ras activation through the somatic inactivation of the nf1 gene seems to be involved in the pathogenesis of nf1-associated gists . contrary to sporadic gists , the nf1-associated gists are characterized by a large number of small - sized tumors , typical location in the small intestine , and rare mutations of the kit or pdgfra . however , occasional mutations of both the kit and the pdgfra have been reported in the nf1-associated gists , and the meaning of these mutations remains unclear [ 3 - 6 ] . we present a case of nf1-associated gists with a missense point mutation of the kit in a 52-year old woman . a 52-year - old woman with a history of nf1 presented with intermittent abdominal pain . she had been diagnosed as nf1 30 years ago and had a family history of nf1 . her skin showed numerous caf au lait spots and multiple cutaneous neurofibromas over the whole body . a physical examination demonstrated a 20  15 cm palpable mass in the left abdomen . the abdominal computed tomography revealed a 15  9  7 cm tumor and several smaller masses along the jejunal loop ( fig . 1 ) . on laparotomy , main tumor and numerous ( more than 50 ) small nodular masses in the jejunum , located over 60 cm of the treitz ligamen 2 ) . segmental resection of the jejunum was performed and the patient recovered uneventfully . the largest tumor was 18  11  6 cm , showed mainly extramural growth and connected to the ulcerative mass at the mucosal side . some of the multiple nodular masses , ranging in size from 0.2 to 4.0 cm , showed intraluminal umbilication . histologically , the tumors consisted of interlacing fascicles of uniform spindle cells with eosinophilic cytoplasm and elongated nuclei ( fig . the largest tumor had increased mitoses ( 19/50 high power fields ) whereas the mitotic count of smaller tumors was less than 5 per 50 high power fields . immunohistochemical staining revealed tumor cells positive for cd117 , cd34 and vimentin , and negative for s-100 and smooth muscle actin(fig . genomic dna was extracted from each paraffin blocks of two tumors , including the extramural and intramural portions of the largest one . exons 9 , 11 , 13 and 17 of kit and exons 12 and 18 of pdgfra were amplified using the polymerase chain reaction ( pcr ) and then directly sequenced . the extramural portion of the largest tumor harbored a missense point mutation ( trp557gly ) of the kit exon 11 ( fig . the intramural portion of the largest tumor , as well as the other tumor , had wild type kit and pdgfra . a 52-year - old woman with a history of nf1 presented with intermittent abdominal pain . she had been diagnosed as nf1 30 years ago and had a family history of nf1 . her skin showed numerous caf au lait spots and multiple cutaneous neurofibromas over the whole body . a physical examination demonstrated a 20  15 cm palpable mass in the left abdomen . the abdominal computed tomography revealed a 15  9  7 cm tumor and several smaller masses along the jejunal loop ( fig . 1 ) . on laparotomy , main tumor and numerous ( more than 50 ) small nodular masses in the jejunum , located over 60 cm of the treitz ligamen 2 ) . segmental resection of the jejunum was performed and the patient recovered uneventfully . the largest tumor was 18  11  6 cm , showed mainly extramural growth and connected to the ulcerative mass at the mucosal side . some of the multiple nodular masses , ranging in size from 0.2 to 4.0 cm , showed intraluminal umbilication . histologically , the tumors consisted of interlacing fascicles of uniform spindle cells with eosinophilic cytoplasm and elongated nuclei ( fig . the largest tumor had increased mitoses ( 19/50 high power fields ) whereas the mitotic count of smaller tumors was less than 5 per 50 high power fields . immunohistochemical staining revealed tumor cells positive for cd117 , cd34 and vimentin , and negative for s-100 and smooth muscle actin(fig . genomic dna was extracted from each paraffin blocks of two tumors , including the extramural and intramural portions of the largest one . exons 9 , 11 , 13 and 17 of kit and exons 12 and 18 of pdgfra were amplified using the polymerase chain reaction ( pcr ) and then directly sequenced . the extramural portion of the largest tumor harbored a missense point mutation ( trp557gly ) of the kit exon 11 ( fig . the intramural portion of the largest tumor , as well as the other tumor , had wild type kit and pdgfra . gastrointestinal stromal tumors ( gists ) are the most common mesenchymal tumors of the gastrointestinal tract , with characteristic morphologic , immunophenotypic and molecular features . the gain of function kit and pdgfra mutations are considered to be a major driving force in the pathogenesis of sporadic , non - familial gists . activating mutations in the kit gene are present in up to 90% of the gists , and 35% of the gists lacking kit mutations have activation mutations in the related receptor tyrosinekinase gene , pdgfra . most of the kit mutations are located on the following exons : 11 ( the juxtamembrane domain ) , 9 ( the extracellular domain ) , 13 ( the tk i domain ) and 17 ( the tk ii domain ) ; conversely , the pdgfra mutations are usually located on the exons 12 or 18 . the kit - jm domain encoded by the exon 11 is the most common mutational " hot spot " in gists . a great majority of the kit exon 11 mutations are deletion / deletion - insertion and missense mutations . they represent the second most common type of kit exon 11 mutations found in gists . these mutations cluster on the 5 ' kit exon 11 and almost exclusively involve the