Prostate Cancer Grading, Staging and Reporting: An Update Cristina Magi-Galluzzi, MD, PhD

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1 Prostate Cancer Grading, Staging and Reporting: An Update Cristina Magi-Galluzzi, MD, PhD Director, Genitourinary Pathology R.J. Tomsich Pathology & Laboratory Medicine Institute Professor of Pathology, Lerner College of Medicine Cleveland Clinic, Cleveland, OH

2 Objectives Discuss relevant modifications of Gleason grading system Update on staging of radical prostatectomy (RP) specimens Review essential reporting parameters for cancer-bearing prostate needle biopsies (PBx)

3 Evolution of Gleason grading Based on Minneapolis VA data accumulated in Architecture evaluated at low-medium magnification Combined 1 st and 2 nd most common pattern to arrive at a Gleason score (GS) 2-10 Gleason Era RP More advanced clinical disease Fewer RPs, which were not entirely processed PBx/TUR No PSA screening Prostatic tissue from TUR specimens Needle biopsy (few thick cores) Modern Era RP Increased volume of cases GS included in predictive models Grading of multiple nodules Tertiary pattern PBx Systematic sampling Thin needle PBx Grading multiple cores from different sites New entities, recently described

4 Gleason Grading of Prostatic Carcinoma Original Gleason scheme 1967 ISUP modified 2005 ISUP modified 2015

5 Gleason Score 2-4 Diagnosis of GS 2-4 PCA should NOT be made on needle Bx Poor reproducibility even among experts Poor correlation with RP grade GS 2-4 PCA may misguide clinicians/patients into believing that tumor is indolent Most cases diagnosed as GS 2-4 in the past represented adenosis JI Epstein AJSP 2000; JI Epstein et al. AJSP, 2005

6 Evolution of original Gleason patterns 1 and 2 - Circumscribed nodule of uniform, single, separate, closely packed glands - Most cases diagnosed as GS 2-4 in the past represented adenosis

7 Evolution of Gleason pattern ISUP modified 2014 ISUP modified Epstein et al. AJSP 29, 2005 Epstein et al. AJSP 40, 2016 Small well-formed glands Small cribriform lesions: exclude HGPIN with IHC Medium to large sized cribriform glands eliminated Small well-formed glands Branched glands are allowed Small cribriform glands All cribriform glands should be graded as pattern 4 - ISUP, prostate cancer grading, Chicago, % consensus

8 2014 ISUP modified Gleason system pattern 3 Well-formed individual glands, discrete unit Variation is size and shape (microcystic and pseudohyperplastic) Branching glands are allowed in pattern 3

9 Evolution of Gleason pattern ISUP modified Epstein et al. AJSP 29, ISUP modified Epstein et al. AJSP 40, 2016 Large cribriform glands Ill-defined glands with poorly-formed lumens Fused microacinar glands Hypernephroma-like tumors All cribriform, fused, poorly formed and glomeruloid glands Hypernephromatoid term should not be used

10 2014 ISUP modified Gleason system pattern 4 Small cribriform Fused Poorly formed Glomeruloid

11 2014 ISUP modified Gleason system pattern 4 Large cribriform Fused microacinar

12 Gleason pattern 4: poorly formed glands

13 Gleason pattern 4: glomeruloid and cribriform glands

14 Evolution of Gleason pattern ISUP modified Epstein et al. AJSP 40, 2016 single cells Small solid cylinders Solid medium to large nests with rosette-like spaces Unequivocal comedonecrosis, even if focal Single cells solid sheets

15 2015 ISUP modified Gleason system pattern 5

16 Pitfalls Fused glands (modified Gleason pattern 4): May be under-graded when present in small foci On the other hand, careful evaluation of multiple tissue levels may be necessary to determine whether few glands are truly fused or simply tangentially cut Ill-defined glands: Ill-defined glands with poorly formed glandular lumina should be graded as pattern 4 Caution should be applied in distinguishing them from very small well-formed glands (modified Gleason pattern 3)

17 GS 3+3=6 vs. GS 3+4=7

18 GS 3+3=6 vs. GS 3+4=7

19 GS 3+3=6 vs. GS 3+4=7

20 2014 ISUP Consensus Conference on Gleason Grading: Recommendations For a diagnosis of Gleason pattern 4, it needs to be seen at x10 lens magnification - Vote: 78% yes Occasional/seemingly poorly formed or fused glands between well-formed glands is insufficient for a diagnosis of pattern 4 - Vote: 85% yes In cases with borderline morphology between Gleason pattern 3 and pattern 4 and crush artifacts, the lower grade should be favored - Vote: 98% yes

