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
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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
22-2-3 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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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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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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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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Author Year # 2nd Reviewers
# Specimens
Reviewer (Profession/
Training)
Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared
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:
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:
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:
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.
22-2-3 Genitourinary Cancer Evidence Summary Page 25
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:
Section 3: Recommendations Development & External Review Process. Page 26
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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,
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