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Similarities and Differences in the 2019 ISUP and GUPS Recommendations on Prostate Cancer Grading: A Guide for Practicing Pathologists

Smith, Steven C. MD, PhD*; Gandhi, Jatin S. MD; Moch, Holger MD; Aron, Manju MD§; Compérat, Eva MD, PhD; Paner, Gladell P. MD; McKenney, Jesse K. MD#; Amin, Mahul B. MD**

Author Information
Advances In Anatomic Pathology: January 2021 - Volume 28 - Issue 1 - p 1-7
doi: 10.1097/PAP.0000000000000287
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Abstract

The year 2019 saw the remarkable experiment of 2 nearly simultaneous position papers on grading and reporting of prostatic adenocarcinoma, convened by the 2 Uropathology surgical pathology subspecialty interest societies, the International Society of Urological Pathology (ISUP) and the Genitourinary Pathology Society (GUPS). The resulting 2 publications1,2 build on decades of scholarship in the grading of prostate cancer since the time it was proposed by Dr Donald Gleason.3–5 Key milestones in this process have included modifications of grade criteria and reporting recommendations implemented in the 2005 ISUP consensus6 as well as the more recent introduction by the Johns Hopkins group,7 interinstitutional validation,8 and endorsement of a system of prognostic Grade Groups by ISUP9,10 and the World Health Organization Classification.11 Dr Gleason’s ideas have evolved into a grading system still driving management more than half a century later, but continued study necessitates constant reassessment and optimization. ISUP and GUPS conducted proceedings to address unresolved questions and emerging challenges driven by rapid technological changes including advanced imaging, molecular diagnostics, and artificial intelligence.

BASIS OF RECOMMENDATION PROPOSALS BY BOTH SOCIETIES

The 2 recommendation documents were somewhat different in their procedures. ISUP council members convened a conference in Nice, France, on September 12, 2019, immediately following the 31st European Congress of Pathology, considering topics delegated to 4 separate working groups. ISUP employed a premeeting survey with 31 questions circulated to members globally; then, at the conference, 93 participants reviewed detailed reports from working groups, and voted in person on 23 statements. A consensus opinion was considered met when two thirds voted in favor. The GUPS White Paper was born from discussions at the March 2019 United States and Canadian Academy of Pathology meeting. A total of 52 international leaders were selected for a process of evidence review for 8 expert-derived topics, integrating findings from 2 separate surveys. One survey was circulated to GUPS membership (211 pathologists completed); another was circulated to several clinician groups and organizations including urologists, medical oncologists, and radiation oncologists. A subset of the results of the clinician survey completed by 371 respondents (the whole of which is the subject of a forthcoming separate publication12) was used to guide the 2019 GUPS White Paper recommendations regarding practices in prostate cancer grading and reporting.

KEY TAKEAWAY MESSAGES FOR PRACTICING PATHOLOGISTS

The authors of this manuscript variously include members of both or either societies, as well as participants in one or the other of the societies’ deliberations; it was prompted by review of both of the newly published documents and a desire to provide a guide to practicing pathologists by systematically assessing their key recommendations and identifying areas of apparent differences. The primary observation is that many are nearly, or in essence, identical, save for a couple of key sticking points for which the authors can certainly understand both sides of the arguments. In fact, the primary purpose for this manuscript and its tabular comparison of the reporting recommendations (Table 1) is to assist practicing pathologists in ongoing conversations with their collaborating clinicians, as departments, institutions, and practice groups choose to implement reporting practices based on one or the other. Indeed, highly nuanced and increasingly quantitative13,14 reporting is a growing opportunity and challenge in Uropathology; a collaborative approach is key so that all involved stakeholders understand which recommendations and standards are used and can help convey implications to patients, who may seek multiple opinions and experience grading or reporting discrepancies related to differences in these key recommendations. Above all, we recommend thorough review of both documents, as both provide authoritative reviews of the literature subtending much of the contemporary state of the art of grading and reporting of prostate cancer.

TABLE 1 - A Comparison of the 2019 ISUP and GUPS Consensus Recommendations
Issue* GUPS 2019 Recommendation ISUP 2019 Recommendation Assessment§
PROSTATE BIOPSY REPORTING
 Gleason pattern 4, reporting and quantitation Reporting percentage recommended in cases with Grade Group 2 and 3 carcinoma Report percentage pattern 4 in biopsies with 3+4=7 and 4+3=7 Agreement
Preferred percentage reporting as either <5% or <10%, then in 10% increments thereafter
Report percent Gleason pattern 4 even in lower grade biopsies within cases with at least one part showing Gleason score 4+4=8 (Grade Group 4)
 Intraductal carcinoma (IDCP) criteria Intraductal proliferation with: dense (>50% of lumen replaced) cribriform glands and/or solid nests and/or marked pleomorphism/necrosis No criteria recommended, proposal of separate consensus conference NA
Atypical intraductal proliferation (AIP) recommended for suspicious but not diagnostic lesions with approximately equal ratio of epithelium to luminal spaces
 IDCP without invasive carcinoma Do not grade IDCP without invasive carcinoma, and add comment on the presence and significance of IDCP Pure IDCP should not be graded Agreement
 IDCP admixed with invasive carcinoma Do not include IDCP in determining the final Gleason score IDCP should be incorporated into the Gleason score Major disagreement
Report the presence of IDCP If IDCP is incorporated into the Gleason score, its presence and significance should still be commented on (Agreement on reporting)
 IDCP with invasive carcinoma, IHC use Perform IHC for basal cell markers if a biopsy shows Gleason score 6 carcinoma and cribriform glands that might represent cribriform carcinoma versus IDCP Unnecessary, as IDCP should be incorporated into the Gleason score assigned Major disagreement
Not necessary to perform basal cell IHC to identify IDCP if the results of the stains would not change the overall highest Gleason score/Grade Group for the case
 Reporting invasive cribriform carcinoma Report the presence or absence of cribriform glands in biopsy specimens with Gleason pattern 4 carcinoma (ie, Gleason score 7 and higher) Invasive cribriform cancer should be commented on in Gleason score 7 and 8 cases Agreement
 Global scoring Optional to report a global Gleason grade, generally No consensus was reached NA
If a global score is given for a case with both targeted and conventional biopsies with different grades, the single global score given should factor in both
 Targeted biopsies, grade assessment When multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core A global Gleason score for each suspicious MRI lesion should be assigned Agreement
 MRI-targeted biopsies without cancer (PIRADS 4-5) Issue was not addressed Report specific benign histologic findings in suspicious MRI-targeted biopsies without cancer NA
RADICAL PROSTATECTOMY REPORTING
 Minor and/or tertiary patterns, general definition A minor tertiary pattern exists when 3 patterns are present, with a minor tertiary Gleason pattern 5 representing ≤5% of the carcinoma. If pattern 5 represents >5%, it should be reported as the secondary pattern Minor/tertiary may occur if 3 grades are present, provided the highest grade carcinoma is <5%; the same rule applies for a minor higher grade pattern if there are only 2 patterns present. Either way, if carcinoma represents ≥ 5%, it should be reported as the secondary pattern Major disagreement
 Tertiary/minor patterns, reporting specifics Rename “tertiary grade pattern” with “minor tertiary pattern 5” Only use “minor tertiary pattern 5” in radical prostatectomy specimens with Grade Groups 2 or 3 (Gleason score 3+4=7 or 4+3=7) Use 5% as the cutoff for what is allowed as a minor tertiary pattern 5; if >5% Gleason pattern 5 is present, then Gleason pattern 5 is considered the secondary Gleason pattern in the Gleason score Minor tertiary pattern 5 should be reported along with the Gleason score and Grade Group Any highest Gleason patterns 4 or 5 present in a radical prostatectomy must account for at least 5% of the tumor to be incorporated as a secondary pattern of the Gleason score Cutoff of ≥5% for a higher grade component to be incorporated into the Gleason score as secondary pattern (As above, Major disagreement on definition/setting) Minor semantic difference regarding >5% versus ≥5% threshold for upgrading to secondary pattern
 IDCP admixed with invasive carcinoma Report the presence of IDCP Do not include IDCP in determining the final Gleason score In cases with invasive carcinoma, IDCP pattern should be incorporated into the Gleason score Major disagreement
 IDCP with invasive carcinoma, IHC use Not necessary to perform basal cell IHC to identify IDCP if the results of the stains would not change the overall highest Gleason score/Grade Group assigned Unnecessary, as IDCP pattern should be incorporated into the Gleason score assigned Major disagreement
 Reporting invasive cribriform carcinoma Report the presence or absence of cribriform glands in specimens with Gleason pattern 4 carcinoma (ie, Gleason score 7 and higher) Invasive cribriform cancer should be commented on in Gleason score 7 and 8 cases Agreement
*Key issues regarding the grading, reporting, and overall assessment of prostatic adenocarcinoma addressed in the 2019 consensuses, reviewed, and selected by the authors.
Recommendations tabulated from the 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.2
Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma.1
§The authors’ assessment of whether the societies’ consensus recommendations are in agreement or disagreement. Major disagreements bolded.
IDCP indicates intraductal carcinoma of the prostate; IHC, immunohistochemical; NA, not available.

