Best Practices for Oncologic Pathology Secondary Review: Genitourinary Cancers

Transcription

1 Evidence Summary ARCHIVED 201 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 201 ARCHIVED Evidence Summary 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 M: Methods and Overview : Breast Cancer : Gastrointestinal Cancers : Genitourinary Cancers : Gynecologic Cancers : Head and Neck Cancers : Hematologic Cancers 22-2-: Lung Cancer : Cutaneous Melanoma and Other Skin Cancers : Central Nervous System (CNS) Tumours : Bone and Soft Tissue Cancers (Sarcoma) * Author affiliations are given in Appendix I

2 EBS For information about the PEBC and the most current version of all reports, please visit the CCO Web site at or contact the PEBC office at: Phone: ext Fax:

3 QUESTION What types of specimens suspected to be or diagnosed as genitourinary cancer 1 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 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 Genitourinary Cancer Evidence Summary Page 1

4 MEDLINE and EMBASE databases were searched from 1995 to May, 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 (1-23), and 41 prostate (4,24-63)]. There are an additional nine studies (64-2) 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 (3,4). The NICE guideline (5) 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 (6,). 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 (8). The European Association of Urology (9) 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 (5) 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 Genitourinary Cancer Evidence Summary Page 2

5 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 2 nd Reviewers Reviewer (Profession/ Training) Lee (2) pathologist in year 2002; pathologist with GU expertise in 2004 Coblentz (3) surgical pathologist; genitourinary pathologist retrospectively reviewed 19 of 24 discordant cases and agreed with 2nd review in all Wayment (4) urologist + pathologist; 3rd (or 4th) pathologist if disagreement Tosoni (5) pathologist with special interest in urinary bladder cancer Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared review of slides from outside cases referred to Cleveland Clinic, 2002 and 2004 for management after resection; stage by TMN, grade by WHO 193 (samples from 2002) or WHO 2003 and WHO/ISUP 199 (samples from 2004); retrospective review of reports by GU pathology specialist patients referred from community hospitals to academic center (University of Virginia) for evaluation, ; review used WHO 193 classification modified to add Grade 4, staging by 19 IUAC/AJCC system retrospective review of records: practice at tertiary referral centre to request pathologic materials for all patients seen in consultation for urologic malignancy; retrospective review of slides of consecutive urinary bladder tumours, , City Hospital Triemli, Zurich; stage and grade according to UICC (1992) and WHO (193) classifications Bladder all transurethral bladder tumor resection specimens; excluded cases where outside pathologist sought a second opinion; major = potential management change as determined by a urologist 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] 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 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 year 2002 year 2004 overall change in histological type change in grade I to III malignancy to no cancer change in stage overall non-urothelial neoplasms inadequate for staging (no musclaris propria) change in stage of Subtype Discrepancy, % Agreement All Major Minor % Kappa (9) bladder 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) Genitourinary Cancer Evidence Summary Page 3

6 Author Year 2 nd van der Meijden (6) Reviewers Reviewer (Profession/ Training) uropathologist comparison of local and review pathology results from EORTC randomized phase III trials comparing adjuvant treatments after transurethral resection, used 194 TMN classification; Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared local pathologist was not usually a uropathologist van Rhijn () pathologist retrospective review of randomly chosen pt1 bladder tumours from two university hospitals, , TMN 2002 for stage Sharkey (8) patients pathologist retrospective central review on pathological specimens in multiinstitutional phase II study of a pharmacological immune enhancer 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 patients with primary pt1 nonmuscle invasive (NMI) bladder cancer, all had transurethral resection of primary bladder tumour cytological (bladder washing) and bladder biopsy specimens from patients with in situ transitional cell carcinoma of the bladder 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 + stage, overall pt1 pta pt1 pt2+ 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) of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 4

