Introduction

Prostate cancer (PCa) is the leading malignancy and second most common cause of death for American man.¹ The standard ultrasound-guided needle biopsy misses 20-30% of clinically significant tumors. Multiparametric MRI (mpMRI) has been subsequently employed in clinical settings to aid PCa diagnosis, to guide biopsy and follow-up with patient. Yet mpMRI-aided PCa diagnoses resulted a significant false positive rate. The misdiagnoses are likely caused by confounding prostatitis or stromal BPH, both exhibiting similar signatures as those in malignancies in DWI. We demonstrate herein inflammatory (~ 5 µm) and cancer cells (≥ 20 µm) in prostate can be detected, distinguished, and quantified via their distinct restricted-isotropic diffusion signatures using the novel Diffusion MRI Histology (D-Histo, a significantly improved version of previously known diffusion basis spectrum imaging²) technique.

Methods and Materials

Patient recruitment: 179 patients with clinical suspicion of prostate cancer and without any preoperative treatment were recruited and scheduled for mpMRI and D-Histo scan in Changhai Hospital, Shanghai, China. Additionally, 6 patients scheduled for prostatectomy were recruited for ex vivo specimen imaging study at Washington University School of Medicine, St. Louis, USA. In vivo MRI: diffusion-weighted MRI data were obtained on a 3T Siemens Skyra scanner with an 18-channel phased-array body receive coil. Single-shot echo-planar diffusion-weighted imaging was performed in transverse view (2×2×4 mm3) using a 25-direction encoding scheme (maximum b-value of 1500 s/mm2) in 8 minutes. Ex vivo MRI: Prostate specimens were examined using a 4.7T Varian MR scanner and a home-made surface coil. A spin-echo diffusion-weighted sequence with 25 diffusion-encoding directions with maximum b-values of 3000 s/mm2 was employed to acquire DWI (in-plane resolution 0.25x0.25x0.5 mm3) in 80 minutes. Histology: Prostate specimen was embedded in paraffin and sectioned in 4-µm-thick slices for H&E staining after prostatectomy. Image analysis: An in-house software analyzed both D-Histo and DTI data. H&E slices were reviewed and graded by an experienced pathologist. Statistical analysis: Student t-test and receiver operating characteristic analysis on the ability of DTI and D-Histo to differentiate benign tissue from PCa was performed.

Results

D-Histo isotropic-diffusion spectrum (ex vivo) successfully detected and distinguished between various pathologies in a specimen (Fig. 1A) from a 66-year-old patient. The hallmarks of inflammation, PCa and stromal tissues corresponded to highly-restricted diffusion (Fig. 1B, 0 – 0.1 mm2/ms), restricted diffusion (Fig. 1B, 0.1 – 0.5 mm2/ms) and hindered diffusion (Fig. 1B, 0.5 – 1 mm2/ms), respectively. Magnified H&E of inflammatory cells, PCa cells and stroma (Fig. 1a, b, c) confirmed the findings. D-Histo also identified inflammatory cells, PCa cells and stroma (Fig. 2B) in PCa region from another 70-year-old patient (Fig. 2A). Magnified H&E of corresponding regions (Fig. 2a, b, c) supported the findings in isotropic-diffusion spectrum. The hypo-intensity regions in T2WI (Fig. 3A) and ADC maps (Fig. 3B) from a 65-year-old patient indicated a prostate with transition zone PCa. D-Histo highly-restricted-fraction map and restricted-fraction map (Fig. 3C, D) revealed the distribution of inflammatory and PCa cells in the corresponding areas; this distinction is absent in ADC map. H&E staining of the prostatectomy specimen revealed areas of inflammatory and PCa cells consistent with those indicated by D-Histo (Fig. 3a, b, c). A 3D-rendered prostate from D-Histo was overlaid on an anatomical T2WI obtained from a 58-year old PCa patient in stage T3A (Fig 4A). PCa suspicion was located in the peripheral zone (pink). Transition zone BPH (gold) and peripheral zone inflammation (blue-green) were also delineated. H&E staining of corresponding whole-mount-section slide showed chronic prostatitis (Fig. 4B, CH), PCa (Fig. 4D), and stromal BPH (Fig. 4E), which were consistent with D-Histo results. Representative mpMRI including T2WI and ADC map (Fig. 4G, H) detected PCa without seeing inflammation. Gd-enhanced T1WI failed to detect PCa (Fig. 4I). We identified 222 PCa regions from 56 biopsy-confirmed PCa patients and 59 benign peripheral zone tissues from 59 biopsy-negative patients through mpMRI. Highly-restricted fraction and restricted-fraction values of PCa regions (highly-restricted: 0.06±0.02, and restricted: 0.27±0.07) were significantly higher (p < 0.001) than those of benign regions (highly-restricted: 0.02±0.02, and restricted: 0.01±0.02). ROC analysis (Fig. 5C, D) revealed high sensitivity and specificity for highly-restricted (AUC: 0.942) and restricted fractions (AUC: 1), differentiating inflammatory cells or PCa cells from benign tissue.

Discussion and Conclusion

Coexisting PCa and prostatitis were noninvasively quantified and differentiated with D-Histo technique and verified by histology in both ex vivo and in vivo conditions for the first time. Accurate localization and quantification of prostate pathologies and structures by D-Histo resolves the unmet needs in PCa imaging. D-Histo shows potential to a more accurate monitoring and evaluation of immunotherapy for PCa.

Acknowledgements

No acknowledgement found.