Gleason Grading of Prostate Cancer.pptx

Gleason Grading of Prostate Cancer

1. Gleason Grading of Prostate Cancer Dr. Indranil Bhattacharya Consultant Pathologist Dept. of Pathology Jagjivan Ram Hospital Mumbai

2. Introduction: Tumour grade is the cornerstone of prostate cancer management. In 1978, the American Cancer Society organized a series of workshops that compared several systems for grading prostate cancer. The outcome was the recommendation that the Gleason grading system should be adopted, because it was “definable, simple, reproducible, and had compelling clinical relevance.” The Gleason system is now the globally utilized system for grading prostate cancer and has proven to be a powerful predictor of patient outcome, regardless of the treatment the patient receives

3. However, the Gleason grading system has undergone several modifications over the years. The reporting rules have become increasingly complicated, which has resulted in reporting variation, even amongst experts, and confusion for practicing pathologists. The Gleason grading system is unusual in that it is based entirely on architectural features of the tumour , rather than the cytological appearances, and is not based on the worst pattern. The Gleason score (GS) takes into account the two most common patterns that are present. Thus, a tumour that is predominantly (95%) pattern 4 would be “down-graded” from GS 8 to 7 by the presence of a minor (5%) component of pattern 3. Unlike other tumour grading systems, there are different rules for reporting the GS in needle biopsy specimens and excision specimens, i.e. radical prostatectomies. Finally, in contrast to other organs, a definitive grade based on the examination of the entire tumour is available in only a minority of patients with organ confined prostate cancer, because most of these patients do not have radical surgery.

4. The development of the Gleason grading system was initiated by an American urologist, George T Mellinger, Chair of Urology at the Minneapolis Veteran’s Hospital.5 In 1960, he set up the Veterans Administration Cooperative Urological Research Group (VACURG), which included urologists, statisticians and pathologists. The VACURG organised large-scale, randomised , prospective clinical trials to compare treatments for prostate cancer and Dr Mellinger suggested devising a grading system for prostate cancer. The Gleason grading system was a “bespoke” system developed for a specific research project with a truly multidisciplinary approach. The lead pathologist, Donald F Gleason, had, as a medical student, been involved in the development of the Minnesota Multiphasic Personality index that sought to standardise the diagnosis of psychiatric conditions using a novel mathematical scale.5 He also had a background in research and was a gifted artist. These diverse skills were critical in the development of the Gleason grading system. Dr Gleason opted to ignore all preconceptions of tumour grading and identified 9 distinct architectural patterns in prostate cancer. He recognised the morphological heterogeneity of prostate cancer and recorded the two most common patterns for each tumour . These patterns were subsequently correlated with patient survival data by statisticians at the National Cancer Institute and the National Institute of Health, led by John C Baillar III. Some of the patterns that had similar biological outcomes were merged, resulting in the five Gleason patterns that we recognise today. The original Gleason grading system involved addition of scores for the primary pattern, the secondary pattern and the clinical stage, resulting in a scale ranging from 3 to 15. The clinical stage was subsequently dropped, resulting in the now familiar histological GS.

5. Definition: In 1966, Dr. Donald Gleason devised grades of 1 - 5 based on glandular architecture and microscopic appearance using a 4x - 10x objective eyepiece that were shown to predict an outcome in prostate cancer.

6. The modification of the Gleason grading system implemented by the International Society of Urological Pathology in 2005 and subsequent revision in 2014 has profoundly impacted how PCa is graded and managed.

7. Terminology Gleason score is the sum of the 2 most prevalent Gleason grades: primary and secondary, designated according to separate rules for biopsy and prostatectomy If only 1 pattern is present, the primary and secondary patterns are given the same grade (ex: 3+3=6) Systematic needle biopsy sets contain cores from different anatomically designated sites Gleason score should be assigned separately for each anatomically designated site Highest score may serve as a basis to determine treatment Additional reporting of a global (case level) Gleason score is optional and global scoring may show a marginal benefit over using highest score according to Trpkov et al. Any glands showing perineural invasion must be excluded in assigning Gleason grading because perineural invasion distorts gland morphology such that Gleason 3 glands resemble Gleason 4

8. Grading rules: Recommendations are based on 3 International Society of Urological Pathology (ISUP) grading consensus conferences: 2005 2014 and 2019 (Nice, France) Consensus of the GU Pathology Society that is nearly identical Minor variances are highlighted Some specimens may show a pattern that is the third most prevalent; this is called a minor pattern

9. In radical prostatectomy Gleason score should be based on the primary and secondary patterns; if a minor pattern constitutes < 5%, the pattern should be mentioned as a minor (tertiary) pattern; any higher grade minor pattern ≥ 5% should be incorporated into the Gleason score and ISUP group as the secondary pattern (2019 consensus). Example: Gleason pattern 3=96% and pattern 4=4%, Gleason score=3+3=6 with minor (tertiary) 4 Example: Gleason pattern 3=95% and pattern 4=5%, Gleason score=3+4=7

