|Year : 2022 | Volume
| Issue : 3 | Page : 192-198
Grading of prostate cancer: Evolution and changing concepts
Vijayalaxmi M Dhorigol, Ranjit P Kangle
Department of Pathology, KAHER's J N Medical College and KLES Dr. Prabhakar Kore Hospital and MRC, Belagavi, Karnataka, India
|Date of Submission||20-Jan-2022|
|Date of Acceptance||14-Mar-2022|
|Date of Web Publication||17-Sep-2022|
Dr. Vijayalaxmi M Dhorigol
H No. 75, Shreedhama. Near Vitthalai Temple, Vaibhav Nagar, 1st Cross, Belagavi - 590 010, Karnataka
Source of Support: None, Conflict of Interest: None
Grading system for prostatic cancer (PC) was first described in1966 by Dr. Donald Gleason. Over the years, histologic, clinical diagnosis and management of PCa have evolved, leading to revisions of the Gleason system first by the International Society of Urological Pathology (ISUP) in 2005 and more recently in 2014. Unlike the original Gleason score (GS) ranging from 2 to 10, the current system no longer assign Scores 2–5, the lowest score being 6. The new grading system of 2014 proposed Five Grade Groups based on revised GS which produces a smaller number of grades with the most significant prognostic differences and may contribute to a decrease in the overtreatment of low-grade PC detected by prostate-specific antigen screening. This review provides an update on the evolution and revision of the Gleason grading system, with a discussion on the deficiencies, benefits, and limitations of the revised and new grading system of ISUP 2005, 2014, and 2019.
Keywords: Gleason grade, Gleason score, prostate cancer, new grading system, International Society of Urological Pathology, needle core biopsies, radical prostatectomy
|How to cite this article:|
Dhorigol VM, Kangle RP. Grading of prostate cancer: Evolution and changing concepts. Indian J Health Sci Biomed Res 2022;15:192-8
| Introduction|| |
Prostate cancer (PC) is the most common cancer among males in the United States in the year 2016 (21% of all cancers) and is responsible for 8% of cancer deaths among men., Gleason grading system is one of the most important and powerful prognostic predictors in PC. PC grading is done using the Gleason scoring (GS) system. Accurate grading plays a very important role in prognosis and therapy. Gleason grading system has evolved significantly over the years and continues to be modified and revised to remain relevant in modern practice. It was first revised in 2005 and recently l at the 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of PC, which allows for a more accurate prognostic and risk stratification.
| Diagnosis of Prostatic Adenocarcinoma|| |
Microscopically, prostatic adenocarcinomas exhibit a wide spectrum of appearances. They have different architectural patterns. The major patterns include medium or small glands, cribriform, diffuse infiltration, and poorly formed glands. A more specific feature of carcinoma is the presence of either a linear row of atypical glands traversing the width of the core or small atypical glands which are seen on both sides of a benign-appearing gland. Basal cells are absent. The most widely recognized cytological feature of prostate adenocarcinoma is prominent nucleoli. The presence of glomerulations, mucinous fibroplasia, and perineural invasion when circumferential is considered to be the three strong indicators of malignancy in prostate., The diagnosis of cancer should not be based on anyone criterion alone. Instead, always rely on a combination of important features.
| Grading of Prostate Cancer- General Aspects|| |
Gleason grading should not be applied in cases with a therapy effect. Regression grading is not routinely done. It is on the patterns and their admixture, as seen on low-power examination, that the Gleason grading system is primarily based. The predominant “primary” tumor pattern and the “secondary” pattern are graded from 1 to 5. When both are added, we get the Gleason score (GS) or sum. In case the tumor has a single pattern throughout, the final score is obtained by multiplying the grade by 2. Tumors with tertiary or minor pattern is reported only if it is of a higher grade., In biopsies, the minor high-grade pattern is incorporated into the GS. Gleason patterns 1 to 2 are not clinically meaningful in modern practice, so the grading system effectively begins at GS 3 + 3.
In most cases, for grading the tumor, the use of × 4 objective is ideal except for few cases that require × 10 objectives, to define back-to-back glands and fused glands. Especially Gleason Pattern 3 must be identified at × 4, so that overgrading can be avoided. Because small well-formed glands when cut tangentially may appear as poorly formed glands on a higher power. GS is usually reported as an equation, for example, 3 + 4 = 7, to avoid confusion.
