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

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

Abdominal Cancers

Unusual pediatric abdominal cancers include the following:

Adrenocortical carcinoma (carcinoma of the adrenal cortex).
Gastric (stomach) cancer.
Cancer of the pancreas.
Colorectal carcinomas.
Neuroendocrine tumors (carcinoid tumors).
Gastrointestinal stromal tumors (GIST).

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.[11,22,23,26]

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.[27]

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.[11,28]
Hyperestrogenism. Hyperestrogenism can also occur.[29]
Cushing syndrome. Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[3-5,11,30]

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.[31,32] Patients with small tumors have an excellent outcome when treated with surgery alone, regardless of histologic features.[6,33,34]
Metastatic disease.[6,26,31,32,34]
Age. Age older than 4 or 5 years.[3,6,31,32,34]
Microscopic tumor necrosis.[34]
Para-aortic lymph node involvement.[34]
Incomplete resection or spillage during surgery.[6,31,32]
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.[35] In pediatric patients, increased expression of MHC class II genes, especially HLA-DPA1, is associated with a better prognosis.[36]

Stage I disease appears to be associated with a better prognosis.[34]

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.[3-5,26,30-33,37]

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.[38] 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.[10,11,39,40]; [5][Level of evidence: 3iiiA]

Treatment options for childhood adrenocortical tumors include the following:

Surgery: An aggressive surgical approach toward the primary tumor and all metastatic sites is recommended when feasible.[41,42] 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.[42,43] Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.[44]
Mitotane and cisplatin-based regimens: In adults, mitotane is commonly used as a single agent in the adjuvant setting after complete resection.[39] Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[1,39]
- 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.[45] (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.[39]
- 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.[11,46]

(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 4,000 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 NCI website and ClinicalTrials.gov website.

Gastric (Stomach) Cancer

Incidence

Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual.[47] 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.[48] 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.[49] Rare cases of familial diffuse gastric cancer associated with CDH1 germline mutations have been reported in adolescents.[50]

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.[47] 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.[48,51]
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:

Surgery.
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.[52] 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.[48] 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

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 4,000 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 NCI website and ClinicalTrials.gov website.

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.[53-56]

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.[55,57] 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.[53,55,58] 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.[59]

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.[53] A highly specific paranuclear dot-like immunoreactivity pattern for CD99 has been described.[60]

Clinical Presentation

Solid pseudopapillary tumor of the pancreas is a very friable tumor, and tumor rupture and hemoperitoneum have been reported.[53,55,58] 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.[53] A retrospective review of the National Cancer Database identified 21 pediatric patients (younger than 18 years) and 348 adult patients with solid pseudopapillary neoplasm of the pancreas.[61] When compared with their adult counterparts, children with solid pseudopapillary neoplasms had similar disease severity at presentation, received similar treatments, and experienced equivalent postoperative outcomes.

Outcome

The outcome of solid pseudopapillary tumors of the pancreas is excellent, with 10-year survival rates exceeding 95%.[59]

Treatment

Treatment options for solid pseudopapillary tumor of the pancreas include the following:

Surgery.
Chemotherapy.

Treatment of solid pseudopapillary tumor of the pancreas is surgical; however, preoperative and operative spillage is not unusual.[62] 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.[58] 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.[63][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.[53,55,58-60] Single-agent gemcitabine has been reported to be effective in cases of unresectable or metastatic disease.[64]

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.[53,65]

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.[66] Pancreatoblastoma has also been associated with familial adenomatous polyposis syndromes.[67]

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.[53] CTNNB1 and IGF2 gene mutations have been described in some cases, suggesting that pancreatoblastoma might result from alterations in the normal pancreas differentiation.[68,69]

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.[65] 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.[66] Metastases are present in 30% to 40% of the patients, usually involving liver, lungs, and lymph nodes.[65]

Outcome

Using a multimodality approach, close to 80% of patients can be cured.[65]

Treatment

Treatment options for pancreatoblastoma include the following:

Surgery.
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.[62,70]

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.[55,65,67,71]

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.[67]

Response has been seen for patients with relapsed or persistent pancreatoblastoma treated with gemcitabine in one case [72] and vinorelbine and oral cyclophosphamide in two cases.[73]

High-dose chemotherapy with autologous hematopoietic stem cell rescue has been reported to be effective in selected cases.[55,74]

Islet Cell Tumors

Incidence and Risk Factors

Islet cell tumors represent approximately 15% of pediatric pancreatic tumors in most series.[55,57,75] 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.[53]

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.[75]
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.[53]

Treatment

Treatment options for islet cell tumors include the following:

Surgery.
Chemotherapy.
Mammalian target of rapamycin (mTOR) inhibitor therapy.

Treatment of islet cell tumors includes medical therapy for control of the syndrome and complete surgical resection.[62] 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.[75,76] (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:[55,57]

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.[53]
Ductal adenocarcinoma. Ductal adenocarcinoma is rare in the first four decades of life and even rarer during childhood and adolescence.[77] 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).[78]

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

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 4,000 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 NCI website and ClinicalTrials.gov website.

Colorectal Carcinoma

Incidence

Carcinoma of the large bowel is rare in the pediatric age group.[79] 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.[80] From 1973 to 2006, the Surveillance, Epidemiology, and End Results (SEER) database recorded 174 cases of colorectal cancer in patients younger than 19 years.[81] Colorectal carcinoma accounts for about 2% of all malignancies in patients aged 15 to 29 years.[82]

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.[83-85]

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.[80,86]

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:[87,88]

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.[89]

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,[79,80,86,90,91] 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.[91-93] 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.[88]

Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRASmutations and other cytogenetic anomalies seen in older patients.[94] 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.[95]

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).[80,83-87,90,91,96-102]

Treatment and Outcome

Most patients present with evidence of metastatic disease,[86] either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[90,96] 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.[91]

Treatment options for childhood colorectal cancer include the following:

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.[80] Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.
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.[103] Other agents, including irinotecan, may be of value.[86][Level of evidence: 3iiiA] No significant benefit has been determined for interferon-alfa given in conjunction with 5-FU/leucovorin.[104]
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.[105][Level of evidence: 2A]
Ipilimumab and nivolumab demonstrated high response rates in pediatric patients aged 12 years and older with microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer who had disease progression after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.[106]
Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[107-110]

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.[83]

Treatment Options Under Clinical Evaluation

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 4,000 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 NCI website and ClinicalTrials.gov website.

Genetic Syndromes Associated With Colorectal Cancer

About 20% to 30% of adult patients with colorectal cancer have a significant history of familial cancer; of these, about 5% have a well-defined genetic syndrome.[111] Hereditary colorectal cancer has two well-described forms:[112,113]

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),[113] NTHL1,[114] juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).[112]

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.[115]
A later study documented immunohistochemical evidence of mismatch repair deficiency in 31% of colorectal carcinoma samples in patients aged 30 years or younger.[116]
A retrospective review of patients younger than 18 years in Germany identified 31 patients with colorectal carcinoma.[117] 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.[118] 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.[119] 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.[120] 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.[121][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.[122]

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.[123]

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.[124-129] Most lung lesions are benign; however, some metastasize.[130]

The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.[130] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.[131] Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.[132]

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.[133][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.[134-136]

Treatment

Treatment options for neuroendocrine tumors of the appendix include the following:

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.[137-140]

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.[137,140-142]

Evidence (appendectomy alone):

The Italian Rare Tumors in Pediatric Age project performed a prospective registry study that evaluated 113 patients with appendiceal neuroendocrine tumors.[141][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.
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.[142]
- 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.
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.[140]
- 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.[133][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.[143] Larger tumor size has been associated with a higher risk of recurrence.[133]

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.[144]

Treatment and Outcome

Treatment options for resectable nonappendiceal neuroendocrine tumors include the following:

Surgery.[145]

Treatment options for unresectable or multifocal nonappendiceal neuroendocrine tumors include the following:

Embolization.[146]
Somatostatin receptor 2 (SSTR2) ligands.[147,148]
Peptide receptor radionuclide therapy.[149]
mTOR inhibitors.[150]
Tyrosine kinase inhibitors.[151]

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.[147,148] 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.[143]

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%.[143]

(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

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 4,000 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 NCI website and ClinicalTrials.gov website.

Gastrointestinal Stromal Tumors (GIST)

Incidence

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[152] These tumors are rare in children.[153] Approximately 2% of all GIST occur in children and young adults.[154-156] In one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[157] 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.[156,158,159]

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.[158,160] The majority of GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[161,162] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[163,164]

Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[158,163,165] 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,[161] 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.[166] 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.[167]

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:[168]

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).[168]

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.[156,158,165] 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.[165]

SDH-deficient GIST can arise within the context of the following two syndromes:[158,169]

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.[156,169,170]
Carney-Stratakis syndrome. Carney-Stratakis syndrome is characterized by paraganglioma and GIST caused by germline mutations of the SDH genes B, C, and D.[162,171]

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).[172,173]

Treatment options for GIST depend on whether a mutation is detected, as follows:

GIST with a KIT or PDGFR mutation: Pediatric patients who harbor KIT or PDGFRmutations are managed according to adult guidelines.
SDH-deficient GIST: Approximately one-half of all wild-type GIST patients are SDH-deficient.[174] 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.[174] 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.[158,175,176] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[158] In the phase III SWOG intergroup trial S0033 (NCT00009906), 20 tumors from patients who were presumed to be wild-type were resequenced.[176] Twelve of these tumors were identified as being SDH mutant, and only one patient (8.3%) experienced a partial response to imatinib.[177] 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.[178] Unlike the adult recommendations, the use of adjuvant imatinib cannot be recommended in children with SDH-deficient GIST.[179]
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.[153,158]

Treatment Options Under Clinical Evaluation

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 4,000 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 NCI website and ClinicalTrials.gov website.
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.

