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Address for correspondence: Hai Jiang, Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79, Hangzhou, Zhejiang Province, 310003, China
Whether one positive core prostate cancer (PCa) is a low-risk disease remains to be determined. We investigated the pathological results of radical prostatectomy specimens diagnosed on single core positive prostate biopsy.
Methods
Between January 2013 and December 2019, A total of 3441 consecutive patients treated with radical prostatectomy in our institution were examined. Among them, 293 patients were diagnosed with single positive core PCa on biopsy, and the clinical parameters and pathological findings of their radical prostatectomy specimens were analyzed.
Results
Of the 293 patients, 108 (36.9%) had undergraded Gleason Scores (GS) based on the biopsy. Positive surgical margins (PSMs), perineural invasion (PNI), extracapsular extension (ECE, pT3a) and seminal vesicle invasion (SVI, pT3b) were found in 16.4%, 15.0%, 3.4% and 2.4% of patients, respectively. In the multivariate analysis, we found that preoperative PSA level predict a significant increased risk of upgraded GS and PSMs, and biopsy GS was is a strong predictor of PNI, upgraded GS, tumor stage pT3 at radical prostatectomy.
Conclusions
Single positive core PCa have clinically significance in the radical prostatectomy specimens, with considerable rates of undergrading for the GS, PNI, PSMs, ECE and SVI. For patients with single positive core PCa, other prognostic factors must be considered in the treatment plan.
The widespread use of PSA screening has resulted in a steady increase in PCa diagnoses and stage migration over the past few decades, although its value remains controversial.
The treatment of localized PCa, including active surveillance (AS), radical prostatectomy (RP), or radiotherapy, is based on several clinicopathological factors such as patients age, PSA levels, preoperative MRI, Gleason score (GS) and clinical stage.
Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005.
Various studies have indicated that the percentage of positive biopsy cores in prostate biopsy was a powerful predictor of adverse clinical outcomes after RP.
The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy.
Predicting disease recurrence in intermediate and high-risk patients undergoing radical prostatectomy using percent positive biopsies: results from CaPSURE.
It is common for tumors to be diagnosed by a single positive core in systemic biopsy and these patients are generally considered to have favorable clinical outcomes or even ‘insignificant cancer’, making them candidates for AS. However, several studies in Western countries have found that a single positive core cannot predict a small volume of tumor, and there may be more extensive disease in the final pathological evaluation of the RP specimens.
The volume of prostate cancer in the biopsy specimen cannot reliably predict the quantity of cancer in the radical prostatectomy specimen on an individual basis.
Can the core length involved with prostate cancer identify clinically insignificant disease in low risk patients diagnosed on the basis of a single positive core?.
In view of the lack of consensus, we evaluate the pathologic results of RP in patients detected on a single positive biopsy, and identified preoperative clinical factors that could predict adverse pathological outcomes.
Methods
The study was a retrospective analysis and approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. All methods were carried out in accordance with relevant guidelines and regulations. We reviewed all patients who underwent RP at our institution from January 2013 to December 2019. A database of 3441 patients was screened for patients diagnosed with a single positive core in the prostate biopsy. The patients who received neoadjuvant hormonal therapy or radiotherapy or patients with stage pT0 cancer were excluded.
A total of 293 patients were included in the analysis. All men underwent transperineal systematic prostate biopsy with ten cores and were treat with open retropubic, laparoscopic (LRP), or robot-assisted laparoscopic radical prostatectomy by different surgeons. Lymph node dissection was selectively performed depending on the surgeon's discretion. The preoperative parameters including the patients’ age, preoperative PSA level, clinical stage, biopsy GS, and the pathological data from the RP specimens including GS, surgical margin status, perineural invasion (PNI), extracapsular extension (ECE, pT3a) and seminal vesicle involvement (SVI, pT3b) were retrieved.
RP specimens were submitted for histopathological examination by two experienced pathologists at our institution. The Gleason score was determined according to the International Society of Urological Pathology 2014 consensus guidelines
The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system.
and categorized into a five-grade group: grade group 1 (Gleason score = 6), grade group 2 (Gleason score 3 + 4 = 7), grade group 3 (Gleason score 4 + 3 = 7), grade group 4 (Gleason score 8), and grade group 5 (Gleason score 9-10). The discrepancy between the GSs from biopsy and RP specimens was analyzed and divided into undergrading (upgraded) and overgrading (downgraded) categories. The 2002 TNM classification system was used for staging PCa.
The patients’ characteristics are presented as frequencies (%) and means ± SD. The rates of concordance and discrepancy between the preoperative and postoperative GSs were evaluated with the kappa coefficient of agreement. Multivariate logistic regression model was constructed to determine whether patient age, preoperative PSA, biopsy GS and clinical stage were predictive of adverse pathological outcomes, including PNI, upgraded GS, PSMs and tumor stage ≥ pT3 in this study. All statistical analyses were performed using SPSS, version 24 (SPSS, Chicago, IL), with significance defined as P < .05.