SIMILARITIES BETWEEN THE GENITOURINARY PATHOLOGY SOCIETY AND INTERNATIONAL SOCIETY OF UROLOGICAL PATHOLOGY RECOMMENDATIONS

These 2 recommendation documents share several important features, which are to be emphasized. The reporting of percentage of Gleason pattern 4 in prostate biopsies with carcinoma showing Grade Group 2 (Gleason score 3+4=7) or Grade Group 3 (Gleason score 4+3=7) carcinoma is emphasized by both; the GUPS White Paper even recommends 10% increments for percentage Gleason pattern 4 reporting (starting with <5% or <10%, followed by 10% incremental increases thereafter). An additional GUPS recommendation was to report percentage Gleason pattern 4 in Grade Group 2 and 3 cores, even in a case with up to a Grade Group 4 (Gleason score 4+4=8) biopsy. Neither society’s recommendations require reporting percentage Gleason pattern 4 at prostatectomy. Both societies’ 2019 recommendations confirm the original 2005 ISUP consensus6 recommendation to report the Gleason score of the primary pattern plus the highest grade pattern for biopsies, such that a focal Gleason pattern 5 is incorporated into the Gleason score and Grade Group reported for the biopsy.

One additional area of similarity in recommendations between the 2 societies regards the issue of grade heterogeneity in biopsy reporting, that of different grades apparent in samples from different sites. Since the time of the 2005 ISUP consensus,6 reporting a separate Gleason score for each separately designated sample (generally, one for each specimen container, unless multiple cores are inked or otherwise clinician specified). While unaddressed in the 2014 ISUP consensus, this recommendation was specifically reaffirmed by vote in the 2019 ISUP consensus,1 and is implicit in the GUPS recommendations.2 The introduction of magnetic resonance imaging (MRI)-guided biopsies into clinical practice, however, has in recent years raised questions again regarding per core versus per site/container reporting, as often multiple cores are sampled from a specific MRI-defined lesion. Fortunately, both the ISUP and GUPS recommendations have endorsed a uniform recommendation to report a grade for each separately designated imaging-defined lesion (whether a single or multiple cores were sampled). GUPS specifies that the “overall grade for [each] lesion is given as if all the involved cores were one long core,” while ISUP recommends “providing a global [Gleason score] for each suspicious MRI lesion.”

