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Unusual Cancers of Childhood Treatment (PDQ®)

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Abdominal Cancers

Abdominal cancers include adrenocortical tumors, carcinomas of the stomach, cancer of the pancreas, colorectal carcinomas, carcinoid tumors, and gastrointestinal stromal tumors. 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 Standard Treatment Options for Renal Cell Carcinoma (RCC) section in the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors for more information.)

Carcinoma of the Adrenal Cortex

Incidence

Adrenocortical tumors encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior. Their incidence 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] 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.[4] Internationally, however, the incidence of adrenocortical tumors appear to vary substantially. The incidence of adrenocortical tumors is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[5-7] 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.[8-12] Female gender is consistently predominant in most studies, with a female to male ratio of 1.6 to 1.[12,13]

Risk factors

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. Germline TP53 mutations are almost always the predisposing factor. In the non-Brazilian cases, relatives of children with adrenocortical tumors often, although not invariably, have a high incidence of other non-adrenal 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).[7] In the Brazilian cases, in contrast, 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.[14] 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.[15] 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 hemihypertrophy syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors.[16] 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.[17] However, less than 1% of children with adrenocortical tumors have these syndromes.[18] The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.[19]

Histology

Unlike adult adrenocortical tumors, histologic differentiation of adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[2,9] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenoma and carcinoma appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.[20] 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.[21,22] However, 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 characteristics, such as venous, capsular, or adjacent organ invasion; tumor necrosis; mitotic rate; and the presence of atypical mitoses.[23]

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.[3,9] Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) due to excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients. Hyperestrogenism can also occur.[26] Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[3,9,12,27] Likewise, nonfunctional tumors are rare (<10%) and tend to occur in older children.[3] 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.

Prognostic factors

In patients with localized disease, younger age (<4 years), virilization alone, normal blood pressure, disease stage I, absence of spillage during surgery, and tumor weight no greater than 200 grams were associated with a greater probability of survival.[28] In a Cox regression model analysis, only stage I, virilization alone, and age 0 to 3 years were independently associated with a better outcome.[3] Available data suggest that tumor size is especially important in children; patients with small tumors have an excellent outcome with surgery alone, regardless of histologic features.[29] The overall probability of 5-year survival for children with adrenocortical tumors is reported to be 54% to 74%.[3,9,10,12,27-29] Exon sequencing and single-nucleotide polymorphism analysis of 45 adrenocortical carcinomas in adults identified two molecular subgroups, one with a favorable prognosis and one with an unfavorable prognosis.[30] The group with a poor prognosis had numerous mutations and DNA methylation alterations; in contrast, the group with a good prognosis had relatively few mutations.

Treatment of adrenocortical tumors

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.[7,31,32]; [12][Level of evidence: 3iiiA] An aggressive surgical approach of the primary tumor and all metastatic sites is recommended when feasible.[33,34] 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).[3,10] 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.[34,35] Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.[36]

Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[1,31] A retrospective analysis in Italy and Germany identified 177 adult patients with adrenocortical carcinoma. Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane. Benefit was present with 1 to 3 g per day of mitotane and was associated with fewer toxic side effects than doses of 3 to 5 g per day.[37] 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 around 4 g/m2, and therapeutic levels were achieved after 4 to 6 months of therapy.[31] In the GPOH-MET 97 trial, mitotane levels greater than 14 mg/L correlated with better survival.[12]

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 three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcoma that arose within the radiation field.[38]

(Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)

Carcinoma of the Stomach

Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual.[39] 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.[40] 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.[41]

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.[39] Symptoms include vague upper abdominal pain, which can be associated with poor appetite and weight loss. Other symptoms may include nausea, vomiting, change in bowel habits, poor appetite, weakness, and Helicobacter pylori infection.[40,42] 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 should include 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.[43] 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.[40] Because of the rarity of stomach cancer in the pediatric age group, little information exists regarding the treatment outcomes of children.

(Refer to the PDQ summary on adult Gastric Cancer Treatment for more information.)

