canaadian jtouhrnal ofolog y volume 4, issue 4 winter 2012 · 2020. 7. 6. · william boyd lecture...
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Test Utilization and the Clinical Laboratory
William Boyd Lecture 2012: Going Viral
Canadian Journal of
Pathology
Publications Agreement Number 40025049 • ISSN 1918-915X
Official Publication of the Canadian Association of Pathologists
www.cap-acp.org
Volume 4, Issue 4 • Winter 2012
t Utilization and the Clinical Laboratory
iafficiall PuPubbllicaicattionion ofof tthhee CanadianCanadian AssAssoociaciattionion ooff PPaattholholoogisgisttss
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VOLUME 4, ISSUE 4 2012
About the Cover
108
110
Editorial: Successful Test Utilization Management Initiatives in a Canadian CentreIrene Sadek, MD, MSC, FRCPC
Éditorial : Initiative fructueuse de gestion de l’utilisation des tests dans un établissement canadienIrene Sadek, MD, MSC, FRCPC
EDITOR-IN-CHIEFJ. Godfrey Heathcote, MA, MB BChir, PhD, FRCPC
EDITORIAL BOARDManon Auger, MD, FRCPC, Cytopathology;
Calvino Cheng, BSc, MD, FRCPC, Pathology Informatics and Quality Management;
Eleftherios Diamandis, BSc, MD, PhD, FRCPC, Medical Biochemistry; David K. Driman, MB ChB, FRCPC, Anatomical Pathology;
Todd F. Hatchette, BSc, MD, FRCPC, Medical Microbiology; Michael J. Shkrum, MD, FRCPC, Forensic Pathology;
Louis D. Wadsworth, MB ChB, FRCPath, FRCPC, Hematopathology
MANAGING EDITORSusan Harrison
COPY EDITOR Susan Harrison
PROOFREADERScott Bryant
ART DIRECTORAndrea Brierley, [email protected]
TR ANSL ATORMarie Dumont
SALE S AND CIRCUL ATION COORDINATORBrenda Robinson, [email protected]
ACCOUNTINGSusan McClung
GROUP PUBLISHERJohn D. Birkby, [email protected]
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Canadian Journal of Pathology • Volume 4, Issue 4, 2012 Contents
Original Articles
For Instructions to Authors, please visit www.andrewjohnpublishing.com/CJP/instructionstoauthors.html
The cover image shows metastatic malignant melanoma in the subcapsular sinus of a sentinel lymph node.
123
CAP-ACP News
112 Message from the Nominating Committee
Practice Matters113 Test Utilization and the Clinical Laboratory
Dr. Curtis Hanson and Elizabeth Plumhoff
Mixed Encapsulated Papillary Carcinoma/Invasive Ductal Carcinoma of the Male Breast with Metastasis to Lymph NodeZhongchuan Will Chen, MDCM, Anna Marie Mulligan, MBBCh, Pauline Henry, MD, Vladimir Iakovlev, MD
A Case of Confused Identity: Which Cancer Does the Lymphatic Metastasis Belong To?Ali Cadili, BA, MSc, MD, Hanin Musbah, Kelly Dabbs, MSc, MD, FRCSC
Uterine Tumour Resembling Ovarian Sex-Cord Tumour with True Sex-Cord DifferentiationManjula Jain, MD, Neha Kawatra Madan, MD, Smita Singh, MD
Conflict and Resolution: William Boyd’s Appointment to the Department of Pathology of the Winnipeg General HospitalGuillermo Quinonez, MD, MS, MA, FRCPC William Boyd Lecture 2012: Going ViralRichard G. Hegele, MD, PhD, FRCPC
118
FOUNDING EDITORJagdish Butany, MBBS, MS, FRCPC
Book Review142 Biomarkers of Kidney Disease
Reviewed by Dawn L. MacLellan, MD, FRCSC
Professional Development/Employment OpportunitiesMcGill UniversityNorthern HealthKingston GeneralUniversity Health Network
122130141143
131
126
136
Canadian Journal of P athology 107Winter 2012
Winter 2012108 Canadian Journal of P athology
Competing interests: None declared
EDITORIAL
We read with interest the comprehensive and
informative article “Test Utilization and the Clinical
Laboratory,” reprinted in this issue of the Canadian Journal
of Pathology and authored by Dr. Curtis Hanson and Elizabeth
Plumhoff of Mayo Medical Laboratories.1 Test utilization
management is not a new concept to most laboratories.
However, now more than ever, appropriate utilization is an
essential component of laboratory operations. With an aging
population, the need for medical intervention and laboratory
tests has increased. In fact, laboratory workload rises by
around 5% every year, and the increasing cost and complexity
of tests necessitate an expansion of the laboratory budget.
Clinical laboratories are faced with a very difficult challenge
in accommodating this growing demand and complexity,
while maintaining the same budget or even absorbing budget
cuts because of shrinking health care funding in Canada.
The sustainability of our laboratory services is in part
dependant on appropriate laboratory utilization to provide
the patients with the right test at the right time and to
maintain quality services. Laboratory professionals are well
positioned to control test utilization, and there are many
points where a laboratory professional can intervene,
including physician education, test ordering guidelines, and
limiting access to certain groups of physicians.
