Undetected Cribriform and Intraductal Prostate Cancer at biopsy is associated with adverse outcomes

Undetected Cribriform and Intraductal Prostate Cancer at biopsy is associated with adverse outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Undetected Cribriform and Intraductal Prostate Cancer at biopsy is associated with adverse outcomes Rui Bernardino, Rui Bernardino, Rui Bernardino, Leyi Yin, Leyi Yin, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4265149/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Oct, 2024 Read the published version in Prostate Cancer and Prostatic Diseases → Version 1 posted 10 You are reading this latest preprint version Abstract Background Intraductal carcinoma (IDC) and cribriform pattern (Crib) of prostate cancer are increasingly recognised as independent prognosticators of poor outcome, both in prostate biopsies and radical prostatectomy (RP) specimens. Objective The aim of our project is to assess the impact of false negative biopsies for these two characteristics on oncological outcomes. Material and Methods Patients who underwent RP between January 2015 and December 2022 were included in the study. Predictors of Biochemical Failure were examined using a multivariate Cox proportional hazards model. Results and Limitation Among the 836 patients who underwent RP, 233 (27.9%) had Crib, and 125 (15.0%) had IDC on prostate biopsy, with 71 (8.5%) patients having both IDC and Crib. Concerning, IDC/Crib status at biopsy, 217 (26%) patients had a false-negative biopsy, 332 (39.7%) had a true-negative biopsy, 256 (30.6%) showed a true-positive biopsy, and 24 (3.7%) exhibited a false-positive biopsy, with respect to either pattern. When comparing false-negative, false-positive, true-negative and true-positive biopsies for IDC/Crib, we found that patients with a false-negative biopsy for IDC/Crib versus those with a true-negative biopsy for IDC/Crib disclosed a rate of advanced pathological stage (≥ pT3) which was twice that of patients with a true-negative biopsy for IDC/Crib: 56.8% versus 28.1%, respectively (p < 0.001). On multivariate Cox analysis, log PSA before RP (hazard ratio [HR] 2.07, 95% CI 1.53–2.82; p < 0.001), a higher percentage of positive cores at biopsy (≥ 33%) (HR 1.68, 95% CI 1.07–2.63; p = 0.024), and false negative biopsy for IDC/Crib (HR 2.14, 95% CI 1.41–3.25; p < 0.001), were each significantly associated with an increased risk of BCR. Conclusions A false-negative biopsy for IDC/Crib is independently associated with higher risk of BCR and advanced pathological stage compared to a true negative biopsy. Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer Biological sciences/Cancer/Cancer screening Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer Biological sciences/Cancer/Cancer screening Biological sciences/Cancer/Cancer screening Prostatic Neoplasms Prostate Biopsy False Negatives Impact on Final Pathology Figures Figure 1 Figure 2 Introduction The consensus conference of 2019 by the International Society of Urological Pathology (ISUP) ( 1 ) and the white paper from the Genitourinary Pathology Society ( 2 ) have established the mandatory inclusion of reporting cribriform growth (Crib) pattern and intraductal prostate cancer (IDC) in routine pathology assessments. These growths are identified as biologically aggressive manifestations of prostate cancer (PCa), including increased genomic instability and hypoxia ( 3 ). The detection of these patterns in prostatectomy specimens has been consistently linked to increased risks of biochemical recurrence (BCR), metastasis and disease-specific mortality ( 4 – 6 ). Furthermore, recent work from our group has also revealed that the presence of IDC on biopsy predicts lymphatic metastasis in PSMA PET/CT scans before treatment ( 7 ). Additionally, among patients with BCR and metastatic disease detected via PSMA PET/CT, the presence of Crib is strongly associated with a lymphatic pattern of metastasis ( 8 ). It is evident that IDC and Crib represent adverse features both on radical prostatectomy (RP) specimens and prostate biopsy samples. However, there has been a lack of studies investigating the oncological outcomes associated with biopsies false-negative for these patterns, and how patients with false-negative biopsies compare to those with true-positive or true-negative biopsies. Indeed, only two studies have previously addressed the issue, with both hampered by relatively small sample sizes and/or lack of clinical outcome data ( 9 , 10 ). There is also consensus that active surveillance is inappropriate for men with IDC or Crib found on biopsy ( 11 ). On the other hand, there is a growing trend towards the use of active surveillance for grade group (GG) 2 PCa ( 12 , 13 ). A significant challenge associated with this clinical scenario is the notable occurrence of false negatives (exceeding 50% in most series) in identifying IDC/Crib as compared to examination of RP specimens ( 14 ). In this regard, it is clinically relevant to evaluate whether false negative biopsy diagnosis is equally associated with the same oncological outcomes when compared to a true negative biopsy for the presence of IDC/Crib. In this study, we aimed to determine the impact of false negative (“missed IDC/Crib at biopsy”) biopsies for IDC/Crib on oncological outcomes, including biochemical recurrence (BCR) and advanced stage (≥ T3) at RP specimen. Material and Methods Study Design, Setting, and Participants Patients who underwent RP at The Princess Margaret Cancer Centre between January 2015 and December 2022 were included in the study (Fig. 1 ). The presence and absence of IDC and Crib in biopsies and radical prostatectomy specimens was adopted as a mandatory element in synoptic reporting at the Department of Pathology in 2015. All pathological slides were read by subspecialty pathologists, but not re-reviewed as part of this study. For men who underwent several biopsies before undergoing prostatectomy, the latest biopsy before the surgery was considered. We excluded patients whose biopsy reports did not specifically reference the presence or absence IDC and Crib at biopsy. Although minor differences in methodology may have existed, our institution's regular ultrasound-guided biopsies involve obtaining at least 12 cores from a standard sextant map, and for (multiparametric magnetic resonance imaging) MRI fusion biopsies, a minimum of 3 cores from each target is routinely acquired. All patients were offered a pre-biopsy MRI, in accordance with current guidelines ( 11 ). The decision to proceed with an MRI versus upfront biopsy was based on a shared decision-making process with the patient, depending on patient anxiety level, wait time, and whether the post-test result would alter performance of a biopsy. If the MRI showed a positive lesion (≥ PIRADS 3), patients were typically offered a combined systematic/targeted biopsy approach. Select patients with a prior negative systematic biopsy may have undergone an MRI targeted-only biopsy” A MAGNETOM® Verio 3T 4-channel, phased array surface coil is used in our institution to perform the MRI. The reporting used in the division is PI-RADS v2. The study received Institutional approval (REB: 22-5908). Informed consented for the specific purpose of this study was waived. Study Outcomes The aim of this study was to assess the impact of false negative biopsies for IDC/Crib on oncological outcomes, including BCR and advanced stage at RP. Advanced stage at pathology was defined as ≥ pT3. Firstly, we aimed to determine whether true negative versus false negative biopsies are independent predictors of BCR. Additionally, we compared the prevalence of unfavorable pathological features in men identified with IDC/Crib in their biopsy samples to those who did not display these features. Time to BCR was defined as the time between treatment and first recorded PSA > 0.2 ng/ml or salvage radiotherapy; patients whose PSA never exceeded those values were censored at date of last PSA assessment. Study Variables IDC was defined as a lumen spanning proliferation of carcinoma cells distending antecedent ducts or glands. Crib was defined as an expansile area of carcinoma cells without intervening stroma or vasculature and with at least the size of an average size (200 µm diameter) benign gland and with multiple punched-out lumina ( 15 ). Immunostaining for basal cell markers to help distinguish between IDC and Crib was performed per case decision ( 16 ). Patient age, PSA prior to RP, PI-RADS score, biopsy approach (transrectal ultrasound-guided template or MRI fusion), biopsy and RP Grade Group (GG), percent pattern 4 at biopsy, presence of IDC/Crib at RP and biopsy, pathological stage, percent cores positive, positive margins and lymph node status at RP were reported. Statistical analysis Summary statistics were used to describe continuous and categorial variables, and stratified by biopsy result. Differences in the distribution of continuous and categorical variables by biopsy result were assessed using the Mann-Whitney U test and Fisher’s Exact/Chi-squared tests, respectively. In the subgroup of patients with a false or true negative biopsy, predictors of BCR-free survival were examined using Cox proportional hazards models with the following predictors: 1) percentage of pattern 4 disease (< 10% vs. ≥10%); 2) biopsy Gleason grade (GG1 vs. GG2 vs. GG3-5); 3) PSA before RP; 4) age; 5) percentage of biopsy positive cores (< 33.3% vs. ≥33.3%); 6) false negative and true negative biopsies. As PSA distribution was skewed, PSA was logarithmically transformed before being incorporated into the model. All statistical analyses were performed using R version 4.2.0 (The R Foundation for Statistical Computing, Vienna, Austria). All hypothesis tests were two-sided and a p-value less than 0.05 was considered statistically significant. Results Overall Cohort Characteristics This study included 836 patients who underwent radical prostatectomy between 2015 and 2022. The median age was 63.3 years (IQR: 59–68). The median serum PSA before RP was 7.6 ng/ml (IQR: 5.4–11.1). Among the 836 patients, 233 (28%) had Crib, and 125 (15%) had IDC on prostate biopsy, with 71 (8.5%) patients having both IDC and Crib. Grade Group distribution at biopsy was as follows: GG1 in 79 patients (9.5%), GG2 in 551 (66%), GG3 in 141 (17%), GG4 in 41 (4.9%), and GG5 in 24 (2.9%) patients. Systematic biopsy was performed in 533 (53%) patients, and MRI fusion biopsy (targeted plus systematic) in 303 (36%). Regarding IDC/Crib on RP, the distribution was as follows: 415 (49.6%) had Crib, 253 (30%) had IDC on final radical prostatectomy pathology, and 195 (23%) patients had both IDC and Crib (Table 1 and supplementary table 1 ). Table 1 Overall cohort patient characteristics (n = 836) Variable Age in years, median (IQR) 63 (59–68) Serum pre RP PSA in ng/ml, median (IQR) 7.6 (5.4–11.1) MRI - PI-RADS, n (%) 1–3 41 (14%) 4–5 259 (86%) Not performed 536 Biopsy Type, n (%) Systematic 533 (64%) MRI-fusion 303 (36%) Biopsy Grade Group, n (%) Grade Group 1 79 (9.5%) Grade Group 2 551 (66%) Grade Group 3 141 (17%) Grade Group 4 41 (4.9%) Grade Group 5 24 (2.9%) Biopsy intraductal, n (%) Present 125 (15%) Absent 711 (85%) Biopsy cribriform, n (%) Present 233 (28%) Absent 603 (72%) Biopsy intraductal or cribriform, n (%) Both present 71 (8.5%) Both absent 549 (66%) Intraductal or cribriform present 287 (34%) Percent Cores Positive, %, median (IQR) 44 (31–59) Percent Pattern 4 at biopsy, %, median (IQR) 10 (5–40) Radical Prostatectomy Pathological Grade Group, n (%) Grade Group 1 87 (10%) Grade Group 2 503 (60%) Grade Group 3 183 (22%) Grade Group 4 23 (2.8%) Grade Group 5 40 (4.8%) Pathologic stage on radical prostatectomy specimen, n (%) T2 440 (53%) T3a 303 (36%) T3b or worse 89 (11%) Not available 4 Presence of intraductal carcinoma on radical prostatectomy specimen, n (%) Yes 253 (30%) No 583 (70%) Presence of cribriform on radical prostatectomy specimen, n (%) Yes 415 (50%) No 421 (50%) Presence of intraductal or cribriform on radical prostatectomy specimen, n (%) Both present 195 (23%) Both absent 363 (43%) Intraductal or cribriform present 473 (57%) Positive margins, n (%) Yes 257 (31%) No 579 (69%) Pelvic lymph node positive, n (%) Yes 39 (6.6%) No 550 (93%) Not performed 247 IQR: Interquartile; PSA: Prostate-specific antigen Pathological Outcomes of Radical Prostatectomy: Comparing False-Negative, True-Negative, True-Positive, and False-Positive Biopsies for IDC/Crib In terms of IDC/Crib status at biopsy, 217 (26%) patients had a false-negative biopsy, 332 (40%) had a true-negative biopsy, 256 (31%) showed a true-positive biopsy, and 24 (3.7%) exhibited a false-positive biopsy, considering either pattern (Table 2 ). When comparing false-negative, false-positive, true-negative and true-positive biopsies for IDC/Crib, we found that patients with a false-negative biopsy for IDC/Crib versus those with a true-negative biopsy for IDC/Crib had double the rates of advanced pathological stage (≥ pT3): 57% versus 28%, respectively (p < 0.001). Patients with a true-positive biopsy for IDC/Crib had a 66% incidence of advanced pathological stage (≥ pT3), whereas those with a false-positive result had a 29% incidence of advanced pathology comparable to those with a true negative (28%, p < 0.001). Table 2 Pathological Outcomes stratified by IDC/Crib biopsy category (n=836). Variable False Negative (n=217) False Positive (n=31) True Negative (n=332) True Positive (n=256) P-value 1 Pathologic stage on radical prostatectomy specimen, n (%) <0.001 T2 93 (43%) 22 (71%) 238 (72%) 87 (34%) ≥T3 122 (57%) 9 (29%) 93 (28%) 168 (66%) Not available 2 0 1 1 Pelvic lymph node positive, n (%) <0.001 Yes 13 (8.0%) 0 1 (0.6%) 25 (11%) No 150 (92%) 24 (100%) 168 (99%) 208 (89%) Not performed 54 7 163 23 Margins, n (%) 0.006 Negative 135 (62%) 26 (84%) 246 (74%) 172 (67%) Positive 82 (38%) 5 (16%) 86 (26%) 84 (33%) 1 Estimated using Fisher’s Exact or Chi-squared tests Regarding lymph node status, 8.0% of the patients with false negative biopsies had positive lymph nodes, compared to 11% of those with a true positive biopsy, and 0% and 0.6% for those with a false positive biopsy and true negative biopsy, respectively (p < 0.001). Concerning margins, the rate of positive margins was higher among patients with false negative biopsies (38%) compared to those with true negative biopsies (26%), while among patients with positive margins, 16% had false positive biopsies and 33% had true positive biopsies (p = 0.006). Preoperative Clinical Characteristics: Comparing Baseline Features of True Positive, False Negative, and True Negative Biopsies for IDC/Crib We also interrogated baseline preoperative patient clinical differences between true positive, false negative biopsies and true negative biopsies for IDC/Crib (supplementary table 2 ). Within our cohort, there were variations in the percentage of biopsies with Grade Group (GG) ≥ 3 among patients with false negative biopsies compared to those with true negative and true positive biopsies (19% vs. 9.3% vs. 49%, respectively, p < 0.001). Conversely, patients with false negative biopsies for IDC/Crib exhibited a lower percentage of GG2/GG1 biopsies compared to those with true negative and true positive biopsies (81% vs. 91% and 51%, respectively, p < 0.001). Similarly, the percentage of pattern 4 at biopsy among patients with true negative biopsies compared to those with false negative and true positive biopsies (median values 5.0% vs. 7.0% vs. 40%, respectively, p < 0.001). The median percentage of positive cores in biopsy samples between patients with true negative biopsies for IDC/Crib compared to those with false negative and true positive biopsies (median values 42% vs. 43% vs. 20%, respectively, p < 0.001). Patients with true-positive biopsies disclosed higher rates of PIRADS 4 or 5 at MRI compared to those with true-negative and false-negative biopsies (93% vs. 86% vs. 77%, p < 0.001). Pre-operative Predictors of Biochemical Recurrence The analysis of the time to BCR after RP (Fig. 2 ) demonstrated that patients with true-positive IDC/Crib biopsies had a lower probability of BCR-free survival, followed by those with false-negative biopsies, while patients with true-negative biopsies exhibited the highest BCR-free survival rates. Table 3 presents the results from the multivariable Cox proportional hazards model. Several factors emerged as independent predictors: log PSA before RP (hazard ratio [HR] 2.07, 95% CI 1.53–2.82; p < 0.001), a higher percentage of positive cores at biopsy (≥ 33%) (HR 1.68, 95% CI 1.07–2.63; p = 0.024), and false negative biopsy for IDC/Crib (HR 2.14, 95% CI 1.41–3.25; p < 0.001). Table 3 Multivariable Cox proportional hazards regression analysis evaluating pre-operative predictors of biochemical recurrence, in subgroup of patients with either true or false negative IDC/Crib biopsy status. Variable Hazard Ratio (95% CI) P-value Age at RP 0.99 (0.96, 1.03) 0.75 Log PSA before RP 2.07 (1.53, 2.82) < 0.001 Percent GG4 0.58 =10% Reference 1.15 (0.70, 1.90) Biopsy Grade Group (GG) 0.42 GG1 GG2 GG3-5 Reference 0.76 (0.29, 1.48) 1.53 (0.67, 3.51) Percent Cores Positive 0.024 =33.3% Reference 1.68 (1.07, 2.63) IDC/Crib biopsy status < 0.001 True Negative False Negative Reference 2.14 (1.41, 3.25) Hypothetical Active Surveillance Subgroup Analysis We have selected a subgroup of patients meeting the following criteria: 1) GG1 or GG2 at biopsy; 2) PSA < 10 ng/ml; 3) percent GG4 at biopsy < 10%; 4) percent of positive cores < 33%; 5) absence of IDC or cribriform pattern at biopsy (subgroup characteristics in supplementary table 3 ). In this subgroup, adverse pathology at RP is defined as follows: 1) ≥ pT3; 2) Positive lymph nodes; 3) GG3 ≥ 3 at RP. This subgroup comprised 59 patients in total. When comparing false negative vs true negative biopsy results, patients with a false negative biopsy exhibited higher rates of advanced pathology (≥ pT3) compared to those with a true negative biopsy (47% vs 12%, p = 0.009) (supplementary table 4 ). Discussion In this study involving 836 individuals who underwent RP, we found that a false-negative biopsy for IDC/Crib is independently associated with a 2.14-fold increased risk of BCR. Additionally, higher preoperative PSA levels and ≥ 33% of cores positive were also independently associated with a 2.07 and 1.68-fold increased risk of BCR, respectively. In addition, in a hypothetical subcohort deemed appropriate for AS, selected patients would have experienced adverse outcomes had their IDC/Crib been missed at biopsy. However, BCR data for this subcohort are still immature and underpowered. We have previously published a study that included 287 patients with IDC/Crib at the final pathology ( 14 ), in which the sensitivity of detection in the prostate biopsy was 52.5%. However, we were unable to analyze pathological outcomes between false-negative, true-negative, false-positive, and