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Evolution in Prostate Cancer Staging: Pathology Updates From AJCC 8th Edition and Opportunities That Remain

Fine, Samson W., MD

doi: 10.1097/PAP.0000000000000200
Review Articles

The Tumor-Nodes-Metastasis system at the core of prognostic staging has been recently updated in the American Joint Committee on Cancer (AJCC) 8th edition, published in 2016. For prostate cancer, significant changes in staging of organ-confined disease, inclusion of a new grade grouping, and provision of levels of evidence for these modifications are part of what differentiates the 8th edition AJCC from prior iterations. Herein, the rationale underlying these changes is detailed. In addition, data elements not well represented in the present system are highlighted as opportunities for fresh study that may impact future AJCC classifications.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY

The authors have no funding or conflicts of interest to disclose.

Reprints: Samson W. Fine, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Room C502, New York, NY 10065 (e-mail: fines@mskcc.org).All figures can be viewed online in color at www.anatomicpathology.com.

As of January 1, 2018, reporting commensurate with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system has been in effect.1 This edition, reflecting the most recent changes to prognostic staging and the Tumor-Nodes-Metastasis (TNM) system, shows continued evolution in a number of organs/disease systems, including the prostate. Revisions in prostate cancer (PCa) staging resulted from the work of a multidisciplinary team of experienced radiation oncologists, urologic surgeons and oncologists, biostatisticians, radiologists, and pathologists. Key data elements were included/excluded or revised based on critical review and provision of levels of evidence.1 Importantly, there were diagnostic modalities, including magnetic resonance imaging, increasingly used in clinical practice, which nonetheless fell below the acceptable level of evidence for inclusion in the AJCC staging system for PCa. The Evidence-based Medicine and Statistics Core, the group that evaluated levels of evidence across organ systems determined that, “… Interobserver reproducibility, issues with patient selection and contradictory results have limited the utility of imaging in clinical staging.”1 These are cautionary words for our pathology community going forward, as new pathologic and/or molecular markers are studied and proposed for integration into staging algorithms.

A comparison of the major changes between the 7th2 and 8th1 editions of the AJCC staging system can be found in Table 1. In the 7th edition, the major anatomic-based change involved extraprostatic extension (EPE) in the form of microscopic bladder neck invasion, which was modified from pT4 to pT3a on the basis of a decade of data showing its diminished relevance in multivariable analyses that included robust pathology details.3–5 Although it may seem surprising, the AJCC 7th edition was the first in which Gleason score (GS) was officially recognized as the preferred grading system for PCa and in which prognostic factors [GS and prostate-specific antigen (PSA) levels] were incorporated with the TNM classification to create prognostic stage groups. In the 8th edition, the major anatomic-based change is in the classification of organ-confined disease. All organ-confined disease is now pathologically staged as T2 without further subcategorization by extent of involvement or laterality. Following progress made in the 7th edition, the updated AJCC requires reporting of histologic grade in the form of GS and grade group (GrdGrp). Finally, AJCC prognostic stage group III, for the first time, includes select organ-confined tumors that have high PSA levels and/or high GS/GrdGrp, a significant divergence from AJCC staging in most organs, in which the anatomic/pathologic extent of tumor is still the only factor determining higher prognostic stage groups. A more detailed rationale for each of these modifications follows.

TABLE 1

TABLE 1

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PATHOLOGIC STAGING OF ORGAN-CONFINED DISEASE

In prior editions, pathologic staging of organ-confined disease was divided in either 3 categories (T2a: less than half of 1 lobe, T2b: ≥half of 1 lobe, T2c: bilateral disease; 4th, 6th, and 7th editions) or 2 categories (T2a: involving 1 lobe, T2b: bilateral disease; 5th edition).2,6–8 There is ample reasoning to justify the classification of all organ-confined disease as pT2. Although a major effort was made in prior AJCC editions to retain pathologic T2 substaging so as to parallel clinical T2 staging, multiple studies have shown poor correlation between the 2. Others have shown that pathologic T2 subcategorization does not convey prognostic information, while pathologists have also shown poor reproducibility in determining less than versus greater than half of 1 lobe (T2a vs. T2b in 4th, 6th, and 7th editions). As importantly, the untenable scenario in which a unilateral large cancer would be assigned a lower T2 stage (T2a or b) than ≥2 minute bilateral cancers (T2c) provides a “common sense” rationale for eliminating pathologic substaging of T2 disease.9–14 Indeed, in a 2009 consensus conference on handling and staging of radical prostatectomy specimens, the International Society of Urological Pathology (ISUP) advocated eliminating pathologic T2 substaging.15 This goal has now been accomplished with the advent of the AJCC 8th edition. This change was assigned a Level of Evidence III, meaning that available evidence was somewhat problematic due to ≥1 factors, including: number/size of individual studies, inconsistency of results, appropriateness of patient populations, or outcomes used in ≥1 study. Nonetheless, the collective reasoning and data were deemed sufficient to support this change in pathologic stage.

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PROSTATE CANCER GRADING AND PROGNOSTIC GRADE GROUPING

PCa grading has undergone significant evolution in the past half century since the seminal descriptions of Donald F Gleason and colleagues.16,17 These changes have been codified in the proceedings of 2 major consensus conferences sponsored by the ISUP in 2005 and 2014,18,19 with the overall result being a narrower and more uniform definition of pattern 3, and an expansion of the morphologic features grouped as pattern 4. In 2013, the group from Johns Hopkins introduced the concept of GrdGrps.20 Before that time, while pathologists had for many years been grading PCa along the full range of GSs, many clinicopathologic studies and management algorithms had grouped these grades into 3 significant categories, ≤6, 7, and 8 to 10. The Hopkins study ushered in the era of increased employment of 5 GrdGrps for prognostication, based largely on the architectural methodology of Gleason grading. A follow-up meta-analysis from 5 institutions, which evaluated ∼21,000 patients who had undergone radical prostatectomy, 16,000 patients with needle biopsy data, and 5500 patients who had undergone radiation therapy,21 validated these GrdGrps. Concurrently, the 2014 ISUP conference addressed the grading of complex patterns of cancer, including cribriform, glomeruloid, and intraductal carcinoma, data elements that now impact the grading parameters incorporated into the AJCC 8th edition reporting.19 These collective efforts have led to wide adoption of the 2014 ISUP GS criteria and GrdGrp for reporting, including by the World Health Organization 2016 classification of urologic tumors,22 by the National Comprehensive Cancer Network guidelines as part of their risk group stratification,23 by the College of American Pathologists (CAP) in updated reporting protocols,24 and by the AJCC 8th edition.1

The Urology academic community, through its journals, has embraced this patient-centered realignment of PCa grading reporting.25 Clinicians discussing management options with patients—specifically active surveillance—can now frame very low-risk disease as GrdGrp 1, as opposed to a GS 6 of 10, a distinction that may have profound differences in perception from the patient perspective.26 Furthermore, better discrimination of GS 7 into GrdGrp 2 versus GrdGrp 3 is helpful in clarifying their different clinicopathologic outcomes21,27,28 and is especially important for the radiation oncology community, in which the difference between GrdGrp 2 and GrdGrp 3 may result in the addition of androgen deprivation/hormonal therapy to radiation alone. These prognostic GrdGrps have been further validated in population-based cohorts, single institution radical prostatectomy, and radiation therapy cohorts as well as in studies looking at endpoints beyond biochemical recurrence (BCR), such as metastasis and death.29–32 On the basis of this evidence, reporting of PCa grading in the AJCC 8th edition, including GS (2014 ISUP criteria)19 and GrdGrp, was assigned a Level of Evidence II, meaning that available evidence was obtained from at least 1 large, well-designed, and well-conducted study with appropriate patients and outcomes, with external validation. Progress in the area of GrdGrps represents an important paradigm for how pathologists may collaborate in the future to move critical changes in grading/staging toward clinical utility.

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AMERICAN JOINT COMMITTEE ON CANCER PROGNOSTIC STAGE GROUPING

The reorganization of AJCC prognostic stage groups for PCa to include prognostic factors other than TNM anatomic variables began in the 7th edition. The modifications continue to a greater extent in the 8th edition (Table 2), highlighted by further subdivisions of AJCC prognostic stage group II by GS/GrdGrp, that is, prognostic stage group IIB refers to organ-confined tumors, with PSA<20 and GS 3+4=7/GrdGrp 2, whereas prognostic stage group IIC is organ-confined disease, PSA<20 and GS 4+3=7/GrdGrp 3 or GS=8/GrdGrp 4. These adjustments reflect the more aggressive biological potential of primary Gleason pattern 4 tumors.27 Most significantly, AJCC prognostic stage group III now includes select organ-confined cases (groups IIIA and IIIC), placed in this higher stage group on the basis of either PSA≥20 or GS 9 to 10/GrdGrp 5 alone. From a pathology perspective, the latter category, while controversial, acknowledges the consistent value of grading, with its contemporary modifications, in prediction of outcomes. This revised prognostic stage grouping has now been validated in at least 1 large study.33

