pancreatic-sparing resections may be possible utilizing a pancreatico-jejunostomy procedure. Surgery is usually curative, although local recurrences occur in 5% to 15% of the cases.[57] A retrospective review of the Italian Pediatric Rare Tumor Registry identified 43 pediatric patients diagnosed with solid pseudopapillary tumor of the pancreas between 2000 and 2018.[61][Level of evidence: 3iiA] The median age at diagnosis was 13.2 years (range, 7–18 years). Only one patient presented with metastatic disease. At follow-up (median, 8.4 years; range, 0–17 years), one recurrence occurred in a patient who had intraoperative rupture, and all patients were alive.
Metastatic disease, usually in the liver, may occur in up to 15% of the cases.[52,54,57-59] Single-agent gemcitabine has been reported to be effective in cases of unresectable or metastatic disease.[62]

Pancreatoblastoma

Incidence and Risk Factors
Pancreatoblastoma accounts for 10% to 20% of all pancreatic tumors during childhood. It is the most common pancreatic tumor of young children and typically presents in the first decade of life, with a median age at diagnosis of 5 years.[52,63]
Patients with Beckwith-Wiedemann syndrome have an increased risk of developing pancreatoblastoma; this syndrome is identified in up to 60% of cases of pancreatoblastoma developing during early infancy and in 5% of children developing pancreatoblastoma later in life.[64] Pancreatoblastoma has also been associated with familial adenomatous polyposis syndromes.[65]
Histology and Molecular Features
This tumor is thought to arise from the persistence of the fetal analog of pancreatic acinar cells. Pathology shows an epithelial neoplasm with an arrangement of acinar, trabecular, or solid formations separated by dense stromal bands.[52] CTNNB1 and IGF2 gene mutations have been described in some cases, suggesting that pancreatoblastoma might result from alterations in the normal pancreas differentiation.[66,67]
Clinical Presentation
Although approximately one-half of the cases originate in the head of the pancreas, jaundice is uncommon. Close to 80% of the tumors secrete alpha-fetoprotein, which can be used to measure response to therapy and monitor for recurrence.[63] In some cases, the tumor may secrete adrenocorticotropic hormone (ACTH) or antidiuretic hormone, and patients may present with Cushing syndrome and the syndrome of inappropriate antidiuretic hormone secretion.[64] Metastases are present in 30% to 40% of the patients, usually involving liver, lungs, and lymph nodes.[63]
Outcome
Using a multimodality approach, close to 80% of patients can be cured.[63]
Treatment
Treatment options for pancreatoblastoma include the following:
  1. Surgery.
  2. Chemotherapy.
Surgery is the mainstay in the treatment of pancreatoblastoma, and a complete surgical resection is required for cure. Because of the common origin in the head of the pancreas, a Whipple procedure is usually required.[60,68]
For large, unresectable, or metastatic tumors, preoperative chemotherapy is indicated; pancreatoblastoma commonly responds to chemotherapy, and a cisplatin-based regimen is usually recommended. The PLADO regimen, which includes cisplatin and doxorubicin, is the most commonly used regimen, and treatment is modeled after the management of hepatoblastoma, with two to three cycles of preoperative therapy, followed by resection and adjuvant chemotherapy.[54,63,65,69]
Although radiation therapy has been used in unresectable or relapsed cases, its role in the treatment of microscopic disease after surgery has not been defined.[65]
Response has been seen for patients with relapsed or persistent pancreatoblastoma treated with gemcitabine in one case [70] and vinorelbine and oral cyclophosphamide in two cases.[71]
High-dose chemotherapy with autologous hematopoietic stem cell rescue has been reported to be effective in selected cases.[54,72]

