Quantification of Microvessel Density in Hepatocellular Carcinoma with Whole-slide Digital Analysis - Its Clinical and Prognostic Significance, and Associations with PDGFR-α, PDGFR-β, and VEGFR2 Público
Fang, Yuanyuan (2012)
Abstract
Quantification of Microvessel Density in Hepatocellular Carcinoma with Whole-slide Digital Aanalysis
- Its Clinical and Prognostic Significance, and Associations with PDGFR-α, PDGFR-β, and VEGFR2
Aims: To investigate the following correlations/associations
related to evaluations of
whole-slide digital analysis of tumors in patients undergoing
resections of hepatocellular
carcinoma (HCC): 1) between two different methods of microvessel
density (MVD)
evaluation, developed respectively; 2) between whole slide digital
analysis and manual
grading of expression of platelet derived growth factor
receptor-α (PDGFR-α), platelet derived growth factor
receptor-β (PDGFR-β), and
vascular endothelial growth factor receptor 2 (VEGFR2); 3) of tumor
MVD with
clinicopathologic characteristics and postoperative overall
survival; and 4) of PDGFR-α,
PDGFR-β, and VEGFR2 expression with MVD, clinicopathologic
characteristics, and
postoperative overall survival.
Methods: Tumor MVD was assessed in 47 patients with resected
HCC using the Aperio
microvessel analysis algorithm after immunostaining for CD31.
Expression of PDGFR-α,
PDGFR-β, and VEGFR2 in HCCs was assessed using the Aperio
positive pixel count
algorithm. Patients were prospectively followed until their
death.
Results: 1) We observed a good agreement between the two MVD
evaluation methods
(r=0.95; kappa=0.87). 2) The average intensity (the inverse of the
optical density) of the
biomarker staining was most highly correlated with manual grading
(r=0.69 for PDGFR-
α; r=0.69 for PDGFR-β; and r=0.82 for VEGFR2). 3) Higher
MVD was statistically
significantly associated with a negative microscopic margin
(p=0.004) and a smaller
tumor size (≤5cm) (p=0.003). A higher MVD and a lower
PDGFR-α expression together
were the most strongly associated with a better overall survival
(HR: 0.014; 95% CI:
0.001,0.23) among female patients without microvascular invasion of
HCCs. 4) We
found no significant associations of PDGFR-α, PDGFR-β,
and VEGFR2, or MVD with
the clinicopathologic characteristics.
Conclusion: There was a good agreement between the two MVD
assessing methods.
Higher MVD was found in small HCCs (<5cm) and HCCs with a
negative microscopic
margin. MVD together with PDGFR-α may be useful as a
prognostic marker combination
among female patients with microvascular invasion of HCCs. Further
prospective studies
with large numbers of patients are needed to fully clarify the
clinical implications of
tumor angiogenesis and its association with VEGFR2, PDGFR-α,
and PDGFR-β.
Table of Contents
Chapter I: Background.................................................................................................................................................... 1
Chapter II: Manuscript
Abstract.................................................................................................................................................................. 8
Introduction.............................................................................................................................................................9
Method
Data collection................................................................................................................................................13
Measurements.................................................................................................................................................15
Statistical analysis...........................................................................................................................................16
Results
Correlation between MVD and adjusted MVD..........................................................................................................18
Correlations between visual and digital evaluations of PDGFR-α, PDGFR-β, and VEGFR2 expression...................................18
Tumor MVD, adjusted MVD, PDGFR-α, PDGFR-β, and VEGFR2 expression according to clinicopathologic characteristics........18
Association of tumor MVD with overall postoperative survival ....................................................................................19
Associations of tumor PDGFR-α, PDGFR-β and VEGFR2 expression with overall postoperative survival................................ 20
Association of tumor PDGFR-α expression combined with MVD with overall postoperative survival .....................................21
Discussion ...............................................................................................................................................................22
References..............................................................................................................................................................27
Tables ....................................................................................................................................................................32
Figures................................................................................................................................................................... 34
Chapter III: SUMMARY....................................................................................................................................................38
APPENDICES
A: MELD score .......................................................................................................................................................... 40
B: Tables .................................................................................................................................................................40
C: Figures ................................................................................................................................................................48
D: Proportional hazards regression diagnostics (univariate survival curves and log-log curves)..................................................51
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