KIT is an Independent Prognostic Marker for Pancreatic Endocrine Tumors

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.

Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries

“…This latter feature showed a significant association with tumour aggressiveness and patients’ shorter survival at univariate analysis ( P < 0.001), which was not retained at multivariate analysis. This result differs from that by Zhang et al [33] who reported that KIT expression was an independent prognostic factor. Concerning EGFR and HER2, neoplastic cells stained for EGFR in 13% (18/140) and for HER2 in 2% (3/140) of samples.…”

Profiling the Tumour Immune Microenvironment in Pancreatic Neuroendocrine Neoplasms with Multispectral Imaging Indicates Distinct Subpopulation Characteristics Concordant with WHO 2017 Classification

“…NETs can also be further subdivided into three subgroups, G1/G2/G3, according to their mitotic index and Ki-67 index. Notably, the biological features of pNENs have been well researched, and the Ki-67 proliferation index as well as CK19 12 , p27 13 , and KIT 14 expression in the tumour cells have been identified as important predictive factors. However, these characteristics are not always a reliable reflection of treatment effectiveness or patient outcome.…”

Molecular pathology and genetics of pancreatic endocrine tumours

“…While earlier papers showed inconsistent results (Fjallskog et al 2003, Koch et al 2006, in more recent studies, a prognostic role for c-KIT has been highlighted. Zhang et al (2009) reported that immunostaining for c-KIT is a significant independent factor associated with poor prognosis in a series of 97 PETs. Corbo et al (2012) analysed a series of 140 PETs and found no mutations of EGFR, HER2 and PDGFRa (PDGFRA), while KIT was mutated in only one case.…”