When multiple cores are submitted and are positive for malignancy, Gleason grade in each core may be different. When the cores are sent in different containers or location designated by inking, grades of each core should be reported separately. It is observed that, when the cores exhibit different grades, the correlation between the highest GS and stage is found to be better than the frequent grade or the average score among the cores, when assessed on RP.,,, However, an overall GS can be reported when multiple fragmented cores are submitted in a single container [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5].
|Figure 1: Prostate adenocarcinoma-Gleason pattern 3. Show well formed, individual glands of varying sizes (H and E, ×100)|
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|Figure 2: Gleason pattern 4. Show Cribriform pattern, neoplastic cells running across the core (H and E, ×100)|
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|Figure 4: Gleason pattern-5. Show comedonecrosis within solid nests and cribriform glands (H and E, ×100)|
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|Figure 5: Gleason pattern 5. Show cells as cords invading the stroma (H and E, ×100)|
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| Evolution of Gleason Grading System|| |
A unique grading system for prostatic adenocarcinoma was first created by Dr. Donald Gleason and Veterans Administration Cooperative Urologic Research Group in 1966, based on architectural pattern of the tumor. He demonstrated 5 prognostic patterns by drawing a simple diagram. Later in 1974, Gleason and Mellinger, based on a study of larger number of patients, further modified definition of pattern 4. The overall grade of the carcinoma was not the highest grade noted. Instead, GS ranging from 2 to 10 was proposed which represented the sum of 2 most common grade patterns. It was observed that increase in score was associated with increase in mortality related to cancer.
Significant changes were introduced in 2005 at the ISUP conference with further modifications in 2014. The resulting grading system is referred to as the “ISUP modified Gleason grading system.”
| Need for Modification of Original Gleason Grading System|| |
Way back in 1974, few biopsies were taken using a thick gauge needle after identifying an area abnormality on palpation. With the advent of needle core biopsies, grading on multiple needle cores submitted from different areas of prostate, grading multiple nodules on the same prostate, reporting of the tertiary patterns had to be addressed. With the use of immunohistochemistry, diagnosis of adenosis and cribriform high-grade PIN could be made confidently. New patterns and new histological variants of prostate adenocarcinoma were identified. Hence, there was a need to adapt the Gleason system to modern practice.
| Changes as per the 2005 International Society of Urological Pathology Consensus Conference|| |
A group of leading urological pathologists from all over the world gathered at the United States and Canadian Academy Pathology Meeting in 2005, to achieve consensus in controversial areas related to the Gleason grading system.,
The diagnosis of GS 2–5 should not be made on needle core biopsy, as these scores do not correlate well or poor reproducibility was noted when compared with the grades in radical prostatectomy., This leads to gradual disappearance of GS 2-4; reporting of GS 5 decreasing from 12.2% to 0.3% on needle biopsy. Even with limited cancer on TURP (stage T1a), the prognosis in cases of GS 2–4 did not differ much when compared to score 5-6. Hence, it was thought that GS less than 6 does not carry much clinical significance and it frequently occurs in the transition and anterior zones of the prostate. It was agreed that Gleason cribriform pattern 3 carcinoma should never be diagnosed. Gleason pattern 4 should be assigned to areas exhibiting glands which are ill-defined and do not have well-formed lumina.
Using modified grading system, the proportion of needle biopsies with GS of 6 reduced and Gleasons score 7 increased. Based on this grading system, organ-confined prostate cancer with GS 6 and negative margins are virtually 100% curable.
Gleason pattern 3
In this pattern, well-formed glands of varying sizes are seen, forming discrete units, infiltrating into and amidst the normal-appearing prostatic glands. The outlines of these glands can be easily traced. Even when biopsies show only a small focus exhibiting pattern 3, a GS 3 + 3 = 6 can be given by assigning primary and secondary patterns, as it is likely to find the same on radical prostatectomy in such cases.
Gleason pattern 4
Contain ill-formed, fused, or cribriform glands. Unless overtly cribriform, Gleason pattern 4 should be cautiously assigned to areas where glands appear complex when associated with perineural invasion and mucinous fibroplasias.