Islet Cell Tumors

Incidence and Risk Factors
Islet cell tumors represent approximately 15% of pediatric pancreatic tumors in most series.[54,56,73] These tumors usually present in middle age and may be associated with multiple endocrine neoplasia type 1 (MEN1) syndrome; less than 5% of islet cell tumors occur in children.[52]
Clinical Presentation
The most common type of functioning islet cell tumor is insulinoma, followed by gastrinoma.
  • Insulinoma. Patients with insulinoma present with fasting hyperinsulinic hypoglycemia; in young children, presentation may include behavioral problems, seizures, or coma.
  • Gastrinoma. Gastrinoma presents with Zollinger-Ellison syndrome, with recurrent peptic ulcers in uncommon locations, and diarrhea due to gastric hypersecretion. While most insulinomas are benign, a significant proportion of gastrinomas are malignant.[73]
  • ACTHoma and VIPoma. Other less common tumors seldom seen in children are the ACTHoma, which presents as Cushing syndrome, and the VIPoma, which presents as Verner-Morrison syndrome.
Nonfunctioning tumors are extremely rare in pediatrics, except when associated with MEN1. Islet cell tumors are typically solitary; when multiple tumors are present, the diagnosis of MEN1 syndrome should be considered.
On imaging, these tumors are usually small and well defined. Somatostatin receptor scintigraphy is useful for the location of islet cell tumors; however, only 60% to 70% express somatostatin receptor.[52]
Treatment
Treatment options for islet cell tumors include the following:
  1. Surgery.
  2. Chemotherapy.
  3. Mammalian target of rapamycin (mTOR) inhibitor therapy.
Treatment of islet cell tumors includes medical therapy for control of the syndrome and complete surgical resection.[60] For patients with malignant tumors and unresectable or metastatic disease, chemotherapy and mTOR inhibitors are recommended.
The management of these tumors in children follows the consensus guidelines established for adult patients.[73,74] (Refer to the PDQ summary on adult Pancreatic Neuroendocrine Tumors [Islet Cell Tumors] Treatment for more information.)

Pancreatic Carcinoma

Incidence and Risk Factors
Pancreatic carcinomas (acinar cell carcinoma and ductal adenocarcinoma) are extremely rare in children. These malignancies represent less than 5% of pediatric pancreatic tumors and include the following:[54,56]
  • Acinar cell carcinoma. Although rare in pediatrics, acinar cell carcinoma is more common than ductal cell adenocarcinoma, the most common pancreatic carcinoma in adults. Acinar cell carcinoma is considered to be the adult counterpart of pancreatoblastoma, and histological differentiation between both entities may be difficult.[52]
  • Ductal adenocarcinoma. Ductal adenocarcinoma is rare in the first four decades of life and even rarer during childhood and adolescence.[75] Ductal adenocarcinoma is associated with several cancer predisposition syndromes, such as hereditary pancreatitis (PRSS1 mutations), familial atypical mole and multiple melanoma (CDKN2mutations), Peutz-Jeghers syndrome and other hereditary nonpolyposis colon carcinomas (STK11 and germline mismatch repair genes), and syndromes associated with DNA repair gene mutations (such as BRCA2 and ATM).[76]
Clinical Presentation
Presenting symptoms are nonspecific and are related to local tumor growth. However, 4% to 15% of adult patients with acinar cell carcinoma may present with a lipase hypersecretion syndrome, manifesting as peripheral polyarthropathy and painful subcutaneous nodules.
Treatment
(Refer to the PDQ summary on adult Pancreatic Cancer Treatment for information about the treatment of pancreatic carcinoma.)

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Colorectal Carcinoma

Incidence

Carcinoma of the large bowel is rare in the pediatric age group.[77] It is seen in one case per 1 million persons younger than 20 years in the United States annually; fewer than 100 cases are diagnosed in children each year in the United States.[78] From 1973 to 2006, the Surveillance, Epidemiology, and End Results (SEER) database recorded 174 cases of colorectal cancer in patients younger than 19 years.[79] Colorectal carcinoma accounts for about 2% of all malignancies in patients aged 15 to 29 years.[80]

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.[81-83]
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.[78,84]
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:[85,86]
  • 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.[87]