true-positive biopsies, as all patients had IDC/Crib in the final pathology. Masoomian et al ( 9 )conducted a study analyzing the concordance rates of cribriform architecture in 245 paired biopsies and surgical specimens. They observed that among GG2 biopsy patients, both false-negative and true-positive biopsies exhibited a more advanced stage compared to true-negative biopsies upon radical prostatectomy. In contrast Hollemans et al ( 10 ) showed that men with true-positive biopsies had a significantly shorter post-operative BCR-free survival compared to those with false-negative biopsies. These studies, however, had relatively small cohorts, with the former demonstrating 245 patients the latter 186 patients. To the best of our knowledge, the clinical outcome of false-negative biopsies for IDC/Crib across the entire Gleason score spectrum in a large dataset has never been reported. When BCR rates among patients with true positive, false negative, and true negative biopsies, those with true negative biopsies exhibited better outcomes, followed by false negatives and true positives, with the latter performing poorly among the three categories (Fig. 2 ). Similarly, comparing false-negative, false-positive, true-negative, and true-positive biopsies for IDC/Crib, we observed that patients with a false-negative biopsy for IDC/Crib had double the rates of advanced pathological stage (≥ T3) compared to those with a true-negative biopsy for IDC/Crib (56.8% versus 28.1%, respectively). Patients with a true-positive biopsy for IDC/Crib had a notably high incidence of advanced pathological stage (≥ pT3) at 65.9%. We hypothesize that false negative biopsies have a lower volume of these adverse pathologies, which positions them between true positives and true negatives in terms of oncological outcomes. This finding aligns with previous research from a limited number of prostatectomy series that utilized biochemical recurrence as the outcome parameter, suggesting that the prognostic impact of IDC and Crib is more qualitative than quantitative ( 13 – 15 ). To indirectly assess the potential impact of our findings on patients enrolled in AS programs, we identified a specific subgroup of patients in our series which meet criteria for AS. When comparing false-negative versus true-negative biopsy results within this subgroup, patients with a false-negative biopsy exhibited higher rates of adverse pathology compared to those with a true-negative biopsy (47.1% vs. 11.9%). This is clinically relevant, considering the consensual opinion that AS is inappropriate for men with IDC or Crib at biopsy. A major concern regarding this clinical recommendation is the high-false negative rate (> 50% in some series) ( 14 ) for the detection of IDC/Crib when comparing to radical prostatectomy specimens. Conversely, a rising inclination is observed in favor of employing active surveillance for GG2 PCa ( 17 ). This finding, unveils a notable concern within this clinical setting, indicating that false-negative biopsies have approximately four times higher rates of adverse pathology compared to true-negative biopsies (47.1% / 11.9% ≈ 3.95). MRI has been associated with controversial results in predicting IDC/Crib ( 18 ). Pinto et al. demonstrated that the extent of disease for Crib-containing tumors is difficult to capture on MRI. Additionally, when comparing MRI lesions of similar dimensions and PIRADS scores, Crib tumors appear to have larger cancer yield on biopsy( 19 ). Mikoshi et al. also reported that neither the presence nor the percentage of IDC was related to MRI detectability ( 20 ). Similarly, within our patient cohort, those with true-positive biopsies had a larger incidence of PIRADS 4 or 5 lesions on MRI in comparison to those with true-negative and false-negative biopsies (93.1% vs. 86% vs. 77.4%). These findings suggest that MRI does not provide adequate classification of these lesions for use in clinical practice. We acknowledge, however, that to determine whether MRI effectively detects cribriform lesions, pathology correlations between surgical specimens and confirmed targeted biopsy IDC/Crib lesions must be conducted. This aspect was beyond the scope of our study. Our findings, represents a significant argument for future research aimed at establishing a dependable biomarker capable of pre-operatively predicting adverse pathology and BCR. There is a (still unmet) need for biomarkers that can differentiate false negative from true negative biopsies. Limitations of this study include its single-center setting and the inherent biases associated with retrospective research, such as selection bias. However, the strength of our study lies in the prospective data collection from a contemporary cohort of patients, facilitated by routine reporting of IDC/Crib from an experienced subspecialty urogenital pathologist in an academic setting, particularly in a center known for its focus on IDC/Crib. This approach mitigates potential biases that could arise from a retrospective pathology review. Notably, the pathology reports from RP did not include information on the volume of IDC or Crib, which restricts our understanding of the correlation between false-negative results and low volume of IDC/Crib. Conclusions A false-negative biopsy for IDC/Crib is independently associated with a 2.14-fold higher risk of BCR compared to a true negative. Because occult IDC/Crib impacts on prognosis, biomarkers capable of signaling its presence in cases with negative biopsy are required and may contribute for improved selection of patients to AS programs. Declarations Previous Presentations: None Funding Sources: None Conflicts of Interest: The authors declare no relevant conflicts of interest Ethics Approval: Appropriate ethics approval was obtained from the University Health Network research ethics board Data Availability Statement: We have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Author Contributions Statement: Conceptualization : RB, BY, RKS, KL, LCP, RH, MW, JC; TVK; NEF; Data Curation: RB, RKS, BY; KL, JC, LCP, RH; TVK; NEF; Formal Analysis: RB, KL; MW, NEF; Methodology: RB, BY, KL, JC; TVK; NEF Supervision: JC,NEF; Writing – original draft: RB. Writing – review & editing: RKS, BY, KL, MW, LCP, RH, JC, TVK; NEF; Funding acquisition: None Acknowledges: RB is supported by the Foundation for Science and Technology (FCT), Portugal (grant no. 2022.13386.BD). We also acknowledge Princess Margaret Foundation. References van Leenders GJLH, van der Kwast TH, Iczkowski KA. The 2019 International Society of Urological Pathology Consensus Conference on Prostate Cancer Grading. Eur Urol. 2021 Jun 1;79(6):707–9. Epstein JI, Amin MB, Fine SW, Algaba F, Aron M, Baydar DE, et al. 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J Clin Pathol [Internet]. 2014 [cited 2023 Sep 26];67(4):313–8. Available from: https://pubmed.ncbi.nlm.nih.gov/24403214/ Masoomian M, Downes MR, Sweet J, Cheung C, Evans AJ, Fleshner N, et al. Concordance of biopsy and prostatectomy diagnosis of intraductal and cribriform carcinoma in a prospectively collected data set. Histopathology. 2019;74(3):474–82. Bernardino R, Sayyid RK, Leão R, Zlotta AR, Kwast T van der, Klotz L, et al. Using active surveillance for Gleason 7 (3+4) prostate cancer: A narrative review. Canadian Urological Association Journal [Internet]. 2023 Dec 21 [cited 2024 Jan 4];18(4). Available from: https://cuaj.ca/index.php/journal/article/view/8539 Bernardino R, Fleshner N. Re: Sensitivity of Multiparametric MRI and Targeted Biopsy for Detection of Adverse Pathologies (Cribriform Gleason Pattern 4 and Intraductal Carcinoma): Correlation of Detected and Missed Prostate Cancer Foci with Whole Mount Histopathology. Eur Urol [Internet]. 2023 [cited 2023 May 12]; Available from: https://pubmed.ncbi.nlm.nih.gov/36792385/ Belue MJ, Blake Z, Yilmaz EC, Lin Y, Harmon SA, Nemirovsky DR, et al. Is prostatic adenocarcinoma with cribriform architecture more difficult to detect on prostate MRI? Prostate [Internet]. 2023 Dec 1 [cited 2024 Jan 4];83(16):1519–28. Available from: https://pubmed.ncbi.nlm.nih.gov/37622756/ Mikoshi A, Miyai K, Hamabe F, Edo H, Ito K, Matsukuma S, et al. MRI-detectability and histological factors of prostate cancer including intraductal carcinoma and cribriform pattern. Prostate. 2022 Mar 1;82(4):452–63. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplTable1IDCCRib2x2table.docx Supplementary table 1 Supptable2baselinestratIDCCribbxstatus.docx Supplementary table 2 SuppTable3AScohort.docx Supplementary table 3 Supptable4ASpathadverseoutcomes.docx.docx Supplementary table 4 Cite Share Download PDF Status: Published Journal Publication published 21 Oct, 2024 Read the published version in Prostate Cancer and Prostatic Diseases → Version 1 posted Editorial decision: revise 03 Sep, 2024 Review # 2 received at journal 13 Aug, 2024 Reviewer # 2 agreed at journal 22 Jul, 2024 Review # 1 received at journal 13 May, 2024 Reviewer # 1 agreed at journal 06 May, 2024 Reviewers invited by journal 06 May, 2024 Editor assigned by journal 19 Apr, 2024 Submission checks completed at journal 17 Apr, 2024 First submitted to journal 16 Apr, 2024 Unknown event 16 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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2","display":"","copyAsset":false,"role":"figure","size":386131,"visible":true,"origin":"","legend":"\u003cp\u003eRates of biochemical recurrence following Radical Prostatectomy among patients with false-negative (blue), true-negative (yellow), and true-positive (gray) biopsy for IDC/Crib\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4265149/v1/fe7b650e7145750bb4c3697b.jpeg"},{"id":67185835,"identity":"6744aa3b-c9e6-4d18-86b9-9b7cb2c4ba17","added_by":"auto","created_at":"2024-10-22 07:10:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1479751,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4265149/v1/e508ad37-7c7e-49af-b787-378933e1a9a0.pdf"},{"id":56549652,"identity":"4383809a-4663-4d98-a983-ae15268c5337","added_by":"auto","created_at":"2024-05-15 15:47:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14719,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary table 1\u003c/p\u003e","description":"","filename":"SupplTable1IDCCRib2x2table.docx","url":"https://assets-eu.researchsquare.com/files/rs-4265149/v1/39a68f2a2a077e962ab95a05.docx"},{"id":56547907,"identity":"ad752589-584c-4808-9451-6614e8b945d5","added_by":"auto","created_at":"2024-05-15 15:39:09","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17327,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary table 2\u003c/p\u003e","description":"","filename":"Supptable2baselinestratIDCCribbxstatus.docx","url":"https://assets-eu.researchsquare.com/files/rs-4265149/v1/3122f261b897c87dbd20c930.docx"},{"id":56547912,"identity":"c1d5b4c3-1e22-4855-a92f-1ebc50f50eef","added_by":"auto","created_at":"2024-05-15 15:39:09","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":16674,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary table 3\u003c/p\u003e","description":"","filename":"SuppTable3AScohort.docx","url":"https://assets-eu.researchsquare.com/files/rs-4265149/v1/653e13aeca97cfb631cfcac7.docx"},{"id":56547911,"identity":"0bc5e20e-1883-4e40-865c-61b64dfff6dc","added_by":"auto","created_at":"2024-05-15 15:39:09","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17338,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary table 4\u003c/p\u003e","description":"","filename":"Supptable4ASpathadverseoutcomes.docx.docx","url":"https://assets-eu.researchsquare.com/files/rs-4265149/v1/66df91f6962b2b9754aa422c.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Undetected Cribriform and Intraductal Prostate Cancer at biopsy is associated with adverse outcomes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe consensus conference of 2019 by the International Society of Urological Pathology (ISUP) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and the white paper from the Genitourinary Pathology Society (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) have established the mandatory inclusion of reporting cribriform growth (Crib) pattern and intraductal prostate cancer (IDC) in routine pathology assessments. These growths are identified as biologically aggressive manifestations of prostate cancer (PCa), including increased genomic instability and hypoxia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The detection of these patterns in prostatectomy specimens has been consistently linked to increased risks of biochemical recurrence (BCR), metastasis and disease-specific mortality (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Furthermore, recent work from our group has also revealed that the presence of IDC on biopsy predicts lymphatic metastasis in PSMA PET/CT scans before treatment (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Additionally, among patients with BCR and metastatic disease detected via PSMA PET/CT, the presence of Crib is strongly associated with a lymphatic pattern of metastasis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is evident that IDC and Crib represent adverse features both on radical prostatectomy (RP) specimens and prostate biopsy samples. However, there has been a lack of studies investigating the oncological outcomes associated with biopsies false-negative for these patterns, and how patients with false-negative biopsies compare to those with true-positive or true-negative biopsies. Indeed, only two studies have previously addressed the issue, with both hampered by relatively small sample sizes and/or lack of clinical outcome data (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is also consensus that active surveillance is inappropriate for men with IDC or Crib found on biopsy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). On the other hand, there is a growing trend towards the use of active surveillance for grade group (GG) 2 PCa (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). A significant challenge associated with this clinical scenario is the notable occurrence of false negatives (exceeding 50% in most series) in identifying IDC/Crib as compared to examination of RP specimens (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In this regard, it is clinically relevant to evaluate whether false negative biopsy diagnosis is equally associated with the same oncological outcomes when compared to a true negative biopsy for the presence of IDC/Crib.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to determine the impact of false negative (\u0026ldquo;missed IDC/Crib at biopsy\u0026rdquo;) biopsies for IDC/Crib on oncological outcomes, including biochemical recurrence (BCR) and advanced stage (\u0026ge;\u0026thinsp;T3) at RP specimen.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design, Setting, and Participants\u003c/h2\u003e \u003cp\u003ePatients who underwent RP at The Princess Margaret Cancer Centre between January 2015 and December 2022 were included in the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The presence and absence of IDC and Crib in biopsies and radical prostatectomy specimens was adopted as a mandatory element in synoptic reporting at the Department of Pathology in 2015. All pathological slides were read by subspecialty pathologists, but not re-reviewed as part of this study. For men who underwent several biopsies before undergoing prostatectomy, the latest biopsy before the surgery was considered. We excluded patients whose biopsy reports did not specifically reference the presence or absence IDC and Crib at biopsy. Although minor differences in methodology may have existed, our institution's regular ultrasound-guided biopsies involve obtaining at least 12 cores from a standard sextant map, and for (multiparametric magnetic resonance imaging) MRI fusion biopsies, a minimum of 3 cores from each target is routinely acquired. All patients were offered a pre-biopsy MRI, in accordance with current guidelines (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The decision to proceed with an MRI versus upfront biopsy was based on a shared decision-making process with the patient, depending on patient anxiety level, wait time, and whether the post-test result would alter performance of a biopsy. If the MRI showed a positive lesion (\u0026ge;\u0026thinsp;PIRADS 3), patients were typically offered a combined systematic/targeted biopsy approach. Select patients with a prior negative systematic biopsy may have undergone an MRI targeted-only biopsy\u0026rdquo; A MAGNETOM\u0026reg;\u0026ensp;Verio 3T 4-channel, phased array surface coil is used in our institution to perform the MRI. The reporting used in the division is PI-RADS v2. The study received Institutional approval (REB: 22-5908). Informed consented for the specific purpose of this study was waived.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Outcomes\u003c/h2\u003e \u003cp\u003eThe aim of this study was to assess the impact of false negative biopsies for IDC/Crib on oncological outcomes, including BCR and advanced stage at RP. Advanced stage at pathology was defined as \u0026ge;\u0026thinsp;pT3. Firstly, we aimed to determine whether true negative versus false negative biopsies are independent predictors of BCR. Additionally, we compared the prevalence of unfavorable pathological features in men identified with IDC/Crib in their biopsy samples to those who did not display these features. Time to BCR was defined as the time between treatment and first recorded PSA\u0026thinsp;\u0026gt;\u0026thinsp;0.2 ng/ml or salvage radiotherapy; patients whose PSA never exceeded those values were censored at date of last PSA assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Variables\u003c/h2\u003e \u003cp\u003eIDC was defined as a lumen spanning proliferation of carcinoma cells distending antecedent ducts or glands. Crib was defined as an expansile area of carcinoma cells without intervening stroma or vasculature and with at least the size of an average size (200 \u0026micro;m diameter) benign gland and with multiple punched-out lumina (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Immunostaining for basal cell markers to help distinguish between IDC and Crib was performed per case decision (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatient age, PSA prior to RP, PI-RADS score, biopsy approach (transrectal ultrasound-guided template or MRI fusion), biopsy and RP Grade Group (GG), percent pattern 4 at biopsy, presence of IDC/Crib at RP and biopsy, pathological stage, percent cores positive, positive margins and lymph node status at RP were reported.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSummary statistics were used to describe continuous and categorial variables, and stratified by biopsy result. Differences in the distribution of continuous and categorical variables by biopsy result were assessed using the Mann-Whitney U test and Fisher\u0026rsquo;s Exact/Chi-squared tests, respectively.