title: Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations.
abstract: Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in >50% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10-50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. dcao1@jhmi.edu
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Cao
authors.forename: Cristina
authors.initials: C
authors.lastname: Antonescu
authors.forename: Grace
authors.initials: G
authors.lastname: Wong
authors.forename: Jordan
authors.initials: J
authors.lastname: Winter
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: N Volkan
authors.initials: NV
authors.lastname: Adsay
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002452:Cell Count; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha