Purpose An update is provided of the Gleason grading system, which has evolved significantly since its initial description. Materials and Methods A search was performed using the MEDLINE® database ...and referenced lists of relevant studies to obtain articles concerning changes to the Gleason grading system. Results Since the introduction of the Gleason grading system more than 40 years ago many aspects of prostate cancer have changed, including prostate specific antigen testing, transrectal ultrasound guided prostate needle biopsy with greater sampling, immunohistochemistry for basal cells that changed the classification of prostate cancer and new prostate cancer variants. The system was updated at a 2005 consensus conference of international experts in urological pathology, under the auspices of the International Society of Urological Pathology. Gleason score 2–4 should rarely if ever be diagnosed on needle biopsy, certain patterns (ie poorly formed glands) originally considered Gleason pattern 3 are now considered Gleason pattern 4 and all cribriform cancer should be graded pattern 4. The grading of variants and subtypes of acinar adenocarcinoma of the prostate, including cancer with vacuoles, foamy gland carcinoma, ductal adenocarcinoma, pseudohyperplastic carcinoma and small cell carcinoma have also been modified. Other recent issues include reporting secondary patterns of lower and higher grades when present to a limited extent, and commenting on tertiary grade patterns which differ depending on whether the specimen is from needle biopsy or radical prostatectomy. Whereas there is little debate on the definition of tertiary pattern on needle biopsy, this issue is controversial in radical prostatectomy specimens. Although tertiary Gleason patterns are typically added to pathology reports, they are routinely omitted in practice since there is no simple way to incorporate them in predictive nomograms/tables, research studies and patient counseling. Thus, a modified radical prostatectomy Gleason scoring system was recently proposed to incorporate tertiary Gleason patterns in an intuitive fashion. For needle biopsy with different cores showing different grades, the current recommendation is to report the grades of each core separately, whereby the highest grade tumor is selected as the grade of the entire case to determine treatment, regardless of the percent involvement. After the 2005 consensus conference several studies confirmed the superiority of the modified Gleason system as well as its impact on urological practice. Conclusions It is remarkable that nearly 40 years after its inception the Gleason grading system remains one of the most powerful prognostic factors for prostate cancer. This system has remained timely because of gradual adaptations by urological pathologists to accommodate the changing practice of medicine.
This review article will cover the evolution of grading of prostate cancer from the original Gleason system in the 1960-1970s to a more patient-centric grading system proposed in 2013 from a group at ...Johns Hopkins Hospital, validated in 2014 by a large multi-institutional study, and subsequently accepted by the World Health Organization (WHO), College of American Pathology (CAP), and the AJCC TNM system. Covered topics include: (1) historical background; (2) 2005 and 2014 International Society of Urological Pathology Grading Conferences; (3) Description of Gleason patterns; (4) new approaches to display Gleason grades; (5) grading variants and variations of acinar adenocarcinoma; (6) reporting rules for Gleason grading reporting secondary patterns of higher grade when present to a limited extent; (7) reporting secondary patterns of lower grade when present to a limited extent; (8) reporting percentage pattern 4; (9) general applications of the Gleason grading system; (10) needle biopsy with different cores showing different grades; (11) radical prostatectomy specimens with separate tumor nodules; and (12) a new grading system for prostate cancer.
The definition of clinically significant prostate cancer is a dynamic process that was initiated many decades ago, when there was already evidence that a great proportion of patients with prostate ...cancer diagnosed at autopsy never had any clinical symptoms. Autopsy studies led to examinations of radical prostatectomy (RP) specimens and the establishment of the definition of significant cancer at RP: tumour volume of 0.5 cm3, Gleason grade 6 Grade Group (GrG) 1, and organ‐confined disease. RP studies were then used to develop prediction models for significant cancer by the use of needle biopsies. The first such model was used to delineate the first active surveillance (AS) criteria, known as the ‘Epstein’ criteria, in which patients with a cancer Gleason score of 3 + 3 = 6 (GrG1) involving fewer than two cores, and <50% of any given core, and a prostate‐specific antigen density of <0.15 ng/ml per cm3 had a minimal risk of significant cancer at RP. These were adopted as components of the ‘very‐low‐risk category’ of the National Comprehensive Cancer Network guidelines, in which AS is supported as a management option. With the increase in the popularity of AS, much research has been carried out to better define significant/insignificant cancer, in order to be able to safely offer AS to a larger proportion of patients without the risk of undertreatment. Research has focused on allowing higher volume tumours, focal extraprostatic extension, and a limited amount of Gleason pattern 4, and the significance of different morphological patterns of Gleason 4. Other areas of research that will probably impact on the field but that are not covered in this review include the molecular classification of tumours and imaging techniques.
The reporting of intraductal carcinoma of the prostate (IDCP) is controversial, with conflicting recommendations having recently been published by the International Society of Urological Pathology ...(ISUP) and the Genitourinary Pathology Society (GUPS). Both recommend that isolated (pure) IDCP should not be graded. However, the ISUP recommends incorporating the IDCP component of invasive prostate cancer in the Gleason score, whereas the GUPS recommends reporting IDCP as a comment, independently of the Gleason score. The arguments for and against incorporating the IDCP component of invasive prostate cancer in the Gleason score are discussed in detail.
What's known on the subject? and What does the study add?
The Gleason scoring system is a well‐established predictor of pathological stage and oncological outcomes for men with prostate cancer. ...Modifications throughout the last few decades – most recently by the International Society of Urological Pathology (ISUP) in 2005 – have attempted to improve the correlation between biopsy and radical prostatectomy Gleason sum and better stratify patients to predict clinical outcomes.
Based on these clinical outcomes and the excellent prognosis for patients with low Gleason scores, we recommend Gleason grades incorporating a prognostic grade grouping which accurately reflect prognosis and are clearly understood by physicians and patients alike.
Objective
To investigate pathological and short‐term outcomes since the most recent Gleason system modifications by the International Society of Urological Pathology (ISUP) in an attempt to divide the current Gleason grading system into prognostically accurate Gleason grade groups.
Patients and Methods
We queried the Johns Hopkins Radical Prostatectomy Database (1982–2011), approved by the institutional review board, for men undergoing radical prostatectomy (RP) without a tertiary pattern since 2004 and identified 7869 men.
Multivariable models were created using preoperative and postoperative variables; prognostic grade group (Gleason grade ≤6; 3 + 4; 4 + 3; 8; 9–10) was among the strongest predictors of biochemical recurrence‐free (BFS) survival.
Results
Significant differences were noted among the Gleason grade groups at biopsy; differences were noted in the race, PSA level, clinical stage, number of positive cores at biopsy and the maximum percentage of positive cores among the Gleason grade groups at RP.
With a median (range) follow‐up of 2 (1–7) years, 5‐year BFS rates for men with Gleason grade ≤6, 3 + 4, 4 + 3, 8 and 9–10 tumours at biopsy were 94.6, 82.7, 65.1, 63.1 and 34.5%, respectively (P < 0.001 for trend); and 96.6, 88.1, 69.7, 63.7 and 34.5%, respectively (P < 0.001), based on RP pathology.
Conclusions
The 2005 ISUP modifications to the Gleason grading system for prostate carcinoma accurately categorize patients by pathological findings and short‐term biochemical outcomes but, while retaining the essence of the Gleason system, there is a need for a change in its reporting to more closely reflect tumour behaviour.
We propose reporting Gleason grades, including prognostic grade groups which accurately reflect prognosis as follows: Gleason score ≤6 (prognostic grade group I); Gleason score 3+4=7 (prognostic grade group II); Gleason score 4+3=7 (prognostic grade group III); Gleason score 4+4=8 (prognostic grade group (IV); and Gleason score 9–10 (prognostic grade group (V).
To assess long-term outcomes of men with favorable-risk prostate cancer in a prospective, active-surveillance program.
