Cribriform morphology area ratio and biochemical recurrence in Gleason score 4 + 4 prostate cancer patients following robot-assisted radical prostatectomy

doi:10.21203/rs.3.rs-2568525/v1

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Cribriform morphology area ratio and biochemical recurrence in Gleason score 4 + 4 prostate cancer patients following robot-assisted radical prostatectomy

https://doi.org/10.21203/rs.3.rs-2568525/v1

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Background Cribriform glands, regardless of their morphology and size, are categorized with Gleason pattern (GP) 4. However, recent studies indicate that the size and percentage of cribriform patterns in GP 4 are associated with risk of biochemical recurrence (BCR). Thus, we aimed to examine the prognostic value of the area and percentage of cribriform patterns in patients with Gleason score (GS) 4 + 4 prostate cancer who underwent robot-assisted radical prostatectomy (RARP).

Methods We investigated 108 patients with GS 4 + 4 prostate cancer who underwent RARP. After digitally scanning the slides, we measured the area of the entire cancer and cribriform patterns. Predictive factors for BCR were explored using the log-rank test and Cox proportional hazard model analyses.

Results Sixty-seven (62.0%) patients had a cribriform architecture in RARP specimens, and thirty-two (29.6%) experienced BCR. Median total cancer area (mm2), cribriform pattern area (mm2), and percentage of cribriform pattern area (% cribriform) were 427.70 (interquartile range [IQR], 171.65–688.53), 8.85 (IQR, 0–98.83), and 2.44 % (IQR, 0–33.70), respectively. In the univariate analyses, higher preoperative serum prostate-specific antigen levels, positive resection margin (RM), advanced pathological T stage, extraprostatic extension, larger total cancer area, larger cribriform morphology area, and higher % cribriform were significantly associated with BCR. Multivariate analysis demonstrated that PSA and % cribriform were independent predictors of BCR.

Conclusions Higher % cribriform was associated with BCR in GS 4 + 4 prostate cancer following RARP.

Cribriform morphology area ratio

Gleason pattern 4

robot-assisted radical prostatectomy

biochemical recurrence

The Gleason grading is currently the most widely used system for grading prostate cancer and is the most important prognostic factor for prostate cancer. The definitions of Gleason patterns (GPs) have been modified over time^1-3. For example, the 2014 International Society of Urological Pathology (ISUP) consensus conference noted that all cribriform glands, regardless of morphology and size, are assigned with Gleason pattern (GP) 4. Further, GP 4 has four main architectural types i.e., cribriform, glomeruloid, poorly formed, and fused³. The cribriform pattern is defined as “a confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification, ×10). There should be no intervening stroma or mucin separating individual or fused glandular structures⁴.”

The presence of a cribriform pattern in radical prostatectomy (RP) specimens has been reported to be independently associated with biochemical recurrence (BCR)^5-7, distant metastasis⁶, and disease-specific death⁸. Furthermore, recent studies have demonstrated that the size and percentage of cribriform patterns in GP 4 are associated with the risk of BCR^9-11. However, these studies focused on Gleason score (GS) 3 + 4 or GS 4 + 3 prostate cancer^{5, 8-10}. To the best of our knowledge, no previous report has investigated the area and percentage of cribriform patterns in GS 4 + 4 prostate cancer. Thus, this study aimed to investigate the association between the area and percentage of the cribriform pattern and BCR after RARP in patients with GS 4 + 4 prostate cancer who underwent robot-assisted RP (RARP).

2.1 Patients and Data Collection

This retrospective study was conducted at Tokyo Medical University in Tokyo, Japan and was approved by the Ethics Committee of Tokyo Medical University (No. T2020-0429). A total of 1,870 consecutive patients who underwent RARP at Tokyo Medical University between June 2006 and December 2018 were reviewed, and 121 patients with GS 4 + 4 were identified. Patients (n=13) who received neoadjuvant therapy or adjuvant therapy before BCR, had unavailable histologic slides, or were not followed up postoperatively, were excluded from the study. Finally, we analyzed 108 patients who underwent RARP and were pathologically diagnosed with GS 4 + 4 prostate cancer.

2.2 Pathological Evaluation and Measurement of the Cancer Area

RP specimens were sampled according to standardized clinical and pathological protocols¹². Tissue-marking dye was applied to determine the extraprostatic extension and resection margin (RM) of prostate cancer. After formalin fixation, we made a horizontal section perpendicular to the posterior surface of the urethral mucosa, with a thickness of approximately 5 mm by a step section. The bladder neck and prostate apex sides were examined by the sagittal section, with the most distal ends equally spaced. The samples were then stained with hematoxylin and eosin.

