Updates in TNM Staging of Prostate Cancer - uscap

Updates in TNM Staging of Prostate Cancer - uscap

Updates in TNM Staging of Prostate Cancer Samson W. Fine, MD Memorial Sloan Kettering Cancer Center AJCC 8TH EDITION – PROSTATE TEAM • Multidiscipli...

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Updates in TNM Staging of Prostate Cancer Samson W. Fine, MD Memorial Sloan Kettering Cancer Center

AJCC 8TH EDITION – PROSTATE TEAM • Multidisciplinary effort • • • • •

Radiation Oncology Urologic Surgery Urologic Oncology Biostatistics Pathology

Updates in TNM Staging of Prostate Cancer

• National Cancer Data Base (NCDB) • Recent publications since 2008 (7th edition) – Focus on quality of manuscripts

• Literature watch from UICC • Levels of evidence (and Guiding Principles) • Guidance of local & national leaders

AJCC Levels of Evidence I. Includes consistent results from multiple large, well-designed and wellconducted national/international studies in appropriate patient populations with appropriate end points and treatments. Prospective/retrospective population-based registry studies acceptable. II. Is obtained from at least one large, well-designed and well-conducted study in appropriate patient populations with appropriate end points and with external validation III. Somewhat problematic because of one or more factors: number, size or quality of individual studies; inconsistency of results across individual studies; appropriateness of patient population or outcomes IV. Insufficient because appropriate studies have not yet been performed

Updates in TNM Staging of Prostate Cancer

How elements were excluded • Based on available data • Critical review of level of evidence • Examples of topics that fell below acceptable level: • Imaging (e.g. MRI) • Molecular markers

• Imaging (does have a new section): • “…inter-observer reproducibility, issues with patient selection and contradictory results have limited the utility of imaging in clinical staging.”

Updates in TNM Staging of Prostate Cancer

Summary of changes: Comparison of 7th & 8th editions 7th EDITION

• Extraprostatic extension in the form of microscopic bladder neck invasion changed from pT4 to pT3a • Gleason score recognized as the preferred grading system • Prognostic factors incorporated into the Prognostic Stage Groups (GS; PSA) Updates in TNM Staging of Prostate Cancer

8TH EDITION • Definition of Primary Tumor: pathologically organ-confined disease = pT2; no longer subclassified by extent of involvement or laterality • Histologic Grade: GS (2014 criteria) and Grade Group [GrdGrp] should both be reported • AJCC Prognostic Stage Groups: Stage III includes select OC tumors based on PSA and/or GS/GrdGrp

Organ-confined disease • 1992: pT2a, b, c • 1997: pT2a, b • 2002: pT2a, b, c • 2010: pT2a, b, c

Updates in TNM Staging of Prostate Cancer

Evidence to change pT2 classification • Substaging does not convey prognostic information • Correlation between cT & pT substaging poor • Unilateral large tumor would be assigned lower pT stage than 2 small b/l cancers • Poor reproducibility: <1/2 v. >1/2 lobe

Stephenson et al. Cancer 2004;100:1646-1649 Updates in TNM Staging of Prostate Cancer

Summary of Changes #1: Definition of Primary Tumor • Pathologically organ-confined disease is considered pT2 and no longer sub-classified by extent of involvement or laterality (III)

Updates in TNM Staging of Prostate Cancer

PROGNOSTIC GRADE GROUPS

BJU Int 2013; 111:753-760

Updates in TNM Staging of Prostate Cancer

• 5 institutions • 21K patients: RP • 16K patients: NB • 5.5K patients: RT • GrdGrp 1 v. GS 6 • discrimination GS7: • GrdGrp 2 v. 3

Eur Urol 2016;69:428-435

Updates in TNM Staging of Prostate Cancer

Br J Cancer 2016;114:1078-1083

Updates in TNM Staging of Prostate Cancer

Eur Urol 2016;69:1135-1141

Summary of Changes #2: Histologic Grade • Gleason score (2014 criteria) & Grade Group should both be reported (II)

Grade Group 1 2 3 4 5

Updates in TNM Staging of Prostate Cancer

Gleason Score ≤6 7 7 8 9 or 10

Gleason Pattern(s) ≤3+3 3+4 4+3 4+4 (3+5/5+3) 4+5, 5+4, or 5+5

2016 WHO GU Classification Table 3.03 Grade group 1: Gleason score < 6 Only individual discrete well-formed glands Grade group 2: Gleason score 3+4=7 Predominantly well-formed glands with lesser component of poorly formed / fused / cribriform glands Grade group 3: Gleason score 4+3=7 Predominantly poorly formed / fused / cribriform glands with lesser component of well-formed glands Grade group 4: Gleason score 4+4=8; 3+5=8; 5+3=8 Only poorly formed / fused / cribriform glands Predominantly well-formed glands and lesser component lacking glands Predominantly lacking glands and lesser component of well-formed glands Grade group 5: Gleason scores 9-10 Lack gland formation (or with necrosis) with or without poorly formed / fused / cribriform glands Updates in TNM Staging of Prostate Cancer

