Oncotarget, 2016-07-05, Vol.7 (27), p.41959-41973
The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.
Prognosis ; Poly-ADP-Ribose Binding Proteins - metabolism ; Humans ; Lung Neoplasms - metabolism ; Ki-67 Antigen - metabolism ; Neuroendocrine Tumors - diagnosis ; GTPase-Activating Proteins - metabolism ; Carcinoid Tumor - metabolism ; Small Cell Lung Carcinoma - metabolism ; Neoplasm Grading ; Biomarkers, Tumor - metabolism ; Lung - radiation effects ; Carcinoma, Large Cell - genetics ; Gene Expression Regulation, Neoplastic - drug effects ; Lung Neoplasms - genetics ; DNA Topoisomerases, Type II - metabolism ; Lung - pathology ; Carcinoma, Large Cell - metabolism ; Carcinoma, Large Cell - diagnosis ; Neuroendocrine Tumors - metabolism ; Kaplan-Meier Estimate ; Poly-ADP-Ribose Binding Proteins - genetics ; Small Cell Lung Carcinoma - genetics ; Neuroendocrine Tumors - genetics ; Carcinoid Tumor - genetics ; Ki-67 Antigen - genetics ; Lung - drug effects ; Small Cell Lung Carcinoma - diagnosis ; DNA Topoisomerases, Type II - genetics ; Biomarkers, Tumor - genetics ; Gene Expression Regulation, Neoplastic - radiation effects ; GTPase-Activating Proteins - genetics ; Lung Neoplasms - diagnosis ; Neoplasm Staging ; Carcinoid Tumor - diagnosis
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