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,[77,78,84,88,89] 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.[89-91] 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.[86]
Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRASmutations and other cytogenetic anomalies seen in older patients.[92] 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.[93]

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).[78,81-85,88,89,94-100]

Treatment and Outcome

Most patients present with evidence of metastatic disease,[84] either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[88,94] 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.[89]
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.[78] 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 5-FU with leucovorin.[101] Other agents, including irinotecan, may be of value.[84][Level of evidence: 3iiiA] No significant benefit has been determined for interferon-alfa given in conjunction with 5-FU/leucovorin.[102]
    A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved PFS and OS in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[103][Level of evidence: 2A]
    Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[104-107]
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.[81]

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

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.[108] Hereditary colorectal cancer has two well-described forms:
  • 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), FAP3 (NTHL1), juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).
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.[109]
  • A later study documented immunohistochemical evidence of mismatch repair deficiency in 31% of colorectal carcinoma samples in patients aged 30 years or younger.[110]
  • A retrospective review of patients younger than 18 years in Germany identified 31 patients with colorectal carcinoma.[111] 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.[112] Some colorectal carcinomas in young people, however, may be associated with a mutation of the adenomatous polyposis coli (APC) gene, which also is associated with an increased risk of brain tumors and hepatoblastoma.[113] Familial adenomatous polyposis (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.[114] 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.[115][Level of evidence: 1iiDiv] 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.[116]
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.[117]

Neuroendocrine Tumors (Carcinoid Tumors)

These tumors, like tracheobronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[118-123] Most lung lesions are benign; however, some metastasize.[124]
The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.[124] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.[125] Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.[126]

Neuroendocrine Tumors of the Appendix

Clinical Presentation
A single-institution retrospective review identified 45 cases of carcinoid tumors in children and adolescents between 2003 and 2016.[127][Level of evidence: 3iiDii] The most common primary site was the appendix (36 of 45 cases). No recurrences were observed among the patients with appendiceal primary tumors treated with appendectomy alone, which supports resection of the appendix without hemicolectomy as the procedure of choice.
Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, and are small, low-grade, localized tumors.[128-130]
Treatment
Treatment options for neuroendocrine tumors of the appendix include the following:
  1. Appendectomy.
In adults, it has been accepted practice to remove the entire right colon in patients with large carcinoid tumors of the appendix (>2 cm in diameter) or with tumors that have spread to the lymph nodes.[131-134]
Study results suggest that appendectomy alone is sufficient treatment for childhood appendiceal carcinoids regardless of size, position, histology, or nodal or mesenteric involvement and that right hemicolectomy is unnecessary in children. Routine follow-up imaging and biologic studies were not beneficial.[131,134-136]
Evidence (appendectomy alone):
  1. The Italian Rare Tumors in Pediatric Age project performed a prospective registry study that evaluated 113 patients with appendiceal neuroendocrine tumors.[135][Level of evidence: 3iiiA] Primary re-excision was not recommended for completely excised tumors smaller than 2 cm except for microscopic/macroscopic residual tumor on the margins of the appendix, in which case cecum resection and pericecal node biopsy was recommended. Decisions about tumors larger than 2 cm were made at the discretion of the primary physicians. However, physicians were discouraged from performing right hemicolectomy unless margins were positive. Of the 113 study participants, 108 had tumors smaller than 2 cm. Thirty-five patients had extension of tumor beyond the appendiceal wall. Five tumors invaded the serosa, and 28 tumors invaded the periappendiceal fat. Margins were clear in 111 of 113 patients.
    • At 41 months of follow-up, 113 of 113 patients were alive.
    • The five patients with tumors larger than 2 cm did well.
    • One patient had resection of the cecum; no residual tumor was found.
    • One patient had a right hemicolectomy (tumor was <2 cm with clear margins, but an octreotide scan was possibly positive; no tumor was found).
    The study concluded that appendectomy alone should be considered curative for most cases of appendiceal neuroendocrine tumors. The procedure of choice is a resection of the appendix without hemicolectomy.
  2. A French multicenter study of children younger than 18 years with neuroendocrine tumors of the appendix was carried out by surveying pediatric surgeons from 1988 to 2012. A total of 114 patients were identified. Risk factors for secondary right hemicolectomy were extension into the mesoappendix, positive margins, size larger than 2 cm, and high proliferative index. Eighteen patients met the above criteria and were observed.[136]
    • All patients were alive and disease free at follow-up.
    • In addition, follow-up radiological studies and biological tests were not found to be helpful.
    The investigator's recommendation was that appendectomy alone is sufficient treatment for neuroendocrine tumors of the appendix.
  3. A systematic review and meta-analysis of 38 studies of appendiceal carcinoid identified 958 cases with a mean age at presentation of 11.6 years. Tumor size was 2 cm or larger in 85% of the cases. Of the 24 papers that reported the status of the margin of resection, 97% had negative margins. Nodal involvement was reported in ten series and was present in 1.4% of cases, with higher rates seen in patients whose tumors were larger than 2 cm (35%). Vascular involvement was seen in 11% of 510 patients, and invasion of the mesoappendix or periappendiceal fat was reported in 29% of 910 patients.[134]
    • According to the European and American Neuroendocrine Tumor Societies, 189 patients met the criteria for a secondary procedure after initial appendectomy but only 69 patients underwent a secondary procedure (n = 43, hemicolectomy; n = 2, ileocecectomy; n = 1, cecectomy; n = 2, ileocolectomy; n = 21, not specified).
    • Of the 120 patients who did not have a secondary procedure, 91 patients had tumors extending to the mesoappendix, 5 patients had vascular invasion, 4 patients had positive margins, 12 patients had tumors 2 cm or larger, 1 patient had a high proliferative index, and 7 patients had positive lymph nodes. No recurrence was reported in patients who had a secondary procedure or those who were observed. Preoperative and postoperative imaging was not helpful in managing the patients.

Nonappendiceal Neuroendocrine Tumors

Clinical Presentation
A single-institution retrospective review identified 45 cases of carcinoid tumors in children and adolescents between 2003 and 2016.[127][Level of evidence: 3iiDii] Extra-appendiceal primary tumors (n = 9) were associated with a higher risk of metastasis and recurrence.
Nonappendiceal neuroendocrine tumors in the abdomen can occur in the pancreas, stomach, and liver. The most common clinical presentation is an unknown primary site. Nonappendiceal neuroendocrine tumors are more likely to be larger, higher grade, or present with metastases.[137] Larger tumor size has been associated with a higher risk of recurrence.[127]
Clinical experience with nonappendiceal neuroendocrine tumors is reported almost entirely in adults. Histopathology is graded by mitotic rate, Ki-67 labeling index, and presence of necrosis into well-differentiated (low grade, G1), moderately differentiated (intermediate grade, G2) and poorly differentiated (high grade, G3) tumors.[138]
Treatment and Outcome
Treatment options for resectable nonappendiceal neuroendocrine tumors include the following:
  1. Surgery.[139]
Treatment options for unresectable or multifocal nonappendiceal neuroendocrine tumors include the following:
  1. Embolization.[140]
  2. Somatostatin receptor 2 (SSTR2) ligands.[141,142]
  3. Peptide receptor radionuclide therapy.[143]
  4. mTOR inhibitors.[144]
  5. Tyrosine kinase inhibitors.[145]
SSTR2 ligands include octreotide, long-acting repeatable octreotide, and lanreotide. Octreotide is not practical for therapy because of its short half-life, requiring frequent repeated administration. Long-acting repeatable octreotide and lanreotide have been evaluated in prospective, randomized, placebo-controlled trials.[141,142] Patient age was not specified in the first trial, and eligibility was restricted to age 18 years and older in the second trial. Neither agent produced significant objective responses in measurable tumors. Both agents were associated with statistically significant increases in PFS and time-to-progression, and both agents are recommended for the treatment of unresectable nonappendiceal neuroendocrine tumors in adults.
Conventional cytotoxic chemotherapy appears to be inactive.[137]
In one retrospective, single-institution study, the 5-year relapse-free survival rate of nonappendiceal neuroendocrine tumors was 41%, and the OS rate was 66%.[137]
(Refer to the Tracheobronchial Tumors section of this summary for information about tracheobronchial carcinoid tumors.)

Metastatic Neuroendocrine Tumors

Treatment of metastatic carcinoid tumors of the large bowel, pancreas, or stomach becomes more complicated and requires treatment similar to that given for adult high-grade neuroendocrine tumors. (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors Treatment for treatment options in patients with malignant carcinoid tumors.)

Treatment Options Under Clinical Evaluation

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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Gastrointestinal Stromal Tumors (GIST)

Incidence

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[146] These tumors are rare in children.[147] Approximately 2% of all GIST occur in children and young adults.[148-150] In one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[151] Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas.
In pediatric patients, GIST are most commonly located in the stomach and almost exclusively affect adolescent females.[150,152,153]

Histology and Molecular Features

Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, the mitotic rate does not appear to accurately predict clinical behavior.[152,154] The majority of GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[155,156] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[157,158]
Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[152,157,159] The lack of SDHB expression in most pediatric GIST implicates cellular respiration defects in the pathogenesis of this disease and supports the notion that this disease is better categorized as SDH-deficient GIST. Furthermore, about 50% of patients with SDH-deficient GIST have germline mutations of the SDH complex, most commonly involving SDHA,[155] supporting the notion that SDH-deficient GIST is a cancer predisposition syndrome and testing of affected patients for constitutional mutations for the SDH complex should be considered.[160] A small percentage of SDH-deficient GIST lack somatic or germline mutations of the SDH complex and are characterized by SDHC promoter hypermethylation and gene silencing and are categorized as SDH-epimutant GIST.[161]
In an observational study carried out at the NCI, 116 patients with presumed wild-type GIST were evaluated, and 95 of these patients had an adequate tumor specimen available for molecular profiling. Among these 95 patients, the investigators identified the following three distinctive subgroups of patients:[162]
  • Group 1 (SDH-competent GIST): Group 1 was comprised of 11 patients who were designated as SDH competent because of positive staining of SDHB and lack of mutations on sequencing. All of these patients were adults, the median age was 46 years, and 64% were female. The tumors arose primarily in the small bowel (9 of 11), one patient had metastases to the peritoneum, and one patient had multifocal disease. Mutational analysis of these tumors identified mutations in the BRAF, NF1, CBL, KIT, and ARID1A genes. With a median follow-up of 8 years, three of these patients (27%) died of progressive disease.
  • Group 2 (SDHX-mutant GIST): Group 2 was comprised of 63 patients who were SDH deficient and contained mutations in the SDHA (n = 34), SDHB (n = 16), SDHC (n = 12), and SDHD (n = 1) complexes. Of the 38 patients with SDH-mutant GIST who had matching germline and tumor DNA, 31 (82%) had the same mutation detected in the germline and the tumor. This group of patients was younger (median age, 23 years), mostly female (62%), and presented with gastric tumors (100%) and multifocal disease (42%). Metastases at presentation were seen in the lymph nodes (65%), liver (21%), and peritoneum (10%). At a median follow-up from diagnosis of 6 years, only three patients (5%) had died.
  • Group 3 (SDHC-epimutant GIST): Group 3 was comprised of 21 patients with SDH-deficient tumors, with SDHC promoter methylation and no structural mutations. The median age at diagnosis was younger (age 15 years) and most patients were female (95%). All tumors arose in the stomach; 72% were multifocal; and metastases were present at diagnosis in the liver (37%), peritoneum (5%), and lymph nodes (38%). At a median follow-up of 7 years, only one patient (5%) with an SDH-epimutant tumor died from disease.
Of the 95 patients that were evaluated at this clinic, 18 patients had syndromic GIST (i.e., Carney triad or Carney-Stratakis syndrome). Among the Carney triad patients, two patients had the complete triad, five patients had SDH mutations, and six patients had epimutant tumors. Seven patients with Carney-Stratakis syndrome had SDH-mutant GIST (n = 6) or SDH-epimutant GIST (n = 1).[162]