kit codons 557 , 559 and 560 . normally kit and pdgfra are activated by their ligands , stem cell factors and pdgfs . ligand binding to the receptor ec domain results in dimerization of the receptors and phosphorylation of the tyrosines in their cytoplasmic tk domains . this leads to a phosphorylation cascade of the tyrosine residues in multiple downstream signaling molecules and to activation of the signal transduction pathways , including the ras / map kinase signaling network . these kit and pdgfra mutations lead to ligand independent dimerization of the receptors and downstream the phosphorylation cascade , ultimately leading to activation of cellular proliferation . in western countries , type 1 neurofibromatosis is a common autosomal dominant inherited disorder , with a prevalence of one in 3,000 live births . the syndrome results from either inherited or spontaneous germ - line mutations in the nf1 gene located at chromosome 17q11.2 , which encodes the tumor suppressor gene , neurofibromin . in addition to multiple cutaneous and deep - seated neurofibromas , patients with nf1 develop other evidence of the disease , including skin manifestations ( e.g. , axillary freckling , caf au lait spots ) , neurologic disorders , extra - intestinal neoplasm and neoplasm of the gastrointestinal tract ( e.g. , ampullary adenocarcinomas , somatostatinomas , and gists ) . the clinico - pathologic characteristics of the gists in nf1 are different from those of sporadic cases ; most cases show multiple gists , predominantly involving the small intestine , and mutations of the kit or pdgfra are rare . neurofibromin , the protein encoded by the nf1 gene , functions as a gtpase - activating protein for ras by catalyzing the hydrolysis of the active ras - gtp to an inactive ras - gdp . additional somatic inactivation of the wild type nf1 allele in the iccs seems to be the molecular event underlying the gist development in the nf1 setting . because of these genetic disorders , patients with nf1 are estimated to develop gists at a rate of at least 45 times higher than sporadic cases and gists are considered as a type of the clinical symptoms seen in nf1 . contrary to the sporadic gists , only occasional kit and pdgfra mutations have been reported in the nf1-associated gists . ten kit / pdgfra mutations have been reported in the 87 investigated patients ( table 1 ) . identified two kit ( e.g. , pro627leu and ile654thr ) and two pdgfra ( e.g. , pro589lys and arg822ser ) missense mutations in two separate tumors of each patient . these mutations do not correspond to the ' gist - type ' of mutations and might therefore be random genetic events related to the tumor progression . yantiss at al .   found a point mutation ( val559asp ) of the kit exon 11 in three tumors from a patient . however , the presence of identical mutations in separated tumors raises the possibility of a germline mutation . additionally , four mutations were identified in two other studies , i.e. , two in - frame deletions ( trp557_lys558del and val560del ) of the exon 11 and one duplication ( ala502_tyr503dup ) of the exon 9 of kit and one pdgfra mutation ( asp842val ) in the exon 18 . one missense mutation ( trp557gly ) of the kit exon 11 was identified in the extramural portion of the largest tumor found in the presented case . we consider that this is a ' gist type ' mutation . both the intramural portion of the largest tumor and the other tumor had wild type kit and pdgfra . the mutational feature of the presented case suggests that this mutation is not the initiation event , but might be an acquired genetic event which occurred at the ' hot spot ' of the kit mutation in the late phase of the development of nf1-associated gists . imatinib mesylate , a selective inhibitor of both kit and pdgfra , blocks these constitutively activated tyrosine kinases . this agent is currently being used as a molecular target drug for treating the gists and is showing a remarkable therapeutic effect on most of the gists . most of the nf1-associated gists lack the kit and pdgfra mutation , therefore imatinib mesylate is not expected to be effective on these multiple tumors . however , there was one report demonstrating the therapeutic effect of imatinib mesylate on the nf1-associated gist with wild type kit and pdgfra . data on the effect of tyrosine kinase inhibitors on the nf1-associated gists with activating mutations are , nevertheless , limited . molecular analysis for more cases is needed to understand the meaning of occasional occurrences of either kit or pdgfra mutations and to characterize their clinical features , including the response to tyrosine kinase inhibitors of the nf1-associated gists , according to the presence of the kit or pdgfra mutations .
multiple jejunalgastrointestinal stromal tumors ( gists ) were found in a 52-year - old woman with a history of neurofibromatosis type 1 . 
 these tumors were composed of interlacing fascicles of uniform spindle cells with eosinophilic cytoplasm . 
 immunohistochemically , the tumor cells were positive for cd117 , cd34 and negative for s-100 , smooth muscle actin . 
 molecular analysis for activating mutations of kit and pdgfra was performed in two tumors . 
 contrary to sporadic gists , the nf1-associated gists are characterized by rare mutations of kit or pdgfra . 
 but , one missense point mutation ( trp557gly ) was identified in kit exon 11 of the extramural portion of the largest tumor in this case . 
 the intramural portion of the largest tumor and the other tumor had wild type kit and pdgfra .