References

Ribeiro RC, Figueiredo B: Childhood adrenocortical tumours. Eur J Cancer 40 (8): 1117-26, 2004. [PUBMED Abstract]
Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993. [PUBMED Abstract]
Michalkiewicz E, Sandrini R, Figueiredo B, et al.: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22 (5): 838-45, 2004. [PUBMED Abstract]
Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27 (7): 867-81, 2003. [PUBMED Abstract]
Redlich A, Boxberger N, Strugala D, et al.: Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 (6): 366-71, 2012. [PUBMED Abstract]
Gulack BC, Rialon KL, Englum BR, et al.: Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). J Pediatr Surg 51 (1): 172-7, 2016. [PUBMED Abstract]
Berstein L, Gurney JG: Carcinomas and other malignant epithelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 11, pp 139-148. Also available online. Last accessed June 04, 2019.
Figueiredo BC, Sandrini R, Zambetti GP, et al.: Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 43 (1): 91-6, 2006. [PUBMED Abstract]
Pianovski MA, Maluf EM, de Carvalho DS, et al.: Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 47 (1): 56-60, 2006. [PUBMED Abstract]
Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al.: Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45 (3): 265-73, 2005. [PUBMED Abstract]
Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: Springer-Verlag, 2012, pp 436-44.
Wasserman JD, Novokmet A, Eichler-Jonsson C, et al.: Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. J Clin Oncol 33 (6): 602-9, 2015. [PUBMED Abstract]
Ribeiro RC, Sandrini F, Figueiredo B, et al.: An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A 98 (16): 9330-5, 2001. [PUBMED Abstract]
Custódio G, Parise GA, Kiesel Filho N, et al.: Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 31 (20): 2619-26, 2013. [PUBMED Abstract]
Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79 (4): 274-8, 1998. [PUBMED Abstract]
Wijnen M, Alders M, Zwaan CM, et al.: KCNQ1OT1 hypomethylation: a novel disguised genetic predisposition in sporadic pediatric adrenocortical tumors? Pediatr Blood Cancer 59 (3): 565-6, 2012. [PUBMED Abstract]
Steenman M, Westerveld A, Mannens M: Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28 (1): 1-13, 2000. [PUBMED Abstract]
El Wakil A, Doghman M, Latre De Late P, et al.: Genetics and genomics of childhood adrenocortical tumors. Mol Cell Endocrinol 336 (1-2): 169-73, 2011. [PUBMED Abstract]
Figueiredo BC, Stratakis CA, Sandrini R, et al.: Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84 (3): 1116-21, 1999. [PUBMED Abstract]
Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8 (3): 163-9, 1984. [PUBMED Abstract]
van Slooten H, Schaberg A, Smeenk D, et al.: Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55 (4): 766-73, 1985. [PUBMED Abstract]
Das S, Sengupta M, Islam N, et al.: Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: Is there a correlation? J Pediatr Surg 51 (11): 1795-1800, 2016. [PUBMED Abstract]
Stojadinovic A, Ghossein RA, Hoos A, et al.: Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20 (4): 941-50, 2002. [PUBMED Abstract]
Almeida MQ, Fragoso MC, Lotfi CF, et al.: Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 93 (9): 3524-31, 2008. [PUBMED Abstract]
West AN, Neale GA, Pounds S, et al.: Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67 (2): 600-8, 2007. [PUBMED Abstract]
Gupta N, Rivera M, Novotny P, et al.: Adrenocortical Carcinoma in Children: A Clinicopathological Analysis of 41 Patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr 90 (1): 8-18, 2018. [PUBMED Abstract]
Pinto EM, Chen X, Easton J, et al.: Genomic landscape of paediatric adrenocortical tumours. Nat Commun 6: 6302, 2015. [PUBMED Abstract]
Gönç EN, Özön ZA, Cakır MD, et al.: Need for comprehensive hormonal workup in the management of adrenocortical tumors in children. J Clin Res Pediatr Endocrinol 6 (2): 68-73, 2014. [PUBMED Abstract]
Ghazi AA, Mofid D, Salehian MT, et al.: Functioning adrenocortical tumors in children-secretory behavior. J Clin Res Pediatr Endocrinol 5 (1): 27-32, 2013. [PUBMED Abstract]
Hanna AM, Pham TH, Askegard-Giesmann JR, et al.: Outcome of adrenocortical tumors in children. J Pediatr Surg 43 (5): 843-9, 2008. [PUBMED Abstract]
McAteer JP, Huaco JA, Gow KW: Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg 48 (5): 1025-31, 2013. [PUBMED Abstract]
Cecchetto G, Ganarin A, Bien E, et al.: Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
Klein JD, Turner CG, Gray FL, et al.: Adrenal cortical tumors in children: factors associated with poor outcome. J Pediatr Surg 46 (6): 1201-7, 2011. [PUBMED Abstract]
