Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q

Yamamoto, Hidetaka; Tobo, Taro; Nakamori, Mari; Imamura, Masakazu; Kojima, Aya; Oda, Yoshinao; Nakamura, Norimoto; Takahira, Tomonari; Yao, Takashi; Tsuneyoshi, Masazumi

doi:10.1007/s00432-008-0514-z

Cited by 47 publications

(41 citation statements)

References 32 publications

(56 reference statements)

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“…In contrast, GISTs arising in NF1 patients often show losses of 14q and 22q. 96 On the basis of gene expression profiling of high-risk versus low-risk GISTs, the high-risk tumors show significant changes in genes regulating the cell cycle, including genes influenced by the PI3 kinase pathway and genes involved in the G2/M checkpoint. 97 A significant fraction of malignant GISTs show inactivation of the tumor suppressor gene CDKN2A (which encodes the cell cycle regulatory protein p16 INK4A ) through chromosome 9p21 deletion, either biallelic or in combination with mutation or promoter methylation.…”

Section: Micro-gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Section: Micro-gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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“…Rather, cell proliferation in NF-1 GIST is associated with the activation of the Ras-mitogen-activated protein kinase pathway, which may be activated via KIT or PDGFRA in association with the inactivation of the NF1 gene. Additionally, loss of heterozygosity at 14q and 22q may contribute to the relatively early phase of tumor development of NF1-GIST (30). The diagnosis of GIST primarily depends on the histopathological and immunohistochemical phenotype.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis type 1 associated with pheochromocytoma and gastrointestinal stromal tumors: A case report and literature review

2016

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Abstract. Neurofibromatosis type 1 (NF1) is a genetic disorder associated with neurofibromin 1 (NF1) gene mutation, which generates an increased risk of variety of tumor types. The current study reports a case involving NF1, pheochromocytoma (PHEO) and gastrointestinal stromal tumors (GIST). A 56-year-old man presented with abdominal pain and polypnea. Clinical investigation revealed multiple diffuse soft-tissue lesions throughout his body, and pigmented macules on the skin. Imaging analyses revealed thoracic scoliosis, multiple subcutaneous nodules in the abdomen and trunk, and a 7.0x7.7x8.9-cm oval-shaped, cystic mass in the left upper abdominal cavity. Immunohistochemical staining indicated that S-100 protein and synaptophysin were highly expressed in adrenal gland neoplasm, whilst CD117 and CD34 were highly expressed in small intestine tumors. The overall clinical and pathological finding suggested a diagnosis of NF1, giant PHEO and small intestinal stromal tumor. In addition, a literature review was conducted to identify the specific clinical features of patients with this condition. Only 11 similar cases have been reported worldwide. In the present study, paroxysmal hypertension occurred in the majority of patients, and GISTs tended to be located in the small intestine. In addition, the present study demonstrated that many of the patients had a poor prognosis. Therefore, the present study indicates that NF1-PHEO-GIST is a special type tumor with varied clinical symptoms, which may be associated with an increased risk for poor prognosis; however, more studies are required to confirm this.

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“…NF1 may also be associated with microtubules and modulate the cyclic adenosine monophosphate (CAMP)–PKA signalling pathway 7. Additionally, loss of heterozygosity (LOH) at 14q and 22q has been identified and may contribute to the relatively early phase of tumour development of NF-1 mutated GIST,8 due to loss of tumour suppressor gene on these chromosomes.…”

Section: Ras-p Mutant Gistsmentioning

confidence: 99%

Molecular and morphological correlation in gastrointestinal stromal tumours (GISTs): an update and primer

Chetty

Serra

2016

J Clin Pathol

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Gastrointestinal stromal tumours (GISTs) are a commonly encountered tumour in routine practice. In the main, the morphology of spindle, epithelioid or mixed are well recognised along with mutations of c-kit. However, there are other genes that are mutated resulting in characteristic clinicopathological correlations. GISTs harbouring platelet-derived growth factor receptor α (PDGFRα) gene mutations lead to a typical morphological constellation of findings: gastric and omental location, gross tumour that is cystic and haemorrhagic, composed of epithelioid, plasmacytoid cells exhibiting pleomorphism, low mitotic count and containing characteristic giant cells with peripherally placed nuclei. These cells are set in a myxoid stroma containing several mast cells. In addition, perivascular/ intratumoural hyalinisation is often seen. These tumours are CD117 and DOG-1 positive. GISTs with SDH mutations are multinodular/bilobed/dumb-bell shape tumour masses with mucosal ulceration and histologically characterised by fibrous bands around and within nodules of epithelioid or mixed epithelioid/spindle cells. Lymphovascular invasion with lymph node metastases are usual. Immunohistochemically, the GISTs are CD117, DOG-1 positive, SDHA negative (if SDHA mutated), SDHA positive (if SDHA intact) and SDHB negative. BRAF and NF-1 mutated GISTs do not have any characteristic morphological features.

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Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q

Cited by 47 publications

References 32 publications

Gastrointestinal stromal tumors: what do we know now?

Gastrointestinal stromal tumors: what do we know now?

Neurofibromatosis type 1 associated with pheochromocytoma and gastrointestinal stromal tumors: A case report and literature review

Molecular and morphological correlation in gastrointestinal stromal tumours (GISTs): an update and primer

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