Results
The characteristics of the 293 patients are presented in Table 1. Only two patients adopt an active surveillance strategy before surgery. It was noted that 17 patients (6.8%) had extraprostatic involvement, and 48 (16.4%) had positive margins even in the patients with one single positive core. No lymph node metastasis was observed. For the concordance between biopsy and RP specimen GSs, an exact match was observed for 49.4% of patients (n = 145); while 108 patients (36.9%) had an undergraded GS at biopsy; 40 (13.7%) had overgraded GS. The kappa-statistic measure of agreement between biopsy and RP specimens was poor (K = 0.247) (Figure 1).
Figure 1Concordance of Gleason scores (GS) between biopsy and radical prostatectomy (RP) specimen. Red filled circles represent concordant scores between biopsy and RP specimen; empty circles represent discordant scores. The size is proportional to the number of cases falling in each combination.
Multivariate logistic regression model was used to analyzed the preoperative factors associated with adverse pathological factors. As shown in Table 2, preoperative serum PSA levels were positively associated with upgraded GS and PSMs, and increasing biopsy GS were associated with increased risk of PNI, extraprostatic involvement and decreased risk of upgraded GS in the RP specimen; Neither age nor clinical stage was predictive of adverse pathological outcomes.
Table 2Multivariate Analysis of Potential Predictors of Adverse Pathological Outcomes
Risk factors
PNI
Upgraded GS
Positive margins
≥ pT3
OR (95%CI)
P value
OR (95%CI)
P value
OR (95%CI)
P value
OR (95%CI)
P value
Age (Continuous)
0.992 (0.948-1.038)
0.724
1.009 (0.975-1.045)
0.596
1.007 (0.963-1.052)
.769
0.955 (0.891-1.024)
.194
PSA (Continuous)
1.006 (0.973-1.040)
0.719
1.036 (1.006-1.066)
0.016
1.037 (1.009-1.066)
.010
1.015 (0.968-1.063)
.543
Biopsy GS (Categorical)
1.418 (1.087-1.850)
0.010
0.468 (0.338-0.648)
< 0.001
1.125 (0.854-1.483)
.403
1.731 (1.193-2.512)
.004
cT stage (Categorical)
1.530 (0.766-3.054)
0.228
1.340 (0.802-2.240)
0.264
1.184 (0.620-2.262)
.609
1.444 (0.491-4.248)
.505
Note: The Biopsy GS was categorized into a five-grade group: grade group 1 (Gleason score = 6), grade group 2 (Gleason score 3 + 4 = 7), grade group 3 (Gleason score 4 + 3 = 7), grade group 4 (Gleason score 8), and grade group 5 (Gleason score 9-10); the cT stage was categorized into cT1 and cT2.
however, the clinical significance of this disease is still in debate. The single positive core PCa was initially considered to be low-risk disease, while several studies had shown that not all of these patients had clinically insignificant cancer in the final pathological evaluation of RP.
192 patients of PCa with a single minute focus (5% or less) of biopsy GS 6 were included, while 22% of the patients had adverse pathological outcomes (including upgrading in 18% and upstaging in 8%) after surgery. Another analysis of 503 Japanese patients with single positive core PCa showed that 258 (51.3%) had ≥ pT2c disease and 160 (32%) had an upgraded GS on their final pathology.
Our results also suggested that the patients with single positive core may not be ideal candidates for AS, as 36.9% had undergraded GSs, 16.4% had PSMs, 15.0% had PNI, 3.4% had ECE and 2.4% had SVI.
Previous studies have found that GS determined by the biopsy was upgraded on the pathologic specimen in 19% to 57% of patients.
Is biopsy Gleason score independently associated with biochemical progression following radical prostatectomy after adjusting for pathological Gleason score?.
The significant discrepancies of the GS between the biopsy and RP specimens might attribute to several factors, such as interobserver variability, the biopsy technique, and the number of biopsy cores. Considering that the GS is one of the most important prognostic factors for PCa, the frequency of GS upgrading has a significant impact on treatment options between AS and curative therapy, especially for the patients with well-differentiated adenocarcinoma diagnosed with single positive core PCa. Our results showed that 36.9% of cases were upgraded after prostatectomy, which was consistent with those published studies. In the multivariate analysis, serum PSA levels were positively associated with GS upgrading, indicating that the higher concordance between biopsy and RP analysis occurred when the patient had a low PSA level. While biopsy GS was a negative predictor of GS upgrading, which supported a cautious approach to categorizing single core positive PCa of GS 6 as insignificant cancer since these patients have a higher risk of higher-grade disease than suggested on initial biopsy.
ECE and SVI are associated with an increased risk of biochemical recurrence (BR) and PCa-specific death
Incidence of upgrading and upstaging in patients with low-volume Gleason score 3+4 prostate cancers at biopsy: finding a new group eligible for active surveillance.
observed that of the 503 patients with a single positive core PCa, 159 (32%) had pathological findings ≥ pT3. Interestingly, this pT3 rate was significantly higher than that in the multiple positive core group (27%). In the present study, 7.2% of the patients became bilateral tumors, 6.8% upstaged to T3 stage, which is much lower than that reported previously. Despite the significant discordance of GS between the biopsy and RP specimens, higher biopsy GS predicted an increased risk of pT3 stage in the multivariate model. Chaux et al
High-grade prostatic adenocarcinoma present in a single biopsy core is associated with increased extraprostatic extension, seminal vesicle invasion, and positive surgical margins at prostatectomy.
