Non-Cancerous Abnormalities That Could Mimic Prostate Cancer

Western University
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Electronic Thesis and Dissertation Repository
6-27-2018 1:00 PM
Non-Cancerous Abnormalities That Could Mimic Prostate Cancer Like Signal in Multi-Parametric MRI Images
Mena Gaed, The University of Western Ontario Supervisor: Dr. Fenster, Aaron, The University of Western Ontario : Dr. Moussa, Madeleine, The University of Western Ontario A thesis submitted in partial fulfillment of the requirements for the Master of Science degree in Pathology © Mena Gaed 2018
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Recommended Citation Gaed, Mena, "Non-Cancerous Abnormalities That Could Mimic Prostate Cancer Like Signal in MultiParametric MRI Images" (2018). Electronic Thesis and Dissertation Repository. 5469. https://ir.lib.uwo.ca/etd/5469
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Abstract
Prostate Cancer (PCa) is the most common non-cutaneous cancer in North American men. Multi-parametric magnatic resonance imaging (mpMRI) has the potential to be used as a non-invasive procedure to predict locations and prognosis of PCa. This study aims to examine non-cancerous pathology lesions and normal histology that could mimic cancer in mpMRI signals. This study includes 19 radical prostatectomy specimens from the London Health Science Centre (LHSC) that were marked with 10 strand-shaped fiducials per specimen which were used as landmarks in histology processing and ex vivo MRI. Initial registration between fiducials on histology and MR images was performed followed by the development of an interactive digital technique for deformable registration of in vivo to ex vivo MRI with digital histopathology images. The relationship between MRI signals and non-cancerous abnormalities that could mimic PCa has not been tested previously in correlation with digital histopathology imaging. The unregistered mp-MRI images are contoured by 4 individual radiology observers according to the Prostate Imaging Reporting and Data System (PI-RADS). Analysis of the radiology data showed prostatic intraepithelial neoplasia (PIN), atrophy and benign prostatic hyperplasia (BPH) as main non-cancerous abnormalities responsible for cancer like signals on mpMRI. This study will help increase the accuracy of detecting PCa and play a role in the diagnosis and classification of confounders that mimic cancer in MR images.
Keywords
Prostate imaging, Prostate non-cancerous abnormalities, Prostate image regestirations, in-vivo prostate MRI, Prostate cancer.
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Acknowledgments
Today is the day: writing a small note of appreciation is the finishing touch on my dissertation. It has been a period of intense learning, not just in the scientific arena, but on a personal level. My appreciation and gratitude to my committee are infinite. Your support and willingness to help will not be forgotten. Special thanks to Dr. Fenster, my supervisor, for his valuable advice, great support, and opportunities to conduct this research. I would also like to thank Dr. Moussa (co-supervisor) for the valuable assistance I have received from her and providing me with the tools to successfully complete my dissertation. To my small family, I dedicate this work to you all; Giustina, Demetrius, and my lovely wife, Mary. Giustina and Demetrius were born during the development of this work. Here are to many late nights of multi-tasking writing and bottle feeding. Thank you for making me laugh when I needed it the most. Thank you to my wife for her love and support, I could not imagine completing this work without you next to me. Finally, I would like to acknowledge with gratitude, my bigger family. I am indebted to my parents who introduced me to the realm of academic excellence. I am grateful for your support in my dreams, encouraging my pursuits and guiding me in the right direction. I cannot forget my amazing siblings for all their love and support. All these years, you guys never cease to amaze me with your surprises. To my brother Michael, I thank you for the long hours of discussions that helped me to focus and complete this research. Even though we do not see each other as often, your support from halfway around the world is always felt. For all these reasons, I dedicate my success and this research to my family!
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Table of Contents
Page Abstract ................................................................................................................ ii
Acknowledgment ................................................................................................. iii
Table of Content .................................................................................................. iv
