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Article of the Month: Combined mpMRI Fusion and Systematic Biopsies Predict the Final Tumour Grading after RP

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Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Angelika Borkowetz, discussing her paper.

If you only have time to read one article this week, it should be this one.

Direct comparison of multiparametric magnetic resonance imaging (MRI) results with final histopathology in patients with proven prostate cancer in MRI/ultrasonography-fusion biopsy

Angelika Borkowetz*, Ivan Platzek†, Marieta Toma‡, Theresa Renner*, Roman Herout*, Martin Baunacke*, Michael Laniado†, Gustavo Baretton‡, Michael Froehner*, Stefan Zastrow* and Manfred Wirth*

 

*Department of Urology, †Department of Radiology and Interventional Radiology, and
‡Department of Pathology, Technische Universitat Dresden, Dresden, Germany

 

Read the full article

Objective

To compare multiparametric magnetic resonance imaging (mpMRI) of the prostate and histological findings of both targeted MRI/ultrasonography-fusion prostate biopsy (PBx) and systematic PBx with final histology of the radical prostatectomy (RP) specimen.

Patients and Methods

A total of 105 patients with prostate cancer (PCa) histopathologically proven using a combination of fusion Pbx and systematic PBx, who underwent RP, were investigated. All patients had been examined using mpMRI, applying the European Society of Urogenital Radiology criteria. Histological findings from the RP specimen were compared with those from the PBx. Whole-mount RP specimen and mpMRI results were directly compared by a uro-pathologist and a uro-radiologist in step-section analysis.

AugAOTM1

Results

In the 105 patients with histopathologically proven PCa by combination of fusion PBx and systematic PBx, the detection rate of PCa was 90% (94/105) in fusion PBx alone and 68% (72/105) in systematic PBx alone (P = 0.001). The combination PBx detected 23 (22%) Gleason score (GS) 6, 69 (66%) GS 7 and 13 (12%) GS ≥8 tumours. Fusion PBx alone detected 25 (26%) GS 6, 57 (61%) GS 7 and 12 (13%) GS ≥8 tumours. Systematic PBx alone detected 17 (24%) GS 6, 49 (68%) GS 7 and 6 (8%) GS ≥8 tumours. Fusion PBx alone would have missed 11 tumours (4% [4/105] of GS 6, 6% [6/105] of GS 7 and 1% [1/105] of GS ≥8 tumours). Systematic PBx alone would have missed 33 tumours (10% [10/105] of GS 6, 20% [21/105] of GS 7 and 2% [2/105] of GS ≥8 tumours). The rates of concordance with regard to GS between the PBx and RP specimen were 63% (n = 65), 54% (n = 56) and 75% (n = 78) in fusion, systematic and combination PBx (fusion and systematic PBx combined), respectively. Upgrading of the GS between PBx and RP specimen occurred in 33% (n = 34), 44% (n = 46) and 18% (n = 19) in fusion, systematic and combination PBx, respectively. γ-correlation for detection of any cancer was 0.76 for combination PBx, 0.68 for fusion PBx alone and 0.23 for systematic PBx alone. In all, 84% (n = 88) of index tumours were identified by mpMRI; 86% (n = 91) of index lesions on the mpMRI were proven in the RP specimen.

Conclusions

Fusion PBx of tumour-suspicious lesions on mpMRI was associated with a higher detection rate of more aggressive PCa and a better tumour prediction in final histopathology than systematic PBx alone; however, combination PBx had the best concordance for the prediction of GS. Furthermore, the additional findings of systematic PBx reflect the multifocality of PCa, therefore, the combination of both biopsy methods would still represent the best approach for the prediction of the final tumour grading in PCa.

Read more articles of the week

Editorial: Role of systematic biopsy in the era of mpMRI and US fusion guidance

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The success of multiparametric MRI (mpMRI) and MRI/ultrasound (US) fusion-guided biopsies in improving the detection of prostate cancer in patients with occult disease (elevated PSA level with prior negative biopsies) and optimising the detection of clinically significant cancer has been reported by centres that have served as early adopters of these techniques [1, 2]. Technological advances in MRI and associated imaging protocols, as well as increased clinical experience with MRI interpretation have led to increased prospective detection and characterisation of clinically significant prostate cancer. This, in conjunction with increasing experience with MRI/US fusion-guided prostate biopsy techniques, has led to the re-evaluation of the contributory role and utility of systematic template US-guided prostate biopsies in the diagnosis of prostate cancer. It is an attractive proposition to forego the systematic biopsy when performing MRI-directed fusion biopsy, as this would minimise the duration, morbidity, and overall cost of the biopsy procedure and post-biopsy pathology processing. However, before adopting this approach, it is important to first consider the potential possibility of missing clinically significant cancer diagnoses when relying on the targeted biopsy cores in isolation.