Pathologic findings in radical prostatectomy specimens from patients eligible for active surveillance with highly selective criteria: a multicenter study.
High-grade prostatic adenocarcinoma present in a single biopsy core is associated with increased extraprostatic extension, seminal vesicle invasion, and positive surgical margins at prostatectomy.
Can a gleason 6 or less microfocus of prostate cancer in one biopsy and prostate-specific antigen level <10 ng/mL be defined as the archetype of low-risk prostate disease?.
We similarly observed a positivity of 16.4% in our patients. In the multivariate model, preoperative PSA was the only independent predictor of PSMs in single positive core patients. However, the RP was performed by several surgeons, using open, laparoscopic or robotic surgical techniques, and the impact of surgeon variability on the incidence of PSMs should not be ignored,
Predictors of positive surgical margins after radical prostatectomy at a single institution: preoperative and pathologic factors, and the impact of surgeon variability and technique on incidence and location.
PNI is a very common pathological entity in RP specimen and an important mechanism of tumor progression through the prostatic capsule. The prognostic significance of PNI remains controversial. Some studies have shown that PNI does not predict BR,
Limited value of perineural invasion in radical prostatectomy specimens as a predictor of biochemical recurrence in Japanese men with clinically localized prostate cancer.
Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy: importance of percentage of biopsies that contain tumor and the presence of biopsy perineural invasion.
while no study has reported the incidence of PNI in patients with single positive core. PNI was found in 15% of our cases, which is much lower than that of patients with multifocal PCa. Understandably, high biopsy GS was associated with a significantly increased risk of PNI in our study.
One strength of our study is the relatively large number of patients included. On the other hand, the main limitation is that the biopsy and RP specimens were examined by two pathologists in our institute, which may lead to interobserver variability, which is common in GS interpretation. In addition, the use of diagnostic multiparametric MRI, such as MRI-TRUS fusion biopsy and direct MRI-guided biopsy, has increased the detection rate of clinically significant PCa.
However, this technique, which may affect the results of the present study, is not available in our hospital. Finally, limited follow-up prevented a thorough examination of biochemical outcomes in patients who experienced upgrading and/or upstaging.
Conclusions
In conclusion, our results show that single positive core PCa should not considered as indolent disease as a certain proportion of them has malignant potential after prostatectomy. Further analysis is required to verify the clinical and pathological characteristics of patients diagnosed with single positive core and develop a nomogram to predict the probability of insignificant PCa.
Clinical Practice Points
•
The widespread use of PSA screening has resulted in a steady increase in the overall proportion of patients diagnosed with single-core positivity on prostate biopsy, but the clinical significance hasn't yet been determined in Chinese men with PCa.
•
We found that there was a greater than 1/3 risk of pathological upgrading in single positive core PCa, and it did not guarantee a favorable pathological outcome after RP.
•
Patients with single positive core PCa may harbor more aggressive disease, and this information may prove valuable when counseling patients regarding outcomes and determining the necessity of definite treatment.
Disclosure
The authors declare no conflicts of interest in the publication of this study
Acknowledgments
This study was supported by the Natural Science Foundation of Zhejiang Province (Grant No. LY18H160010 ).
Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005.
The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy.
Predicting disease recurrence in intermediate and high-risk patients undergoing radical prostatectomy using percent positive biopsies: results from CaPSURE.
The volume of prostate cancer in the biopsy specimen cannot reliably predict the quantity of cancer in the radical prostatectomy specimen on an individual basis.
Can the core length involved with prostate cancer identify clinically insignificant disease in low risk patients diagnosed on the basis of a single positive core?.
The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system.
Is biopsy Gleason score independently associated with biochemical progression following radical prostatectomy after adjusting for pathological Gleason score?.
Incidence of upgrading and upstaging in patients with low-volume Gleason score 3+4 prostate cancers at biopsy: finding a new group eligible for active surveillance.
High-grade prostatic adenocarcinoma present in a single biopsy core is associated with increased extraprostatic extension, seminal vesicle invasion, and positive surgical margins at prostatectomy.
Pathologic findings in radical prostatectomy specimens from patients eligible for active surveillance with highly selective criteria: a multicenter study.
Can a gleason 6 or less microfocus of prostate cancer in one biopsy and prostate-specific antigen level <10 ng/mL be defined as the archetype of low-risk prostate disease?.
Predictors of positive surgical margins after radical prostatectomy at a single institution: preoperative and pathologic factors, and the impact of surgeon variability and technique on incidence and location.
Limited value of perineural invasion in radical prostatectomy specimens as a predictor of biochemical recurrence in Japanese men with clinically localized prostate cancer.
Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy: importance of percentage of biopsies that contain tumor and the presence of biopsy perineural invasion.
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