10. In needle biopsy Most prevalent pattern is graded as primary and any amount of a worst pattern is graded as secondary Example: Gleason pattern 3=96% and pattern 4=4%, Gleason score=3+4=7 Example: Gleason pattern 3=95% and pattern 4=5%, Gleason score=3+4=7

11. Epidemiology In 2014, the ISUP and World Health Organization adopted a simplified patient centric grading system composed of 5 prognostic grade groups as proposed in 2013 based on data and subsequently validated by biochemical recurrence hazard ratios on cases from 5 large academic centers Grade groups are as follows: Gleason score 3+3=6 Gleason score 3+4=7 Gleason score 4+3=7 Gleason score 8 (4+4=8, 3+5=8, 5+3=8) Gleason score ≥ 9 (4+5=9, 5+4=9, 5+5=10) Note that Gleason grades 1 and 2 are no longer recommended for use, since those patterns of cancer have an outcome no different from grade 3; moreover, pure grade 3 cancer almost never metastasizes and is reasonable to treat by active surveillance, which has sparked speculation about whether it should even be labeled cancer. Divisions of Gleason score 3+4=7 from 4+3=7 and of 8 from 9-10, which had often been bundled together for prognostic and research purposes, are supported by studies showing significantly different outcomes. Percentage of grade 4 or 5, when heterogeneous grades are present, should be mentioned in all specimens, although biopsy and prostatectomy have different rules for scoring.

12. Grade group 4 is heterogeneous as it includes 4+4=8, 3+5=8 and 5+3=8, with recent data showing no or minimal long term outcome difference when present as the highest score in biopsy sampling; instead, the presence or absence of cribriform growth of cancer was a significant prognosticator If tumor is minimal on biopsy (≤ 1 mm), Gleason score does not predict tumor stage and this can be noted on the report (ex: in a minimal focus with pattern 4, rather than doubling to 4+4=8, tumor can be designated on the report as too small for scoring) Targeted biopsies detect a higher percentage of pattern 4 than systemic ones and are less likely to be upgraded on prostatectomy

13. Evolution of grading of special prostate cancer patterns Histologic pattern 2005 consensus 2014 consensus 2019 consensus Branched / undulating glands Include as Gleason 3 Cribriform (under Gleason scheme: mostly 3, sometimes 4) 4 but can be 3 if much larger than benign gland, round and has loose cells Always 4 Always 4 and presence or absence should be specified for 3+4, 4+3 or 4+4 Glomeruloid variant No consensus , 3 versus 4 Always 4 -- Mucinous variant No consensus, some favored 4 Depends on growth pattern regardless of mucin; could be 3, 4 or 5 -- Small cell (pure) Do not grade -- -- Intraductal, pure form -- Do not grade Do not grade Intraductal, associated with invasive cancer -- -- Include in estimating the percentage of grade 4, instead of keeping it separate Ductal 4+4=8 -- -- Adenoid cystic / basal cell carcinoma -- Do not grade Do not grade

14. Microscopic (histologic) description Discontinued Gleason grades 1 and 2 It was agreed at the 2014 consensus conference that Gleason grades 1 and 2 should be discontinued because grade 1 or 2 cancer in needle biopsy does not predict better prostatectomy findings than grade 3 and these grades show marked interpathologist variability Gleason score of 1+1=2 was originally described as single, separate, closely packed, uniform round glands arranged in a circumscribed nodule with pushing borders; many of such cases would, with the benefit of today's immunostains , be referred to as atypical adenomatous hyperplasia (AAH or adenosis)

15. Gleason grade 3 Single, separate glands May be either minute or large and cyst-like; glands have an irregularly separated, ragged, poorly defined edge, looser than a nodule and are infiltrative Key feature is retention of at least a wisp of stroma intervening between neighboring glands Tangentially cut glands may appear as if they are poorly formed but should not get graded as a 4 unless poorly formed and fused glands persist on several levels Patterns of Gleason grade 3 prostatic adenocarcinoma: Most common pattern is well formed, relatively uniform glands infiltrating between benign glands; glands may be angulated or compressed, separated by > 1 gland diameter Small glands with pinpoint lumina, glands still separate Medium sized glands with undulating luminal contours or large glands or branching Large glands with a pseudo-atrophic appearance Cribriform cancer no longer qualifies as Gleason 3, even if the glands are similar in size to normal glands

16. Gleason grade 4 Key finding is coalescent or fused glands with > 1 lumen and absence of intervening stroma between adjacent glands Patterns of Gleason grade 4 prostatic adenocarcinoma: Most common is small acinar structures, some with well formed lumina, fusing into cords or chains; may be undergraded as Gleason 3 Cribriform (often merging with papillary, see by consensus has a confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification 10x); there should be no intervening stroma or mucin separating individual or fused glandular structures. Nodule of a cribriform gland should be larger than normal prostate gland Large nodules of cribriform Gleason 4 lack supporting stroma and tend to fragment Thus, fragments of cribriform glands on needle biopsy represent Gleason 4 Hypernephroid pattern, with nests of clear cells resembling renal cell carcinoma; small, hyperchromatic nuclei; fusion of acini into more solid sheets with the appearance of back to back glands without intervening stroma

