endoscopic mucosal resection in barrett’s esophagus...

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Endoscopic Mucosal Resection in Barrett’s EsophagusAssociated Neoplasia: Recommendations For Pathological Evaluation And Reporting

http://www.cap-acp.org

CAP-ACP67th

AnnualScientificMeeting

Hyatt Regency, Vancouver, BCJuly 9-12, 2016

Program to include:◆ Pathologist Assistants Program◆ Junior Scientist Award Lecture◆ Cam Coady Slide Seminar◆ William Boyd Lecture◆ Awards Banquet◆ Special Interest Groups◆ President’s Reception◆ Workshops◆ Poster Presentations◆ Satellite Symposia◆ Networking◆ Industry Partners

See www.cap-acp.org/2016meeting.php for more information

The CAP-ACP Annual Meeting consists of two days of workshops (Saturday and Sunday) followed by two days of symposia. There is a half day with proffered paper/posters and a half day of CAP-ACP specifi c awards lectures. There are two evenings of special interest group and specialty network meetings. The overall meeting is under the supervision of the Annual Meetings Committee with subcommittees including the LOC, CPD Committee, CAP-ACP Sections and the CAP-ACP Awards Committee.

The Local Organizing Committee, under the direction of Chair, Dr. Martin Trotter have confi rmed that the President’s Reception will be held at the Museum of Anthropology, UBC (transportation is provided) and that they will be assisting with the PA program to include a wet-lab on Sunday morning at St. Paul’s Hospital.

This event is an Accredited Group Learning Activity (Section 1) as defi ned by the Maintenance of Certifi cation program of the Royal College of Physicians and Surgeons of Canada. This activity was approved by the Canadian Association of Pathologists.Through an agreement between the Royal College of Physicians and Surgeons of Canada and the American Medical Association, physicians may convert Royal College MOC credits to AMA PRA Category 1 Credits™.Through an agreement between the Royal College of Physicians and Surgeons of Canada and the European Union of Medical Specialists (UEMS) physicians may convert Royal College MOC credits to ECMEC®.

Confi rmed speakers to date:Dr. Mary Bronner is our invited Cam Coady Slide Seminar speaker and will be giving a talk titled: “GI Tract Mucosal Biopsy” on Tuesday, July 12, 1400-1700.

The Forensic Pathology section has invited Dr. C. Paul Johnson, a Forensic Pathologist from the UK (Liverpool). He has a research interest in, and will be presenting on “Traumatic Subarachnoid Haemorrhage and the Mechanisms of Vertebral Artery Trauma”.

The Humanities/International Health Symposium speakers will be Dr. Maadh Aldouri, from the Royal College of Pathologists, UK, sharing a talk on his “Experience with Labskills Africa Project”, and Dr. Phil Clement, who will be giving a talk on “The History of Endometrial Carcinoma”.

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Canadian Journal of P athology 3Winter 2015

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EDITOR-IN-CHIEFGeorge M Yousef, MD, PhD FRCPC (Path)

EDITOR EMERITUSJ. Godfrey Heathcote, MA, MB, BChir, PhD, FRCPC

EDITORIAL BOARDMarie Abi Daoud, MD, MHSc, FRCPC; Hala Faragalla MD, FRCPC; Louis Gaboury, M.D., Ph.D., F.R.C.P.(C), F.C.A.P.; John Gartner, MD CM, FRCPC; Laurette Geldenhuys, MD,

FRCPC; Nadia Ismiil, MBChB, FRCPC; Jason Karamchandani, MD; Adriana Krizova MD, MSc, FRCPC; David Munoz, MD, MSc, FRCPC; Christopher

Naugler, MD, FRCPC; Tony Ng, MD, PhD FRCPC; Sharon Nofech-Mozes, MD; Maria Pasic, PhD, FCACB;

Aaron Pollett, MD, MSc, FRCPC; Harman Sekhon, MD, PhD, FCAP; Monalisa Sur, MBBS, FCPath, MMed.,

MRCPath, FRCPC; Aducio Thiesen, MD, PhD, MSc, FRCPC;Stephen Yip, MD, PhD, FRCPC

FOUNDING EDITORJagdish Butany, MBBS, MS, FRCPC

MANAGING EDITORRose Simpson

EDITORIAL CONTENT MANAGERHeather Dow

ART DIRECTORAmanda Zylstra, [email protected]

TRANSLATORAnouk Jaccarini

SALES AND CIRCULATION COORDINATORBrenda Robinson, [email protected]

ACCOUNTINGSusan McClung

GROUP PUBLISHERJohn D. Birkby, [email protected]

VOLUME 7 • ISSUE 4

Contents

Omental cholelithiasis and bile granuloma with surrounding decidualized cells (H&E).

About the Cover

4 Editorial/Éditorial JyotsnaBatra,MSc,PhD,GeorgeMYousef,MD,PhDFRCPC(Path)

6 Letters to the Editor Omental Cholelithiasis: A Histologic Correlation EmilyA.Goebel,MD;JoannaC.Walsh,MBBCh,MRCP(UK),FRCP(C)

7 Statutory and Common Law Protection of Laboratory Quality Assurance Data in Canada MaireA.Duggan,MD,FRCPC,TamaraTrotter,MLT

Original Articles 8 Standard Terminology and Nomenclature for Pancreaticobiliary Cytology: A review of the guidelines from the Papanicolaou society MalcolmSchinstine,PhD,MD

17 Missing Data was Common in Pathology Reports of Vulvar Carcinoma: A Population Based Ontario Cohort

LisaBarberaMD,LilianGien,MD,RinkuSutradhar,PhD,GillianThomas,MD,AlCovens,MD,LaurieElit,MD,AnthonyFyles,MD,EileenRakovitch,MD,YingLiuMSc,MahmoudKhalifa,MD

25 Endoscopic Mucosal Resection (EMR) In Barrett’s Esophagus Associated Neoplasia: Recommendations For Pathological Evaluation And Reporting

JenniferA.Muir,MD,NormanMarcon,MD,JavierAranda-Hernandez,MD, MariaCirocco,BScN,SaharAl-Haddad,MD,CatherineJ.Streutker,MD, AndreaGrin,MD

CAP-ACP67th

AnnualScientificMeeting

Hyatt Regency, Vancouver, BCJuly 9-12, 2016

Program to include:◆ Pathologist Assistants Program◆ Junior Scientist Award Lecture◆ Cam Coady Slide Seminar◆ William Boyd Lecture◆ Awards Banquet◆ Special Interest Groups◆ President’s Reception◆ Workshops◆ Poster Presentations◆ Satellite Symposia◆ Networking◆ Industry Partners

See www.cap-acp.org/2016meeting.php for more information

The CAP-ACP Annual Meeting consists of two days of workshops (Saturday and Sunday) followed by two days of symposia. There is a half day with proffered paper/posters and a half day of CAP-ACP specifi c awards lectures. There are two evenings of special interest group and specialty network meetings. The overall meeting is under the supervision of the Annual Meetings Committee with subcommittees including the LOC, CPD Committee, CAP-ACP Sections and the CAP-ACP Awards Committee.

The Local Organizing Committee, under the direction of Chair, Dr. Martin Trotter have confi rmed that the President’s Reception will be held at the Museum of Anthropology, UBC (transportation is provided) and that they will be assisting with the PA program to include a wet-lab on Sunday morning at St. Paul’s Hospital.

This event is an Accredited Group Learning Activity (Section 1) as defi ned by the Maintenance of Certifi cation program of the Royal College of Physicians and Surgeons of Canada. This activity was approved by the Canadian Association of Pathologists.Through an agreement between the Royal College of Physicians and Surgeons of Canada and the American Medical Association, physicians may convert Royal College MOC credits to AMA PRA Category 1 Credits™.Through an agreement between the Royal College of Physicians and Surgeons of Canada and the European Union of Medical Specialists (UEMS) physicians may convert Royal College MOC credits to ECMEC®.

Confi rmed speakers to date:Dr. Mary Bronner is our invited Cam Coady Slide Seminar speaker and will be giving a talk titled: “GI Tract Mucosal Biopsy” on Tuesday, July 12, 1400-1700.

The Forensic Pathology section has invited Dr. C. Paul Johnson, a Forensic Pathologist from the UK (Liverpool). He has a research interest in, and will be presenting on “Traumatic Subarachnoid Haemorrhage and the Mechanisms of Vertebral Artery Trauma”.

The Humanities/International Health Symposium speakers will be Dr. Maadh Aldouri, from the Royal College of Pathologists, UK, sharing a talk on his “Experience with Labskills Africa Project”, and Dr. Phil Clement, who will be giving a talk on “The History of Endometrial Carcinoma”.

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http://cap-acp.org/2016meeting.php

Winter 20154 Canadian Journal of P athology

EDITORIAL

Screening for Prostate Cancer Risk: Fantasy or RealityProstate cancer is the most commonly diagnosed malignancy worldwide, affecting 233,000 men annually in the US alone. While the 5-year survival rate for localized disease approaches 100%, extraprostatic invasion results in a poor prognosis, thus early diagnosis to improve overall mortality is the goal.1 Prostate-specific antigen testing has been used to screen prostate cancer and has led to reduction in prostate cancer–related mortality over the last two decades. However, use of a single threshold of PSA has been criticized, as approximately two-thirds of men with elevated serum PSA levels will not have cancer on biopsy.

Recently, two large studies on PSA screening efficacy have been published: in the European trial (ERSPC) it reduced mortality by ~20-30 %,2,3 while in the US-based trial (PLCO), no reduction in mortality was observed.4 Both studies showed that PSA testing leads to over-diagnosis by ~50 %,5 which leads to overtreatment and associated co-morbidities, causing unnecessary costs and reduced quality of life. It should be also noted that US Preventive Service Task Force (USPSTF) recommends against prostate cancer specific antigen screening for prostate cancer. Moreover, recent clinical trials show that the outcome of active surveillance is comparable to radical prostatectomy for patient with low risk disease.6 Thus, the value of screening for prostate cancer risk has been recently challenged identifying a critical need for new diagnostic biomarkers that could minimize over detection by reducing the number of false-positive results, and which can distinguish indolent and aggressive disease.

Derivatives of PSA have been suggested in an attempt to improve its performance.7 Additional novel approaches include the PCA3-based urine test, Circulating Tumor Cells, circulating miRNAs, and 4K score as well as multiparametric magnetic resonance imaging.8 Changes to epigenetic patterns are also emerging. Similarly, common genetic variants have the capacity for differentiating patient risk.9 For instance, Nam et al. developed a nomogram that, by combining four identified SNPs, can predict an individual’s risk of developing prostate cancer.10 In a recent study, genetic scoring has been shown to be a better measurement of inherited risk of prostate cancer than family history.11 In a study by Kader et al., addition of 33 genetic markers to the classification of prostate cancer risk resulted in 33% of men reclassified into a different risk quartile with the net reclassification benefit of 10% (p=0.002).12,13

Since a single marker is unlikely to suffice, multi-modal strategies look more promising. In our effort to develop new “genomic” screening tests for prostate cancer risk, the accepted WHO criteria for screening should be fulfilled, including the presence of an agreement on policy of whom to treat and also the presence of scientific evidence for screening program effectiveness. Identifying reproducible, robust biomarkers will require large combined efforts from multiple disciplines and implementation strategies to be adopted in clinics.

1. Cheville, J.C., et al., Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancer-specific survival. Cancer, 2002. 95(5): p. 1028-36.2. Schroder, F.H., PSA screening--a review of recent studies. Eur J Cancer, 2009. 45 Suppl 1: p. 402-4.3. Roobol, M.J., et al., A risk-based strategy improves prostate-specific antigen-driven detection of prostate cancer. Eur Urol, 2010. 57(1): p. 79-85.4. Andriole, G.L., et al., Mortality results from a randomized prostate-cancer screening trial. N Engl J Med, 2009. 360(13): p. 1310-9.5. Draisma, G., et al., Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst, 2009. 101(6): p. 374-83.6. Klotz, L., Active surveillance for low-risk prostate cancer. Curr Urol Rep, 2015. 16(4): p. 24.7. Bantis, A. and P. Grammaticos, Prostatic specific antigen and bone scan in the diagnosis and follow-up of prostate cancer. Can diagnostic significance of PSA be

increased? Hellenic journal of nuclear medicine, 2012. 15(3): p. 241-6.8. Blute, M.L., Jr., et al., Addressing the need for repeat prostate biopsy: new technology and approaches. Nat Rev Urol, 2015. 12(8): p. 435-44.9. Srinivasan, S., J.A. Clements, and J. Batra, Single nucleotide polymorphisms in clinics: Fantasy or reality for cancer? Crit Rev Clin Lab Sci, 2015: p. 1-11.10. Nam, R.K., et al., Utility of incorporating genetic variants for the early detection of prostate cancer. Clinical cancer research : an official journal of the American

Association for Cancer Research, 2009. 15(5): p. 1787-93.11. Sun, J., et al., Genetic score is an objective and better measurement of inherited risk of prostate cancer than family history. European urology, 2013. 63(3): p. 585-7.12. Kader, A.K., et al., Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative

biopsy: findings from the REDUCE trial. European urology, 2012. 62(6): p. 953-61.13. Turner, A.R., A.K. Kader, and J. Xu, Utility of genome-wide association study findings: prostate cancer as a translational research paradigm. Journal of internal

medicine, 2012. 271(4): p. 344-52.

Jyotsna Batra, Australian Prostate Cancer Research Centre, Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, AustraliaGeorge M Yousef, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, CanadaCorrespondence may be directed to [email protected]

mailto:Jyotsna.batra%40qut.edu.au?subject=


Le dépistage des risques de cancer de la prostate : rêve ou réalité?Le cancer de la prostate est le type de tumeur maligne le plus souvent diagnostiqué dans les pays développés; il touche chaque année 233 000 hommes aux États-Unis seulement. Lorsque la maladie est localisée, le taux de survie après cinq ans est de presque 100 %. Le pronostic est cependant moins bon en cas d’extension extra-prostatique; l’objectif est donc d’obtenir un diagnostic précoce afin d’améliorer le taux de survie 1. On utilise le test de l’antigène prostatique spécifique (APS) pour dépister le cancer de la prostate, ce qui a entraîné une réduction de la mortalité au cours des deux dernières décennies. Cependant, l’utilisation d’un seuil unique d’APS est remise en question, car chez environ les deux tiers des hommes dont le niveau d’APS est élevé, la biopsie ne révèle pas de cancer.

Deux grandes études sur l’efficacité du dépistage par l’APS ont été publiées récemment : selon l’étude européenne (ERSPC), ce test réduit la mortalité d’environ 20 à 30 %2, 3, alors que selon l’étude américaine (PLCO), on ne constate aucune réduction du taux de mortalité 4. Selon les deux études, le test d’APS mène à un surdiagnostic d’environ 50 %5, et à un surtraitement et à des comorbidités connexes, ce qui entraîne des coûts inutiles et réduit la qualité de vie. Il faut également souligner que le Groupe de travail américain sur les services de prévention (USPSTF) s’est prononcé contre l’utilisation du test de l’antigène prostatique spécifique pour dépister le cancer de la prostate. De plus, de récents essais cliniques ont montré que les résultats d’une surveillance active se comparaient à ceux d’une prostatectomie radicale pour les patients ayant une maladie de la prostate à faible risque6. On a donc récemment remis en question la valeur du dépistage des risques de cancer de la prostate et mis en lumière l’urgence de trouver de nouveaux biomarqueurs afin de minimiser la surdétection, de réduire le nombre de faux positifs et de distinguer les formes indolentes des formes agressives de la maladie.

On a suggéré l’utilisation de dérivés de l’APS pour améliorer le rendement du test7. Parmi les approches novatrices, il faut aussi compter le test d’urine basé sur le PCA3, les cellules tumorales circulantes (CTC), le micro-ARN circulant, et la cote 4K, de même que l’imagerie à résonance magnétique multiparamétrique 8. Les changements au profil épigénétique présentent aussi un potentiel important. De la même façon, des variantes génétiques courantes peuvent permettre une différenciation du risque9. Par exemple, Nam et coll. ont mis au point un nomogramme clinique combinant quatre SNP connus pour prédire le risque de développer un cancer de la prostate10. Une étude récente a montré que l’évaluation génétique était une meilleure mesure du risque héréditaire de cancer de la prostate que l’histoire familiale11. Dans une étude menée par Kader et coll., on a ajouté 33 marqueurs génétiques à la classification des risques de cancer de la prostate, ce qui a entraîné une reclassification de 33 % des hommes dans un quartile de risque différent, avec un avantage net de 10 % (p = 0,002)12, 13.

Comme il est peu vraisemblable qu’un seul marqueur suffise, les stratégies multimodales sont les plus prometteuses. Lorsqu’on cherche à créer de nouveaux tests « génomiques » de dépistage du risque de cancer de la prostate, il faut respecter les critères reconnus de l’OMS pour le dépistage, notamment quant à l’existence de politiques sur le choix des patients à traiter ainsi que de preuves scientifiques de l’efficacité des programmes de dépistage. Pour identifier des biomarqueurs reproductibles et robustes, il faudra déployer des efforts importants dans plusieurs disciplines en milieu préclinique, de même que des stratégies à adopter en clinique.

1. Cheville, J.C. et coll., “Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancer-specific survival”, Cancer, vol. 95, no 5 (2002), p. 1028–1036.

2. Schroder, F.H., “PSA screening–a review of recent studies”, Eur J Cancer, 45 Suppl. 1 (2009), p. 402–404.3. Roobol, M.J., et coll., “A risk-based strategy improves prostate-specific antigen-driven detection of prostate cancer”, Eur Urol, vol. 57, no 1 (2010) p. 79-85.4. Andriole, G.L., et coll., “Mortality results from a randomized prostate-cancer screening trial”, N Engl J Med, vol. 360, no 13 (2009), p. 1310–1319.5. Draisma, G., et coll., “Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context”, J Natl Cancer Inst, vol. 101, no 6

(2009), p. 374–383.6. Klotz, L., “Active surveillance for low-risk prostate cancer”, Curr Urol Rep, vol. 16, no 4 (2015), p. 24.7. Bantis, A. and P. Grammaticos, “Prostatic specific antigen and bone scan in the diagnosis and follow-up of prostate cancer. Can diagnostic significance of PSA be

increased?”, Hellenic journal of nuclear medicine, vol. 15, no 3 (2012), p. 241–246.8. Blute, M.L., Jr., et coll.,”Addressing the need for repeat prostate biopsy: new technology and approaches”, Nat Rev Urol, vol. 12, no 8 (2015), p. 435–444.9. Srinivasan, S., J.A. Clements, and J. Batra, “Single nucleotide polymorphisms in clinics: Fantasy or reality for cancer?”, Crit Rev Clin Lab Sci (2015), p. 1–11.10. Nam, R.K., et coll., “Utility of incorporating genetic variants for the early detection of prostate cancer”, Clinical cancer research: an official journal of the American

Association for Cancer Research, vol. 15, no 5 (2009), p. 1787–1793.11. Sun, J., et coll., “Genetic score is an objective and better measurement of inherited risk of prostate cancer than family history”, European urology, vol. 63, no 3 (2013),

p. 585–587.12. Kader, A.K., et coll., “Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative

biopsy: findings from the REDUCE trial”, European urology, vol. 62, no 6 (2012), p. 953–961.13. Turner, A.R., A.K. Kader, and J. Xu, “Utility of genome-wide association study findings: prostate cancer as a translational research paradigm”, Journal of internal

medicine, vol. 271, no 4 (2012), p. 344–352.

Centre australien de recherche sur le cancer de la prostate – QLD, Institut de santé et d’innovation biomédicale et École des sciences biomédicales, Institut de recherche translationnelle, Université de technologie du Queensland (Brisbane, Australie). George M. Yousef, Département de pathologie et de médecine de laboratoire, Université de Toronto (Toronto, Canada) Pour toute correspondance : [email protected]

ÉDITORIAL

mailto:Jyotsna.batra%40qut.edu.au?subject=


Omental Cholelithiasis: A Histologic CorrelationWe read with great interest the recent article by Noy and Dupré, Omental Cholelithiasis: A Potential Mimic of Peritoneal Carcinomatosis.1 The article provides macroscopic images of omental cholelithiasis. We would like to report a recent similar case of omental cholelithiasis and provide histologic images to complement the gross images provided by the previous authors.

The case is that of a 35-year-old woman who underwent cesarean section for an abnormal fetal heart rate. At the time of surgery, inspection of the vesicouterine peritoneum revealed several small firm nodules that were clinically suspected to be endometriosis or an inflammatory reaction surrounding surgical clips from a previous operation. Gross examination showed diffuse submillimeter yellow gritty nodules.

Microscopic examination revealed cystically dilated spaces within the peritoneal tissue, many of which contained yellow, filamentous, refractile, non-polarizable material with a crystalline appearance. The cystic spaces were lined by a thin layer of histiocytes and multinucleate giant cells (Figures 1 and 2). In keeping with the recent pregnancy, decidualized stromal cells were focally identified in the background tissue (Figure 1).

On review, this patient had undergone a laparoscopic cholecystectomy 2 years prior for acute cholecystitis and gallstone pancreatitis. Gross examination of the gallbladder had revealed a small mural defect, more than 100 luminal stones and several spilled stones in the specimen container. These findings are consistent with a diagnosis of omental cholelithaisis secondary to gallbladder perforation and intra-abdominal spillage of gallstones at the time of laparoscopic cholecystectomy. As stated in the previous article, this can occur in up to 16% of cholecystectomies and more than one third of the spilled stones are not retrieved.1,2

Omental cholelithiasis /peritoneal bile granulomas can be mistaken for a malignant or other process.1,2 Pathologists and surgeons should be aware of this entity as it is a potential diagnostic pitfall, especially at frozen section / intraoperative consultation.

References1. Noy S, Dupré M. Omental Cholelithiasis: A Potential Mimic of Peritoneal

Carcinomatosis. Can J Pathol Winter 2015, 27. 2. McVeigh G, McComiskey M, McCluggage WG. Peritoneal bile granulomas

identified at cesarean section and mimicking disseminated malignancy. Int J Surg Pathol 2012;20:89-91.

Emily A. Goebel, MD; Joanna C. Walsh, MBBCh, MRCP (UK), FRCP(C)Department of Pathology and Laboratory Medicine, London Health Sciences Centre and Western University

LETTER TO THE EDITOR

Figure 1. Omental cholelithiasis and bile granuloma with surrounding decidualized cells (H&E).

Figure 2. High power view of a bile granuloma with a rim of histiocytes and multinucleate giant cells (H&E).


LETTER TO THE EDITOR

Statutory and Common Law Protection of Laboratory Quality Assurance Data in CanadaIn the article entitled Statutory and Common Law Protection of Laboratory Quality Assurance Data in Canada, the judicial interpretation and application of the statutory protection from disclosure of laboratory quality assurance (QA) were examined by Singh D and Duggan M.A. (Canadian Journal of Pathology 2012; 4: 54-58).They found that compliance with statutory protection was narrowly interpreted by Canadian courts and that the quality assurance committees (QACs) of Alberta Health Services (AHS) were compliant with the protection afforded by section 9 of the Alberta Evidence Act. However, the QA groups or committees formed locally within the provincial laboratories (internal QACs) were not eligible for protection. Consequently, laboratory QA data were not legally protected from disclosure to any party or individual who might request access to it. This would include access to the QA data of individual and identifiable laboratory professionals. Of note, simply naming an internal laboratory committee a QAC does not ensure legal protection; the committee must be officially constituted in compliance with the provincial Act that provides the protection. The purpose of this letter is to provide a brief update to that publication on the steps taken in Alberta to establish eligibility for and implementation of section 9 protection of QA data gathered by provincial laboratories for the mandated AHS Anatomical Pathology Quality Assurance Plan (AHS AP QA Plan). The Plan is province wide and includes both public and private laboratories. It is governed by the AHS Anatomical Pathology Quality Assurance Implementation Strategy Development Team (AHS AP Quality Team).

Eligibility for Section 9 protection of the internal laboratory QACs engaged in the AHS AP QA Plan was awarded in March 2014 by the AHS Quality and Safety Committee approximately 27 months after the request was initiated by the co-chairs (MAD and TT) of the AHS AP Quality Team. Sponsorship of the request by the Provincial Medical/Scientific Director of AHS Laboratory Services (Dr. James Wesenberg) and the AHS Vice President Quality and Chief Medical Officer (Dr. Verna Yiu), and a strategic alliance with the executive director of AHS Patient Safety (Ms. Paula Beard) were critical in moving the request forward and in achieving success. The delay in gaining eligibility was mainly due to debate amongst AHS key stakeholder services including legal services as to whether source data for the AHS AP QA Plan from individual and identifiable laboratory professionals should be protected from disclosure. The opponents argued that if the data was protected it could not be used to identify underperforming individuals. The proponents counter-argued the AHS AP

QA Plan was designed to monitor and evaluate laboratory performance at a systems level using aggregate data and not at an individual level using identifiable data. Since this was the scope the provincial laboratories supported when they agreed to implement it, broadening the scope after the fact would jeopardize its full implementation and implementation of any future AHS QA Plans in the Pathology and Laboratory Medicine sphere. Since the safety afforded patients by the province wide implementation of the AHS AP QA plan was of paramount importance to the stakeholders, and the dependence of the Plan’s aggregate data on the collection of QA data from individuals was understood, eligibility for section 9 protection of internal laboratory QACs engaged in AHS AP QA Plan activities and any future AHS Pathology and Laboratory Medicine Plans was agreed upon. Central to the agreement was the reassurance that AHS and the College of Physicians and Surgeons of Alberta had other systems in place to assess the performance of individual laboratory professionals and these systems would be triggered should underperformance by an individual be highlighted by the Plan’s data.

Implementation of section 9 protected internal laboratory QACs was completed over the ensuing months principally by restructuring and rebranding the existing QACs as subcommittees of the pre-existing section 9 protected AHS QAC structure. They are now fully operational and engaged in the monitoring and evaluation of the AHS AP QA Plan data. Any data from an identifiable laboratory professional is now legally protected from disclosure. On a cautionary note however, section 9 protection does not extend to every QA activity performed by an individual. It only extends to those which are prescribed by AHS Pathology and Laboratory Medicine QA Plans.

We hope that by sharing this account, others may benefit from our experience.

Maire A. Duggan MD, FRCPC. Medical Co-Chair Alberta Health Services Anatomical Pathology Quality Assurance Implementation Strategy Development Team. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AlbertaTamara Trotter MLT, Co-Chair Alberta Health Services Anatomical Pathology Quality Assurance Implementation Strategy Development Team and Provincial Anatomical Pathology Quality Lead. Laboratory Services Quality, Safety and Integration Team. Chinook Regional Hospital, Lethbridge, Alberta.


ORIGINAL ARTICLE

Standard Terminology and Nomenclature for Pancreaticobiliary Cytology: A Review of the

Guidelines from the Papanicolaou SocietyMalcolm Schinstine, PhD, MD

Malcolm Schinstine, PhD, MD is a Clinical Associate Professor at the Cummings School of Medicine. Correspondence can be addressed to [email protected]

Competing interests: None declared.This article has been peer reviewed.

IntroductionIn anatomic pathology, the fruit of the pathologist’s labors is the diagnosis. Most of the time,

the diagnosis is clear and understood by the intended audience, i.e., the ordering clinician

or radiologist. Unfortunately, sometimes the diagnosis is misinterpreted or misunderstood

leading to inappropriate treatment, including unnecessary surgery. Although a variety of

circumstances can lead to misunderstanding, the use of descriptive or otherwise non-definitive

diagnosis is a major cause of clinician confusion.

One way to reduce misunderstandings is to standardize the terms and nomenclature used

by cytopathologists to make a diagnosis. The Bethesda Systems for cervical1 and thyroid

cytopathology2 for example, are two such systems designed to standardize diagnoses. The use

of these standardized systems has reduced diagnostic variability between cytopathologists and

allows clinicians to be more confident in the treatment regimens they pursue subsequent to a

particular diagnosis.

Recently, the Papanicolaou Society introduced diagnostic guidelines for the standardization

of terminology and nomenclature for pancreaticobiliary cytology specimens.3 The categories

suggested by the guidelines are listed in Table 1. In this review, the terms nomenclature and

diagnostic categories for pancreaticobiliary cytology are briefly summarized and explained,

including example diagnoses. The

Papanicolaou Society has also published

guidelines for the use of ancillary studies,4

indications for cytologic studies of pancreatic

lesions,5 techniques for cytologic sampling

of the pancreas,6 and treatment options.7

These subjects are not covered in the present

manuscript.

Table 1.

Proposed Terminology Classifications for Lesions of the Pancreaticobiliary System

1. Nondiagnostic

2. Negative (for malignancy)

3. Atypical

4. Neoplastic: benign and other

5. Suspicious (for malignancy)

6. Positive/Malignant

mailto:malcolm.schinstine%40cls.ab.ca?subject=


SCHINSTINE

IntroductionEn anatomopathologie, le pathologiste cherche à produire un diagnostic; la plupart du temps, ce diagnostic est clair et bien compris par son destinataire, c’est-à-dire le clinicien ou le radiologiste qui a demandé l’examen. Malheureusement, le diagnostic est parfois mal interprété ou mal compris, ce qui peut mener à un traitement inadéquat, voire à une chirurgie inutile. Diverses circonstances peuvent mener à ce type d’erreur, mais le recours à un diagnostic descriptif ou à un autre diagnostic non définitif est une cause importante de confusion chez les cliniciens.

L’un des moyens d’éviter ce type d’erreur est de normaliser les termes et la nomenclature utilisés par les cytopathologistes pour établir un diagnostic. C’est l’objectif des systèmes de Bethesda employés pour la cytopathologie du col utérin1 et de la thyroïde,2 par exemple. L’utilisation de ces systèmes a réduit la variabilité des diagnostics entre les cytopathologistes et a permis aux cliniciens de choisir un traitement avec davantage de confiance.

Récemment, la Papanicolaou Society a publié des lignes directrices sur la normalisation de la terminologie et de la nomenclature des diagnostics établis à partir de prélèvements cytologiques pancréatico biliaires.3 Le tableau 1 dresse la liste des catégories suggérées dans ces lignes directrices. Nous résumons et expliquons ici brièvement les termes, la nomenclature et les catégories de diagnostics en cytologie pancréatico-biliaire, avec des exemples de diagnostics. La Papanicolaou Society a également publié des lignes directrices sur l’utilisation d’examens connexes,4 les indications de l’examen cytologique de lésions pancréatiques,5 les techniques de prélèvement cytologique du pancréas6 et les possibilités de traitement,7 mais ces sujets ne sont pas couverts dans le présent article.

Category I. NondiagnosticSimilar to other classifications schemes, a category is needed

to describe the situation where a specimen lacks the cellularity

and/or cytologic integrity to achieve a diagnosis. Issues

obfuscating diagnoses may be technical or involve sampling.

In order to utilize the “Nondiagnostic” category,

radiographic and clinical data must be considered in

addition to the findings, or lack thereof, gleaned from the

cytology slide. A specimen is not necessarily Nondiagnostic

just because there is a lack of epithelial cells to adequately

assess for dysplasia or malignancy. For example, epithelial

cells would not be expected in an aspirate of a pseudocyst

and the lack of epithelial cells in this case does not make the

aspirate Nondiagnostic. Similarly, abundant mucin may be

the only evidence for sampling of a mucinous cyst and the

lack of epithelial cells in this aspirate does not necessarily

render the specimen Nondiagnostic. Cyst fluid containing

elevated carcinoembryonic antigen (CEA) may be sufficient

to render a diagnosis of a neoplastic mucinous cyst, even in

the absence of an epithelial component. Importantly, the

presence of atypia (dysplasia) always precludes the use of

the “Nondiagnostic” category.

DefinitionThe “Nondiagnostic” category is defined by a specimen

where there is no diagnostic information regarding

the nature of the solid or cystic lesion sampled. For

example, a mucinous cyst where there is no evidence of

background mucin, an epithelial component, elevated

fluid CEA, or KRAS/GNAS mutation may be classified as

“Nondiagnostic”. A specimen containing epithelial cells

may also be rendered “Nondiagnostic” if the epithelial cells

are obscured by blood or if the cells are poorly preserved

severely limiting interpretation.


STANDARD TERMINOLOGY AND NOMENCLATURE FOR PANCREATICOBILIARY CYTOLOGY

Example Diagnoses1. Evaluation limited by scant cellularity

Nondiagnostic

Insufficient cell content or cyst fluid levels for cytologic

or ancillary testing.

2. Evaluation limited by preparation artifact

Nondiagnostic

Cells entrapped and obscured by blood clot and fibrin.

Category II. Negative (for Malignancy)The negative category implies the absence of malignant cells

or any cytologic atypia (dysplasia). A descriptive negative

interpretation without a specific diagnosis, e.g., chronic

pancreatitis or pseudocyst, is not synonymous with a benign

lesion. A descriptive negative diagnosis implies the sample

is sufficiently cellular and no cytologic atypia is identified.

This may include the presence of normal pancreatic tissue

in the setting where the radiologic findings are unclear or

nebulous, i.e., no definitive mass lesion. In the situation

where a radiographic or clinically distinct mass is present and

interpreted as adenocarcinoma, the presence of only normal

pancreatic tissue should be considered as a false negative.

The false negative rate for aspiration of solid pancreatic

masses averages 15%.8 For cystic lesions, the false negative

rate is as high as 60% and is usually due to scant specimen

cellularity.9 The lack of high-grade epithelial atypia in an

aspirate of a pancreatic cyst has a high negative predictive

value for malignancy.10

Specimens deemed “negative” should also take into account

the ancillary tests available to the cytopathologist. If an

institution lacks the ability to test cyst fluid for elevated

CEA or KRAS at the time of cytologic interpretation, then a

specimen containing mucinous debris may be categorized as

“negative” with a statement questioning whether identified

mucin is lesional or from gastrointestinal contamination. A

similar specimen at an institution where ancillary testing is

available may diagnose the specimen as “neoplastic: other”

if the CEA fluid levels are significantly elevated. In both

situations, the radiographic features and clinical impression

should be considered.

Pancreaticobiliary brushings offers special diagnostic

challenges often due to known, or unknown, underlying

disease(s), e.g., primary sclerosing cholangitis, and/or the

presence of a stent. The latter circumstance is frequently

associated with marked reactive change requiring the

implementation of strict cytologic criteria to arrive at a

malignant diagnosis. Another factor contributing to the high

false negative rate for pancreaticobiliary brush specimens

is the difficulty of obtaining sufficient, well preserved

diagnostic cells.

DefinitionThe definition of a “negative” cytology specimen is one

with adequate cellularity and/or extracellular material

that correlates with radiographic and/or clinical findings.

A specific diagnosis should be rendered when possible

(see Table 2).

Example Diagnoses1. Satisfactory for evaluation

Negative for Malignancy

Benign and reactive ductal epithelium, acinar tissue,

mixed inflammation, and background necrotic and

calcific debris; compatible with chronic pancreatitis.

2. Satisfactory for evaluation


Nonmucinous cyst fluid with no epithelial cells and

numerous hemosiderin-laden macrophages, suggestive

of serous cystadenoma (see comment).

Comment: Low CEA and amylase fluid levels support

the diagnosis (if the information is available).

Table 2.

Specific Benign Diagnoses That Should Be Rendered When Possible

1. Benign pancreaticobiliary tissue in the setting of vague fullness with no definitive pancreatic mass

2. Autoimmune pancreatitis

3. Chronic pancreatitis

4. Acute pancreatitis

5. Pseudocyst

6. Lymphoepithelial cyst

7. Splenule/accessory spleen




Cyst fluid with inflammation and histiocytes,

amorphous yellow pigment, and no cyst lining epithelial

cells; suggestive of a pseudocyst (see comment).

Comment: Low CEA and markedly elevated amylase levels

support the diagnosis (if the information is available).

Category III. AtypicalThe “Atypical” category is used when the cytologic or

extracellular features are beyond what is recognized as normal,

but fall short of outright high-grade dysplasia or malignancy.

Theses aspirates cannot be classified as “Negative” because

mild cytologic atypia, be it neoplastic or reactive, is present.

In addition, sometimes evaluation of these specimens is

limited by artifact or by the lack of sufficient cellularity.

This category has historically included specimens with

reactive atypia (change), low cellularity, dysplasia

(premalignant changes), and cases where the cytologist

is exercising caution. According to one study, the risk of

malignancy in the “Atypical” category for pancreatic and

bile duct brushings is approximately 44%.11 For solid

pancreatic masses, the risk of malignancy approaches 82%.12

Aspirates diagnosed as “Atypical” connote the possibility of

neoplasia, most likely low grade, when there is insufficient

cytologic evidence for the specimen to be placed in the

“Suspicious” or “Positive for Malignancy” categories.

Traditionally, most dysplastic mucinous cysts have been

placed in the “Atypical” (high grade) or “Negative” (low

grade) categories. Often, the placement of mucinous cysts

into more definitive diagnostic categories is hampered

by the lack of a standardized classification system. It is

important that aspirates of mucinous cysts, with or without

high-grade dysplasia, be properly identified so that proper

treatment algorithms can be followed.

DefinitionThe “Atypical” category should only be used when an

aspirate is sufficiently cellular and possesses cytoplasmic,

nuclear, and/or architectural features not considered

normal or overtly reactive. Moreover, the morphologic

features should be inadequate for definitive determination

of a neoplastic or overtly malignant process. The cytologic

findings may also not be sufficient to explain clinical or

radiographic findings. For lesions placed in this category,

follow-up evaluation is usually strongly suggested.

Example Diagnoses

1. Evaluation limited by scant cellularity

Atypical

Atypical bile duct epithelium with background acute

inflammation, suggestive of repair.

2. Evaluation limited by preparation artifact

Atypical

Atypical cells obscured by crush artifact.

3. Evaluation limited by scant cellularity

Atypical

Atypical bile duct epithelium with mucinous metaplasia

and mild nuclear atypia.

Category IV. Neoplastic The neoplastic category is divided into two distinct sub-

categories, “Neoplastic: benign” and Neoplastic: other”. The

former category includes neoplasms that are clearly benign,

serous cystadenoma being the quintessential example. The

“Neoplastic: other” category includes numerous neoplasms

that are pre-invasive (e.g., mucinous cystadenoma with

low-grade dysplasia) or with low-grade malignant behavior

(e.g., pancreatic neuroendocrine tumor).

Category IVa. Neoplastic: benignAs mentioned, this category is best represented by

pancreatic serous cystadenoma. Other benign neoplasia,

such as cystic teratoma and Schwannoma, are also included

in this category, but are extremely rare.

Serous cystadenomas are composed of fine fibrous septae

lined by bland cuboidal cells with clear cytoplasm (glycogen

rich). Other than for occasional degenerative or reactive

cells, atypia is minimal or absent. Aspirations of this entity

may be hemorrhagic due to numerous small capillaries

traversing the fibrous septae. Because of the hemorrhagic

nature of the lesion, aspirates may be populated by numerous

hemosiderin-laden macrophages. In fact, as compared to

mucinous cystic neoplasms, up to 63% of aspirates of serous

cystadenomas contain hemosiderin-laden macrophages.13

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In addition to cytologic, radiologic, and clinical features

indicating a diagnosis of serous cystadenomas, low fluid

CEA levels (typically less than 5 ng/ml) and relatively low

amylase levels are characteristic of the entity. As a caveat

though, some mucinous cystic neoplasms also have low

fluid CEA levels and occasional serous cystadenomas may

have elevated CEA levels.14-16

DefinitionThe definition of the “Neoplastic: benign” category requires a

sufficiently cellular and representative aspirate, with or without

supporting radiographic, clinical, or ancillary information,

diagnostic of a benign neoplasm, e.g., serous cystadenoma.

Example Diagnoses1. Evaluation limited by scant cellularity

Neoplasm: benign

Scant specimen; nonmucinous cuboidal epithelial

cells and numerous hemosiderin-laden macrophages

compatible with serous cystadenoma (see comment).

Comment: Low fluid CEA (0.5 ng/ml) and amylase

levels (150 U/ml) support the diagnosis (if available).

Category IVb. Neoplastic: otherThe purpose of this category is to provide a place for tumors

with an uncertain or low-grade malignant potential. The

addition of this category allows these neoplasms NOT to

be classified as “Atypical” or “Suspicious for Malignancy,”

possible avoiding inappropriate management. The use of

this category also brings pancreatic cytologic diagnoses more

in line with the 2010 WHO classification and terminology

of pancreatic lesions. This category is the most important

contribution of the Papanicoloau Society guidelines.

The “Neoplastic: other” category is populated by several

neoplastic entities with preinvasive features and/or low-

malignant potential. This group of neoplasms includes

1) Intraductal papillary mucinous neoplasia (IPMN; with

low-, intermediate-, or high-grade dysplasia), 2) mucinous

cystic neoplasia (MCN; with low-, intermediate-, or

high-grade dysplasia), 3) pancreatic neuroendocrine

tumor (PanNET), 4) solid-pseudopapillary neoplasia,

5) intraductal papillary neoplasm of the bile ducts, and

5) gastrointestinal stromal tumor (GIST).

DefinitionThis category connotes a premalignant (e.g., IPMN with

low-, intermediate-, or high-grade dysplasia) or low-grade

malignant potential (e.g., PanNET). Mucinous epithelia

with low-grade changes in brushing specimens should

still be classified as “Atypical” because of the unclear

management of these lesions.

Pancreatic Neuroendocrine TumorWhen used, the diagnosis of PanNET describes a well-

differentiated neoplasm. This term should be used regardless

of whether the tumor is in a primary site or represents

a metastasis. In contrast to PanNET, neuroendocrine

carcinoma is the terminology that should be used for

high-grade large cell neuroendocrine carcinoma or small

cell carcinoma. These overtly malignant tumors should be

placed in the “Positive (for malignancy)” category if there

are enough cytologic features to do so.

PanNET infers a well-differentiated proliferation of

pancreatic neuroendocrine cells forming a mass greater

than 0.5 cm. The tumor cells may or may not be functional

and may or may not exhibit aggressive features in histologic

specimens. These tumors do have malignant potential, but

the tumors are usually slow growing and early tumors may be

curable. PanNET is placed in the “Neoplastic: other” category

to distinguish them from more highly aggressive malignant

tumors and to offer management flexibility in patients, e.g.,

the elderly, where the benefits of surgery are not certain.

Solid-Pseudopapillary Neoplasm (SPN)SPN usually occurs in young females and exhibit solid and

cystic features on imaging. These tumors are low-grade, but

do demonstrate the ability to metastasize. When diagnosed,

these tumors are almost always resected. However, because

SPN is considered a low-grade malignancy, it should be

categorized as “Neoplastic: other”.

