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Evidence Summary 22-2-3 ARCHIVED 2017
A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO)
Best Practices for Oncologic Pathology Secondary Review: Genitourinary Cancers
John Srigley, Glenn G Fletcher, Jack Barkin, Rodney Henry Breau,
Andrew Loblaw, Madeleine Moussa, Linda Sugar, and Aaron Pollett *
Report Date: June 26, 2014
An assessment conducted in October 2017 ARCHIVED Evidence Summary
22-2-3. This means that the document will no longer be maintained but may still
be useful for academic or other information purposes. The PEBC has a formal and
standardized process to ensure the currency of each document
(PEBC Assessment & Review Protocol)
This Evidence Summary is part of an eleven-report series.
Please refer to #22-2-M for background and methodology.
#22-2-M: Methods and Overview
#22-2-1: Breast Cancer
#22-2-2: Gastrointestinal Cancers
#22-2-3: Genitourinary Cancers
#22-2-4: Gynecologic Cancers
#22-2-5: Head and Neck Cancers
#22-2-6: Hematologic Cancers
#22-2-7: Lung Cancer
#22-2-8: Cutaneous Melanoma and Other Skin Cancers
#22-2-9: Central Nervous System (CNS) Tumours
#22-2-10: Bone and Soft Tissue Cancers (Sarcoma)
* Author affiliations are given in Appendix I
EBS 22-2-3
For information about the PEBC and the most current version of all reports, please visit the
CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: [email protected]
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 1
QUESTION What types of specimens suspected to be or diagnosed as genitourinary cancer1 should
or should not have routine secondary pathology review? INTRODUCTION
This report is part of a series of reports on secondary pathology review in cancer diagnosis. The reader should consult document #22-2-M: Methods and Overview for a more detailed background to the project, definitions, and limitations of secondary review, and methodology used. Only a brief summary of the methods is given below, along with any details specific to genitourinary pathology.
METHODS
The evidence-based reports developed by the Cancer Care Ontario (CCO) Program in Evidence-Based Care (PEBC) use the methods of the Practice Guidelines Development Cycle (1). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and key details extracted by DK and reviewed by GF of the PEBC.
The body of evidence in this review is primarily comprised of comparative studies on interobserver accuracy or agreement. The systematic review is intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through CCO. All work produced by the PEBC is editorially independent from the Ministry.
Definition of Secondary Pathology Review
In this series of documents, secondary pathology review is defined as review of pathology specimens by a second pathologist that is not initiated by the primary pathologist due to uncertainty and is most frequently at the request of the patient or treating clinician, or multidisciplinary case conference (MCC) process, or as standard practice to review all cases at a cancer centre prior to treatment. Consultation or review at the request of the primary pathologist or prior to finalization of the primary pathologist’s report is NOT included in this definition. Literature Search Strategy and Study Selection Criteria
Details of the search strategy and inclusion/exclusion criteria are provided in report #22-2-M of this series, and only a brief summary is included here. In December 2009, a search for practice guidelines was conducted in the National Guideline Clearing House (USA), National Institute for Health and Clinical Excellence (NICE, UK), Scottish Intercollegiate Guidelines Network (SIGN), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN, USA), National Health and Medical Research Council (NHMRC, Australia), New Zealand Guidelines Group (NZZG), Canadian Medical Association’s CMA Infobase: Clinical Practice Guidelines, Association of Directors of Anatomic and Surgical Pathology, College of American Pathologists (CAP), and the Canadian Association of Pathologists (CAP-ACP). The SAGE Directory of Cancer Guidelines was searched in May 2012.
1 Cancer includes precancerous conditions that need to be distinguished from cancer, that may progress to cancer, or for which there is not general agreement as to whether they should be termed as cancer.
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22-2-3 Genitourinary Cancer Evidence Summary Page 2
MEDLINE and EMBASE databases were searched from 1995 to May 7, 2013. Articles with terms related to both pathology (including cytology or histology) and diagnostic discrepancy were retrieved. For inclusion in this report, articles had to include review of the same specimens by a second pathologist (excluding review at the original pathologist’s request), be related to the diagnosis of genitourinary cancers or aspects of cancer such as grade or subtype, and report on diagnostic discrepancy or agreement between two (or more) pathologists. RESULTS
For genitourinary cancers, the search resulted in 126 articles, of which 64 were reproducibility studies as described in document #22-2-M. The 62 studies on genitourinary cancers that report agreement or disagreement between initial and secondary pathology review are summarized in Table 1 [15 bladder or kidney (2-16), seven testes or penis (17-23), and 41 prostate (4,24-63)]. There are an additional nine studies (64-72) that include genitourinary cancers along with other cancers. While data were not extracted from the reproducibility studies, these may be of interest to some readers and address specialized areas of pathologic interpretation and areas where more research or standardization is necessary. The publications are therefore listed separately in Appendix II. Guidelines
Canadian and European consensus guidelines recommend the review of testicular germ cell cancer specimens by a pathologist experienced in testis cancer pathology (73,74). The NICE guideline (75) recommends specimens for testicular cancer be reviewed by a specialist pathologist who deals with testicular tumours at a specialized centre. The International Consultation on Urologic Diseases/Société Internationale d’Urologie (SIU/ICUD) consensus guidelines recommend both nonseminomatous germ cell tumours of the testis and seminoma be assessed by pathologists with expertise in testicular cancer (76,77). SIGN recommends the review of testicular germ cell tumours at a specialist treatment centre by a pathologist with a special interest and experience in germ cell tumours (78).
The European Association of Urology (79) recommends secondary review of slides for urothelial carcinoma, particularly in T1, CIS, and high-grade lesions. The pathological report should specify the grade, depth of tumour invasion, and whether the lamina propria and sufficient muscle are present in the specimen.
NICE (75) recommends prostate biopsies suggestive of cancer and for which radical treatment is being considered be reviewed by the pathologist member of the specialist urological cancer team at the treatment. Alberta Health Services (80) recommends that central/reference pathologist(s) review specimens for prostate cancer.
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22-2-3 Genitourinary Cancer Evidence Summary Page 3
Table 1. Pathologic discrepancy rates between primary and secondary review pathologists: Genitourinary cancers.
(Note: For ease of reading please print this table or enlarge (zoom) it to 120% on the computer monitor.) Author Year # 2nd
Reviewers #
Specimens Reviewer
(Profession/ Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Bladder
Lee (2) 2010 1 194 pathologist in
year 2002;
pathologist
with GU
expertise in
2004
review of slides from
outside cases referred to
Cleveland Clinic, 2002 and
2004 for management
after resection; stage by
TMN, grade by WHO 1973
(samples from 2002) or
WHO 2003 and WHO/ISUP
1997 (samples from
2004); retrospective
review of reports by GU
pathology specialist
all transurethral bladder tumor
resection specimens; excluded
cases where outside
pathologist sought a second
opinion; major = potential
management change as
determined by a urologist
year 2002
year 2004
overall
change in histological type
change in grade I to III
malignancy to no cancer
change in stage
78
116
194
194
194
194
194
33
27
29
28
23
25
3.1
2.1
4.1
16
67
73
71
Coblentz (3) 2001 1 131 surgical
pathologist;
genitourinary
pathologist
retrospectively
reviewed 19 of
24 discordant
cases and
agreed with
2nd review in
all
patients referred from
community hospitals to
academic center
(University of Virginia) for
evaluation, 1996-1999;
review used WHO 1973
classification modified to
add Grade 4, staging by
1977 IUAC/AJCC system
biopsy or TUR diagnosis of
urothelial carcinoma of the
bladder; only significant
discrepancies with regard to
the diagnosis, stage, grade, or
tumor histologic type that
could affect clinical decisions;
[actual treatment change
determined by chart review of
clinical and pathologic
outcomes given in parentheses]
overall
→ non-urothelial neoplasms
→ inadequate for staging (no musclaris
propria)
change in stage
131
126
18
3
4
15
18 (9)
15
82
85
Wayment (4) 2011 2 117 urologist +
pathologist; 3rd
(or 4th)
pathologist if
disagreement
retrospective review of
records: practice at
tertiary referral centre to
request pathologic
materials for all patients
seen in consultation for
urologic malignancy;
2002-2008
all patients seen in consultation
for urologic malignancy;
major=potential for significant
change in prognosis or
treatment options, minor=did
not alter prognosis or
treatment options
bladder 83 9.6 8.4 1.2 90
Tosoni (5) 2000 1 301 pathologist
with special
interest in
urinary bladder
cancer
retrospective review of
slides of consecutive
urinary bladder tumours ,
1988-94, City Hospital
Triemli, Zurich; stage and
grade according to UICC
(1992) and WHO (1973)
classifications
histological diagnosis of all
superficial bladder carcinomas
initially defined as pT1 plus 66
randomly selected stage pTa;
review staging but initial grade
more closely matched clinical
progression
*biopsies with carcinoma with
stromal invasion but lacking
fragments of muscular bladder
wall considered at least pT1
stage
pTa (all changes were pTa→pT1)
pT1
pT1 → pTa
pT1 → at least pT1*
pT1 → pT2+
grade
grade 1
grade 1→ grade 3
grade 2 (mostly to grade 3)
grade 3 (all to grade 2)
301
66
235
298
67
151
80
36
8
44
35
6
3
42
67
7
49
9
64
92
56
58
33
51
91
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22-2-3 Genitourinary Cancer Evidence Summary Page 4
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
van der
Meijden (6)
2000 1 1400 uropathologist comparison of local and
review pathology results
from EORTC randomized
phase III trials comparing
adjuvant treatments after
transurethral resection,
used 1974 TMN
classification;
local pathologist was not
usually a uropathologist
histological specimens at study
entry from patients with
primary or recurrent stage Ta-
T1 transitional cell bladder
cancer; examined different
slides from same tissue block
T category
Ta
Ta →T1
Ta→T2+
T1
T1 →Ta
T1→T2+
T2 or greater
T2+ →Ta
T2+ → T1
grade, overall
grade 1
grade 2
grade 3
combined T stage and grade, patients
with non-invasive disease
TaG1
T1G3
T1G3 →invasive T2+
1369
757
581
31
1273
560
553
160
1175
392
88
104
31
10
9
1
57
52
5
32
13
19
43
47
40
39
38
43
50
11
11
69
90
43
68
57
53
60
61
62
57
50
van Rhijn (7) 2010 1 164 pathologist retrospective review of
randomly chosen pT1
bladder tumours from two
university hospitals, 1983-
2006, TMN 2002 for stage
patients with primary pT1 non-
muscle invasive (NMI) bladder
cancer, all had transurethral
resection of primary bladder
tumour
stage, overall
pT1 → pTa
pT1 → pT2+
164 18
15
4
82
Sharkey (8) 1997 1 54 patients pathologist retrospective central
review on pathological
specimens in multi-
institutional phase II study
of a pharmacological
immune enhancer
cytological (bladder washing)
and bladder biopsy specimens
from patients with in situ
transitional cell carcinoma of
the bladder
biopsies: benign, dysplasia, Ca in situ,
papillary, Flat (invasive)
benign
benign→ dysplasia
benign → transitional Ca in situ
dysplasia
dysplasia → benign
dysplasia → transitional Ca in situ
dysplasia → papillary Ca
Ca in situ
Ca in situ →benign
Ca in situ → dysplasia
Ca in situ → papillary Ca
papillary → dysplasia
cytology: negative/atypia, suspicious,
positive, insufficient
cytology upgraded
patients ineligible (misclassification in
initial biopsies ; was not transitional cell
carcinoma)
159
39
27
69
20
217
54
38
36
31
5
70
37
30
4
29
3
22
4
5
34
30
13
62
64
30
71
95
66
87
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22-2-3 Genitourinary Cancer Evidence Summary Page 5
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Isfoss (9) 2011
a
1 88 expert
uropathologist;
consensus of
expert + 2
general
pathologists if
discrepancy
blind review of all urinary
bladder surgical
specimens received 2004-
2005 at Telemark Hospital
(Norway) for study of
diagnostic features;
overlaps with Isfoss et al,
2011b
assess accuracy of original
nonexpert papillary urothelial
neoplasia (PUN) grading and
staging; only samples with PUN
present and evaluable for grade
and stage and with follow-up
specimens were included;
original diagnosis by 1999 WHO
scheme, review by 2004 WHO
scheme
agreement of PUN grade
low malignant potential/atypical
(LMP-PUN)
low-grade (LG-PUN, Grade 1)
high-grade (HG-PUN, Grades 2-3)
invasion status (pTa, pT1, pT2+)
88
6
23
59
88
18
83
48
0
22
82
17
52
100
78
0.53
0.66
Isfoss (10) 2011
b
3 81 2 general
pathologists
and one
uropathologist;
consensus if a
disagreement
consecutive bladder tissue
samples reevaluated
blindly for IUN; 81
specimens from 53
patients; overlaps with
Isfoss et al, 2011a
interobserver variation in
histopathologic diagnosis of
carcinoma in situ (CIS) and
dysplasia (collectively
intraurothelial neoplasia, IUN);
excluded samples without
follow-up, uncertain stage of
PUN, no evaluable flat mucosa,
used WHO 2004 scheme
classification: dysplasia, CIS, AUS (atypia of
unknown significance), no IUN (PUN)
PUN (IUN, dysplasia +CIS) → other
PUN → CIS
PUN → dysplasia
81
75
59
61
45
15
41
39
Bladder - Urine Samples
Raitanen (11) 2002 1 575 cytopathologist multicenter study;
consecutive samples read
by local pathologist (19
institutions) then sent for
central review, 1997-99.