Cancer of the Pancreas

Malignant pancreatic tumors are rare in children and adolescents with an incidence of 0.46 cases per 1 million (younger than 30 years).[44-47] Tumors included in this general category can arise at any site within the pancreas. Cancers of the pancreas may be classified as adenocarcinomas, squamous cell carcinomas, acinic cell carcinomas, liposarcomas, lymphomas, papillary-cystic carcinomas, pancreatoblastomas, malignant insulinomas, glucagonomas, and gastrinomas.[48-52] Several cases of primitive neuroectodermal tumor of the pancreas have been reported in children and young adults.[53] Pancreatoblastoma is reported to be associated with Beckwith-Wiedemann syndrome and Cushing syndrome.[54,55]

Most malignant pancreatic tumors are carcinomas and do not secrete hormones, although some tumors secrete insulin, which can lead to symptoms of weakness, fatigue, hypoglycemia, and coma.[47,48,56] If the tumor interferes with the normal function of the islet cells, patients may have watery diarrhea or abnormalities of salt balance. Both carcinoma of the pancreas and pancreatoblastoma can produce active hormones and can be associated with an abdominal mass, wasting, and pain.[57-59] At times, there is obstruction of the head of the pancreas, which is associated with jaundice and gastrointestinal bleeding. Elevation of alpha-fetoprotein has been seen in pancreatoblastoma and acinar cell carcinoma.[51,60-62]

Diagnosis of pancreatic tumors is usually established by biopsy, using laparotomy or a minimally invasive surgery (e.g., laparoscopy). A diagnosis can be achieved only after ruling out various benign and cancerous lesions.

Solid pseudopapillary neoplasm of the pancreas is a rare tumor of borderline malignancy that has been reported in children but more commonly occurs in young women.[63-66] Treatment consists of complete tumor resection (ideally without biopsy). Metastases may occur, but in general, prognosis is good following surgery alone.[52,67,68]; [69][Level of evidence: 3iiA]; [70][Level of evidence: 3iiDi]; [71][Level of evidence: 3iiDiii]

Treatment includes various surgical procedures to remove the pancreas and duodenum or removal of part of the pancreas. Complete resection is usually possible and long-term survival is likely, although pancreatoblastoma has a high recurrence rate.[49,60]; [72][Level of evidence: 3iiA] A series of 31 patients aged 4 to 18.7 years included 21 patients with solid pseudopapillary tumor, four with neuroendocrine tumor, four with pancreatoblastoma, and one with an unclassified spindle-cell tumor. Treatment was surgical removal in 29 patients. The 3-year survival rate for patients with pseudopapillary tumor was 100%.[73][Level of evidence 3iiA] For pediatric patients, the effectiveness of radiation therapy is not known. Chemotherapy may be useful for treatment of localized or metastatic pancreatic carcinoma. The combination of cisplatin and doxorubicin has produced responses in pancreatoblastoma prior to tumor resection.[74,75] Postoperative treatment with cisplatin, doxorubicin, ifosfamide, and etoposide has also produced responses in patients with pancreatoblastoma, although surgery is the mainstay of therapy.[62]; [76][Level of evidence: 3iiiA] Other agents that may be of value include 5-FU, streptozotocin, mitomycin C, carboplatin, gemcitabine, and irinotecan.[77] Response rates and survival rates generally are not good.

(Refer to the PDQ summary on adult Pancreatic Cancer Treatment for more information.)

Colorectal Carcinoma

Incidence

Carcinoma of the large bowel is rare in the pediatric age group. It is seen in one per 1 million persons younger than 20 years in the United States annually, and fewer than 100 cases are diagnosed in children each year in the United States.[78] From 1973 to 2006, the Surveillance, Epidemiology, and End Results database recorded 174 cases of colorectal cancer in patients younger than 19 years.[79]

Clinical presentation

The most common presenting symptom in children is abdominal pain. Other signs and symptoms include rectal bleeding, change in bowel habits, weight loss, and nausea and vomiting; the median duration of symptoms before diagnosis was about 3 months in one series.[78,80,81] 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 an abdominal mass, weight loss, decreased appetite, and blood in the stool. Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.

