NF1-Associated Gastrointestinal Stromal Tumors Have Unique Clinical, Phenotypic, and Genotypic Characteristics

Lundberg Laboratory for Cancer Research, Department of Pathology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
American Journal of Surgical Pathology (Impact Factor: 5.15). 09/2005; 29(9):1170-6. DOI: 10.1097/01.pas.0000159775.77912.15
Source: PubMed


Gastrointestinal stromal tumors (GIST) have been reported to occasionally occur in patients with neurofibromatosis type 1 (NF1). This study aims to describe the phenotypic and genotypic characteristics of GIST in NF1 patients and attempts to elucidate the relationship between them. We analyzed GIST arising in 15 NF1 patients (8 males and 7 females, 19-82 years of age). Eleven patients had multiple GISTs (3 to >100 tumors) ranging from 1 mm to 10 cm in size and predominantly involving the small intestine including the duodenum. Tumors were symptomatic in 8 patients and incidental findings in the remaining 7 patients. Microscopically, the tumors cells were typically spindled and the mitotic rate low; 9 patients had tumors classified as very low or low risk and 6 as intermediate risk GIST. Nine patients were treated surgically and none developed metastases or died of disease. Immunohistochemical stains for CD117 were strongly positive in 47 of 50 GIST; they also accentuated hyperplastic foci (diffuse and focal) of the interstitial cells of Cajal that were often associated with microscopic GIST in the surrounding intestinal muscle wall. No KIT or PDGFRA mutations were detected in 24 GIST from 12 patients using dHPLC analysis and DNA sequencing. We conclude that patients with NF1 have a high risk of developing GIST. NF1-associated GIST are also phenotypically and genotypically distinct from sporadic GIST, indicating that different pathogenetic mechanisms are involved in their evolution.

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    • "The American Journal of Surgical pathology 2005 9 36 [18] "
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    ABSTRACT: Aims: The objectives of this study were (a) to report our experience regarding the association between neurofibromatosis type 1 (NF1) and gastrointestinal stromal tumors (GISTs); (b) to provide a systematic review of the literature in this field; and (c) to compare the features of NF1-associated GISTs with those reported in sporadic GISTs. Methods: We reported two cases of NF1-associated GISTs. Moreover we reviewed 23 case reports/series including 252 GISTs detected in 126 NF1 patients; the data obtained from different studies were analyzed and compared to those of the sporadic GISTs undergone surgical treatment at our centre. Results: NF1 patients presenting with GISTs had a homogeneous M/F ratio with a mean age of 52.8 years. NF1-associated GISTs were often reported as multiple tumors, mainly incidental, localized at the jejunum, with a mean diameter of 3.8 cm, a mean mitotic count of 3.0/50 HPF, and KIT/PDGFR α wild type. We reported a statistical difference comparing the age and the symptoms at presentation, the tumors' diameters and localizations, and the risk criteria of the NF1-associated GISTs comparing to those documented in sporadic GISTs. Conclusions: NF1-associated GISTs seem to have a distinct phenotype, specifically younger age, distal localization, small diameter, and absence of KIT/PDGRF α mutations.
    International Journal of Surgical Oncology 12/2013; 2013:398570. DOI:10.1155/2013/398570
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    • "FGS-associated GISTs resemble the sporadic kinase-mutant forms in terms of gender balance, anatomic distribution, and prevalence of spindlecell morphology. GISTs occurring in the context of the autosomal dominant disorder neurofibromatosis type 1 (NF1, OMIM 162200), while generally WT for KIT and PDGFRA, typically present in the small bowel and possess spindle-cell morphology (Andersson et al., 2005; Miettinen et al., 2006a). GISTs in these patients also tend to manifest later in life, and these patients manifest the cutaneous and ocular findings associated with NF1 in addition to their pre-disposition for GISTs and various nervous system tumors. "
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    ABSTRACT: Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.
    Frontiers in Oncology 05/2013; 3:117. DOI:10.3389/fonc.2013.00117
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    • "The majority of gastrointestinal stromal tumors (GIST) harbor gain-of-function mutations in KIT or PDGFRA, resulting in the activation of the downstream pathways PI3K/AKT, Ras/MAPK, and JAK/STAT3, and playing a crucial role in tumorigenesis [1,2]. A subset of GIST lack specific KIT or PDGFRA mutations and form a heterogeneous group, including NF1, Carney Triad (CT), Carney-Stratakis Syndrome (CSS), pediatric and young adult GIST, and a small proportion (<10%) of sporadic adult GIST [3-8]. The mechanisms involved in the tumorigenesis of GIST lacking KIT or PDGFRA mutations are still poorly understood. "
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    ABSTRACT: Background A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II. Methods Next generation sequencing was applied on five pediatric and one young adult WT GIST, by whole exome capture and SOLiD 3-plus system sequencing. The putative mutations were first confirmed by Sanger sequencing and then screened on a larger panel of 11 pediatric and young adult WT GIST, including 5 in the context of Carney triad. Results A germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform. An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort. Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors. Results were further confirmed by immunohistochemistry for both SDHA and SDHB, which showed a concurrent loss of expression of both proteins in SDHA-mutant lesions, while the remaining WT tumors showed only loss of SDHB expression. Conclusions Germline and/or somatic aberrations of SDHA occur in a small subset of KIT/PDGFRA WT GISTs, outside the Carney’s triad and are associated with loss of both SDHA and SDHB protein expression. Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults. Although pediatric GIST consistently display alterations of SDHB protein expression, further molecular studies are needed to identify the crucial genes involved in their tumorigenesis.
    BMC Cancer 09/2012; 12(1):408. DOI:10.1186/1471-2407-12-408 · 3.36 Impact Factor
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