More complex is the issue of the pathologist specifying a “global” or “case level” Gleason score based on cancer in all cores, which tends to be a geographically variable practice based on conventions and expectations in different countries. In some areas the practice is to assume that the case level Gleason score is simply the highest seen in any one biopsy, while others report an integrative score of findings across different involved sites.1,2 Neither of these options for assessment of a case level Gleason score was endorsed in the 2005 consensus6 nor subsequently9; the 2019 ISUP consensus voting did not reach consensus in favor of case level Gleason scoring in general, nor how the case level score should be assessed, nor whether to assign such a score in a case showing different grades between an MRI-targeted sample and concurrent systematic biopsies.1 In this area, GUPS regards assigning a global or case level Gleason score as optional, generally. But, if one is to be rendered, GUPS recommends that the grades of carcinoma seen in targeted and conventional systematic biopsies (even if discordant) should both be factored into the case level “global” grade. The optimal way to integrate these both, however, was considered by GUPS to be in need of further study. Lastly, ISUP recommends reporting the specifics of benign histologic findings seen in negative biopsies of high suspicion MRI targets; GUPS did not address this issue.

PRIMARY DISCORDANCES BETWEEN THE GENITOURINARY PATHOLOGY SOCIETY AND INTERNATIONAL SOCIETY OF UROLOGICAL PATHOLOGY RECOMMENDATIONS

Accounting for Minor or Tertiary Patterns in Prostatectomy Specimens

It is regarding the issue of minor or tertiary higher-grade patterns seen at prostatectomy that a degree of discordance between GUPS and ISUP recommendations exists. Since the 2005 consensus6 it had been recommended to report the primary (most prevalent) and secondary (second most prevalent) patterns seen as the Gleason score of a prostatectomy, with an option to comment on a less prevalent higher grade tertiary pattern. Yet, neither the 2005 nor 20149 ISUP consensuses addressed the question of a cutoff for the maximum amount of a higher grade pattern before it might be considered, and reported as, the secondary pattern. Some interval expert guidance had suggested a maximum 5% cutoff15 for a minor high-grade pattern 5. The implication is that a case with any greater proportion of Gleason pattern 5 should be reported with Gleason pattern 5 as the secondary pattern in the definitive Gleason score assigned. In the end, for a prostatectomy with three patterns of carcinoma, both the 2019 GUPS and ISUP recommendations agree with the principle of a 5% cutoff as the maximum amount of highest grade pattern that may be present, above which it should be designated as the secondary pattern in the Gleason score. There remains only a slight semantic difference regarding the cutoff, in that GUPS recommends upgrading if the Gleason pattern 5 represents >5%, versus ISUP recommending upgrading if Gleason pattern is ≥5%.

The concrete difference regards the scenario of a small amount of higher grade carcinoma in a prostatectomy only showing 2 patterns, for example, a prostatectomy showing only Gleason pattern 3 with <5% Gleason pattern 4 (or 5). In this scenario, the ISUP recommendation would be to report it as 3+3=6 with a minor higher grade pattern. In the GUPS recommendations, this scenario does not exist definitionally, as tertiary is specified explicitly as the presence of 3 different patterns. Thus, to GUPS a prostatectomy with 96% Gleason pattern 3 and 4% Gleason pattern 4 would not be “tertiary” and instead reported as a Grade Group 2 carcinoma with primary pattern of 3 and secondary pattern of 4.

