DISCLOSURE PROBLEM ISSUES WITH GLEASON GRADING OF I have nothing - PowerPoint PPT Presentation

DISCLOSURE PROBLEM ISSUES WITH GLEASON GRADING OF � I have nothing to disclose ADENOCARCINOMA OF THE PROSTATE Peter A. Humphrey, MD, PhD Yale University School of Medicine New Haven, Connecticut GLEASON GRADING GLEASON GRADE DRAWING NON-ISSUES � “Simplified drawing � Gleason grade is one of histologic patterns, of the most powerful, emphasizing degree if not the most of glandular powerful indicator of differentiation in outcome for patients relation to stroma” – with prostate cancer DONALD F. GLEASON, 1977 � Gleason grade is in routine clinical use 1

NEEDLE BIOPSY GLEASON 2010 AJCC Anatomic Stage/Prognostic Groups GRADE : CLINICAL UTILITY � Predict prognosis � Predict small, potentially harmless cancers � Select patients for active surveillance � Used in treatment selection (both primary and adjuvant) � Predict response to therapy � Used as criterion (usually one of many) for enrollment into clinical trials APPLICATION OF GLEASON ISSUES WITH GLEASON GRADING GRADING TO TISSUE � Application : intraprostatic cancer only, without treatment effect � Adoption of modified Gleason grading schemes SAMPLES � Upgrading and downgrading � Subjectivity and reproducibility � Assign Gleason grade to all prostatic tissue � Overgrading and undergrading samples, even to minimal carcinoma in � Detection of high-grade adenocarcinoma needle biopsy tissue � High-grade patterns not in ISUP 2005 � High-grade tertiary pattern � Not applicable to FNA samples � Outcome of 8 vs. 9-10 and prognostic grade groups � Not applicable to carcinoma outside the � % 4/5 high-grade cancer prostate, or to metastatic deposits � High-grade cancer at margins � Added value of molecular markers 2

EFFECT OF ANDROGEN GLEASON GRADING NOT DEPRIVATION THERAPY ON RECOMMENDED GLEASON GRADE BEFORE AFTER MODIFIED ISUP GLEASON INTERNATIONAL SOCIETY OF SCHEME 2005 AND AFIP 2011 UROLOGICAL PATHOLOGY (ISUP) SCHEME CONSENSUS CONFERENCE : HIGHLIGHTS � Proceedings published in Am J Surg Pathol 29 (Sept.): 1228-1242, 2005 � Modification: Vast majority of cribriform carcinomas are pattern 4 � Single cells – not pattern 3 � Variants : can grade adenocarcinoma variants. Don’t grade small cell carcinoma Original Gleason scheme AFIP modified 2011 ISUP modified 2005 3

GLEASON GRADE PATTERN 4 : CRIBRIFORM CRIBRIFORM GLANDS ADENOCARCINOMA � Rounded cribriform 3s usually associated with typical cribriform 4 � Chromosomal abnormalities more like 5 � Outcome : associated with biochemical failure, metastasis-free survival, and disease specific survival after radical prostatectomy Am J Clin Pathol 2011; 136:98; Am J Surg Pathol 2013; 37:1855 Mod Pathol 2015; 28:457 Am J Surg Pathol 2013 GLEASON SCORE 2-4 IN COLLEGE OF AMERICAN PATHOLOGISTS 2009 AND ISUP 2005 NEEDLE BIOPSY : PITFALL RECOMMENDATIONS FOR LIMITED SECONDARY PATTERN <5% � In needle biopsy tissue do not equate minimal � In needle biopsy specimens where there is a amount of carcinoma minor component and where the secondary with score 2-4 component is of higher grade it should be � Ideally should be a rare reported. So : 96% 3 and 4% 4, score =7 to non-existent diagnosis � If the secondary pattern is lower grade, it in peripheral zone needle need not be reported . So : 96% pattern 4 biopsy tissue and 4% pattern 3, score = 8 4

APPLICATION OF ISUP MODIFIED GLEASON INCREASING GLEASON GRADE OVER GRADING SYSTEM TO NEEDLE BIOPSY : TIME AND THE WILL ROGERS EFFECT PERCENTAGE OF CASES IN EACH CATEGORY (J Urol 180:548, 2008) � When the Okies left Gleason score Standard Modified Oklahoma and moved to California, they raised the Gleason Gleason average intelligence level in both states. 2-4 0.6 0 � For prostate cancer upgrading has resulted in 5-6 68 49 an apparent improvement in clinical outcomes 7 26 40 � JNCI 97:1248, 2005 � Mitchell RE, et al. Urology 70:706, 2007 8-10 6 11 Modified Gleason scoring showed stronger association with outcome after radical prostatectomy APPLICATIONS OF THE Classical Gleason Grading vs. Modified MODIFIED GLEASON GRADING Gleason Grading : Clinical Outcome SCHEME � Overall 6 of 8 studies demonstrate improvement using modified rather than classical grading (reviewed in Int Urol Nephrol 2013) � Modified Gleason score was a more accurate predictor of prognosis than original score (Berney DM et al. BJU Int 2007; 100: 1240). � Validation of prognostic value of modified Gleason grading system after upgrading of classic Gleason grade 3+3=6 to modified score of 7 or 8 (Am J Surg Pathol 2012; 36:838) AJSP 2012; 36:838 5

