Histologic Grading of Prostatic Adenocarcinoma Can Be Further Optimized

Abstract

Histologic grading remains the gold standard for prognosis in prostate cancer, and assessment of Gleason score plays a critical role in active surveillance management. We sought to optimize the prognostic stratification of grading and developed a method of recording and studying individual architectural patterns by light microscopic evaluation that is independent of standard Gleason grade. Some of the evaluated patterns are not assessed by current Gleason grading (eg, reactive stromal response). Individual histologic patterns were correlated with recurrence-free survival in a retrospective postradical prostatectomy cohort of 1275 patients represented by the highest-grade foci of carcinoma in tissue microarrays. In univariable analysis, fibromucinous rupture with varied epithelial complexity had a significantly lower relative risk of recurrence-free survival in cases graded as 3+4=7. Cases having focal "poorly formed glands," which could be designated as pattern 3+4=7, had lower risk than cribriform patterns with either small cribriform glands or expansile cribriform growth. In separate multivariable Cox proportional hazard analyses of both Gleason score 3+3=6 and 3+4=7 carcinomas, reactive stromal patterns were associated with worse recurrence-free survival. Decision tree models demonstrate potential regrouping of architectural patterns into categories with similar risk. In summary, we argue that Gleason score assignment by current consensus guidelines are not entirely optimized for clinical use, including active surveillance. Our data suggest that focal poorly formed gland and cribriform patterns, currently classified as Gleason pattern 4, should be in separate prognostic groups, as the latter is associated with worse outcome. Patterns with extravasated mucin are likely overgraded in a subset of cases with more complex epithelial bridges, whereas stromogenic cancers have a worse outcome than conveyed by Gleason grade alone. These findings serve as a foundation to facilitate optimization of histologic grading and strongly support incorporating reactive stroma into routine assessment.

<p>Shh Overexpression Is Correlated with GRP78 and AR Expression in Primary Prostate Cancer: Clinicopathological Features and Outcomes in a Chinese Cohort</p>

“…There was no significant difference in the expression of AR in normal or tumor samples (p>0.05); however, higher AR expression was associated with a shorter survival time, compared to low expression of AR (p>0.05). Across cancer subgroups (Gleason scores=6, 7,8,9,10), in the high AR expression group, the group with Gleason score=10 had the shortest survival. The low/medium AR expression group had similar results, those with Gleason score=10 had the shortest survival, when compared with other groups (p<0.05) (Figure 4).…”

“…Further, due to the limitations of biopsy sampling, biopsy grading may be inconsistent with the prostatectomy specimen. 8,9 Therefore, prostate cancer patients with apparently identical morphologies may have different survival rates, partly due to variable subjective observations. However, generally, patients with higher Gleason scores usually have worse prognoses than those with low scores.…”

Interaction of prostate carcinoma-associated fibroblasts with human epithelial cell lines in vivo

“…Quantitation of prostate tumor stromal changes have demonstrated that this is a useful measure of clinical outcomes, providing additional prognostic information over Gleason grade (McKenney et al, 2016). Seminal work on prostate cancer stromal grading showed that the two groups of tumors that are most aggressive are, 1) those with almost no stromal involvement, these seem to be independent of their microenvironment from early in their pathogenesis; and, 2) tumors that exhibit an abundant stromogenic response, where the stroma appears to be a major contributor to tumor growth and invasion (Ayala et al, 2003).…”

“…Seminal work on prostate cancer stromal grading showed that the two groups of tumors that are most aggressive are, 1) those with almost no stromal involvement, these seem to be independent of their microenvironment from early in their pathogenesis; and, 2) tumors that exhibit an abundant stromogenic response, where the stroma appears to be a major contributor to tumor growth and invasion (Ayala et al, 2003). Reactive stroma grading (RSG) is an independent predictive factor for PCa biochemical recurrence and PCa specific death (Ayala et al, 2011, McKenney et al, 2016, Saeter et al, 2015, 2016, Yanagisawa et al, 2007). …”

“…Reactive stromal grading (RSG) is an independent system based upon stromal phenotypes to divide tumors into one of four reactive stromal grades (0–3) (Yanagisawa et al, 2007, 2008). RSG provides a predictive factor for biochemical recurrence and disease-specific death in prostate cancer patients (Saeter et al, 2015, 2016) and can add significant predictive value to Gleason grading (McKenney et al, 2016). In contrast to clonal somatic gene studies, many differences have been found in gene expression between CAF and normal fibroblasts.…”