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Article of the Week: Accuracy of prostate biopsies for predicting Gleason score in radical prostatectomy specimens: nationwide trends 2000–2012

Every Week the Editor-in-Chief selects an Article of the Week 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.

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

Accuracy of prostate biopsies for predicting Gleason score in radical prostatectomy specimens: nationwide trends 2000–2012

Daniela Danneman*, Linda Drevin, Brett Delahunt, Hemamali Samaratunga§¶David Robinson**, Ola Bratt††‡‡, Stacy Loeb§§ Par Stattin¶¶*** and Lars Egevad*†††

 

*Department of Oncology-Pathology, Karolinska Institute, Stockholm, † Regional Cancer Centre, Uppsala University Hospital, Uppsala, Sweden, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand, §Aquesta Pathology, The University of Queensland School of Medicine, Brisbane, Qld, Australia, **Department of Urology, Ryhov County Hospital, Jonkoping, Sweden, ††Department of Urology, Cambridge University Hospitals, Cambridge, UK, ‡‡Department of Translational Medicine, Lund University, Lund, Sweden, §§Department of Urology and Population Health, New York University and Manhattan Veterans Affairs Medical Centre, New York, NY, USA, ¶¶Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea University, Umea, ***Department of Surgical Sciences, Uppsala University, Uppsala, Umea, and †††Department of Pathology, Karolinska University Hospital, Stockholm, Sweden

 

Abstract

Objectives

To investigate how well the Gleason score in diagnostic needle biopsies predicted the Gleason score in a subsequent radical prostatectomy (RP) specimen before and after the 2005 International Society of Urological Pathology (ISUP) revision of Gleason grading, and if the recently proposed ISUP grades 1–5 (corresponding to Gleason scores 6, 3 + 4, 4 + 3, 8 and 9–10) better predict the RP grade.

Patients and Methods

All prostate cancers diagnosed in Sweden are reported to the National Prostate Cancer Register (NPCR). We analysed the Gleason scores and ISUP grades from the diagnostic biopsies and the RP specimens in 15 598 men in the NPCR who: were diagnosed between 2000 and 2012 with clinical stage T1–2 M0/X prostate cancer on needle biopsy; were aged ≤70 years; had serum PSA concentration of <20 ng/mL; and underwent a RP <6 months after diagnosis as their primary treatment.

aotw-jan-4-2017-results

Results

Prediction of RP Gleason score increased from 55 to 68% between 2000 and 2012. Most of the increase occurred before 2005 (nine percentage points; P < 0.001); however, when adjusting for Gleason score and year of diagnosis in a multivariable analysis, the prediction of RP Gleason score decreased over time (odds ratio [OR] 0.98; P < 0.002). A change in the ISUP grades would have led to a decreasing agreement between biopsy and RP grades over time, from 68% in 2000 to 57% in 2012, with an OR of 0.95 in multivariable analysis (P < 0.001).

Conclusion

Agreement between biopsy and RP Gleason score improved from 2000 to 2012, with most of the improvement occurring before the 2005 ISUP grading revision. Had ISUP grades been used instead of Gleason score, the agreement between biopsy and RP grade would have decreased, probably because of its separation of Gleason score 7 into ISUP grades 2 and 3 (Gleason score 3 + 4 vs 4 + 3).

Editorial: The prognostic value of prostate biopsy grade – Forever a product of sampling

The ability to project clinical outcomes based on limited data is crucial to the practice of medicine. This principle is particularly germane to the management of prostate cancer, where clinical outcomes vary widely. In the current issue of BJUI, Danneman et al. [1] assess pathological grade concordance between diagnostic needle biopsy and subsequent radical prostatectomy specimens from 2000 to 2012. The authors observed increased concordance of biopsy and prostatectomy Gleason scores over the time period (from 55% in 2000 to 68% in 2012) with the majority of improvement occurring before 2005. Interestingly, concordance decreased over time (from 68 to 57%) with use of the newly revised grading system. These and other findings led to the proposal that increased concordance was attributable more to the elimination of Gleason scores 2–5 than the systematic change in grading itself.

We commend the authors for exploring this important topic. Our ability to derive meaningful information on disease biology and behaviour from biopsy specimens is essential to counselling patients on the many available management options. At the same time, biopsy grading is inherently limited in its ability to predict overall prostate pathology because it is not only dependent on architecture and morphology, but also on the, admittedly minimal, sample of tissue obtained. As such, we should be cautious in using terms such as ‘undergrading’ in describing biopsy specimens, which may have been properly graded, but simply lacked the higher grade tumour observed at prostatectomy. In reality, such a phenomenon represents undersampling rather than undergrading, and there is hope that such undersampling will decrease with improved methods of detection, such as multiparametric MRI/TRUS fusion-guided biopsy.

Notably, the authors refer to the updated grading system, which was first described by Dr Epstein and validated in a multi-institutional study [2] before the 2014 International Society of Urological Pathology (ISUP) consensus conference, as ISUP grades 1–5. For clarity, it should be noted that the initial report and validation of the new system [2], the 2014 ISUP consensus conference proceedings [3] and the WHO 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs [4], have all described the new system based on grade groups 1–5. Consistent use of the adopted terminology will be helpful moving forward.

Nonetheless, there are several potential explanations for the patterns observed in the present study. As the authors note, lower concordance based on the grade group system can be largely explained by the more precise classification of Gleason score 7 cancers. Based on evidence of disparate outcomes in Gleason score 3+4 = 7 and 4+3 = 7 disease [5], the ISUP system distinctly classifies these cancers as prognostic grades 2 and 3, respectively. Certainly, when compared with a system in which Gleason score 7 represents a single classification, one would expect poorer concordance in the more widely distributed group. We believe the clinical utility of separating these classifications far outweighs a modest decrease in concordance, which may be explained by other factors in any case. Previous studies have shown the importance of subdividing the Gleason score 7 population when comparing grading systems [6]. Furthermore, details are not provided as to whether a global grade was assigned to biopsy, a common practice in Sweden, which is not the currently recommended practice. That 5–7% of specimens received a Gleason score < 6 calls into question whether contemporary recommendations were fully adopted during the study period.

Regardless, Danneman et al. elegantly highlight the frequency with which biopsy and prostatectomy grades are discordant, and the fact that, to date, pathological grading remains a subjective practice. As noted, there are widespread efforts to address both of these issues, including the use of targeted biopsies and tissue-based genomic markers. Until these practices are well-validated and widely implemented, there are several reasons to believe the most recent grade group system will improve contemporary practice, despite limited concordance. For one, use of a more intuitive scale ranging from 1 to 5 should prove easier for patients to understand, a significant consideration in light of the information overload patients absorb with a new diagnosis of cancer. Furthermore, available data to this point demonstrate excellent prognostic value. In one study from Johns Hopkins, the revised Grade Group system showed improved accuracy for predicting 5-year metastasis (C-index 0.80 vs 0.70) and 10-year prostate cancer-specific mortality (C-index 0.77 vs 0.64) as compared with the original Gleason score [7].

Until truly objective methods of pathological assessment emerge, additional validation of the new grade group system is likely to further support its use moving forward. As Danneman et al. point out, however, we must keep in mind that biopsy, although perhaps our most useful tool, captures only a small fraction of the overall picture.

Jeffrey J. Tosoian* and Jonathan I. Epstein*,,‡ *James Buchanan

 

Brady Urological Institute and Department of Urology, Department of Pathology, Johns Hopkins University School of Medicine, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

 

References

 

 

2 Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic gleason grade grouping: data based on the modied gleason scoring system. BJU Int 2013; 111: 75360

 

 

4 Moch H, Humphrey P, Ulbright T, Reuter V. WHO classication of tumours: pathology and genetics.Tumours of the Urinary and Male Reproductive System. Lyon, France:IARC Press; 2016.

 

5 Eggener SE, Scardino PT, Walsh PC et al. Predicting 15-year prostate cancer specic mortality after radical prostatectomy. J Urol 2011; 185: 86975

 

6 Lee MC, Dong F, Stephenson AJ, Jones JS, Magi-Galluzzi C, Klein EAThe Epstein criteria predict for organ-conned but not insignicant disease and a high likelihood of cure at radical prostatectomy. Eur. Urol 2010; 58: 905

 

 

Article of the week: Rethinking inflammation in PCa

Every week the Editor-in-Chief selects the Article of the Week 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.

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

Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (PSA) concentration in the Finnish prostate cancer screening trial

Tytti H. Yli-Hemminki*, Marita Laurila*, Anssi Auvinen, Liisa Määttänen§, Heini Huhtala, Teuvo L.J. Tammela and Paula M. Kujala*

*Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Department of Pathology, Seinäjoki Central Hospital, Seinäjoki, School of Health Sciences, University of Tampere, Tampere, §Finnish Cancer Registry, Helsinki, and Department of Urology, Tampere University Hospital and University of Tampere, Tampere, Finland

T. H. Y.-H. and M. L. contributed equally to this study.

OBJECTIVE

• To assess whether histological signs of inflammation are associated with an increased risk of subsequent prostate cancer (PCa) in men with elevated serum prostate-specific antigen (PSA) concentrations and benign initial biopsy.

MATERIALS AND METHODS

• Study subjects were men aged 54–67 years with an elevated PSA (≥4 ng/mL or 3–4 ng/mL and free to total PSA ratio ≤0.16 or positive digital rectal examination), but a benign biopsy result within the Finnish population-based randomised screening trial for PCa, which started in 1996.

• A total of 293 prostate biopsies without PCa or suspicion of malignancy from the first screening round in the Tampere centre were re-evaluated by a uropathologist to assess histological inflammation.

• Results of the subsequent screening rounds were obtained from the trial database and PCa diagnoses made outside the screening were obtained from the Finnish Cancer Registry.

• The median length of follow-up was 10.5 years.

• Cox regression analysis was used to assess PCa risk after the initial benign biopsy.

RESULTS

• Histological inflammation was found in 66% of the biopsies.

• Subjects with inflammation at the biopsy had a slightly lower PCa risk in the second screening round (18 vs 27%, rate ratio 0.69, 95% confidence interval [CI] 0.35–1.34) relative to men without inflammation. In further follow-up, the PCa risk remained nonsignificantly lower (hazard ratio [HR] 0.71, CI 0.46–1.10; P = 0.13). The risk was not appreciably affected by adjustment for age, PSA, prostate volume and family history of PCa (HR 0.67, CI 0.42–1.07; P = 0.092).

CONCLUSIONS

• Histological inflammation in a prostate biopsy among men with an initial false-positive screening test was not associated with an increased risk of subsequent PCa, but instead with a decreased risk which was of borderline significance.

• Inflammation in prostate biopsy is not a useful risk indicator in PCa screening.

 

Read Previous Articles of the Week

 

Editorial: Does inflammation reduce the risk of prostate cancer?

Chronic inflammation is thought to play an aetiological role in tumorigenesis in several cancers including bladder, oesophagus and liver [1]. Molecular studies show that it plays a critical role in several stages of the carcinogenic process including tumour initiation, promotion, metastases and response to therapy. However the role in prostate cancer is less clear and to date, clinical studies are inconclusive.

The article in this issue of BJUI by Yli-Hemminki et al. [2] appears to show an inverse association with histological inflammation and the risk of prostate cancer. Using data from the Finnish subgroup of the European Randomised Study of Prostate Cancer Screening (ERSPC) study they examined 293 patients with previous negative biopsies over a 10.5-year period and reported an 18% risk of prostate cancer in men with inflammation on initial biopsy (34 of 101 men) as opposed to 27% in those without inflammation (51 of 192 men). Perhaps somewhat surprisingly, histological inflammation did not appear to be significantly associated with PSA concentration, although it did appear that the free/total PSA ratio was higher in men with inflammation.

One potential confounding factor is that inflammation may also play a role in the pathogenesis of BPH. A large scale study showed that the odds ratio for BPH was 8.0 with a history of prostatitis [3]. Furthermore, the Medical Therapy of Prostatic Symptoms (MTOPS) study showed that men with inflammation had a significantly higher risk of BPH progression and acute urinary retention. These factors may impact on PSA levels and the chance of a subsequent prostate biopsy. However, the authors report that the inverse association of prostate cancer and inflammation did not alter when corrected for prostate volume, PSA level and age.

Significantly, those patients who screened positive at first biopsy were already excluded as were those with a suspicion of prostate cancer, such as a small atypical focus. Despite this, the study group probably represents high-risk patients, as they had all previously met the criteria for the first round of biopsies. This is borne out by the fact that the risk of prostate cancer was significantly increased when the men with inflammation on biopsy were compared with the initially screened negative men (hazard ratio 4.3). Unfortunately, we do not know what the rate of inflammation was in the control arm as they were screened negative and hence no biopsies were taken.

The significance of PSA level or prostatic intraepithelial neoplasia was not specifically investigated, although the reported rates were 32.1% and 7.5% respectively. Overall the incidence of inflammation was reported as 65%, but this included both acute and chronic inflammation. A smaller number of patients were given grade 2/3 chronic inflammation (80 and 20 patients, respectively) and only 14 patients had grade 2/3 acute, indicating most had milder degrees of inflammation. Whether this is a representative sample is not entirely clear. As the authors comment, published rates of histological inflammation do vary significantly from 8 to 99% and this does appear to vary according to detection method.

Several case-control studies and a meta-analysis [4] have shown that there is a significant increase in the relative risk of prostate cancer in men with prostatitis; however, these epidemiological studies all suffer from selection bias, in that men with clinical symptoms are more likely present and to be investigated and followed up by a Urologist. This study [2] only examines the role of histological inflammation and, at least partially, removes the selection bias associated with clinical symptoms, although it could still be argued that men with clinical prostatitis may be more likely to present for screening. This study represents a highly selected group of patients that are high risk for prostate cancer and no firm conclusions can be drawn on the general population. As inflammation is so common in prostate specimens, further high-quality large-scale studies are needed with similar long-term follow-up.

Miles A. Goldstraw and Roger S. Kirby
The Prostate Centre, London, UK

References

  1. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860–867
  2. Yli-Hemminski T, Laurila M, Auvinen A et al. Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (PSA) concentration in the Finnish prostate cancer screening trial. BJU Int 2013; 112: 735–741
  3. Alcarez A, Hammerer P, Tubaro A, Schroder FH, Castro R. Is there evidence of a relationship between benign prostatic hyperplasia and prostate cancer? Findings of a literature review. Eur Urol 2009; 55: 864–875
  4. Dennis LK, Lynch CF, Torner JC. Epidemiologic association between prostatitis and prostate cancer. Urology 2002; 60: 78–83
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