Curative intervention was recommended for disease reclassification to higher ...cancer grade or volume on prostate biopsy. Primary outcomes were overall, cancer-specific, and metastasis-free survival. Secondary outcomes were the cumulative incidence of reclassification and curative intervention. Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model.
A total of 1,298 men (median age, 66 years) with a median follow-up of 5 years (range, 0.01 to 18.00 years) contributed 6,766 person-years of follow-up since 1995. Overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years. The cumulative incidence of grade reclassification was 26% at 10 years and was 31% at 15 years; cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years. The median treatment-free survival was 8.5 years (range, 0.01 to 18 years). Factors associated with grade reclassification were older age (hazard ratio HR, 1.03 for each additional year; 95% CI, 1.01 to 1.06), prostate-specific antigen density (HR, 1.21 per 0.1 unit increase; 95% CI, 1.12 to 1.46), and greater number of positive biopsy cores (HR, 1.47 for each additional positive core; 95% CI, 1.26 to 1.69). Factors associated with intervention were prostate-specific antigen density (HR, 1.38 per 0.1 unit increase; 95% CI, 1.22 to 1.56) and a greater number of positive biopsy cores (HR, 1.35 for one additional positive core; 95% CI, 1.19 to 1.53).
Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.
Abstract Background Prior studies assessing the correlation of Gleason score (GS) at needle biopsy and corresponding radical prostatectomy (RP) predated the use of the modified Gleason scoring system ...and did not factor in tertiary grade patterns. Objective To assess the relation of biopsy and RP grade in the largest study to date. Design, setting, and participants A total of 7643 totally embedded RP and corresponding needle biopsies (2004–2010) were analyzed according to the updated Gleason system. Interventions All patients underwent prostate biopsy prior to RP. Measurements The relation of upgrading or downgrading to patient and cancer characteristics was compared using the chi-square test, Student t test, and multivariable logistic regression. Results and limitations A total of 36.3% of cases were upgraded from a needle biopsy GS 5–6 to a higher grade at RP (11.2% with GS 6 plus tertiary). Half of the cases had matching GS 3 + 4 = 7 at biopsy and RP with an approximately equal number of cases downgraded and upgraded at RP. With biopsy GS 4 + 3 = 7, RP GS was almost equally 3 + 4 = 7 and 4 + 3 = 7. Biopsy GS 8 led to an almost equal distribution between RP GS 4 + 3 = 7, 8, and 9–10. A total of 58% of the cases had matching GS 9–10 at biopsy and RP. In multivariable analysis, increasing age ( p < 0.0001), increasing serum prostate-specific antigen level ( p < 0.0001), decreasing RP weight ( p < 0.0001), and increasing maximum percentage cancer/core ( p < 0.0001) predicted the upgrade from biopsy GS 5–6 to higher at RP. Despite factoring in multiple variables including the number of positive cores and the maximum percentage of cancer per core, the concordance indexes were not sufficiently high to justify the use of nomograms for predicting upgrading and downgrading for the individual patient. Conclusions Almost 20% of RP cases have tertiary patterns. A needle biopsy can sample a tertiary higher Gleason pattern in the RP, which is then not recorded in the standard GS reporting, resulting in an apparent overgrading on the needle biopsy.
Purpose This review addresses the controversies that persist relating to the prognosis and reporting of tumor volume in adenocarcinoma of the prostate. Materials and Methods A search was performed ...using the MEDLINE database and referenced lists of relevant studies to obtain articles addressing the quantification of cancer on radical prostatectomy and needle biopsy. Results In the 2010 TNM classification system T2 tumor at radical prostatectomy is subdivided into pT2a (unilateral tumor occupying less than ½ a lobe), pT2b (unilateral tumor greater than ½ a lobe) and pT2c (bilateral tumor). This pathological substaging of T2 disease fails on several accounts. In most studies pT2b disease almost does not exist. By the time a tumor is so large that it microscopically occupies more than ½ a lobe, in the majority of cases there is bilateral (pT2c) tumor. An even greater flaw of the substaging system for stage pT2 disease is the lack of prognostic significance. In reporting pathologically organ confined cancer, it should be merely noted as pT2 without further subclassification. The data are conflicting as to the independent prognostic significance of objective measurements of tumor volume in radical prostatectomy specimens. The most likely explanation for the discordant results lies in the strong correlation of tumor volume with other prognostic markers such as extraprostatic extension and positive margins. In studies where it is statistically significant on multivariate analysis, it is unlikely that knowing tumor volume improves prediction of prognosis beyond routinely reported parameters to the degree that it would be clinically useful for an individual patient. An alternative is to record tumor volume as minimal, moderate or extensive, which gives some indication to the urologist as to the extent of disease. Not only does providing an objective measurement not add useful prognostic information beyond what is otherwise routinely reported by the pathologist, but many objective measurements done in routine practice will likely not be an accurate indicator of the true tumor volume. There is also a lack of consensus regarding the best method of measuring tumor length when there are multiple foci in a single core separated by benign intervening prostatic stroma. Some pathologists, this author included, consider discontinuous foci of cancer as if it was 1 uninterrupted focus, the rationale being that these discontinuous foci are undoubtedly the same cancer going in and out of the plane of section. Measuring the cancer from where it starts to where it ends on the core gives the minimal length of cancer in the prostate. Others measure each focus individually, and the sum of these measurements is considered the cancer length on the core. Quantifying cancer with an ocular micrometer to record the total length or percent length of cancer is time-consuming, and the data are conflicting whether this is superior to other, simpler methods and whether any potential differences in predictive accuracy would translate into changes in clinical management. It is recommended that at a minimum the number of positive cores be recorded, unless fragmented involved cores preclude evaluation, along with at least 1 other more detailed measurement such as the percent of core involvement or length of cancer. Conclusions Consensus has been reached on some of the issues relating to quantifying tumor volume in prostate cancer, such as the lack of utility of substaging pT2 disease. Other questions such as whether to include or subtract intervening benign prostate tissue on prostate needle cores will require additional studies. Finally, matters such as the need to quantify cancer at radical prostatectomy or which method of quantifying cancer on needle biopsy is superior will likely remain contentious due to the close interrelationship and redundancy of prognostic variables.
Whether Grade Group 1 (GG1) prostate cancer is really cancer remains controversial.
Favoring renaming GG1 with a noncancerous diagnosis are: fear of the term cancer, which will lead to overtreatment ...of GG1; and indolence of GG1. Favor designating GG1 as cancer are: morphologically, GG1 may be indistinguishable from GG2 to GG5 and GG1 is invasive (lacks basal cells), can show perineural invasion and extraprostatic extension; molecularly, GG1 has many of the hallmarks of prostate cancer; calling GG1 noncancer would lead to inconsistencies and confusion in reporting; sampling error with GG1 on biopsy can miss higher grade cancer; removing the label of cancer in men with GG1 on biopsy may make it challenging to insure follow-up during active surveillance; the prognosis of treated GG1 may not be the same if GG1 called noncancer and not treated; with Grade Group terminology, GG1 is more intuitive to patients as lowest grade cancer; and patients are increasingly adopting active surveillance, recognizing that not all prostate cancers are the same and GG1 can be followed carefully and safely on active surveillance.
There is strong support for retaining the carcinoma designation for GG1.
Abstract Background Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, ...8–10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3 + 4 = 7 and 4 + 3 = 7 are often considered the same prognostic group. Objective To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. Design, setting, and participants Between 2005 and 2014, 20 845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. Outcome measurements and statistical analysis Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. Results and limitations In the surgery cohort, we found large differences in recurrence rates between both Gleason 3 + 4 versus 4 + 3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3 + 4, 4 + 3, 8, and 9–10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five–grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. Conclusions The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. Patient summary We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.
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