\u003c/p\u003e \u003cp\u003eIn the subgroup of patients with a false or true negative biopsy, predictors of BCR-free survival were examined using Cox proportional hazards models with the following predictors: 1) percentage of pattern 4 disease (\u0026lt;\u0026thinsp;10% vs. \u0026ge;10%); 2) biopsy Gleason grade (GG1 vs. GG2 vs. GG3-5); 3) PSA before RP; 4) age; 5) percentage of biopsy positive cores (\u0026lt;\u0026thinsp;33.3% vs. \u0026ge;33.3%); 6) false negative and true negative biopsies. As PSA distribution was skewed, PSA was logarithmically transformed before being incorporated into the model.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using R version 4.2.0 (The R Foundation for Statistical Computing, Vienna, Austria). All hypothesis tests were two-sided and a p-value less than 0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eOverall Cohort Characteristics\u003c/h2\u003e\n\u003cp\u003eThis study included 836 patients who underwent radical prostatectomy between 2015 and 2022. The median age was 63.3 years (IQR: 59\u0026ndash;68). The median serum PSA before RP was 7.6 ng/ml (IQR: 5.4\u0026ndash;11.1). Among the 836 patients, 233 (28%) had Crib, and 125 (15%) had IDC on prostate biopsy, with 71 (8.5%) patients having both IDC and Crib. Grade Group distribution at biopsy was as follows: GG1 in 79 patients (9.5%), GG2 in 551 (66%), GG3 in 141 (17%), GG4 in 41 (4.9%), and GG5 in 24 (2.9%) patients. Systematic biopsy was performed in 533 (53%) patients, and MRI fusion biopsy (targeted plus systematic) in 303 (36%). Regarding IDC/Crib on RP, the distribution was as follows: 415 (49.6%) had Crib, 253 (30%) had IDC on final radical prostatectomy pathology, and 195 (23%) patients had both IDC and Crib (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and supplementary table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eOverall cohort patient characteristics (n\u0026thinsp;=\u0026thinsp;836)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge in years, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (59\u0026ndash;68)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSerum pre RP PSA in ng/ml, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.6 (5.4\u0026ndash;11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMRI - PI-RADS, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u0026ndash;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (14%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u0026ndash;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e259 (86%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot performed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e536\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBiopsy Type, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSystematic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e533 (64%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMRI-fusion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e303 (36%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBiopsy Grade Group, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79 (9.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e551 (66%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e141 (17%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (4.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (2.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBiopsy intraductal, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePresent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125 (15%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbsent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e711 (85%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBiopsy cribriform, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePresent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e233 (28%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbsent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e603 (72%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBiopsy intraductal or cribriform, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBoth present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71 (8.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBoth absent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e549 (66%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntraductal or cribriform present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e287 (34%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePercent Cores Positive, %, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44 (31\u0026ndash;59)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePercent Pattern 4 at biopsy, %, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (5\u0026ndash;40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRadical Prostatectomy Pathological Grade Group, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87 (10%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e503 (60%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e183 (22%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (2.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade Group 5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (4.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePathologic stage on radical prostatectomy specimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e440 (53%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT3a\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e303 (36%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT3b or worse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89 (11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot available\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePresence of intraductal carcinoma on radical prostatectomy specimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e253 (30%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e583 (70%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePresence of cribriform on radical prostatectomy specimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e415 (50%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e421 (50%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePresence of intraductal or cribriform on radical prostatectomy specimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBoth present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e195 (23%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBoth absent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e363 (43%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntraductal or cribriform present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e473 (57%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePositive margins, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e257 (31%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e579 (69%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePelvic lymph node positive, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (6.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e550 (93%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot performed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e247\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\"\u003eIQR: Interquartile; PSA: Prostate-specific antigen\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003ePathological Outcomes of Radical Prostatectomy: Comparing False-Negative, True-Negative, True-Positive, and False-Positive Biopsies for IDC/Crib\u003c/h3\u003e\n\u003cp\u003eIn terms of IDC/Crib status at biopsy, 217 (26%) patients had a false-negative biopsy, 332 (40%) had a true-negative biopsy, 256 (31%) showed a true-positive biopsy, and 24 (3.7%) exhibited a false-positive biopsy, considering either pattern (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). When comparing false-negative, false-positive, true-negative and true-positive biopsies for IDC/Crib, we found that patients with a false-negative biopsy for IDC/Crib versus those with a true-negative biopsy for IDC/Crib had double the rates of advanced pathological stage (\u0026ge;\u0026thinsp;pT3): 57% versus 28%, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with a true-positive biopsy for IDC/Crib had a 66% incidence of advanced pathological stage (\u0026ge;\u0026thinsp;pT3), whereas those with a false-positive result had a 29% incidence of advanced pathology comparable to those with a true negative (28%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003ctable border=\"1\" width=\"662\"\u003e\u003ccaption\u003e\n\u003cp\u003eTable 2\u003c/p\u003e\n\u003cp\u003ePathological Outcomes stratified by IDC/Crib biopsy category (n=836).