Neoplastic Mucinous Cysts of the Pancreas, IPMN and MCNIPMN and MCN are the two most common neoplastic

mucinous cysts of the pancreas. Cytologic diagnosis of

these tumors is supplemented by knowledge of the clinical


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findings, radiographic features, and by biochemical and/or

molecular cyst fluid analysis.

Management guidelines have become more conservative

for mucinous cysts due to the prevalence of incidental

pancreatic cysts in the general population, especially the

elderly. MCNs, although almost always low grade, are

usually found in the mid to distal pancreas and can be

resected by distal pancreatectomy. Main duct and combined

type IPMNs are always resected due to the high risk of

malignancy; however, for most mucinous cystic neoplasms

of the pancreas without high-grade dysplasia or carcinoma,

conservative management is reasonable.

For the pathologist, the task involves accurate grading of the

cyst epithelium to determine if conservative management

is possible or if more radical management is needed. This

task is made more difficult by a specimen with few epithelial

cells or cells that are poorly preserved. Moreover, many

of the specimens contain mucin contamination from the

stomach or duodenum. Regardless, it is contingent upon

the pathologist to be able to distinguish low-grade from

high-grade dysplasia as the latter lesions may benefit from

more definitive surgical resection.

Mucinous Cystic Neoplasia (MCN)These tumors are usually multiloculated, mucin-producing

neoplasms with an adjacent ovarian-type stroma occurring

almost exclusively in women. These tumors are usually not

connected to the pancreatic ductal system.

Cytologically, these tumors are graded by the degree of nuclear

and architectural atypia, i.e., low-grade, intermediate-grade,

high-grade dysplasia (non-invasive) and invasive mucinous

carcinoma. A similar neoplasm occurs in the biliary tract and

shares the same cytologic features.

Intraductal Papillary Mucinous Neoplasm (IPMN)IPMNs (including intraductal tubulopapillary neoplasms),

as their name implies, are primarily a neoplastic proliferation

of ductal epithelium. There are three types of IPMNs:

1) main-duct IPMN, 2) branch duct (BD)-IPMN, and

3) combined-type IPMN. The main-duct IPMN generally

causes dilatation of the main pancreatic duct or the entire

pancreas. These neoplasms usually have an intestinal-type

epithelium (MUC 5AC, MUC 2, and CDX-2 positive) and,

by definition, display at least intermediate grade dysplasia.

BD-IPMNs primarily are found in the uncinate process

and manifest as cysts adjacent to the non-dilated main

pancreatic duct. These cysts are most often lined by a gastric

foveolar-type epithelium displaying intermediate- to high-

grade dysplasia. One caveat is tumors lined by a low-grade

gastric foveolar-type epithelium may be confused with

contaminating gastric epithelium. Invasive carcinomas

arising from BD-IPMNs are usually tubular with a prognosis

similar to conventional pancreatic adenocarcinoma.

In addition to intestinal and gastric foveolar-type epithelia,

IPMNs may be lined by a pancreatcobiliary and oncocytic

type epithelium. Pancreaticobiliary-type epithelium is

relatively rare and is considered high-grade by definition.

Oncocytic-type epithelium is the least common and features

cells with an eosinophilic granular cytoplasm, large nucleus,

and a prominent nucleolus. It is not possible or necessary to

distinguish between the epithelial types in intermediate to

high-high grade dysplastic IPMNs.

Intraductal Papillary Neoplasm of Bile Ducts (IPN-BD) and GISTIPN-BDs share many of the clinical and pathological features

of IPMNs. Composed of a papillary proliferation of mucin-

producing neoplastic cells, this entity can occur anywhere in

the ductal system. The four types of epithelium associated

with IPMNs (intestinal, gastric foveolar, pancreaticobiliary,

oncocytic) can also be found in IPN-BD, but show a different

distribution pattern.17,18 These lesions are more likely to be

sampled by brushing than by fine needle aspiration.

GISTs are very rare primary pancreatic tumors, but can be

found in peripancreatic locations (omentum, mesentery,

duodenum, and stomach). Typically, these tumors express

c-kit protein (CD117 positive) and are also CD34 and

DOG1 immunoreactive. A cell block may greatly facilitate

definitive diagnosis.

Ancillary TestsAs mentioned previously, ancillary biochemical and/



or molecular tests may greatly aid in making a definitive

diagnosis. For cyst fluids, the determination of the levels

of CEA and amylase are invaluable to help determine

the classification of the cyst, i.e., mucinous versus non-

mucinous. A cyst fluid CEA level greater than 200 ng/ml

is strongly supportive of a mucinous cyst. In contrast, low

fluid CEA levels cannot be used by itself to diagnose non-

mucinous cysts as a low CEA level does not necessarily

exclude a mucinous cyst. In addition, CEA levels cannot

distinguish between benign and malignant cysts.

The level of fluid amylase is another parameter useful in

analyzing pancreatic cysts. For example, fluid amylase

levels are usually elevated (typically in the thousands) in

pseudocysts. Amylase levels cannot be used to distinguish

between IPMN and MCN. And finally, serous cystadenoma

and PanNET usually have low CEA and amylase levels.

KRAS testing may also prove useful for the diagnosis of

mucinous cysts.19 Similarly, the detection of GNAS in

pancreatic cyst supports the diagnosis of IPMN.20 Neither

the detection of KRAS or GRAS can distinguish between

pre-malignant lesions versus an invasive malignancy.


Neoplastic: other

Mucinous cyst fluid with low-grade dysplasia (see

comment)

Comment: Benign-appearing mucinous epithelial cells

in a background of thick mucin (CEA levels can be

reported if available).


Neoplastic: other

Well-differentiated neuroendocrine tumor (see

comment)

Comment: Synaptophysin and CD56 immunostains

support the diagnosis. The proliferative index, as

indicated by Ki67 immunocytochemstry is less than 2%.


Neoplastic: other

Solid-pseudopapillary neoplasm.

Category V. Suspicious (for malignancy)This category has traditionally been used for pancreatic

adenocarcinoma, but may be used for any malignant

neoplasm. The use of this category is recommended for any

high-grade, aggressive neoplasm where there is inadequate

cytologic features to make a definitive malignant diagnosis.

It is important to remember that “suspicious for” does

not mean “diagnostic of,” so surgical intervention is

inappropriate unless there is supporting clinical and

radiographic data in addition to the cytologic findings.

In a specimen with a paucity of cellularity precluding a

definitive diagnosis, the “Atypical” category should be

used. However, if the aspirate contains cells and/or tissue

fragments of clearly neoplastic epithelium, but for which

there is insufficient tissue for confirmatory ancillary studies,

the “Suspicious” category should be utilized.

Interpretation of pancreatic aspirates is sometimes hindered

by several factors necessitating indeterminate categorization

of the neoplasm, i.e., “Suspicious.” The first mitigating

factor is the level of differentiation displayed by some

pancreatic adenocarcinomas. Second is the possibility of

few diagnostic cells in the aspirate. Finally, gastrointestinal

(GI) contamination may be severe enough to obscure

the presence of malignant cells. GI contaminates can also

confound interpretation if the contaminating GI epithelium

are themselves atypical, either through injury or a reactive

process. If the listed factors confound the delivery of a

definitive diagnosis, the “Suspicious” category may be used.

Another mimicker of malignancy that must be considered is

autoimmune pancreatitis. This entity is a well-known pitfall

of adenocarcinoma of the pancreaticobiliary system. For all

these confounding factors, when criteria are stringently used

and there is high clinical and radiographic suspicion for

malignancy, the diagnosis of “Suspicious (for malignancy)”

most likely represents cancer.21-23

Definition“Suspicious (for malignancy)” may be used when there

are insufficient features to make a definitive diagnosis

of a malignant neoplasm (usually pancreatic ductal

adenocarcinoma). The cytologic findings are highly


suspicious for malignancy, but the quantitative and

qualitative characteristics of the aspirate are inadequate to

render a conclusive diagnosis. The cytologic features should

be atypical enough where a malignant process is considered

more probable than not.


Suspicious (for malignancy)

Rare markedly atypical cells suspicious for

adenocarcinoma.


Suspicious (for malignancy)

Mucinous cyst with high-grade dysplasia and abundant

background necrosis, suspicious for invasive carcinoma.

Category VI. Positive for MalignancyMost malignancies diagnosed in the pancreas (~90%) are

conventional pancreatic ductal adenocarcinomas. The

specificity of a malignant diagnosis from pancreatic fine

needle aspiration or biliary brush is very high, ~90-95%.24-31

In order to obtain this high level of diagnostic specificity, strict

interpretation and implementation of features associated

with malignancy must be used. However, strict adherence to

criteria defining malignancy will mitigate sensitivity. One-way

to increase diagnostic yield, and potentially sensitivity, is rapid

onsite evaluation.32-34 This is especially true for solid masses.

DefinitionThis category includes malignancies exhibiting unequivocal

cytologic evidence of malignancy. Included in this category

are pancreatic ductal adenocarcinoma and its variants,

cholangiocarcinoma, acinar cell carcinoma, high-grade

neuroendocrine carcinoma (i.e., large cell and small cell),

pancreatoblastoma, adenosquamous carcinoma, lymphoma,

sarcomas, and metastases to the pancreas.


Positive (for malignancy)

Adenocarcinoma.


Positive (for malignancy)

Malignant glandular and squamous epithelial cells,

compatible with adenosquamous carcinoma.

Recommended Approach to the Cytologic Analysis of Pancreatic and Biliary Tract CystsIn addition to outlining the guidelines for the standardization

of terminology and nomenclature for pancreaticobiliary

cytology, the Papanicolaou Society also provided guidance

on how to evaluate cystic neoplasms of the pancreas and

biliary tract. When encountering a cystic neoplasm of

the pancreas or biliary tract, two fundamental questions

should be addressed: 1) is the cyst mucinous or non-

mucinous? and 2) is high-grade dysplasia present or not?

For overtly malignant appearing aspirates, the “Positive (for

malignancy)” category should be used. For those cysts with

less than definitive cytologic evidence of malignancy, the

‘Neoplastic: other’ category should be used.

Determining whether aspirated cyst fluid is mucinous or

not can be initially assessed during the time of collection, if

the specimen is evaluated on site by the cytopathologist or

cytotechnologist. Otherwise, information provided by the

gastroenterologist may help determine the nature of the cyst,

i.e., is the fluid thick and viscous or thin and watery. Thicker

fluid can be directly applied to a slide and a smear prepared.

Less viscous cystic fluid is best processed as a cytospin

preparation. Placing the fluid in a preservation or transport

medium may dilute the fluid making the identification of

mucin on the slide difficult or impossible to detect.

The aspirate may also be contaminated with mucin from the

gastrointestinal tract. Thick, colloid-like mucin is most likely

neoplastic whereas thin mucin with naked, grooved nuclei

most likely represents gastrointestinal contamination.3

Mucin populated with cellular cyst debris is also most likely

neoplastic.

Biochemical (elevated CEA) or molecular analysis (KRAS)

of the fluid can also be used to help document a fluid is

neoplastic. It is important to remember, however, that a

low CEA level or the absence of KRAS does not necessarily

exclude a mucinous cyst.

Determining whether high-grade dysplasia is present or not

requires the microscopic examination of epithelial cells.

If overt evidence of malignancy is not present, it is best

to interpret the aspirate as either low-grade or high-grade

dysplasia. A recent article describing the characteristics

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distinguishing low-grade from high-grade atypia in

pancreatic cyst fluid has been published.35 According to

these authors, increased nuclear-to-cytoplasmic ratio, an

abnormal chromatin pattern, and background necrosis are

the most important cytologic features for determining a

pancreatic cyst at high-risk for malignancy.

The approach to evaluate cysts arising from the biliary tract

has not been as well characterized as those in the pancreas.

It is assumed IPMNs and MCNs originating from the biliary

tract share the same cytologic features as their counterparts

in the pancreas. The role of CEA levels and KRAS is not as

well established in biliary-derived cysts.

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19. Khalid A, Zahid M, Finkelstein SD, et al., Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: A report of the PANDA study. Gastrointest Endosc 2009; 69:1095-1102.

20. Wu J, Matthaei H, Maitra A. et al., Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 2011; 3:92ra66.

21. Eloubeidi MA, Jhala D, Chhieng DC, et al., Yield of endoscopic ultrasound-guided fine-needle aspiration biopsy in patients with suspected pancreatic adenocarcinoma. Cancer 2003; 99:285-292.

22. Bhutani MS, Hawes RH, Baron PL, et al., Endoscopic ultrasound guided fine needle aspiration of malignant pancreatic lesions. Endoscopy 1997; 29:854-858.

23. Faigel DO, Ginsberg GG, Bentz JS, et al., Endoscopic ultrasound-guided real-time fine-needle aspiration biopsy of the pancreas in cancer patients with pancreatic lesions. J Clin Oncol 1997; 15:1439-1443.

24. Turner BG, Cizginer S, Agarwal D, et al., Diagnosis of pancreatic neoplasia with EUS and FNA: A report of accuracy. Gastrointest Endosc 2005; 71:91-98.

25. Ylagan LR, Edmundowicz S, Kasal K, et al., Endoscopic ultrasound guided fine-needle aspiration cytology of pancreatic carcinoma: A 3-year experience and review of the literature. Cancer 2002; 96:362-369.

26. Volmar KE, Vollmer RT, Routbort MJ, et al., Pancreatic and bile duct brushing cytology in 1000 cases: Review of findings and comparison of preparation methods. Cancer 2006; 108:231-238.

27. Layfield LJ, Wax TD, Lee JG, et al., Accuracy and morphologic aspects of pancreatic and biliary brushings. Acta Cytol 1995; 39-11-18.

28. Ylagan LR, Liu LH, Maluf HM, Endoscopic bile duct nbrushing of malignant pancreatic biliary strictures: Retrospective study with comparison of conventional smear and ThinPrep techniques. Diagn Cytopathol 2003; 28:196-204.

29. Eloubeidi M, Chen VK, Eltoum IA et al., Endoscopic ultrasound-guided fine needle aspiration biopsy of patients with suspected pancreatic cancer: Diagnostic accuracy and acute and 30-day complications. Am J Gastroenterol 2003; 98:2663-2668.

30. Eloubeidi MA, Tamhane A. EUS-guided FNA of solid pancreatic masses: A learning curve with 300 consecutive procedures. Gastrointest Endosc 2005; 62:700-708.

31. Adamson S, Olsen M, Jendresen MB, et al., Endo-biliary brush biopsy: Intra- and interobserver variation in cytological evaluation of brushings from bile duct strictures. Scand J Gastroenterol 2006; 41:597-603.

32. Hebert-Magee S, Bae S, Varadarajulu S, et al., The presence of a cytopathologist increases the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration cytology for pancreatic adenocarcinoma: A meta-analysis. Cytopathology 2013; 24:159-171.

33. Klapman JB, Logrono R, Dye CE, et al., Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 2003; 98:1289-1294.

34. da Cunha Santos G, Ko HM, Saieg MA, et al., “The petals and thorns” of ROSE (rapid on-site evaluation). Cancer Cytopathol 2013; 121:4-8.

35. Pitman MB, Centeno BA, Daglilar ES, et al., Cytologic criteria of high-grade epithelial atypia in the cyst fluid of pancreatic intraductal papillary mucinous neoplasms. Cancer Cytopathol 2014; 122:40-47.


Missing Data Was Common In Pathology Reports Of Vulvar Carcinoma: A Population

Based Ontario Cohort

Lisa Barbera,MD1,2,3;Lilian Gien,MD3,4; Rinku Sutradhar,PhD2,3,5; Gillian Thomas, MD1; Al Covens, MD4; Laurie Elit, MD6; Anthony Fyles, MD1,4; Eileen Rakovitch, MD1,2,3; Ying Liu, MSc3; Mahmoud Khalifa, MD4,7

1Department of Radiation Oncology, University of Toronto2Department of Health Policy, Management and Evaluation, University of Toronto3Institute for Clinical Evaluative Sciences, Toronto4Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Toronto5Dalla Lana School of Public Health, University of Toronto6Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON7Department of Lab Medicine and Pathology, University of MinnesotaCorrespondence may be directed to Lisa Barbera at [email protected]

Preliminary versions of this work have been presented at the 2014 annual meeting of the Society of Gynecologic Oncology (SGO) in Tampa, FL and The Society of Gynecologic Oncology in Canada (GOC) in Niagara Falls, Canada.

This article has been peer reviewed.Competing interests: None to declare

Funding source: This study was conducted with the support of the Canadian Cancer Society Research Institute and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the MOHLTC is intended or should be inferred.

Lisa Barbera, MD, Lilian Gien, MD, Rinku Sutradhar, PhD, Gillian Thomas, MD, Al Covens, MD, Laurie Elit, MD, Anthony Fyles, MD, Eileen Rakovitch, MD, Ying Liu, MSc, Mahmoud Khalifa, MD

ORIGINAL ARTICLE

AbstractPurpose: We conducted a population based patterns of care study of vulvar carcinoma. This paper describes the completeness of pathology reporting for this cohort.

Methods: This is a retrospective population-based cohort study. We obtained all pathology records available from the provincial cancer registry for primary invasive squamous cell carcinoma of the vulva diagnosed between 1998 and 2007. Original pathology reports of vulva specimens pertaining to initial management were included. Abstracted variables included tumor size, grade, depth of invasion, thickness, margin status, lympho-vascular space invasion (LVSI), date, institution and pathologist type.

Results: 1011 vulvar resection reports were identified. Overall, 16% of reports were complete for all variables. Frequency of reporting each individual variable improved over time as did overall completeness. Peripheral margins were as reported most frequently (88%) and thickness was reported least frequently (43%). Gyne-pathologists reported each variable more frequently than general pathologists (48% complete for all variables vs. 22%). There was significant variation by institution. The largest improvement was observed in a single institution that implemented a checklist midway through the study period.


MISSING DATA VULVA CANCER REPORTS

Conclusions: Pathology reports for vulva carcinoma are frequently missing information important for clinical decision making. Checklists or synoptic reporting are likely to improve the amount of missing information.

(Keywords: vulvar carcinoma, quality of reporting, synoptic reporting, missing data)

RésuméObjectif : Nous avons mené une étude sur les modèles de soins pour le cancer de la vulve. L’article porte sur l’exhaustivité des rapports de pathologie pour la cohorte étudiée.

Méthodologie : Il s’agit d’une étude de cohorte rétrospective basée sur une population. Nous avons extrait du registre de la province tous les dossiers de pathologie concernant un carcinome épidermoïde primitif invasif de la vulve diagnostiqué entre 1998 et 2007, y compris les rapports des analyses pathologiques effectuées sur des prélèvements de tissus vulvaires lors de la prise en charge initiale. Les variables examinées sont notamment la taille, le grade et l’épaisseur de la tumeur, la profondeur de l’invasion, l’état des marges, l’invasion de l’espace lymphovasculaire, la date, l’établissement et le type de pathologiste.

Résultats : Nous avons étudié 1011 rapports de résection vulvaire. Dans l’ensemble, 16 % des rapports comportent toutes les variables. La consignation de chacune des variables s’améliore au fil du temps, de même que l’exhaustivité globale. L’état des marges est la variable consignée le plus fréquemment (88 %), alors que l’épaisseur est celle qui est rapportée le moins fréquemment (43 %). Les gynécopathologistes consignent chacune des variables plus fréquemment que les pathologistes généralistes (48 % des premiers consignent toutes les variables, contre 22 % pour les seconds). Il y a une différence importante d’un établissement à l’autre. L’amélioration la plus importante s’est produite dans un établissement qui s’est doté d’une liste de vérification au milieu de la période étudiée.

Conclusions : Dans les rapports de pathologie sur les cancers de la vulve, il manque souvent des données importantes pour la prise de décisions cliniques. L’utilisation de listes de vérification ou de fiches synoptiques pourrait vraisemblablement améliorer la situation.


BARBERA ET AL.

IntroductionHigh quality pathology reporting is of vital importance to

decision making in oncology. The foundation of oncologic

practice is to choose therapy based on risk of recurrence.

Usually, one or more pathologic features define the level

of risk for a patient which guides subsequent choice for

management. For vulvar carcinoma, ascertaining the level

of risk for groin node involvement is pivotal for planning

management. Several pathologic criteria inform this

decision but the most critical feature is depth of tumor

invasion below the basement membrane. The risk of nodal

involvement increases with increasing depth of invasion1

and the decision to surgically assess the groins is based on

depth >1mm. When the nodes are involved, adjuvant nodal

radiotherapy is typically recommended to improve overall

survival.2 Failure to manage the groins optimally may result

in increased groin relapse which is uniformly fatal.3

Prior research has demonstrated that pathologists frequently

omit important elements required for optimal care in

common cancers such as lung4 or colorectal.5 Synoptic

reporting has been shown to improve the completeness of

oncologic pathology reports.6,10 The province of Ontario

has been moving to synoptic reporting over the past

decade. Vulvar carcinoma has only been recently included

in this initiative in spite of the availability of a checklist of

important pathologic features since 1994.11

This team of investigators has conducted a population-based

patterns of care study for vulvar carcinoma in the province of

Ontario for incident cases between 1998 and 2007. As part of

this study, we collected all pathology reports for this cohort.

The purpose of this paper is to describe the completeness

of pathology reporting for vulva cancer in the province of

Ontario using a contemporary, population-based cohort.

MethodsThis is a retrospective population-based cohort study. The

pathology reports, which are the focus of this study, were

obtained as part of a larger study to evaluate patterns of

care for vulvar carcinoma. The study was conducted with

approval from the Sunnybrook Health Sciences Research

Ethics Board.

We obtained all pathology records available from the

provincial cancer registry for primary invasive squamous

cell carcinoma of the vulva (ICD 9 184.1-184.4) diagnosed

between 1998 and 2007. Original pathology reports of vulva

specimens, pertaining to initial management, are included in

this report. Reports issued as a second pathological opinion

or pathology review, are not included in this report.

Two investigators (LB, LG) abstracted all pathology reports

collecting data on tumor size, grade, depth of invasion,

thickness, margin status (deep and peripheral) and

lympho-vascular space invasion (LVSI).12 These are factors

known to have prognostic importance for recurrence and

survival. A report was considered complete when all of

these variables were described. Other abstracted variables

included: procedure date, reporting institution, specimen

size and pathologist type (general versus gyne-pathologist).

A report was assigned to the year in which it was issued,

not the patient’s year of diagnosis. The specimen was

considered a resection when the specimen size was greater

than 1.5cm. Pathologist type was assigned based on a list of

individuals known to have either completed additional sub-

specialty training (in gyne-pathology) or are the recognized

regional expert who would accept cases for consultation.

The abstraction process was validated by re-abstracting

25 reports by both reviewers. In 60% of the reports there

was 99-100% agreement. In all reports there was >95%

agreement.

The analysis is descriptive. Proportions are compared

with chi-square tests. Trends over time are compared with

the Cochrane-Armitage test for trend. Data analysis was

conducted using SAS 9.2.

ResultsWe identified 1830 original vulva specimen reports

pertaining to 1109 patients. 819 were vulvar biopsies

(defined as specimen size <1.5cm). A total of 1011

were vulvar resections which are the focus of this study.

Reports for these specimens were issued from 75 different

institutions. Almost half of the reports were issued from 6

higher volume centres. The study did not quantify the total

number of unique pathologists.



Figure 1. Proportion of vulva pathology reports with all variables recorded, by year. Number of reports contributing to analysis shown for each year.

Figure 2. Proportion of vulva pathology reports will all variables recorded by year and institution. Each institution contributed the following number of cases across all years: B: n=155, C n=178, D n=153, E n=169.


BARBERA ET AL.

Figure 3. Proportion of vulva pathology reports will a specific variable recorded, by year.

Figure 4. Proportion of vulva pathology reports with a specific variable recorded, by institution. Each institution contributed the following number of cases across all years: A: 64, B: n=155, C n=178, D n=153, E n=169, Fn=51.



Figure 1 demonstrates the proportion of reports with

complete information for tumor size, grade, depth of

invasion, thickness, LVSI and margin status by year. Overall,

only 16% of reports were complete. The completeness of

reporting increased with time (p<0.0001) with a peak value

of 25%. There was a noticeable change in 2002; however,

no provincial initiative was identified that could have

influenced pathology reporting. An analysis of the 4 largest

volume centres by year (>100 cases in total, other centres

had too few cases to analyze by year) demonstrated that

one centre (centre E) was the main driver of the provincial

change over time (Figure 2, p<0.0001). On further inquiry

we confirmed that this institution adopted a pathology

checklist for vulvar carcinoma that year. We secondarily

evaluated reports that were complete for depth, LVSI and

margin only. When this more limited number of variables

was included, 39% of the reports were considered to be

complete.

Figure 3 demonstrates the proportion of reports which

described each individual variable by year. Peripheral

margin status was reported most often. Thickness was

reported least often. The proportion of cases that reported

depth of invasion increased over time from about 30% to

about 70% (p<0.0001). Tumor size and LVSI also improved,

to a lesser degree (p<0.0001and p=0.003 respectively).

Figure 4 demonstrates the proportion of reports that

described a particular variable, by centre. The top six centres

reporting the largest volume of cases are shown (>50 cases).

Many other centres contributed data, but typically had

only a few cases in total. All centres consistently reported

on peripheral margin status. Although there was significant

variation by centre for the remaining variables, there was

no pattern for which variables were reported or omitted by

centre.

Gyne-pathologists were more likely to have complete reports

than general pathologists, 21% versus 8% respectively

(p<00001). The same observation was made when a

complete report was defined with depth, LVSI and margin

(48% versus 22%, p<0.0001). Missing data was common for

Figure 5. Proportion of vulva pathology reports with a specific variable recorded, by pathologist type. There were n=661 reports from gyne-pathologists and n=349 reports from general pathologists.


both specialists and generalists. Figure 5 shows the frequency

of reporting for each variable by pathologist type.

DiscussionWe conducted a retrospective population based cohort

study of the patterns of care of vulvar carcinoma in Ontario.

As part of this study we reviewed the pathology reports for

1011 vulva resections and observed a high proportion of

incomplete reports. This improved over time but the change

was primarily driven by the adoption of a checklist within

a single large volume centre. From a provincial perspective,

the completeness rate did not exceed 25%. Depth of

invasion was increasingly reported over time approaching

80% completeness by the end of the observation window.

This study contributes two important findings. The first

important finding is that we observed the completeness

for vulvar carcinoma reporting to be poor during the time

of this cohort. While any individual variable was reported

the majority of the time, it was very common for at least

one variable to be missing rendering the report incomplete.

We are not aware of any studies in the literature describing

pathology reporting exclusively for vulvar carcinoma.

Amongst gynecologic malignancies, pathology reporting

for endometrial cancer has been typically viewed as

problematic.13 However, even when narrative reporting

was used for endometrial carcinoma in Ontario, the

completeness rate was much higher than for vulvar

carcinoma, 79% compared with 16% from our study.6 Since

endometrial cancer is more common than vulvar cancer,

perhaps pathologists are more familiar with which features

are key in clinical decision making. In some circumstances,

reports may be incomplete for legitimate technical reasons,

for example, poor specimen orientation.

The second important finding is the impact of synoptic

reporting for vulvar carcinoma. Prior research has clearly

demonstrated that, in other malignancies, synoptic

reporting is associated with more complete reports when

compared with narrative reports.6 However, there is very

little data in the gynecologic oncology literature in general

and none that we could identify specifically related to vulvar

carcinoma, in spite of the publication of a vulvar carcinoma

pathology checklist in 1994.11 Cancer Care Ontario has

initiated the provincial adoption of synoptic reporting

across all cancer sites. More common cancers were

addressed first. Synoptic reporting for vulvar carcinoma

began in 2008, therefore, one would expect that this has

improved completeness rates. Our data confirms that

one centre increased completeness of reporting with the

adoption of a checklist in 2002. This centre’s completeness

rate did decline in subsequent years. From a management

perspective this demonstrates the importance of efforts to

maintain change, including on-going quality assurance.

The implications of incomplete reporting for vulvar

carcinomas are significant. Incomplete data hinders optimal

clinical decision making. One of the few randomized trials in

vulvar cancer2 demonstrated improved survival for patients

with groin node involvement who received adjuvant nodal

radiotherapy. Incomplete pathology information about

the primary may result in sub-optimal decision making

regarding the need for surgical groin node evaluation and

adjuvant groin irradiation. Close margins are associated

with increased local relapse.14 The absence of complete

information about margin status may result in sub-optimal

decisions about the need for adjuvant radiation or a re-

excision.