7 Author Year 2 nd Isfoss (9) 2011 a Isfoss (10) 2011 b Reviewers Reviewer (Profession/ Training) 1 88 expert uropathologist; consensus of expert + 2 general pathologists if discrepancy general pathologists and one uropathologist; consensus if a disagreement Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared blind review of all urinary bladder surgical specimens received at Telemark Hospital (Norway) for study of diagnostic features; overlaps with Isfoss et al, 2011b consecutive bladder tissue samples reevaluated blindly for IUN; 81 specimens from 53 patients; overlaps with Isfoss et al, 2011a Raitanen (11) cytopathologist multicenter study; consecutive samples read by local pathologist (19 institutions) then sent for central review, Classed as negative or positive (Papanicolaou classes I-III or IV-V), graded by WHO 193 system, staged by TNM 198 Ajit (12) unknown cases from at Tata Memorial Hospital (India) were reviewed retrospectively Lohse (13) urologic pathologist review of renal cell carcinoma (RCC) originally diagnosed at the Mayo Clinic and treated with radical nephrectomy 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 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 Bladder - Urine Samples 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 urine specimens from patients with suspected primary bladder cancer, final diagnosis by histology then all cases critically reviewed Kidney modified Fuhrman grade, 4- tiered grading system based on nuclear atypia 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+) classification: dysplasia, CIS, AUS (atypia of unknown significance), no IUN (PUN) PUN (IUN, dysplasia +CIS) other PUN CIS PUN dysplasia 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 overall negative urothelial carcinoma negative inadequate sample nuclear grade of clear cell RCC upgraded downgraded nuclear grade of papillary RCC upgraded downgraded nuclear grade of chromophobe RCC upgraded downgraded of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 5

8 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Ficarra (14) uropathologist with experience with RCC Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared retrospective slide review of renal cell carcinoma cases at University of Verona, Italy, to determine reproducibility of Fuhrman nuclear grade Huang (15) pathologist central pathology review of samples from the National Wilms Tumor Study -5 (NWTS-5), Vujanic (16) various trials pathologist central pathology review (CPR) in International Pediatric Oncology Society (SIOP) trials and United Kingdom Wilms Tumour 3 (UKWT3) trial; ; retrospective analysis of discrepancies Gunia (1) pathologists grading using Broder s grading system (BGS); reviewed selected representative slides from each case Malhotra (18) pathologists retrospective chart review and review of slides of penile cancer cases , to confirm diagnosis and stage (AJCC TNM staging system) Naumann (19) experienced pathologist and 3rd year resident in general pathology retrospective review: comparison of local and review pathologists' diagnoses, ; histological reassessment according to TNM and WHO classifications of grade and stage pathology slides from all patients who had undergone surgical treatment for conventional renal cell carcinoma (RCC) specimens diagnosed as clear cell sarcoma of the kidney (CCSK), rhabdoid tumor of the kidney (RTK), cellular mesoblastic nephroma (CMN) material from renal tumor trials in children; reported diagnostic differences excluding purely stage discrepancies; major = clinically significant discrepancy or inappropriate treatment Penis consecutive patients with surgically treated penile squamous cell carcinomas, reviewed conventionally stained histology slides 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 patients with squamous cell carcinoma of the penis, tumour-free surgical margins, original histopathology used current TNM guidelines overall grade 1 grade 2 grade 3 grade 4 of Subtype Discrepancy, % Agreement All Major Minor % Kappa overall SIOP 6 (1980-8), 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 (198-91), except stage SIOP ( ), except stage stage UKWT3 trial ( ), except stage stage grade, Pathologist A grade, Pathologist B overall, well or moderately differentiated grade and stage grade overall grade 1 grade 2 grade 3 stage overall stage T1 stage T Genitourinary Cancer Evidence Summary Page 6

9 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Lee (20) histopathologists? Delaney (21) specialist urological histopathologist Albers (22) reference pathologist for clinical trial Swaro (23) histopathologists with special interest in urological pathology Netto (24) urologic pathologist Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared central review prior to management decisions at the regional referral centre (Southampton University Hospital, UK), ; retrospective review of reports central review prior to management decisions at the regional referral centre (Southampton University Hospital, UK), ; retrospective review of reports Review by reference pathologist to confirm eligibility for clinical trial central review at University Hospital Birmingham, UK before treatment ; retrospective audit of reports for discrepancy and completeness Testes all testicular specimens for suspected tumour (five biopsies, 201 orchidectomies); recommend central review due to low incidence 291 testicular specimens (280 orchidectomies, 11 biopsies) from 15 local hospitals ; recommend central histopathologic review histologically confirmed nonseminomatous testicular germ cell tumors (NSGCT) after orchidectomy as reported by the local pathologist patients with testicular tumours tumour type tumour elements in NSGCTs vascular invasion in NSGCTs vascular invasion in NSGCTs, excluding cases with no comment 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 of Subtype Discrepancy, % Agreement All Major Minor % Kappa NSGCT seminoma tumour type components of NSGCT lymphovascular and cord invasion Prostate Prostatectomy (see also Biopsy ) 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 8/9, 13% of all samples) Downgraded (mostly 8, 4% of all samples) change by 2 Gleason score points tumour extent (0/256 upstaged, /256 down-staged) seminal vesicle invasion margin status (+ve -ve) lymph node status change in progression free survival estimate Genitourinary Cancer Evidence Summary Page