Bulzico D, de Faria PA, de Paula MP, et al.: Recurrence and mortality prognostic factors in childhood adrenocortical tumors: Analysis from the Brazilian National Institute of Cancer experience. Pediatr Hematol Oncol 33 (4): 248-58, 2016. [PUBMED Abstract]
Leite FA, Lira RC, Fedatto PF, et al.: Low expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT). Pediatr Blood Cancer 61 (11): 1940-8, 2014. [PUBMED Abstract]
Pinto EM, Rodriguez-Galindo C, Choi JK, et al.: Prognostic Significance of Major Histocompatibility Complex Class II Expression in Pediatric Adrenocortical Tumors: A St. Jude and Children's Oncology Group Study. Clin Cancer Res 22 (24): 6247-6255, 2016. [PUBMED Abstract]
Sandrini R, Ribeiro RC, DeLacerda L: Childhood adrenocortical tumors. J Clin Endocrinol Metab 82 (7): 2027-31, 1997. [PUBMED Abstract]
Pinto EM, Rodriguez-Galindo C, Pounds SB, et al.: Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children's Oncology Group Study. J Clin Oncol 35 (35): 3956-3963, 2017. [PUBMED Abstract]
Zancanella P, Pianovski MA, Oliveira BH, et al.: Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 28 (8): 513-24, 2006. [PUBMED Abstract]
Hovi L, Wikström S, Vettenranta K, et al.: Adrenocortical carcinoma in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report. Med Pediatr Oncol 40 (5): 324-6, 2003. [PUBMED Abstract]
Stewart JN, Flageole H, Kavan P: A surgical approach to adrenocortical tumors in children: the mainstay of treatment. J Pediatr Surg 39 (5): 759-63, 2004. [PUBMED Abstract]
Hubertus J, Boxberger N, Redlich A, et al.: Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klin Padiatr 224 (3): 143-7, 2012. [PUBMED Abstract]
Kardar AH: Rupture of adrenal carcinoma after biopsy. J Urol 166 (3): 984, 2001. [PUBMED Abstract]
Gonzalez RJ, Shapiro S, Sarlis N, et al.: Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery 138 (6): 1078-85; discussion 1085-6, 2005. [PUBMED Abstract]
Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007. [PUBMED Abstract]
Driver CP, Birch J, Gough DC, et al.: Adrenal cortical tumors in childhood. Pediatr Hematol Oncol 15 (6): 527-32, 1998 Nov-Dec. [PUBMED Abstract]
Curtis JL, Burns RC, Wang L, et al.: Primary gastric tumors of infancy and childhood: 54-year experience at a single institution. J Pediatr Surg 43 (8): 1487-93, 2008. [PUBMED Abstract]
Subbiah V, Varadhachary G, Herzog CE, et al.: Gastric adenocarcinoma in children and adolescents. Pediatr Blood Cancer 57 (3): 524-7, 2011. [PUBMED Abstract]
American Cancer Society: Cancer Facts and Figures-2000. Atlanta, Ga: American Cancer Society, 2000.
Guilford P, Hopkins J, Harraway J, et al.: E-cadherin germline mutations in familial gastric cancer. Nature 392 (6674): 402-5, 1998. [PUBMED Abstract]
Saf C, Gulcan EM, Ozkan F, et al.: Assessment of p21, p53 expression, and Ki-67 proliferative activities in the gastric mucosa of children with Helicobacter pylori gastritis. Eur J Gastroenterol Hepatol 27 (2): 155-61, 2015. [PUBMED Abstract]
Ajani JA: Current status of therapy for advanced gastric carcinoma. Oncology (Huntingt) 12 (8 Suppl 6): 99-102, 1998. [PUBMED Abstract]
Chung EM, Travis MD, Conran RM: Pancreatic tumors in children: radiologic-pathologic correlation. Radiographics 26 (4): 1211-38, 2006 Jul-Aug. [PUBMED Abstract]
Perez EA, Gutierrez JC, Koniaris LG, et al.: Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg 44 (1): 197-203, 2009. [PUBMED Abstract]
Dall'igna P, Cecchetto G, Bisogno G, et al.: Pancreatic tumors in children and adolescents: the Italian TREP project experience. Pediatr Blood Cancer 54 (5): 675-80, 2010. [PUBMED Abstract]
Brecht IB, Schneider DT, Klöppel G, et al.: Malignant pancreatic tumors in children and young adults: evaluation of 228 patients identified through the Surveillance, Epidemiology, and End Result (SEER) database. Klin Padiatr 223 (6): 341-5, 2011. [PUBMED Abstract]
Rojas Y, Warneke CL, Dhamne CA, et al.: Primary malignant pancreatic neoplasms in children and adolescents: a 20 year experience. J Pediatr Surg 47 (12): 2199-204, 2012. [PUBMED Abstract]
Papavramidis T, Papavramidis S: Solid pseudopapillary tumors of the pancreas: review of 718 patients reported in English literature. J Am Coll Surg 200 (6): 965-72, 2005. [PUBMED Abstract]
Estrella JS, Li L, Rashid A, et al.: Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution. Am J Surg Pathol 38 (2): 147-57, 2014. [PUBMED Abstract]
Laje P, Bhatti TR, Adzick NS: Solid pseudopapillary neoplasm of the pancreas in children: a 15-year experience and the identification of a unique immunohistochemical marker. J Pediatr Surg 48 (10): 2054-60, 2013. [PUBMED Abstract]
Leraas HJ, Kim J, Sun Z, et al.: Solid Pseudopapillary Neoplasm of the Pancreas in Children and Adults: A National Study of 369 Patients. J Pediatr Hematol Oncol 40 (4): e233-e236, 2018. [PUBMED Abstract]