Classed as negative or
positive (Papanicolaou
classes I-III or IV-V),
graded by WHO 1973
system, staged by TNM
1978
patients newly diagnosed or
during follow-up with
histologically confirmed
transitional cell carcinoma of
the urinary bladder and high
quality urine samples; local and
review cytology detected 39
and 31% of primary cancers,
both detected 18% of cases
during follow-up
pts with primary bladder cancer, overall
(-ve/+ve)
stage - superficial (Ta, T1)
stage - invasive
grade - grade 1
grade - grade 2-3
pts under follow-up, overall (-ve/+ve)
recurrence - yes
recurrence - no
129
100
29
44
84
446
119
327
14
13
17
9
17
5
10
3
86
87
83
91
83
95
90
97
0.70
0.68
0.65
0.45
0.67
0.60
0.65
0.40
Ajit (12) 2010 1 652 unknown cases from 2000-2004 at
Tata Memorial Hospital
(India) were reviewed
retrospectively
urine specimens from patients
with suspected primary bladder
cancer, final diagnosis by
histology then all cases critically
reviewed
overall
negative → urothelial carcinoma
negative → inadequate sample
652
238
238
22
7.6
51
78
92
49
Kidney
Lohse (13) 2002 1 2042 urologic
pathologist
review of renal cell
carcinoma (RCC) originally
diagnosed at the Mayo
Clinic and treated with
radical nephrectomy
1970-98
modified Fuhrman grade, 4-
tiered grading system based on
nuclear atypia
nuclear grade of clear cell RCC
upgraded
downgraded
nuclear grade of papillary RCC
upgraded
downgraded
nuclear grade of chromophobe RCC
upgraded
downgraded
1733
222
87
44
35
8
51
44
7
45
38
7
56
49
55
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22-2-3 Genitourinary Cancer Evidence Summary Page 6
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Ficarra (14) 2004 1 388 uropathologist
with
experience
with RCC
retrospective slide review
of renal cell carcinoma
cases at University of
Verona, Italy, 1986-2000
to determine
reproducibility of
Fuhrman nuclear grade
pathology slides from all
patients who had undergone
surgical treatment for
conventional renal cell
carcinoma (RCC)
overall
grade 1
grade 2
grade 3
grade 4
388
111
141
108
28
40
60
40
27
11
60
40
60
73
89
0.44
Huang (15) 2006 1 39 pathologist central pathology review
of samples from the
National Wilms Tumor
Study -5 (NWTS-5) , 1995-
2002
specimens diagnosed as clear
cell sarcoma of the kidney
(CCSK), rhabdoid tumor of the
kidney (RTK), cellular
mesoblastic nephroma (CMN)
overall 33 18 82
Vujanic (16) 2009 1 various
trials
pathologist central pathology review
(CPR) in International
Pediatric Oncology Society
(SIOP) trials and United
Kingdom Wilms Tumour 3
(UKWT3) trial; 1980-2007;
retrospective analysis of
discrepancies
material from renal tumor trials
in children; reported diagnostic
differences excluding purely
stage discrepancies; major =
clinically significant discrepancy
or inappropriate treatment
SIOP 6 (1980-87), stages I-III
SIOP UK 2001 trial (2001-), except stage
stage
rapid CPR ( ≤ 14 days from
nephrectomy), diagnosis or stage
delayed CPR
SIOP 9 trial (1987-91), except stage
SIOP 93 01 (1993-2001), except stage
stage
UKWT3 trial (1991-2001), except stage
stage
834
400
400
248
152
487
1424
1424
783
783
9.0
6.0
9.5
13
20
17
14
14
3.5
17
13
20
91
94
91
87
80
83
86
86
97
83
Penis
Gunia (17) 2013 2 147 pathologists grading using Broder’s
grading system (BGS);
reviewed selected
representative slides from
each case
consecutive patients with
surgically treated penile
squamous cell carcinomas,
reviewed conventionally
stained histology slides
grade, Pathologist A
grade, Pathologist B
147
147
12
31
88
69
0.692
0.495
Malhotra (18) 2009 2 10 pathologists retrospective chart review
and review of slides of
penile cancer cases 1988-
2004, to confirm diagnosis
and stage (AJCC TNM
staging system)
patients diagnosed with stage 1
penile squamous cell carcinoma
(SSC). Patients underwent
partial or total penectomy with
local control of disease and no
evidence of local recurrence
overall, well or moderately differentiated 10 20 80
Naumann (19) 2009 2 75 experienced
pathologist and
3rd year
resident in
general
pathology
retrospective review:
comparison of local and
review pathologists'
diagnoses, 1996-2005;
histological reassessment
according to TNM and
WHO classifications of
grade and stage
patients with squamous cell
carcinoma of the penis,
tumour-free surgical margins,
original histopathology used
current TNM guidelines
grade and stage
grade overall
grade 1
grade 2
grade 3
stage overall
stage T1
stage T2
73
73
15
41
17
75
39
28
44
33
27
34
35
16
21
11
56
67
73
66
65
84
79
89
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22-2-3 Genitourinary Cancer Evidence Summary Page 7
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Testes
Lee (20) 1999 1 206 histo-
pathologists?
central review prior to
management decisions at
the regional referral
centre (Southampton
University Hospital, UK),
1992-97; retrospective
review of reports
all testicular specimens for
suspected tumour (five
biopsies, 201 orchidectomies);
recommend central review due
to low incidence
tumour type
tumour elements in NSGCTs
vascular invasion in NSGCTs
vascular invasion in NSGCTs, excluding
cases with no comment
206
109
109
59
43
55
20
6
57
45
80
Delaney (21) 2005 1 291 specialist
urological
histo-
pathologist
central review prior to
management decisions at
the regional referral
centre (Southampton
University Hospital, UK),
1998-2002; retrospective
review of reports
291 testicular specimens (280
orchidectomies, 11 biopsies)
from 15 local hospitals ;
recommend central
histopathologic review
overall tumour type
classical seminoma
pure NSGCT
combined seminoma and NSGCT
presence of intratubular germ cell
neoplasia , IGCN
tumour elements in NSGCTs
vascular invasion in NSGCT
291
164
72
50
291
126
126
3.8
4.3
0
2.0
17
41
10
4 96
96
100
98
83
59
90
Albers (22) 2008 1 382 reference
pathologist for
clinical trial
Review by reference
pathologist to confirm
eligibility for clinical trial
histologically confirmed
nonseminomatous testicular
germ cell tumors (NSGCT) after
orchidectomy as reported by
the local pathologist
NSGCT → seminoma 382 1.8 98
Swaro (23) 2007 2 63 histo-
pathologists
with special
interest in
urological
pathology
central review at
University Hospital
Birmingham, UK before
treatment 2004-2005;
retrospective audit of
reports for discrepancy
and completeness
patients with testicular
tumours
tumour type
components of NSGCT
lymphovascular and cord invasion
≈ 57
≈54
7
48
9
7 93
52
91
Prostate – Prostatectomy Specimens (see also Biopsy Specimens)
Netto (24) 2011 1 257 urologic
pathologist
blind central review at
Johns Hopkins Hospital
for clinical trial (TAX
3501), Gleason score by
WHO/ISUP 2005 criteria
radical prostatectomy patients
with high-risk prostate cancer
(predicted 5 year PFS of <=60%)
Gleason score
Upgraded (mostly 7→8/9, 13% of all
samples)
Downgraded (mostly 8→7, 4% of all
samples)
change by 2 Gleason score points
257
257
257
257
30
22
7
11
70
tumour extent (70/256 upstaged, 7/256
down-staged)
seminal vesicle invasion
margin status (+ve ↔ -ve)
lymph node status
change in progression free survival
estimate
256
256
256
210
257
30
7
11
1
13
70
93
89
99
87
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22-2-3 Genitourinary Cancer Evidence Summary Page 8
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Goodman (25) 2012 2 (3 if
disagree)
388 urologic
pathologists
stratified random sample
of prostate cancer cases;
reviewed digital images;
gold standard was that
agreed by 2 second
review pathologists;
second review scored
using 2005 ISUP system
(initial review by 2005
system only in some
facilities), did not assess
tertiary patterns
120 prostatectomies , report
original pathology vs. final (gold
standard consensus)
Gleason Pattern & Score: prostatectomy
under-grading
over-grading
pattern
score
GS 2-6 → other
GS 2-6 → 7
GS 7 → other
GS 7 → 8-10
GS 8-10 → other
GS 8-10→ 7
120
120
120
120
65
43
12
36
12
48
40
43
43
21
7
67
58
52
60
57
79
33
0.37
0.38
Kuroiwa (26) 2010 1 2015 uropathologist
retrospective central
review of RP specimens in
Clinicopathological
Research Group for
Localized Prostate Cancer
disease registry, Japan (50
institutions) , 1997-2005;
central review GS
assigned according to the
2005 ISUP consensus [GS
scoring system revised
between original and
review diagnosis]
RP specimens from patients
with cT1c-3 prostate cancer
and no preoperative therapy
Gleason score
Gleason pattern
overgrading
undergrading
diagnosis 1997-2003
diagnosis 2004-2005
GS 2-6→ other
GS 2-6 → 7
GS 7 → other
GS 7→ 8-10
GS 8-10 → other
GS 8-10 → 7
extracapsular extension
seminal vesicle invasion
lymph node involvement
positive surgical margin
1774
1774
981
793
634
864
276
1630
1639
1914
1579
34
45
19
26
52
37
45
43
16
3.7
53
52
18
2.4
0.4
13
66
55
48
63
55
84
47
82
98
100
87
0.59
0.82
0.93
0.73
Stark (27) 2009 3 816 pathologists;
reviewed
independently,
reviewed until
consensus
retrospective
standardized review ≈
2008, blinded to original
pathology report and
clinical data, of patients
in the Physicians' Health
Study and the Health
Professionals Follow-Up
Study, 1984-2004
prostatectomy (n=693) and
biopsy (n=119) specimens of
patients diagnosed with
prostate cancer
misdiagnosis (not prostate cancer)
Gleason pattern, prostatectomy
1985-1988
1994-97
2001-2004
Gleason score, prostatectomy
GS 2-6 → other
GS 2-6 → 7
GS 7 → other
GS 7→ 8-10
GS 8-10 → other
GS 8-10 → 7
816
693
693
392
226
75
0.5
71
63
56
52
32
18
47
44
99
29
37
44
68
53
0.23
0.33
0.44
Chuang (28) 2008 1 186 ? second opinion after sign-
out, The Johns Hopkins
Hospital, 1993-2004
RP specimens with areas of
capsular incision (CI) in
otherwise organ-confined
disease
margin positive, CI
margin positive, difficult to distinguish CI
from EPE
143
36
17
47
83
53
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 9
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
van der Kwast
(29)
2006 1 552 pathologist
with
experience in
urogenital
pathology
central review of
pathological stage and
surgical margin status in
EORTC 22911 trial,
1992-2001
RP specimens; pathological
stage pT3 and/or positive
surgical margin at local
pathology
seminal vesicle invasion
positive
negative
extraprostatic extension
positive
negative
surgical margin status
positive
negative
543
123
420
547
429
118
524
315
209
6.7
21
1.2
32
35
19
27
26
29
94
79
99
68
65
81
73
74
71
0.83
0.33
0.45
Berney (30) 2007 1-3 1791 review by 3
genitourinary
pathologists for
first 100 cases,
1 pathologist
for rest except
contentious or
negative cases
(≈ 10%)
central retrospective
review of pathological
specimens from patients
in UK from 6 cancer
registries; 1990-96
patients diagnosed with
clinically localized prostatic
cancer and treated by watchful
waiting or hormonal therapy,
age < 76 at time of pathological
diagnosis and with baseline PSA
measurement; IHC rarely used
in this time period, and not in
any of the misdiagnosed cases
cases reassigned to non-malignant diagnosis
Needle biopsy
TURP specimens
1791
≈895
≈895
7.4
3.0
12
93
97
88
Berney (31)
2007 1-3 1656 genitourinary
pathologists; 3
pathologists for
first 100 cases
and 10% of
rest (difficult
cases)
retrospective central
review of original
diagnostic pathological
specimens within a
multicenter study of
watchful-waiting vs.