21 Gleason grading of prostate cancer variants Ductal GP4 (GP5 if necrosis present) Sarcomatoid GP5 (glandular component graded separately) Mucinous grading based on its underlying growth pattern extract mucin and grade architecture Signet ring cells GP5 Atrophic GP3 Foamy gland GP3 or 4 (depending on architecture) Pseudohyperplastic GP3 Small cell/ne not graded Squamous not graded Basaloid not graded Intraductal carcinoma not graded (ISUP 2014, WHO 2016)

22 Impact of modified Gleason grading system GS6 is lowest score on PBx (confusing for patients and clinicians) Current GS6 has little propensity to recur or metastasize Several morphologies previously considered pattern 3 are currently assigned a Gleason pattern 4 - GS6 tumors have decreased - GS7 tumors have increased Inter-observer reproducibility and PBx PR concordance have improved GS7 includes patients with different prognosis: - 3+4=7 have better prognosis than 4+3=7

23 New 5-Grade Group system (ISUP & WHO) S Grade group 1 GS 6 Only individual discrete well-formed glands Grade group 2 GS 3+4=7 Predominantly well-formed glands with lesser component of poorly-formed/fused/cribriform glands Grade group 3 GS 4+3=7 Predominantly poorly-formed/fused/cribriform glands with a lesser component of well-formed glands Grade group 4 GS 4+4=8 GS 3+5=8 GS 5+3=8 Only poorly-formed/fused/cribriform glands Predominantly well-formed glands with a lesser component lacking glands Predominantly lacking glands or with a lesser component of well-formed glands Grade group 5 GS 9/10 Lacks gland formation (or with necrosis) with or w/o poorly-formed/fused/cribriform glands Pierorazio et al. BJU Int 2013; Epstein JI et al. AJSP 2016

24 Recurrence-free progression after RP stratified by Bx grade Grade group 1 Grade group 2 Grade group 3 Grade group 4 Grade group 5 Epstein JI et al. Eur Urol 2016

25 RFP following RP stratified by RP grade Grade group 1 Grade group 2 Grade group 3 Grade group 4 Grade group 5

26 Hazard ratio for biochemical recurrence Bx GS HR for BCR* RP GS HR for BCR* Grade group 1 GS 6 Reference GS 6 Reference Grade group 2 GS 3+4=7 2.5 GS 3+4=7 1.9 Grade group 3 GS 4+3=7 5.7 GS 4+3=7 5.1 Grade group 4 GS 4+4=8 9.1 GS 4+4=8 8.0 Grade group 5 GS GS Low risk GS 6 Reference GS 6 Reference Intermediate GS7 3.4 GS 3+4=7 2.7 High risk GS GS 4+3=7 8.5 * Multivariate hazard ratio (HR) for biochemical recurrence (BCR) Epstein JI et al. Eur Urol 2016

27 Independent surgical validation of the new prostate cancer grade-grouping system 3,694 men treated with RP; median follow-up 52.7 months Spratt et al. BJUI 2016

28 Independent validation of the prognostic capacity of PCA grade grouping system for radiation treated patients 847 men treated with definitive external beam radiation at a single center median follow-up 88 months 5-grade group system improved prognostic discrimination for brfs, DMFS, PCSS compared to three-tiered system (GS 6, 7, 8-10) Figure 2 Spratt et al. Prostate Cancer Prostatic Dis 2016

29 Validation of a contemporary PCA grading system using PCA death as outcome 988 men with PCA on PBx were treated conservatively; grade was assigned to each core as well as an overall grade; max. FU 232 mos. Worst Grade Group Overall Grade Group Berney et al. British Journal of Cancer 2016

30 Take home points Diagnosis of GS 2-4 should NOT be made on PBx GS 6 (Grade Group 1) is the lowest grade possible Small well-formed glands should be graded as pattern 3 All cribriform glands should be graded as pattern 4 Glomeruloid, fused and poorly-formed glands should be graded as pattern 4 In cases with borderline morphology between Gleason pattern 3 and pattern 4, the lower grade should be favored New prostate cancer Grade Group system reflects more accurately the prognosis of each group