\u003c/p\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e\u003cstrong\u003eFalse Negative (n=217)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e\u003cstrong\u003eFalse Positive (n=31)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e\u003cstrong\u003eTrue Negative (n=332)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u003cstrong\u003eTrue Positive\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n=256)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003eP-value\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u003cstrong\u003ePathologic stage on radical prostatectomy specimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; T2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e93 (43%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e22 (71%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e238 (72%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e87 (34%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026ge;T3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e122 (57%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e9 (29%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e93 (28%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e168 (66%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp; Not available\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e\u0026nbsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e\u0026nbsp;0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u003cstrong\u003ePelvic lymph node positive,\u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Yes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e13 (8.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1 (0.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e25 (11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; No\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e150 (92%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e24 (100%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e168 (99%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e208 (89%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Not performed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e163\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u003cstrong\u003eMargins,\u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Negative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e135 (62%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e26 (84%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e246 (74%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e172 (67%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Positive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"99\"\u003e\n\u003cp\u003e82 (38%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"97\"\u003e\n\u003cp\u003e5 (16%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e86 (26%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e84 (33%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eEstimated using Fisher\u0026rsquo;s Exact or Chi-squared tests\u003c/p\u003e\n\u003cp\u003eRegarding lymph node status, 8.0% of the patients with false negative biopsies had positive lymph nodes, compared to 11% of those with a true positive biopsy, and 0% and 0.6% for those with a false positive biopsy and true negative biopsy, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Concerning margins, the rate of positive margins was higher among patients with false negative biopsies (38%) compared to those with true negative biopsies (26%), while among patients with positive margins, 16% had false positive biopsies and 33% had true positive biopsies (p\u0026thinsp;=\u0026thinsp;0.006).\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"ItalicUnderline\"\u003ePreoperative Clinical Characteristics: Comparing Baseline Features of True Positive, False Negative, and True Negative Biopsies for IDC/Crib\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eWe also interrogated baseline preoperative patient clinical differences between true positive, false negative biopsies and true negative biopsies for IDC/Crib (supplementary table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWithin our cohort, there were variations in the percentage of biopsies with Grade Group (GG)\u0026thinsp;\u0026ge;\u0026thinsp;3 among patients with false negative biopsies compared to those with true negative and true positive biopsies (19% vs. 9.3% vs. 49%, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Conversely, patients with false negative biopsies for IDC/Crib exhibited a lower percentage of GG2/GG1 biopsies compared to those with true negative and true positive biopsies (81% vs. 91% and 51%, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, the percentage of pattern 4 at biopsy among patients with true negative biopsies compared to those with false negative and true positive biopsies (median values 5.0% vs. 7.0% vs. 40%, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median percentage of positive cores in biopsy samples between patients with true negative biopsies for IDC/Crib compared to those with false negative and true positive biopsies (median values 42% vs. 43% vs. 20%, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with true-positive biopsies disclosed higher rates of PIRADS 4 or 5 at MRI compared to those with true-negative and false-negative biopsies (93% vs. 86% vs. 77%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003ePre-operative Predictors of Biochemical Recurrence\u003c/h2\u003e\n\u003cp\u003eThe analysis of the time to BCR after RP (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) demonstrated that patients with true-positive IDC/Crib biopsies had a lower probability of BCR-free survival, followed by those with false-negative biopsies, while patients with true-negative biopsies exhibited the highest BCR-free survival rates. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results from the multivariable Cox proportional hazards model. Several factors emerged as independent predictors: log PSA before RP (hazard ratio [HR] 2.07, 95% CI 1.53\u0026ndash;2.82; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), a higher percentage of positive cores at biopsy (\u0026ge;\u0026thinsp;33%) (HR 1.68, 95% CI 1.07\u0026ndash;2.63; p\u0026thinsp;=\u0026thinsp;0.024), and false negative biopsy for IDC/Crib (HR 2.14, 95% CI 1.41\u0026ndash;3.25; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariable Cox proportional hazards regression analysis evaluating pre-operative predictors of biochemical recurrence, in subgroup of patients with either true or false negative IDC/Crib biopsy status.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHazard Ratio (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at RP\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99 (0.96, 1.03)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLog PSA before RP\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.07 (1.53, 2.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePercent GG4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;10%\u003c/p\u003e\n\u003cp\u003e\u0026gt;=10%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003cp\u003e1.15 (0.70, 1.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBiopsy Grade Group (GG)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGG1\u003c/p\u003e\n\u003cp\u003eGG2\u003c/p\u003e\n\u003cp\u003eGG3-5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003cp\u003e0.76 (0.29, 1.48)\u003c/p\u003e\n\u003cp\u003e1.53 (0.67, 3.51)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePercent Cores Positive\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;33.3%\u003c/p\u003e\n\u003cp\u003e\u0026gt;=33.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003cp\u003e1.68 (1.07, 2.63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eIDC/Crib biopsy status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTrue Negative\u003c/p\u003e\n\u003cp\u003eFalse Negative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003cp\u003e2.14 (1.41, 3.25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eHypothetical Active Surveillance Subgroup Analysis\u003c/h2\u003e\n\u003cp\u003eWe have selected a subgroup of patients meeting the following criteria: 1) GG1 or GG2 at biopsy; 2) PSA\u0026thinsp;\u0026lt;\u0026thinsp;10 ng/ml; 3) percent GG4 at biopsy\u0026thinsp;\u0026lt;\u0026thinsp;10%; 4) percent of positive cores\u0026thinsp;\u0026lt;\u0026thinsp;33%; 5) absence of IDC or cribriform pattern at biopsy (subgroup characteristics in supplementary table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). In this subgroup, adverse pathology at RP is defined as follows: 1)\u0026thinsp;\u0026ge;\u0026thinsp;pT3; 2) Positive lymph nodes; 3) GG3\u0026thinsp;\u0026ge;\u0026thinsp;3 at RP. This subgroup comprised 59 patients in total. When comparing false negative vs true negative biopsy results, patients with a false negative biopsy exhibited higher rates of advanced pathology (\u0026ge;\u0026thinsp;pT3) compared to those with a true negative biopsy (47% vs 12%, p\u0026thinsp;=\u0026thinsp;0.009) (supplementary table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study involving 836 individuals who underwent RP, we found that a false-negative biopsy for IDC/Crib is independently associated with a 2.14-fold increased risk of BCR. Additionally, higher preoperative PSA levels and \u0026ge;\u0026thinsp;33% of cores positive were also independently associated with a 2.07 and 1.68-fold increased risk of BCR, respectively. In addition, in a hypothetical subcohort deemed appropriate for AS, selected patients would have experienced adverse outcomes had their IDC/Crib been missed at biopsy. However, BCR data for this subcohort are still immature and underpowered.\u003c/p\u003e \u003cp\u003eWe have previously published a study that included 287 patients with IDC/Crib at the final pathology (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), in which the sensitivity of detection in the prostate biopsy was 52.5%. However, we were unable to analyze pathological outcomes between false-negative, true-negative, false-positive, and true-positive biopsies, as all patients had IDC/Crib in the final pathology.