hormonal therapy in UK,
1990-96
men <76 years old at time of
pathological diagnosis with
clinically localized prostatic
cancer;
subset with GS included in
both reports (454 diagnosed by
TURP, 347 by needle biopsy)
cancer (discrepancy = cancer not
confirmed), biopsy or TURP samples
GS, overall, TURP
GS 2-6 → other
GS 2-6 → 7
GS 7 → other
GS 7→ 8-10
GS 8-10 → other
GS 8-10 → 7
discrepancy = GS changed by ≥ 2, TURP
1656
454
371
37
46
454
8
91
37
25
73
62
26
24
71
92
9
63
27
74
29
Prostate - Biopsy Specimens
Initial Biopsies, Including Benign, Suspected, Atypical, and/or Precancerous samples
Arista-Nasr
(32)
2006 2 100 pathologists,
consensus of 2
pathologists
(20 yr and 3 yr
experience)
detailed revision of
prostate biopsies with
original benign diagnosis,
2000-2001
one hundred consecutive
patients with first prostate
biopsy diagnosed as benign
overall; benign → potentially malignant
( 5 cases of ASAP, 3 cases with glands with
xanthomatous cytoplasm, 1 with scarce
atypical cells in prostatic stroma)
100 9 91
Patel (33) 2008 1 87 cases senior surgical
pathologist
review of prior negative
prostatic needle biopsies
following a new diagnosis
of prostatic
adenocarcinoma
prostatic core needle biopsies
diagnosed as PIN (n=23), small
acinar proliferation suspicious
for carcinoma (n-=21) or no
evidence of carcinoma (n=43)
but patients later diagnosed
with adenocarcinoma
initially negative samples →
adenocarcinoma (both cases Gleason 3+3)
87 2.3 98
Wolters (34) 2010 2 196 urologic
pathologists
discordant biopsies in
European Randomized
Study of Screening for
Prostate Cancer (ERSPC),
1993-2008; biopsies if
PSA level ≥ 4.0 ng/mL or
review of initial prostate needle
biopsy set for patients in
a screening trial with a benign
initial diagnosis and diagnosis of
adenocarcinoma in a
subsequent screening round;
benign (adenocarcinoma on follow-up)
benign → ASAP
benign → adenocarcinoma
All missed cancers were Gleason score 6
(3+3)
196 18
10
8
82
90
92
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 10
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
abnormal digital rectal
examination or transrectal
ultrasound (TRUS) [biopsy
only if PSA ≥ 3.0 ng/mL in
last year of study].
authors extrapolated a false-
negative rate for the entire
study of 2.4% (1.1% cancer,
1.3% ASAP)
Bostwick (35) 2007 2 251 consensus of 2
urological
pathologists
prospectively evaluated
all "2nd opinion" prostate
biopsies referred to them
March-April 2006
consecutive patients who were
diagnosed and finalized by
outside referring pathologist as
having high grade PIN (high
grade PIN, PIN2, PIN3, PIN2-3)
high grade PIN → refuted (false positive)
[most common findings in false positive
specimens were basal cell hyperplasia,
benign epithelium, low-grade PIN, reactive
changes, cribriform hyperplasia, atrophy,
post-atrophic hyperplasia]
251 24 76
Marshall (36)
Marshall (81)
(study details)
2011
2006
1 448 central
pathology
review
central pathology review
of patients with HGPIN in
prostate cancer
prevention trial, SWOG
(Southwest Oncology
Group) S9917, 2000-2006
biopsy-confirmed diagnosis of
HGPIN with no evidence of
cancer, PSA >=10 ng/mL
HGPIN not confirmed
HGPIN → cancer
HGPIN → no HGPIN
448
1.6
1.3
0.2
98
Oxley (37) 2011 1 4192 pathologist
with special
interest in
uropathology
initial report by 15
histopathologists
(including 2 with interest
in uropathology and
deemed specialists who
also did the reviews),
years 2002-2008 (includes
samples from Oxley, 2005)
all prostatic core biopsies, were
classified as benign, atypical not
amounting to HGPIN, HGPIN,
suspicious for malignancy,
prostatic adenocarcinoma
all samples, change in any category
false negative: benign, atypical not HGPIN,
or HGPIN that were changed to suspicious
or adenocarcinoma
excluding initial report by specialist
false-positive: adenocarcinoma changed
to other category
excluding initial report by specialist
benign
to atypia
to HGPIN
to suspicious
to cancer
atypia
to HGPIN
to suspicious
HGPIN
to benign
to suspicious
to cancer
suspicious
to cancer
cancer
to benign
to HGPIN
to suspicious
4192
2367
1299
1680
907
1790
58
484
135
1703
3.5
1.7
2.7
0.5
1.0
6.5
0.4
4.2
0.7
1.2
10
8.6
1.7
1.9
0.6
0.2
1.0
3.7
3.7
0.5
0.3
0.1
0.2
96
98
97
99
99
93
90
98
96
99
Oxley (38) 2005 1 658,
from 595
patients
pathologist
with special
interest in
uropathology
central review of cores
reported by 8 general
histopathologists, year
2002 only
all prostatic core biopsies
originally report as benign (negative)
benign changed to contain tumour
benign changed to suspicious, HGPIN,
atypia
initially reported as prostate cancer
false positive (change to benign)
increase in Gleason score
331
260
4
0.6
3
10
0
5
94
90
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 11
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Jara-Lazaro
(39)
2010 1 326
pathologist
with
uropathology
interest
queries submitted for a
second opinion, 73% from
clinicians and 27% from
pathologists.
89% core biopsy, 8.2%
TURP, 2.5% radical
prostatectomy
comparison of original
diagnosis (benign, atypical,
HGPIN, adenocarcinoma) and
Gleason score with review
diagnosis for prostate
consultations; major = clinically
significant change in
management approach (benign
↔ malignant, malignant →
HGPIN)
overall (diagnosis and GS)
upgraded on 2nd
review
diagnosis (category)
benign
to HGPIN
to atypical
to cancer (Gleason 3+3)
atypical or HGPIN
atypical
to benign
to HGPIN
to Gleason 3+3
to Gleason 3+4
HGPIN
to benign
acinar adenocarcinoma
to benign
to HGPIN
to other Gleason score
GS 2-6
GS 2-6 → 7
GS 7
GS 7 → 8-9
GS 8-9 → 7
326
326
326
54
20
11
9
245
165
47
33
56
40
12
17
9
2
6
80
91
55
9
18
9
67
67
64
4
2
58
73
43
55
34
33
7
7
44
88
83
20
9
33
36
27
45
67
Helpap (40) 2005 1 106 uropathologist comparison of submitting
diagnosis and final
diagnosis, Germany, 2003
prostate punch biopsies: small
suggestion lesions
overall
cancer changed to suspected/atypical
suspected/typical changed to cancer
inconspicuous/non-diagnostic to
suspected/atypical
1041
407
419
215
40
3
62
70
60
97
38
30
Chan (41) 2005 1 684 urological
pathologist
second opinion requested
by patients (n=148) and
urologists (n=437) or both
(n=99), Johns Hopkins
Hospital, year 2001
prostate needle biopsies.