10 Author Year 2 nd Reviewers Goodman (25) (3 if disagree) Reviewer (Profession/ Training) 388 urologic pathologists Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared 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 Kuroiwa (26) uropathologist retrospective central review of RP specimens in Clinicopathological Research Group for Localized Prostate Cancer disease registry, Japan (50 institutions), ; central review GS assigned according to the 2005 ISUP consensus [GS scoring system revised between original and review diagnosis] 120 prostatectomies, report original pathology vs. final (gold standard consensus) RP specimens from patients with ct1c-3 prostate cancer and no preoperative therapy Gleason Pattern & Score: prostatectomy under-grading over-grading pattern score GS 2-6 other GS 2-6 GS other GS 8-10 GS 8-10 other GS 8-10 Gleason score Gleason pattern overgrading undergrading diagnosis diagnosis GS 2-6 other GS 2-6 GS other GS 8-10 GS 8-10 other GS 8-10 extracapsular extension seminal vesicle invasion lymph node involvement positive surgical margin of Subtype Discrepancy, % Agreement All Major Minor % Kappa Stark (2) 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, Chuang (28) ? second opinion after signout, The Johns Hopkins Hospital, prostatectomy (n=693) and biopsy (n=119) specimens of patients diagnosed with prostate cancer RP specimens with areas of capsular incision (CI) in otherwise organ-confined disease misdiagnosis (not prostate cancer) Gleason pattern, prostatectomy Gleason score, prostatectomy GS 2-6 other GS 2-6 GS other GS 8-10 GS 8-10 other GS 8-10 margin positive, CI margin positive, difficult to distinguish CI from EPE Genitourinary Cancer Evidence Summary Page 8

11 Author Year 2 nd van der Kwast (29) Reviewers Reviewer (Profession/ Training) pathologist with experience in urogenital pathology Berney (30) review by 3 genitourinary pathologists for first 100 cases, 1 pathologist for rest except contentious or negative cases ( 10%) Berney (31) genitourinary pathologists; 3 pathologists for first 100 cases and 10% of rest (difficult cases) Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared central review of pathological stage and surgical margin status in EORTC trial, central retrospective review of pathological specimens from patients in UK from 6 cancer registries; retrospective central review of original diagnostic pathological specimens within a multicenter study of watchful-waiting vs. hormonal therapy in UK, Initial Biopsies, Including Benign, Suspected, Atypical, and/or Precancerous samples RP specimens; pathological stage pt3 and/or positive surgical margin at local pathology patients diagnosed with clinically localized prostatic cancer and treated by watchful waiting or hormonal therapy, age < 6 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 men <6 years old at time of pathological diagnosis with clinically localized prostatic cancer; subset with GS included in both reports (454 diagnosed by TURP, 34 by needle biopsy) Prostate - Biopsy seminal vesicle invasion positive negative extraprostatic extension positive negative surgical margin status positive negative cases reassigned to non-malignant diagnosis Needle biopsy TURP specimens cancer (discrepancy = cancer not confirmed), biopsy or TURP samples GS, overall, TURP GS 2-6 other GS 2-6 GS other GS 8-10 GS 8-10 other GS 8-10 discrepancy = GS changed by 2, TURP of Subtype Discrepancy, % Agreement All Major Minor % Kappa Arista-Nasr (32) pathologists, consensus of 2 pathologists (20 yr and 3 yr experience) Patel (33) cases senior surgical pathologist Wolters (34) urologic pathologists detailed revision of prostate biopsies with original benign diagnosis, review of prior negative prostatic needle biopsies following a new diagnosis of prostatic adenocarcinoma discordant biopsies in European Randomized Study of Screening for Prostate Cancer (ERSPC), ; biopsies if PSA level 4.0 ng/ml or one hundred consecutive patients with first prostate biopsy diagnosed as benign 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 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; overall; benign potentially malignant ( 5 cases of ASAP, 3 cases with glands with xanthomatous cytoplasm, 1 with scarce atypical cells in prostatic stroma) initially negative samples adenocarcinoma (both cases Gleason 3+3) benign (adenocarcinoma on follow-up) benign ASAP benign adenocarcinoma All missed cancers were Gleason score 6 (3+3) Genitourinary Cancer Evidence Summary Page 9