17. Intraductal carcinoma, when admixed with invasive carcinoma, should be counted as Gleason 4 and not counted separately for quantitation purposes. Its presence and significance should be mentioned This emphasizes the adverse influence which has a unique phenotype of certain driver mutations as shown by Khani et al. Glomeruloid pattern (2014 consensus), a rare small cribriform variant, contains a tuft of cells that is mostly detached from its surrounding duct space except for a single point of attachment Hypernephroid pattern, with nests of clear cells resembling renal cell carcinoma; small, hyperchromatic nuclei; fusion of acini into more solid sheets with the appearance of back to back glands without intervening stroma Research and 2014 consensus support grading all cribriform cancer as Gleason 4 because the presence and amount of cribriform cancer carries a distinctly adverse prognosis for recurrence and for death from cancer Its presence or absence in Gleason 4 cancer should be commented on Note: patients with Gleason 8 at biopsy may have Gleason 7 at prostatectomy due to unsampled Gleason 3 Note: basal cell markers are crucial in distinguishing cribriform high grade prostatic intraepithelial neoplasia, cribriform intraductal carcinoma and invasive cribriform carcinoma Rarely, pure intraductal carcinoma occurs in biopsy specimens Rare in totally embedded prostatectomies as shown by Robinson In its pure form it should not be graded Diagnosis of intraductal carcinoma has modest reproducibility

18. Gleason grade 5 Grade 5 has 2 patterns: Comedo -necrosis: central necrosis with intraluminal necrotic cells or karyorrhexis within papillary / cribriform spaces; caution should be exercised since many such foci have demonstrable basal cells, making them intraductal carcinoma instead; thus, immunostaining is recommended if this would alter the grade group Single cells, possibly forming cords, possibly with vacuoles (signet ring cells) but without glandular lumens; this pattern may mimic lymphocytes at low power Gleason 5 pattern has moderately good reproducibility, although certain patterns are more problematic Gleason 5 cancer is often missed or underdiagnosed on needle biopsy Presence of Gleason grade 5 in prostate biopsy specimens predicts higher rates of metastasis and death compared with Gleason 4+4=8 cancer and even the smallest amounts of 5 predict outcome after prostatectomy

19. Sample pathology report Prostate, left lateral, prostate needle core biopsy: Prostatic adenocarcinoma, Gleason score 4+3=7 (Grade group 3) involving 2 of 4 cores and 30% of the tissue (40%, 2 mm and 20%, 4 mm) (60% of the tumor is Gleason pattern 4, not cribriform) Prostate, radical prostatectomy: Prostatic adenocarcinoma, Gleason score 3+3=6 with tertiary 4 (Grade group 1) (Gleason pattern 3=96% and pattern 4=4%)

20. Q uestion # 1 Per the 2019 ISUP consensus conference, a prostate biopsy report for high grade cancer must include: A case level global Gleason score A grade if the entire cancer focus consists of perineural invasion Both a primary and secondary grade for tumor measuring less than 1 mm For Gleason grade 4, a mention of whether or not cribriform / large gland pattern is present Gleason grades 1 and 2, if present

21. Ans: D.   For Gleason grade 4, a mention of whether or not cribriform / large gland pattern is present. By consensus, the presence of cribriform carcinoma should be reported. Gleason grades 1 and 2 are discontinued. Grading is not recommended for perineural invasion because perineural invasion distorts gland morphology (grade 3 looks like 4). For tumor that is 1 mm or less, only 1 grade needs to be assigned, avoiding doubling Gleason 4 to 4+4=8, which would be misleading if cancer in other cores is mostly Gleason 3. A case level global score is optional.

22. This field from a prostate biopsy shows: Entirely Gleason 3 cancer Entirely Gleason 4 cancer Entirely Gleason 5 cancer Mixture of Gleason 3 and Gleason 4 cancer Mixture of Gleason 4 and Gleason 5 cancer Q uestion # 2

23. Ans: B.   Entirely Gleason 4 cancer. The tumor consists entirely of ragged and fused glands. Discrete, round to angulated gland spaces, separated by stroma, diagnostic of Gleason 3 are not present. Single cells without glandular lumen formation, diagnostic of Gleason 5 are not present.

24. Gleason grade 3

25. Gleason grade 3

26. Gleason grade 4

27. Gleason grade 4

28. Gleason grade 4

29. Gleason grade 5

30. Conclusion: The Gleason grading system that was initiated by a surgeon, created by a pathologist and developed by a statistician predated serum PSA testing, systematic 18-gauge needle biopsy protocols and immunohistochemistry. It has undergone a series of modifications, initially by Veterans Administration Cooperative Urological Research Group and later by the International Society of Urological Pathologists following consensus meetings in 2005 and 2014. Precision of grading becomes less important if the pathologist uses judgment to determine the Gleason score most suitable for that patient, communicates this data effectively in the report and helps clinicians interpret the information correctly