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.[82-84]

Diagnostic evaluation and staging

Diagnostic studies that may be of value include examination of the stool for blood, studies of liver and kidney function, measurement of carcinoembryonic antigen, and 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.[85-87]

Most reports also suggest that children present with more advanced disease than do adults, with 80% to 90% of patients presenting with Duke stage C/D or TNM stage III/IV disease (refer to the Stage Information for Colon Cancer section of the PDQ summary on adult Colon Cancer Treatment for more information about staging).[78,81-85,88-95]

Histology

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,[78,81,90] 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.[96] These tumors arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls.[86] Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRAS mutations and other cytogenetic anomalies seen in older patients.[97]

Treatment and survival

Most patients present with evidence of metastatic disease,[81] either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[88,90] Complete surgical excision is the most important prognostic factor and should be the primary aim of the surgeon, but in most instances this is impossible; removal of large portions of tumor provides little benefit for those with extensive metastatic disease.[78] Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.

Current therapy includes the use of radiation for rectal and lower colon tumors, in conjunction with chemotherapy using 5-FU with leucovorin.[98] Other agents, including irinotecan, may be of value.[81][Level of evidence: 3iiiA] No significant benefit has been determined for interferon-alpha given in conjunction with 5-FU/leucovorin.[99] A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved progression-free survival and overall survival (OS) in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[100]

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 curative potential.[82]

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.[101] The incidence of these syndromes in children has not been well defined. In one review, 16% of patients younger than 40 years had a predisposing factor for the development of colorectal cancer.[102] A later study documented immunohistochemical evidence of mismatch repair deficiency in 31% of colorectal carcinoma samples in patients aged 30 years or younger.[103] The most common genetic syndromes associated with the development of colorectal cancer are shown in Tables 3 and 4.

Table 3. Common Genetic Syndromes Associated With Adenomatous Polyposis
SyndromeGeneGene FunctionHereditary Pattern
Attenuated familial adenomatous polyposisAPC (5’ mutations), AXIN2Tumor suppressorDominant
Familial adenomatous polyposis (Gardner syndrome)APC Tumor suppressorDominant
Lynch syndrome (hereditary nonpolyposis colorectal cancer)MSH2, MLH1, MSH6, PMS2, EPCAM Repair/stabilityDominant
Li-Fraumeni syndromeTP53 (p53)Tumor suppressorDominant
MYH-associated polyposisMYH (MUTYH)Repair/stabilityRecessive
Turcot syndromeAPC Tumor suppressorDominant
MLH1 Repair/stabilityDominant
Table 4. Common Genetic Syndromes Associated With Hamartomatous Polyps
SyndromeGeneGene FunctionHereditary Pattern
Cowden syndromePTEN Tumor suppressorDominant
Juvenile polyposis syndromeBMPR1A, SMAD4, ENG Tumor suppressorDominant
Peutz-Jeghers syndromeSTK11 Tumor suppressorDominant

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.[104] 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.[105] The familial APC 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.[106] A double-blind, placebo-controlled, randomized phase I trial in children aged 10 to 14 years with familial adenomatous polyposis (FAP) reported that celecoxib at a dose of 16 mg/kg/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.[107][Level of evidence: 1iiDiv] The role of celecoxib in the management of FAP is not known.

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.[108]

Carcinoid Tumors

These tumors, like bronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[109-114] Most lung lesions are benign; however, some metastasize.[115]

Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, and are small, localized tumors; simple appendectomy is the therapy of choice.[116,117] For larger (>2 cm) tumors or tumors that have spread to local nodes, cecectomy or rarely, right hemicolectomy, is the usual treatment. It has become 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 nodes; however, this practice remains controversial.[118] The German Society of Pediatric Oncology and Hematology has maintained a registry of appendiceal neuroendocrine tumors since 1997. They reported on 237 children and adolescents.[119][Level of evidence: 3iiDii] A second surgery or lymph node sampling was performed in 60 patients; infiltration of lymph nodes was found in 9 of these 60 patients. The group recommended secondary right hemicolectomy in completely resected appendiceal neuroendocrine tumors only for tumors larger than 15 mm and local follow-up resection with lymph node sampling for incompletely removed tumors smaller than 15 mm. These recommendations are controversial. There are no reported cases of recurrence of appendiceal carcinoid tumors in children and adolescents following surgical resection without right hemicolectomy. Observation alone may be adequate follow-up after resection of appendiceal carcinoid tumors.

