Treatment of Recurrent Pediatric Gastrointestinal Stromal Tumors

CASE REPORT

Gastrointestinal stromal tumors (GISTs) in pediatric and adolescent patients differ significantly from those in adults. The differences in clinical, genetic, and biologic features have important implications for the medical management of pediatric GISTs.

The patient was an 18-year-old Hispanic male who initially presented to his primary care physician, at the age of 12, with complaints of lower gastrointestinal bleeding. His hemoglobin was 6 g/dL, and an esophagogastroduodenoscopy (EGD) revealed ulcerated gastric lesions and a small tumor in the esophagus. At that time, he underwent an antrectomy with posterior gastroenterostomy, jejunostomy, and biopsy of the mesenteric lymph nodes. Nine tumors were removed in a gastric resection, and the pathology showed a GIST that was C-KIT (CD117), vimentin, and CD34 positive with a mitotic rate of 1/10 high power fields. The patient subsequently had follow-up semiannual endoscopies with no evidence of recurrent disease.

Five years later, the patient developed abdominal pain. An ultrasound detected free fluid in the abdomen and pelvis as well as three hepatic nodules (the largest was 6.2 cm). The patient underwent a laparoscopy, and 2 L of bloody fluid was removed. The source of the bleeding was not identified. The subsequent work-up included a magnetic resonance cholangiopancreatography (MRCP), which again showed multiple liver lesions and a dominant mass within the lower medial portion of the right lobe of the liver. The mass compressed the proximal common bile duct at the level of the porta hepatis, resulting in minimal narrowing of the central intrahepatic bile ducts. A 3.6-cm lobulated mass was also seen in the left upper quadrant and appeared to be arising from the stomach. A triple-phase computed tomographic (CT) scan of the liver showed that the liver and left upper quadrant masses had increased in size within a 2-month period.

The patient had a full-body positron emission tomographic (PET) scan that showed increased metabolic uptake in the left paratracheal region and aortopulmonary (AP) window lymph node. Additional areas of uptake included a left upper quadrant mass at the anterior gastric wall, and two lesions in the liver, one in the posterior segment of the right lobe and one in the left lobe. Mutational analysis of the tumor revealed no mutations in exon 9 or 11 of the KIT or the PDGFRA (platelet-derived growth factor receptor alpha) gene, and it was also SDHB (succinate dehydrogenase complex, subunit B) deficient. The patient's case was reviewed by a multidisciplinary team at the National Institutes of Health (NIH), and the disease was thought to be surgically unresectable because there were lesions in both lobes of the liver. The patient was then started on sunitinib at a dose of 37.5 mg daily.

DISCUSSION

GISTs are the most common mesenchymal tumors of the GI tract.¹ The annual incidence of GISTs in the United States is approximately 4000 to 6000 cases. They occur predominantly in middle-aged and older individuals, rarely in those younger than 40.² The cell of origin is thought to be the interstitial cells of Cajal.³ In most adult GIST cases, a mutation in the KIT gene leads to abnormal activation and results in oncogenic signaling in the cell.⁴ About 95% of GISTs arising in adults overexpress KIT. The second most common mutation occurs in the PDGFRA gene.⁵ In adults, KIT-negative GISTs are more often of the epithelioid type, and they present more commonly in the omentum and mesentery.⁶ The response to imatinib varies, depending on the location of the mutation in the KIT gene. GISTs with KIT exon 11 mutations respond most frequently to imatinib.⁷

The percentage of patients younger than 21 years with GISTs is estimated to be 0.5% to 2.7%.⁸ Most pediatric GISTs are located in the stomach, usually in the antrum.⁹ Pediatric GISTs are more common in girls, whereas the distribution between the sexes is roughly equal in adults. Adult GISTs most often have a spindle cell morphology, whereas pediatric GISTs have an epithelioid morphology.¹⁰ More than 85% of pediatric GISTs lack mutations in the KIT or PDGFRA gene.¹¹ Pediatric GISTs can occur sporadically or in association with four specific genetic syndromes: familial GIST with a germline KIT mutation, GIST and neurofibromatosis type 1, the Carney triad, and Carney-Stratakis Syndrome.⁴ The Carney triad is characterized by the development of GISTs, extra-adrenal paragangliomas, and pulmonary chondromas. The most common site of GISTs in these patients is the stomach, primarily the antrum, and patients most commonly present with gastrointestinal bleeding. Multifocality and nodal metastases are often seen. The most frequent combination is GISTs associated with a pulmonary chondroma.¹²

Carney-Stratakis syndrome is caused by germ-line mutations in the succinate dehydrogenase (SDH) gene, subunits B, C, and D, and it is characterized by the presence of paragangliomas and GISTs.¹³ It is inherited in an autosomal dominant pattern with incomplete penetrance. The mean age at diagnosis is 19 years, and the most common site of involvement is the stomach. Most tumors have a spindle cell histology. In the largest study, 11 of the 12 original patients were still alive, despite the presence of multiple tumors and metastases at the time of presentation.¹⁴ Table 1 outlines characteristics of pediatric GIST, the Carney Triad, and the Carney-Stratakis Syndrome.

Table 1.

Clinicopathologic characteristics of pediatric GIST, the Carney Triad, and Carney-Stratakis Syndrome^{12, 13, 15}

	Pediatric GIST	Carney Triad	Carney-Stratakis Syndrome
Mean age at diagnosis, y	14	22	19
Histology	Epithelioid or mixed	Epithelioid	Spindle cell
Genetic predisposition	SDH germ-line mutation	Unknown	SDH germ-line mutation
Most common site of involvement	Stomach multifocal lymph nodes	Stomach	Stomach
Associated neoplasms	Unknown	Paragangliomas	Paragangliomas
		Pulmonary chondromas

The frontline therapy for adult patients with metastatic GISTs is imatinib. However, pediatric GISTs usually do not respond to imatinib. Some groups have evaluated the utility of alternative tyrosine kinase inhibitors in the management of pediatric GISTs after the failure of imatinib therapy. Janeway and colleagues¹⁵ reported that in a group of 7 patients with imatinib-refractory disease who received treatment with sunitinib, partial response or stable disease was observed in 6 of 7 patients for an average of 15 months, without significant toxicity. Other drugs that inhibit KIT, such as dasatinib and nilotinib, are still under investigation for the treatment of refractory GISTs.¹⁶

The risk stratification in adult patients with GIST is based on tumor size, mitotic index, and location of the primary tumor.¹⁷ There is currently no risk stratification system for pediatric GISTs. The literature suggests that pediatric GISTs have an indolent course compared with adult lesions, but are more prone to metastasis. Pediatric patients can have a prolonged survival even in the absence of tyrosine kinase inhibitor therapy. In one series, 83% of patients developed metastatic disease, but only one succumbed, 11 years after diagnosis.¹¹

CONCLUSIONS

GISTs are very uncommon in pediatric patients, and they differ from adult GISTs biologically, clinically, and prognostically. Because of the rarity of the disease, patients should be managed in the context of a clinical trial and in tertiary centers familiar with the treatment of the disease.