Histopathologic Features and Transcriptomic Signatures Do Not Solve the Issue of Magnetic Resonance Imaging-Invisible Prostate Cancers: A Matched-Pair Analysis

Abstract

Background: Multiparametric magnetic resonance imaging (mpMRI) is pivotal in prostate cancer (PCa) diagnosis, but some clinically significant (cs) PCa remain undetected. This study aims to understand the pathological and molecular basis for csPCa visibility at mpMRI.

Methods: We performed a retrospective matched-pair cohort study, including patients undergoing radical prostatectomy (RP) for csPCa (i.e., ISUP grade group ≥ 2) from 2015 to 2020, in our tertiary-referral center. We screened for inclusion in the "mpMRI-invisible" cohort all consecutive men (N = 45) having a negative preoperative mpMRI. The "mpMRI-visible" cohort was matched based on age, PSA, prostate volume, ISUP grade group. Included patients underwent radiological and pathological open-label revisions and characterization of the tumor mRNA expression profile (analyzing 780 gene transcripts, signaling pathways, and cell-type profiling). We compared the clinical-pathological variables and the gene expression profile between matched pairs. The analysis was stratified according to histological characteristics and lesion diameter.

Results: We included 34 patients (17 per cohort); mean age at RP and PSA were 70.5 years (standard deviation [SD] = 7.7), 7.1 ng/mL (SD = 3.3), respectively; 65% of men were ISUP 2. Overall, no significant differences in histopathological features, tumor diameter and location, mRNA profile, pathways, and cell-type scores emerged between cohorts. In the stratified analysis, an upregulation of cell adhesion and motility, of extracellular matrix remodeling and of metastatic process pathways was present in specific subgroups of mpMRI-invisible cancers.

Conclusions: No PCa pathological or gene-expression hallmarks explaining mp-MRI invisibility were identified. Aggressive features can be present both in mpMRI-invisible and -visible tumors.

Keywords: MRI invisible; diagnostic imaging; expression profiling; genomic; nanostring; prostate cancer (clinically significant).

Figure 1

Two illustrative cases of MRI‐invisible clinically significant prostate cancers (csPCa). (1) A 64‐year‐old patient presenting with a positive digital rectal examination and a PSA value of 2.47 ng/mL, being diagnosed with a Gleason score 3 + 4 lesion in the posterolateral left peripheral zone; (2) a 72‐year‐old patient with a negative rectal examination and a PSA value of 7.6 ng/mL, diagnosed with a Gleason score 3 + 4 lesion in the posterolateral right peripheral zone. (A–D) display the MRI: (A) shows the high‐b‐value (1000 s/mm²) DW image, (B) the ADC map, (C) the Axial T2‐weighted MR image, and (D) the DCE image. Overall the MRI findings were negative for both patients. Additionally, (E) exhibits the corresponding histopathology map of csPCa (inked in black or blue). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Comparison between mpMRI‐invisible (case) and mpMRI‐visible (control) csPCa. (A) Volcano plot showing the gene expression profile with control as baseline; (B) Boxplot of different pathways involved in cancer progression. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Comparison between mpMRI‐invisible (case) and mpMRI‐visible (control) csPCa stratified for primary pattern 3. (A) Volcano plot showing the gene expression profile with control as baseline; (B) Boxplot of statistically significant pathways involved in immune response and cancer progression; (C) Boxplot of statistically significant immune cells all more present in mpMRI‐visible csPCa. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Comparison between mpMRI‐invisible (case) and mpMRI‐visible (control) csPCa stratified for glomeruloid/cribriform growth pattern (A), for the absence of foamy cells (B) and (C) for tumor diameter < 12 mm. (A1, B1, C1) Volcano plots showing the gene expression profile with control as baseline according to the stratification; (A2, B2, B3, C2) Boxplots of statistically significant pathway involved in cancer progression according to the stratification. [Color figure can be viewed at wileyonlinelibrary.com]