Pathological Information Needed From RP

Specimen For Locally Advanced Disease :

Margins, Lymph Nodes, and What Else?

Neal D Shore, MD, FACS

Carolina Urologic Research Center

Myrtle Beach, SC

St Gallen,APCCC:2017

Disclosures

• Research/Consulting: AbbVie, Amgen,

Astellas, Bayer, Dendreon, Ferring, Genomic

Health, Innocrin, Inovio, Janssen, MDxHealth,

Myovant, Myriad, Neogenomics, Pfizer,

Sanofi, Tolmar

• Stocks/Equity: None

RP Goals:

• Low Risk: PSA <10, Gleason ≤ 6, and clinical stage T1 or T2

• Intermediate Risk: PSA 10-20, and/or Gleason 7

• High Risk: PSA >20, Gleason ≥ 8, or clinical stage ≥T3

• (a) eradication of the cancer with negative surgical margins, (b) preservation of urinary function, and (c) preservation of erectile function, when appropriate.

• Positive surgical margins may be associated with higher rates of cancer recurrence;surgical techniques( preservation of urinary and erectile function) may result in positive margins

• How can the pathologist optimize assistance? Implications for adjuvant(precisio/personalized) therapy? Clinical trial enrollment?

Surgeon Needs

• Trifecta: Cured, Potent, & Continent Patient

• Pathologic Information: Likelihood Adjuvant

Therapy; Additional Molecular tests?

• Musts vs Maybes

• No intraoperative or postoperative

complications

• No calls after dinner hours

• Endless adulation

Pathologic Features of High Risk for

Prostate Cancer Progression Following

Prostatectomy

• Gleason grade 8-10

• Stage ≥pT3a

• Margin positive

• LN positive

Significance of Tertiary (<5%) HG Gleason Pattern*

HG = high-grade

*Tertiary pattern is defined as a third Gleason pattern in a tumor that occupies less than 5% of the tumor.

Pan CC, et al. Am J Surg Pathol. 2000;24:563-9.

Pro

gre

ssio

n-F

ree

Pro

bab

ilit

y

Months to Progression

0 40 80 120 160 200 240

0.00

0.25

0.50

0.75

1.00

GS 7

GS 5-6 with tertiary 4/5

GS 5-6 162 128 99 64 64 77 82 60

58 47 44

32 16

7 1

1 6

2 9 8 41 22

29 26 1

2

3 3

35 52

69 72

77 1

3

Months to Progression

0 40 80 120 160 200 240

0.00

0.25

0.50

0.75

1.00

GS 8

GS 7 with tertiary 5

9 2

1

8 41

22 29

72

77

GS 7

1 1

1

12

8 13

4 4

6

7

2

1

1

1 4

69 52

35 26

Pro

gre

ssio

n-F

ree

Pro

bab

ilit

y

The impact of TP5 of Gleason score 7 in radical

prostatectomy specimens is still significant using

contemporary grading. Moreover, TP5 was independently

associated with biochemical recurrence. However, 3+4=7

with TP5 behaves like 4+3=7 in terms of biochemical

recurrence-free survival rate.

Borhan, Epstein. Significance of Gleason Score 7 With Tertiary Pattern 5 at Radical

Prostatectomy Urology 2017; 100: 175-9

Classification of Prostate Cancer Using 5-tiered Prognostic Grade Groupings

• 2014 ISUP (Nov. 2014, Chicago)

– Voted to adopt 5-teired system (90% consensus)

– Recommended that percent high grade patterns be specified for

groups II and III

– All modifications to Gleason system should be used in

classification

The overall Gleason score is based on the core with the highest Gleason score. Gleason

scores can be grouped and range from Prognostic Grade Group I (most favorable) to

Prognostic Grade Group V (least favorable).

Gleason score ≤ 6: Prognostic Grade Group I

Gleason score 3 + 4 = 7: Prognostic Grade Group II

Gleason score 4 + 3 = 7: Prognostic Grade Group III

Gleason score 8: Prognostic Grade Group IV

Gleason score 9-10: Prognostic Grade Group V

Predicting 15-year prostate cancer specific

mortality after radical prostatectomy1

Margin status not independently associated with PCSM

1. Eggener SE, et al. J Urol 2011;185:869-75.

http://dx.doi.org/10.1016/j.juro.2010.10.057

PCSM (black areas) and mortality from competing causes (gray areas) by

pathological stage and patient age at diagnosis.

N=23,910 across 5 institutions

Surgical Margins

• Positive margin one vs multiple sites

• Report location(improve technique), albeit no incontrovertible evidence specific site predicts dz progression

• Extent tumor @PSM( 3mm cutpoint or negative –focal-extensive) correlates: recurrence rate 14 vs 53%(Emerson);87-60-35, 5 yr recurrence free(Epstein)

• Consensus: report extraprostatic extension(mm) but no need report Gleason score

International Society of Urological Pathology, ‘05, ‘09, ‘14

High percent tumor volume predicts biochemical recurrence

after radical prostatectomy in pathological stage T3a

prostate cancer with a negative surgical margin1

1. You D, et al. Int J Urol 21:484-9, 2014

20 NOV 2013 DOI: 10.1111/iju.12348

Cribriform cancer highly associated with

biochemical recurrence in men treated

with prostatectomy

Iczkowski KA, et al. Digital quantification of five high-grade prostate cancer patterns, including the

cribriform pattern, and their association with adverse outcome. Am J Clin Pathol 2011;136:98-107.

Lymph Nodes

Standard PLND should be mandatory in high-risk patients and is recommended for the intermediate group.

• Standard PLND: include all lymphatic tissue along the external iliac vein from the lymph node of Cloquet distally to the bifurcation of the common iliac vein proximally and includes all lymphatic tissue in the obturator fossa.

•

• Evidence and opinions on the role of extended PLND in high-risk patients are divided. An ePLND may entail the removal of lymph nodes medial and lateral to the internal iliac vessels up to and around the bifurcation of the common iliac artery, with the genitofemoral nerve as the lateral limit.

International Society of Urological Pathology, ‘05, ‘09, ‘14

ePLND

• Extending landing sites potential disease

beyond obturator fossa to hypogatsric to

external iliacs to presacral?

• Morbidity vs disease control(Ex.Bladder Ca)

• Inadequate templates, different surgeons and

single institution series

• Briganti (EAU’15) 5% ln risk nomogram,

ePLND as the standard

Briganti et al. Pelvic Lymph Node Dissection in Prostate Cancer: The Mystery Is Taking Shape EAU 2013; 63: 459-61.

Joniau S et al. Mapping of pelvic lymph node metastases in prostate cancer Eur Urol 2013; 63: 450-8.

Ji J et al. Is the impact of the extent of lymphadenectomy in radical prostatectomy related to the disease risk? J Surg Res 2013; 178: 779-84.

Seminal Vesicles and Lymph Nodes

• LNs: frozen sections only of value high risk(

proceed with RP? Pendulum shift eradicate

oligomets?)

• LNs: submission vs optimal sampling varies

greatly.

• Diameter largest ln more predictive than #

pos lns or extranodal extension.

International Society of Urological Pathology, ‘05, ‘09, ‘14

Specimen Handling

• What is the ideal warm ischemia time(time without fixation), to avoid altering protein,DNA,or RNA confirmation, whilst preserving microscopic/immunohistochemichal features?

• Fresh samples-avoid formalin effect quality nucleic acids(fragmentation) and proteins(cross linking), impact future assay analytes

• Implications commercially and research available genomic assays?

• pT0:0.07-4.2%( neoadjuvant endocrine therapy vs mix up, thus ensure supply chain integrity)

• Cost and Time

International Society of Urological Pathology, ‘05, ‘09, ‘14

Genomic Correlates to the Newly Proposed

Grading Prognostic Groups for Prostate Cancer1

Fig. 1. Landscape of somatic copy number alterations from 426 prostate cancer cases

ordered by prognostic grading group from 1 (low) to 5 (high). Blue denotes deletions; red

denotes amplifications.

1. Rubin MA, Girelli G, Demichelis F. Eur Urol 2015.

http://dx.doi.org/10.1016/j.eururo.2015.10.040

Molecular Assays

• Prolaris (CCP Score);Decipher( Gene

Classifier)

• Increase DNA RM defects & T3 dz Castro et

al ,JCO ’13

• Alleles associated progression risk; e.g.,

HSD3B1 genotype(variant vs wild type): point

mutation may influence gonadal vs

adrenogenic therapeutic response, inform

trial selection vs adjuvant ADT(+/- ARSI)

• Who will order: surgeon or pathologist?

Hearn et al, Lancet Oncol. 2016, 17(10):1435

Conclusions

• Cancer grade is a strong indicator of prognosis

• The 5-tier Prognostic Grade Groupings proposed by the

2014 ISUP offer excellent prognostic stratification

– Easily understandable

– Validation studies have confirmed clinical utility

• Patients considered as high risk for progression following

prostatectomy represent a heterogeneous group

– Many will not develop metastasis or die of prostate cancer

– Molecular assays to inform intensity monitoring, adjuvant therapy

, and clinical trials

Conclusions

• High Gleason score, seminal vesicle invasion and LN

metastasis are adverse pathological features that portend

a higher risk of PCSM

• The impact of positive surgical margins is controversial

– Location, extent and grade of tumor at margin may improve

prognostic value

• Tumor volume, particularly of high grade component, may

impact risk of progression

• Emerging role for biomarkers to improve risk stratification

Real World Pathology Concerns

• Cost,time and accessibility: additional

sampling and assays

• Enhancing expertise and uniformity of

technique/interpretation: community vs GU

Pathologist

• Integrative strategies: surgeon and

pathologist, transition value based care

• Cancer tissue preservation: “Save The

Tumor”

Thank You

St Gallen,APCCC:2017