Major = significant =potentially
results in a change in therapy or
prognosis (change in category
except atypia↔ HGPIN;
change in GS ≤ 4 ↔ 6+, 5/6 ↔
7+, 7 ↔ 8+ )
overall
change in category (benign, atypia,
HGPIN, cancer)
cancer to other
to benign
to atypia
HGPIN to other
atypia to other
HGPIN/atypia to other
to benign
to cancer
benign to other
to cancer
to HGPIN
cancer, change in GS or category
change in GS
684
684
386
52
204
256
42
386
386
26
7
2
5
25
63
55
14
37
17
7
10
26
35
24
7
2
5
13
61
52
14
37
17
7
10
26
19
74
93
75
37
45
83
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 12
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Cases Diagnosed as Prostate Cancer, most include Gleason Score
Berg (42) 2011 1 350 uropathologist re-evaluation of all
patients referred for
curative treatment of
prostate cancer at a
tertiary referral hospital
(Copenhagen University
Hospital Rigshospitalet)
2007-2008, used 2005
WHO/ISUP system
prostate core needle biopsies,
Gleason score grouped into not
evaluable, <= 5, 6, 7, and 8-10
diagnosis of prostate cancer
tumour laterality
apical involvement
Gleason score
not evaluable/not assigned
6
6 → 7
6→8-10
7
7 → 6
7→ 8-10
8-10 (all 8-10 → 7)
change in clinical evaluation (tests) due to
review
change in surgical planning due to review
350
350
350
350
51
118
135
39
350
160
0
7
8
23
29
36
30
2
9
2
6
10
20
13
100
93
92
77
71
64
91
90
80
87
0.67
Brimo (43) 2010 1 855 general surgical
pathologists
with extensive
experience
with prostate
pathology;
consulted with
1-2 urologic
pathology
experts for
discrepancies
mandatory second
opinion review of cases
referred for RP in 2008 at
Johns Hopkins Hospital;
GS assigned according to
the 2005 ISUP consensus
prostate needle biopsy surgical
pathology reports for patients
with prostate cancer referred
for RP; major GS discrepancy=
change impacting treatment by
placing the patient in a
different risk category (6, 7, 8-
10)
cancer → to atypical or benign
GS, overall
GS 6 ( all 6 → 7)
GS 7
GS 7→ 6
GS 7 → 8-10
GS 8-10
GS 8-10 → 6
GS 8-10 → 7
855
844
512
269
63
1.3
15
7
24
16
8
36
3
33
1.3
15
7
24
36
99
85
93
76
64
Truesdale (44) 2011 1 331
biopsies,
100 patients
GU pathologist re-evaluation of outside
needle core biopsy
diagnosis prior to surgery,
2005-2009, used 2005
ISUP system
men with positive core needle
biopsies who underwent
robotic-assisted radical
prostatectomy; 331 cores in
100 patients
Gleason score in biopsies
primary grade
secondary grade
% core involvement
331
331
331
331
33
8
28
7
67
92
72
93
0.55
0.77
0.44
Al-Hussain (45)
[may include
cases reported
in Fajardo
Fajardo (46)]
2012 1 300 leader in the
field of
urological
pathology
consultation files at The
Johns Hopkins Hospital
from 2009-2010; only
cases with final diagnosis
by original pathologist,
most requested by patient
or treating physician
prostate biopsy cases in which
Gleason pattern 5 was
identified on review
Gleason pattern 5 not identified
original Gleason score increased
original score decreased
GS ≤ 7 → GS 8-10
300
49
68
1
20
Fajardo (46) 2011 1 59 leader in the
field of
urological
pathology
2nd opinion at Johns
Hopkins Hospital at the
behest of clinicians or
patients; ISUP 2005
system
consecutive needle biopsy
cases scored as Gleason pattern
5 on review; 59 cases
comprising 138 parts;
considered the highest Gleason
score in a multicore specimen
as the overall Gleason score
Gleason score, discrepancy of original
compared to review (reverse of most of
the data in this table), pattern 5 missed by
initial pathologist
original Gleason score increased
original score decreased
Gleason pattern 5 not identified
59
138
138
138
58
73
4
49
42
27
96
51
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 13
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Goodman (25) 2012 2 (3 if
disagree)
388 urologic
pathologists
stratified random sample
of prostate cancer cases;
reviewed digital images;
gold standard was that
agreed by 2 second
review pathologists;
second review scored
using 2005 ISUP system
(initial review by 2005
system only in some
faciliites), did not assess
tertiary patterns
268 biopsies, report original
pathology vs. final (gold
standard consensus)
Gleason Pattern & Score: biopsy
pattern
score
2-6 (all except 1 case → 7 )
7
7→ 8-10 (rest go to 2-6)
8-10 (all → 7 )
undergrading
overgrading
264
264
139
80
45
44
35
37
18
11
29
31
13
56
65
63
83
89
71
0.61
0.60
Kuroiwa (47) 2011 2 1629 Uropathologist
Note: GS
scoring system
revised
between
original and
review
diagnosis
retrospective central
review of prostate biopsy
specimens in
Clinicopathological
Research Group for
Localized Prostate Cancer,
disease registry, Japan (48
institutions), 1997-2005;
second review GS
assigned according to the
2005 ISUP consensus
biopsy specimens from patients
with Stage cT1c-T3 disease and
no preoperative therapy that
underwent RP
biopsy, pattern, overall (5 groups)
score (2-4, 5-6, 7, 8-10)
GS 2-6
GS 2-6 → 7 (rest go to 8-10)
GS 7
GS 3+4=7
GS 4+3=7
GS 7→ 8-10 (rest go to 2-6)
GS 8-10
GS 8-10 → 7 (rest go to 2-6)
1629
1629
794
794
571
379
192
571
264
264
48
41
43
41
25
41
56
11
45
40
52
59
57
59
75
59
44
89
55
60
Kishimoto (48) 2012 1 247 pathologist
with
genitourinary
expertise
change in NCCN
classification that would
make a difference to
therapy (PPB indicated for
classification as good or
intermediate risk
excluding GS 4+3); 2005-
2010
Biopsies from patients referred
by outside hospitals to a
permanent prostate
brachytherapy (PPB) institute
for treatment of prostate
cancer
pathologic discrepancy on slides
change to no malignancy or atypical
Gleason grade change
upgrade
downgrade
treatment change based on pathology
slide review
247
247
41
2.4
38
31
6.9
12
59
Grubb (49) 2013 1 24 pathologist Central pathology review
in follow-up after clinical
trial, Gleason scoring
system unknown for local
pathologists, classic
(1966) system for review
biopsy if prostate cancer
suspected (130/216 cases due
to rising PSA levels), only
central review of positive
samples
diagnosis of prostate cancer →other (2
atypical small acinar proliferation, 1 no
cancer)
24 12 88
Wayment (4) 2011 2 117 urologist +
pathologist; 3rd
(or 4th)
pathologist if
disagreement
retrospective review of
records: practice at
tertiary referral centre to
request pathologic
materials for all patients
seen in consultation for
urologic malignancy;
2002-2008
all patients seen in consultation
for urologic malignancy; major
= significant change in
prognosis or treatment (e.g.,
Gleason grade resulting in
change in risk stratification,
presence ↔ absence of
cancer) ; minor=no change in
prognosis or treatment options
overall disagreements
( risk stratification: 6 cases intermediate →
high, 1 case low →high, 3 cases high→
intermediate, 1 case ASAP→ glandular
atrophy, 1 case high→ high)
117 10 8.5 1.7 90
D'Souza (50) 2012 151 genitourinary
pathologists
central review of all
specimens from patients
referred to Sunnybrook
Health Sciences Centre in
prostate needle-core biopsies;
classified as low (GS 2-6),
intermediate (GS 7), or high (GS
8-10 risk category
change in risk category
GS 2-6
GS 2-6 → 7
GS 2-6 → 8-10
151
98
28
33
28
5
72
67
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 14
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
2003; extracted primary
and secondary Gleason
score, number of sites, %
involvement, perineural
invasion, extracapsular
extension from original
and 2nd review reports
GS 7 (all 7 → 8-10)
GS 8-10
GS 8-10 → 2-6
GS 8-10 → 7
missing elements in external reports
primary Gleason score
secondary Gleason score
number of biopsy sites
overall % involvement
perineural involvement
extracapsular extension
24
29
13
24
3
21
0
1
21
18
19
23
87
76
Barqawi (51) 2011 1 100 urologic
pathologist
review of all needle core
biopsies (NCB) diagnosed
by outside pathologists in
patients referred to 2nd
institution for
management, 2001-2003
patients with original "outside"
NCB evaluation, 2nd "in-house"
evaluation and diagnosis of
prostatectomy specimen;
excludes samples sent for
second opinion
Gleason scores
1st pathologist compared to
prostatectomy
2nd pathologist compared to
prostatectomy
100
100
100
12
59
48
88
41
52
Sooriakumaran
(52)
2005 1 83 pathologist
with special
interest in
prostate cancer
routine specialist review
of all diagnostic biopsies;
retrospective review of
records from 19 month
period with complete
pathology datasets
biopsies of all patients with
prostate cancer referred for
brachytherapy; major =change
in Gleason rating that altered
clinical risk (Seattle Risk
Grouping, SRG)
Gleason score, overall
GS 2-5
GS 2-5 → 6
GS 2-5 → 7
GS 6
GS 6 → 5
GS 6 → 7
GS 7 (all 7 → 8-9)
GS 8-9
83
28
43
9
3
48
79
54
25
26
5
21
22
67
19 52
21
74
78
33
0.27
Fine (53) 2008 1 1455 pathologists retrospective review of
reports: outside
institution Gleason score
of needle biopsies
compared to review at
Johns Hopkins Hospital,
2002-2003
patients with prostate cancer;
reports available for outside
and Johns Hopkins needle
biopsy and radical
prostatectomy samples
Gleason score, needle biopsy
GS 2-4 (n=22 →5/6, n=1→7)
GS 5-6
GS 5-6 →7
GS 5-6 → 8-10
GS 7
GS 7 → 5-6
GS 7 → 8-10
GS 8-10
GS 8-10 →5-6
GS 8-10 → 7
1455
23
1057
343
32
18
100
8
7.4
0.6
40
35
5
59
6
53
82
0
92
60
41
van der Kwast
(54)
2003 1
2
1500
450
pathologist
pathologist
second review of prostate
needle biopsies, to end of
2002
cases diagnosed as
adenocarcinoma on needle
biopsies from participants to
screening programme with
elevated PSA
false positive, centre 1
false positive, centre 2
≈1500
450
0.3
0.2
99
99
Coard (55) 2004 1 90 pathologist retrospective review of all
prostate biopsy specimens
diagnosed as
adenocarcinoma at
University Hospital of the
West Indies, year 2000
interobserver comparison of
Gleason scores in prostate
needle biopsy specimens
diagnosed as adenocarcinoma
overall
6
6→ 7
6 → 8-10
7
7 → 6
7→ 8-10
8-10
90
34
28
28
40
44
35
9
36
7
29
14
60
56
64
86
ES 22-2-3
22-2-3 Genitourinary Cancer Evidence Summary Page 15
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
8-10 →6
8-10 → 7
within one grade
< 7
≥ 7
overall, grouped as < 7 or ≥ 7
90
34
56
90
4
11
6
44
5
20
94
56
95
80
0.54
Thomas (56) 2007 1 1323 genitourinary
pathologists
mandatory pathology
review of all patients
being considered for
brachytherapy at British
Columbia Cancer Centre,
1998-2005; data analyzed
retrospectively for before
and after 2002
biopsy specimens from all
patients who underwent
prostate brachytherapy with
central pathology review prior
to treatment; major =treatment
change = change from low risk
(GS ≤ 6, requires
brachytherapy alone) to
intermediate risk (GS7, adds
androgen deprivation). GS 8+
or upgraded to 8+ were
excluded as they are not
considered for brachytherapy
overall, Gleason score
discrepancy = GS changed by ≥ 2
1998-2001
discrepancy = GS changed by ≥ 2
2002-2005
discrepancy = GS changed by ≥ 2
GS 3-5
GS 3-5 → 6
GS 3-5 → 7
GS 6
GS 6 → 5
GS 6→ 7
GS 7 (all GS 7 → 6)
1323
1323
542
542
781
781
175
883
245
25
5
32
9
21
2
75
63
11
17
1
16
8
15
13
16
75
95
68
91
79
98
25
83
92
Nguyen (57) 2004 3 602 genitourinary
pathologist
second opinion at
academic centre after
being diagnosed with
prostate cancer based on
a needle biopsy at a non-
academic institution,
1989-2001; retrospective
review of records
patients who presented to a
genitourinary oncologist for a
second opinion. 648 reviews of
602 patients. Major = change
in treatment recommendation,
corresponding to change in risk
group from low to
intermediate/ high or vice versa
discrepancy = GS changed by ≥ 1
discrepancy = GS changed by ≥ 2
change in risk group (low, intermediate,
high)
GS 2-5
GS 2-5→ 6
GS 2-5→7
GS 2-5→ 8-10
GS 6
GS 6 → 2-5
GS 6 → 7
GS 6 → 8-10
GS 7
GS 7 → 6
GS 7 → 8-10
GS 8-10
GS 8-10 → 6
GS 8-10 → 7
648
648
648
105
257
198
88
44
11
14
94
69
25
1
38
2
35
2
15
5
10
33
1
32
9.1
56
89
6
62
85
67
Renshaw (58) 2003 1 416 urologic
pathologist
comparison of original GS
and reviewer's score,
1987-2000
prostate biopsies from men
treated at a single community-
based institution; major=
different prognostic group
GS, overall
GS, years 1987-1996
GS, years 1996-2000
416
187
229
41
49
34
≈ 20 59
51
66
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22-2-3 Genitourinary Cancer Evidence Summary Page 16
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Wurzer (59) 1998 1 538 pathologist:
specialist in
prostate
pathology
interinstitutional: all
samples from outside
institutions are reviewed
at Fox Chase Cancer
Center to confirm
diagnosis of malignancy,
1993-96. Retrospective
review of these records
prostate biopsies diagnosed as
adenocarcinoma at outside
pathology departments in
patients being evaluated for
radiation therapy; major =
treatment modification based
on Gleason score and/or
presence of PNI
overall, based mainly on Gleason score
GS change ≥ 2
538
39
13
5
61
Epstein (60) 1996 1 535 general surgical
pathologist, 3rd
surgical
pathologist if
discordant
interinstitutional:
mandatory second
pathological review of
needle biopsies prior to
surgery at Johns Hopkins
Hospital, 1993-94
consecutive men referred for
RP with initial diagnosis of
adenocarcinoma of the
prostate
overall (diagnosis went from
adenocarcinoma to benign)
535 1.3 1.1 99
Steinberg (61) 1997 1 390 pathologists comparison of outside
institution and Johns
Hopkins Hospital biopsy
grade, 1994
original needle biopsy GS in
patients with biopsy-proven
prostatic adenocarcinoma and
RP
GS overall
GS 2-6
GS 2-6 → 7
GS 2-6 → 8-10
GS 7
GS 7 → 2-6
GS 7 → 8-10
GS 8-10
GS 8-10 → 2-6
GS 8-10 → 7
390
307
70
13
38
17
16
1
30
24
6
62
31
31
62
83
70
38
Berney (31)
2007 1-3 1656 genitourinary
pathologists; 3
pathologists for
first 100 cases
and 10% of
rest (difficult
cases)
retrospective central
review of original
diagnostic pathological
specimens within a
multicenter study of
watchful-waiting vs.