In this issue of BJUI, Borkowetz et al. [3] report their results of biopsy histological yields on systematic biopsies compared with MRI/US fusion biopsies in their series of patients who underwent radical prostatectomy (RP). These results corroborate previously reported comparisons of fusion biopsy of suspicious lesions on MRI performed concurrently with systematic biopsy, consistently showing an improved detection of both overall prostate cancer foci and, more importantly, an improved detection of clinically significant higher grade cancer foci [1, 2]. It is important to note that the overall detection rate and detection rate for clinically significant prostate cancer was highest when fusion and systematic biopsies were evaluated in conjunction with each other. Another important factor to consider when evaluating the utility and value of these biopsy techniques is the concordance of the pathology of the biopsy specimen with the final pathology of the RP specimen, the ‘gold standard’. The concordance of Gleason grade assigned on targeted fusion-biopsy cores and RP outperformed that of systematic biopsy cores and RP. This, in essence, suggests that targeted biopsy can perform as well, and likely better, than the systematic biopsy approach of sampling the prostate with a systematic-sextant approach, which has been the long standing standard of care for the diagnosis of prostate cancer. Again, it is important to note that the greatest concordance in this study was achieved when the results of the fusion and systematic biopsy cores were combined.

The question now arises regarding the ‘cost’ for the incremental improvement in cancer detection provided by the combination of both MRI-directed fusion biopsy and the systematic biopsy approach. The improved negative predictive value parallels the increased sensitivity for cancer detection by having a larger sampling of the prostate by augmenting the number of biopsy cores sampled and submitted for histopathological evaluation. The area under the curve for detection of clinically significant cancer reported by Borkowetz et al. [3] was not improved by adding systematic biopsies to the targeted biopsies. However, this experience described a mixed population of patients, most of whom had undergone prior prostate biopsy with benign pathology. This creates an enriched population who likely harbours prostate cancers that are more occult to the systematic biopsy approach, thus improving the diagnostic yield of MRI-directed biopsies even further. This is concordant with the work presented by Mendhiratta et al. [4], where systematic biopsies added little to the diagnosis of clinically significant prostate cancer in a population of men undergoing MRI/US fusion-guided biopsy after prior cancer-negative biopsy sessions.

Alternatively, current datasets for biopsy naïve patients have not shown the same degree of convincingly improved detection with targeted biopsies over systematic biopsies. In fact, Delongchamps et al. [5] recently reported a slightly lower rate of overall cancer detection with fusion-guided targeted biopsies vs systematic biopsy cores; however, the difference in detection of clinically significant prostate cancer was not statistically significant. Further study of the role of targeted biopsy in the biopsy naïve patient population is warranted, as there is suggestion that cancer detection efficiency per needle core is significantly improved with MRI-directed biopsies over systematic biopsies [6]. Alternatively, in patients with prior negative systematic biopsies and continued clinical suspicion for prostate cancer, a repeat biopsy session with targeted cores alone may be appropriate, particularly as these patients have previously undergone standard-of-care, extended sextant biopsy.

Read the full article
Jason A. Pietryga* and Soroush Rais-Bahrami*,†
*Department of Radiology, and †Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA

 

References

 

1 Siddiqui MM, Rais-Bahrami S, Turkbey B et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015; 313: 390–7

 

2 Sonn GA, Chang E, Natarajan S et al. Value of targeted prostate biopsy using magnetic resonance-ultrasound fusion in men with prior negative biopsy and elevated prostate-specific antigen. Eur Urol 2014; 65: 809–15

 

3 Borkowetz A, Platzek I, Toma M et al. Direct comparison of multiparametric magnetic resonance imaging (MRI) results with final histopathology in patients with proven prostate cancer in MRI/ultrasonography-fusion biopsy. BJU Int 2016; 118:213–20

 

4 Mendhiratta N, Meng X, Rosenkrantz AB et al. Prebiopsy MRI and MRI-ultrasound fusion-targeted prostate biopsy in men with previous negative biopsies: impact on repeat biopsy strategies. Urology 2015; 86:1192–9

 

5 Delongchamps NB, Portalez D, Bruguiere E et al. Are MRI-TRUS-guided targeted biopsies non-inferior to TRUS-guided systematic biopsies for the detection of prostate cancer in patients with a single suspicious focus on multiparametric prostate MRI? Results of a multicentric controlled trial. J Urol 2016; [Epub ahead of print]. DOI: 10.1016/ j.juro.2016.04.003

 

6 Siddiqui MM, George AK , Rubin R et al. Comparison of biopsy efficiency between MR/Ultrasound fusion guided biopsy and standard extended-sextant biopsy in men with MR-visible lesions in the prostate. J Natl Cancer Inst 2016;108: pii: djw039. DOI: 10.1093/jnci/djw039

 

Video: Combined mpMRI Fusion and Systematic Biopsies Predict the Final Tumour Grading after RP

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Direct comparison of multiparametric magnetic resonance imaging (MRI) results with final histopathology in patients with proven prostate cancer in MRI/ultrasonography-fusion biopsy

Angelika Borkowetz*, Ivan Platzek†, Marieta Toma‡, Theresa Renner*, Roman Herout*, Martin Baunacke*, Michael Laniado†, Gustavo Baretton‡, Michael Froehner*, Stefan Zastrow* and Manfred Wirth*

 

*Department of Urology, †Department of Radiology and Interventional Radiology, and
‡Department of Pathology, Technische Universitat Dresden, Dresden, Germany

 

Read the full article

Objective

To compare multiparametric magnetic resonance imaging (mpMRI) of the prostate and histological findings of both targeted MRI/ultrasonography-fusion prostate biopsy (PBx) and systematic PBx with final histology of the radical prostatectomy (RP) specimen.

Patients and Methods

A total of 105 patients with prostate cancer (PCa) histopathologically proven using a combination of fusion Pbx and systematic PBx, who underwent RP, were investigated. All patients had been examined using mpMRI, applying the European Society of Urogenital Radiology criteria. Histological findings from the RP specimen were compared with those from the PBx. Whole-mount RP specimen and mpMRI results were directly compared by a uro-pathologist and a uro-radiologist in step-section analysis.

AugAOTM1

Results

In the 105 patients with histopathologically proven PCa by combination of fusion PBx and systematic PBx, the detection rate of PCa was 90% (94/105) in fusion PBx alone and 68% (72/105) in systematic PBx alone (P = 0.001). The combination PBx detected 23 (22%) Gleason score (GS) 6, 69 (66%) GS 7 and 13 (12%) GS ≥8 tumours. Fusion PBx alone detected 25 (26%) GS 6, 57 (61%) GS 7 and 12 (13%) GS ≥8 tumours. Systematic PBx alone detected 17 (24%) GS 6, 49 (68%) GS 7 and 6 (8%) GS ≥8 tumours. Fusion PBx alone would have missed 11 tumours (4% [4/105] of GS 6, 6% [6/105] of GS 7 and 1% [1/105] of GS ≥8 tumours). Systematic PBx alone would have missed 33 tumours (10% [10/105] of GS 6, 20% [21/105] of GS 7 and 2% [2/105] of GS ≥8 tumours). The rates of concordance with regard to GS between the PBx and RP specimen were 63% (n = 65), 54% (n = 56) and 75% (n = 78) in fusion, systematic and combination PBx (fusion and systematic PBx combined), respectively. Upgrading of the GS between PBx and RP specimen occurred in 33% (n = 34), 44% (n = 46) and 18% (n = 19) in fusion, systematic and combination PBx, respectively. γ-correlation for detection of any cancer was 0.76 for combination PBx, 0.68 for fusion PBx alone and 0.23 for systematic PBx alone. In all, 84% (n = 88) of index tumours were identified by mpMRI; 86% (n = 91) of index lesions on the mpMRI were proven in the RP specimen.

Conclusions

Fusion PBx of tumour-suspicious lesions on mpMRI was associated with a higher detection rate of more aggressive PCa and a better tumour prediction in final histopathology than systematic PBx alone; however, combination PBx had the best concordance for the prediction of GS. Furthermore, the additional findings of systematic PBx reflect the multifocality of PCa, therefore, the combination of both biopsy methods would still represent the best approach for the prediction of the final tumour grading in PCa.

Read more articles of the week

Article of the Month: Further Evidence that Bladder Cancer Patients should Stop Smoking

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Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post. Smoking in a daily basis can affect your lungs, make sure to improve your indoor air quality just by checking out the latest blaux portable ac reviews.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Trends in the risk of second primary cancer among bladder cancer survivors: a population-based cohort of 10 047 patients

Joris Muller*,†, Pascale Grosclaude‡,§, Benedicte Lapotre-Ledoux§,, Anne-Sophie Woronoff§,**, Anne-Valerie Guizard§,††, Simona Bara§,‡‡, Marc Colonna§,§§, Xavier Troussard§,¶¶, Veronique Bouvier§,***, Brigitte Tretarre§,†††, Michel Velten*,†,§,‡‡‡ and Jeremie Jegu*,†,§
*Bas-Rhin Cancer Registry, EA 3430, FMTS, University of Strasbourg, †Department of Public Health, University Hospital of Strasbourg, Strasbourg, ‡Tarn Cancer Registry, Albi, §
Francim: Reseau francais des registres des cancers, Toulouse, Somme Cancer Registry, Department of Hygiene and Public Health, University Hospital of Amiens, Amiens, **Doubs and Belfort Territory Cancer Registry, University Hospital of Besancon, Besancon, ††Calvados General Cancer Registry, Cancers & Preventions, U 1086 Inserm, Francois Baclesse Centre, Caen, ‡‡Manche Cancer Registry, Cotentin Hospital, Cherbourg-Octeville, §§Isere Cancer Registry, University Hospital of Grenoble, Grenoble, ¶¶Basse-Normandie Haematological Malignancies Cancer Registry, University Hospital of Caen, ***Calvados Digestive Cancer Registry, Cancers & Preventions, U 1086 Inserm, Francois Baclesse Centre, Caen, †††Herault Cancer Registry, Research Center, Montpellier , and ‡‡‡Department of Epidemiology and Biostatistics, Paul Strauss Center, Strasbourg, France
Read the full article

Objectives

To determine whether the risk of second primary cancer (SPC) among patients with bladder cancer (BCa) has changed over past years.

Materials and Methods

Data from 10 French population-based cancer registries were used to establish a cohort of 10 047 patients diagnosed with a first invasive (≥T1) BCa between 1989 and 2004 and followed up until 2007. An SPC was defined as the first subsequent primary cancer occurring at least 2 months after a BCa diagnosis. Standardized incidence ratios (SIRs) of metachronous SPC were calculated. Multivariate Poisson regression models were used to assess the direct effect of the year of BCa diagnosis on the risk of SPC.

JulAOTW1Results

Results

The risk of new malignancy among BCa survivors was 60% higher than in the general population (SIR 1.60, 95% confidence interval [CI] 1.51–1.68). Male patients presented a high risk of SPC of the lung (SIR 3.12), head and neck (SIR 2.19) and prostate (SIR 1.54). In multivariate analyses adjusted for gender, age at diagnosis and follow-up, a significant increase in the risk of SPC of the lung was observed over the calendar year of BCa diagnosis (P for linear trend 0.010), with an SIR increasing by 3.7% for each year (95% CI 0.9–6.6%); however, no particular trend was observed regarding the risk of SPC of the head and neck (P = 0.596) or the prostate (P = 0.518).

Conclusions

As the risk of SPC of the lung increased between 1989 and 2004, this study contributes more evidence to support the promotion of tobacco smoking cessation interventions among patients with BCa.

Read more articles of the week

Editorial: Analysis of Genetics to Identify Susceptibility to Secondary Malignancies in Patients with BCa

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A study by Muller et al. [1] evaluated a cohort of 10 047 patients diagnosed with a first invasive (≥T1) bladder cancer and found that independent of gender and age, the risk of subsequent lung cancer was increased. This is not surprising considering the strong association of both bladder and lung cancer with tobacco, which is the main risk factor for both malignancies. While the authors limited their analysis to patients with invasive disease, the same association of bladder and lung cancer probably holds true for patients with non-invasive disease. An important question this raises is whether urologists should be more proactive in screening for lung cancer in their patients with bladder cancer. While chest radiographs are commonly used to monitor patients who undergo cystectomy, they are not routinely used for patients with non-invasive disease. Furthermore, the recommendations for screening for lung cancer based on the National Lung Cancer Screening Trial (NLST) involve use of low-dose chest CT, which is rarely done routinely by urologists [2]. In the Muller et al. [1] study, despite the large cohort and median follow-up of 3.1 years, there were still only 295 cases of lung cancer. This was three-times the expected incidence but overall a low rate.

One interesting consideration is whether use of genetic factors may be useful to identify which patients might be at higher risk at baseline for subsequent secondary cancers. Currently, single nucleotide polymorphism (SNP) analysis is not used clinically in screening but other genetic abnormalities such as BRCA (BReast Cancer gene) mutations and Lynch syndrome have been used to identify secondary malignancies. However, identifying individuals at higher risk of developing cancer may inform clinicians and allow for a more targeted screening strategy, even in patients of increased baseline risk.

The USA National Cancer Institute performed genome-wide association studies (GWAS) for 49 492 patients with cancer and 34 131 controls to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers [3]. They calculated that at least 24% and 7% of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Only four pairs of cancers had marginally statistically significant correlations including bladder and lung.

While tobacco is the major cause of lung cancer, only ≈10% of smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. The International Lung Cancer Consortium pooled genotype data for SNPs at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 patients with lung cancer and 14 954 control subjects [4]. Associations between 15q25 and the risk of lung cancer were replicated in White ever-smokers (rs16969968) but there was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, they confirmed statistically significant associations in Whites for both rs2736100 and rs402710 and identified similar associations in Asians. Zhang et al. [5] undertook a gene–smoking interaction analysis in a GWAS of lung cancer in Han Chinese population of 5 408 subjects (2 331 patients and 3 077 controls) using a two-phase designed case-control study. They identified two SNPs associated with lung cancer and smoking, including one with a synergistic interaction (rs4589502) and one with an antagonistic interaction (rs131629).

There have also been several studies evaluating SNPs and risk of bladder cancer. A study of 1 595 patients and 1 760 controls, stratified for smoking habits, found that different SNP combinations were relevant in smokers and non-smokers [6]. In smokers, polymorphisms involved in detoxification of cigarette smoke carcinogens were most relevant (GSTM1 [glutathione S-transferase μ1], rs11892031), in contrast to those in non-smokers where MYC (v-myc avian myelocytomatosis viral oncogene homolog) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A) near polymorphisms (rs9642880, rs1014971) were the most influential. A study of genome-wide interaction of smoking and bladder cancer risk based on data from 3 002 patients and 4 411 controls with validation in a separate dataset identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use [7]. These studies of genetic polymorphisms add evidence regarding the impact of gene–environment interactions, which influence the detrimental effects of tobacco on risk of bladder cancer.

There are other genetic polymorphisms that have been found to increase risk of tobacco-related malignancies. A study of polymorphisms inNAT2 (N-acetyltransferase 2 [arylamine N-acetyltransferase]), GSTM1, NAT1, GSTT1 (GST θ1), GSTM3, and GSTP1 (GST π1) in 1 150 patients with bladder cancer and 1 149 controls found that compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (odds ratio 1.4, 95% CI 1.2–1.7), which was stronger for cigarette smokers than for never smokers. No significant associations were found with the other polymorphisms [8]. The overall association for GSTM1 was also robust (P < 0.001) but was not modified by smoking status (P = 0.86).

While it may be too early to apply GWAS to all patients who smoke, a trial focusing on those with other tobacco-related malignancies may identify cohorts where screening for other malignancies is not only effective but also practical.

Read the full article
Yair Lotan, Professor of Urology
Department of Urology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA

 

References

 

1 Muller J, Grosclaude P, Lapotre-Ledoux B et al. Trends in the risk of second primary cancer among bladder cancer survivors: a population-based cohort of 10 047 patients. BJU Int 2016; 118: 53–9

 

2 National Lung Screening Trial Research Team, Aberle DR, Adams AM et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395–409

 

3 Sampson JN, Wheeler WA, Yeager M et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst 2015; 107: pii: djv279. doi: 10.1093/jnci/djv279

 

4 Truong T, Hung RJ, Amos CI et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 2010; 102: 959–71

 

5 Zhang R, Chu M, Zhao Y et al. A genome-wide gene-environment interaction analysis for tobacco smoke and lung cancer susceptibility. Carcinogenesis 2014; 35: 1528–35

 

6 Schwender H, Selinski S, Blaszkewicz M et al. Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLoS One 2012; 7: e51880

 

7 Figueroa JD, Han SS, Garcia-Closas M et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 2014; 35: 1737–44

 

8 Garcia-Closas M, Malats N, Silverman D et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005; 366: 649–59

 

Article of the Month: Gleason Grading in the Spotlight

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Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Klaus Brasso, discussing his paper.

If you only have time to read one article this week, it should be this one.

The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading – a matched pair analysis

Kasper D. Berg*, Frederik B. Thomsen*, Camilla Nerstrøm*, Martin A. Røder*, Peter
Iversen*, Birgitte G. Toft†, Ben Vainer† and Klaus Brasso*

 

*Department of Urology, Copenhagen Prostate Cancer Center and †Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

 

Read the full article

Objectives

To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4).

Patients and methods

A matched-pair analysis was conducted. In all, 215 patients with Gleason score 6 or 7 (3 + 4) prostate cancer on biopsy who underwent RP before 31 December 2005 (pre-ISUP group), were matched 1:1 by biopsy Gleason score, clinical tumour category, PSA level, and margin status to patients undergoing RP between 1 January 2008 and 31 December 2011 (post-ISUP group). Patients were followed until BCR defined as a PSA level of ≥0.2 ng/mL. Risk of BCR was analysed in a competing-risk model.

JunAOTMResults

Results

The median follow-up was 9.5 years in the pre-ISUP group and 4.8 years in the post-ISUP group. The 5-year cumulative incidences of BCR were 34.0% and 13.9% in the pre-ISUP and post-ISUP groups, respectively (P < 0.001). The difference in cumulative incidence applied to both patients with Gleason score 6 (P < 0.001) and 7 (3 + 4) (P = 0.004). There was no difference in the 5-year cumulative incidence of BCR between patients with pre-ISUP Gleason score 6 and post-ISUP Gleason score 7 (3 + 4) (P = 0.34). In a multiple Cox-proportional hazard regression model, ISUP 2005 grading was a strong prognostic factor for BCR within 5 years of RP (hazard ratio 0.34; 95% confidence interval 0.22–0.54; P < 0.001).

Conclusion

The revision of the Gleason grading system has reduced the risk of BCR after RP in patients with biopsy Gleason score 6 and 7 (3 + 4). This may have consequences when comparing outcomes across studies and historical periods and may affect future treatment recommendations.

Read more articles of the week

Editorial: Current Gleason score 3 + 4 = 7: has it lost its significance compared with its historical counterpart?

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Berg et al. [1] report that patients classified as Gleason score 7 (3 + 4) according to the revised grading system published in 2005 are to some extent similar to patients with pre-2005 Gleason score 6, at least in terms of risk of biochemical recurrence. The logical but not necessarily correct conclusion is that current patients with Gleason score 7 on biopsy are appropriate candidates for active surveillance.

What must be kept in mind is that, using the post-2005 revised grading system, approximately 25% of men with Gleason score 3 + 4 = 7 on biopsy have either 3 + 4 = 7 with tertiary pattern 5 or >4 + 3 = 7 in the corresponding radical prostatectomy [1]. With the exception of men with a limited life expectancy, these men need definitive therapy for their potentially life-threatening cancer. Numerous studies have shown that extended biopsies, whether they are >10- or 12-core, are associated with less upgrading than sextant biopsies [2]. In the report by Berg et al. [1], the median number of cores sampled before 2005 was 6 with an interquartile range (IQR) of 6–6 compared with a median (IQR) of 10 (10–12) cores after 2005. Consequently, in their cohorts, the pre-2005 group of men with Gleason score 3 + 3 = 6 were more likely to have unsampled higher grade cancer and a correspondingly worse prognosis more closely approximating post-2005 better-sampled Gleason score 3 + 4 = 7 cancers.

Berg et al. [1] further claim that the prognostic and clinical value of Gleason score 7 has been weakened since the 2005 modifications. In fact, the revised grading system more accurately reflects prostate cancer biology than the pre-2005 Gleason system. The major consequence of the modification, as Berg et al. [3] illustrate, has been the better prognosis associated with post-2005 Gleason score 6 cancer because patterns associated with more aggressive behaviour have been shifted to Gleason score 7. Historically, a diagnosis of Gleason score 6 cancer, even at radical prostatectomy, was not as predictive of ‘good’ behaviour, and had a higher rate of progression with some men even dying from prostate cancer [4]. Currently, Gleason score 6 cancer at radical prostatectomy has a 96% cure rate at 5 years, even including cases with extraprostatic extension and positive margins [3]. Several studies have shown that post-2005 pure Gleason score 6 cancers at radical prostatectomy are incapable of metastasizing to lymph nodes [4]. Berg et al. are correct, however, that men with a post-2005 grade of Gleason Score 3 + 4 = 7 have a better prognosis than those graded prior to 2005. As a consequence, it has been recommended that pathologists should record the percent pattern 4 in cases with Gleason score 7 on biopsy for men being considered for active surveillance [5]. For the appropriate patient, depending on age, comorbidity, extent of cancer, MRI findings, patient desire, etc., could be a candidate for active surveillance with Gleason score 3 + 4 = 7 if the pattern 4 is limited. Currently, this information is not transparent in most pathology reports.

A new grading system, first proposed in BJUI by this author, and verified in a large multi-institutional study, resulted in a simplified five-grade group system that more accurately reflects the biology of prostate cancer than the pre-2005 grading system [3, 6]. Men with Gleason score 6 cancers need to be reassured that their cancer is the lowest grade that is currently assigned, despite Gleason scores ranging from 2 to 10. In addition, I have talked to some patients with Gleason score 3 + 4 = 7 who think that they are going to die in the near future because their score of 7 was closer to highest grade of 10 than the lowest grade of 2. With the new grading system, patients can be reassured that they have a Grade group 1 (3 + 3 = 6) out of 5, which is the lowest grade, or a Grade group 2 (Gleason score 3 + 4 = 7) out of 5, which is still a relatively low grade.

Read the full article
Jonathan I. Epstein
Departments of Pathology, Urology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

 

References

 

1 Berg KD, Thomsen FB, Nerstrom C et al. The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading – a matched pair analysis. BJU Int 2016; 117: 883–9

 

2 Epstein JI, Feng Z, Trock BJ , Pierorazio PM. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur Urol 2012; 61: 1019–24

 

3 Epstein JI, Zelefsky MJ, Sjoberg DD et al. A contemporary prostate cancer grading system: a validated alternative to Gleason score. Eur Urol 2016; 69: 428–35

 

4 RossHM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI. Do adenocarcinomas of the prostate with Gleason score (GS) ≤ 6have the potential to metastasize to lymph nodes? Am J Surg Pathol 2012; 36: 1346–52

 

5 Kryvenko ON, Epstein JI. Prostate cancer grading: a decade after the 2005 modified Gleason grading system. Arch Pathol Lab Med 2016; [Epub ahead of print]

 

6 Pierorazio PM, Walsh PW, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int 2013; 111: 753–60

 

Video: Gleason Grading in the Spotlight

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The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading – a matched pair analysis

Kasper D. Berg*, Frederik B. Thomsen*, Camilla Nerstrøm*, Martin A. Røder*, Peter Iversen*, Birgitte G. Toft†, Ben Vainer† and Klaus Brasso*

 

*Department of Urology, Copenhagen Prostate Cancer Center and †Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

 

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Objectives

To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4).

Patients and methods

A matched-pair analysis was conducted. In all, 215 patients with Gleason score 6 or 7 (3 + 4) prostate cancer on biopsy who underwent RP before 31 December 2005 (pre-ISUP group), were matched 1:1 by biopsy Gleason score, clinical tumour category, PSA level, and margin status to patients undergoing RP between 1 January 2008 and 31 December 2011 (post-ISUP group). Patients were followed until BCR defined as a PSA level of ≥0.2 ng/mL. Risk of BCR was analysed in a competing-risk model.

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Results

The median follow-up was 9.5 years in the pre-ISUP group and 4.8 years in the post-ISUP group. The 5-year cumulative incidences of BCR were 34.0% and 13.9% in the pre-ISUP and post-ISUP groups, respectively (P < 0.001). The difference in cumulative incidence applied to both patients with Gleason score 6 (P < 0.001) and 7 (3 + 4) (P = 0.004). There was no difference in the 5-year cumulative incidence of BCR between patients with pre-ISUP Gleason score 6 and post-ISUP Gleason score 7 (3 + 4) (P = 0.34). In a multiple Cox-proportional hazard regression model, ISUP 2005 grading was a strong prognostic factor for BCR within 5 years of RP (hazard ratio 0.34; 95% confidence interval 0.22–0.54; P < 0.001).

Conclusion

The revision of the Gleason grading system has reduced the risk of BCR after RP in patients with biopsy Gleason score 6 and 7 (3 + 4). This may have consequences when comparing outcomes across studies and historical periods and may affect future treatment recommendations.

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Article of the Month: IFES to manage non-neuropathic UAB in children

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Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Sanam Ladi Seyedian, discussing her paper.

If you only have time to read one article this week, it should be this one.

Transcutaneous interferential electrical stimulation for the management of non-neuropathic underactive bladder in children: a randomised clinical trial

 

Abdol-Mohammad Kajbafzadeh, Lida Sharifi-Rad*, Seyedeh-Sanam Ladi-Seyedian and Sarah Mozafarpour

 

Department of Pediatric Urology, Pediatric Urology Research Center, and *Department of Physical Therapy, Children’s Hospital Medical Center, Pediatric Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran

 

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Objectives

To assess the efficacy of transcutaneous interferential electrical stimulation (IFES) and urotherapy in the management of non-neuropathic underactive bladder (UAB) in children with voiding dysfunction.

Patients and Methods

In all, 36 children with UAB without neuropathic disease [15 boys, 21 girls; mean (sd) age 8.9 (2.6) years] were enrolled and then randomly allocated to two equal treatment groups comprising IFES and control groups. The control group underwent only standard urotherapy comprising diet, hydration, scheduled voiding, toilet training, and pelvic floor and abdominal muscles relaxation. Children in the IFES group likewise underwent standard urotherapy and also received IFES. Children in both groups underwent a 15-session treatment programme twice a week. A complete voiding and bowel habit diary was completed by parents before, after treatment, and 1 year later. Bladder ultrasound and uroflowmetry/electromyography were performed before, at the end of treatment course, and at the 1-year follow-up.

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Results

The mean (sd) number of voiding episodes before treatment was 2.6 (1) and 2.7 (0.76) times/day in the IFES and control groups, respectively, which significantly increased after IFES therapy in IFES group, compared with only standard urotherapy in the control group [6.3 (1.4) vs 4.7 (1.3) times/day, P < 0.002). The mean (sd) bladder capacity before treatment was 424 (123) and 463 (121) mL in the control and IFES groups, respectively, which decreased significantly at 1 year after treatment in the IFES group compared with the controls, at 227 (86) vs 344 (127) mL (P < 0.01). Maximum urine flow increased and voiding time decreased significantly in the IFES group compared with controls at the end of treatment sessions and 1 year later (P < 0.05). All the children had abnormal flow curves at the beginning of the study. The flow curve became normal in 14/18 (77%) of the children in the IFES group and six of 18 (33%) in the control group by the end of follow-up (P < 0.007). At the end of the treatment course, night-time wetting was improved in all children who had this symptom before the treatment in the IFES group (P < 0.01).

Conclusion

Combining IFES and urotherapy is a safe and effective therapy in the management of children with UAB.

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Editorial: The vexing problem of UAB in children – a viable alternative

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Underactive bladder, as defined by the International Children’s Continence Society (ICCS; impaired detrusor contractility that leads to low voiding frequency (<3 voids/day), hesitancy, incomplete bladder emptying, and high post-void residual urine volumes (PVRs) that may produce UTI and urinary incontinence) has been a vexing problem for many paediatric providers to manage.

Antimuscarinic and α-agonist drugs have not proven effective to warrant their recommendation, and urotherapy, which demystifies the condition and tries to teach children to void often, take the time to urinate, use correct posture, and promote dietary habits that seem to adjudicate fluid intake, resulting in appropriate urine production and regular bowel movements, have not fully solved the problems in all patients. More invasive therapies, i.e., percutaneous tibial nerve stimulation, intravesical electrical stimulation, and sacral neuromodulation provide some improvement in mollifying symptoms but long-term responses do not seem to be sustainable. Intermittent catheterisation, which immediately achieves bladder emptying on a timely schedule, is often a therapy that children and their parents prefer to avoid. All these management options with their varying responses have left patients resigned as their symptoms persist and their parents frustrated.

Kajbafzadeh et al. [1], in a study reported in this issue of the Journal, have clearly shown the value and potential promise of interferential electrical stimulation (IFES) for non-neuropathic underactive bladder in children. IFES changes bladder dynamics so that urinary frequency, bladder contractility, and PVRs improve to the extent that incontinence, both daytime and night-time, as well as UTIs, resolve. Although it is time consuming, as one would expect all therapies that reverse pathological processes might be, the promise that long-term responses remain salient is a testament to its worthiness. As a reference, Kajbafzadeh et al. [2] recently published similar responses in a randomised clinical trial of children with primary monosymptomatic enuresis, using standard urotherapy (as used in this current study [1]) with and without IFES, which revealed statistically significant improvement in enuretic episodes, both initially and after 1 year in those children treated with IFES. In a previous randomly allocated report of 30 children with myelomeningocele and detrusor overactivity, IFES was substantially effective in 20 vs 10 who were ‘sham controlled’ [3].

The authors [1] do indicate deficiencies in their study, the most glaring of which is the absence of a ‘sham’ group of children who should have ‘received’ IFES treatment without any actual ES. In clinical practice this is almost impossible to achieve. Long-term urodynamic data would also have been helpful in solidifying these responses when compared to pre-treatment investigations but again having families assent to a study that involves catheterising their child for this purpose is nearly impossible.

The authors did not comment on the improvement in bowel function these children may experience in the immediate period after treatment or in the long-term, but given the emphasis on better toileting it is presumed lower gastrointestinal function would have been helped as well. In addition, the authors [1] have left us wondering if these improved toileting habits changed the propensity towards UTIs over time. Nor have they expressed any improvement in behavioural issues as a result of this programme, or what effect, if any, has occurred regarding school performance and social interaction. It is now up to these pioneers, as well as future investigators, to lead the way to engage a child’s entire milieu and his family responses, to the acceptability of this treatment programme. Looking beyond just the immediacy of an IFES regimen and its effects on the urinary and gastrointestinal systems will surely tell us if this management schema truly has large scale merit for a wider cohort. That kind of communication would surely be an impetus for scientifically minded clinicians to delve into the ‘whys’ of its positive pathophysiological effects.

I commend the authors for their exceptional work and desire to find an effective, minimally invasive treatment that has long-term sustainability. The gauntlet has been dropped, only to be picked up by others (or these same providers) to address and answer the additional concerns and questions posed by this editorial.

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Stuart B. Bauer
Department of Urology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA, 02115, USA

 

References

 

1 Kajbafzadeh AM, Sharifi-Rad L, Ladi-Seyedian SS, Mozafarpour S. Transcutaneous interferential electrical stimulation for the management of non-neuropathic underactive bladder in children: a randomised clinical trial. BJU Int 2016; 117: 793–800

 

2 Kajbafzadeh AM, Sharifi-Rad L, Mozafarpour S, Ladi-Seyedian SS. Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial. Pediatr Nephrol 2015; 30: 1139–45

 

3 Kajbafzadeh AM, Sharifi-Rad L, Baradaran N, Nejat F. Effect of pelvic floor interferential electrostimulation on urodynamic parameters and incontinency of children with myelomeningocele and detrusor overactivity. Urology 2009; 74: 324–9

 

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