List of Tables .......................................................................................................vii
List of Figures .....................................................................................................viii
List of Abbreviations ...........................................................................................xi
Chapter 1 .............................................................................................................. 1
1 Introduction ................................................................................................ 1 1.1 Prostate Cancer Epidemiology .............................................................. 1 1.1.1 Race and Ethnicity ..................................................................... 2 1.1.2 Age ............................................................................................ 4 1.1.3 Family and socioeconomic status .............................................. 4 1.1.4 Diet ............................................................................................ 5 1.1.5 Obesity ....................................................................................... 5 1.2 Anatomy and Histology of Prostate Gland ............................................ 6 1.2.1 Prostate Gland Anatomy ............................................................ 6 1.2.2 Embryology of the Prostate Gland ............................................ 9 1.2.3 Microscopic Anatomy of Prostate Gland .................................. 9 1.2.3.1 Peripheral Zone (PZ)......................................................10 1.2.3.2 Central Zone (CZ) .........................................................10 1.2.3.3 Transition Zone (TZ) ....................................................13 1.2.3.4 Anterior Fibromuscular Stroma (AFMS) ......................13 1.2.3.5 Prostate Gland Capsule .................................................14 1.2.4 Vascular Supply .........................................................................14 1.2.5 Neurovascular Bundles of The Prostate ....................................15
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1.2.6 Normal Histology of Prostate Gland .........................................15 1.2.7 Mimicker of Prostate Cancer .....................................................17
1.2.7.1 Atrophy .........................................................................17 1.2.7.1.1 Simple Atrophy (SA) ..................................18 1.2.7.1.2 Post-Atrophic Hyperplasia (PAH) ..............18 1.2.7.1.3 Simple Atrophy with a Cystic Formation ...19 1.2.7.1.4 Partial Atrophy ............................................19
1.2.7.2 Prostatic intraepithelial neoplasia (PIN) ......................22 1.2.7.3 Benign Prostatic Hyperplasia (BPH) ...........................27 1.3 Screening ...............................................................................................32 1.3.1 Prostate Specific Antigen (PSA) ...............................................32 1.3.1.1 Age and Race-Specific Range ......................................33 1.3.1.2 Free (PSA) Vs. Total (PSA) .........................................35 1.3.2 Prostate Cancer Diagnosis ........................................................35 1.4 Magnetic Resonance Imaging (MRI) ....................................................37 1.4.1 T2 Weighted (T2W) ..................................................................38 1.4.2 Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) ....................................................................41 1.4.3 Dynamic Contrast Enhanced (DCE) .........................................42 1.5 Prostate Imaging and Reporting Data System (PI-RADS) ....................46 1.6 Rational ..................................................................................................52 1.7 Hypothesis ..............................................................................................52 1.8 Specific Aim ..........................................................................................52
Chapter 2 ..............................................................................................................53
2 Material and Methods ...................................................................................53 2.1 Materials ................................................................................................53 2.2 Methods .................................................................................................56 2.2.1 Fiducials Processing ..................................................................56 2.2.2 Ex-Vivo MRI imaging ...............................................................62
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2.2.3 2.2.4