hormonal therapy in UK,
1990-1996
men <76 years old at time of
pathological diagnosis with
clinically localized prostatic
cancer;
subset with GS included in
both reports (454 diagnosed by
TURP, 347 by needle biopsy)
cancer (discrepancy = cancer not
confirmed), biopsy or TURP samples
GS, overall, biopsy
GS 2-6
GS 2-6 → 7
GS 7
GS 7 → 8-10
GS 8-10
GS 8-10 → 7
discrepancy = GS changed by ≥ 2, biopsy
1656
34
263
263
49
49
36
36
347
8
86
58
39
57
37
33
31
58
92
14
63
75
27
38
74
76
42
Winter (62)
Pilepich (63)
1997
1997
1 977 pathologist central pathology review
of patients with prostate
cancer in clinical trial
(RTOG 85-31) , 1987-1992;
discrepancy data in
abstract only
Patients with prostate cancer,
grouped as Gleason score 2-5,
6-7, or 8-10; numbers in each
group estimated based on
proportion in 2nd review in
other publication; 15% of
patients had prostatectomy
Gleason score
GS 2-5
GS 6-7
GS 8-10
760
115
405
240
64
30
27
36
70
73
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22-2-3 Genitourinary Cancer Evidence Summary Page 17
Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
# Specimens of Subtype
Discrepancy, % Agreement
All Major Minor % Kappa
Studies that reported on genitourinary and other cancers, specific types not indicated
Prescott (64) 1995 1 21 review at regional cancer
treatment centre
cases with confident 1st
diagnosis, excluded cases
where 2nd opinion sought
testis 21 29 0 29 71
Kronz (65) 1999 1 2167 mandatory 2nd opinion;
all cases referred to
treating institution,
excludes consult cases
with uncertain diagnosis
major modification in therapy
or prognosis, does not include
change only in histologic grade
or stage; limited number of
cases as most were seen by the
dermatology department
genitourinary system (prostate, bladder) 2167 1.2 99
Murphy (66) 2001 1 150 pathologist
with expertise
in urological
pathology
consecutive urological cases
with pathological specimens;
discrepancies with clinical
impact on prognosis or
treatment; major = impact on
treatment
all: prostate, bladder, urethra, testis, kidney,
penis
prostate
bladder, urethra
150
97
47
19
18
21
9
7
13
81
82
79
Weir (67) 2003 1 118 interinstitutional, at
request of clinical staff of
treating institution
compared 1st and treating
institution reports; major
=clinical impact
genitourinary (histological samples) 118 9 5 4 91
Ahmed (68) 2004 1 13 2nd opinion at major
referral centre
reviewed at Aga Khan
University, Pakistan; most sent
by clinicians, some by primary
pathologists
male genital tract 13 38 62
Tsung (69) 2004 1 29 pathologists patients referred to
cancer center for therapy
or second opinion
all cases referred to treating
institution; major discrepancies
(benign to malignant or vice
versa), different type of
neoplasm, change in N or M of
TMN classification
prostate
kidney and bladder
10
19
10
5
90
95
Raab (70) 2005 1 591 pathologist review after sign-out conferences, external review,
internal QA, physician request;
self-report of 100 consecutive
specimens at 74 institutions;
major=harm or near miss
genital, male
urinary tract
kidney
355
181
55
7
7
5
2
3
2
93
93
95
Renshaw (71) 2006 1 41 Internal blinded review;
1/6 of cases from new
pathologists, rest random
major error leads to
amendment, minor error
requires no action
all discrepancies 41 0 0 0 100
Lu (72) 2009 1 141 external consultation kidney and bladder
prostate
penis
95
34
12
5
3
8
Abbreviations: GS=Gleason score; ATYP=atypical; PIN=prostatic intraepithelial neoplasia ; HGPIN=high-grade prostatic intraepithelial neoplasia; CI=capsular incision; EPE=extra-prostatic extension; PC=prostate cancer; RP=radical prostatectomy; PSA=prostate specific antigen; ASAP=atypical small acinar proliferation; NSGT= nonseminomatous germ cell tumours; TURP=transurethral resection of the prostate.
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Studies from Literature Search (Table 1) Most of the included studies did not indicate the clinical significance of the
discrepancies reported. The authors of this review relied mostly on studies with stated clinical significance (changes in management) or where this significance could be determined based on the description of the type of changes in diagnosis. A. Bladder Cancer
Three studies (2-4) in Table 1 reported major (significant or clinically relevant) discrepancy rates of 8%, 18%, and 25% for bladder cancers, with 15% to 16% discrepancy due to changes in stage (2,3).
In studies of Ta/T1 cancers, overall discrepancy rates of 18% to 36% for stage (5-7) and 42% to 43% for grade (5,6) were reported. While these studies did not report clinical relevance, changes between lamina propria invasion (T1) and detrusor muscle invasion (≥T2) are considered to be important as different treatments may be recommended based on this finding. Studies reveal that 3% to 9% of T1 specimens are upstaged on secondary review. One study (6) included a small number (n=31) of T2+ specimens, of which 32% were downstaged to Ta or T1.
Only two studies in the literature review reported on urine cytology specimens (11,12). One was in a subset of patients with histologically confirmed bladder cancer (11). For primary cancers, the detection rate was 39% by the local pathologist and 31% by the review pathologist, with a 14% discrepancy rate; detection rate was 18% during follow-up. In the other study, 51% of negative samples were considered inadequate upon review, while 8% were changed to carcinoma (12). B. Kidney Cancer
No studies were found on secondary review of renal tumour biopsy specimens and only two studies in the literature review (13,14) addressed secondary review of renal cell carcinoma tumour grade.
C. Upper Urinary Tract Urothelial Carcinoma
No studies were found in the literature review on secondary review in upper urinary tract endoscopic specimens. D. Urethral Cancer
No studies were found in the literature review on secondary review of urethral cancer.
E. Penile Cancer No studies on the secondary review of penis biopsy specimens were included in the
literature review. Two studies reporting secondary review in penectomy specimens (17,19) found 12% to 33% discrepancy in grade (including 85% discrepancy in grade 3 cases) and 16% discrepancy in the stage of penile cancer (19). An additional very small study (18) reviewed 10 penile squamous cell carcinoma cases and found discrepancy in degree of differentiation in two cases (20%). F. Testicular Cancer
Three studies reported 4% to 7% major discrepancy rate for tumour type (mainly in orchidectomy specimens) and 41% to 48% overall discrepancy rate in tumour elements or components for nonseminomatous testicular germ cell tumours (NSGCTs) (20,21,23). One study (20) reported 55% discrepancy in vascular invasion (20% discrepancy if cases without
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mention of vascular invasion were excluded), and the other studies reported 9% to 10% discrepancy. G. Prostate Cancer
While there were a large number of studies reporting discrepancies in diagnosis, the data was initially difficult to interpret. Table 1 was therefore reorganized, and the studies were regrouped into type of specimen (biopsy or prostatectomy). When sufficient details were given in the studies, discrepancies were grouped into categories of Gleason score (2-6, 7, 8-10) as changes between these groups have the most clinical relevance. Of additional importance was the system used to measure Gleason score, with the 2005 ISUP system being the most current/relevant. Studies starting prior to 2005 were considered not to have used this system unless indicated otherwise and are therefore not part of the discussion of the Gleason score.
i) Biopsy Oxley et al (37) found 3.5% of all cases and 6.5% of benign cases had discrepancy
(2% changed to suspicious or cancer). Jara-Lazaro et al (39) reported 6% of benign specimens and 27% of atypical specimens were rediagnosed as cancer. Chan et al (41) also reported 7% of benign and 21% of high-grade prostatic intraepithelial neoplasia (HGPIN)/atypia were changed to cancer. Wolters et al (34) conducted a prostate cancer screening trial and extrapolated the false-negative rate (missed adenocarcinoma or atypical small acinar proliferation [ASAP]) to be 2.4% among patients with biopsies.
Berg et al (42) found discrepancy in 36% of GS 6 cases (30% GS 6 →GS 7), while Brimo et al (43) found 7% discrepancy (all upgraded to GS 7). Goodman et al (25) and Kuroiwa et al (47) found 37% and 43% of GS 2-6 cases upgraded (almost all to GS 7).