Sacco Casamassima MG, Gause CD, Goldstein SD, et al.: Pancreatic surgery for tumors in children and adolescents. Pediatr Surg Int 32 (8): 779-88, 2016. [PUBMED Abstract]
Crocoli A, Grimaldi C, Virgone C, et al.: Outcome after surgery for solid pseudopapillary pancreatic tumors in children: Report from the TREP project-Italian Rare Tumors Study Group. Pediatr Blood Cancer : e27519, 2018. [PUBMED Abstract]
Maffuz A, Bustamante Fde T, Silva JA, et al.: Preoperative gemcitabine for unresectable, solid pseudopapillary tumour of the pancreas. Lancet Oncol 6 (3): 185-6, 2005. [PUBMED Abstract]
Bien E, Godzinski J, Dall'igna P, et al.: Pancreatoblastoma: a report from the European cooperative study group for paediatric rare tumours (EXPeRT). Eur J Cancer 47 (15): 2347-52, 2011. [PUBMED Abstract]
Chisholm KM, Hsu CH, Kim MJ, et al.: Congenital pancreatoblastoma: report of an atypical case and review of the literature. J Pediatr Hematol Oncol 34 (4): 310-5, 2012. [PUBMED Abstract]
Glick RD, Pashankar FD, Pappo A, et al.: Management of pancreatoblastoma in children and young adults. J Pediatr Hematol Oncol 34 (Suppl 2): S47-50, 2012. [PUBMED Abstract]
Honda S, Okada T, Miyagi H, et al.: Spontaneous rupture of an advanced pancreatoblastoma: aberrant RASSF1A methylation and CTNNB1 mutation as molecular genetic markers. J Pediatr Surg 48 (4): e29-32, 2013. [PUBMED Abstract]
Isobe T, Seki M, Yoshida K, et al.: Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma. Cancer Res 78 (4): 865-876, 2018. [PUBMED Abstract]
Lindholm EB, Alkattan AK, Abramson SJ, et al.: Pancreaticoduodenectomy for pediatric and adolescent pancreatic malignancy: A single-center retrospective analysis. J Pediatr Surg 52 (2): 299-303, 2017. [PUBMED Abstract]
Défachelles AS, Martin De Lassalle E, Boutard P, et al.: Pancreatoblastoma in childhood: clinical course and therapeutic management of seven patients. Med Pediatr Oncol 37 (1): 47-52, 2001. [PUBMED Abstract]
Belletrutti MJ, Bigam D, Bhargava R, et al.: Use of gemcitabine with multi-stage surgical resection as successful second-line treatment of metastatic pancreatoblastoma. J Pediatr Hematol Oncol 35 (1): e7-10, 2013. [PUBMED Abstract]
Dhamne C, Herzog CE: Response of Relapsed Pancreatoblastoma to a Combination of Vinorelbine and Oral Cyclophosphamide. J Pediatr Hematol Oncol 37 (6): e378-80, 2015. [PUBMED Abstract]
Hamidieh AA, Jalili M, Khojasteh O, et al.: Autologous stem cell transplantation as treatment modality in a patient with relapsed pancreatoblastoma. Pediatr Blood Cancer 55 (3): 573-6, 2010. [PUBMED Abstract]
Jensen RT, Cadiot G, Brandi ML, et al.: ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 95 (2): 98-119, 2012. [PUBMED Abstract]
Kulke MH, Benson AB 3rd, Bergsland E, et al.: Neuroendocrine tumors. J Natl Compr Canc Netw 10 (6): 724-64, 2012. [PUBMED Abstract]
Lüttges J, Stigge C, Pacena M, et al.: Rare ductal adenocarcinoma of the pancreas in patients younger than age 40 years. Cancer 100 (1): 173-82, 2004. [PUBMED Abstract]
Rustgi AK: Familial pancreatic cancer: genetic advances. Genes Dev 28 (1): 1-7, 2014. [PUBMED Abstract]
da Costa Vieira RA, Tramonte MS, Lopes LF: Colorectal carcinoma in the first decade of life: a systematic review. Int J Colorectal Dis 30 (8): 1001-6, 2015. [PUBMED Abstract]
Saab R, Furman WL: Epidemiology and management options for colorectal cancer in children. Paediatr Drugs 10 (3): 177-92, 2008. [PUBMED Abstract]
Ferrari A, Casanova M, Massimino M, et al.: Peculiar features and tailored management of adult cancers occurring in pediatric age. Expert Rev Anticancer Ther 10 (11): 1837-51, 2010. [PUBMED Abstract]
Bleyer A, O’Leary M, Barr R, et al., eds.: Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. Bethesda, Md: National Cancer Institute, 2006. NIH Pub. No. 06-5767. Also available online. Last accessed January 31, 2019.
Kaplan MA, Isikdogan A, Gumus M, et al.: Childhood, adolescents, and young adults (≤25 y) colorectal cancer: study of Anatolian Society of Medical Oncology. J Pediatr Hematol Oncol 35 (2): 83-9, 2013. [PUBMED Abstract]
Kim G, Baik SH, Lee KY, et al.: Colon carcinoma in childhood: review of the literature with four case reports. Int J Colorectal Dis 28 (2): 157-64, 2013. [PUBMED Abstract]
Sultan I, Rodriguez-Galindo C, El-Taani H, et al.: Distinct features of colorectal cancer in children and adolescents: a population-based study of 159 cases. Cancer 116 (3): 758-65, 2010. [PUBMED Abstract]
Hill DA, Furman WL, Billups CA, et al.: Colorectal carcinoma in childhood and adolescence: a clinicopathologic review. J Clin Oncol 25 (36): 5808-14, 2007. [PUBMED Abstract]
Pratt CB, Rao BN, Merchant TE, et al.: Treatment of colorectal carcinoma in adolescents and young adults with surgery, 5-fluorouracil/leucovorin/interferon-alpha 2a and radiation therapy. Med Pediatr Oncol 32 (6): 459-60, 1999. [PUBMED Abstract]