TABLE 2

TABLE 2

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INCLUSION OF RECOMMENDED RISK ASSESSMENT TOOLS

The final change from previous editions is the evaluation of PCa risk assessment tools by the Precision Medicine Core of the AJCC 8th edition team,34 which sought to determine whether any could be recommended for routine use. Fifteen available prognostic models for PCa were considered, each containing a multivariable model in which factors predicted a future clinical outcome. It is sobering to note that only 2 models met all of the criteria for inclusion—both of these based on data from large phase III trials in metastatic prostate cancer (PCa) patients, with external validation.35,36 Thirteen models were rejected, including all 9 dealing with localized disease. To understand this phenomenon, one must recognize the inclusion/exclusion criteria of the Precision Medicine Core. Inclusion criteria such as: (a) use of overall survival/disease-specific survival/disease-specific mortality as an endpoint, (b) generalizability (ie, would the model be valid in future patients) and external validation of the given model, (c) whether calibration of the model was assessed and provided in the relevant manuscript, and (d) whether the model provided sufficient detail to implement it in other settings (ie, the manuscript provides the model equation or free access to it), were major reasons why a number of models could not be recommended. Among exclusion criteria, some models provided no information on the number of patients with missing values in the validation data set(s), potentially introducing large bias.34 These are important matters for pathologists to consider in the future, both in terms of how we conduct studies (which cohorts and endpoints to choose, appropriate validation sets, and generalizability) and the use of robust biostatistical methodology and expertise. Most acutely, in the case of PCa, pathologists will need to partner with clinical colleagues to establish scenarios in which BCR is deemed an appropriate endpoint for PCa predictive models.

Although the AJCC system has seen continued evolution in the 7th and now 8th editions, there are a number of prognostic variables not currently represented in the stage groupings. These variables may be newly relevant due to changes in the current edition, or may be well-known, but may not yet have garnered the robust level of evidence/data necessary to mandate change. In some cases, whereas AJCC reporting is seemingly simple, reporting of data elements in practice has become increasingly complex, such that there is significant disparity and a question of what is truly the most clinically relevant information. An example from each of these categories will be highlighted as areas that would benefit from well-designed studies to inform future editions of the AJCC staging system.

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ROLE OF TUMOR QUANTITATION IN PROGNOSTIC STAGING

In manuscripts from the 2000s, multiple groups demonstrated that total tumor volume was a predictor of PCa outcomes (BCR) in univariate analysis, yet did not add important predictive accuracy when controlling for known prognostic factors such as PSA, grade, stage, and surgical margin status.37–39 Nonetheless, in the proceedings of the 2009 ISUP consensus conference on radical prostatectomy handling, staging, and reporting, a majority of experienced genitourinary pathology participants were in favor of reporting tumor volume/quantitation in some form15; there was no agreement, however, on the ideal way to measure tumor volume and the significant issue of interobserver reproducibility was expressed.15 Subsequently, even though little new information has been added to the literature, recently revised CAP and International Collaboration on Cancer Reporting (ICCR) reporting protocols for radical prostatectomy recommend or require reporting “tumor quantitation,”24,40 with CAP leaving to the pathologist’s discretion whether one would report estimated (%) volume of radical prostatectomy tissue involved and/or millimeters linear length of the dominant tumor nodule mass in greatest dimension.24

As there is currently no widely accepted method for quantitation, this is a seemingly a premature recommendation. Nonetheless, the notion of including tumor quantitation in staging may be important in light of the removal of pathologic T2 subcategorization in the AJCC 8th edition. In radical prostatectomies with organ-confined disease, which still constitute a large percentage of resected cases, without subcategories indicating the extent of tumor, grade/stage/margin status are the only current pathologic prognostic factors. While it remains to be seen whether robust data can be generated to support its inclusion in prognostic staging, mandated reporting of tumor quantitation in radical prostatectomy specimens provides a window to relook at various methods. Hopefully, studies in the coming years will provide evidence to support/reject the notion that tumor quantitation is an important prognostic factor and if so, to describe the most reproducible method for its assessment.

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EXTENT OF EXTRAPROSTATIC EXTENSION

The basic boundary of the prostate is a condensed fibromuscular layer of prostatic stroma. EPE refers to the presence of tumor beyond the borders of the gland. While this terminology may convey ease in application, it is highly dependent on anatomic location. Although the boundary is usually intact in the posterior and posterolateral aspects of the gland, this is not the case in the apex, anterior, or bladder neck regions.41,42 Moreover, even in regions with a well-defined edge to the prostate, tumor-related or biopsy-related fibrous change may cause difficulty in evaluation of extraprostatic tumor spread. Not surprisingly, interobserver variability studies among pathologists evaluating EPE have reported the most variation in areas and cases without clear anatomic landmarks.43,44

Once the presence of EPE has been established, some method of quantitation is routine.42 The 2 most common approaches are those of Epstein et al45 and Wheeler et al46 which both distinguish “focal” from “established” (nonfocal) EPE. The former defines “focal” as a few neoplastic glands just outside the prostate with any more glands being “established,” whereas the latter defines “focal” as extraprostatic tumor occupying <1 high-power field in no more than 2 sections and “established” (Fig. 1) as any degree more than that.45,46 Using these subjective, yet readily applied criteria, meaningful separation of pT3a patients can be achieved. EPE is a significant parameter in nearly all postoperative tools predicting BCR, yet in the AJCC system, focal and nonfocal/established EPE are grouped together as pT3a, reflecting their similar PCa-specific and overall survival.47 Importantly, a recent large study has suggested that for most GSs, men with nonfocal/established EPE have worse BCR-free survival that those with focal EPE, the latter behaving more like organ-confined disease.48 Additional study in appropriately selected cohorts therefore seems indicated to determine whether substratification of pT3a is warranted and if so, whether future AJCC staging of PCa can be tailored to the BCR scenario.