12 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Bostwick (35) consensus of 2 urological pathologists Marshall (36) Marshall (81) (study details) central pathology review Oxley (3) pathologist with special interest in uropathology Oxley (38) , from 595 patients pathologist with special interest in uropathology Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared abnormal digital rectal examination or transrectal ultrasound (TRUS) [biopsy only if PSA 3.0 ng/ml in last year of study]. prospectively evaluated all "2nd opinion" prostate biopsies referred to them March-April 2006 central pathology review of patients with HGPIN in prostate cancer prevention trial, SWOG (Southwest Oncology Group) S991, initial report by 15 histopathologists (including 2 with interest in uropathology and deemed specialists who also did the reviews), years (includes samples from Oxley, 2005) central review of cores reported by 8 general histopathologists, year 2002 only authors extrapolated a falsenegative rate for the entire study of 2.4% (1.1% cancer, 1.3% ASAP) consecutive patients who were diagnosed and finalized by outside referring pathologist as having high grade PIN (high grade PIN, PIN2, PIN3, PIN2-3) biopsy-confirmed diagnosis of HGPIN with no evidence of cancer, PSA >=10 ng/ml all prostatic core biopsies, were classified as benign, atypical not amounting to HGPIN, HGPIN, suspicious for malignancy, prostatic adenocarcinoma all prostatic core biopsies 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] HGPIN not confirmed HGPIN cancer HGPIN no HGPIN 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 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 of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 10

13 Author Year 2 nd Jara-Lazaro (39) Reviewers Reviewer (Profession/ Training) pathologist with uropathology interest Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared queries submitted for a second opinion, 3% from clinicians and 2% 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 2 nd 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 GS GS 8-9 GS 8-9 of Subtype Discrepancy, % Agreement All Major Minor % Kappa Helpap (40) uropathologist comparison of submitting diagnosis and final diagnosis, Germany, 2003 Chan (41) urological pathologist second opinion requested by patients (n=148) and urologists (n=43) or both (n=99), Johns Hopkins Hospital, year 2001 prostate punch biopsies: small suggestion lesions 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 +, 8+ ) overall cancer changed to suspected/atypical suspected/typical changed to cancer inconspicuous/non-diagnostic to suspected/atypical 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 Genitourinary Cancer Evidence Summary Page 11

14 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Cases Diagnosed as Prostate Cancer, most include Gleason Score Berg (42) uropathologist re-evaluation of all patients referred for curative treatment of prostate cancer at a tertiary referral hospital (Copenhagen University Hospital Rigshospitalet) , used 2005 WHO/ISUP system Brimo (43) general surgical pathologists with extensive experience with prostate pathology; consulted with 1-2 urologic pathology experts for discrepancies Truesdale (44) biopsies, 100 patients Al-Hussain (45) [may include cases reported in Fajardo Fajardo (46)] GU pathologist leader in the field of urological pathology Fajardo (46) leader in the field of urological pathology Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared mandatory second opinion review of cases referred for RP in 2008 at Johns Hopkins Hospital; GS assigned according to the 2005 ISUP consensus re-evaluation of outside needle core biopsy diagnosis prior to surgery, , used 2005 ISUP system consultation files at The Johns Hopkins Hospital from ; only cases with final diagnosis by original pathologist, most requested by patient or treating physician 2nd opinion at Johns Hopkins Hospital at the behest of clinicians or patients; ISUP 2005 system prostate core needle biopsies, Gleason score grouped into not evaluable, <= 5, 6,, and 8-10 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,, 8-10) men with positive core needle biopsies who underwent robotic-assisted radical prostatectomy; 331 cores in 100 patients prostate biopsy cases in which Gleason pattern 5 was identified on review 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 diagnosis of prostate cancer tumour laterality apical involvement Gleason score not evaluable/not assigned (all 8-10 ) change in clinical evaluation (tests) due to review change in surgical planning due to review cancer to atypical or benign GS, overall GS 6 ( all 6 ) GS GS 6 GS 8-10 GS 8-10 GS GS 8-10 Gleason score in biopsies primary grade secondary grade % core involvement Gleason pattern 5 not identified original Gleason score increased original score decreased GS GS 8-10 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 of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 12

15 Author Year 2 nd Reviewers Goodman (25) (3 if disagree) Reviewer (Profession/ Training) 388 urologic pathologists Kuroiwa (4) Uropathologist Note: GS scoring system revised between original and review diagnosis Kishimoto (48) pathologist with genitourinary expertise Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared 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 retrospective central review of prostate biopsy specimens in Clinicopathological Research Group for Localized Prostate Cancer, disease registry, Japan (48 institutions), ; second review GS assigned according to the 2005 ISUP consensus change in NCCN classification that would make a difference to therapy (PPB indicated for classification as good or intermediate risk excluding GS 4+3); Grubb (49) pathologist Central pathology review in follow-up after clinical trial, Gleason scoring system unknown for local pathologists, classic (1966) system for review Wayment (4) urologist + pathologist; 3rd (or 4th) pathologist if disagreement D'Souza (50) genitourinary pathologists retrospective review of records: practice at tertiary referral centre to request pathologic materials for all patients seen in consultation for urologic malignancy; central review of all specimens from patients referred to Sunnybrook Health Sciences Centre in 268 biopsies, report original pathology vs. final (gold standard consensus) biopsy specimens from patients with Stage ct1c-t3 disease and no preoperative therapy that underwent RP Biopsies from patients referred by outside hospitals to a permanent prostate brachytherapy (PPB) institute for treatment of prostate cancer biopsy if prostate cancer suspected (130/216 cases due to rising PSA levels), only central review of positive samples 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 prostate needle-core biopsies; classified as low (GS 2-6), intermediate (GS ), or high (GS 8-10 risk category Gleason Pattern & Score: biopsy pattern score 2-6 (all except 1 case ) 8-10 (rest go to 2-6) 8-10 (all ) undergrading overgrading biopsy, pattern, overall (5 groups) score (2-4, 5-6,, 8-10) GS 2-6 GS 2-6 (rest go to 8-10) GS GS 3+4= GS 4+3= GS 8-10 (rest go to 2-6) GS 8-10 GS 8-10 (rest go to 2-6) pathologic discrepancy on slides change to no malignancy or atypical Gleason grade change upgrade downgrade treatment change based on pathology slide review diagnosis of prostate cancer other (2 atypical small acinar proliferation, 1 no cancer) 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) change in risk category GS 2-6 GS 2-6 GS of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 13

16 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Barqawi (51) urologic pathologist Sooriakumaran (52) pathologist with special interest in prostate cancer Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared 2003; extracted primary and secondary Gleason score, number of sites, % involvement, perineural invasion, extracapsular extension from original and 2nd review reports review of all needle core biopsies (NCB) diagnosed by outside pathologists in patients referred to 2nd institution for management, routine specialist review of all diagnostic biopsies; retrospective review of records from 19 month period with complete pathology datasets Fine (53) pathologists retrospective review of reports: outside institution Gleason score of needle biopsies compared to review at Johns Hopkins Hospital, van der Kwast (54) pathologist pathologist second review of prostate needle biopsies, to end of 2002 Coard (55) pathologist retrospective review of all prostate biopsy specimens diagnosed as adenocarcinoma at University Hospital of the West Indies, year 2000 patients with original "outside" NCB evaluation, 2nd "in-house" evaluation and diagnosis of prostatectomy specimen; excludes samples sent for second opinion biopsies of all patients with prostate cancer referred for brachytherapy; major =change in Gleason rating that altered clinical risk (Seattle Risk Grouping, SRG) patients with prostate cancer; reports available for outside and Johns Hopkins needle biopsy and radical prostatectomy samples cases diagnosed as adenocarcinoma on needle biopsies from participants to screening programme with elevated PSA interobserver comparison of Gleason scores in prostate needle biopsy specimens diagnosed as adenocarcinoma GS (all 8-10) GS 8-10 GS GS 8-10 missing elements in external reports primary Gleason score secondary Gleason score number of biopsy sites overall % involvement perineural involvement extracapsular extension Gleason scores 1st pathologist compared to prostatectomy 2nd pathologist compared to prostatectomy Gleason score, overall GS 2-5 GS GS 2-5 GS 6 GS 6 5 GS 6 GS (all 8-9) GS 8-9 Gleason score, needle biopsy GS 2-4 (n=22 5/6, n=1 ) GS 5-6 GS 5-6 GS GS GS 5-6 GS 8-10 GS 8-10 GS GS 8-10 false positive, centre 1 false positive, centre 2 overall of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 14

