Analysis of separate training and validation radical prostatectomy cohorts identifies 0.25 mm diameter as an optimal definition for "large" cribriform prostatic adenocarcinoma

Abstract

Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p < 0.001). In addition, two different subset analyses of low-intermediate risk cases (cases with Gleason score ≤ 3 + 4 = 7; and cases with Gleason score = 3 + 4 = 7/4 + 3 = 7) likewise demonstrated patients with largest cribriform diameter >0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

Fig. 1. Sample histologic images of training cohort TMA spots containing cribriform glands and how cribriform size is measured.

A Yellow dashed lines indicate how cribriform gland size is measured using longest cross-sectional distance rather than longitudinal measurement (green dashed line), which can overestimate tangentially sectioned and branching glands. B Yellow dashed lines indicate diameter of the largest cribriform gland in each spot (with smaller cribriform gland diameters indicated in green dashed line).

Fig. 2. Kaplan–Meier curves for recurrence-free survival in full training cohort.

A Cribriform present vs absent. B–C Using various incremental cut-offs for cribriform size. D Cribriform size ≤0.25 mm vs >0.25 mm.

Fig. 3. Kaplan–Meier curves for recurrence-free survival in training cohort: subset analysis.

A–C GS ≤ 3 + 4 = 7 subset. D GS = 3 + 4 = 7/4 + 3 = 7 subset. GS = Gleason score.

Fig. 4. Kaplan-Meier curves for outcomes in validation cohort.

A Biochemical recurrence. B Metastasis-free survival. C Prostate cancer survival.