All prostate specimens after RARP were diagnosed by two pathologists (R.I. and T.N.). All slides were digitally scanned (virtual slides) using a Nano Zoomer (Hamamatsu Photonics K.K., Japan). Figure 1 shows five sample slides with manually annotated cribriform and cancer areas. Figure 1A represents the entire slide (H&E, ×4) and Figure 1B demonstrates a magnified picture of the cribriform pattern of corresponding slides in Figure 1A (H&E, ×100). Each area was digitally calculated. The cribriform pattern had two forms, i.e., either one interconnecting large cribriform area or many non-interconnecting small cribriform fields. However, we did not distinguish between these two forms. Further, if many non-interconnecting small cribriform patterns were observed, we encircled all the small cribriform patterns and summed the marked areas as cribriform areas. We examined all the slides to measure total cancer and cribriform pattern areas. The percentage of cribriform pattern areas (% cribriform) was calculated as follows:

% cribriform = cribriform morphology area/ total cancer area

2.3 Follow-Up

Prostate-specific antigen (PSA) follow-up was performed every 1 to 3 months following RARP, while BCR was defined as a rise in PSA levels ≥0.2 ng/ mL, twice consecutively. If the PSA level after RARP was ≥0.2 ng/mL, the recurrence day was defined as the day of surgery.

2.4 Statistical Analysis

The endpoint of the study was BCR. The correlations between continuous variables were analyzed using Spearman’s rank correlation coefficient. Variables of the different groups were compared using the Mann–Whitney U test and categorical parameters were analyzed using the chi-squared test. BCR-free curves were constructed using the Kaplan–Meier method, and the statistical significance of differences was evaluated using the log-rank test. Univariate and multivariate analyses were performed using the Cox regression model.

For all analyses, statistical significance was set at P <0.05. Statistical analyses were performed using SPSS version 27 (IBM Corp., Armonk, New York, USA).

Patient characteristics and pathological outcomes are shown in Table 1. The cribriform pattern was identified in 67 patients (62.0%), and 32 (29.6%) patients had experienced BCR, with a mean follow-up of 36.5 months. The presence of a cribriform pattern was significantly associated with BCR. The 3 -year BCR-free rate in patients with cribriform GP 4 was significantly lower than that in patients without cribriform GP 4 (56.3% vs 80.3%; p=0.014; Figure 2).

The median total cancer area (mm²) and cribriform pattern area (mm²) were 427.70 (interquartile range [IQR], 171.65–688.53) and 8.85(IQR, 0–98.83), respectively, and the median % cribriform was 2.44% (IQR, 0–33.70) (Table 2). The associations among the total cancer area, cribriform pattern area, % cribriform, and clinicopathological parameters are shown in Table 3. Preoperative PSA level, pathological T stage, RM, lymphatic invasion, perineural invasion, extraprostatic extension, seminal vesicle invasion, and the existence of tertiary 5 were associated with the total cancer area. Pathological T stage was associated with cribriform morphology area, but other factors were not. There was no association between % cribriform and clinicopathological parameters.

Association between BCR, Total Cancer Area, Cribriform Pattern Area, % Cribriform, and Clinicopathological Parameters.

The results of the Cox regression analysis are shown in Table 4. In the univariate analyses, higher preoperative serum PSA levels, positive RM, advanced pathological T stage, extraprostatic extension, larger total cancer area, larger cribriform morphology area, and higher % cribriform were significantly associated with BCR. Multivariate analysis demonstrated that PSA (hazard ratio [HR], 1.061; 95% confidence interval [CI], 1.011–1.113; p=0.017) and % cribriform (HR, 1.018; 95% CI, 1.001–1.036; p=0.041) were independent predictors of BCR.

As reported previously¹³, % cribriform was categorized by setting up effectual cutoff values. The best discriminating cutoff point, or the value that had the most significant P-value on a log-rank test, was determined by testing all possible cutoff points within the central 80% of the distribution of values. All cutoff points were rounded to clinically relevant or convenient values, and % cribriform values were categorized into three groups (0 vs. >0 to 50 vs. >50). The 3-year BCR-free rates were 80.3% in group 0, 62.7% in group >0 to 50, and 39.1% in group > 50, and there was a statistically significant difference between the groups (p=0.003, Figure 3).

In this study, we digitally measured the area of total cancer and cribriform patterns. The total cancer area, cribriform pattern area, and % cribriform were significantly associated with BCR after RARP. Finally, we demonstrated that preoperative PSA and % cribriform were independent predictors of BCR in patients with GS 4 + 4 at RARP.

To date, many studies have demonstrated the presence of cribriform patterns in RP specimens to be associated with poorer prognosis^{5-11, 14-16}.