31 Update on Staging

32 Handling and reporting of RP specimens Handling of RP specimens (Samaratunga et al. Mod Pathol 24, 2011) - prostate weight without seminal vesicles should be obtained - prostate should be measured in three dimensions - surface of gland should be inked with at least two colors - apex and base regions should be sampled by cone method/sagittal sectioning T2 substaging and PCa volume (van der Kwast et al. Mod Pathol 24, 2011) - pt2 substages of PCa in RP specimens is optional - some quantitative measure of tumor volume should be obtained - dominant/index tumor likely represents the tumor with highest grade and/or stage

33 Handling and reporting of RP specimens Extraprostatic extension (EPE), lymphovascular invasion (LVI) and locally advanced disease (Magi-Galluzzi et al. Mod Pathol 24, 2011) - EPE is defined as presence of PCa beyond confines of prostate gland - In posterior, posterolateral, and lateral regions of prostate, PCa admixed with periprostatic adipose tissue is most easily recognized manifestation of EPE - Presence of PCa in skeletal muscle does not constitute EPE - When EPE is identified, location and extent should be documented

34 EPE - Tumor admixed with periprostatic adipose tissue

35 EPE - Tumor at level of or beyond periprostatic adipose tissue

36 EPE - Tumor within loose connective tissue or perineural spaces

37 EPE -Tumor nodule bulging beyond normal prostate contour

38 EPE -Tumor extend beyond contour of normal prostate (apex)

39 Handling and reporting of RP specimens Microscopic bladder neck involvement (Magi-Galluzzi et al. Mod Pathol 24, 2011) Presence of neoplastic cells within smooth muscle bundles of bladder neck in absence of benign glandular tissue Should be staged as pt3a, not pt4

40 Handling and reporting of RP specimens Lymphovascular invasion (LVI) (Magi-Galluzzi et al. Mod Pathol 24, 2011) - Unequivocal presence of tumor cells within endothelial-lined spaces with no underlying muscular walls - Documentation of presence of LVI in RP is critical

41 Handling and reporting of RP specimens Seminal vesicles (SVI) involvement (Berney et al. Mod Pathol 24, 2011) - Tumor invades muscular wall of extraprostatic seminal vesicle - Equivalent to pt3b

42 Handling and reporting of RP specimens Surgical margin involvement (Tan et al. Mod Pathol 24, 2011) - Tumor (extraprostatic or intraprostatic) that extends to inked surface (surgical tissue plane) of prostate gland - Important to document location and extent of positive margins (linear length)

43 Handling and reporting of RP specimens Lymph nodes (LN) involvement (Berney et al. Mod Pathol 24, 2011) - LN metastasis is important for adequate staging of PCa in RP - Size/diameter of largest metastatic focus appears to be one of most significant predictors of cancer specific survival

44 Reporting minor high-grade pattern (tertiary pattern) on RP specimens If tertiary pattern 5 is >5% on RP, it is assigned as secondary pattern, rather than tertiary pattern: Gleason pattern 4 (60%) + pattern 3 (30%) + pattern 5 (10%) = Gleason score 4+5=9 If tertiary pattern 5 is 5% on RP, it is assigned as tertiary pattern: Gleason pattern 4 (70%) + pattern 3 (25%) + pattern 5 (5%) = Gleason score 4+3=7 with tertiary pattern 5 Tertiary pattern does not impact Grade Groups If only two patterns are present (98% pattern 4 and 2% pattern 5), both are included in final GS

45 Update on Reporting

46 Essential reporting parameters for cancerbearing prostate needle biopsies (PBx) Histologic type (acinar vs. nonacinar and other tumor types) - Ductal adenocarcinoma - Small cell carcinoma - Sarcomatoid carcinoma - Intraductal carcinoma Gleason grade and score Location of positive cores (based on biopsy site) Tumor quantification: - # and % of positive biopsy cores - Linear % or length (mm) of core involved by PCa - Total % or length of carcinoma in all biopsy cores Other (reported only if present) - Perineural invasion (PNI) - Extraprostatic extension (EPE) - Seminal vesicle invasion (SVI)

47 Reporting Limited Secondary Patterns of Lower and Higher Grade and Tertiary Pattern on PBx In a setting of high-grade PCa, ignore lower patterns if <5% High-grade tumor in ANY quantity on PBx (at low to medium magnification) should be included within GS In a setting of three patterns, most common (primary pattern) is added to highest pattern 4 3 <5% Previous GS 4+3= Modified GS 4+4=8 4 pattern 3 5 Previous GS 3+3=6 (tertiary 4/5) ---- Modified GS 3+4=7 or 3+5=8 <5% pattern 3 pattern 4 5 Previous GS 3+4=7 with tertiary Modified GS 3+5=8