The strength of this study is that it is population-based

which minimizes selection bias. Our observations are a

potential concern for any other jurisdiction not using

synoptic reporting. The pathology reports were abstracted

by two physicians who are content experts. Re-abstraction

showed a high level of agreement. The dataset is a high

quality reflection of real world practice. One limitation was

that we were unable to comment on the accuracy of the

reporting. This would have required a centralized review

of all cases. In addition, we are unable to comment on

frequency of poorly oriented specimens; however, this

is unlikely to be responsible for all of the missing data

described. Since it is difficult to determine the intent of the

surgical procedure in a retrospective fashion, we limited

this analysis to specimens larger than 1.5cm in size. Missing

data for the smaller specimens was as common, if not worse

than reported here. For example, in our dataset, depth was

missing in more than 80% of the reports for specimens less

than 1.5cm. Arguably, the decision to do a lymph node

BARBERA ET AL.



dissection was actually based on the biopsy information and

not the resection specimen, in which case our results may

have under-estimated the clinical implications.

Synoptic reporting for vulvar carcinoma is being introduced

province-wide. Our data strongly suggests that synoptic

reporting results in more complete reporting of pathologic

factors key to clinical management decision making. Our

data also illustrate the need to include uncommon diagnoses

in wide scale quality initiatives.

Referencs1. Homesley H, Bundy BN, Sedlis A et al. Prognostic Factors for Groin Node

Metastasis in Squamous Cell Carcinoma of the Vulva. Gynecol Oncol. 1993;49:279-283.

2. Homesley H, Bundy BN, Sedlis A et al. Radiation Therapy versus Pelvic Node Resection for Carcinoma of the Vulva with Positive Groin Nodes. Obstet Gynecol. 1986;68:733-739.

3. Stehman FB, Bundy BN, Thomas G et al. Groin dissection versus groin radiation in carcinoma of the vulva. I J Radiation Oncology Biology Physics. 1992;24:389-396.

4. Gephardt GN, Baker PB. Lung carcinoma surgical pathology report adequacy: a College of American Pathologists Q-Probes study of over 8300 cases from 464 institutions. Arch Pathol Lab Med. 1996;120:922-927.

5. Zarbo RJ. Interinstitutional assessment of colorectal carcinoma surgical pathology report adequacy. A College of American Pathologists Q-Probes study of practice patterns from 532 laboratories and 15,940 reports. Arch Pathol Lab Med. 1992;116:1113-1119.

6. Srigley JR, McGowan T, Maclean A et al. Standardized synoptic cancer pathology reporting: a population-based approach. J Surg Oncol. 2009;99:517-524.

7. Casati B, Bjugn R. Structured electronic template for histopathology reporting on colorectal carcinoma resections: five-year follow-up shows sustainable long-term quality improvement. Arch Pathol Lab Med. 2012;136:652-656.

8. Kench JG, Clouston DR, Delprado W et al. Prognostic factors in prostate cancer. Key elements in structured histopathology reporting of radical prostatectomy specimens. Pathology. 2011;43:410-419.

9. Idowu MO, Bekeris LG, Raab S et al. Adequacy of surgical pathology reporting of cancer: a College of American Pathologists Q-Probes study of 86 institutions. Arch Pathol Lab Med. 2010;134:969-974.

10. Branston LK, Greening S, Newcombe RG et al. The implementation of guidelines and computerised forms improves the completeness of cancer pathology reporting. The CROPS project: a randomised controlled trial in pathology. Eur J Cancer. 2002;38:764-772.

11. Robboy SJ, Bentley RC, Krigman H et al. Synoptic reports in gynecologic pathology. Int J Gynecol Pathol. 1994;13:161-174.

12. Greene LA, Branton, P., Montag, A., Oliva, E., and Kumarasen, C. Protocol for the examination of specimens from patients with carcinoma of the vulva. College of American Pathologists. 2011.

13. Scholten AN, Smit VTHB, Beerman H et al. Prognostic significance and interobserver variability of histologic grading systems for endometrial carcinoma. Cancer. 2004;100:764-762.

14. Heaps JM, Fu YS, Montz FJ et al. Surgical -Pathologic Variables Predictive of Local Recurrence in Squamous Cell Carcinoma of the Vulva. Gynecol Oncol. 1990;38:309-314.

15. Khalifa MA, Dodge J, Covens A et al. Slide review in gynecologic oncology ensures completeness of reporting and diagnostic accuracy. Gynecol Oncol. 2003;90:425-430.

ErratumCanadian Journal of Pathology, Volume 6, Issue 3, 2014 Invited Editorial

The Crisis in Cytotechnology in Ontario: Disruptive Practice Patterns and Technology (p. 68)

The following reference is to be removed: “QMPLS. (2013). Committee Comments CYTO-1305-PP Patterns-of-Practice Survey. Toronto, Ontario: Quality Management Program - Laboratory Services”.

The cited document is not available in the public domain and it is IQMH policy that such internal documents are not referenced in the public domain.


Endoscopic Mucosal Resection (EMR) In Barrett’s Esophagus Associated Neoplasia:

Recommendations For Pathological Evaluation And Reporting

Jennifer A. Muir, MD1, Norman Marcon, MD2, Javier Aranda-Hernandez, MD2, Maria Cirocco, BScN2, Sahar Al-Haddad, MD1, Catherine J. Streutker, MD1, Andrea Grin, MD1

1Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, Canada2Division of Gastroenterology, Department of Medicine, St. Michael’s Hospital, Toronto, ON, CanadaCorrespondence may be directed to Andrea Grin at [email protected]

This article has been peer reviewed.Competing interests: None

Jennifer A. Muir, MD, Norman Marcon, MD, Javier Aranda-Hernandez, MD, Maria Cirocco, BScN, Sahar Al-Haddad, MD, Catherine J. Streutker, MD, Andrea Grin, MD

ORIGINAL ARTICLE

AbstractEndoscopic mucosal resection (EMR) is a minimally-invasive technique increasingly adopted for resection of superficial neoplasia arising in Barrett’s esophagus (BE). High-grade dysplasia or adenocarcinoma confined to the mucosa (pT1a) should be treated by EMR rather than esophagectomy, as this has been shown to attain similar long-term survival with lower immediate morbidity and mortality rates. As the prevalence of BE continues to rise and gastroenterologists gain comfort with EMR, it is likely that pathologists in both academic and community settings will evaluate more EMR specimens in the future. Accurate assessment of EMR specimens depends upon appropriate macroscopic handling and microscopic diagnosis. Specimens should be pinned flat prior to fixation and the margins should be inked with a vivid colour both to help orient the fragments during embedding and for assessment of their relationship to invasive lesions. The specimen should then be serially sectioned at 2 mm intervals and submitted sequentially for histological evaluation. Microscopic assessment should include the histological type, grade, stage, tumour size, margin status, and distance of carcinoma from the margin, as well as the presence or absence of lymphovascular invasion and tumour budding. Depth of invasion should be reported according to the AJCC 7th edition or the Vieth and Stolte system with special attention paid to the frequent finding of a duplicated muscularis mucosae. Evaluation of EMR specimens according to these recommendations will allow consistency among pathologists and ensure that patient prognosis and treatment decisions are based on complete and accurate information.

Keywords: Endoscopic mucosal resection (EMR), Barrett’s esophagus, esophageal adenocarcinoma, dysplasia

mailto:GrinA%40smh.ca?subject=


ENDOSCOPIC MUCOSAL RESECTION (EMR) IN BARRETT’S ESOPHAGUS ASSOCIATED NEOPLASIA

RÉSUMÉLa résection muqueuse endoscopique (RME) est une technique peu invasive de plus en plus utilisée pour la résection de néoplasies superficielles dans l’œsophage de Barrett (OB). Une dysplasie de haut grade ou un adénocarcinome confiné à la muqueuse (pT1a) devrait être traité par RME plutôt que par une œsophagectomie, avec un taux de survie à long terme semblable et une réduction de la mortalité et de la morbidité immédiates. Au fur et à mesure que la prévalence de l’OB augmentera et que les gastroentérologues apprivoiseront la RME, les pathologistes auront davantage de prélèvements de RME à analyser. La précision de ces analyses dépend du traitement macroscopique et du diagnostic microscopique. Les échantillons doivent être épinglés à plat avant la fixation, et les marges doivent être encrées avec une couleur vive pour aider à orienter les fragments pendant l’enrobage et à évaluer leur relation avec des lésions invasives. Les échantillons doivent ensuite sectionnés en coupes sériées de 2 mm et soumis séquentiellement à l’évaluation histologique. L’analyse microscopique doit comprendre le type histologique, le grade, le stade et la taille de la tumeur, l’état des marges, la distance entre le carcinome et la marge ainsi que la présence ou l’absence d’invasion lymphovasculaire et de bourgeonnement tumoral. La profondeur de l’invasion doit être consignée selon la 7e édition du manuel de l’AJCC ou le système de Vieth et Stolte, avec une attention particulière pour le dédoublement fréquent de la musculaire muqueuse. L’application de ces recommandations à l’analyse des échantillons de RME améliorera la cohérence des résultats et permettra d’obtenir des données complètes et précises pour établir le pronostic et choisir le traitement.

Introduction Endoscopic mucosal resection (EMR) is a technique for

minimally-invasive removal of superficial mucosal lesions

in the gastrointestinal tract. It has been increasingly applied

in recent years for staging and management of dysplasia and

early neoplasia arising in Barrett’s esophagus (BE). Clinical

guidelines now recommend EMR for the treatment of high-

grade dysplasia (HGD) and early adenocarcinoma confined

to the esophageal mucosa, scenarios that would have led to

surgical management in the past.1-3

Other therapies such as radiofrequency ablation,

argon plasma coagulation, photodynamic therapy, and

cryotherapy may be used, but while these ablative modalities

allow for treatment of larger areas of mucosa, they preclude

histological evaluation and are not recommended for

treatment of adenocarcinoma or HGD associated with

endoscopically-visible lesions.2,4 Similarly, a technique

called endoscopic mucosal dissection (ESD) provides

another alternative to EMR. It is practised mainly in Japan

and involves dissection within the submucosa to remove

early lesions en bloc rather than piecemeal.4 In this review,

we focus on EMR as it is widely used in Canada, and given

the rising incidence of BE and associated neoplasia in

North America and gastroenterologists’ growing comfort

with EMR, pathologists are more likely to encounter

EMR specimens in the future. At our centre we handle

approximately 800-1000 EMR specimens per year. The

purpose of this review is to provide some background

information about EMR, as well as a practical set of

recommendations for processing and reporting of EMR

specimens by Canadian pathologists.


MUIR ET AL.

Who Benefits from EMR?EMR is recommended for staging and treatment of patients

with BE who present with HGD and optical abnormalities

on endoscopy, as well as for patients with adenocarcinoma

confined to the mucosa (American Joint Committee on

Cancer [AJCC] pT1a lesions).1-3 In such patients, EMR has

similar long-term survival but lower immediate morbidity

and mortality when compared to esophagectomy.5,6 EMR is

indicated in HGD associated with visible lesions both because

of the high incidence of progression to adenocarcinoma (up

to 6% per year) and to ensure that the patient has not been

under-staged or over-staged by biopsies, which occurs in

about 24-55% of cases.7-10 EMR may also be indicated in

select patients with carcinoma invading beyond the mucosa

when these patients would have a high risk of morbidity

and mortality with esophagectomy. In such cases, EMR

may be considered curative when tumours show limited

invasion into the submucosa (pT1b) and favourable

histological parameters associated with a low-risk of lymph

node involvement2 (well-differentiated carcinoma, no

lymphovascular invasion, and no tumour budding).

The management of patients with low-grade dysplasia

(LGD) continues to be controversial, given the variable

rates of progression to HGD or cancer in the literature (0.5-

13% per year).1-3 Such wide variation may be partially due

to poor interobserver agreement in the diagnosis of LGD

among pathologists (kappa values of 0.13-0.49 among

expert GI pathologists).11,12 Currently, we feel that patients

with multifocal and persistent LGD should be treated

endoscopically.13

Endoscopic Assessment and TreatmentThere are two main EMR techniques used. They have

similar success rates, and selection usually depends on

operator preference. First, in the cap-snare technique

(Inoue cap), a transparent cap is attached to the tip of the

endoscope. This cap has a rim on the distal edge that is able

to fit and hold an expanded snare placed through the scope.

Following submucosal lifting by solution injection, the

mucosa is sucked into the cap forming a pseudopolyp, the

snare is closed and electrocautery is applied for resection

of the specimen. The multiband ligation system (Duette)

consists of a cap, preloaded with six outer rubber bands,

that is attached to the tip of the scope. A pseudopolyp is

formed by suctioning mucosa into the cap, the rubber band

is deployed using a triggering device, and the pseudopolyp

is resected using a snare (Figure 1). These two suction

modalities usually ensure that muscularis propria is not

involved in the pseudopolyp.

Specimen Handling and Macroscopic Assessment EMRs of esophageal lesions typically range in size from

1-2 cm in greatest dimension. Specimens should be gently

stretched and pinned flat with cut surface down on stiff

paper, cardboard, cork, wax or Styrofoam board (Figure

2A), ideally at the time of resection. Pinning helps to

minimize retraction of the muscularis mucosae and rolling

of the margins. Specimens should then be fixed by floating

them tissue-down in 10% neutral buffered formalin for a

period of at least 6 hours. Following fixation, the size of the

specimen should be measured and pins carefully removed.

Figure 1. The technique of endoscopic mucosal resection (EMR). A) The endoscopic appearance of Barrett’s esophagus; note the darker, salmon-pink tongues of columnar mucosa extending upward from the gastroesophageal junction. B) In the multiband ligation (Duette) system, a pseudopolyp is formed by suctioning mucosa into the cap, and a band is placed around the pseudopolyp, which is then removed using a snare. C) The endoscopic appearance of the esophagus following EMR.


In most cases, multiple unoriented EMRs of a single area

are received, therefore, only the deep resection margin is

of interest to the endoscopist and a single ink colour may

be used to mark the deep resection margins. Using a vivid

colour helps to orient the specimen perpendicularly during

embedding. In cases where only one EMR specimen is

removed or when one area of interest is taken out separately

from the other fragments and appropriately oriented, the

lateral margins are of interest and should be marked with a

different ink colour.

After inking, the specimen should be serially sectioned into

slices approximately 2 mm in thickness and embedded on

edge (Figure 2B). Specimens should always be submitted in

toto, as any dysplastic or malignant lesions may be focal and

because it is essential to document the maximum depth of

invasion accurately. Slices should be submitted sequentially

from one end of the specimen to the other, with no more

than four slices per cassette.

Microscopic Assessment In our institution, 4 levels are initially performed on each

block: levels 1 and 3 are stained with H&E, level 2 with

hematoxylin phloxine saffron (HPS) to facilitate evaluation

of the muscularis mucosae, and level 4 with H&E with Alcian

blue to highlight intestinal metaplasia. The main features

which should be documented on microscopic assessment

are listed in Table 1. The esophageal carcinoma synoptic

report mandated by the College of American Pathologists

is completed for each case with invasive carcinoma. In our

institution, we most often receive multiple unoriented EMR

specimens but only one synoptic report is completed. In these

cases, some items listed in the synoptic report, particularly

the proximal and distal resection margins, are not applicable

and only the deep resection margin may be evaluated.


Figure 2. Macroscopic assessment and processing of EMR specimens. A) The specimen is gently stretched and pinned flat on a firm surface with the mucosa side up, then fixed in 10% neutral buffered formalin for at least six hours. It is seen here following fixation. B) A vivid colour of ink has been applied to the deep margin and the specimen has been serially sectioned at 2 mm intervals and submitted sequentially for histological examination.

Table 1. Minimum reporting data for endoscopic mucosal resection (EMR) specimens.

Histological type WHO classification

Tumour size Estimated using greatest dimension on one slide or measured across EMR specimens

Histological grade well/moderate/poor/undifferentiated

Depth of invasion AJCC and Vieth & Stolte system

Margin status positive/negative

Distance to deep margin mm

Lymphovascular invasion present/absent

[WHO=World Health Organization; AJCC=American Joint Committee on Cancer]


MUIR ET AL.

Figure 3. Various patterns of adenocarcinoma are seen in Barrett’s neoplasia, and recognizing invasive carcinoma can sometimes be challenging. Indicators of malignancy include: A) Dilated glands filled with necrotic debris (inset); B) A never-ending/anastomosing gland pattern; C) Complex architecture, including papillary and micropapillary formations; D) Small and irregular or angulated glands; E) Cribriforming. In some cases, carcinoma may be very well-differentiated, with abnormal gland shape and location being the primary indicators of malignancy (F-H). Submucosal gland ducts must be distinguished from invasive carcinoma (arrow in H points to a duct with a double-layered lining; see also Figure 6D-F). Note that intramucosal carcinoma typically does not incite a desmoplastic reaction. [Hematoxylin & eosin]



Figure 4. A) The duplicated muscularis mucosae (dMM) is seen on hematoxylin and eosin (H&E) staining superficial to the original muscularis mucosae (oMM). The presence of larger calibre vessels can help to identify the submucosa. B) Both the dMM and the oMM are highlighted by immunohistochemistry for desmin. The fibres of the dMM tend to be more delicate and wispy.


MUIR ET AL.

RecognizingcarcinomaThe distinction between HGD and intramucosal carcinoma

(IMC) in BE can be challenging, and interobserver

variability is high even among expert pathologists

(κ = 0.30).14 Identifying invasive IMC is made more difficult

by the fact that carcinoma confined to the esophageal

mucosa does not typically incite a desmoplastic reaction.15

Features which suggest carcinoma include the presence of

necrosis in dilated gland lumens, small angulated glands,

complex architecture, single neoplastic cells in the lamina

propria, cribriforming, or a never-ending/anastomosing

gland pattern (Figure 3).14 In many institutions, IMC and

HGD are treated identically, but in some centres, HGD

may be treated endoscopically while IMC may trigger

esophagectomy.14,16 Pathologists should be aware of the

clinical implications of diagnoses at their institutions,

and the threshold for expert consultation should be low.

Given the high interobserver variability in the diagnosis

of dysplasia and carcinoma in BE, it is recommended that

at least two pathologists, including one with expertise in

gastrointestinal pathology, come to a consensus diagnosis

in all cases of dysplasia and carcinoma, as well as cases

deemed indefinite for dysplasia.2,17

Assessingdepthofinvasion:theduplicatedmuscularismucosaeOne of the challenges of assessing depth of invasion in the

esophagus arises in the setting of duplication of the muscularis

mucosae (MM) (Figure 4A), which occurs in about 79% of

cases of BE.18 This duplication appears to occur only in BE,

not in other esophageal processes such as squamous cell

carcinoma.15,19 Histologically, the duplicated layer (dMM) is

superficial to the original MM (oMM) and in 85% of cases is

comprised of more delicate, wispy bundles of smooth muscle

compared to the oMM.20 To distinguish the submucosa from

the lamina propria between the dMM and oMM, it is helpful

to note that the submucosa may contain submucosal glands

and will frequently harbour thick-walled blood vessels. Of

note, in about half of cases, normal or dysplastic benign

glands may become entrapped between MM layers or within

the dMM itself (but not within the oMM).15,20 These must be

distinguished from invasive carcinoma.

Figure 5. There are two systems for reporting depth of invasion in esophageal EMR specimens, the AJCC system (A) and the Vieth & Stolte system (B). While they both classify submucosal invasion as sm1, sm2, or sm3, they differ in their classifications of mucosal invasion. In the AJCC system, m1 represents carcinoma in situ (i.e. HGD), m2 is lamina propria invasion, and m3 is invasion into the muscularis mucosae (dMM, oMM, or the space between them), while in the Vieth and Stolte system, m1 represents lamina propria invasion, m2 is invasion of the dMM, m3 is invasion of the space between the dMM and oMM, and m4 is invasion of the oMM. [Ep=epithelium, LP=lamina propria, dMM=duplicated muscularis mucosae, oMM=original muscularis mucosae, SM=submucosa, MP=muscularis propria.]



Figure 6. Pitfalls in the microscopic assessment of EMR specimens. A) Rolling under of the edges of the mucosa may mimic a positive deep margin. The mucosa in this region may also be cauterized and may be ‘inked’ which further adds to confusion. B) Mucosal trauma during suctioning of the mucosa to lift it during resection can cause loss of the superficial epithelium and accumulation of fibrin, mimicking ulceration. This may also complicate assessment of dysplasia, since surface maturation cannot be evaluated. C) Pinning of the specimen may push fragments of mucosa towards the deep margin, mimicking invasion in cases without invasive carcinoma or suggesting a deeper than actual level of invasion if the pin was introduced through an area of invasive carcinoma. D) Submucosal glands or ducts may mimic invasive carcinoma, but a lobular architecture is preserved. E) Invasive carcinoma is seen at the top left, high grade dysplasia at the top right, and a submucosal gland duct at the bottom right. The duct may initially be mistaken for carcinoma, giving the impression of a deeper level of invasion. However, the double-layered duct lining (F) is evidence that this is not carcinoma. [Hematoxylin & eosin]


MUIR ET AL.

Occasionally, duplication of the MM can lead to errors

in staging. It is important that pathologists take care not

to mistake the dMM for the oMM, or the oMM for the

muscularis propria, which would lead to an over-assessment

of the depth of invasion (i.e. pT1b or pT2 rather than pT1a).

Furthermore, since the dMM is not universally present and

when present it is frequently patchy,18 pathologists must not

mistake invasion through a superficial smooth muscle layer

as invasion through the dMM only, when in fact the dMM

is absent and the carcinoma is invading through the oMM

into the submucosa.

While the dMM is usually not difficult to identify in well-

oriented EMR specimens, cases with extensive tumour

involvement, cautery artefact, poor orientation, or

extensive fibrosis can pose a challenge. In such cases, we

have found immunohistochemical staining with desmin to

be particularly helpful in highlighting both the oMM and

dMM in cases where they appear indistinct on H&E or HPS

(Figure 4B). While desmin does not differentiate between

the oMM and dMM, it accentuates the wispy fibres of the

duplicated layer, making it easier to identify when present.

ReportingdepthofinvasionThere are two widely used methods to report depth of

invasion in EMR specimens—the AJCC system21 and

the Vieth & Stolte system.22 These systems differ in how

they classify invasion within the mucosa but they are

identical in their subdivisions of the submucosa, dividing

it into superficial, middle, and deep thirds (sm1, sm2, and

sm3 respectively; Figure 5). Though this is useful and

reproducible in esophagectomy specimens, it is difficult

to apply in a standardized fashion to EMR specimens,

where the amount of submucosa present depends on the

depth of the resection performed. In most EMR specimens

with submucosal invasion and a negative deep resection

margin, the depth of invasion can be presumed to be sm1.

In these cases, a numerical measurement of the depth of

invasion and width of tumour within the submucosa is also

reported as this gives clinicians an estimate of the amount

of submucosal invasion, which guides clinical management

in some cases. Depth of invasion is measured from the

deepest point of the overlying oMM or an imaginary line

in continuity with most of the oMM. While this approach

has not been validated in esophageal EMR specimens, a

measurement of submucosal invasion width and depth has

been shown to be predictive of lymph node involvement in

EMRs of early gastric cancer.23

Regarding mucosal subdivisions, the AJCC system was

designed to be applied to both squamous cell carcinoma

and adenocarcinoma of the esophagus, so duplication

of the muscularis mucosae (which does not occur in

squamous cell carcinoma) is not taken into account. As

such, there are three levels of mucosal invasion in the AJCC

system, and four in the Vieth & Stolte system (Figure 5).

We recommend using the Vieth & Stolte system because it

offers a more precise description of the depth of invasion in

the setting of a dMM.

DepthofinvasionandprognosisThe depth of invasion of carcinoma arising in BE is

an important prognostic factor and can direct future

treatment. Carcinomas confined to the mucosa have only

a 1-2% risk of lymph node metastases—lower than the

mortality risk with esophagectomy—whereas carcinomas

invading the submucosa have a risk of lymph node

metastases of approximately 20% and may trigger surgical

intervention.24-27 Overall survival is also dependent on depth

of invasion, with 5-year survival reported at 74-100% for

IMC compared to 53-58% for submucosal carcinoma.28,29

It is unclear whether the risk of lymph node metastases

increases with depth of invasion within the mucosa itself

(i.e. m1 vs. m2 vs. m3 vs. m4). Some studies have found no

difference in metastases or survival based on mucosal depth

of invasion,15,30,31 a finding which is supported by evidence

that the distribution of lymphatics between the dMM

and the oMM is similar to that of the superficial lamina

propria.32 However, because lymph node metastases are so

rare in early esophageal carcinoma, these studies included

only 1-3 patients with IMC and lymph node metastases;

therefore, a significant difference may be obscured by

type II error. Conversely, a recent meta-analysis reported

that 8/9 patients with IMC metastatic to lymph nodes had

AJCC m3 tumours, while 1/9 had an m2 tumour.24 Since

some evidence exists that depth of invasion within the

mucosa may affect prognosis, we recommend reporting this



feature. Consistent reporting of mucosal depth of invasion

is also necessary for future research to address prognostic

significance.

Similarly, the data is mixed as to whether deeper

submucosal invasion (sm2-3) confers a higher risk of

lymph node metastases and poorer survival compared to

superficial submucosal invasion (sm1). Some studies have

found lower rates of lymph node metastases and better

survival in sm1 patients,28,33 but others fail to confirm

this.34 Nevertheless, some clinical guidelines suggest EMR

for patients with low risk sm1 invasion (well-differentiated

carcinoma, no lymphovascular invasion) who are high-risk

surgical candidates.2 The risk of lymph node metastases in

sm1 invasion is reported to be 1-22%, with most estimates

near the lower end of that range, which is why EMR may

represent a lower risk than that of esophagectomy in some

patients.25,28,33-35

MarginstatusThe presence of carcinoma at the margins of an EMR

specimen is one of the strongest indicators for further

treatment because of the high risk of residual/recurrent

carcinoma. In one study, patients with positive deep

margins at EMR who were followed with subsequent

endoscopic surveillance and biopsy had residual carcinoma

in 7/8 (86%) cases, despite the use of photodynamic

therapy in four.36 In addition, positive deep margins have

been shown to be an independent predictor of poorer

overall survival (hazard ratio 1.67; 95% confidence interval

1.09–2.55; p=0.02).29

A margin should be considered positive only when there

is carcinoma present directly at the margin. The presence

of dysplasia at a margin should be noted, but does not

constitute a positive margin. In most cases, EMR specimens

are resected piecemeal and it is not possible to determine the

status of peripheral margins. In such cases, the endoscopist

must judge the completeness of resection at the time of the

procedure. Microscopic status of the deep resection margin

should still be reported in these cases.

The distance in millimetres to the deep margin should

be reported to document completeness of resection.2

While close (<1mm) circumferential margins have been

shown to portend worse prognosis in esophagectomy

specimens37,38 and in EMR for gastric carcinoma (<2mm),39

we are not aware of any studies investigating the prognostic

significance of the distance to margins in esophageal EMR.

In our experience, the deep resection margin of EMR

specimens containing adenocarcinoma with a depth of

invasion m4 or greater may often be close (i.e. 0.1 mm or

less) due to the size and nature of EMRs.

TumourbuddingTumour budding, defined as single cells or detached clusters

of <5 cells at the advancing front of a carcinoma, has been

shown to be an independent risk factor for nodal metastases

and poorer overall survival in superficial (pT1) esophageal

adenocarcinoma.40 However, one important issue in the

literature about tumour budding is the lack of consensus

regarding what defines significant (or so-called “high-

grade”) budding. The definition suggested by Ueno et al.41

is the most commonly used, and has proven prognostic

significance in colorectal carcinoma. This definition states

that high-grade budding constitutes 10 or more buds of

<5 cells each per 250x field (0.385 mm2). While some have

proposed the use of cytokeratins to improve visualization

of buds, it should be noted that definitions like Ueno’s

were developed on H&E-stained sections, and routine

application of cytokeratin results in higher rates of high-

grade budding.

We recommend reporting high-grade budding according

to Ueno’s definition (≥10 buds per 250x field) if it is noted

in esophageal EMR specimens. As literature accumulates

about the role of budding in esophageal carcinoma, the

presence of high-grade budding may increasingly influence

treatment decisions.

OtherfeaturestoreportLymphovascular invasion and tumour grade affect survival

and risk of lymph node metastases,26,29,30,34 and in some

cases, particularly early (sm1) submucosal invasion, may


MUIR ET AL.

influence further treatment (see Depth of invasion and

prognosis above). D2-40 immunohistochemistry may be

helpful, particularly in cases with submucosal invasion

or poorly differentiated tumour where lymphovascular

invasion is more likely and may be inconspicuous on H&E.

Larger tumour size has also been shown to confer a worse

prognosis,26 and tumour size should be reported. In cases

of piecemeal resection, tumour size must be estimated;

this may be given as the greatest dimension on one slide or

estimated by adding the tumour size across multiple EMRs.

The method used to obtain tumour size should be noted.

Perineural invasion may also be reported, but does not

appear to have strong prognostic significance.42-44

PitfallsandartefactsIn addition to the pitfalls of the duplicated muscularis

mucosae and entrapped glands discussed above, common

pitfalls and histological artefacts encountered in EMR

specimens are illustrated in Figure 6.

ConclusionEMR specimens should be treated as surgical specimens

with macroscopic and microscopic assessment performed

according to the recommendations discussed above. A

standardized approach to the processing and reporting of

EMR specimens will ensure that accurate diagnoses are

made and that subsequent treatment decisions are based

on high-quality information.

REFERENCES:1. Spechler SJ, Sharma P, Souza RF et al. American Gastroenterological Association

medical position statement on the management of Barrett’s esophagus. Gastroenterology 2011; 140: 1084-1091.

2. Fitzgerald RC, di Pietro M, Ragunath K et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut 2014; 63: 7-42.

3. Whiteman DC, Appleyard M, Bahin FF et al. Australian clinical practice guidelines for the diagnosis and management of Barrett’s Esophagus and Early Esophageal Adenocarcinoma. J Gastroenterol Hepatol 2015.

4. Subramanian CR, Triadafilopoulos G. Endoscopic treatments for dysplastic Barrett’s esophagus: resection, ablation, what else? World J Surg 2015; 39: 597-605.

5. Pech O, Bollschweiler E, Manner H et al. Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett’s esophagus at two high-volume centers. Ann Surg 2011; 254: 67-72.

6. Prasad GA, Wu TT, Wigle DA et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology 2009; 137: 815-823.

7. Bhat YM, Furth EE, Brensinger CM, Ginsberg GG. Endoscopic Resection with Ligation Using a Multi-Band Mucosectomy System in Barrett’s Esophagus with High-Grade Dysplasia and Intramucosal Carcinoma. Therap Adv Gastroenterol 2009; 2: 323-330.

8. Larghi A, Lightdale CJ, Memeo L et al. EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett’s esophagus. Gastrointest Endosc 2005; 62: 16-23.

9. Rastogi A, Puli S, El-Serag HB et al. Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia: a meta-analysis. Gastrointest Endosc 2008; 67: 394-398.

10. Ayers K, Shi C, Washington K, Yachimski P. Expert pathology review and endoscopic mucosal resection alters the diagnosis of patients referred to undergo therapy for Barrett’s esophagus. Surg Endosc 2013; 27: 2836-2840.

11. Wani S, Falk GW, Post J et al. Risk factors for progression of low-grade dysplasia in patients with Barrett’s esophagus. Gastroenterology 2011; 141: 1179-1186, 1186.e1171.

12. Duits LC, Phoa KN, Curvers WL et al. Barrett’s oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel. Gut 2015; 64: 700-706.

13. Phoa KN, van Vilsteren FG, Weusten BL et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. Jama 2014; 311: 1209-1217.

14. Downs-Kelly E, Mendelin JE, Bennett AE et al. Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett’s esophagus biopsies. Am J Gastroenterol 2008; 103: 2333-2340; quiz 2341.

15. Abraham SC, Krasinskas AM, Correa AM et al. Duplication of the muscularis mucosae in Barrett esophagus: an underrecognized feature and its implication for staging of adenocarcinoma. Am J Surg Pathol 2007; 31: 1719-1725.

16. Takubo K, Vieth M, Aida J et al. Histopathological diagnosis of adenocarcinoma in Barrett’s esophagus. Dig Endosc 2014; 26: 322-330.

17. Bennett C, Vakil N, Bergman J et al. Consensus statements for management of Barrett’s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012; 143: 336-346.

18. Appelman HD, Streutker C, Vieth M et al. The esophageal mucosa and submucosa: immunohistology in GERD and Barrett’s esophagus. Ann N Y Acad Sci 2013; 1300: 144-165.

19. Takubo K, Sasajima K, Yamashita K et al. Double muscularis mucosae in Barrett’s esophagus. Hum Pathol 1991; 22: 1158-1161.

20. Lewis JT, Wang KK, Abraham SC. Muscularis mucosae duplication and the musculo-fibrous anomaly in endoscopic mucosal resections for barrett esophagus: implications for staging of adenocarcinoma. Am J Surg Pathol 2008; 32: 566-571.

21. Holscher AH, Vallbohmer D, Bollschweiler E. Early Barrett’s carcinoma of the esophagus. Ann Thorac Cardiovasc Surg 2008; 14: 347-354.

22. Vieth M, Stolte M. Pathology of early upper GI cancers. Best Pract Res Clin Gastroenterol 2005; 19: 857-869.

23. Kim JY, Kim WG, Jeon TY et al. Lymph node metastasis in early gastric cancer: evaluation of a novel method for measuring submucosal invasion and development of a nodal predicting index. Hum Pathol 2013; 44: 2829-2836.

24. Dunbar KB, Spechler SJ. The risk of lymph-node metastases in patients with high-grade dysplasia or intramucosal carcinoma in Barrett’s esophagus: a systematic review. Am J Gastroenterol 2012; 107: 850-862; quiz 863.

25. Manner H, Pech O, Heldmann Y et al. Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion. Clin Gastroenterol Hepatol 2013; 11: 630-635; quiz e645.

26. Leers JM, DeMeester SR, Oezcelik A et al. The prevalence of lymph node metastases in patients with T1 esophageal adenocarcinoma a retrospective review of esophagectomy specimens. Ann Surg 2011; 253: 271-278.

27. Spechler SJ, Sharma P, Souza RF et al. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology 2011; 140: e18-52; quiz e13.

28. Liu L, Hofstetter WL, Rashid A et al. Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive (T1) esophageal adenocarcinoma. Am J Surg Pathol 2005; 29: 1079-1085.

29. Leggett CL, Lewis JT, Wu TT et al. Clinical and Histologic Determinants of Mortality for Patients With Barrett’s Esophagus-Related T1 Esophageal Adenocarcinoma. Clin Gastroenterol Hepatol 2015; 13: 658-664.e653.



30. Estrella JS, Hofstetter WL, Correa AM et al. Duplicated muscularis mucosae invasion has similar risk of lymph node metastasis and recurrence-free survival as intramucosal esophageal adenocarcinoma. Am J Surg Pathol 2011; 35: 1045-1053.

31. Kaneshiro DK, Post JC, Rybicki L et al. Clinical significance of the duplicated muscularis mucosae in Barrett esophagus-related superficial adenocarcinoma. Am J Surg Pathol 2011; 35: 697-700.

32. Hahn HP, Shahsafaei A, Odze RD. Vascular and lymphatic properties of the superficial and deep lamina propria in Barrett esophagus. Am J Surg Pathol 2008; 32: 1454-1461.

33. Westerterp M, Koppert LB, Buskens CJ et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 2005; 446: 497-504.

34. Barbour AP, Jones M, Brown I et al. Risk stratification for early esophageal adenocarcinoma: analysis of lymphatic spread and prognostic factors. Ann Surg Oncol 2010; 17: 2494-2502.

35. Sepesi B, Watson TJ, Zhou D et al. Are endoscopic therapies appropriate for superficial submucosal esophageal adenocarcinoma? An analysis of esophagectomy specimens. J Am Coll Surg 2010; 210: 418-427.

36. Mino-Kenudson M, Brugge WR, Puricelli WP et al. Management of superficial Barrett’s epithelium-related neoplasms by endoscopic mucosal resection: clinicopathologic analysis of 27 cases. Am J Surg Pathol 2005; 29: 680-686.

37. Ahmad J, Loughrey MB, Donnelly D et al. Prognostic value of added stratification of circumferential resection margin status in oesophageal carcinoma. Histopathology 2013; 62: 752-763.

38. Chan DS, Reid TD, Howell I, Lewis WG. Systematic review and meta-analysis of the influence of circumferential resection margin involvement on survival in patients with operable oesophageal cancer. Br J Surg 2013; 100: 456-464.

39. Lauwers GY, Forcione DG, Nishioka NS et al. Novel endoscopic therapeutic modalities for superficial neoplasms arising in Barrett’s esophagus: a primer for surgical pathologists. Modern Pathology 2009; 22: 489-498.

40. Landau MS, Hastings SM, Foxwell TJ et al. Tumor budding is associated with an increased risk of lymph node metastasis and poor prognosis in superficial esophageal adenocarcinoma. Mod Pathol 2014; 27: 1578-1589.

41. Ueno H, Murphy J, Jass JR et al. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 2002; 40: 127-132.

42. Tsai MK, Jeng JY, Lee WJ et al. Adenocarcinoma of the gastric cardia: prognostic significance of pathologic and treatment factors. J Formos Med Assoc 1995; 94: 535-540.

43. Torres C, Turner JR, Wang HH et al. Pathologic prognostic factors in Barrett’s associated adenocarcinoma: a follow-up study of 96 patients. Cancer 1999; 85: 520-528.

44. Khan OA, Alexiou C, Soomro I et al. Pathological determinants of survival in node-negative oesophageal cancer. Br J Surg 2004; 91: 1586-1591.

The CAP-ACP Annual Meeting is a fully accredited scientifi c conference held over four days, usually in June or July. The meeting is comprised of:

• scientifi c sessions including workshops, symposia, award lectures, platform presentations, poster sessions, and industry-sponsored events

• a Pathologists’ Assistants conference

• business meetings of the CAP-ACP Executive, Council, Sections and Committees

• the Annual General Meeting of the Association

• social events, including a president’s reception, exhibitors’ wine-and-cheese, and awards banquet

• vendors/exhibitors trade show

Regardless of whether you are a practicing pathologist, a resident, a pathologists’ assistant, a medical student, a technologist, a laboratory administrator, or an industry partner, the Annual Meeting is the perfect venue to interact with your colleagues, to update your medical knowledge in a wide range of competencies, and to enjoy time in a beautiful Canadian city.

Accreditation:

These conferences are Accredited Group Learning Activities (Section 1) as defi ned by the Maintenance of Certifi cation program of the Royal College of Physicians and Surgeons of Canada. These activities are approved by the Canadian Association of Pathologists.

Through an agreement between the Royal College of Physicians and Surgeons of Canada and the American Medical Association, physicians may convert Royal College MOC credits to AMA PRA Category 1 Credits™. Information on the process to convert Royal College MOC credit to AMA credit is found at:

www.ama-assn.org/go/internationalcme.

2017 Charlottetown, PEI June 10-13 Delta Convention Centre

2018 Quebec City, QC July 7-10 Hilton Quebec

http://www.ama-assn.org/ama/pub/education-careers/continuing-medical-education/physicians-recognition-award-credit-system/other-ways-earn-ama-pra-category/international-programs.page

Left Page • Double Page Spread

Eighty-two percent of patients included in the study had stage M1c disease and 73% had received two or more prior therapies including ipilimumab for metastatic disease.1,2

For more information on KEYTRUDA, please contact your Merck Oncology representative.

Pr KEYTRUDATM DEMonsTRATED EfficAcY

CI=confidence interval. PD-1=programmed cell death receptor-1.† Comparative clinical significance unknown. ‡ The efficacy of KEYTRUDA for this indication was investigated in a phase 1, multicentre, uncontrolled, open-label, dose-comparative cohort of Trial 1. To be eligible,

patients needed to be refractory to ipilimumab (defined as confirmed progression following at least 2 doses of ipilimumab and within 6 months of the last dose of ipilimumab). Patients were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of KEYTRUDA every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Note that the 10 mg/kg dosing is not a recommended dose. Assessment of tumour status was performed every 12 weeks.

§ Based on patients with a confirmed response by independent review, including independent radiology and oncology reviews, using confirmed responses and Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

¶ See the product monograph for complete dosing, dosing adjustments and administration recommendations.

References: 1. KEYTRUDA Product Monograph. Merck Canada Inc. May 19, 2015. 2. Robert C, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384:1109-17.

KEYTRUDA (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation-positive, following a BRAF or MEK inhibitor. An improvement in survival or disease-related symptoms has not yet been established. KEYTRUDA has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization.

Overall response rate (n=89) (primary endpoint; 95% CI: 15, 34)1

1 complete response and 20 partial responses

24% Response duration in patients who responded to therapy (n=21) (secondary endpoint)1

of responses were ongoing at the time of analysis and the median duration of response was not reached (median follow-up of 8 months; minimum of 6 months)

86%

In an uncontrolled, open-label study of patients with unresectable or metastatic melanoma, previously treated with ipilimumab, KEYTRUDA demonstrated:1,2‡§

The first monoclonal antibody designed to block the PD-1 receptor to be available for the treatment of metastatic melanoma†

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Clinical use: Safety and efficacy of KEYTRUDA have not yet been established in children <18 years of age.Relevant warnings and precautions: • Immune-mediated adverse reactions including:

– Pneumonitis– Colitis– Hepatitis– Nephritis– Endocrinopathies including hypophysitis,

type 1 diabetes and thyroid disorders– Other immune-mediated adverse events

including uveitis, myositis and severe skin reactions (reported in less than 1% of patients)

• Infusion-related reactions• Not recommended in pregnant women

• In nursing women, a decision should be made whether to discontinue breast-feeding or KEYTRUDA taking into account the benefit of breast-feeding for the child and the benefit of KEYTRUDA therapy for the woman

• Has not been studied in patients with moderate or severe hepatic impairment

• Has not been studied in patients with severe renal impairment • Monitor for thyroid and liver function during treatment For more information:Before prescribing KEYTRUDA, please consult the product monograph available at http://www.merck.ca/assets/en/pdf/products/KEYTRUDA-PM_E.pdf for important information relating to adverse reactions, drug interactions and dosing information which have not been discussed in this document. The product monograph is also available by calling us at 1-800-567-2594 or by email at [email protected].

Dosing

2 mg/kg administered as an intravenous infusion

over 30 min every 3 weeks

… until disease progression or unacceptable toxicity.1¶

KEYTRUDA™ is a trademark of Merck Sharp & Dohme Corp. Used under license.© 2015 Merck Canada Inc. All rights reserved.Merck Canada Inc., Kirkland, Quebec H9H 4M7

ONCO-1150561-0000 JL 2016

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