Table 4. Common Genetic Syndromes Associated With Hamartomatous Polyps continued...
The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver. Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms. Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.
Gastrointestinal Stromal Tumors (GIST)
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults. These tumors are rare in children. Approximately 2% of all GIST occur in children and young adults;[116,117,118] in one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas. 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.[120,121]
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.[120,122]
- 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.[118,122,123]
- Carney-Stratakis syndrome is characterized by paraganglioma and GIST due to germline mutations of the SDH genes B, C, and D.[124,125]
Familial GIST and neurofibromatosis 1–associated GIST occur in patients older than 40 years.[121,126,127]
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.[120,128] 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.[120,129] 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.[120,129,130] 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.[130,131]
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. 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.