Clinical Features

Most pediatric patients with GIST are diagnosed during the second decade of life with anemia-related gastrointestinal bleeding. In addition, pediatric GIST have a high propensity for multifocality (23%) and nodal metastases.[150,152,159] These features may account for the high incidence of local recurrence seen in this patient population. Despite these features, patients have an indolent course characterized by multiple recurrences and long survival.[159]
SDH-deficient GIST can arise within the context of the following two syndromes:[152,163]
  • Carney triad. Carney triad is a syndrome characterized by the occurrence of GIST, lung chondromas, and paragangliomas. In addition, about 20% of patients have adrenal adenomas and 10% have esophageal leiomyomas. GIST are the most common (75%) presenting lesions in these patients. To date, no coding sequence mutations of KIT, PDGFR, or the SDH genes have been found in these patients.[150,163,164]
  • Carney-Stratakis syndrome. Carney-Stratakis syndrome is characterized by paraganglioma and GIST caused by germline mutations of the SDH genes B, C, and D.[156,165]

Treatment

Once the diagnosis of pediatric GIST is established, referral to medical centers with expertise in the treatment of GIST should be considered, with all samples evaluated for mutations in KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[166,167]
Treatment options for GIST depend on whether a mutation is detected, as follows:
  1. GIST with a KIT or PDGFR mutation: Pediatric patients who harbor KIT or PDGFRmutations are managed according to adult guidelines.
  2. SDH-deficient GIST: Approximately one-half of all wild-type GIST patients are SDH-deficient.[168] For most pediatric patients with SDH-deficient GIST, because of its indolent course, surgical resection of localized disease is recommended while avoiding extensive surgery and repeated surgical resections. These recommendations are supported by a study of 76 patients with wild-type GIST who underwent surgery for newly diagnosed and recurrent disease.[168] In this study, only 9% of patients experienced a fatal event, whereas 71% (54 patients) developed recurrence or progression at a median of 2.5 years. For this population, the 1-year event-free survival (EFS) was 73%, the 5-year EFS was 24%, and the 10-year EFS was 16%. Factors associated with an increased risk of recurrence included metastatic disease and elevated mitotic rate; SDH status and extent of surgical resection did not influence the risk of recurrence. Among 33 patients who underwent reoperation for recurrent disease, each subsequent resection was associated with a lower EFS.
    Responses to imatinib and sunitinib in pediatric patients with SDH-deficient GIST are uncommon and consist mainly of disease stabilization.[152,169,170] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[152] In the phase III SWOG intergroup trial S0033 (NCT00009906), 20 tumors from patients who were presumed to be wild-type were resequenced.[170] Twelve of these tumors were identified as being SDH mutant, and only one patient (8.3%) experienced a partial response to imatinib.[171] In another study, sunitinib appeared to show more activity, with one partial response and five cases of stable disease in six children with imatinib-resistant GIST.[172] Unlike the adult recommendations, the use of adjuvant imatinib cannot be recommended in children with SDH-deficient GIST.[173]
    Given the indolent course of the disease in pediatric patients, it is reasonable to avoid extensive initial surgeries and to withhold subsequent resections unless they are needed to address only symptoms such as obstruction or bleeding.[147,152]

Treatment Options Under Clinical Evaluation

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 are examples of national and/or institutional clinical trials that are 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 using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
  • NCT03165721 (A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine [SGI-110], in Children and Adults With Wild-Type GIST, Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer): Participants will be injected with SGI-110 under the skin each day for 5 days. This cycle will repeat every 28 days. The cycles repeat until toxicity occurs or the disease progresses.
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