title: KIT is an independent prognostic marker for pancreatic endocrine tumors: a finding derived from analysis of islet cell differentiation markers.
abstract: Prediction of the biologic behavior of pancreatic endocrine tumor (PET) without local invasion or metastasis is often difficult. The 2004 World Health Organization (WHO) classification uses size, angioinvasion, mitotic activity, and Ki-67 index as prognostic criteria. Recently, cytokeratin 19 (CK19) was shown to be another prognostic marker, but the mechanism by which CK19 predicts prognosis is unknown. As CK19 is the first cytokeratin expressed in all epithelial cells in fetal pancreas, we sought to test expression of other markers of islet cell differentiation including KIT, Pdx-1, Pax4, and Pax6 in PET and correlation of these markers with clinical behavior. Clinical information and histology was reviewed in 97 PETs. All tumors were classified according to WHO criteria and a tumor, node, and metastases stage system. Immunohistochemistry was performed using antibodies to Ki-67, KIT, CK19, Pdx-1, Pax4, and Pax6. Associations of clinicopathologic and immunohistochemical features with prognosis were evaluated using Cox proportional hazards regression models. WHO and tumor, node, and metastases classifications, mitotic counts and Ki-67 labeling, infiltrative border, necrosis, perineural invasion, extrapancreatic extension, tumor size, and positive CK19 and KIT expression were significantly associated with death from disease in a univariate setting. In multivariate analysis, only WHO criteria and KIT expression were shown to be independent. An immunohistochemical classification system was derived from a combination of KIT and CK19 expression: low risk (KIT-/CK19-), intermediate risk (KIT-/CK19+), and high risk (KIT+/CK19+). Survival, metastases, and recurrence of PET were significantly different among the 3 groups. These results indicate that KIT is a new and independent prognostic marker for PETs. The classification system derived from KIT and CK19 was able to predict clinical behavior of PET.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Zhang.lizhi@mayo.edu
authors: Lizhi
authors: L
authors: Zhang
authors: Thomas C
authors: TC
authors: Smyrk
authors: Andre M
authors: AM
authors: Oliveira
authors: Christine M
authors: CM
authors: Lohse
authors: Shuya
authors: S
authors: Zhang
authors: Michele R
authors: MR
authors: Johnson
authors: Ricardo V
authors: RV
authors: Lloyd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002454:Cell Differentiation; D002851:Chromatography, High Pressure Liquid; D005136:Eye Proteins / Q000096:biosynthesis; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D053539:Keratin-19 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000145:classification* / Q000401:mortality / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012097:Repressor Proteins / Q000096:biosynthesis; D019089:Stem Cell Factor / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D005136:Eye Proteins; D018398:Homeodomain Proteins; D053539:Keratin-19; C491709:PAX4 protein, human; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D019089:Stem Cell Factor; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein