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Editorial: Are historical studies relevant in the setting of grade migration?

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While randomized controlled trials are the ‘gold standard’ for comparative effectiveness research, it is important that they be taken in context of their limitations. This is especially true in surgical trials for prostate cancer. For one, factors such as blinding and allocation concealment are often impossible in surgery, and surgeon skill may have a large impact [1]. What is more, it can take over a decade before interventions yield detectable differences in prostate cancer survival. Consequently, shifts in diagnosis and management may make historical clinical trial findings less useful for contemporary patients. For example, the landmark Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) showed a survival benefit for men treated with radical prostatectomy rather than observation during the 1989–1999 time period [2] but management in the study differed from contemporary practice as, in the 1990s, strict ‘active surveillance’ protocols did not exist.

In addition to shifts in management, men diagnosed with prostate cancer today differ from those diagnosed in previous decades. This was shown by Dalela et al. [3] who compared registry‐based data from the USA with data on patients enrolled in the Prostate Cancer Intervention Versus Observation (PIVOT) trial, and found significant differences between the two cohorts.

In a similar vein, Cazzaniga et al. [4] designed an elegant study to assess the generalizability of the SPCG‐4 to contemporary cohorts of men with prostate cancer. They focused on histological grading and compared the natural history of men in the SPCG‐4 study to men in similar grade categories diagnosed approximately one decade later in Sweden.

The contemporary cohort was made up of men with localized prostate cancer drawn from the Swedish National Prostate Cancer Register (NPCR). Men in the NPCR diagnosed in 2005–2006 had lower prostate cancer‐specific and all‐cause mortality compared to men with similar grade cancer in the SPCG‐4 (hazard ratios 0.46, 95% CI 0.19–1.14, and 0.66, 95% CI 0.46–0.95, respectively). While some of the observed differences in survival may have been attributable to improved treatments, Cazzaniga et al. hypothesized that grade migration was to blame.

As expected, the authors found a shift in Gleason grading, with a decrease in Gleason Grade Group (GGG) 1 disease, corresponding to a historical score of Gleason 3 + 3 = 6, and a concurrent increase in GGG2 and GGG3 disease, corresponding to historical scores of 3 + 4 = 7 and 4 + 3 = 7, respectively. Importantly, these differences in prostate cancer‐specific and all‐cause mortality were mitigated after compensating for grade migration by increasing GGG by one for the NPCR group; in other words, men in the SPCG‐4 treated in the 1990s had similar prostate cancer‐specific and all‐cause mortality to men in a later period with a one‐unit higher GGG.

Grade migration has been a gradual process, which was hastened by the major 2005 International Society of Urological Pathology revision that recategorized some Gleason patterns from 3 to 4. Changes in 2014 further refined these, and the concept of grade groups was introduced by Epstein two years later. Older cases of Gleason score 6 cancer include histological patterns, such as cribriform and poorly formed glands, which today would be considered Gleason pattern 4.

Grade migration was also demonstrated by Danneman et al. [5] who analysed the Gleason scoring of prostate biopsies from the NPCR in Sweden for the period 1998–2011. There was an increasing incidence of low‐risk cancer (cT1 20% in 1998 to 51% in 2011) and a concurrent decrease in high‐risk cancers (cT3 29% to 16%), reflecting earlier detection. With earlier diagnosis from screening, one would expect a shift towards lower grades at diagnosis, but they found the opposite. Among low‐risk tumours (stage cT1 and PSA 4–10 ng/mL) the proportion of Gleason score 7–10 increased from 16% to 40%. Among high‐risk tumours (stage cT3 and PSA 20–50 ng/mL) the proportion of Gleason 7–10 increased from 65% to 94%.

Gleason score reclassification was also addressed by Albertsen et al. [6], who had prostate biopsy slides for the period 1990 to 1992 re‐reviewed by an experienced pathologist in 2002–2004. They found an upward shift in Gleason grading, with 55% of the samples upgraded, 14% downgraded, and 31% unchanged. Comparing matched cohorts of historical vs contemporary patients with prostate cancer, one might erroneously infer better survival. This illusory change in prognosis is known as the ‘Will Rogers phenomenon’.

While randomized trials such as the SPCG‐4 represent one of the highest levels of clinical evidence, it is important to keep in mind that these trials have limitations. Given the interval changes in grading criteria for prostatic adenocarcinoma, predicting clinical outcomes based on historical cohorts is rarely as simple as it may seem. While the fundamental conclusions of the SPGC‐4 remain valid, the finding that Gleason grade did not modify the effect of prostatectomy on survival is now less certain. Physicians should therefore use caution when inferring prognosis based on those results.

Cazzaniga et al. should be congratulated for this important work which will help physicians better counsel patients making decisions based on trials like the SPCG‐4.

References

  1. Trinh QD, Cole AP, Dasgupta P. Weighing the evidence from surgical trials. BJU Int 2017; 119: 659–60
  2. Bill‐Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–17
  3. Dalela D, Karabon P, Sammon J et al. Generalizability of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) results to contemporary North American men with prostate cancer. Eur Urol 2017; 71: 511–4
  4. Cazzaniga W, Garmo H, Robinson D, Holmberg L, Bill‐Axelson A, Stattin P. Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study. BJU Int 2019; 123: 421–8
  5. Danneman D, Drevin L, Robinson D, Stattin P, Egevad LJ. Gleason inflation 1998–2011: a registry study of 97,168 men. BJU Int 2015; 115: 248–55
  6. Albertsen PC, Hanley JA, Barrows GH et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005; 97: 1248–53C

 

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

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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

 

Read the full article

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).

Read more articles of the week

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

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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.

Read the full article

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

 

1 Danneman D, Drevin L, Delahunt B et al. Accuracy of prostate biopsies for predicting Gleason score in radical prostatectomy specimens: nationwide trends 2000–2012. BJU Int 2017; 119: 50–6

 

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

 

3 Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. 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. Am J Surg Pathol 2016; 40:244–52

 

4 Moch H, Humphrey P, Ulbright T, Reuter V. WHO classification 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 specific mortality after radical prostatectomy. J Urol 2011; 185: 869–75

 

6 Lee MC, Dong F, Stephenson AJ, Jones JS, Magi-Galluzzi C, Klein EA. The Epstein criteria predict for organ-confined but not insignificant disease and a high likelihood of cure at radical prostatectomy. Eur. Urol 2010; 58: 90–5

 

7 Faraj SF, Bezerra SM, Yousefi K et al. Clinical validation of the 2005 ISUP gleason grading system in a cohort of intermediate and high risk men undergoing radical prostatectomy. PLoS One 2016; 11: e0146189

 

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

 

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

New Gleason grading system: Statement from the Editors of six journals

/4 Comments/by

The International Society of Urologic Pathology (ISUP) has completed a consensus process to modify and clarify the Gleason scoring system for prostate cancers (1). Five grade groups have been defined with tumors of ISUP Grade Group 1 being the least aggressive and having the lowest likelihood of progression, whereas those of ISUP Grade Group 5 have the highest likelihood of early systemic spread. This new system provides clearer guidance for pathologists to classify cancers on the basis of gland morphology, and it aligns better with contemporary management including active surveillance.

The editors of the major uro-oncology journals believe this is a helpful change for clinicians, researchers, and patients alike and are eager to help this system establish itself in the reporting of pathologic grade. To that end we are now asking investigators to use the ISUP system in the reporting of prostate cancers in their publications. As the grade groups correspond largely with current Gleason scores 6, 3+4, 4+3, 8, 9 and 10, the translation should be relatively simple. Over the next one to two years, side-by-side reporting of old and new histology may temporarily be necessary. We do recognize that some institutional and national databases are not set up to make the translation and exceptions will be granted in these cases.

Anthony Zietman MD
International Journal of Radiation Oncology Biology Physics

Joseph Smith MD
Journal of Urology

Eric Klein MD
Urology

Michael Droller MD
Urologic Oncology

Prokar Dasgupta MSc MD FRCS
BJUI

James Catto MBChB PhD FRCS
European Urology

Reference

  1. Epstein JI, Egevad L, Amin MB et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference of Gleason Grading of Prostatic Carcinoma. Am. J. Surg. Pathol. 2016, 40: 244-252.

 

 

 

Controversies in management of high-risk prostate and bladder cancer

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CaptureRecently, there has been substantial progress in our understanding of many key issues in urological oncology, which is the focus of this month’s BJUI. One of the most substantial paradigm shifts over the past few years has been the increasing use of radical prostatectomy (RP) for high-risk prostate cancer and increasing use of active surveillance for low-risk disease [1,2]. 
Consistent with these trends, this month’s BJUI features several useful articles on the management of high-risk prostate cancer. The first article by Abdollah et al. [3] reports on a large series of 810 men with D’Amico high-risk prostate cancer (PSA level >20 ng/mL, Gleason score 8–10, and/or clinical stage ≥T2c) undergoing robot-assisted RP (RARP). Despite high-risk characteristics preoperatively, 55% had specimen-confined disease at RARP, which was associated with higher 8-year biochemical recurrence-free (72.7% vs 31.7%, P < 0.001) and prostate cancer-specific survival rates (100% vs 86.9%, P < 0.001). The authors therefore designed a nomogram to predict specimen-confined disease at RARP for D’Amico high-risk prostate cancer. Using PSA level, clinical stage, maximum tumour percentage quartile, primary and secondary biopsy Gleason score, the nomogram had 76% predictive accuracy. Once externally validated, this could provide a useful tool for pre-treatment assessment of men with high-risk prostate cancer. 
Another major controversy in prostate cancer management is the optimal timing of postoperative radiation therapy (RT) for patients with high-risk features at RP. In this month’s BJUI, Hsu et al. [4] compare the results of adjuvant (≤6 months after RP with an undetectable PSA level), early salvage (administered while PSA levels at ≤1 ng/mL) and late salvage RT (administered at PSA levels of >1 ng/mL) in 305 men with adverse RP pathology from the USA Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. At 6.2 years median follow-up, late salvage RT was associated with significantly higher rates of metastasis and/or prostate cancer-death. By contrast, there was no difference in prostate cancer mortality and/or metastasis between early salvage vs adjuvant RT. A recent study from the USA National Cancer Data Base reported infrequent and declining use of postoperative RT within 6 months for men with adverse RP pathology, from 9.1% in 2005 to 7.3% in 2011 [5]. As we await data from prospective studies comparing adjuvant vs early salvage RT, the results of Hsu et al. [4] are encouraging, suggesting similar disease-specific outcomes if salvage therapy is administered at PSA levels of <1 ng/mL. 
Finally, this issue’s ‘Article of the Month’ by Baltaci et al. [6] examines the timing of second transurethral resection of the bladder (re-TURB) for  high-risk non-muscle-invasive bladder cancer (NMIBC). The management ofbladder cancer at this stage is a key point to improve the overall survival of bladder cancer. Re-TURB is already recommended in the European Association of Urology guidelines [7], but it remains controversial as to whether all patients require re-TURB and what timing is optimal. The range of 2–6 weeks after primary TURB was established based on a randomised trial assessing the effect of re-TURB on recurrence in patients treated with intravesical chemotherapy [8], but it has not been subsequently tested in a randomised trial. Baltaci et al. [6], in a multi-institutional retrospective review of 242 patients, report that patients with high-risk NMIBC undergoing early re-TURB (14–42 days) have better recurrence-free survival vs later re-TURB (73.6% vs 46.2%, P < 0.01). Although prospective studies are warranted to confirm their results, these novel data suggest that early re-TURB is significantly associated with lower rates of recurrence and progression.
 
 
References

1 Cooperberg MR, Carroll PR. Trends in management for patients with localized prostate cancer, 1990–2013. JAMA 2015; 314: 80–2

 

2 Loeb S, Berglund A, Stattin P. Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer. J Urol 2013; 190: 1742–9

 

3 Abdollah F, Klett DE, Sood A et al. Predicting pathological outcomes in patients undergoing robot-assisted radical prostatectomy for high- risk prostate cancer: a preoperative nomogram. BJU Int 2015; 116: 703–12

 

4 Hsu CC , Paciorek AT, Cooperberg MR, Roach M 3rd, Hsu IC, Carroll PR. Postoperative radiation therapy for patients at high-risk of recurrence after radical prostat ectomy: does timing matter? BJU Int 2015; 116: 713–20

 

5 Sineshaw HM, Gray PJ, Efstathiou JA, Jemal A. Declining use of radiotherapy for adverse features after radical prostatectomy: results from the National Cancer Data Base. Eur Urol 2015; [Epub ahead of print]. DOI: 10.1016/ j.eururo.2015.04.003

 

6 Baltacı S, Bozlu M, Yıldırım A et al. Significance of the interval between first and second transurethral resection on recurrence and progression rates in patients with high-ris k non-muscle-invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guerin. BJU Int 2015; 116: 721–6

 

7 Babjuk M, Bohle A, Burger M et al. European Association of Urology Guidelines on Non-Muscle-Invasive Bladder Cancer (Ta, T1, and CIS). Available at: https://uroweb.org/wp-content/uploads/EAU-Guidelines- Non-muscle-invasive-Bladder-Cancer-2015-v1.pdf. Accessed September 2015

 

8 Divrik RT, Yildirim U, Zorlu F, Ozen H. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol 2006; 175: 1641–4

 

Stacy Loeb – Department of Urology, Population Health, and the Laura and Isaac Perlmutter Cancer Center, New York University, New York City, NY, USA

 

Maria J. Ribal – Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain

 
 

Is Gleason 6 really cancer?

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The recently published Viewpoint of the National Cancer Institute working group on “Overdiagnosis and Overtreatment in Cancer” by Esserman and colleagues [1] raises continued discussion as to whether some lesions currently classified as carcinomas should have the designation of “cancer” removed, based on low rates of progression, death, and other adverse outcomes. Pertinent to those interested in urology, a central example in the article is prostatic adenocarcinoma.

One simple answer to this question is that to a small extent, a subgroup of prostatic lesions has already been reclassified as not cancer: In current practice, needle biopsy or radical prostatectomy specimens with an overall Gleason score (GS) of 5 or less are now quite rare in current practice. This shift is due in part to modern updates to the Gleason grading system [2], under which many tumors now reach thresholds for GS6 or above. However, at least some lesions previously considered adenocarcinoma with a low overall GS would now be categorized as atypical adenomatous hyperplasia or adenosis in the era of immunohistochemistry for markers of prostatic basal cells. Nonetheless, the current and more controversial debate surrounds whether some (or all?) tumors currently classified as GS6 could be recategorized as not “cancer”.

Arguments against removing the cancer designation from some prostatic adenocarcinomas:

A major difficulty from the pathologic standpoint in adopting a non-cancer nomenclature for some tumors (such as GS6 adenocarcinomas) is that the Gleason pattern 3 component of a GS 3+3=6 tumor (small, round prostatic glands that lack a basal cell layer and infiltrate between benign glands) is for all intents and purposes identical to the Gleason pattern 3 component of a GS 3+4=7 or higher prostate cancer. These similarities are not limited exclusively to the microscopic appearance but also include a number of immunohistochemical and molecular features, as summarized in a recent article addressing this question [3]. Therefore, no pathologic features are as yet defined that ideally predict whether Gleason pattern 3 glands in a biopsy specimen represent a pure GS6 tumor or a component of higher-grade tumor in which the high-grade component is not represented. Not surprisingly, it is not unusual for tumors with GS6 on needle biopsy to be upgraded to GS7 at radical prostatectomy [3], particularly when a high tumor volume is present in the needle biopsy.

Gleason pattern 3 glands from a GS7 tumor, identical to those of a GS6 tumor.

To compare to other cancers with low risk of aggressive behavior, basal cell carcinoma and squamous cell carcinoma of the skin similarly show locally infiltrative properties, supporting their classification as carcinomas by a classical pathologic definition. Despite that the word “carcinoma” continues to be used for these tumors, most patients are not concerned that they have a life-threatening disease and these lesions are even excluded from the American Cancer Society statistics regarding cancers [4]. In the same way, Gleason pattern 3 glands exhibit infiltrative growth by extending between benign glands, invading nerves, and sometimes extending outside of the prostate. This difference in mindset regarding some types of “cancers” could be considered supportive evidence for the assertion in the recent Melbourne Consensus Statement that uncoupling prostate cancer diagnosis from intervention may be more appropriate than removing its “cancer” nomenclature.


This small GS6 adenocarcinoma was an incidental finding in a radical cystoprostatectomy specimen for bladder cancer but surprisingly extended into periprostatic fat via this focus of perineural invasion.

Supporting removal of the cancer designation from some prostatic adenocarcinomas:

A valid argument of the NCI Viewpoint is that a neoplasm should have a substantive rate of progression and patient death if it is to be considered a cancer. Likewise, others have questioned whether low-volume GS6 tumors fulfill other molecular and pathogenetic hallmarks of cancer, such as unlimited replicative potential and other features [5].

In general, benign and malignant neoplasms can be regarded as having some prototypical gross and microscopic pathologic characteristics, such as a circumscribed vs infiltrative growth and homogeneous vs pleomorphic cell population. However, differentiating benign from malignant lesions also relies heavily on parameters specific to the organ involved. Clear cell renal cell carcinoma, another genitourinary tract tumor, often does not possess these prototypical features of malignancy. Tumors often form a well-circumscribed mass without an “invasive” growth pattern and they often are composed of a uniform population of cells. However, based on known behavior of these tumors, their status as a malignancy is not in doubt. Conversely, renal oncocytoma is a benign neoplasm that shares some of these general features (a round mass composed of a homogeneous population of renal tubular cells). Occasionally oncocytomas appear infiltrative by extending into the perinephric fat or renal vein, yet their status as benign is also not the subject of debate. If some prostate cancers do not have a substantial likelihood of resulting in progression and death, they may not meet an important criterion for a diagnosis of cancer, despite that other features, such as infiltration of tissues, invasion of nerves, and loss of the basal cell layer are characteristic of a malignant neoplasm.

Since a diagnosis of GS6 by needle biopsy is not always predictive of a radical prostatectomy overall GS6, a major challenge to such an approach would be to determine where such a cutoff could be drawn between “cancer” and “not cancer” [5]. If based on tumor volume, it would be difficult to conceptualize that a small amount of GS6 glands would be regarded as a benign lesion, whereas a large amount of identical glands would represent a malignant lesion. Alternatively, the presence of Gleason pattern 4 could used as the point of differentiation (GS7 or above). In the endometrium, a disorganized proliferation of crowded glands with some cytologic features of cancer is regarded as complex atypical hyperplasia. Diagnosis of adenocarcinoma is then reserved for proliferations with a confluent growth of these glands, similar to the threshold for recognizing a component of cribriform glands as Gleason pattern 4. A limitation to such an approach, however, is that a substantial fraction of patients with a needle biopsy GS6 are upgraded to GS7 at radical prostatectomy, as discussed above. Likewise, the ability to treat and monitor GS6 adenocarcinoma nonsurgically is not quite analogous to that of endometrial hyperplasia.

Higher magnification of image 2 shows Gleason pattern 3 glands invading a nerve with ganglion cells.

Other points of discussion

The NCI Viewpoint also suggests that high-grade prostatic intraepithelial neoplasia (HGPIN) no longer be considered cancer or even neoplasia.  A comparison to ductal carcinoma in situ (DCIS) of the breast for this argument is somewhat flawed, as HGPIN neither contains the word “carcinoma” nor is justification for treatment in and of itself. Its status as a risk factor for a future cancer even remains debated. The proposal to remove “neoplasia” from HGPIN is also a confusing one, particularly as cervical cancer is noted as an example of the successful application of screening, in which “cervical intraepithelial neoplasia” is the preferred term for precancerous lesions. The authors suggest the designation “indolent lesions of epithelial origin” (IDLE) for cancers in this category to convey their low likelihood of aggressive behavior. However, would recognizing the status of these lesions as at least premalignant neoplasms be more appropriate?

Likely a typographical error in the Viewpoint is that the authors also cite reclassification of urothelial papilloma as papillary urothelial neoplasm of low malignant potential [1]. Since urothelial papilloma has never been considered a malignant neoplasm, the authors likely meant reclassifying “grade 1 urothelial carcinoma” to papillary urothelial neoplasm of low malignant potential.

References
[1]        Esserman LJ, Thompson IM, Reid B. Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement. JAMA. 2013 Jul 29:

[2]        Epstein JI, Allsbrook WC, Jr., Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005 Sep: 29:1228-42

[3]        Carter HB, Partin AW, Walsh PC, et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol. 2012 Dec 10: 30:4294-6

[4]        Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan: 63:11-30

[5]        Ahmed HU, Arya M, Freeman A, Emberton M. Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Lancet Oncol. 2012 Nov: 13:e509-17

 

Sean Williamson is Senior Staff Pathologist in the Department of Pathology and Laboratory Medicine, Henry Ford Health System, Detroit MI, USA. @Williamson_SR

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