Updates in TNM Staging of Prostate Cancer

Revisions to CAP Protocols • In addition to Primary/Secondary/Tertiary Gleason patterns and Total Gleason Score • Grade Group ___ Grade group 1 ___ Grade group 2 ___ Grade group 3 ___ Grade group 4 ___ Grade group 5 Updates in TNM Staging of Prostate Cancer

AJCC Prognostic Stage Groups Prognostic Stage Group I IIA IIB IIC IIIA IIIB IIIC IVA IVB

T

N

M

PSA

Grade Group

cT1a-c, cT2a pT2 cT1a-c, cT2a cT2b-c T1-2 T1-2 T1-2 T1-2 T3-4 Any T Any T Any T

N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N0

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

< 10 < 10 ≥ 10 < 20 < 20 < 20 < 20 < 20 ≥ 20 Any Any Any Any

1 1 1 1 2 3 4 1–4 1–4 5 Any Any

Updates in TNM Staging of Prostate Cancer

Am J Surg Pathol 2012;36:1346-1352

Stage I includes a pT staged tumor

Updates in TNM Staging of Prostate Cancer

AJCC Prognostic Stage Groups Prognostic Stage Group I IIA IIB IIC IIIA IIIB IIIC IVA IVB

T

N

M

PSA

Grade Group

cT1a-c, cT2a pT2 cT1a-c, cT2a cT2b-c T1-2 T1-2 T1-2 T1-2 T3-4 Any T Any T Any T

N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N0

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

< 10 < 10 ≥ 10 < 20 < 20 < 20 < 20 < 20 ≥ 20 Any Any Any Any

1 1 1 1 2 3 4 1–4 1–4 5 Any Any

Updates in TNM Staging of Prostate Cancer

Summary of Changes #3: AJCC Prognostic Stage Groups • Stage II further subdivided by Gleason Score/Grade Group •Stage III includes select organ-confined tumors based on PSA and Gleason Score/Grade Group (II) Updates in TNM Staging of Prostate Cancer

AJCC-Prostate Registry Data Collection Variables • Tertiary/Limited Gleason patterns (prostatectomy) • Number of cores positive / # of cores examined • For + cores: u/l, b/l, beyond prostate • Metastatic sites Updates in TNM Staging of Prostate Cancer

Evaluation of Risk Assessment Tools • 15 available prognostic models evaluated = multivariable model where factors predict a clinical outcome in the future • 13 models rejected, including all 8 for localized disease • 2 models met all of the criteria – both based on data from large phase III trials in metastatic pts. that were externally validated Approved Prognostic Tool

Reference

Metastatic castration-resistant prostate cancer

Halabi et al. J Clin Oncol 2014;32:671-677

Metastatic castration-resistant prostate cancer treated with second-line therapy

Halabi et al. J Natl Cancer Inst 2013;105:17291737

Updates in TNM Staging of Prostate Cancer

Precision Medicine Core Inclusion/Exclusion Criteria • Inclusion Criteria:

• Inclusion Criteria:

• OS/DSS/DSM

• Calibration assessed & provided

• Model addresses clinically relevant Q

• Model validated over time frame / in practice setting relevant to contemporary pts.

• Model includes relevant predictors • Validation study: which pts. used to evaluate & data sets I/E criteria • Generalizability & external validation

• What treatment(s) were applied if any and with what frequency • Development +/- validation of prediction model appears as peer-reviewed journal article

• Well-defined prognostic time zero • All predictors known at time zero and clearly defined • Sufficient detail to implement model (i.e. equation) or free access to it • Measure of discrimination must be reported (usually as CI) on the validation data sets (VDS)

Updates in TNM Staging of Prostate Cancer

• Exclusion Criteria: • Substantial proportion of pts. with no follow-up in VDS • No info on # of pts. w/ missing values in VDS • # of events in VDS is small

What’s Not Included • Tumor Volume • Extent of extraprostatic extension (EPE) • Subclassification of (+) Surgical Margins

Updates in TNM Staging of Prostate Cancer

Tumor Volume/Size • Well-established correlation with grade, stage, tumor progression • Visual estimate quantitation and/or maximum diameter • Fail to show IPV