Grading Intraductal Carcinoma With Concomitant Invasive Carcinoma

By far the most significant and complex discordance between the ISUP and GUPS recommendations regards the issue of intraductal carcinoma of the prostate (IDCP),16–19 its definitions, and its potential contribution to grade assessment. The 2019 ISUP consensus publication reviewed the spectrum of proposed definitions for IDCP but proposed that a separate meeting would be needed to address “definitional ambiguities.”1 In contrast, GUPS recommended criteria of intraductal “dense cribriform glands and/or solid nests and/or marked pleomorphism/necrosis. Dense cribriform glands are defined as >50% of the gland composed of epithelium relative to luminal spaces; where the ratio is approximately equal, it is prudent to be conservative and diagnose the lesion as not meeting full criteria.” The GUPS document suggests use of the term “atypical intraductal proliferation” or “AIP,” with an explanatory comment, in such cases, noting half of respondents reported using this designation. Beyond criteria, it bears note that, echoing the 2014 ISUP consensus recommendation,9 both groups continue to recommend against assigning a Gleason score to “pure” intraductal carcinoma, encountered without concomitant invasive carcinoma. Importantly, both groups recommend reporting the presence of IDCP in both biopsies and prostatectomies.

The principal component of the discrepancy between the GUPS and ISUP recommendations regards the scenario of when IDCP is present with concomitant invasive carcinoma; specifically, the issue is whether the pattern seen within the IDCP (cribriform as would be Gleason pattern 4, solid and/or comedonecrosis as would be Gleason pattern 5, if invasive) should be incorporated into the Gleason score and Grade Group assigned. Much has been written about this controversy20–24 and surveys have documented significant differences in practices among surgical pathologists.25,26 To our minds, much of the disagreement regards the operational implications of the (otherwise widely accepted) fact that often it is very difficult or impossible to tell (without the added time and resources to perform basal cell immunostains) whether a carcinomatous proliferation seen histologically represents IDCP or simply a larger acinar formation of invasive carcinoma. For this reason, it can be assumed that much of our field’s heritage of prognostic study of Gleason scores, including practically all data prior to widespread use of basal cell immunostains, incorporated the patterns seen in IDCP into the grade assigned. This reason, plus the increasingly recognized fact that comedonecrosis very often but not always is intraductal27,28 raises real questions regarding fundamental grading criteria, and whether they can be applied generally without the added cost of immunostains in a significant number of cases. Certainly, grading IDCP “into the carcinoma” would have operational advantages.

Conversely, it is also unclear what proportion of previously studied cases might see a different Gleason score reported based on inclusion or exclusion of IDCP from the score and whether overall prognosis by Grade Group could be impacted. While some data suggest only a small proportion of total cases might see grade changes if IDCP areas are excluded from the grade assigned,29 other emerging data seem to suggest that a nontrivial subset of cases with IDCP (~20%) might be affected by a grade change.30 The GUPS recommendation to perform immunohistochemistry for basal cell markers at biopsy if otherwise Grade Group 1 carcinoma is seen admixed with atypical cribriform proliferations raising a differential of IDCP versus invasive Gleason pattern 4 echoes this concern. For the (we believe quite infrequent) subset of cases where IDCP may represent a precursor lesion31 found admixed alongside lower grade invasive carcinoma, inclusion of a noninvasive intraductal cribriform, solid, or comedonecrosis pattern in the grading might foreseeably trigger an inappropriately aggressive treatment.32–34 In the end, we believe that the issue of grading vis-à-vis IDCP will only be resolved by long-term data, linked to prognosis, based on cohorts with contemporary extended and targeted biopsy templates. In addition, comparative data regarding clinicians’ management patterns for different grades of carcinoma with and without presence of IDCP may be useful to determine which elements actually impact management in a meaningful way.

INTERNATIONAL SOCIETY OF UROLOGICAL PATHOLOGY AND GENITOURINARY PATHOLOGY SOCIETY AND EMERGING CONCEPTS IN GRADING AND PROGNOSTICATION