Specimens slicing, Histopathology Processing and Digital Contouring .................................................................................62 Registrations ..............................................................................67

Chapter 3 ..............................................................................................................68

3 Results ...........................................................................................................68 3.1 Analysis of MRI contoured areas ..........................................................68 3.2 Analysis of histology areas corresponding to MRI ................................74 3.3 Analysis of PI-RADS score corresponding to Histopathology Digital Images ........................................................................................77

Chapter 4 ..............................................................................................................84

4 Discussion and Conclusion ...........................................................................84

Chapter 5 ..............................................................................................................92

5 Reference .......................................................................................................92

Curriculum Vitae .............................................................................................. 106

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List of Tables
Page Table 1.1: Proposed prostate-specific antigen age-specific reference range ......34 Table 1.2: PI-RADS scoring system classification criteria for T2W image assessment for the peripheral zone .......................................................................49 Table 1.3: PI-RADS scoring system classification criteria for T2W image assessment for the Transition zone .......................................................................49 Table 1.4: PI-RADS scoring system classification criteria for Diffusion Weighted Imaging (DWI) image assessment ........................................................................50 Table 1.5: Interpretation of PI-RADS score assessment .....................................51 Table 2.1: The color coding scheme used for contouring cancer and noncancerous lesions on digital histopathology images ............................................64 Table 3.1: Summary of the total non-cancerous lesions on digital histology image areas corresponding to the contoured MRI areas delineated by four Radiology observers ...............................................................................................................76 Table 3.2: The total non-cancerous areas on digital histopathology and their contour frequency by radiology observers on corresponding mpMRI images ....83
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List of Figures
Page Figure 1.1: World map presenting the distribution of prostate cancer incidence worldwide per 100,000 ......................................................................................... 3 Figure 1.2: International incidence and mortality of prostate cancer worldwide per 100,000 .......................................................................................................... 3 Figure 1.3: The urethral structures at the level of verumontanum ...................... 8 Figure 1.4: Peripheral zone .................................................................................12 Figure1.5: Central Zone ......................................................................................12 Figure 1.6: Simple atrophy .................................................................................20 Figure 1.7: Post-Atrophic Hyperplasia ...............................................................20 Figure 1.8: Simple atrophy with cystic formation ..............................................21 Figure 1.9: Partial atrophy ..................................................................................21 Figure 1.10: Histopathology digital images for a whole-mount prostate section with PIN features .................................................................................................25 Figure 1.11: Whole-mount prostate formalin block with BPH features and their digital (H&E) histopathology image.....................................................................29 Figure 1.12: Glandular elements of BPH ............................................................31 Figure 1.13: Stromal elements of BPH ...............................................................31 Figure 1.14: In-vivo prostate multiparametric MRI and its corresponded digital histopathology images ..........................................................................................44 Figure 1.15: Twenty-seven region of interest standardized PI-RADS scheme ...51 Figure 2.1: Overview of the steps in our method used in prostate specimen processing .............................................................................................................55
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Figure 2.2: Prostate gland with three 18G cannulas with inserted threads after removing the style ................................................................................................58
Figure 2.3: Prostate gland after threads soaking in Magnevist & dye ................58
Figure 2.4: The external fiducials obtained from a pig kidney by using breast biopsy needle .......................................................................................................59
Figure 2.5: The anterior and posterior surface of prostate gland post-fiducials application ............................................................................................................59
Figure 2.6: Internal and external fiducials marking in formalin block and digital histopathology image ...........................................................................................60
Figure 2.7: High power digital histopathology images showing 3 visible inked internal fiducials marking ....................................................................................61
Figure 2.8: Histopathology digital images for a whole-mount prostate section showing several contours with there color-coded scheme ...................................65
Figure 3.1: True Positive mpMRI contours correlated with adenocarcinoma Gleason grade 3 on digital histopathology image.................................................68
Figure 3.2: False positive mpMRI contour correlated to an area with atrophic glands ...................................................................................................................69
Figure 3.3: False positive mpMRI contour correlated to area with Benign Prostatic Hyperplasia (BPH) ................................................................................69
Figure 3.4: False positive mpMRI contour correlated to area with Prostatic Intraepithelial Neoplasia (PIN) ............................................................................70
Figure 3.5: Histogram demonstrates the total PI-RADS scores assessment performed by the 4 radiology observers and their corresponding histopathology findings .................................................................................................................72
Figure 3.6: Histogram of the frequency of the PI-RADS score of contoured areas on mpMRI by each observer separated by the histologically identified noncancerous lesion on HDI ......................................................................................73
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Figure 3.7: Histogram of the frequency of the PI-RADS score of the individual non-cancerous lesions ..........................................................................................76 Figure 3.8: Histogram characterizing the total frequency of each PI-RADS score assessment provided by four observers and their corresponding non-cancerous lesions on HDI .....................................................................................................78 Figure 3.9: Histograms of the frequency of total assessment of PI-RADS score 3 for each of the four observers ...............................................................................79 Figure 3.10: Histograms of the frequency of total assessment of PI-RADS score 4 for each of the four observers ..............................................................................80 Figure 3.11: Histograms of the frequency of total assessment of PI-RADS score 5 for each of the four observers ..............................................................................81
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