Best Practices for Oncologic Pathology Secondary Review ...€¦ · Best Practices for Oncologic Pathology Secondary Review: Genitourinary Cancers John Srigley, Glenn G Fletcher,

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

https://www.cancercareontario.ca/sites/ccocancercare/files/PEBCHandbook.pdf

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]

http://www.cancercare.on.ca/

mailto:[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.

http://www.guideline.gov/

http://www.nice.org.uk/guidance/index.jsp

http://www.sign.ac.uk/guidelines/index.html

http://www.sign.ac.uk/guidelines/index.html

http://www.asco.org/ASCO/Quality+Care+%26+Guidelines/Practice+Guidelines

http://www.nccn.org/

http://www.nccn.org/

http://www.nhmrc.gov.au/publications/subjects/cancer.htm

http://www.nhmrc.gov.au/publications/subjects/cancer.htm

http://www.nzgg.org.nz/

http://www.cma.ca/index.cfm/ci_id/54316/la_id/1.htm

http://www.cma.ca/index.cfm/ci_id/54316/la_id/1.htm

http://www.adasp.org/

http://www.adasp.org/

http://www.cap.org/

http://www.cap-acp.org/

http://www.cap-acp.org/

http://www.cancerview.ca/cv/portal/Home/TreatmentAndSupport/TSProfessionals/ClinicalGuidelines/GRCMain/GRCSAGE/GRCSAGESearch?tool-tip-fr=Normes+et+recommandations+sur+le+cancer+pour+les+professionnels+de+la+sant%C3%A9+au+Canada&_afrLoop=1992147435458833&ti

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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


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)





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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# Specimens


Training)





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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# Specimens


Training)





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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# Specimens


Training)





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),


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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# Specimens


Training)





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


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



# Specimens


Training)





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


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)


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


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



# Specimens


Training)





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



# Specimens


Training)





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



# Specimens


Training)





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



# Specimens


Training)





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


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


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



# Specimens


Training)





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;


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



# Specimens


Training)





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


2002-2005


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,


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



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

ES 22-2-3



# Specimens


Training)





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)


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


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

ES 22-2-3



# Specimens


Training)





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.

ES 22-2-3


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

ES 22-2-3


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.

ES 22-2-3


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

http://www.cap.org/

ES 22-2-3


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.

ES 22-2-3


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.

ES 22-2-3


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.

ES 22-2-3


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.

https://www.cancercare.on.ca/toolbox/qualityguidelines/clin-program/surgery-ebs/

https://www.cancercare.on.ca/toolbox/qualityguidelines/clin-program/surgery-ebs/

https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=14044

mailto:ccopgi.mcmaster.ca

ES 22-2-3


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]

http://www.cancercare.on.ca/

mailto:[email protected]

Section 3: Recommendations Development & External Review Process. Page 26

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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.

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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.


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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72. Lu ZF, Yin HL, Du J, Shi QL, Li NY, Jin XZ, et al. Analysis of 12 206 cases of external pathology consultation. [Chinese]. Zhonghua bing li xue za zhi [Chinese Journal of Pathology] 2009;38(10):678-81.

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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).

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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.

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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.


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.


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.


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.

35. Mikami Y, Manabe T, Epstein JI, Shiraishi T, Furusato M, Tsuzuki T, et al. Accuracy of gleason grading by practicing pathologists and the impact of education on improving agreement. Hum Pathol. 2003;34(7):658-65.

36. Mulay K, Swain M, Jaiman S, Gowrishankar S. Gleason scoring of prostatic carcinoma: Impact of a web-based tutorial on inter- and intra-observer variability. Indian J Pathol Microbiol. 2008;51(1):22-5.

37. Oyama T, Allsbrook WC, Jr., Kurokawa K, Matsuda H, Segawa A, Sano T, et al. A comparison of interobserver reproducibility of Gleason grading of prostatic carcinoma in Japan and the United States.[Erratum appears in Arch Pathol Lab Med. 2005 Nov;129(11):1368]. Arch Pathol Lab Med. 2005;129(8):1004-10.

38. Ozdamar SO, Sarikaya S, Yildiz L, Atilla MK, Kandemir B, Yildiz S. Intraobserver and interobserver reproducibility of WHO and Gleason histologic grading systems in prostatic adenocarcinomas. Int Urol Nephrol. 1996;28 (1):73-7.

39. Singh RV, Agashe SR, Gosavi AV, Sulhyan KR. Interobserver reproducibility of Gleason grading of prostatic adenocarcinoma among general pathologists. Indian J Cancer. 2011;48(4):488-95.

40. Veloso SG, Lima MF, Salles PG, Berenstein CK, Scalon JD, Bambirra EA. Interobserver agreement of Gleason score and modified Gleason score in needle biopsy and in surgical specimen of prostate cancer. Int Braz J Urol. 2007;33(5):639-46; discussion 47-51.

41. Wright KC, Harnden P, Moss S, Berney DM, Melia J. A practical application of analysing weighted kappa for panels of experts and EQA schemes in pathology. J Clin Pathol. 2011;64 (3):257-60.

Renal, Urinary, Bladder (42-64) 42. Al-Aynati M, Chen V, Salama S, Shuhaibar H, Treleaven D, Vincic L. Interobserver and

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