48 Reporting % pattern 4 in Bx and RP specimens in which GS7 is highest grade 2014 consensus conference recommended reporting % pattern 4 in GS7 tumors (particularly 3+4), since it may have implications for management (active surveillance, radiation therapy) 3+4=7 PCA with minimal pattern 4 (<5%) on PBx is associated with low-risk tumor on RP (Huang et al. AJSP 2014, Kir at al. Ann Diagn Pathol 2016) Since cribriform morphology is associated with worse prognosis, cribriform glands may be incorporated in into grading practice in the future Large cribriform pattern 4 and IDC-P are significant prognostic factors in determining outcome (Trudel D et al. Eur J Cancer. 2014, Flood et al. Virchows Arch 2016) JI Epstein et al. AJSP 2017

49 Reporting GS7 PCA on Needle Biopsy Prostate, left base, biopsy (A) - Adenocarcinoma of the prostate Gleason score 3+4=7 (Grade Group 2), involving 10% of one of two cores and measuring 1 mm. Gleason pattern 4 represents approximately 5% of the tumor Cribriform pattern 4 is not identified Prostate left mid, biopsy (B) - Benign prostatic tissue. Prostate, left apex, biopsy (C) - Adenocarcinoma of the prostate Gleason score 3+4=7 (Grade Group 2), involving 20% of one of two cores and measuring 2 mm. Gleason pattern 4 represents approximately 10% of the tumor Cribriform pattern 4 is identified

50 Tumor quantification in PBx Fraction of positive cores (# of biopsy cores involved by PCa out of total number of cores) Linear extent (% or mm) of cancer length in each core Total % or length of cancer in all biopsy cores Greatest % or length of cancer involvement Amount of cancer in single core with largest amount of tumor ^ fragmentation may preclude accurate assessment From Montironi el al. Eur Urol 2012

51 Measuring discontinuous foci of PCA on PBx Discontinuous involvement by multiple PCA foci separated by benign tissue No consensus on quantification method: a. Adding foci and ignoring benign intervening prostatic tissue (additive quantification) b. Assessing discontinuous foci as a single focus (linear quantification, end-to-end measurement) Both methods showed excellent correlation with % of tumor at RP; linear quantification improved prediction of PCA extent Discontinuous tumor on PBx often (78%) results from a single tumor focus b a Schultz et al. AJSP 2013; Arias-Stella et al AJSP 2015

52 Perineural invasion (PNI) on PBx Present in 11-37% of PCA on PBx It has been advocated as a marker of EPE; its independent value as a predictor of stage has not been established Despite variable findings, PNI is reported by a large majority of pathologists; it should be reported if identified (CAP protocol)

53 EPE on needle core biopsy

54 Seminal vesicles (SV) invasion on PBx SV Bx in PCa staging is controversial, but may alter treatment decisions Intermediate- and highrisk patients who elect RT may undergo SV Bx (~ 10% are +) Patients with SV invasion can be managed by a combined approach of seed implantation + EBRT Stone et al. Brachytherapy 2012

55 Intraductal carcinoma of the prostate (IDC-P) Distinct entity in 2016 WHO Malignant secretory cells that grow within and expand prostatic ducts/acini Associated with adverse prognostic features at RP: - High GS, large tumor, EPE, SVI, + margins Independent predictor of outcome - poor response to ADT and neoadjuvant chemo - associated with early recurrence after XRT

56 Intraductal carcinoma of the prostate (IDC-P) 17% of RP cases 2.8% of PBx with high-grade invasive PCA (mean GS 8) % of PBx without invasive PCA p63/erg

57 IDC-P on PBx: reporting recommendations IDC-P + invasive PCA Gleason pattern 4 or 5: - Reporting IDC-P provides prognostic information IDC-P + invasive PCA Gleason pattern 3: - Grade PCA and document presence of IDC-P - Recommend re-biopsy within 3 months or definitive therapy Isolated IDC-P: - Grading is NOT recommended - Report with a comment (clinical significance) - Recommend re-biopsy within 3 months or definitive therapy (depending on extension)

58 Take home message Pathologist s role is not limited to accurate PCA diagnosis, but includes reporting essential elements useful to estimate its malignant potential Pathological parameters need to be: - Accurate - Reproducible - Consistently reported to improve and individualize patient s treatment

59 Thank you!