Among these studies, three evaluated the prognostic value of the size and percentage of the cribriform pattern^9-11. First, Iczkowski et al. conducted a case-control study to evaluate the association between histologic patterns, including cribriform patterns and BCR. In their study, cribriform patterns were divided into two (small cribriform pattern: medium-sized acinar spaces with rounded contours, no solid foci, and ≤12 lumens; large cribriform pattern: expansive cribriform to focally solid large acini with >12 lumens). They demonstrated that the presence of both large and small cribriform patterns was significantly associated with BCR, and that BCR was associated with the cumulative area sum of cribriform cancer with an odds ratio of 1.173. Second, Chen et al. also studied the prognostic value of the size and percentage of cribriform patterns in GS 7 prostate cancer. They used the criteria of the cribriform size proposed by Iczkowski et al., and % cribriform GP 4 was analyzed as a dichotomous parameter (≤20% vs. >20%). They demonstrated that a large cribriform pattern and percentage of cribriform GP 4 were significantly associated with BCR on univariate analyses. However, neither a large cribriform pattern nor the percentage of cribriform GP 4 was an independent factor for BCR in their study. Lastly, Hollemanns et al. studied the association between recurrence and cribriform size in ISUP grade 2 prostate cancer patients. Herein, small and large cribriform patterns were distinguished based on the diameter being at least twice the size of the adjacent preexisting normal glands. A large cribriform pattern was associated with a higher percentage of GP 4 and extraprostatic extensions. Finally, they demonstrated that a large cribriform pattern was an independent predictor of BCR in patients with ISUP grade 2 prostate cancer. In the studies described above, larger cribriform patterns tended to be associated with BCR.

However, these three studies covered various GS such as GS 3 + 4, GS 4 + 3, and GS 4 + 4, and the criteria used for size differed among them. It has been reported that the cribriform pattern is more common in GS 4 + 3 than GS 3 + 4 cancers, and that the percentage of GP 4 is associated with BCR⁵. However, evaluation of the prognostic value of the area and percentage of cribriform GP 4 may be affected by the percentage of GP other than GP 4. Therefore, in this study, we investigated the prognostic value of the cribriform pattern and % cribriform in GS 4 + 4 in RARP specimens. Finally, we demonstrated that PSA and % cribriform were independent predictors of BCR in patients with GS 4 + 4 at RARP. Additionally, BCR was associated with cumulative % cribriform cancer, with a hazard ratio of 1.018.

There was a significant difference in the BCR-free rates among the three % cribriform groups (% cribriform = 0, >0 to 50, and >50).

Although this study provides important insights into the association between % cribriform with BCR in GS 4 + 4 patients who underwent RARP, it has several limitations. First, because this study was a retrospective analysis of data collected from a single institution, the number of included cases was relatively small. Second, we did not obtain disease-specific or overall survival data because of the relatively short follow-up period. Third, we did not evaluate the size of the cribriform pattern based on previous reports. Therefore, a future study evaluating the prognostic value of cribriform pattern size is necessary. Finally, other architectural types with GP 4, such as glomeruloid, poorly formed, and fused glands were not investigated in this study. Further, the cribriform pattern was the most prevalent among the GP 4 architectures. However, a combination of more than two architectures has also been recognized in GP 4⁵. In addition, although the presence of a cribriform pattern has been reported to be independently associated with an increased risk of BCR, the presence of a glomeruloid architecture has been reported to be associated with a reduced risk of BCR⁵. Further studies that evaluate the prognostic value of area and percentage of each GP 4 pattern in patients with GS 4 + 4 are needed.

Despite these limitations, our study is the first to demonstrate an association between the area and percentage of cribriform patterns and BCR. The 2014 ISUP consensus conference introduced a new grade group system in which GS 7 was divided into two grade groups (Group 2, GS 3 + 4; Group 3, GS 4 + 3)³, indicating that the proportion of GP 4 is important. Furthermore, a later ISUP consensus conference in 2019 recommended reporting the percentage of GP 4 for all GS 7 (Group 2 and Group 3) in biopsies, along with the presence of cribriform pattern¹⁷. We hope that our data will be useful for future studies of prostate cancer grading systems.

This study demonstrated that PSA and % cribriform were independent predictors of BCR in patients with GS 4 + 4 following RARP. It is important to monitor the patient’s postoperative course and consider adjuvant therapy such as radiotherapy or hormonal therapy. However, further studies are required to validate these findings.

Acknowledgements

The authors thank all the subjects included in this study. This study was supported by the Department of Urology and Anatomic Pathology, Tokyo Medical University.

Author's contributions

KS and YO performed the project design. All authors contributed to data collection and the review conception. KS finished the manuscript. All authors read and approved the final manuscript.

ETHICS STATEMENT

This study was approved by the Ethics Committee of the Tokyo Medical University (No. T2020-0429). As this was a retrospective study, we explained the details of this study to the patients in a public letter. Therefore, the need for informed consent was waived by the Ethics Committee of Tokyo Medical University.

Competing interests

The authors have no relevant financial interests to disclose.

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Tables 1-4 are available in the supplementary files section.

No competing interests reported.

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Cribriform morphology area ratio and biochemical recurrence in Gleason score 4 + 4 prostate cancer patients following robot-assisted radical prostatectomy

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