VALUE OF CLASSIFICATION OF UPGRADING AND DOWNGRADING : CORRELATION OF NEEDLE BIOPSY PURE MODIFIED PATTERN 3 AND WHOLE GLAND GLEASON � PURE MODIFIED GRADE GLEASON SCORE 6 IS RELATIVELY � 43% exact correlation; within 1 score unit for 77% of INDOLENT : 3,789 cases (pre-ISUP 2005) � 6s DO NOT � Upgrading : 35% 6s in needle to 7 or greater at RP METASTASIZE TO (Epstein JI : The Gleason Grading System, 2013) LYMPH NODES (>14,000 � Downgrading : 25% 7 or greater in needle to less CASES) (AJSP 2012; 36:1346) than 7 at RP (J Urol 2008; 179:1335) � NO CANCER-SPECIFIC DEATHS AFTER � Sources of error : borderline cases, tissue sampling RADICAL error, tissue distortion, pathologist experience, PROSTATECTOMY (BJU observer variability, not accounting for tertiary grade Int July 2014; Epub) REPRODUCIBILITY PREDICTORS OF UPGRADING (pre 2005 ISUP) AND DOWNGRADING � Exact intraobserver agreement in 42-78% � Clinical sampling : # needle cores taken in 5 studies; within +/- 1 score unit in � Age and clinical stage : not helpful (but stage is present in nomograms and age in one) 72-87% of cases � Serum PSA : often correlates with upgrading � Exact interobserver agreement in 36-81% � Prostate size : Larger size associated with less upgrading (median 61%) in 9 studies; slight to � Cancer extent on biopsy : ½ of papers positive substantial agreement as assessed by � Perineural invasion : 3 studies positive kappa (0.13-0.78) � Imaging : More studies needed Epstein JI : The Gleason Grading System , 2013 6

REPRODUCIBILITY CAUSES OF POOR REPRODUCIBILTY (pre 2005 ISUP) Pre 2005 ISUP Current issues : � Highest levels of agreement attained � Undergrading � Definition of fused with use of whole mounts, by glands � Cribriform proliferations urologic pathologists, and after � Tangential sectioning of � Low-grade carcinomas educational programs (such as 3s vs. poorly-formed 4s � Borderline patterns that courses and web-based tutorial) � Number of single cells are at the interface needed to diagnose 5 between two patterns � Experience and education most � Grade heterogeneity with � Larger tumors with more critical in enhancing reproducibility multiple cores positive than two patterns Hum Pathol 32:74, 2001 OVERGRADING OF CROWDED 3 VS. FUSED 4 PATTERN 3 AS 4 � Crowded glands � Pattern 3B (small glands) � Tangentially sectioned glands � Branching glands � Crush or poor sectioning artifact � Glands with perineural invasion � Collagenous micronodules Epstein JI : The Gleason Grading System , 2013 7

HIGH-GRADE DIAGNOSIS HIGH-GRADE DIAGNOSIS CHALLENGE CHALLENGE : FUSION VS. : 3B VS. POORLY FORMED GLANDS TANGENTIAL SECTION POORLY FORMED GLANDS PATTERN 3A PATTERN 3B CRUSH/THERMAL UNDERGRADING IN DISTORTION NEEDLE BIOPSY TISSUE � MINIMAL AMOUNT OF CARCINOMA DOES NOT EQUAL LOW-GRADE CARCINOMA � DIFFICULT TO APPRECIATE INFILTRATIVE PATTERNS GLEASON GRADE 3 +3 = SCORE OF 6 8

UNDERDIAGNOSIS OF PATTERN 5 in UNDERGRADING PATTERN RADICAL PROSTATECTOMY 5 � In one series of 59 needle core cases, pattern 5 was missed by referring pathologist in 58% of cases � Patterns missed : comedonecrosis (100%), cords (55%), single cells (51%), and solid sheets (39%) � Pattern 5 more often missed when it was not the primary pattern AJSP 2011; 35:1706 FOAMY GLAND DETECTION OF HIGH GLEASON ADENOCARCINOMA : GRADE CRITICAL PATTERN 5 MISSED J Urol 185:869,2011 9

HIGH-GRADE GLEASON GLEASON GRADE PATTERN 4 : PATTERN 4 in NEEDLE BIOPSY CHAINS � Ill-defined glands with poorly-formed glandular lumina (57%) � Fused microacinar glands (53%) � Cribriform glands (25%) � Chains (4%) � Glomeruloid (3%) � Hypernephromatoid (0.3%) � AJSP 36:900-907, 2012 GLEASON GRADE PATTERN 4 : GLEASON GRADE PATTERN 4 : GLOMERULOID STRUCTURES HYPERNEPHROMATOID Issue : Some have graded as 3 10

HIGH-GRADE GLEASON PATTERN 5 NOT PATTERN 5 in NEEDLE RECOGNIZED in ISUP 2005 BIOPSY � Single cells (53%) � SINGLE FILE (some � Single file (40%) may consider cords – but cords are thick rope-like � Cords (35%) structures) � Small solid nests (24%) � SMALL SOLID NESTS � SOLID CYLINDERS � Solid sheets (19%) � Comedocarcinoma (2%) � Solid cylinders (0.3%) GLEASON GRADE PATTERN 5 : GLEASON GRADE PATTERN 5 : SINGLE CELLS LINEAR ARRAY 11

GLEASON GRADE PATTERN 5 : GLEASON GRADE PATTERN 5 : CORDS SMALL SOLID NESTS GLEASON PATTERN 5 : GLEASON GRADE PATTERN 5 : SOLID SHEETS SMALL SOLID NESTS NOT IN ISUP 2005; PROPOSED AS 5 : AJSP 2012; 36:900-907 12