Kauffman WM, Jenkins JJ 3rd, Helton K, et al.: Imaging features of ovarian metastases from colonic adenocarcinoma in adolescents. Pediatr Radiol 25 (4): 286-8, 1995. [PUBMED Abstract]
Postgate A, Hyer W, Phillips R, et al.: Feasibility of video capsule endoscopy in the management of children with Peutz-Jeghers syndrome: a blinded comparison with barium enterography for the detection of small bowel polyps. J Pediatr Gastroenterol Nutr 49 (4): 417-23, 2009. [PUBMED Abstract]
Ferrari A, Rognone A, Casanova M, et al.: Colorectal carcinoma in children and adolescents: the experience of the Istituto Nazionale Tumori of Milan, Italy. Pediatr Blood Cancer 50 (3): 588-93, 2008. [PUBMED Abstract]
Poles GC, Clark DE, Mayo SW, et al.: Colorectal carcinoma in pediatric patients: A comparison with adult tumors, treatment and outcomes from the National Cancer Database. J Pediatr Surg 51 (7): 1061-6, 2016. [PUBMED Abstract]
Tricoli JV, Seibel NL, Blair DG, et al.: Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer. J Natl Cancer Inst 103 (8): 628-35, 2011. [PUBMED Abstract]
Khan SA, Morris M, Idrees K, et al.: Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg 51 (11): 1812-1817, 2016. [PUBMED Abstract]
Bleyer A, Barr R, Hayes-Lattin B, et al.: The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer 8 (4): 288-98, 2008. [PUBMED Abstract]
Tricoli JV, Boardman LA, Patidar R, et al.: A mutational comparison of adult and adolescent and young adult (AYA) colon cancer. Cancer 124 (5): 1070-1082, 2018. [PUBMED Abstract]
Chantada GL, Perelli VB, Lombardi MG, et al.: Colorectal carcinoma in children, adolescents, and young adults. J Pediatr Hematol Oncol 27 (1): 39-41, 2005. [PUBMED Abstract]
Durno C, Aronson M, Bapat B, et al.: Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma. Gut 54 (8): 1146-50, 2005. [PUBMED Abstract]
Karnak I, Ciftci AO, Senocak ME, et al.: Colorectal carcinoma in children. J Pediatr Surg 34 (10): 1499-504, 1999. [PUBMED Abstract]
LaQuaglia MP, Heller G, Filippa DA, et al.: Prognostic factors and outcome in patients 21 years and under with colorectal carcinoma. J Pediatr Surg 27 (8): 1085-9; discussion 1089-90, 1992. [PUBMED Abstract]
Radhakrishnan CN, Bruce J: Colorectal cancers in children without any predisposing factors. A report of eight cases and review of the literature. Eur J Pediatr Surg 13 (1): 66-8, 2003. [PUBMED Abstract]
Sharma AK, Gupta CR: Colorectal cancer in children: case report and review of literature. Trop Gastroenterol 22 (1): 36-9, 2001 Jan-Mar. [PUBMED Abstract]
Taguchi T, Suita S, Hirata Y, et al.: Carcinoma of the colon in children: a case report and review of 41 Japanese cases. J Pediatr Gastroenterol Nutr 12 (3): 394-9, 1991. [PUBMED Abstract]
Madajewicz S, Petrelli N, Rustum YM, et al.: Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. Cancer Res 44 (10): 4667-9, 1984. [PUBMED Abstract]
Wolmark N, Bryant J, Smith R, et al.: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90 (23): 1810-6, 1998. [PUBMED Abstract]
Blanke CD, Bot BM, Thomas DM, et al.: Impact of young age on treatment efficacy and safety in advanced colorectal cancer: a pooled analysis of patients from nine first-line phase III chemotherapy trials. J Clin Oncol 29 (20): 2781-6, 2011. [PUBMED Abstract]
Overman MJ, Lonardi S, Wong KYM, et al.: Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol 36 (8): 773-779, 2018. [PUBMED Abstract]
Saltz LB, Clarke S, Díaz-Rubio E, et al.: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26 (12): 2013-9, 2008. [PUBMED Abstract]
Heinemann V, von Weikersthal LF, Decker T, et al.: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (10): 1065-75, 2014. [PUBMED Abstract]
Van Cutsem E, Tabernero J, Lakomy R, et al.: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30 (28): 3499-506, 2012. [PUBMED Abstract]
Grothey A, Van Cutsem E, Sobrero A, et al.: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381 (9863): 303-12, 2013. [PUBMED Abstract]
Gatalica Z, Torlakovic E: Pathology of the hereditary colorectal carcinoma. Fam Cancer 7 (1): 15-26, 2008. [PUBMED Abstract]
Hampel H: Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am 18 (4): 687-703, 2009. [PUBMED Abstract]
Briggs S, Tomlinson I: Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol 230 (2): 148-53, 2013. [PUBMED Abstract]
Broderick P, Dobbins SE, Chubb D, et al.: Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review. Gastroenterology 152 (1): 75-77.e4, 2017. [PUBMED Abstract]
O'Connell JB, Maggard MA, Livingston EH, et al.: Colorectal cancer in the young. Am J Surg 187 (3): 343-8, 2004. [PUBMED Abstract]
