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 Open Access

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

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
Keyword	HCC MVD Scanscope whole slide digital image analysis survival analysis
Committee Chair / Thesis Advisor	Bostick, Roberd M, Emory University Farris III, Alton B, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs Hospital or other health care provider

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