\u003c/p\u003e \u003cp\u003eMasoomian et al (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)conducted a study analyzing the concordance rates of cribriform architecture in 245 paired biopsies and surgical specimens. They observed that among GG2 biopsy patients, both false-negative and true-positive biopsies exhibited a more advanced stage compared to true-negative biopsies upon radical prostatectomy. In contrast Hollemans et al (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) showed that men with true-positive biopsies had a significantly shorter post-operative BCR-free survival compared to those with false-negative biopsies. These studies, however, had relatively small cohorts, with the former demonstrating 245 patients the latter 186 patients.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, the clinical outcome of false-negative biopsies for IDC/Crib across the entire Gleason score spectrum in a large dataset has never been reported.\u003c/p\u003e \u003cp\u003eWhen BCR rates among patients with true positive, false negative, and true negative biopsies, those with true negative biopsies exhibited better outcomes, followed by false negatives and true positives, with the latter performing poorly among the three categories (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Similarly, comparing false-negative, false-positive, true-negative, and true-positive biopsies for IDC/Crib, we observed that patients with a false-negative biopsy for IDC/Crib had double the rates of advanced pathological stage (\u0026ge;\u0026thinsp;T3) compared to those with a true-negative biopsy for IDC/Crib (56.8% versus 28.1%, respectively). Patients with a true-positive biopsy for IDC/Crib had a notably high incidence of advanced pathological stage (\u0026ge;\u0026thinsp;pT3) at 65.9%. We hypothesize that false negative biopsies have a lower volume of these adverse pathologies, which positions them between true positives and true negatives in terms of oncological outcomes. This finding aligns with previous research from a limited number of prostatectomy series that utilized biochemical recurrence as the outcome parameter, suggesting that the prognostic impact of IDC and Crib is more qualitative than quantitative (\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo indirectly assess the potential impact of our findings on patients enrolled in AS programs, we identified a specific subgroup of patients in our series which meet criteria for AS. When comparing false-negative versus true-negative biopsy results within this subgroup, patients with a false-negative biopsy exhibited higher rates of adverse pathology compared to those with a true-negative biopsy (47.1% vs. 11.9%). This is clinically relevant, considering the consensual opinion that AS is inappropriate for men with IDC or Crib at biopsy. A major concern regarding this clinical recommendation is the high-false negative rate (\u0026gt;\u0026thinsp;50% in some series) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) for the detection of IDC/Crib when comparing to radical prostatectomy specimens. Conversely, a rising inclination is observed in favor of employing active surveillance for GG2 PCa (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). This finding, unveils a notable concern within this clinical setting, indicating that false-negative biopsies have approximately four times higher rates of adverse pathology compared to true-negative biopsies (47.1% / 11.9% \u0026asymp; 3.95).\u003c/p\u003e \u003cp\u003eMRI has been associated with controversial results in predicting IDC/Crib (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Pinto et al. demonstrated that the extent of disease for Crib-containing tumors is difficult to capture on MRI. Additionally, when comparing MRI lesions of similar dimensions and PIRADS scores, Crib tumors appear to have larger cancer yield on biopsy(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Mikoshi et al. also reported that neither the presence nor the percentage of IDC was related to MRI detectability (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Similarly, within our patient cohort, those with true-positive biopsies had a larger incidence of PIRADS 4 or 5 lesions on MRI in comparison to those with true-negative and false-negative biopsies (93.1% vs. 86% vs. 77.4%). These findings suggest that MRI does not provide adequate classification of these lesions for use in clinical practice. We acknowledge, however, that to determine whether MRI effectively detects cribriform lesions, pathology correlations between surgical specimens and confirmed targeted biopsy IDC/Crib lesions must be conducted. This aspect was beyond the scope of our study.\u003c/p\u003e \u003cp\u003eOur findings, represents a significant argument for future research aimed at establishing a dependable biomarker capable of pre-operatively predicting adverse pathology and BCR. There is a (still unmet) need for biomarkers that can differentiate false negative from true negative biopsies.\u003c/p\u003e \u003cp\u003eLimitations of this study include its single-center setting and the inherent biases associated with retrospective research, such as selection bias. However, the strength of our study lies in the prospective data collection from a contemporary cohort of patients, facilitated by routine reporting of IDC/Crib from an experienced subspecialty urogenital pathologist in an academic setting, particularly in a center known for its focus on IDC/Crib. This approach mitigates potential biases that could arise from a retrospective pathology review. Notably, the pathology reports from RP did not include information on the volume of IDC or Crib, which restricts our understanding of the correlation between false-negative results and low volume of IDC/Crib.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eA false-negative biopsy for IDC/Crib is independently associated with a 2.14-fold higher risk of BCR compared to a true negative. Because occult IDC/Crib impacts on prognosis, biomarkers capable of signaling its presence in cases with negative biopsy are required and may contribute for improved selection of patients to AS programs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003ePrevious Presentations:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no relevant conflicts of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e Appropriate ethics approval was obtained from the University Health Network research ethics board\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eWe have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement:\u0026nbsp;\u003c/strong\u003eConceptualization\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eRB, BY, RKS, KL, LCP, RH, MW, JC; TVK; NEF; Data Curation: RB, RKS, BY; KL, JC, LCP, RH; TVK; NEF; Formal Analysis: RB, KL; MW, NEF; Methodology: RB, BY, KL, JC; TVK; NEF Supervision: JC,NEF; Writing \u0026ndash; original draft: RB. Writing \u0026ndash; review \u0026amp; editing: RKS, BY, KL, MW, LCP, RH, JC, TVK; NEF; Funding acquisition: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledges:\u0026nbsp;\u003c/strong\u003eRB is supported by the Foundation for Science and Technology (FCT), Portugal (grant no. 2022.13386.BD). We also acknowledge Princess Margaret Foundation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003evan Leenders GJLH, van der Kwast TH, Iczkowski KA. The 2019 International Society of Urological Pathology Consensus Conference on Prostate Cancer Grading. Eur Urol. 2021 Jun 1;79(6):707\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eEpstein JI, Amin MB, Fine SW, Algaba F, Aron M, Baydar DE, et al. The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer. Arch Pathol Lab Med. 2021 Apr 1;145(4):461\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eChua MLK, Lo W, Pintilie M, Murgic J, Lalonde E, Bhandari V, et al. A Prostate Cancer \u0026ldquo;Nimbosus\u0026rdquo;: Genomic Instability and SChLAP1 Dysregulation Underpin Aggression of Intraductal and Cribriform Subpathologies. Eur Urol. 2017 Nov 1;72(5):665\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eBernardino RM, Carvalho R, Severo L, Alves M, Papoila AL, Pinheiro C. Prostate cancer with cribriform pattern: Exclusion criterion for active surveillance? Arch Ital Urol Androl. 2020 Oct 2;92(3):235\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eKweldam CF, Wildhagen MF, Steyerberg EW, Bangma CH, Van Der Kwast TH, Van Leenders GJLH. Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer. Modern Pathology. 2015 Mar 1;28(3):457\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eHollemans E, Verhoef EI, Bangma CH, Rietbergen J, Helleman J, Roobol MJ, et al. Large cribriform growth pattern identifies ISUP grade 2 prostate cancer at high risk for recurrence and metastasis. Mod Pathol. 2019 Jan 1;32(1):139\u0026ndash;46. \u003c/li\u003e\n\u003cli\u003eBernardino R, Sayyid RK, Lajkosz K, Al-Daqqaq Z, Tiwari R, Cockburn J, et al. Intraductal Prostate Cancer Affinity for Lymphatic-Predominant Metastases Through 18F-DCFPyL‒Prostate-Specific Membrane Antigen‒Positron Emission Tomography/CT Scans in Pretreatment Prostate Cancer Patients. J Urol [Internet]. 2024 Feb [cited 2024 Feb 6]; Available from: https://pubmed.ncbi.nlm.nih.gov/38299501/\u003c/li\u003e\n\u003cli\u003eBernardino R, Sayyid RK, Al-Daqqaq Z, Tiwari R, Cockburn J, Vijayakanthan S, et al. Lymphotropic Pattern of Prostate-specific Membrane Antigen\u0026ndash;detected Metastases Among Biochemically Recurrent Radical Prostatectomy Patients with Cribriform Disease. Eur Urol Focus [Internet]. 