Goel A, Nagasaka T, Spiegel J, et al.: Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin Gastroenterol Hepatol 8 (11): 966-71, 2010. [PUBMED Abstract]
Weber ML, Schneider DT, Offenmüller S, et al.: Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes. Pediatr Blood Cancer 63 (4): 611-7, 2016. [PUBMED Abstract]
Erdman SH: Pediatric adenomatous polyposis syndromes: an update. Curr Gastroenterol Rep 9 (3): 237-44, 2007. [PUBMED Abstract]
Turcot J, Despres JP, St Pierre F: Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 2: 465-8, 1959 Sep-Oct. [PUBMED Abstract]
Vogelstein B, Fearon ER, Hamilton SR, et al.: Genetic alterations during colorectal-tumor development. N Engl J Med 319 (9): 525-32, 1988. [PUBMED Abstract]
Lynch PM, Ayers GD, Hawk E, et al.: The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol 105 (6): 1437-43, 2010. [PUBMED Abstract]
Pratt CB, Jane JA: Multiple colorectal carcinomas, polyposis coli, and neurofibromatosis, followed by multiple glioblastoma multiforme. J Natl Cancer Inst 83 (12): 880-1, 1991. [PUBMED Abstract]
Heath JA, Reece JC, Buchanan DD, et al.: Childhood cancers in families with and without Lynch syndrome. Fam Cancer 14 (4): 545-51, 2015. [PUBMED Abstract]
Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79 (4): 813-29, 1997. [PUBMED Abstract]
Deans GT, Spence RA: Neoplastic lesions of the appendix. Br J Surg 82 (3): 299-306, 1995. [PUBMED Abstract]
Doede T, Foss HD, Waldschmidt J: Carcinoid tumors of the appendix in children--epidemiology, clinical aspects and procedure. Eur J Pediatr Surg 10 (6): 372-7, 2000. [PUBMED Abstract]
Quaedvlieg PF, Visser O, Lamers CB, et al.: Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. Ann Oncol 12 (9): 1295-300, 2001. [PUBMED Abstract]
Broaddus RR, Herzog CE, Hicks MJ: Neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) presenting at extra-appendiceal sites in childhood and adolescence. Arch Pathol Lab Med 127 (9): 1200-3, 2003. [PUBMED Abstract]
Foley DS, Sunil I, Debski R, et al.: Primary hepatic carcinoid tumor in children. J Pediatr Surg 43 (11): e25-8, 2008. [PUBMED Abstract]
Tormey WP, FitzGerald RJ: The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid. Postgrad Med J 71 (839): 542-5, 1995. [PUBMED Abstract]
Delaunoit T, Rubin J, Neczyporenko F, et al.: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors. Mayo Clin Proc 80 (4): 502-6, 2005. [PUBMED Abstract]
More J, Young J, Reznik Y, et al.: Ectopic ACTH syndrome in children and adolescents. J Clin Endocrinol Metab 96 (5): 1213-22, 2011. [PUBMED Abstract]
Degnan AJ, Tocchio S, Kurtom W, et al.: Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
Pelizzo G, La Riccia A, Bouvier R, et al.: Carcinoid tumors of the appendix in children. Pediatr Surg Int 17 (5-6): 399-402, 2001. [PUBMED Abstract]
Hatzipantelis E, Panagopoulou P, Sidi-Fragandrea V, et al.: Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece. J Pediatr Gastroenterol Nutr 51 (5): 622-5, 2010. [PUBMED Abstract]
Henderson L, Fehily C, Folaranmi S, et al.: Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience. J Pediatr Surg 49 (10): 1513-7, 2014. [PUBMED Abstract]
Dall'Igna P, Ferrari A, Luzzatto C, et al.: Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions. J Pediatr Gastroenterol Nutr 40 (2): 216-9, 2005. [PUBMED Abstract]
Wu H, Chintagumpala M, Hicks J, et al.: Neuroendocrine Tumor of the Appendix in Children. J Pediatr Hematol Oncol 39 (2): 97-102, 2017. [PUBMED Abstract]
Boxberger N, Redlich A, Böger C, et al.: Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer 60 (1): 65-70, 2013. [PUBMED Abstract]
Njere I, Smith LL, Thurairasa D, et al.: Systematic review and meta-analysis of appendiceal carcinoid tumors in children. Pediatr Blood Cancer 65 (8): e27069, 2018. [PUBMED Abstract]
Virgone C, Cecchetto G, Alaggio R, et al.: Appendiceal neuroendocrine tumours in childhood: Italian TREP project. J Pediatr Gastroenterol Nutr 58 (3): 333-8, 2014. [PUBMED Abstract]
de Lambert G, Lardy H, Martelli H, et al.: Surgical Management of Neuroendocrine Tumors of the Appendix in Children and Adolescents: A Retrospective French Multicenter Study of 114 Cases. Pediatr Blood Cancer 63 (4): 598-603, 2016. [PUBMED Abstract]
Boston CH, Phan A, Munsell MF, et al.: A Comparison Between Appendiceal and Nonappendiceal Neuroendocrine Tumors in Children and Young Adults: A Single-institution Experience. J Pediatr Hematol Oncol 37 (6): 438-42, 2015. [PUBMED Abstract]
Enzler T, Fojo T: Long-acting somatostatin analogues in the treatment of unresectable/metastatic neuroendocrine tumors. Semin Oncol 44 (2): 141-156, 2017. [PUBMED Abstract]
Ambe CM, Nguyen P, Centeno BA, et al.: Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience. Cancer Control 24 (5): 1073274817729076, 2017 Oct-Dec. [PUBMED Abstract]