One newer theme that has been recommended for reporting by both 2019 manuscripts is the presence of cribriform pattern of growth in invasive carcinoma. Cribriform pattern, which was originally depicted as a pattern in a spectrum spanning Gleason patterns 3 and 4 in Gleason’s schematic drawings and recommendations but subsequently explicitly excluded from pattern 3 by ISUP consensus opinions from 2005 to 2014,6,9 has been the subject of much scholarship in recent years. Overall, there is striking uniformity in association of cribriform pattern with endpoints associated with disease aggression.35–41 Although we note neither society renders specific (nor, perhaps most importantly, minimal) criteria for diagnosis of cribriform pattern, both societies recommend reporting the presence of invasive cribriform carcinoma. Specifically, GUPS recommends reporting the presence of cribriform glands in biopsy and radical prostatectomy specimens showing Gleason pattern 4 carcinoma; ISUP recommends reporting the presence of cribriform pattern 4 in biopsies and prostatectomies with Gleason score 7 or 8. In the case of the GUPS publication, there is a note that there may be variable adoption of reporting of cribriform pattern, overall, based on local, institutional, and clinician preferences. Finally, with regards to emerging concepts, a recommendation shared between the societies’ recommendations was against adoption (at least at this time) of any of the several proposed novel or substantially modified grading systems, some of which incorporate in novel ways cribriform and/or IDCP, stromal features, or quantitation of percentages of higher grade patterns.1,2

Both societies have also assessed the state of the art regarding currently available adjunctive testing; for GUPS this was done in the 2019 white paper itself,2 while for ISUP this was a part of a separate 2019 consultation on the molecular pathology of urogenital cancers.42 In the area of immunohistochemistry and/or fluorescence in situ hybridization studies for key parameters such as Ki67 labeling index43,44 and PTEN assessment,45–47 GUPS recommended that neither marker was ready for routine clinical use. Somewhat in contrast, ISUP has recommended that Ki67 and PTEN assessment are potentially useful prognostic biomarkers in the subset of Grade Group 1 and 2 biopsies where active surveillance (AS) is contemplated, cautioning nonetheless that additional dedicated studies in this population are warranted.42 Both groups have also noted very promising findings from commercially available assays assessing RNA expression as were recently incorporated into the NCCN guidelines as a potential adjunct for consideration in AS.48 Both societies’ reports caution nonetheless that additional validation is needed in contemporary AS cohorts, with comparative cost and efficacy studies versus the foregoing immunohistochemical markers, and robust assessment of the impact of preanalytical and analytical variables on such tests.2,42 The remarkable promise of advanced computational methods (artificial intelligence) in pathology49 and prostate cancer pathologic assessment specifically21,50–53 did not escape notice of either society documents.1,2 Both encouraged research in this area, both opining that none of these techniques are ready for clinical application.

SUMMARY

Cumulatively, our side by side assessment of these 2 contemporary recommendations reveals an important point, amplifying the areas of shared recommendations: that 2 independent groups of experienced, scholarly pathologists assessed the literature and reached nearly all of the same conclusions. Where divergent, including around the issue of whether or not to grade IDCP patterns into the overall grade assessed, we recommend choosing one or the other recommendation to apply uniformly in practice with fellow departmental or institutional colleagues, in consultation with local urologist, oncologist, and radiation oncologist stakeholders. Which of the 2 sets recommendations is used may be referenced in report comments, documenting the approach taken, especially for the key divergent scenario where incorporating (or excluding) the pattern seen in extensive IDCP admixed with invasive carcinoma into the grade assessment could change the definitive Grade Group assigned for a case. For the record, we have among the authorship of this manuscript individuals using both of the societies’ recommendations regarding IDCP, grading, and reporting. As much as grading practices have already evolved in the time between Dr Gleason and contemporary Grade Groups and criteria, it is tempting to speculate that between histology, artificial intelligence/image analysis approaches, and molecular assays, we may sometime soon have an integrated approach to grade assessment quite different and beyond current practice. In the meantime, we are also hopeful that these technologies will help us define which of the (ever) growing number of histologic variables we currently assess and report separately is most important in informing clinical decision making.

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Keywords:

prostate cancer; Gleason grading; grade groups; cribriform pattern; intraductal carcinoma of the prostate

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