2023 May [cited 2023 Jun 1];0(0). Available from: http://www.eu-focus.europeanurology.com/article/S2405456923001165/fulltext\u003c/li\u003e\n\u003cli\u003eMasoomian M, Downes MR, Sweet J, Cheung C, Evans AJ, Fleshner N, et al. Concordance of biopsy and prostatectomy diagnosis of intraductal and cribriform carcinoma in a prospectively collected data set. Histopathology [Internet]. 2019 Feb 1 [cited 2023 May 28];74(3):474\u0026ndash;82. Available from: https://pubmed.ncbi.nlm.nih.gov/30160779/\u003c/li\u003e\n\u003cli\u003eHollemans E, Verhoef EI, Bangma CH, Schoots I, Rietbergen J, Helleman J, et al. Concordance of cribriform architecture in matched prostate cancer biopsy and radical prostatectomy specimens. Histopathology [Internet]. 2019 [cited 2023 May 28];75(3):338\u0026ndash;45. Available from: https://pubmed.ncbi.nlm.nih.gov/31045262/\u003c/li\u003e\n\u003cli\u003eProstate Cancer - INTRODUCTION - Uroweb [Internet]. [cited 2023 May 29]. Available from: https://uroweb.org/guidelines/prostate-cancer\u003c/li\u003e\n\u003cli\u003eBernardino R, Sayyid RK, Le\u0026atilde;o R, Zlotta AR, van der Kwast T, Klotz L, et al. Increasing trend of utilising active surveillance for Gleason Score 7 (3 + 4) prostate cancer. BJU Int [Internet]. 2023 Dec 1 [cited 2024 Jan 4];132(6). Available from: https://pubmed.ncbi.nlm.nih.gov/37606994/\u003c/li\u003e\n\u003cli\u003eAl Hussein Al Awamlh B, Barocas DA, Zhu A, Tosoian JJ, Ponsky L, Negoita S, et al. Use of Active Surveillance vs Definitive Treatment Among Men With Low- and Favorable Intermediate-Risk Prostate Cancer in the US Between 2010 and 2018. JAMA Intern Med [Internet]. 2023 Apr 3 [cited 2023 May 11]; Available from: https://pubmed.ncbi.nlm.nih.gov/37010836/\u003c/li\u003e\n\u003cli\u003eBernardino RM, Sayyid RK, Lajkosz K, Al-Daqqaq Z, Cockburn JG, Chavarriaga J, et al. Limitations of Prostate Biopsy in Detection of Cribriform and Intraductal Prostate Cancer. Eur Urol Focus [Internet]. 2023 Sep [cited 2023 Sep 24]; Available from: https://pubmed.ncbi.nlm.nih.gov/37696743/\u003c/li\u003e\n\u003cli\u003eTreurniet KM, Trudel D, Sykes J, Evans AJ, Finelli A, Van Der Kwast TH. Downgrading of biopsy based Gleason score in prostatectomy specimens. J Clin Pathol [Internet]. 2014 [cited 2023 Sep 26];67(4):313\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/24403214/\u003c/li\u003e\n\u003cli\u003eMasoomian M, Downes MR, Sweet J, Cheung C, Evans AJ, Fleshner N, et al. Concordance of biopsy and prostatectomy diagnosis of intraductal and cribriform carcinoma in a prospectively collected data set. Histopathology. 2019;74(3):474\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eBernardino R, Sayyid RK, Le\u0026atilde;o R, Zlotta AR, Kwast T van der, Klotz L, et al. Using active surveillance for Gleason 7 (3+4) prostate cancer: A narrative review. Canadian Urological Association Journal [Internet]. 2023 Dec 21 [cited 2024 Jan 4];18(4). Available from: https://cuaj.ca/index.php/journal/article/view/8539\u003c/li\u003e\n\u003cli\u003eBernardino R, Fleshner N. Re: Sensitivity of Multiparametric MRI and Targeted Biopsy for Detection of Adverse Pathologies (Cribriform Gleason Pattern 4 and Intraductal Carcinoma): Correlation of Detected and Missed Prostate Cancer Foci with Whole Mount Histopathology. Eur Urol [Internet]. 2023 [cited 2023 May 12]; Available from: https://pubmed.ncbi.nlm.nih.gov/36792385/\u003c/li\u003e\n\u003cli\u003eBelue MJ, Blake Z, Yilmaz EC, Lin Y, Harmon SA, Nemirovsky DR, et al. Is prostatic adenocarcinoma with cribriform architecture more difficult to detect on prostate MRI? Prostate [Internet]. 2023 Dec 1 [cited 2024 Jan 4];83(16):1519\u0026ndash;28. Available from: https://pubmed.ncbi.nlm.nih.gov/37622756/\u003c/li\u003e\n\u003cli\u003eMikoshi A, Miyai K, Hamabe F, Edo H, Ito K, Matsukuma S, et al. MRI-detectability and histological factors of prostate cancer including intraductal carcinoma and cribriform pattern. Prostate. 2022 Mar 1;82(4):452\u0026ndash;63. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"prostate-cancer-and-prostatic-diseases","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"pcan","sideBox":"Learn more about [Prostate Cancer and Prostatic Diseases](http://www.nature.com/pcan/)","snPcode":"41391","submissionUrl":"https://mts-pcan.nature.com/cgi-bin/main.plex","title":"Prostate Cancer and Prostatic Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Prostatic Neoplasms, Prostate Biopsy, False Negatives, Impact on Final Pathology","lastPublishedDoi":"10.21203/rs.3.rs-4265149/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4265149/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntraductal carcinoma (IDC) and cribriform pattern (Crib) of prostate cancer are increasingly recognised as independent prognosticators of poor outcome, both in prostate biopsies and radical prostatectomy (RP) specimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe aim of our project is to assess the impact of false negative biopsies for these two characteristics on oncological outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who underwent RP between January 2015 and December 2022 were included in the study. Predictors of Biochemical Failure were examined using a multivariate Cox proportional hazards model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults and Limitation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 836 patients who underwent RP, 233 (27.9%) had Crib, and 125 (15.0%) had IDC on prostate biopsy, with 71 (8.5%) patients having both IDC and Crib. Concerning, IDC/Crib status at biopsy, 217 (26%) patients had a false-negative biopsy, 332 (39.7%) had a true-negative biopsy, 256 (30.6%) showed a true-positive biopsy, and 24 (3.7%) exhibited a false-positive biopsy, with respect to either pattern. When comparing false-negative, false-positive, true-negative and true-positive biopsies for IDC/Crib, we found that patients with a false-negative biopsy for IDC/Crib versus those with a true-negative biopsy for IDC/Crib disclosed a rate of advanced pathological stage (≥ pT3) which was twice that of patients with a true-negative biopsy for IDC/Crib: 56.8% versus 28.1%, respectively (p \u0026lt; 0.001). On multivariate Cox analysis, log PSA before RP (hazard ratio [HR] 2.07, 95% CI 1.53–2.82; p \u0026lt; 0.001), a higher percentage of positive cores at biopsy (≥ 33%) (HR 1.68, 95% CI 1.07–2.63; p = 0.024), and false negative biopsy for IDC/Crib (HR 2.14, 95% CI 1.41–3.25; p \u0026lt; 0.001), were each significantly associated with an increased risk of BCR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA false-negative biopsy for IDC/Crib is independently associated with higher risk of BCR and advanced pathological stage compared to a true negative biopsy.\u003c/p\u003e","manuscriptTitle":"Undetected Cribriform and Intraductal Prostate Cancer at biopsy is associated with adverse outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-15 15:39:04","doi":"10.21203/rs.3.rs-4265149/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-09-03T09:57:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-13T21:07:20+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-22T23:36:39+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-05-13T05:49:21+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-05-06T16:50:13+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-06T16:15:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-19T11:02:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-17T07:59:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Prostate Cancer and Prostatic Diseases","date":"2024-04-16T18:32:12+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-04-16T07:44:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"prostate-cancer-and-prostatic-diseases","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"pcan","sideBox":"Learn more about [Prostate Cancer and Prostatic Diseases](http://www.nature.com/pcan/)","snPcode":"41391","submissionUrl":"https://mts-pcan.nature.com/cgi-bin/main.plex","title":"Prostate Cancer and Prostatic Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"940d3154-ca5c-44df-b75b-53b3126bb343","owner":[],"postedDate":"May 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31579719,"name":"Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer"},{"id":31579720,"name":"Biological sciences/Cancer/Cancer screening"},{"id":31579721,"name":"Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer"},{"id":31579722,"name":"Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer"},{"id":31579723,"name":"Biological sciences/Cancer/Cancer screening"},{"id":31579724,"name":"Biological sciences/Cancer/Cancer screening"}],"tags":[],"updatedAt":"2024-10-22T07:10:34+00:00","versionOfRecord":{"articleIdentity":"rs-4265149","link":"https://doi.org/10.1038/s41391-024-00910-3","journal":{"identity":"prostate-cancer-and-prostatic-diseases","isVorOnly":false,"title":"Prostate Cancer and Prostatic Diseases"},"publishedOn":"2024-10-21 04:00:00","publishedOnDateReadable":"October 21st, 2024"},"versionCreatedAt":"2024-05-15 15:39:04","video":"","vorDoi":"10.1038/s41391-024-00910-3","vorDoiUrl":"https://doi.org/10.1038/s41391-024-00910-3","workflowStages":[]},"version":"v1","identity":"rs-4265149","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4265149","identity":"rs-4265149","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}