In the original grading system, glands which exhibited regular cribriform pattern were included in Gleason pattern 3, while those with irregular ragged edges in pattern 4. It was observed that biochemical changes, positive margins, extraprostatic extension, recurrence, and cancer-related mortality were associated with cribriform pattern.,,,, Hence, cribriform pattern and poorly formed glands should be Gleason pattern 4. With this, the Gleason grade on biopsy and on radical prostatectomy correlated well. Furthermore, the prediction of tumor volume, margins, prostatectomy stage, and biochemical recurrence improved.,,,, Glomeruloid morphology was considered when cribriform structures were seen within the lumen of dilated glands with a single point of attachment, as the structure resembles a glomerulus in the kidney. However, there was no agreement on what grade to assign to this morphology. Later, it was found that in most of the cases, Gleason pattern 4 or higher grade was associated with these structures.
Gleason pattern 5
Assigned when there is the presence of cords of cells, solid nests, single cells, tumor cells in sheets, or occasional gland space formation. Cribriform glands or solid nests with comedonecrosis also represent this pattern. There is no notable change in Gleason pattern 5 in modern practice.
| Reporting Limited Secondary Patterns and Tertiary Patterns|| |
When <5% of tumor area in a high-grade cancer is occupied by lower-grade patterns, they should be ignored. If on a needle core biopsy, 96% is Gleason pattern 4 and only 4% constitute Gleason pattern 3, it is to be reported as GS 8 (4 + 4), which would have been 4 + 3 = 7 according to original system. However, the same is not true for secondary pattern of a higher grade. If, 96% is Gleason pattern 3 and only 4% constitute pattern 4, it should be reported as 3 + 4 = 7.
On needle biopsies, a third pattern (Tertiary pattern) if present is of lower grade, should be ignored. Tumors with patterns 3, 4, and 5 are categorized as high-grade tumors with GS constituting 8-10, wherein sum of the primary pattern and highest grade is considered. This is in contrast to the old system, where sum of the most prevalent and second most prevalent patterns would be considered.
In radical prostatectomies (RP) which may have multifocal tumors, every dominant nodule must be assigned a separate GS. Experts define a tertiary pattern for RP, when a third component is present and exhibits a pattern higher than the primary and secondary pattern, and constitute <5% of the entire tumor tissue. However, if it occupies >5% of the tumor, record it as the secondary pattern. The GS in RP is given as sum of primary and secondary patterns with a comment on the tertiary pattern. As on needle biopsy, if the most common and highest Gleason pattern is added in these RP specimens, the result does not represent the tumor behavior accurately.,
Risk of recurrence increases and lies between GS category without a tertiary pattern and the subsequent higher GS category, when tertiary RP Gleason patterns are present. The current score can then be reported with the modified score as, GS 3 + 4 = 7 with tertiary pattern 5 (GS 7.5). The presence of tertiary patterns is usually associated with biochemical recurrence and higher pathological stage when compared to those without tertiary patterns.,
Clinical risk stratification
Risk stratification for the management of prostate cancer patients can be developed by using GS, Clinical stage and prostate-specific antigen (PSA). D'Amico classification system and National Comprehensive Cancer Network are the most widely used risk stratification systems. Based on GS, can be categorized as low risk (GS: 2–6), intermediate-risk (GS: 7), and high risk (GS: 8–10).
| The 2014 IUSP Modified New Grading System|| |
Since the scoring ranged from 2 to 10, the score of 6 though assigned the lowest, gave a false implication to the patients as having an aggressive cancer or cancer with intermediate prognosis. Assuming a similar prognosis, scores being incorrectly grouped together was observed for therapeutic purposes. This became particularly important for the Gleason's score 7 since those with score 4 + 3 had 3-fold increased risk of incidence of metastasis at diagnosis and significantly worse prognosis than score 3 + 4. Patients with GS4 + 3 prostate cancers have higher PSA levels at diagnosis.
Hence, a new grading system was proposed by Epstein JI in 2013. This was based on data from John Hopkins Hospital grading them into 5 Grade groups according to prognosis, which was validated in a multi-institutional study and consensus obtained for adopting it in the 2014 consensus conference. More recently, two studies have provided some validating data for ISUP grading based on a variety of outcomes.,
This new system with group grades has been accepted by the WHO 2016 Edition on Pathology and Genetics. It is recommended that new grading system be used along with Gleason grading, for example, GS 3 + 4 = 7 (Grade Group 2).
The newgrading system gave more accurate stratification, simplified the number of grading categories to only 5 group grades (1-5), with a scope for different pattern combinations. It reduced the possibility of overtreatment of indolent cancer, with Grade group 1 being considered the lowest against Gleasons score 6 with the potential to reduce overtreatment of indolent prostate cancer.,
Current guidelines, recent changes, and limitations
The ISUP 2014 New grading system comprises 5 Grade Groups based on the modified GS groups.