Bostwick and Ma (35) reported 24% of HGPIN was refuted (all downgraded), while Marshall et al (36) and Oxley and Sen (37) reported HGPIN specimens had discrepancy rates of 1.6% and 1.9% respectively, of which 1.3% and 1.0% were changed to cancer.
ii) Prostatectomy
Margin status and presence of extraprostatic extension (pT3) influence recommendations for adjuvant therapy. Samples with positive margins had discrepancy in 11% to 26% of cases (24,26,28,29). Seminal vesicle invasion had discrepancy in 2% to 7% of cases. The study by van der Kwast et al (29), which included only cases either pT3 or with positive surgical margins, subdivided the data and reported 21% discrepancy for cases positive for seminal vesicle invasion and 1% discrepancy for negative cases, and also found 32% discrepancy in extraprostatic extension status.
DISCUSSION
The secondary review of a cancer pathology case may be requested for a number of reasons: 1) the original report is incomplete; 2) knowledge of high interobserver variability in diagnosis and prognostic descriptors related to specific tumour; 3) routine institutional policy and practice. When key information is missing such as subtype, grade, or margin status, the oncologist may contact the original pathologist to have the report completed or may request a secondary pathology review that can either be a complete review or one that is focused on specific information. Discrepancies between original and review pathology reports may also arise because of a difference in interpretation between the reviewing and original pathologist. There is significant variability in interpretations rendered by pathologists, especially in areas such as diagnostic thresholds, grading issues, and subtleties of staging.
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In general, initial (primary) cancer pathology reporting should be done in a synoptic fashion following the CAP protocols (http://www.cap.org) and based on the American Joint Commission on Cancer (AJCC) staging standards (82). CCO and the CAP/APC have endorsed the CAP cancer checklists as the content standard for pathology reporting (83,84). Synoptic reporting can help ensure that reports are complete, and in Ontario the CCO Databook (84) indicates the following CAP cancer checklists are expected to be reported electronically to CCO by April 1, 2013:
bladder (biopsy, transurethral resection), urethra (urethrectomy, cystectomy/ cystoprostatectomy, anterior exenteration), ureter (resection), kidney (nephrectomy), renal pelvis (resection/nephroureterectomy), adrenal gland (biopsy, resection), penis (biopsy, penectomy, circumcision), prostate gland (biopsy, prostatectomy, resection, enucleation specimen), and testis (orchiectomy, lymphadenectomy).
As of the writing of this review (October 2013), this reporting has not been fully implemented and synoptic reporting is required for cancer resection specimens but not diagnostic biopsies.
Most of the studies in this evidence summary compared an initial pathology review by a general anatomic pathologist (usually not specified) with a secondary review by a pathologist with genitourinary expertise at a cancer treatment centre. They did not directly address who should perform secondary review. In Canada there is no definitive standard for a subspecialist or recognized expertise in genitourinary pathology (see the overview document (#22-2-M), though we suggest considerations should include membership in the International Society of Urologic Pathology (ISUP) or the recently formed Canadian Network of Urologic Pathologists (CNUP), fellowship or specialized training in genitourinary pathology, participation in genitourinary MCCs, or a large portion of practice in genitourinary pathology. In Ontario most secondary review will be in cancer centres where pathology specialization occurs.
While the authors believe that secondary review may not be required when the primary pathologist was an expert, the evidence base did not directly address this situation, and, therefore, secondary review when the primary pathologist had genitourinary expertise should continue to be decided on a case-by-case basis or by institutional policy. However, it is noted that specimens may need review if the nature of samples falls outside the subspecialty of a genitourinary pathologist. Penile and testicular cancers should be reviewed by a genitourinary pathologist with expertise in these cancers. A. Bladder Cancer
While the discrepancy rates for transurethral biopsy/resections are high, the authors’ experience is that most cases in which the primary pathology report is complete and definitive do not change upon secondary review. Cases in which some uncertainty is expressed in the initial pathology report (equivocal diagnosis) are more likely to have a change upon secondary pathology review.
Relatively high discrepancy rates (18-43%) were reported for stage and grade of Ta/T1 cancers. While these studies did not report clinical relevance, changes between lamina propria invasion (T1) and detrusor muscle invasion (≥T2) are considered to be important as different treatments may be recommended based on this finding. These studies suggest some benefit in reviewing all T1/T2 bladder cancers; however, this may not be feasible. Discrepancies are likely more clinically relevant for transurethral biopsy/resection specimens
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reported as stage T2 bladder cancer and for stage T1 cancers that are equivocal/suspicious for muscle invasion.
The usefulness of urine samples in cancer diagnosis is uncertain, and there is insufficient evidence to reach any conclusions regarding secondary pathology review. B. Kidney Cancer
While the use of renal tumour biopsy may be increasing, the authors’ experience is that due to the small amount of tissue and specialized nature these specimens should be reviewed by a pathologist with expertise in reviewing needle biopsies of renal neoplasms. For completely resected tumours via partial or radical nephrectomy, secondary review of grade, stage, and diagnosis is not essential since, for most patients, there are currently no established adjuvant treatments.
C. Upper Urinary Tract Urothelial Carcinoma
While no studies were located in the literature review, the authors’ experience is that stage is difficult to assign for endoscopic specimens of urothelial carcinoma and management decisions are instead based on tumour grade and radiographic findings. When grade has been assigned this is an indication of complete pathology reporting and no further pathology review is usually required.
D. Urethral Cancer
Urethral cancer is uncommon/rare, and, therefore, many general anatomic pathologists are unlikely to be aware of distinguishing features (see H below). E. Penile Cancer
No studies on secondary review of penis biopsy specimens were included in the literature review. As both dermatologists/dermatopathologists and genitourinary pathologists are often uncomfortable with or lack sufficient expertise in penile cancers, diagnosis should be by a pathologist with expertise in both dermatopathology and pathology of the penis. In the case of biopsy prior to surgery, either secondary pathology review or rebiopsy and review by an expert should be performed.
The included studies found 12% to 33% discrepancy in grade and stage of penile cancer, and a small study found 20% discrepancy in the degree of differentiation. As both grade and lymphovascular invasion (LVI) are clinically important, these studies support secondary pathology review in penile cancer. Additionally, the experience of the authors is that penile cancer is a rare disease, often poorly diagnosed.
Central management (including pathology review) should be considered due to the low number of cases and specialized diagnostic and surgical requirements. F. Testicular Cancer
The authors consider the assessment of vascular invasion to be particularly important for stage I cancers. Testicular cancer specimens are very difficult to read, and most pathologists do not see enough specimens to be adept at diagnosis. Special molecular markers may be required for classification, and these are not widely available. Direct or secondary review by a gastrointestinal pathology expert is supported by the data above. As recommended in CCO PEBC Guideline #3-18 (85), the management of testicular cancers is best performed in a multidisciplinary environment within centres familiar with the management of the disease.
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G. Prostate Cancer It is difficult to determine small foci of cancer (sometimes defined as tumour
occupying ≤ 5% of one biopsy core and/ or measuring ≤ 1mm linear extent) in prostate biopsy samples). The extent of involvement will determine management, and, therefore, secondary pathology review is justified for all biopsy specimens with a diagnosis of minimal (limited) volume/small foci of cancer or with ASAP in order to ensure other foci or-high grade foci are not missed.
There is considerable discrepancy in Gleason grade in prostate tissue biopsies; however, treatment may vary greatly because of the acceptance of active surveillance for minimal volume low-grade prostate cancers compared to more aggressive treatment for larger volume or higher grade cancer. While criteria vary, generally active surveillance is considered for patients with GS ≤ 6 with less than three cores positive and maximum of 20% per core. A CCO PEBC guideline on active surveillance is currently being prepared (expected completion Summer 2014) and can be referred to for further guidance (86). A document is also being prepared by CAP/ISUP on the critical role of the pathologist in active surveillance and deals with the pathologic issues of active surveillance.
The authors consider that the routine review of all HGPIN specimens is not justified, but that pathologists need to be aware that some specimens classified as HGPIN are actually intraductal spread or intraductal carcinoma (IDC), which are highly malignant (Gleason 8). Specimens with atypical proliferation warrant secondary review.
In prostatectomy specimens, margin status and the presence of extraprostatic
extension (pT3) influence recommendations for adjuvant therapy. There was considerable discrepancy in cases identified to have positive margins, seminal vesicle invasion, or extraprostatic extension, and, therefore, secondary pathology review is warranted. H. Rare Tumours
No studies of rare genitourinary tumours, unusual variants, and emerging diseases were included in the literature review. However, general anatomic pathologists are unlikely to see many of these special or rare cancers and are less likely to be aware of the distinguishing features. Misdiagnosis would have clinical significance.
I. Childhood Cancers
Pediatric pathology is a highly specialized field and is not addressed in this document. Guidelines such as those by American Academy of Pediatrics (87) and NICE (88) recommend diagnosis should be by specialists in pediatric pathology due to the relative rarity, small biopsies, and different features compared to adult cases. CONCLUSIONS A. Bladder Cancer
Transurethral biopsy/resections should have secondary pathology review when the initial report suggests the diagnosis of bladder cancer is equivocal (cases not “clear-cut” or definite), for stage T2 bladder cancer, and for stage T1 cancers that are equivocal/ suspicious for muscle invasion. No conclusions are made regarding secondary review of urine cytology specimens. B. Kidney Cancer
Renal tumour biopsy specimens should be reviewed by a pathologist with expertise in kidney tumour pathology. Routine secondary pathology review of completely resected kidney tumours is not required.
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C. Upper urinary Tract Urothelial Carcinoma Routine secondary pathology review is not required for endoscopic specimens of
urothelial carcinoma if grade has been assigned.
D. Urethral Cancer As urethral cancer is considered rare, a secondary pathology review should be
conducted. E. Penile Cancer
Biopsy specimens with suspicion of, or diagnosis of, penile cancer should be reviewed by a dermatopathologist with penile cancer expertise and/or genitourinary pathologist with penile cancer expertise. Penectomy specimens should be reviewed by a genitourinary pathologist with expertise in this area. Central management (including pathology review) in specialized centers should be considered. F. Testicular Cancer
Specimens with suspicion of, or diagnosis of, testicular cancer should have secondary pathology review or direct referral to an expert genitourinary pathologist. Central management (including pathology review) in specialized centers should be considered. G. Prostate Cancer
Biopsy specimens with diagnosis of minimal (limited) volume/small foci of cancer, with ASAP, or with unusual intraductal and/or atypical cribriform proliferation should have secondary pathology review. Biopsy specimens from patients who are being considered for active surveillance should have secondary pathology review to confirm the Gleason score. Prostatectomy specimens with positive margins, or with seminal vesicle invasion or extraprostatic extension, or stage T3 warrant secondary pathology review. H. Rare Cancers
Secondary pathology review is recommended for rare tumours, unusual variants, and emerging diseases. FUTURE RESEARCH
While the following issues were not within the direct scope of the document, the authors felt they should be considered.
The Working Group discussed a model of care of locoregional networks tied to cancer
centers, with general pathologists → locoregional experts (special interest) → Ontario experts if needed.
A list of experts accepting consults for various fields of pathology may be useful, especially for newer pathologists and those serving in more remote areas.
