Microscale characterisation of prostate cancer tissue using ultrasound shear wave elastography and optical techniques to study peritumoural extracellular matrix in clinically localised prostate cancer

Abstract

Abstract For decades, the stiffness difference detected using digital rectal examination (DRE) has been a useful technique for suspecting Prostate cancer (PCa). However, the ability of DRE alone for detecting PCa remains poor. Cancerous tissues tend to be stiffer than the adjacent normal tissues, and the biophysical and biochemical properties of the tumour microenvironment (TME) are different from those of normal tissues. The alteration of matrix stiffness is an immediate effect of contractility-driven Extracellular matrix (ECM) re-modelling, and tissue elasticity is a result of increased cell density and collagen formation, hence changes in elasticity can indicate an abnormal pathological mechanism. The ability to detect tissue elasticity accurately and early can lead to a more reliable diagnosis and prognosis of diseases. Ultrasound shear wave elastography (USWE) is a promising imaging technique that measures tissue modulus and is increasingly applied for cancer detection. In this thesis, the first and second studies were to assess the application of both multiparametric magnetic resonance imaging (mpMRI) and USWE in precisely determining the size of PCa lesions, and the correlation of quantitative tissue stiffness measurements obtained by USWE with Prostate Imaging-Reporting and Data System (PI-RADS) scoring of mpMRI using Gleason scores (GS) of radical prostatectomies as a reference standard. 3D-printed patient-specific moulds were used to guide histopathology radical prostatectomy. The first study population included 202 men with clinically localized PCa opting for radical surgery. A significant number of men had underestimation of PCa using mpMRI (82.1%; 87/106) or USWE (64.6%; 62/96). On average tumour size was underestimated by a median size of 7mm in mpMRI, and 1mm in USWE. There were 327 cancerous lesions (153 for mpMRI and 174 for USWE). mpMRI and USWE underestimated the majority of cancerous lesions (108/153; 70.6%) and (88/174; 50.6 %) respectively. Validation cohort data confirmed these findings mpMRI had a nearly 20% higher underestimation rate than USWE (χ2 (1, N= 327) = 13.580, p= 0.001); especially in the mid and apical level of the gland. Clinically non-significant cancers were underestimated in significantly higher numbers in comparison to clinically significant cancers. Size measurement of prostate cancers on preoperative imaging utilising maximum linear extent technique, underestimated the extent of cancer. PCa size measurements irrespective of location within the gland or clinical significance are significantly underestimated by both imaging modalities in men undergoing radical prostatectomy. The second study included 196 men with localised PCa who were prospectively recruited into the study and had quantitative prostate tissue stiffness measurements in kilopascals (kPa) using transrectal USWE prior to radical prostatectomy. PI-RADS scores of mpMRI were also obtained in all the men. Imaging and histopathology of radical prostatectomy specimens were oriented to each other using patient-specific customised 3D moulds to guide histopathology grossing of radical prostatectomy specimens. All included patients had confirmed PCa on Transrectal ultrasound-guided prostate biopsy (TRUS-PBX), had both USWE and mpMRI imaging data and underwent radical prostatectomy. Chi-square test with a 95% confidence interval was used to assess the difference between GS of radical prostatectomy and PI-RADS classification, as well as GS of radical prostatectomy and stiffness in kPa using USWE. The correlation coefficient (r) was calculated in order to investigate the relation between PI-RADS classification and tissue stiffness in kPa. There was a statistically significant correlation between USWE-measured tissue stiffness and GS (χ2 (2, N = 196) = 23.577, p < 0.001). Also, there was a statistically significant correlation be