This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric gastrointestinal stromal tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Incidence

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[1] These tumors are rare in children.[2] Approximately 2% of all GIST occur in children and young adults.[3-5] In one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[6] 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.[5,7,8]

Clinical Features

Most pediatric patients with gastrointestinal stromal tumors (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.[1-3] 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 tumor recurrences and long survival rates.[2]

Histology and Molecular Features

Histologically, pediatric gastrointestinal stromal tumors (GIST) have a predominance of epithelioid or epithelioid/spindle cell morphology. Unlike adult GIST, the mitotic rate does not appear to accurately predict clinical behavior in pediatric patients.[1,2] Most GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[3,4] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[5,6]

Gastrointestinal tumors without a definitive line of differentiation should be evaluated for NTRK alterations.[7] Mesenchymal tumor of the gastrointestinal tract is characterized by the presence of NTRK rearrangements and is a separate entity from GIST. In a report of eight cases of mesenchymal tumors, six occurred in children. Four of these patients had lesions that were enriched for NTRK3 fusions, consistent with the diagnosis of infantile fibrosarcoma of the gastrointestinal tract.[7]

Activating variants of KIT and PDGFRA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[1,5,8]

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 pathogenic variants of the SDH complex, most commonly involving SDHA.[3] This finding supports the concept that SDH-deficient GIST is a cancer predisposition syndrome, and testing of affected patients for constitutional variants for the SDH complex should be considered.[9]

SDH-deficient GIST can arise within the context of the following two syndromes:[1,10]

• 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 variants of KIT, PDGFRA, or the SDH genes have been found in these patients.[10-12]
• Carney-Stratakis syndrome. Carney-Stratakis syndrome is characterized by paraganglioma and GIST caused by germline pathogenic variants of the SDHB, SDHC, and SDHD genes.[4,13]

A small percentage of SDH-deficient GIST lack somatic or germline variants of the SDH complex. These tumors are characterized by SDHC promoter hypermethylation and gene silencing, and they are categorized as GIST with an SDHC epigenetic variant.[14]

In an observational study done at the National Cancer Institute, 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:[15]

• Group 1 (SDH-competent GIST): Group 1 included 11 patients who were designated as SDH competent because of positive staining of SDHB and lack of variants 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. Variant analysis of these tumors identified variants 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-variant GIST): Group 2 included 63 patients who were SDH deficient. Variants were observed in the SDHA (n = 34), SDHB (n = 16), SDHC (n = 12), and SDHD (n = 1) complexes. Of the 38 patients with SDH-variant GIST who had matching germline and tumor DNA, 31 (82%) had the same variant 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, three patients (5%) had died.
• Group 3 (GIST with an SDHC epigenetic variant): Group 3 included 21 patients with SDH-deficient tumors, with SDHC promoter methylation and no structural variants. 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. Metastases were present at diagnosis in the liver (37%), peritoneum (5%), and lymph nodes (38%). At a median follow-up of 7 years, one patient (5%) with GIST with an SDHC epigenetic variant died of their 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 variants, and six patients had epigenetic variants. Seven patients with Carney-Stratakis syndrome had SDH-variant GIST (n = 6) or GIST with an SDHC epigenetic variant (n = 1).[15]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3-5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]
  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as Gastrointestinal Stromal Tumors Treatment.

Treatment of Childhood Gastrointestinal Stromal Tumors

Treatment options for pediatric gastrointestinal stromal tumors (GIST) include the following:

1. Observation.
2. Surgery.
3. Targeted therapy.

Once the diagnosis of pediatric GIST is established, patients should be referred to medical centers with expertise in the treatment of GIST.[1,2]

Given the indolent course of the disease in pediatric patients, it is reasonable to avoid extensive initial surgeries and to withhold subsequent resections unless needed to address symptoms such as obstruction or bleeding.[3,4]

Tumor samples are evaluated for variants in KIT (exons 9, 11, 13, 17), PDGFRA (exons 12, 14, 18), and BRAF (V600E).[1,2] Treatment options for GIST depend on whether a variant is detected.

GIST with a KIT or PDGFRA variant: Pediatric patients who harbor KIT or PDGFRA variants are managed like adults. For more information, see Gastrointestinal Stromal Tumors Treatment.

Succinate dehydrogenase (SDH)-deficient GIST: Approximately one-half of all patients with wild-type GIST are SDH deficient.[5] For most pediatric patients with SDH-deficient GIST, surgical resection of localized disease is recommended because of its indolent course. Extensive surgery and repeated surgical resections should be avoided.

This approach is supported by a study of 76 patients with wild-type GIST who underwent surgery for newly diagnosed and recurrent disease.[5]

• Only 9% of patients experienced a fatal event, whereas 71% (54 patients) developed tumor recurrence or progression at a median of 2.5 years.
• For this population, the 1-year event-free survival (EFS) rate was 73%, the 5-year EFS rate was 24%, and the 10-year EFS rate 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 rate.

In patients with SDH-deficient GIST, responses to imatinib, regorafenib, vandetanib, sunitinib, and guadecitabine are uncommon.[3,6-9]

1. In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[3]
2. In the phase III SWOG Cancer Research Network intergroup S0033 (NCT00009906) trial, 20 tumors from patients presumed to have wild-type disease were resequenced.[8]

   • Twelve of these tumors were identified as having SDH variants, and only one patient (8.3%) experienced a partial response to imatinib.[10]
3. In another study, sunitinib appeared to show more activity.[11]

   • In six children with imatinib-resistant GIST, one patient had a partial response, and five patients had stable disease.
4. The combination of olaparib and temozolomide produced symptomatic relief and response in one pediatric patient with multiply relapsed SDH-deficient GIST who had osseous and mediastinal disease.[12]
5. In a phase II trial of guadecitabine, no partial or complete responses were seen in seven patients (aged 18–57 years) with recurrent or refractory SDH-deficient GIST.[13]

Unlike recommendations for adults, the use of adjuvant imatinib cannot be recommended in children with SDH-deficient GIST.[14]

Treatment Options Under Clinical Evaluation for Childhood Gastrointestinal Stromal Tumors

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, see the ClinicalTrials.gov website.

Latest Updates to This Summary (09/05/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary