Best Practices for Oncologic Pathology Secondary Review ...

Evidence Summary #22-2-2

A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO)

Best Practices for Oncologic Pathology Secondary Review: Gastrointestinal Cancer Aaron Pollett, Glenn G Fletcher, David Hurlbut, Paul Karanicolas, Mahmoud Khalifa, Cathy Streutker, and John Srigley *

Report Date: June 26, 2014

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

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]

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QUESTION What types of specimens suspected to be or diagnosed as gastrointestinal cancer1 should or should not have routine secondary pathology review? INTRODUCTION This report is part of a series of reports on pathology secondary 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 gastrointestinal 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 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 and companion recommendations are 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 usually initiated at the request of the patient or treating clinician, multidisciplinary case conference (MCC) process, or quality control protocol, 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. 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 samples by a second pathologist (excluding review at the original pathologist’s request), be related to the diagnosis of gastrointestinal cancer or aspects of cancer such as 1

Cancer includes precancerous conditions that need to be distinguished from cancer, which may progress to cancer, or for which there is not general agreement as to whether they should be termed as cancer. #22-2-2 Gastrointestinal Cancer Evidence Summary

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grade or subtype, and report on diagnostic discrepancy or agreement between two (or more) pathologists. RESULTS For gastrointestinal cancers (esophageal, colorectal, and gastric cancers, as well as cancers of the liver and pancreas), the search resulted in 103 articles, of which 68 were reproducibility studies. The 35 studies on gastrointestinal cancer (2-36) that report agreement or disagreement between the initial and secondary pathology review are summarized in Table 1. There are an additional 12 studies that include gastrointestinal cancer along with other cancers (37-49). The study by Ahmed et al (42) reported a discrepancy rate of 33% but included samples submitted at the request of the primary pathologist. Rates in the other large studies (> 100 samples) were 1.2% to 6% for all discrepancies and 0.9% to 3% for major discrepancies (37,39,41,43-46,49). While data was not extracted from the reproducibility studies, these may be of interest to some readers and address specialized areas of pathologic interpretation, especially areas where more research or standardization is necessary. The publications are therefore listed separately in Appendix II. Studies from Literature Search (Table 1) A. Esophageal Cancer The study by Peng et al (2) reviewed false-negative brush cytology and mucosal biopsy samples from patients with adenocarcinoma of the esophagus or esophagogastric junction who underwent preoperative chemoradiation. The false-negative results for brush cytology samples were 40%; pathologic review indicated that pathology misinterpretation was the cause of 30% of the error in the samples reviewed, which would be equivalent to interpretation error in 12% of brush biopsy samples. For mucosal biopsy, accuracy was 36%, and interpretation error accounted for only 2% of the false-negative results. The rest of the studies involve patients with Barrett’s esophagus. Studies are on the diagnosis, dysplasia grade, or presence of intestinal metaplasia (IM). Lorinc et al (6) reported a diagnostic discrepancy rate of 4% to 12% with hematoxylin and eosin (H&E) staining. Agreement on dysplasia presence and type for three review pathologists increased from kappa =0.24 using H&E to kappa=0.72 with p53 immunohistochemistry (IHC). Two large studies (7,9) report 3% and 12% discrepancy rates for identifying the presence of IM, while several studies report discrepancy rates in grade of dysplasia of 28% to 90%. Yerian (50) reviews the histology in Barrett’s esophagus and concludes that the diagnosis of dysplasia should be confirmed by a pathologist experienced in Barrett’s esophagus before aggressive therapy is contemplated. The study by Stolte et al (11), in which a secondary review was performed by a pathologist with considerable experience in Barrett’s diagnostics, found that 15% of specimens with initial diagnosis of high-grade intraepithelial neoplasia (HGIEN) had no IEN on review, and secondary review would thus avoid overtreatment in these patients. A higher portion (77%) of HGIEN had a review diagnosis of cancer, though this is considered less clinically relevant as both lead to treatment. Hulscher et al (4) reported 28% discrepancy in high-grade dysplasia, of which all were considered to result in a change in therapy. For low grade dysplasia, some studies (3,7) found that a GI specialist did not perform better than a general pathologist, though Pech et al (8) reported less disagreement for GI pathologists (18% versus 50%). Two large studies (7,9) report 3% and 12% discrepancy on presence of IM, while several studies report discrepancy in the grade of dysplasia of 28% to 90%. Hulscher et al (4) indicated 90% discrepancy in low-grade dysplasia diagnoses, but all discrepancies were considered minor (affecting follow-up but not immediate therapy).

#22-2-2 Gastrointestinal Cancer Evidence Summary

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Table 1. Pathologic discrepancy rates between primary and secondary review pathologists: gastrointestinal cancer. (Note: for ease of reading, a suggestion is to print this table or enlarge (zoom) it to 120% on the computer monitor.)

Author

# 2nd # Reviewer Year Reviewers Specimens (Profession/ Training)

Type of Review, Notes

Sample Description, Notes

Peng (2)

2009

review of false negative brush cytology samples

patients with esophageal or esophagogastric junction (EGJ) adenocarcinoma who underwent preoperative combination chemoradiation (CRT)

Sample Subtype, Change or Item Compared

# Specimens of Subtype

Discrepancy, % All Major Minor

Agreement % Kappa

Esophagus 2

67

pathologists

false negative cases, discrepancy due to interpretation brush cytology

27

30

70

mucosal biopsy

41

2

98

43

Pathologist GI-1

30

70

Pathologist GI-2

44

56

Barrett's Esophagus Skacel (3)

Hulscher (4)

Baak (5)

Lorinc (6)

Kerkhof (7)

2000

2001

2002

2005

2007

3

1

1

3

1

43

GI pathologists

30

143

115

920

pathologist with special GI interest

blind review to determine variability of low grade dsyplasia diagnosis

patients with Barrett's esophagus, 43 samples originally coded as low-grade dysplasia (LGD) plus 57 others for blinding purposes

original diagnosis of low grade dysplasia

2nd opinion at specialized diagnosis /treatment centre

reassessment, including IHC, of biopsies diagnosed as Barrett's esophagus; major changed therapy, minor affects follow-up comparison of dysplasia grades in Barrett's esophagus

grade of dysplasia high grade dysplasia low grade dysplasia

30 18 10

50 28 90

grade of dysplasia

143

65

35

high grade dysplasia

23

48

52

low grade dysplasia

71

93

7

indefinite

22

73

27

0

100

consecutive biopsies

pathologists: 1 blinded comparison, special interest in GI, evaluation of IHC 1 resident, 1 from county hospital

expert GI pathologists

Blinded review by expert in trial to determine follow-up frequency

Pathologist GI-3

84

no dysplasia

27

biopsies diagnosed as Barrett's esophagus stained with H&E were compared to original diagnosis, and reevaluated for dysplasia using p53 and Ki67 IHC. Kappa for the 3 pathologists (dysplasia presence and type) increased from 0.24 using H&E to 0.72 with p53 IHC

diagnosis of Barrett's esophagus (H&E only) Observer 1

115

biopsy specimens from patients with Barrett's esophagus

presence of intestinal metaplasia (IM) patients with IM: grade of dysplasia


16 17 28 90

50 72 10

9

91

Observer 2

12

88

Observer 3

4

96

920

3

97

793

28

72

first pathologist was non-expert

698

28

72

first pathologist was expert

95

31

69

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Author





Pech (8)

2007

consecutive patients, reviewed in blinded fashion

initial diagnosis of low grade intraepithelia neoplasia (LGIN) in Barrett's esophagus; reclassified as no neoplasia, LGIN, HGIN, Barrett's carcinoma

original diagnosis of low grade dysplasia

Corley (9)

2009

Sonwalkar (10)

2010

Stolte (11)

2012

2

50

1

616

3

41

275

specialized GI pathologists

pathologist

slide review

experienced histopathologists

Pathologist with considerable experience in Barrett’s diagnostics

Second opinion review; checked by follow-up in 75% of patients


pathologist 1 (general) vs. final consensus pathologist 1 vs. pathologist 2 (specialist) pathologist 1 vs. pathologist 3 (specialist) pathologist 2 vs. pathologist 3


Agreement % Kappa

50

50

70

30

-0.17

76

24

-0.17

18

82

0.69 0.42

Barrett's esophagus: presence of intestinal metaplasia (IM) reproducibility of esophageal initial diagnosis of intestinal metaplasia intestinal metaplasia diagnosis initial diagnosis of gastric or columnar metaplasia

616

12

88

580

12

88

36

14

86

interobserver variation in indefinite dysplasia (IND) in Barrett's esophagus; 61 IND slides (41 patients) and 60 other slides Primary diagnosis of high grade intraepithelial neoplasia (HGIEN) in Barrett’s esophagus

original diagnosis of indefinite dysplasia histopathologist P1 histopathologist P2 histopathologist P3

41 66 93 71

34 7 29

HGIEN  HGIEN→ no IEN  HGIEN→ LGIEN  HGIEN→ Barrett Ca  2nd review compared to follow-up diagnosis

275

93 15 1 77 16

7 85 99 23

207

0.41

Anal Colquhoun (14)

2003

3

190

histopathologists, expert in field of anorectal pathology

representative samples of entire spectrum of anal dysplasia

Severity of anal dysplasia Pathologist 1 Pathologist 2 Pathologist 3 Complete agreement, original and reviewers

0.38 0.48 0.60 68

32

35

65

Colorectal Yoon (12)

2002

2 (consensus)

326

pathologists

central review in trial colorectal polyps detected at to determine efficacy colonoscopies: second of aspirin to reduce interpretation on new sections colonic adenoma recurrence


Non adenomatous polyps

71

Adenomas adenomatous nature

255

4

96

0.67

histological type (tubular, tubulo-villous, villous) degree of dysplasia (mild, moderate, severe, carcinoma in situ) degree of dysplasia (low or high)

255

33

67

0.46

255

44

56

0.26

255

20

80

0.34

histological type + degree of dysplasia

255

64

36

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Author




Terry (13)

2002

colorectal adenomatous polyp histological type cases from colonoscopy-based degree of dysplasia (5 categories) case-control study degree of dsyplasia (high versus low grade)

Komuta (15)

Denis (16)

BustamanteBalen (17)

Khalid (18)

Lu (19)

2004

2009

2009

2009

2010

1

3

2

1

3

3

318

pathologists

central review compared to community pathologists

71

pathologists

88

experienced gastrointestinal pathologists

central review vs. diagnosis from 4 study sites using uniform pathology criteria slides reviewed in blinded fashion, unaware of initial or each other's results

300

195

40

1402

expert GI pathologists

advanced adenomas initially initial diagnosis of severe dysplasia or diagnosed in endoscopy based carcinoma in situ case-control studies of adenomatous polyps endoscopic removal of  malignant colorectal polyps malignant polyps identified as carcinoma in situ on review  T stage (depth of tumour)  resection margin status  Level of invasion (Haggitt's classification)  histology grade (well vs. moderately differentiated) blind to original colorectal polyps detected by benign polyps diagnosis and other fecal occult blood test malignant polyps expert; 155 slides colorectal cancer screening; histological type needed joint exam to included all serrated reach consensus adenomas (71), Tis (77) and T1 serrated adenoma carcinomas (39), rest random degree of dysplasia (114). [comment: histological type + degree of dysplasia inconsistencies between table diagnosis extrapolated to all screened and text]

pathologists, special unaware of previous interest in GI diagnosis

GI pathologists

GI subspecialist or special interest


187 hyperplastic polyps (Hp) and 7 serrated adenomas (SA) from colonoscopies; reevaluated as HP, SA, traditional serrated adenoma (TSA), sessile serrated adenoma (SSA). [inconsistencies and missing data] diagnosis in 2001, consecutive proximal colon review in 2007; aware polyps ≥ 5 mm in size of original diagnosis originally interpreted as hyperplastic polyps search for sessile serrated adenomas

colorectal polyps biopsied endoscopically with original diagnosis of hyperplastic polyps (HP); cases rediagnosed as sessile serrated adenomas (SSA) were studied




Agreement % Kappa 0.31 0.05 0.14

18

82

14

86

0.52 0.56 0.58 0.14 261

65

36

29

36

35

26

292

53

47

70

84

16

297

38

62

63

37

2560

55

27

28

45

Pathologist 1

142

45

55

Pathologist 2

183

9

91

type/subtype of hyperplastic polyps

hyperplastic changed to sessile serrated adenoma Pathologist A Pathologist B Pathologist C hyperplastic changed to sessile serrated adenoma (other changes not recorded)

0.16

1402

43 30 85 5.8

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57 70 15

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Author van Putten (20)



2011

first evaluated by either a general or expert pathologist, then reevaluated by expert pathologist

1

Kennecke (21)

2012

1

Huang (22)

2013

2

440

38

expert pathologist

pathologist

95 Gastrointestinal specimens pathologists (83 cases)



 adenomatous or non-adenomatous nature  initially by general pathologist  initially by expert pathologist  adenomas: non-advanced vs. advanced  initially by general pathologist  initially by expert pathologist  low-grade vs. high-grade dysplasia  tubular/tubulo-villous vs. villous adenoma clinical drug trial: patients with locally advanced tumour stage central pathology or low rectal cancer stage II-IV; review after review at surgical specimens after the local institution neoadjuvant chemotherapy and radiation. major discrepancy affected the primary endpoint (pCR rate) Retrospective review, WHO classification criteria, 2006-2010, originally diagnosed by several pathologists in both academic and community hospitals

randomly selected polyps from Dutch randomized population-based colorectal cancer screening programme (CORERO 1)

Rectal polyps diagnosed originally as sessile serrated adenoma (SSA), serrated polyp, or hyperplastic polyp (HP) with features of SSA



Agreement % Kappa

440

4

96

0.88

324 116 322

4 4 17

96 96 83

0.89 0.86 0.58

230 92 322 315

20 11 6 18

80 89 94 82

0.56 0.64 0.62 0.55

38

16

26 52

42 100

58 0

78

40

60

gastrointestinal, other than liver missing or unclear information diagnostic disagreement

106

18 3 15

local vs control reader benign, malignant, dubious categories dubious/negative vs others local vs final (panel) dubious/negative vs others

1223

 SSA → other (HP-P or HP)  HP with features of SSA → HP, HP-P, inflammatory-type polyp, SA unclassifiable  SSA or HP + SSA features → HP-P

8

84

HP-P is HP with mucosal prolapse

GI, various Hahm (23)

Piaton (24)

2001

2011

1

106

1; 7 (consensus)

1223

GI pathologist

Academic cytopathologist (control reader) aware of specimen type but blinded to previous diagnosis; panel of 7 cytopathologists

review at request of treating physicians; exclude 2nd opinion requested by referring pathologist Local readers (primary review) then control reader blinded to previous diagnosis; discordant cases, concordant positive results, and random selection of negative concordant cases reviewed jointly by panel of 7 cytopathologists (final diagnosis)

All discrepant diagnoses were reviewed by a 3rd pathologist; major =significant change in therapy or prognosis; minor=minimal change Study on detection of intraperitoneal free cancer cells (IFCCs) from serous fluids in patients undergoing surgery for non-gynecologic peritoneal adenocarcinomas previously ascertained by histopathology; excluded primary peritoneal malignancies (malignant mesothelioma and pseudomyxoma peritnei) or benign tumours


272

8 5 13 3

Page 6

8

1 4

82 97 85

92 96 87 97

0.59 0.70 0.93

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Author



Plummer (25)

1997

chemoprevention trial biopsy of precancerous on stomach cancer stomach lesions; stratified random sample with 10 subjects each for 5 diagnostic categories based on original diagnosis prospective study; hyperplastic gastric polyps: review by reference review of samples with pathologist relevant diagnostic difference between biopsy and polypectomy or focal carcinomas initial diagnosis of high reclassified as low grade grade (HGD) or severe dysplasia (LGD), HGD, dysplasia of the gastric suspicious for invasive epithelium by carcinoma, or intramucosal endoscopic biopsy carcinoma (IMC) using the Vienna system cases for second consecutive cases diagnosed opinion as stomach cancer, suspected stomach cancer, suspected neoplasia, adenoma





Agreement % Kappa

42 22 24 8 38

59 78 76 92 62

43

57

Gastric 2

50

pathologist

Muehldorfer (26)

2002

1

21

pathologist

Sarela (27)

2005

3

22

specialists in gastrointestinal histopathology

Vieth (28)

2010

1

738

Pathologist X vs baseline (Y or Z) Pathologist Y vs baseline (X or Z) Pathologist X vs Y on review intestinal metaplasia superficial, chronic or atrophic gastritis

32 33 49 13 32

histological classification, biopsy + polypectomy samples

high grade/severe dysplasia reclassified pathologist 1 pathologist 2 pathologist 3

18 15 16

39 67 81

61 33 19

overall

738

51

49

pseudoneoplastic regeneration

138

38

62

Low grade adenoma (41% downgraded, 48% carcinoma) cancer or suspected cancer

119

89

11

300

28

72

signet ring cell carcinoma

56

10

90

Pancreas Nitecki

1995

2

186

(29)

Conlon (30)

Logrono (31)

1996

2000

1

1

one internal and one retrospective review external pathologist of histological specimens from patients surviving > 3 years

131

36

cytopathologists

patients with pathologic diagnoses of ductal adenocarcinoma who underwent potentially curative pancreatic resection. Excluded those with palliative surgery, pure intraductal or endocrine pancreatic tumours; cancers arising in bile duct, duodenum, ampulla of Vater

3-year survivors (2nd review)

31

39

all patients (assumes non-survivors were correctly diagnosed, no 2nd review of these)

186

6

retrospective review of pathologic material from patients surviving > 5 years

patients with histologically confirmed diagnosis of invasive ductal adenocarcinoma of the pancreas who underwent resection with curative intent

5-year survivors (2nd review)

25

52

all patients (assumes non-survivors were correctly diagnosed, no 2nd review of these)

131

10

slide review of false negative cases , not blinded

pancreatobiliary brushing false negative due to interpretation cytology specimens false negative due to technical (slide determined false negative by preparation) errors histology or clinical correlation

36 36

17 17


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83 83

0.69

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Author


Luttges (32)

2000

1

70

CarpelanHolmstrom (33)

2005

3

24

Niedergethmann (34)

2008

1

207

Pomianowska (35)

2012

2 (consensus)

207

Kulesza (36)

2004

1

64




review of grading and ductal adenocarcinoma of the tumour grade proliferation index (PI) head of the pancreas from proliferation index partial duodenopancreatectomy expertise in slide review, double cases in registry with PDAC determined wrong on review pancreatic pathology blinded pancreatic cancer and > 5 year survival recorded as histologically proven pancreatic ductal adenocarcinoma (PDAC) pathologist review to look for reevaluated pancreatic cystic/small tumours reevaluated as unidentified cases of resections initially diagnosed IPMN intraductal papillary- as cystic or small solid samples initially diagnosed as IPMN mucinous neoplasms tumours (excluded typical (IPMN) diagnoses such as ductal adenocarcinoma, chronic pancreatitis) experienced Surgery, primary and Classification of tumour origin Classification of tumour origin pancreatic review pathology at a in patients undergoing  DBC pathologists blinded third-level referral pancreatoduodenectomy for  Pancreas to original diagnosis institution periampullary adenocarcinoma  Ampulla  Duodenum


initial experienced, 2nd in 1st year of training


Agreement % Kappa

26

74

0.17 0.52

24

58

42

207

26

74

43

0

100

207 31 71 75 30

27 13 23 39 16

73 87 77 61 84

0.64

Liver cytopathologists

independent grading of core needle biopsy samples of hepatocellular carcinoma (HCC)

grades of well differentiated (WD), moderately differentiated (MD), poorly differentiated (PD); also compared to "true" diagnosis determined from excisional biopsy

agreement among cytopathologists well differentiated HCC

26

0.66

moderately differentiated HCC

22

0.32

poorly differentiated HCC

12

accuracy compared to "true" diagnosis

60

0.53 41

59

Studies that reported on several cancer sites Lind (37)

1995

1

528

Prescott (38)

1995

1

13

Kronz (39)

1999

1

1083

Layfield (40)

2002

1

20

pathologists

peer review after 1st pathologist finished report; excluded cases where consensus could not be reached review at regional cancer treatment centre

all diagnostic surgical pathology biopsies; major error=clinically significant; minor=no treatment change

gastrointestinal

cases with confident 1st diagnosis, excluded cases where 2nd opinion sought

gastrointestinal tract

mandatory 2nd opinion

all cases referred to treating gastrointestinal tract (4/13 institution, excludes consult discrepancies non-cancer related) cases with uncertain diagnosis

review of outside cytology material


528

23

1

2

8

15

1

77

99

liver

11

27

18

9

73

bile duct, liver, pancreas total

20

25

20

5

75

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Author





Weir (41)

2003

1

191

182

5

2004

1

52

liver, gall bladder, biliary tract, pancreas, salivary glands

52

33

67

Tsung (43)

2004

1

122

compared 1st and treating institution reports; major=clinical impact reviewed at Aga Khan University, Pakistan; most sent by clinicians, some by primary pathologists major discrepancies: benign to malignant or vice versa, different type of neoplasm, change in N or M of TMN classification

histological samples: gastrointestinal

Ahmed (42)

interinstitutional, at request of clinical staff of treating institution 2nd opinion at major referral centre

gastrointestinal tract

105

1

99

liver

17

6

94

conferences, external review, gastrointestinal and other internal QA, physician request; hepatobiliary self-report of 100 consecutive specimens at 74 institutions

1850

6

1.4

94

240

7

0.4

93

major error leads to amendment, minor error requires no action

1143

3

0.2

97

Raab (44)

Renshaw (45)

2005

2006

1

1

2090

pathologists

pathologist

1143

2007

Raab (47)

2008

1

87

Bomeisl (48)

2009

1

78

Lu (49)

2009

1

834

subspecialists

all surgical pathology cases referred to cancer center for therapy or second opinion

review after sign-out

Internal blinded rapid review; 1/6 of cases from new pathologists, rest random focused review of specific case types

colectomy specimens; major error=clinically significant, minor=no treatment change Cytopathologist or interinstitutional major =2 step deviation anatomic pathologist consultation, FNA, (unsatisfactory, benign, prior to treatment or atypical, suspicious, patient requested 2nd malignant) or change in opinion treatment or prognosis external consultation

gastrointestinal, all discrepancies


reviewer missed lesion

Discrepancy, % All Major Minor 3

0.6

colon

87

Liver Pancreas

78 24

12 12

6

29

9 8

3 4

digestive system

834

2

liver, gall

73

3

16

pancreas

16

6

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95

99

73


2

Agreement % Kappa

88 88

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B. Gastric Cancer Four studies reported on pathology review in gastric cancer. The largest study by Vieth et al (28) found a 51% discrepancy in cases diagnosed as stomach cancer, suspected cancer, or suspected neoplasia/adenoma that had been sent for second opinion. The same study (28) found a 28% discrepancy in cases diagnosed as gastric cancer or suspected cancer. While the reason for second opinion could not be determined, the high discrepancy rate may reflect the fact that second opinion is more likely requested in the most difficult cases. The study by Sarela et al (27) found that dysplasia initially graded as high or severe was reclassified by three pathologists in 44%, 73%, and 81% of samples. Plummer et al (25) reported discrepancy rates of 22% to 42% for precancerous lesions. Vieth et al (28) found 89% of low-grade adenoma had discrepancies, with 41% downgraded and 48% upgraded to carcinoma. C. Colorectal Cancer One study (21) reporting on secondary review in colorectal cancer used neoadjuvant therapy and radiation, and, therefore, the results cannot be applied to colorectal cancer generally. Seven studies (12,13,15-19) deal with colorectal polyps. Denis et al (16) tested polyps found after fecal occult blood test screening and estimated 55% discrepancy in histological type or degree of dysplasia, including 27% major and 28% minor. Yoon et al (12) reported a 33% discrepancy in histological type of adenomas and 44% discrepancy in degree of dysplasia. Studies reported 18% discrepancy in the diagnosis of advanced adenomas (13). The reinterpretation of hyperplastic polyps led to a change to sessile serrated adenoma in 6% of samples in one study (19), and changes of 43%, 30%, and 85% by three pathologists in another study (18). While the studies report large discrepancy rates, it should be noted that pathologic diagnosis of serrated adenoma has improved recently due to increased experience with these lesions and changes in classification systems, and thus several of the papers (e.g., (18,19)) are no longer relevant to current practice. Some of the authors indicate there is large variation among gastrointestinal (GI) pathologists, existing morphological criteria are not reproducible, and, therefore, clarification of nomenclature for serrated polyps is required. The study by Komuta et al (15) reported that 14% of malignant colorectal polyps had the diagnosis changed to carcinoma in situ on review. The study by Denis et al (16) reported 26% of malignant polyps had misclassification with potential impact on the treatment. D. Anal Cancer One study on anal dysplasia (14) was located; it found only poor to moderate agreement in grading. Complete concordance on the severity of anal dysplasia among the original and three review pathologists was observed in 32% of cases. They concluded that a better tool for the assessment of dysplasia is required, possibly including a simplified grading system and molecular biology markers. E. Pancreatic Cancer A review of false negative pancreatobilliary brushing cytology specimens (31) found 17% false-negative cases were due to pathologic misinterpretation and 17% due to technical errors such as slide preparation. Ductal adenocarcinomas of the head of the pancreas had a 26% discrepancy in histopathological grade between the original and review results (32), though this may be of limited relevance as one of the pathologists was inexperienced (first year of training). Cases recorded in a cancer registry as histologically proven pancreatic ductal adenocarcinoma with > 5 year survival were found to have a wrong diagnosis based on


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pathology review in 58% of cases. Samples initially identified as cystic or small tumours were reclassified as intraductal papillary-mucinous neoplasms in 26% of cases (34). F. Liver Cancer Kulesza et al (36) reported on the agreement of cytopathologists in grading core needle biopsy (CNB) samples of hepatocellular carcinoma (HCC). Kappa values for agreement were 0.53, 0.32, and 0.66 for poorly, moderately, and well-differentiated HCC, respectively. There was 41% discrepancy in grade between the CNB and excisional biopsies. No studies specifically on liver resection specimens were found in the systematic review. Interinstitutional reviews which included several cancer sites report 6% to 33% discrepancies for liver samples, and major discrepancies of 0.4% to 9%. Tsung et al (43) reported on several types of surgical pathology samples and indicated discrepancy in one out of 17 liver samples (6%). A survey on the impact of review after sign-out by Raab et al (44) included self-reported results from 74 institutions. For hepatobiliary samples, there were discrepancies in 7% of samples, including 0.4% that were judged major. Clinical Practice Guidelines The SIGN guideline on the management of esophageal and gastric cancer (51) recommends that diagnoses of invasive malignancies in esophageal or gastric cancer should be reviewed by a specialist GI pathologist at an appropriate multidisciplinary meeting. There is significant inter- and intra-observer variation among Western pathologists in the diagnosis of dysplasia and intramucosal cancer in patients with esophageal and gastric cancer. The revised Vienna classification for reporting dysplasia should be used. Grading is reasonably good for high-grade dysplasia/intramucosal adenocarcinoma and ‘no dysplasia’ but less reliable for grades in between. Low-grade dysplasia is often overdiagnosed by non-specialist pathologists. Where radical intervention is contemplated on the basis of high-grade dysplasia or early adenocarcinoma, the diagnosis should be validated by a second pathologist experienced in this area, and further biopsies should be taken if there is uncertainty. The evaluation of suspected high-grade dysplasia in Barrett’s esophagus biopsies should be undertaken with knowledge of the clinical and endoscopic background, and biopsies should be reviewed at a multidisciplinary meeting with access to the clinical information. European guidelines (European Union/IARC) for quality assurance in colorectal cancer screening and diagnosis (52) states that variation exists in evaluating high-risk features of pT1 colorectal cancer, and consideration should be given to obtaining an opinion from a second histopathologist if surgical resection is recommended. The European Society for Medical Oncology (ESMO) Guideline on gastrointestinal stromal tumours (53) recommends expert pathological second opinion in all cases when the original diagnosis is made outside reference centres. The PEBC/CCO Guideline on Hepatic, Pancreatic, and Biliary Tract (HPB) Surgical Oncology Standards (54) recommends a comprehensive approach to the investigation of HPB patients in specialized centres. Sophisticated technology and diagnostic expertise, especially in imaging and pathology, may not be widely available but is often required to sort out the more difficult cases. There needs to be a specialized liver pathologist onsite. A pathologist with a special interest in HPB diseases and a commitment to developing the appropriate expertise is required. The International Gastric Cancer Linkage Consortium consensus guideline on hereditary diffuse gastric cancer (HDGC) (55) recommends expert histopathological confirmation of these early lesions. Confirmation by an independent histopathologist with experience in this area is strongly recommended for precursor lesions of early invasive signet ring cell carcinoma (in situ signet ring cell carcinoma, pagetoid spread of signet ring cells


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below the preserved epithelium of glands, and foveolae). As experience in the observation of prophylactic gastrectomies for HDGC is quite limited in most pathology departments due to the rarity of these surgical specimens, the guideline recommends centres of excellence be established worldwide, along with a virtual bank of lesions observed in the setting of HDGC. It is essential that clinical experiences and research progress are combined in order to benefit patient management. The UK/Ireland guideline on gastroenteropancreatic neuroendocrine tumours (NETs) (56) recommends management by a multidisciplinary team (MDT) at a referral centre which includes specialist physicians in NETs (gastroenterologists, oncologists and/or endocrinologists), surgeons, radiologists, nuclear medicine specialists, histopathologists, and clinical nurse specialists. Pathologists dealing with NETs should have a special interest in endocrine or gastrointestinal pathology or participate in a network with the opportunity for pathology review. DISCUSSION In some of the studies, missing information was a major reason for secondary review. Specimens with reports that are missing key information such as type, grade, or margins need to be referred back to the primary pathologist or have secondary pathology review. Initial (primary) pathology reports should include synoptic reporting, as stipulated in the CAP protocols (see http://www.cap.org), which are based on the American Joint Commission on Cancer (AJCC) standards (57). CCO and the CAP/APC have endorsed the CAP cancer checklists as the content standard for pathology reporting (58,59). Synoptic reporting can help ensure that reports are complete, and in Ontario such reports are currently required for resection specimens (esophagus, gallbladder, hepatocellular carcinoma, intrahepatic bile ducts, pancreas, perihilar bile ducts, small intestine and ampullla neuroendocrine tumours, small intestine, stomach) (59). Most studies base dealt with primary review by pathologists without specific expertise in gastrointestinal cancer, followed by secondary pathology review by a specialist prior to treatment, or retrospective evaluation to verify the diagnosis or specific features. There is only limited information on secondary review when the primary pathologist is a gastrointestinal pathologist, and this should continue to be decided on a case-by-case basis or institutional policy. The authors believe that secondary review, when conducted, should be by a gastrointestinal pathologist; however, the evidence extracted did not directly address this issue. In Canada there is no precise definition of a gastrointestinal pathologist. In Ontario most secondary review will be in cancer centres where pathology specialization occurs. A. Barrett’s Esophagus The SIGN guideline (51) recommends secondary pathology review whenever radical intervention is contemplated based on high-grade dysplasia or early adenocarcinoma. Current practice in Ontario is to review biopsies prior to surgery, and the studies in Table 1 support review of high-grade dysplasia. For low-grade dysplasia specimens there is considerable variability between pathologists and in different practices. While underdiagnosis is an issue, the value of routine secondary review is questionable. Most patients will receive follow-up and thus further diagnosis at a later date; whether or not follow-up is planned may be a consideration in deciding on secondary pathology review. B. Gastric Cancer The SIGN guideline (51) recommends secondary pathology review whenever radical intervention is contemplated based on high-grade dysplasia or early adenocarcinoma. In


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Ontario, HER2 testing is currently mandated for gastric and gastroesophageal junction adenocarcinomas (60) (letters from Jennifer Hart, Manager, Pathology & Laboratory Medicine Program, Cancer Care Ontario: “Gastric HER2/Neu testing FAQ's – final” 2011 Nov; “Gastric HER2/Neu testing update” 2012 Dec 19). CCO guidelines indicate that these should be sent at the time of the first diagnosis. Through the course of this testing, the gastrointestinal pathologist is performing a limited review in order to do the HER2 testing; this is predominantly in the areas of tumour type (intestinal versus diffuse) and grade. An inability to assess the HER2 status due to uncertainty regarding the diagnosis of gastric cancer would be part of the pathology report. The authors consider high-grade dysplasia in the stomach as fairly rare and, therefore, there is a high level of suspicion that warrants confirmation by a secondary pathology review. There was a very high discrepancy rate for low-grade gastric dysplasia, though most cases will receive follow-up and rebiopsy. C. Colorectal Cancer Most of the studies reported on colorectal polyps, generally detected on colonoscopy or screening studies. Guidelines on the classification and reporting of colorectal polyps such as those recently developed by the Pan-Canadian Consensus Group should be followed (61,62). The experience of the authors is that a diagnosis of colorectal cancer is usually straightforward, with few discrepancies, and does not warrant routine secondary review for specimens diagnosed as colorectal cancers or non-malignant colorectal polyps. Secondary pathology review should be considered for malignant polyps (adenomas containing early invasive adenocarcinomas) as these had misclassification with potential treatment impact. For malignant polyps, specific factors such as margin, stage, grade, lymphovascular space invasion, and budding as well as possible overcalling of misplaced epithelium are important and may be influenced by technical issues during sample processing. Several studies have reported high interobserver variation among pathologists assessing dysplasia in ulcerative colitis (a subtype of IBD) (63-66). No studies of flat dysplasia in IBD were included in the evidence base. The authors’ experience is that flat dysplasia is difficult to diagnose and has the potential for mistreatment. Both low- and high-grade flat dysplasia are significantly correlated with concurrent invasive carcinoma, and the diagnosis will lead to the potential consideration of colectomy. Current practice in Ontario is to have a gastrointestinal pathologist review specimens with evidence of flat dysplasia. D. Anal Cancer The only study found concluded a better tool for assessment of dysplasia may be required. E. Pancreas and Ampulla of Vater Most of the studies in the evidence review dealt with resected specimens but are of limited relevance due to the age of the studies (i.e., not using current methodology) and/or specific subgroups studied. The PEBC/CCO document Hepatic, Pancreatic, and Biliary Tract (HPB) Surgical Oncology Standards (54) as implemented in Ontario (67) recommends that all pancreatic surgery should be done at a specialized centre with multidisciplinary care including a pathologist with special interest and expertise in HPB diseases. The experience of the authors is that diagnosis of ampullary cancer is very difficult, and many pathologists are unfamiliar with this disease. A correct diagnosis is important as it will determine whether or not surgery is required. Some gastrointestinal pathologists are less experienced than cytologists in diagnosing uncommon cytology samples, and, therefore, ampullary and periampullary cytology or brush


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cytology specimens should be reviewed by a cytopathologist or gastrointestinal pathologist familiar with these lesions. Biopsies are usually for diagnosis or treatment planning for unresectable cancer, and current practice in Ontario is that biopsy and pathology review are to be performed at an HPB Cancer Centre. F. Liver Cancer The authors consider HCC to be a very difficult diagnosis that warrants review by a specialist. This recommendation is consistent with the PEBC/CCO document Hepatic, Pancreatic, and Biliary Tract (HPB) Surgical Oncology Standards (54), as implemented in Ontario (67), which recommends that all specimens should be viewed by a pathologist with a special interest in HPB diseases and a commitment to developing the appropriate expertise. It is the experience of the authors that biopsies in cases with a liver mass have a higher likelihood of being cancer. Such biopsies, if initially reviewed by a pathologist in the community, should have secondary review by a gastrointestinal pathologist at a HPB centre. G. Gastrointestinal Stromal Tumours (GIST) and Neuroendocrine Tumours (NET) No studies on secondary pathology review in GIST or NET specimens were found in the evidence review. ESMO (53) recommends an expert pathological second opinion in all cases of GIST when the original diagnosis is made outside reference centres. A consensus guideline (56) by members of the UK and Ireland Neuroendocrine Tumour Society (endorsed by the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland, the British Society of Gastrointestinal and Abdominal Radiology) recommends that pathologists dealing with NETs should have a special interest in endocrine or gastrointestinal pathology, or participate in a network with the opportunity for pathology review; the management of patients should be decided by multidisciplinary teams. H. Appendiceal Mucinous Tumours This continues to be one of the "problem areas" in gastrointestinal pathology, mostly due to the controversies existing around the tumour classification and nomenclature. Since this is an evolving area of practice, the current literature does not have evidence to support specific recommendations for secondary review. At this time, the authors see greater value for pathologists to stay current in their knowledge regarding these issues and to establish clear communication with the radiologists and surgeons within their own institutions. CONCLUSIONS A. Barrett’s Esophagus Specimens with diagnosis of high-grade dysplasia in Barrett’s Esophagus had a high rate of clinically relevant discrepancy and, therefore, warrant secondary review. There were high discrepancy rates for low-grade dysplasia, though most patients will receive follow-up and thus further diagnosis at a later date. B. Gastric Cancer Gastric cancers should have secondary pathology review prior to treatment. In Ontario this review many occur during HER2 testing. The authors consider high-grade dysplasia in the stomach as fairly rare, and, therefore, there is a high level of suspicion that warrants confirmation by secondary pathology review. There was a very high discrepancy rate for lowgrade gastric dysplasia, though most cases will receive follow-up and rebiopsy. C. Colorectal


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Routine secondary pathology review is not required for specimens diagnosed as colorectal cancers or non-malignant colorectal polyps. Secondary pathology review should be considered for malignant polyps (adenomas containing early invasive adenocarcinomas). A gastrointestinal pathologist should review specimens with evidence of flat dysplasia in IBD patients. D. Anal Cancer As evidence is extremely limited (one study) no conclusions are made. E. Pancreas and Ampulla of Vater Pancreatic resection specimens should be reviewed by a pathologist with special interest and expertise in HPB disease. Ampullary and periampullary cytology or brush cytology specimens should be reviewed by a cytopathologist or gastrointestinal pathologist familiar with these lesions. Biopsy specimens should be reviewed by a gastrointestinal pathologist. F. Liver Cancer Liver biopsies in cases with a liver mass and all liver resection specimens should be reviewed by a pathologist with special interest and expertise in HPB disease. G. Gastrointestinal Stromal Tumours (GIST) and Neuroendocrine Tumours (NET) As mandated by CCO in Ontario, the minimum data set of the synoptic report and all diagnostic parameters for gastrointestinal stromal tumors and neuroendocrine tumours need to be reported. If the local laboratory cannot meet these requirements then specimens should be sent to a laboratory with expertise in these tumour types. Other guidelines recommend that pathologists dealing with NETs should have a special interest in endocrine or gastrointestinal pathology. H. Appendiceal Mucinous Tumours Controversies exist around classification and nomenclature of appendiceal mucinous tumours. Pathologists need to stay current in their knowledge and establish clear communication with the radiologists and surgeons within their own institutions. 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. 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


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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, Roxanne Cosby, Sheila McNair, Hans Messersmith, and Leslie Souter, for providing feedback on draft versions.  Denise Kam for providing research assistance and for managing communication among the working group and with the reviewers.  Julia Shen 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: Gastrointestinal Cancers Working Group, with their affiliations and conflict of interest information, is provided in Appendix 1.

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]


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Appendix I. Members of the Pathology Secondary Review Working Group and conflicts of interest. Pathology Secondary Review Working Group: Gastrointestinal Cancers  Dr. David Hurlbut, Department of Pathology and Molecular Medicine, Kingston General Hospital; Associate Professor, Pathology and Molecular Medicine, Queens University, Kingston  Dr. Paul Karanicolas, Surgical Oncologist, Sunnybrook Health Sciences Centre; Assistant Professor of Surgery, University of Toronto  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 Catherine J Streutker, Director, Surgical Pathology, St. Michael’s Hospital;, Associate Professor, Laboratory Medicine and Pathobiology, University of Toronto  Dr. Mahmoud Abdel-Fattah Khalifa, Joint Chief, Anatomic Pathology, University Health Network and Sunnybrook Health Sciences Centre; Professor, Department of Laboratory Medicine & Pathobiology and Department of Obstetrics & Gynaecology, 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 CS reported consulting fees and grants from Hollman-LaRoche to validate HER2 testing in gastroesophageal/gastric adenocarcinomas and create an information document.


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Appendix II. Reproducibility studies (data not extracted). Gastrointestinal (1-17) 1. Clayton AC, Bentz JS, Wasserman PG, Schwartz MR, Souers RJ, Chmara BA, et al. Comparison of ThinPrep preparations to other preparation types in gastrointestinal cytology: Observations from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med. 2010;134(8):1116-20. 2. Della Mea V, Forti S, Puglisi F, Bellutta P, Finato N, Dalla Palma P, et al. Telepathology using Internet multimedia electronic mail: Remote consultation on gastrointestinal pathology. J Telemed Telecare. 1996;2(1):28-34. 3. Kasamatsu E, Bravo LE, Bravo JC, Aguirre-Garcia J, Flores-Luna L, Nunes-Velloso MdC, et al. [Reproducibility of histopathologic diagnosis of precursor lesions of gastric carcinoma in three Latin American countries]. Salud Publica Mex. 2010;52(5):386-90. 4. Lauwers GY, Shimizu M, Correa P, Riddell RH, Kato Y, Lewin KJ, et al. Evaluation of gastric biopsies for neoplasia: Differences between Japanese and Western pathologists. Am J Surg Pathol. 1999;23(5):511-8. 5. McLaren KM, Burnett RA, Goodlad JR, Howatson SR, Lang S, Lee FD, et al. Observer variability in the Goseki grouping of gastric adenocarcinoma in resection and biopsy specimens. Histopathology. 2003;42(5):472-5. 6. Ogino J, Asanuma H, Hatanaka Y, Matsuno Y, Gotoda H, Muraoka S, et al. Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas. Pathol Int. 2013;63(2):102-7. 7. Ozcan A, Karslioglu Y, Kurt B, Onguru O, Gunhan O. Quantitative evaluation of immunohistochemical staining in gastrointestinal stromal tumors. Anal Quant Cytol Histol. 2007;29(3):159-65. 8. Pagni F, Zannella S, Ronchi S, Garanzini C, Leone BE. HER2 status of gastric carcinoma and corresponding lymph node metastasis. Pathol Oncol Res. 2013;19(1):103-9. 9. Rugge M, Correa P, Dixon MF, Hattori T, Leandro G, Lewin K, et al. Gastric dysplasia: The Padova international classification. Am J Surg Pathol. 2000;24(2):167-76. 10. Schlemper RJ, Itabashi M, Kato Y, Lewin KJ, Riddell RH, Shimoda T, et al. Differences in diagnostic criteria for gastric carcinoma between Japanese and western pathologists.[Erratum appears in Lancet 1997 Aug 16;350(9076):524]. Lancet. 1997;349(9067):1725-9. 11. Schlemper RJ, Kato Y, Stolte M. Well-differentiated adenocarcinoma or dysplasia of the gastric epithelium: Rationale for a new classification system. Verh Dtsch Ges Pathol. 1999;83:62-70. 12. Schlemper RJ, Kato Y, Stolte M. Diagnostic criteria for gastrointestinal carcinomas in Japan and Western countries: Proposal for a new classification system of gastrointestinal epithelial neoplasia. J Gastroenterol Hepatol. 2000;15 Suppl:G49-57. 13. Schlemper RJ, Kato Y, Stolte M. Review of histological classifications of gastrointestinal epithelial neoplasia: Differences in diagnosis of early carcinomas between Japanese and Western pathologists. J Gastroenterol. 2001;36(7):445-56. 14. Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000;47(2):251-5. 15. Shibata A, Longacre TA, Puligandla B, Parsonnet J, Habel LA. Histological classification of gastric adenocarcinoma for epidemiological research: Concordance between pathologists. Cancer Epidemiol Biomarkers Prev. 2001;10(1):75-8.


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16. 17.

Talebkhan Y, Mohammadi M, Rakhshani N, Abdirad A, Fayaz Moughadam K, Fereidooni F. Interobserver variations in histopathological assessment of gastric pathology. Pathology (Phila). 2009;41(5):428-32. Yamaguchi U, Hasegawa T, Sakurai S, Sakuma Y, Takazawa Y, Hishima T, et al. Interobserver variability in histologic recognition, interpretation of KIT immunostaining, and determining MIB-1 labeling indices in gastrointestinal stromal tumors and other spindle cell tumors of the gastrointestinal tract. Appl Immunohistochem Mol Morphol. 2006;14(1):46-51.

Colorectal (18-41) 18. Bean SM, Meara RS, Vollmer RT, Conner MG, Crowe DR, Novak L, et al. p16 improves interobserver agreement in diagnosis of anal intraepithelial neoplasia. J Low Genit Tract Dis. 2009;13 (3):145-53. 19. Chandler I, Houlston RS. Interobserver agreement in grading of colorectal cancersfindings from a nationwide web-based survey of histopathologists. Histopathology. 2008;52(4):494-9. 20. Chetty R, Gill P, Govender D, Bateman A, Chang HJ, Deshpande V, et al. International study group on rectal cancer regression grading: Interobserver variability with commonly used regression grading systems. Hum Pathol. 2012;43(11):1917-23. 21. Costantini M, Sciallero S, Giannini A, Gatteschi B, Rinaldi P, Lanzanova G, et al. Interobserver agreement in the histologic diagnosis of colorectal polyps. the experience of the multicenter adenoma colorectal study (SMAC). J Clin Epidemiol. 2003;56(3):209-14. 22. Cross SS, Betmouni S, Burton JL, Dube AK, Feeley KM, Holbrook MR, et al. What levels of agreement can be expected between histopathologists assigning cases to discrete nominal categories? A study of the diagnosis of hyperplastic and adenomatous colorectal polyps. Mod Pathol. 2000;13(9):941-4. 23. Ensari A, Bilezikci B, Carneiro F, Dogusoy GB, Driessen A, Dursun A, et al. Serrated polyps of the colon: How reproducible is their classification? Virchows Arch. 2012;461(5):495-504. 24. Farris AB, Misdraji J, Srivastava A, Muzikansky A, Deshpande V, Lauwers GY, et al. Sessile serrated adenoma: Challenging discrimination from other serrated colonic polyps. Am J Surg Pathol. 2008;32(1):30-5. 25. Fenger C, Frisch M, Jass JJ, Williams GT, Hilden J. Anal cancer subtype reproducibility study. Virchows Arch. 2000;436(3):229-33. 26. Foss FA, Milkins S, McGregor AH. Inter-observer variability in the histological assessment of colorectal polyps detected through the NHS Bowel Cancer Screening Programme. Histopathology. 2012;61(1):47-52. 27. Glatz K, Pritt B, Glatz D, Hartmann A, O'Brien MJ, Blaszyk H. A multinational, internetbased assessment of observer variability in the diagnosis of serrated colorectal polyps.[Erratum appears in Am J Clin Pathol. 2007 Aug;128(2):348]. Am J Clin Pathol. 2007;127(6):938-45. 28. Harris EI, Lewin DN, Wang HL, Lauwers GY, Srivastava A, Shyr Y, et al. Lymphovascular invasion in colorectal cancer: An interobserver variability study. Am J Surg Pathol. 2008;32(12):1816-21. 29. Jensen P, Krogsgaard MR, Christiansen J, Braendstrup O, Johansen A, Olsen J. Observer variability in the assessment of type and dysplasia of colorectal adenomas, analyzed using kappa statistics. Dis Colon Rectum. 1995;38(2):195-8. 30. Kirsch R, Messenger DE, Riddell RH, Pollett A, Cook M, Al-Haddad S, et al. Venous invasion in colorectal cancer: Impact of an elastin stain on detection and interobserver


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31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

agreement among gastrointestinal and nongastrointestinal pathologists. Am J Surg Pathol. 2013;37(2):200-10. Lim CH, Dixon MF, Vail A, Forman D, Lynch DAF, Axon ATR. Ten year follow up of ulcerative colitis patients with and without low grade dysplasia. Gut. 2003;52(8):112732. Littleford SE, Baird A, Rotimi O, Verbeke CS, Scott N. Interobserver variation in the reporting of local peritoneal involvement and extramural venous invasion in colonic cancer. Histopathology. 2009;55(4):407-13. Lytwyn A, Salit IE, Raboud J, Chapman W, Darragh T, Winkler B, et al. Interobserver agreement in the interpretation of anal intraepithelial neoplasia. Cancer. 2005;103(7):1447-56. Mahajan D, Downs-Kelly E, Liu X, Pai RK, Patil DT, Rybicki L, et al. Reproducibility of the villous component and high-grade dysplasia in colorectal adenomas