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RELATED PEBC GUIDELINES
Morash C, Tey R, Klotz L, McGowan T, Srigley J, Evans A, et al. Active surveillance for the management of localized prostate cancer. Toronto, ON: Cancer Care Ontario; 2014 [expected release 2014; draft reviewed 2013 Oct 15]. Program in Evidence-Based Care Practice Evidence-Based Series No.:17-9. Available from: [final version to be posted at:
https://www.cancercare.on.ca/toolbox/qualityguidelines/clin-program/surgery-ebs/].
Chung P, Mayhew L, Warde P, Winquist E, Lukka H, Members of the Genitourinary Cancer Disease Site Group. Management of stage I seminoma. Toronto, ON: Cancer Care Ontario (CCO); 2008 [in review 2012 Nov 28; 2008 Jan 30]]. Program in Evidence-Based Care Evidence-Based Series No.: 3-18 IN REVIEW. Available from:
https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=14044. UPDATING
This series of evidence summaries on secondary pathology review will be considered current for three years. The evidence summaries will then be designated as archived and indicated as such on the CCO website. These reports will not undergo annual assessment. They will not be updated unless required as the basis of a new guideline by the Pathology and Laboratory Medicine Program (PLMP). CONFLICT OF INTEREST
In accordance with the PEBC Conflict of Interest (COI) Policy, the authors were asked to disclose potential conflicts of interest. For the Working Group, potential conflicts of interest that were declared are summarized in Appendix I. The COIs declared did not disqualify any individuals from performing their designated role in the development of this review, in accordance with the PEBC COI Policy. To obtain a copy of the policy, please contact the PEBC office by email at ccopgi.mcmaster.ca ACKNOWLEDGEMENTS AND AUTHORSHIP
The Pathology & Medicine Program and the working group would like to thank the following individuals for their assistance in developing this report:
Dr John Srigley, Dr Sandy Boag, Glenn Fletcher, Dr Suhas Joshi, Dr Mahmoud Khalifa, and Dr Brendan Mullen for taking the lead in the overall pathology secondary review project.
Melissa Brouwers, Sheila McNair, Hans Messersmith, Caroline Zwaal, and Norma Varela for providing feedback on draft versions.
Denise Kam for assisting with data extraction, providing research assistance, and for managing communication among the working group and with the reviewers.
Eric Yung for conducting a data audit.
Carol De Vito for copyediting.
Jennifer Hart and Dana Wilson-Li of Cancer Care Ontario. A complete list of the members of the Best Practices for Oncologic Pathology
Secondary Review: Genitourinary Cancers Working Group, with their affiliations and conflict of interest information, is provided in Appendix 1.
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Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health
and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care.
Copyright
This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
Disclaimer
Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer
Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.
Contact Information
For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at:
Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: [email protected]
Section 3: Recommendations Development & External Review Process. Page 26
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35. Bostwick DG, Ma J. Over-diagnosis of high-grade prostatic intraepithelial neoplasia: A prospective study of 251 cases. BJU Int. 2007;100(5):1036-9.
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38. Oxley J. Reviewing negative prostatic core biopsies for the multidisciplinary team meeting. Histopathology. 2005;47(6):643-4.
39. Jara-Lazaro AR, Thike AA, Tan PH. Diagnostic issues in second opinion consultations in prostate pathology. Pathology (Phila). 2010;42(1):6-14.
40. Helpap B. [Small suggestive lesions of the prostate. Histological and immunohistochemical analyses -- report of the uropathology consultation service]. Pathologe. 2005;26(6):398-404.
41. Chan TY, Epstein JI. Patient and urologist driven second opinion of prostate needle biopsies. J Urol. 2005;174(4 Pt 1):1390-4; discussion 4; author reply 4.
42. Berg KD, Toft BG, Roder MA, Brasso K, Vainer B, Iversen P. Prostate needle biopsies: Interobserver variation and clinical consequences of histopathological re-evaluation. APMIS. 2011;119(4-5):239-46.
43. Brimo F, Schultz L, Epstein JI. The value of mandatory second opinion pathology review of prostate needle biopsy interpretation before radical prostatectomy. J Urol. 2010;184(1):126-30.
44. Truesdale MD, Cheetham PJ, Turk AT, Sartori S, Hruby GW, Dinneen EP, et al. Gleason score concordance on biopsy-confirmed prostate cancer: Is pathological re-evaluation necessary prior to radical prostatectomy? BJU Int. 2011;107(5):749-54.
45. Al-Hussain TO, Nagar MS, Epstein JI. Gleason pattern 5 is frequently underdiagnosed on prostate needle-core biopsy. Urology. 2012;79(1):178-81.
46. Fajardo DA, Miyamoto H, Miller JS, Lee TK, Epstein JI. Identification of Gleason pattern 5 on prostatic needle core biopsy: Frequency of underdiagnosis and relation to morphology. Am J Surg Pathol. 2011;35(11):1706-11.
47. Kuroiwa K, Shiraishi T, Naito S, Clinicopathological Research Group for Localized Prostate Cancer Investigators. Gleason score correlation between biopsy and prostatectomy specimens and prediction of high-grade Gleason patterns: Significance of central pathologic review. Urology. 2011;77(2):407-11.
48. Kishimoto R, Saika T, Bekku K, Nose H, Abarzua F, Kobayashi Y, et al. The clinical impact of pathological review on selection the treatment modality for localized prostate cancer in candidates for brachytherapy monotherapy. World J Urol. 2012;30(3):375-8.
49. Grubb RL, Andriole GL, Somerville MC, Mahoney C, Manyak MJ, Castro R. The REDUCE follow-up study: Low rate of new prostate cancer diagnoses observed during a 2-year, observational, followup study of men who participated in the REDUCE trial. J Urol. 2013;189(3):871-7.
50. D'Souza N, Loblaw DA, Mamedov A, Sugar L, Holden L. Prostate cancer pathology audits: Is central pathology review still warranted? Can J Urol. 2012;19(3):6256-60.
51. Barqawi AB, Turcanu R, Gamito EJ, Lucia SM, O'Donnell CI, Crawford ED, et al. The value of second-opinion pathology diagnoses on prostate biopsies from patients referred for management of prostate cancer. Int J Clin Exp Pathol. 2011;4(5):468-75.
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52. Sooriakumaran P, Lovell DP, Henderson A, Denham P, Langley SEM, Laing RW. Gleason scoring varies among pathologists and this affects clinical risk in patients with prostate cancer. Clin Oncol. 2005;17(8):655-8.
53. Fine SW, Epstein JI. A contemporary study correlating prostate needle biopsy and radical prostatectomy Gleason score. J Urol. 2008;179(4):1335-8; discussion 8-9.
54. Van der Kwast TH, Lopes C, Martikainen PM, Pihl CG, Santonja C, Neetens I, et al. Report of the Pathology Committee: False-positive and false-negative diagnoses of prostate cancer. BJU Int. 2003;92 Suppl 2:62-5.
55. Coard KC, Freeman VL. Gleason grading of prostate cancer: Level of concordance between pathologists at the University Hospital of the West Indies. Am J Clin Pathol. 2004;122(3):373-6.
56. Thomas CW, Bainbridge TC, Thomson TA, McGahan CE, Morris WJ. Clinical impact of second pathology opinion: A longitudinal study of central genitourinary pathology review before prostate brachytherapy. Brachytherapy. 2007;6(2):135-41.
57. Nguyen PL, Schultz D, Renshaw AA, Vollmer RT, Welch WR, Cote K, et al. The impact of pathology review on treatment recommendations for patients with adenocarcinoma of the prostate. Urol. 2004;22(4):295-9.
58. Renshaw AA, Schultz D, Cote K, Loffredo M, Ziemba DE, D'Amico AV. Accurate Gleason grading of prostatic adenocarcinoma in prostate needle biopsies by general pathologists. Arch Pathol Lab Med. 2003;127(8):1007-8.
59. Wurzer JC, Al-Saleem TI, Hanlon AL, Freedman GM, Patchefsky A, Hanks GE. Histopathologic review of prostate biopsies from patients referred to a comprehensive cancer center: Correlation of pathologic findings, analysis of cost, and impact on treatment. Cancer. 1998;83(4):753-9.
60. Epstein JI, Walsh PC, Sanfilippo F. Clinical and cost impact of second-opinion pathology. Review of prostate biopsies prior to radical prostatectomy. Am J Surg Pathol. 1996;20(7):851-7.
61. Steinberg DM, Sauvageot J, Piantadosi S, Epstein JI. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol. 1997;21(5):566-76.
62. Winter K, Grignon D, Pajak TF, Pilepich M, Byhardt R, Lawton C, et al. The need for central pathology tumor grading in prostate cancer using radiation therapy oncology group (RTOG) 8531. Int J Radiat Oncol Biol Phys. 1997;39(2 (Suppl 1)):Abstract A1007, 219.
63. Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol. 1997;15(3):1013-21.
64. Prescott RJ, Wells S, Bisset DL, Banerjee SS, Harris M. Audit of tumour histopathology reviewed by a regional oncology centre. J Clin Pathol. 1995;48(3):245-9.
65. Kronz JD, Westra WH, Epstein JI. Mandatory second opinion surgical pathology at a large referral hospital. Cancer. 1999;86(11):2426-35.
66. Murphy WM, Rivera-Ramirez I, Luciani LG, Wajsman Z. Second opinion of anatomical pathology: A complex issue not easily reduced to matters of right and wrong. J Urol. 2001;165(6 Pt 1):1957-9.
67. Weir MM, Jan E, Colgan TJ. Interinstitutional pathology consultations. A reassessment. Am J Clin Pathol. 2003;120(3):405-12.
68. Ahmed Z, Yaqoob N, Muzaffar S, Kayani N, Pervez S, Hasan SH. Diagnostic surgical pathology: The importance of second opinion in a developing country. J Pak Med Assoc. 2004;54(6):306-11.
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69. Tsung JSH. Institutional pathology consultation. Am J Surg Pathol. 2004;28(3):399-402. 70. Raab SS, Nakhleh RE, Ruby SG. Patient safety in anatomic pathology: Measuring
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type and diagnosis: Identifying cases for directed blinded review. Am J Clin Pathol. 2006;126(5):736-9.
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73. Schmoll HJ, Souchon R, Krege S, Albers P, Beyer J, Kollmannsberger C, et al. European consensus on diagnosis and treatment of germ cell cancer: A report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol. 2004;15(9):1377-99.
74. Wood L, Kollmannsberger C, Jewett M, Chung P, Hotte S, O'Malley M, et al. Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010;4(2).
75. Haward RA, Richards M, Barret J, Batt G, Brennan A, Hanson J, et al. Guidance on cancer services. Improving outcomes in urological cancers: The manual. London (UK): National Institute for Clinical Excellence (NICE); 2002 [cited 2012 May 31]. Available from: http://www.nice.org.uk/nicemedia/pdf/Urological_Manual.pdf
76. Stephenson AJ, Aprikian AG, Gilligan TD, Oldenburg J, Powles T, Toner GC, et al. Management of low-stage nonseminomatous germ cell tumors of testis: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Suppl):S444-55.
77. Warde P, Huddart R, Bolton D, Heidenreich A, Gilligan T, Fossa S. Management of localized seminoma, stage I-II: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Suppl):S435-43.
78. Howard G, Borgaonkar S, Brooks M, Brush J, Brown J, Dodds D, et al. Management of adult testicular germ cell tumours: A national clinical guideline. Edinburgh (UK): Scottish Intercollegiate Guidelines Network (SIGN); 2011 [cited 2012 May 31]. Scottish Intercollegiate Guidelines Network 124. Available from: http://sign.ac.uk/pdf/sign124.pdf.