• No accepted standard for measurement of tumor volume • Needs to be appropriate for routine clinical practice • Even “objective” measures subject to issues of: • Total v. subtotal embedding • Processing effects: shrinkage; irregular sectioning • Dominant/index tumor v. overall volume/size

Tumor Quantitation Intraglandular extent (%) Maximum size of dominant nodule (mm) International Collaboration on Cancer Reporting

Tumor Quantitation % of prostate involved by tumor Tumor size (dominant nodule, if present): Greatest dimension: + Additional dimensions: CAP Protocols

Updates in TNM Staging of Prostate Cancer

mm x

mm

PROSTATIC ADENOCARCINOMA Prostatic Capsule • Not a true “capsule” • Condensation of fibromuscular stroma • Covers most of the posterolateral prostate • Anterior / Apex / Bladder neck • Indistinct • Not present

The Prostatic “Capsule”: Does It Exist? Ayala AG, et al. Am J Surg Pathol 1989 Updates in TNM Staging of Prostate Cancer

PROSTATIC ADENOCARCINOMA Prognostic Factors for PSA Progression • Prognostic Factor

P

Risk Ratio

• Preop PSA

.001

1.02

• Gleason sum

.001

2.01

• Tumor volume

.704

1.01

• Level of PCI

.001

• Level 3F vs 0-2

.019

2.03

• Level 3E vs 0-2

.001

3.88

• SVI

.002

2.00

Wheeler TM et al. Hum Pathol

• +LN

.001

2.55

1998; 29:856-862

Updates in TNM Staging of Prostate Cancer

• 10,750 RP pts. • No EPE: 7843 (73%) • F-EPE: 1258 (12%) • NF-EPE: 1649 (15%)

Extent of Extaprostatic Extension

Updates in TNM Staging of Prostate Cancer

Urology 2015;85:161-164

Surgical Margin Positivity pT2, +SM

Tumor at inked margin in an area of capsular incision

Updates in TNM Staging of Prostate Cancer

pT3a, +SM

Tumor at inked margin in an area of extraprostatic extension

Positive Surgical Margins: Meta-Analysis J Urol 2009; 182:1357-1363 pT2

pT3a

pT3b

GS6

GS7

GS>8

Number and extent of M+ correlated with BCR Did not improve predictive accuracy v. +/- margin alone Updates in TNM Staging of Prostate Cancer

Further Subclassification of +SM

Margin status

• Independent Predictive Value for BCR

Gleason score at margin [if >1 +SM, record highest score]: REC

• Location • Extent • One v. multiple • Length in mm

• Grade at +SM (GG, GS)

• Limited follow up • Limited # of events **Lack of randomized study to see if early adjuvant RT = decreased risk of BCR

Location(s): REQ Extent (total) [if >1 +SM, record cumulative length]: REC

International Collaboration on Cancer Reporting

Margins Margin involved by invasive carcinoma: Focal (<3mm) REQ Nonfocal (>3mm) Linear length of +SM: mm REC Location of +SM: REQ Gleason PATTERN at +SM: Pattern 3 REC Pattern 4 or 5 CAP Protocols

Updates in TNM Staging of Prostate Cancer

Disclosure of Relevant Financial Relationships USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Samson W. Fine declares he has no conflict(s) of interest to disclose.

Updates in TNM Staging of Prostate Cancer

Updates in TNM Staging of Prostate Cancer: References

Andreoiu M, Cheng L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol. 2010;41(6):781-793. Ayala AG, Ro JY, Babaian R, et al. The prostatic capsule: does it exist? Its importance in the staging and treatment of prostatic carcinoma. Am J Surg Pathol. 1989;13(1):21-27. Ball MW, Partin AW, Epstein JI. Extent of extraprostatic extension independently influences biochemical recurrence-free survival: evidence for further pT3 subclassification. Urology. 2015;85(1):161-164. Berney DM, Beltran L, Fisher G, et al. Validation of a contemporary prostate cancer grading system using prostate cancer death as outcome. Br J Cancer. 2016;114(10):1078-1083. Cao D, Kibel AS, Gao F, et al. The Gleason score of tumor at the margin in radical prostatectomy is predictive of biochemical recurrence. Am J Surg Pathol. 2010;34(7):994-1001. Eichelberger LE, Koch MO, Eble JN, et al. Maximum tumor diameter is an independent predictor of prostate-specific antigen recurrence in prostate cancer. Mod Pathol. 2005;18(7):886-890. Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016;40(2):244-252. Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score. Eur Urol. 2016;69(3):428-435. Fine SW, Amin MB, Berney DM, et al. A contemporary update on pathology reporting for prostate cancer: biopsy and radical prostatectomy specimens. Eur Urol. 2012;62(1):20-39. Freedland SJ, Partin AW, Epstein JI, et al. Biochemical failure after radical prostatectomy in men with pathologic organ-confined disease: pT2a versus pT2b. Cancer. 2004;100(8):1646-1649. Hong SK, Han BK, Chung JS, et al. Evaluation of pT2 subdivisions in the TNM staging system for prostate cancer. BJU Int. 2008;102(9):1092-1096. Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol. 2016;70(1):106-119. Kates M, Sopko NA, Han M, et al. Importance of Reporting the Gleason Score at the Positive Surgical Margin Site: Analysis of 4,082 Consecutive Radical Prostatectomy Cases. J Urol. 2016;195(2):337-342. Kattan MW, Hess KR, Amin MB, et al. American Joint Committee on Cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine. CA Cancer J Clin. 2016;66(5):370-374.