17 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Thomas (56) genitourinary pathologists Nguyen (5) genitourinary pathologist Renshaw (58) urologic pathologist Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared mandatory pathology review of all patients being considered for brachytherapy at British Columbia Cancer Centre, ; data analyzed retrospectively for before and after 2002 second opinion at academic centre after being diagnosed with prostate cancer based on a needle biopsy at a nonacademic institution, ; retrospective review of records comparison of original GS and reviewer's score, 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 (GS, adds androgen deprivation). GS 8+ or upgraded to 8+ were excluded as they are not considered for brachytherapy 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 prostate biopsies from men treated at a single communitybased institution; major= different prognostic group within one grade < overall, grouped as < or overall, Gleason score discrepancy = GS changed by discrepancy = GS changed by discrepancy = GS changed by 2 GS 3-5 GS GS 3-5 GS 6 GS 6 5 GS 6 GS (all GS 6) discrepancy = GS changed by 1 discrepancy = GS changed by 2 change in risk group (low, intermediate, high) GS 2-5 GS GS 2-5 GS GS 6 GS GS 6 GS GS GS 6 GS 8-10 GS 8-10 GS GS 8-10 GS, overall GS, years GS, years of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 15

18 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Wurzer (59) pathologist: specialist in prostate pathology Epstein (60) general surgical pathologist, 3rd surgical pathologist if discordant Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared interinstitutional: all samples from outside institutions are reviewed at Fox Chase Cancer Center to confirm diagnosis of malignancy, Retrospective review of these records interinstitutional: mandatory second pathological review of needle biopsies prior to surgery at Johns Hopkins Hospital, Steinberg (61) pathologists comparison of outside institution and Johns Hopkins Hospital biopsy grade, 1994 Berney (31) genitourinary pathologists; 3 pathologists for first 100 cases and 10% of rest (difficult cases) Winter (62) Pilepich (63) retrospective central review of original diagnostic pathological specimens within a multicenter study of watchful-waiting vs. hormonal therapy in UK, pathologist central pathology review of patients with prostate cancer in clinical trial (RTOG 85-31), ; discrepancy data in abstract only 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 consecutive men referred for RP with initial diagnosis of adenocarcinoma of the prostate original needle biopsy GS in patients with biopsy-proven prostatic adenocarcinoma and RP men <6 years old at time of pathological diagnosis with clinically localized prostatic cancer; subset with GS included in both reports (454 diagnosed by TURP, 34 by needle biopsy) Patients with prostate cancer, grouped as Gleason score 2-5, 6-, or 8-10; numbers in each group estimated based on proportion in 2nd review in other publication; 15% of patients had prostatectomy overall, based mainly on Gleason score GS change 2 overall (diagnosis went from adenocarcinoma to benign) GS overall GS 2-6 GS 2-6 GS GS GS 2-6 GS 8-10 GS 8-10 GS GS 8-10 cancer (discrepancy = cancer not confirmed), biopsy or TURP samples GS, overall, biopsy GS 2-6 GS 2-6 GS GS 8-10 GS 8-10 GS 8-10 discrepancy = GS changed by 2, biopsy Gleason score GS 2-5 GS 6- GS 8-10 of Subtype Discrepancy, % Agreement All Major Minor % Kappa Genitourinary Cancer Evidence Summary Page 16

19 Author Year 2 nd Reviewers Reviewer (Profession/ Training) Prescott (64) review at regional cancer treatment centre Kronz (65) mandatory 2nd opinion; all cases referred to treating institution, excludes consult cases with uncertain diagnosis Murphy (66) pathologist with expertise in urological pathology Weir (6) interinstitutional, at request of clinical staff of treating institution Ahmed (68) nd opinion at major referral centre Tsung (69) pathologists patients referred to cancer center for therapy or second opinion Type of Review, Notes Sample Description, Notes Sample Subtype, Change or Item Compared Studies that reported on genitourinary and other cancers, specific types not indicated cases with confident 1st diagnosis, excluded cases where 2nd opinion sought 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 consecutive urological cases with pathological specimens; discrepancies with clinical impact on prognosis or treatment; major = impact on treatment compared 1st and treating institution reports; major =clinical impact reviewed at Aga Khan University, Pakistan; most sent by clinicians, some by primary pathologists 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 Raab (0) pathologist review after sign-out conferences, external review, internal QA, physician request; self-report of 100 consecutive specimens at 4 institutions; major=harm or near miss Renshaw (1) Internal blinded review; 1/6 of cases from new pathologists, rest random major error leads to amendment, minor error requires no action of Subtype Discrepancy, % Agreement All Major Minor % Kappa testis genitourinary system (prostate, bladder) all: prostate, bladder, urethra, testis, kidney, penis prostate bladder, urethra genitourinary (histological samples) male genital tract prostate kidney and bladder genital, male urinary tract kidney all discrepancies Lu (2) external consultation kidney and bladder prostate penis 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 Genitourinary Cancer Evidence Summary Page 1