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Section 3: Recommendations Development & External Review Process. Page 32
Appendix I. Members of the Pathology Secondary Review Working Group and conflicts of
interest.
Pathology Secondary Review Working Group: Genitourinary Cancers
Dr. Jack Barkin, Urologist; Chief of Staff, Humber River Hospital; Assistant Professor,
Department of Surgery, University of Toronto
Dr. Rodney Henry Breau, Surgical Oncologist, Department of Urology, The Ottawa
Hospital; Associate Scientist, Clinical Epidemiology, Ottawa Hospital Research
Institute; Assistant Professor of Surgery, Faculty of Medicine, University of Ottawa
Surgical Oncologist, Division of Urology, The Ottawa Hospital
Dr. Andrew Loblaw, Radiation Oncologist, Sunnybrook Health Sciences Centre,
Toronto
Dr. Madeleine Moussa, Pathologist, London Health Sciences Centre; Professor, Department of Pathology, The University of Western Ontario, London
Dr. Aaron Pollett, Pathologist, Mount Sinai Hospital, Toronto; Assistant Professor, Laboratory and Medicine and Pathobiology, University of Toronto; Chair, Pathology and Laboratory Medicine Program (PLMP), Cancer Care Ontario
Dr. John Srigley, Pathologist and Chief of Laboratory Medicine, Credit Valley Hospital,
Mississauga; Professor (part-time), Pathology and Molecular Medicine, McMaster
University; Chair (until April 2013), Pathology and Laboratory Medicine Program
(PLMP), Cancer Care Ontario
Dr. Linda Sugar, Pathologist, Sunnybrook Health Sciences Centre; Professor,
Laboratory Medicine and Pathobiology, University of Toronto
Glenn Fletcher, Health Research Methodologist, PEBC, Cancer Care Ontario/McMaster
University, Hamilton
Denise Kam, Research Assistant, PEBC, Cancer Care Ontario/McMaster University,
Hamilton
Jennifer Hart, Manager - Clinical Programs, Cancer Care Ontario, Toronto
Dana Wilson-Li, Policy and Research Analyst, Pathology and Laboratory Medicine
Program, Cancer Care Ontario, Toronto
JB declared grants or research support (Medicalm Advisory Board) from Abbott,
Amgen, Astellas, Astra Zeneca, Ferring, Palladin, Sanofi and was a co-author/investigator for
clinical trials in BHOS- Bone Health Observational Study (Astra Zeneca), Delay Trial: Firmagon
for the management of castrate resistant prostate cancer (Ferring).
The other members did not declare any conflicts.
Section 3: Recommendations Development & External Review Process. Page 33
Appendix II. Reproducibility studies (data not extracted).
Prostate (1-13) 1. Allam CK, Bostwick DG, Hayes JA, Upton MP, Wade GG, Domanowski GF, et al.
Interobserver variability in the diagnosis of high-grade prostatic intraepithelial neoplasia and adenocarcinoma. Mod Pathol. 1996;9(7):742-51.
2. Arista-Nasr J, Cortes E, Keirns C, Hatchett A, Loria A. Diagnostic concordance in biopsies of deceptive prostatic carcinoma. Rev Invest Clin. 1996;48(4):289-96.
3. Epstein JI, Grignon DJ, Humphrey PA, McNeal JE, Sesterhenn IA, Troncoso P, et al. Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol. 1995;19(8):873-86.
4. Evans AJ, Henry PC, Van der Kwast TH, Tkachuk DC, Watson K, Lockwood GA, et al. Interobserver variability between expert urologic pathologists for extraprostatic extension and surgical margin status in radical prostatectomy specimens. Am J Surg Pathol. 2008;32(10):1503-12.
5. Harnden P, Coleman D, Moss S, Kodikara S, Griffin NR, Melia J. Evaluation of the use of digital images for a national prostate core external quality assurance scheme. Histopathology. 2011;59(4):703-9.
6. Harnden P, Coleman D, Moss S, Kodikara S, Patnick J, Melia J. Prostatic pathology reporting in the UK: Development of a national external quality assurance scheme. Histopathology. 2008;52(2):147-57.
7. Lessells AM, Burnett RA, Howatson SR, Lang S, Lee FD, McLaren KM, et al. Observer variability in the histopathological reporting of needle biopsy specimens of the prostate. Hum Pathol. 1997;28(6):646-9.
8. Novis DA, Zarbo RJ, Valenstein PA. Diagnostic uncertainty expressed in prostate needle biopsies. A College of American Pathologists Q-probes Study of 15,753 prostate needle biopsies in 332 institutions. Arch Pathol Lab Med. 1999;123(8):687-92.
9. Rodriguez-Urrego PA, Cronin AM, Al-Ahmadie HA, Gopalan A, Tickoo SK, Reuter VE, et al. Interobserver and intraobserver reproducibility in digital and routine microscopic assessment of prostate needle biopsies. Hum Pathol. 2011;42(1):68-74.
10. Van der Kwast TH, Evans A, Lockwood G, Tkachuk D, Bostwick DG, Epstein JI, et al. Variability in diagnostic opinion among pathologists for single small atypical foci in prostate biopsies.[Erratum appears in Am J Surg Pathol. 2010 May;34(5):688 Note: Pihl, C G[removed]]. Am J Surg Pathol. 2010;34(2):169-77.
11. Weiss MA. High-grade prostatic intraepithelial neoplasia: A study of pathologists' responses in the College of American Pathologists Performance Improvement Program in Diagnostic Surgical Pathology. Arch Pathol Lab Med. 2001;125(3):440-2.
12. Wolfson WL. Interobserver variability among expert uropathologists. Am J Surg Pathol. 2009;33(5):801; author reply -2.
13. Wright KC, Melia J, Moss S, Berney DM, Coleman D, Harnden P. Measuring interobserver variation in a pathology EQA scheme using weighted kappa for multiple readers. J Clin Pathol. 2011;64(12):1128-31.
Prostate – Gleason Score (14-41) 14. Abdollahi A, Meysamie A, Sheikhbahaei S, Ahmadi A, Moradi-Tabriz H, Bakhshandeh M,
et al. Inter/intra-observer reproducibility of Gleason scoring in prostate adenocarcinoma in Iranian pathologists. Urology Journal. 2012;9(2):486-90.
15. Allsbrook WCJ, Mangold KA, Johnson MH, Lane RB, Lane CG, Amin MB, et al. Interobserver reproducibility of Gleason grading of prostatic carcinoma: Urologic pathologists. Hum Pathol. 2001;32(1):74-80.
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16. Allsbrook WCJ, Mangold KA, Johnson MH, Lane RB, Lane CG, Epstein JI. Interobserver reproducibility of Gleason grading of prostatic carcinoma: General pathologist. Hum Pathol. 2001;32(1):81-8.
17. Bova GS, Parmigiani G, Epstein JI, Wheeler T, Mucci NR, Rubin MA. Web-based tissue microarray image data analysis: Initial validation testing through prostate cancer gleason grading. Hum Pathol. 2001;32(4):417-27.
18. Burchardt M, Engers R, Muller M, Burchardt T, Willers R, Epstein JI, et al. Interobserver reproducibility of Gleason grading: Evaluation using prostate cancer tissue microarrays. J Cancer Res Clin Oncol. 2008;134(10):1071-8.
19. De la Taille A, Viellefond A, Berger N, Boucher E, De Fromont M, Fondimare A, et al. Evaluation of the interobserver reproducibility of Gleason grading of prostatic adenocarcinoma using tissue microarrays. Hum Pathol. 2003;34(5):444-9.
20. Egevad L. Reproducibility of Gleason grading of prostate cancer can be improved by the use of reference images. Urology. 2001;57(2):291-5.
21. Egevad L, Algaba F, Berney DM, Boccon-Gibod L, Comperat E, Evans AJ, et al. Interactive digital slides with heat maps: A novel method to improve the reproducibility of Gleason grading. Virchows Arch. 2011;459(2):175-82.
22. Freeman VL, Coard KCM, Wojcik E, Durazo-Arvizu R. Use of the Gleason system in international comparisons of prostatic adenocarcinomas in blacks. Prostate. 2004;58(2):169-73.
23. Glaessgen A, Hamberg H, Pihl C-G, Sundelin B, Nilsson B, Egevad L. Interobserver reproducibility of percent Gleason grade 4/5 in total prostatectomy specimens. J Urol. 2002;168(5):2006-10.
24. Glaessgen A, Hamberg H, Pihl C-G, Sundelin B, Nilsson B, Egevad L. Interobserver reproducibility of modified Gleason score in radical prostatectomy specimens. Virchows Arch. 2004;445(1):17-21.
25. Glaessgen A, Hamberg H, Pihl C-G, Sundelin B, Nilsson B, Egevad L. Interobserver reproducibility of percent Gleason grade 4/5 in prostate biopsies. J Urol. 2004;171(2 Pt 1):664-7.
26. Griffiths DFR, Melia J, McWilliam LJ, Ball RY, Grigor K, Harnden P, et al. A study of Gleason score interpretation in different groups of UK pathologists; techniques for improving reproducibility. Histopathology. 2006;48(6):655-62.
27. Helin H, Lundin M, Lundin J, Martikainen P, Tammela T, Helin H, et al. Web-based virtual microscopy in teaching and standardizing Gleason grading. Hum Pathol. 2005;36(4):381-6.
28. Helpap B, Kristiansen G, Beer M, Kollermann J, Oehler U, Pogrebniak A, et al. Improving the reproducibility of the Gleason scores in small foci of prostate cancer--suggestion of diagnostic criteria for glandular fusion. Pathol Oncol Res. 2012;18(3):615-21.
29. Kiss F, Lakner G, Csellar M, Nagy P, Toth A, Vittay G. Reproducibility of histopathologic grading in prostatic carcinoma. Kappa statistical analysis in the Gleason and Bocking Bocking system. [Hungarian]. Orv Hetil. 1997;138 (19):1195-9.
30. Kronz JD, Silberman MA, Allsbrook WC, Jr., Epstein JI. A web-based tutorial improves practicing pathologists' gleason grading of images of prostate carcinoma specimens obtained by needle biopsy: Validation of a new medical education paradigm. Cancer. 2000;89(8):1818-23.
31. Latour M, Amin MB, Billis A, Egevad L, Grignon DJ, Humphrey PA, et al. Grading of invasive cribriform carcinoma on prostate needle biopsy: An interobserver study among experts in genitourinary pathology. Am J Surg Pathol. 2008;32(10):1532-9.
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32. McKenney JK, Simko J, Bonham M, True LD, Troyer D, Hawley S, et al. The potential impact of reproducibility of Gleason grading in men with early stage prostate cancer managed by active surveillance: A multi-institutional study. J Urol. 2011;186(2):465-9.
33. McLean M, Srigley J, Banerjee D, Warde P, Hao Y. Interobserver variation in prostate cancer Gleason scoring: Are there implications for the design of clinical trials and treatment strategies? Clin Oncol (R Coll Radiol). 1997;9(4):222-5.
34. Melia J, Moseley R, Ball RY, Griffiths DFR, Grigor K, Harnden P, et al. A UK-based investigation of inter- and intra-observer reproducibility of Gleason grading of prostatic biopsies. Histopathology. 2006;48(6):644-54.
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