- Grade Group 1: GS ≤6
- Grade Group 2: GS 3 + 4 = 7
- Grade Group 3: GS 4 + 3 = 7
- Grade Group 4: GS 8
- Grade Group 5: GS s 9 and 10
The grade groups of the new grading system accurately predict the progression as compared to GS-based risk stratification categories. The prognostic curves were similar on biopsy (where patients received radiation and/or hormonal therapy) as well as radical prostatectomy. However, as higher-grade cancer which may not be sampled may be present in approximately 20% of cases, follow-up is still needed. A grade group when higher indicates a greater chance of disease which is not organ-confined and worse outcome. New grading system strongly correlated with AJCC staging system and prostate cancer-specific mortality in biopsy specimens taken from population treated conservatively.
| Grading for Variants|| |
Grading of the variants of prostate adenocarcinoma was proposed as follows.,,,
Atrophic pattern, pseudohyperplastic adenocarcinoma, and PIN-like adenocarcinoma - Gleason pattern 3.
Foamy gland carcinoma, Collagenous micronodules - Based on the underlying architecture, usually GS 7.
Vacuoles - when present in single cells of Gleason pattern 5, may mimick a true signet ring cell carcinoma.
Glomeruloid morphology - Gleason pattern 4.
Intraductal carcinoma - not graded but mention its association with high-grade invasive cancer.
Mucinous adenocarcinoma - applied ignoring the mucin - GS s of 7 or 8.
Ductal adenocarcinoma - Gleason pattern 4 or 5 with necrosis.
Pleomorphic giant cell adenocarcinoma - GS of 9.
Small cell carcinoma - not graded.
GS 8 indicate a combination of patterns 3 and 5, 5 and 3, or 4 and 4. The former two combinations of GS 8 have less favorable outcome than the latter. However, the new grading system classify all these combinations under Grade group 4. Hence, tumors containing pattern 5 should be reclassified or grouped under Grade group 5.
In GS 7 tumors, low proportions of pattern 4 have a relatively favorable outcome, similar to Grade 1 (3 + 3) tumors. Hence, the percentage of pattern 4 may influence the prognosis and is of significance. Reporting of percentage of pattern 4 present is important in IUSP grade2 cases (3 + 4) where a small volume of pattern 4 is present, which may be important to determine the necessity for active surveillance
Lot of new data due to development in imaging lead to certain modifications by the 2019 ISUP consensus. Following are the recommendations given. For all GS 7 biopsies, the % of GP4 has to be reported. The term “minor” is preferred to “tertiary.” In biopsies, minor pattern with higher grade to be included in GS so that prediction of prostatectomy lesions is better whereas in RPs if the tumor contains >5% tertiary pattern it has to be reported in GS grading. If <5%, then mention as minor pattern along with the grade. The IDC grade has to be incorporated in GS when associated with an invasive component. If no invasive component then at least mention its presence and the significance. For each biopsy site, a separate GS is to be reported. However, aggregate GS can be reported for each suspicious lesion in magnetic resonance imaging.
Artificial intelligence (AI) has a role to play in the diagnosis of prostate cancer. AI prescribes the biopsies, creates algorithms, and improves efficacy in diagnosis, quantification of tumor, and grading. However, it could be a challenge to handle urothelial, rectal carcinomas, or lymphomas.
According to few studies, there is an overlap with respect to prognosis, between individual grades., Whether predictive accuracy of new grade groups is greater than the old grading, still remains unclear. According to a validation study, the accuracies of prognostic models are not improved by new grade groups when compared to the current three-tier classification.,,
| Summary|| |
The Gleason Grading of the prostatic adenocarcinoma with its evolution and ISUP modifications in 2005, 2014, and 2019 continues to be a powerful predictor of prognosis in Prostatic adenocarcinomas. The New prognostic Grade grouping is simpler, more accurately reflects the prostate cancer biology, provides better understanding, and improves reproducibility. The WHO recommends the use of a new grading system in conjunction with Gleason score. Biochemical recurrence and adverse pathology are predicted when the percentage of Gleason grade 4 disease increase in biopsies. The New grading system with its modifications will be of great help to assist clinicians to determine different therapeutic strategies for prostatic adenocarcinoma patients. Moreover, ML-based systems might be of help in future not only to support grading but also in identifying the prognostic markers based on newer patterns and stromal features.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]