Kikuchi E, Scardino PT, Wheeler TM, et al. Is tumor volume an independent prognostic factor in clinically localized prostate cancer? J Urol. 2004;172(2):508-511. Leapman MS, Cowan JE, Simko J, et al. Application of a Prognostic Gleason Grade Grouping System to Assess Distant Prostate Cancer Outcomes. Eur Urol. 2016 Dec 8. [Epub ahead of print]. Loeb S, Folkvaljon Y, Robinson D, et al. Evaluation of the 2015 Gleason Grade Groups in a Nationwide Population-based Cohort. Eur Urol. 2016;69(6):1135-1141. Magi-Galluzzi C, Evans AJ, Delahunt B, et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic extension, lymphovascular invasion and locally advanced disease. Mod Pathol. 2011;24(1):26-38. Magi-Galluzzi C, Montironi R, Epstein JI. Contemporary Gleason grading and novel Grade Groups in clinical practice. Curr Opin Urol. 2016;26(5):488-492. Mathieu R, Moschini M, Beyer B, et al. Prognostic value of the new Grade Groups in Prostate Cancer: a multi-institutional European validation study. Prostate Cancer Prostatic Dis. 2017 Jan 10. [Epub ahead of print]. Moch H, Humphrey PA, Ulbright TM, Reuter VE (Eds.): WHO Classification of Tumours of the Urinary System and Male Genital Organs (4th Edition). IARC: Lyon 2016. NCCN Guidelines Version 1.2017 Staging – Prostate Cancer Pierorazio PM, Walsh PC, Partin AW, et al. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013;111(5):753-760. Ploussard G, Drouin SJ, Rode J, et al. Location, extent, and multifocality of positive surgical margins for biochemical recurrence prediction after radical prostatectomy. World J Urol. 2014;32(6):1393-1400. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes? Am J Surg Pathol. 2012;36(9):1346-1352. Samaratunga H, Montironi R, True L, et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 1: specimen handling. Mod Pathol. 2011;24(1):6-15. Shikanov S, Song J, Royce C, et al. Length of positive surgical margin after radical prostatectomy as a predictor of biochemical recurrence. J Urol. 2009;182(1):139-144. Spratt DE, Cole AI, Palapattu GS, et al. Independent surgical validation of the new prostate cancer gradegrouping system. BJU Int. 2016;118(5):763-769. Spratt DE, Jackson WC, Abugharib A, et al. Independent validation of the prognostic capacity of the ISUP prostate cancer grade grouping system for radiation treated patients with long-term follow-up. Prostate Cancer Prostatic Dis. 2016;19(3):292-297.

Stephenson AJ, Wood DP, Kattan MW, et al. Location, extent and number of positive surgical margins do not improve accuracy of predicting prostate cancer recurrence after radical prostatectomy. J Urol. 2009;182(4):1357-1363. Tan PH, Cheng L, Srigley JR, et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 5: surgical margins. Mod Pathol. 2011;24(1):48-57. Udo K, Cronin AM, Carlino LJ, et al. Prognostic impact of subclassification of radical prostatectomy positive margins by linear extent and Gleason grade. J Urol. 2013;189(4):1302-1307. van der Kwast TH, Amin MB, Billis A et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume. Mod Pathol. 2011;24(1):16-25. van Oort IM, Witjes JA, Kok DE, et al. The prognostic role of the pathological T2 subclassification for prostate cancer in the 2002 Tumour-Nodes-Metastasis staging system. BJU Int. 2008;102(4):438-441. Viers BR, Sukov WR, Gettman MT, et al. Primary Gleason grade 4 at the positive margin is associated with metastasis and death among patients with Gleason 7 prostate cancer undergoing radical prostatectomy. Eur Urol. 2014;66(6):1116-1124. Wheeler TM, Dillioglugil O, Kattan MW, et al. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer. Hum Pathol. 1998;29(8):856-862.