Table 1 Studies evaluating the reactive stroma as a biomarker in prostate cancer.

From: “Stromal cells in prostate cancer pathobiology: friends or foes?”

Author (year)

Main findings

Ayala et al., (2003; ref. 29.)

⁃ Development of the reactive stroma grading (RSG) system:

▫ RSG 0: tumours with 0–5% stroma

▫ RSG 1: tumours with 5–15% stroma

▫ RSG 2: tumours with 15–50% stroma

▫ RSG 3: tumours with >50% stroma

⁃ Evaluation of TMA cores by Masson’s trichrome stain from 545 patients

⁃ Volume of reactive stroma was a significant predictor of biochemical disease-free survival

⁃ Worst survival in patients with RSG 0 or RSG 3

Yanagisawa et al., (2007; ref. 68.)

⁃ RSG evaluated using H&E–stained sections of prostate biopsies from 224 patients

⁃ Patients with RSG 1 and 2 had better survival than those with RSG 0 and 3

⁃ RSG was an independent predictor of recurrence

⁃ RSG is independent of Gleason 7 (either 4 + 3 or 3 + 4)

Ayala et al., (2011; ref. 65.)

⁃ Evaluation of the predictive value of the %RGS 3 in the entire tumour

⁃ 872 whole-mount, H&E–stained prostatectomy specimens

⁃ %RSG 3 was an independent predictor of biochemical recurrence

⁃ Higher %RSG 3 patients had a significantly decreased biochemical recurrence-free survival than those with lower %RSG 3

Billis et al., (2013; ref. 66.)

⁃ 266 H&E–stained needle prostatic biopsies

⁃ Increasing RSG was associated with higher clinical stage, preoperative PSA, Gleason score, and with more extensive tumours in radical prostatectomies

⁃ Only RSG 3 was associated with biochemical recurrence, but only on univariate analysis

Wu et al., (2014; ref. 67.)

⁃ 148 biopsies from patients with advanced PCa (cT3-cT4) before castration therapy, evaluated by Masson’s trichrome

⁃ RSG was inversely correlated with Gleason scores

⁃ Significant association between RSG and development of castration-resistant PCa in patients with initial Gleason score of 6–7

Saeter et al., (2015; ref. 64.)

⁃ Population-based study using H&E biopsies from 318 patients

⁃ RSG was associated with PCa-specific mortality in multivariate Cox regression analysis

McKenney et al., (2016; ref. 70.)

⁃ TMA cores from 1275 radical prostatectomies (Canary Retrospective Cohort) evaluated by H&E

⁃ Among the multiple architectural features assessed, cores were evaluated for presence/absence of RSG 3

⁃ RSG 3 was associated with decreased post-surgery recurrence-free survival

⁃ RSG 3 was associated with worse survival when Gleason score 3 + 4 = 7 carcinomas alone were considered

Saeter et al., (2016; ref. 62.)

⁃ Population-based study using H&E biopsies from 318 patients

⁃ Perineural invasion (PNI) was associated with high RSG

⁃ The prognostic effect of PNI is dependent on an association with reactive stroma

Saeter et al., (2016; ref. 63.)

⁃ Population-based study using H&E biopsies from 283 patients

⁃ Patients with concomitant lymphovascular invasion (LVI) and high RSG were at high risk for PCa-specific death.

Ruder et al., (2022; ref. 69.)

⁃ Refinement of the original 4-tiers RSG to a binary system (qRS):

▫ qRS negative: tumours with <34% reactive stroma

▫ qRS positive: tumours with >34% reactive stroma

⁃ Algorithm-based quantification of reactive stroma

⁃ TMA cores from biopies and radical prostatectomies from different cohorts evaluated by H&E; > 1000 patients in total

⁃ qRS >34% was associated with worse outcomes (biochemical recurrence or PCa-specific death), after correcting for Gleason score and PSA

  1. H&E hematoxylin-eosin staining, PCa prostate cancer, PSA prostate-specific antigen, TMA tissue microarray.