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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