A MEDLINE search did not find any documented cases of childhood localized appendiceal carcinoid in children younger than 18 years with complete resection who relapsed.[120] Treatment of metastatic carcinoid tumors of the large bowel or stomach becomes more complicated and requires treatment similar to that given for colorectal carcinoma. (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors for therapeutic options in patients with malignant carcinoid tumors.)

The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.[115] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.[121] Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.[122]

Gastrointestinal Stromal Tumors (GIST)

Incidence

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[123] These tumors are rare in children.[124] Approximately 2% of all GIST occur in children and young adults;[125-127] in one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[128] Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas. In pediatric patients, GIST are most commonly located in the stomach and usually occur in adolescent females.[129,130]

Risk factors

Pediatric GIST can arise within the context of tumor predisposition syndromes. Approximately 10% of pediatric cases of GIST are associated with Carney triad or Carney-Stratakis syndrome.[129,131]

  • 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 succinate dehydrogenase (SDH) genes have been found in these patients.[127,131,132]
  • Carney-Stratakis syndrome is characterized by paraganglioma and GIST due to germline mutations of the SDH genes B, C, and D.[133,134]

Familial GIST and neurofibromatosis 1–associated GIST occur in patients older than 40 years.[130,135,136]

Histology and molecular genetics

Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, their mitotic rate does not appear to accurately predict clinical behavior.[129,137] Most pediatric patients with GIST present 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.[129,138] These features may account for the high incidence of local recurrence seen in this patient population.

Pediatric GIST is biologically different from adult GIST. Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only 11% of pediatric GIST.[129,138,139] In addition, unlike adult KIT mutant GIST, pediatric GIST have minimal large-scale chromosomal changes and the expression of insulin-like growth factor 1 receptor (IGF1R) expression is significantly higher and amplified in these patients, suggesting that administration of an IGF1R inhibitor might be therapeutically beneficial in these patients.[139,140]

Recent studies have revealed that about 12% of patients with wild-type GIST and a negative history of paraganglioma have germline mutations in the SDHB or C gene. In addition, using immunohistochemistry, SDHB expression is absent in all pediatric wild-type GIST, implicating cellular respiration defects in the pathogenesis of this disease. Furthermore, these findings support the notion that pediatric patients with wild-type GIST should be offered testing for constitutional mutations for the SDH complex.[141] The routine use of immunohistochemistry has documented lack of SDHB expression in 94% of children younger than 20 years with wild-type GIST and some investigators now favor the term SDH-deficient GIST. This group of patients lack KIT, PDGFR, and BRAF mutations in the primary tumor and lack SDHB immunoreactivity in the tumor. SDH-deficient GIST more commonly affects females, has an indolent clinical course, and occurs in the stomach.[134]

Treatment of GIST

Once the diagnosis of pediatric GIST is established, it is recommended that patients be seen at centers with expertise in the treatment of GIST and that all samples be subjected to mutational analysis for KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[142,143]

Treatment of GIST varies based on whether a mutation is detected:

  • GIST with a KIT or PDGFR mutation: Pediatric patients who harbor KIT or PDGFR mutations should be managed according to adult guidelines.
  • Wild-type GIST (no mutation): For most pediatric patients with wild-type GIST complete surgical resection of localized disease is recommended as long as it can be accomplished without significant morbidity (i.e., gastrectomy). When feasible, wedge resections are an acceptable surgical option. Since lymph node involvement is relatively common in younger patients, searching for overt or occult nodal involvement should be encouraged. Given the indolent course of the disease in pediatric patients, it is reasonable to withhold extensive and mutilative surgeries and to carefully observe children with locally recurrent or unresectable asymptomatic disease.[124,129]

    A randomized clinical trial in adults demonstrated that administration of adjuvant imatinib mesylate improved event-free survival in adult patients with GIST but this benefit was restricted to those with KIT exon 11 and PDGFR mutations, and thus the use of this agent in the adjuvant setting in pediatric wild-type GIST cannot be recommended.[144] Responses to imatinib and sunitinib in pediatric patients with wild-type GIST are uncommon and consist mainly of disease stabilization.[129,145,146] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[129] In another study, the clinical activity of sunitinib in six children with imatinib-resistant GIST was reported as one partial response and five stable disease.[147]

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  • Updated: October 29, 2014