Elf AK, Andersson M, Henrikson O, et al.: Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial. World J Surg 42 (2): 506-513, 2018. [PUBMED Abstract]
Rinke A, Wittenberg M, Schade-Brittinger C, et al.: Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology 104 (1): 26-32, 2017. [PUBMED Abstract]
Caplin ME, Pavel M, Ćwikła JB, et al.: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371 (3): 224-33, 2014. [PUBMED Abstract]
Brabander T, Teunissen JJ, Van Eijck CH, et al.: Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 30 (1): 103-14, 2016. [PUBMED Abstract]
Gajate P, Martínez-Sáez O, Alonso-Gordoa T, et al.: Emerging use of everolimus in the treatment of neuroendocrine tumors. Cancer Manag Res 9: 215-224, 2017. [PUBMED Abstract]
Liu IH, Kunz PL: Biologics in gastrointestinal and pancreatic neuroendocrine tumors. J Gastrointest Oncol 8 (3): 457-465, 2017. [PUBMED Abstract]
Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 22 (18): 3813-25, 2004. [PUBMED Abstract]
Pappo AS, Janeway K, Laquaglia M, et al.: Special considerations in pediatric gastrointestinal tumors. J Surg Oncol 104 (8): 928-32, 2011. [PUBMED Abstract]
Prakash S, Sarran L, Socci N, et al.: Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol 27 (4): 179-87, 2005. [PUBMED Abstract]
Miettinen M, Lasota J, Sobin LH: Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 29 (10): 1373-81, 2005. [PUBMED Abstract]
Benesch M, Wardelmann E, Ferrari A, et al.: Gastrointestinal stromal tumors (GIST) in children and adolescents: A comprehensive review of the current literature. Pediatr Blood Cancer 53 (7): 1171-9, 2009. [PUBMED Abstract]
Cypriano MS, Jenkins JJ, Pappo AS, et al.: Pediatric gastrointestinal stromal tumors and leiomyosarcoma. Cancer 101 (1): 39-50, 2004. [PUBMED Abstract]
Pappo AS, Janeway KA: Pediatric gastrointestinal stromal tumors. Hematol Oncol Clin North Am 23 (1): 15-34, vii, 2009. [PUBMED Abstract]
Benesch M, Leuschner I, Wardelmann E, et al.: Gastrointestinal stromal tumours in children and young adults: a clinicopathologic series with long-term follow-up from the database of the Cooperative Weichteilsarkom Studiengruppe (CWS). Eur J Cancer 47 (11): 1692-8, 2011. [PUBMED Abstract]
Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130 (10): 1466-78, 2006. [PUBMED Abstract]
Miettinen M, Lasota J: Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol 53: 514-9, 2014. [PUBMED Abstract]
Miettinen M, Wang ZF, Sarlomo-Rikala M, et al.: Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35 (11): 1712-21, 2011. [PUBMED Abstract]
Janeway KA, Liegl B, Harlow A, et al.: Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res 67 (19): 9084-8, 2007. [PUBMED Abstract]
Tarn C, Rink L, Merkel E, et al.: Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proceedings of the National Academy of Sciences 105 (24): 8387-92, 2008. Also available online Exit Disclaimer. Last accessed June 04, 2019.
Agaram NP, Laquaglia MP, Ustun B, et al.: Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14 (10): 3204-15, 2008. [PUBMED Abstract]
Janeway KA, Kim SY, Lodish M, et al.: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108 (1): 314-8, 2011. [PUBMED Abstract]
Killian JK, Miettinen M, Walker RL, et al.: Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med 6 (268): 268ra177, 2014. [PUBMED Abstract]
Boikos SA, Pappo AS, Killian JK, et al.: Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2 (7): 922-8, 2016. [PUBMED Abstract]
Otto C, Agaimy A, Braun A, et al.: Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. Diagn Pathol 6: 52, 2011. [PUBMED Abstract]
Carney JA: Carney triad: a syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors. J Clin Endocrinol Metab 94 (10): 3656-62, 2009. [PUBMED Abstract]
Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [PUBMED Abstract]
Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
Janeway KA, Weldon CB: Pediatric gastrointestinal stromal tumor. Semin Pediatr Surg 21 (1): 31-43, 2012. [PUBMED Abstract]
Weldon CB, Madenci AL, Boikos SA, et al.: Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol 35 (5): 523-528, 2017. [PUBMED Abstract]
Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368 (9544): 1329-38, 2006. [PUBMED Abstract]
Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347 (7): 472-80, 2002. [PUBMED Abstract]
Heinrich MC, Rankin C, Blanke CD, et al.: Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol 3 (7): 944-952, 2017. [PUBMED Abstract]
Janeway KA, Albritton KH, Van Den Abbeele AD, et al.: Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer 52 (7): 767-71, 2009. [PUBMED Abstract]
Dematteo RP, Ballman KV, Antonescu CR, et al.: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9669): 1097-104, 2009. [PUBMED Abstract]