FIGURE 1

FIGURE 1

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POSITIVE SURGICAL MARGIN SUBCATEGORIZATION

In both the 7th and 8th AJCC editions, a positive surgical margin (Figs. 2, 3) at radical prostatectomy is indicated with an R1 descriptor.1,2 While this convention reflects a dichotomous—positive versus negative—data element which is readily gleaned from standard pathology reports, the treatment of positive margins has become increasingly complex in practice. Manuscripts published at the end of the last decade have framed an ongoing deliberation regarding subcategorization of positive surgical margins in PCa. One report was a meta-analysis of prior studies looking at the effect of positive surgical margins in radical prostatectomy specimens across GSs and pathologic T stage. The study showed independent predictive value for the number (multiple vs. solitary) and extent [focal (a few glands in 1 section) vs. extensive] of positive surgical margins on BCR outcomes, yet found that these parameters did not add important predictive accuracy beyond dichotomous (positive vs. negative) surgical margin status.49 The second set of studies were single institution reports which evaluated the impact of linear length of positive surgical margin on the likelihood of BCR and demonstrated that linear length of margin >3 versus ≤3 mm showed statistically significant differences in BCR rates.50,51

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

Since these publications, there has been increased interest in positive surgical margins subcategorization, mostly focused on 2 parameters: length of margin positivity and highest GS at the margin. While a number of studies have found independent predictive value for each factor,52–57 few have examined the added predictive value or clinical utility of these parameters beyond that conveyed by positive versus negative margin status alone.58–60 In 2016 to 2017, presumably based on the majority of published findings, revised protocols for radical prostatectomy reporting (CAP/ICCR) have begun to recommend, and in some cases require, reporting of positive surgical margins subcategorization. For example, CAP worksheets now require quantitation of tumor at a positive surgical margin, expressed as < or ≥3 mm of linear length of margin positivity; assigning a GS at a positive surgical margin is also recommended.24,40

Adjuvant radiation therapy in the postradical prostatectomy setting is the administration of external beam radiotherapy in the absence of objective evidence that the disease has recurred or persisted, for example, an undetectable PSA.61,62 Although 3 randomized trials have demonstrated that adjuvant radiation therapy in the setting of adverse pathologic features (ie, pT3b or positive surgical margin) may delay BCR,63–65 their interpretation is biased by the inclusion of patients who never achieved undetectable PSA levels following radical prostatectomy, who are best-considered early BCR patients who received early salvage, rather than adjuvant, radiotherapy. Given that observation followed by salvage radiotherapy when BCR occurs has also been associated with durable cancer control, and postoperative adjuvant radiotherapy is associated with short-term and long-term side effects, many centers will wait to intervene until PSA rises.

One may postulate therefore, that the reporting of subcategories of surgical margin positivity (eg, number, location, length, GS at margin) should be evaluated in this context, with the crucial question being: will independent prognostic value for predicting BCR with any given mode of positive surgical margin subcategorization alter clinical practice? A randomized clinical trial administering adjuvant therapy to patients with a given finding (eg, >3 mm linear length of margin positivity) versus observation for those without the finding would certainly help determine whether such an intervention would prolong BCR. In the absence of such evidence, it is questionable whether any mode of subclassification of positive surgical margins will definitively impact patient management, the ultimate goal of reporting.

Pathology reporting at its best provides updated and relevant information regarding diagnosis, staging, and risk stratification to be used in outcome prediction and guiding therapy. Hence, there should be a reluctance to include data elements that will not risk stratify in an actionable way. Given that current AJCC prognostic staging dichotomizes assessment of positive surgical margins (positive: R1; negative: no descriptor),1 one may argue that further study with significant input from clinical colleagues is necessary to determine whether there are truly any positive margin subcategories worthy of inclusion as standard data elements in either pathology reports or AJCC staging.

In summary, AJCC prognostic staging for PCa has continued to evolve in the current 8th edition, with significant input from the pathology community impacting the inclusion of grading and anatomic-based staging parameters. The ability to incorporate refined PCa reporting elements should drive future statistically robust and clinically relevant studies that will inform future AJCC editions.

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Keywords:

prostate cancer; staging; TNM; AJCC; grading; quantitation; extraprostatic extension; surgical margin

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