In our experience at a large Canadian academic centre,
physician education about test indication and appropriateness
is most successful when the test-ordering guidelines are
enforced by the laboratory.2 The Canadian Diabetes
Association’s 2008 Clinical Practice Guidelines indicate that
HbA1C should be tested no more frequently than every
3 months.3 As might have been expected from previous
reports,4 physician education led to a negligible decrease in
testing. However, the introduction of a rule that the test is
cancelled by the laboratory if an HbA1C result was reported
in the laboratory information system in the previous 90 days
led to an 8% decrease in HbA1C testing. Surprisingly,
18 months after implementation of this rule, the laboratory
continues to receive inappropriate HbA1C requests, and the
cancellation rate remains the same. Ideally, we need to reach
a state where inappropriate testing is not ordered in the first
place to avoid sample collection and processing. To achieve
this will require a lot more education and dialogue with the
clinicians.
Over the past 2 years, 31 cancellation rules based on similar
principles have been implemented in our laboratories. For the
vast majority, between 1 and 8% of the tests subject to
utilization rules are cancelled. These rules result in the
cancellation of approximately 61,000 tests per year. The
estimated reagent costs of those cancelled tests are around
$160,000 annually, and the reduced workload has allowed
technologists to be redeployed to other areas of the laboratory
that are experiencing an appropriate increase in workload.
The laboratory remains flexible in implementing those
utilization rules. Physicians are able to request exemptions, if
warranted for clinical reasons, by indicating on the requisition
or calling the pathologist; but discussions with physicians are
taking place in an effort to curtail overuse of exemption
requests. We now include previous test results in the
cancellation comment to ensure that the physician is aware
of the latest test results. Hopefully, easier access to previous
results will decrease re-orders, which may occasionally be
necessary. One of the challenges the laboratory faces in this
process is that the procedure for cancelling tests is labour
intensive. Collaboration is ongoing with those in pathology
informatics to determine a more efficient process for
implementing rules and allowing for exceptions to be handled
by the laboratory information system instead of manually.
Our laboratory serves both academic and community
physicians; they have different practice patterns, which further
complicates test utilization management. Another approach
to controlling test utilization described in the Mayo article is
limiting test ordering to a certain group of physicians. In our
experience, limiting access to ordering HLA-B27 to certain
groups of specialists (ophthalmologists, rheumatologists, and
Successful Test Utilization Management Initiatives in a Canadian Centre
Canadian Journal of P athology 109Winter 2012
SADEK
orthopedic surgeons) resulted in a major decrease from 2,500
tests per year to a more appropriate 200 tests per year. Testing
has remained stable at the lower level for over 5 years.
Our successful initiatives underscore the importance and
usefulness of a test utilization management program in the
laboratory in our cost-conscious health care system. We have
found that utilization management has allowed savings of
several hundred thousands of dollars while maintaining high-
quality patient care. Utilization test management programs
will differ from one centre to another5,6 but have become a
mandatory component of a clinical laboratory. While other
test utilization initiatives – such as informing physician groups
of their test ordering patterns, and screening orders for
expensive tests and those that may need referral to another
laboratory (e.g., cytogenetic and molecular diagnostics) –
have been implemented in our laboratory, cancellation of
inappropriate, high-volume tests has resulted in the most
savings without affecting patient care.
Over the past years, our experience in utilization management
has grown. We have been able to stimulate physician groups
to question their ordering patterns. We aim to change the
ordering physician culture from that of a fisherman, casting
a wide net of test orders hoping to catch the right test, to that
of a hunter, ordering only the required tests.
Irene Sadek, MD, MSC, FRCPCHead, Division of Hematopathology Chair, Laboratory Utilization CommitteeDepartment of Pathology and Laboratory MedicineCapital District Health Authority, Halifax, Nova Scotia
References1. Hanson C, Plumhoff E. Test utilization and the clinical laboratory. Communiqué
2012;37(3):1–5.
2. McHugh J, Afghan R, O’Brien E, et al. Impact of the introduction of guidelines
on vitamin B12�testing. Clin Chem 2012;58(2):471–5.
3. Canadian Diabetes Association. 2008 Clinical Practice Guidelines. Toronto
(ON): The Association; 2008.
4. Axt-Adam P, van der Wouden JC, van der Does E. Influencing behavior of
physicians ordering laboratory tests: a literature study. Med Care
1993;31(9):784–94.
5. Kim JY, Dzik WH, Dighe AS, Lewandrowski KB. Utilization management in a
large urban academic medical center. Am J Clin Pathol 2011;135:108–18.
6. Bunting PS, Van Walraven C. Effect of a controlled feedback intervention on
laboratory test ordering by community physicians. Clin Chem
2004;50(2):321–6.
C’est avec grand intérêt que nous avons pris
connaissance de l’article exhaustif et instructif sur
l’utilisation des tests au laboratoire clinique (« Test
Utilization and the Clinical Laboratory »1) de Curtis Hanson
et Elizabeth Plumhoff des Laboratoires médicaux Mayo,
reproduit dans le présent numéro de Canadian Journal of
Pathology. La gestion de l’utilisation des tests n’a rien de
nouveau dans la plupart des laboratoires. Le sujet resurgit
avec d’autant plus d’actualité aujourd’hui que l’utilisation
appropriée des tests constitue à l’évidence un
incontournable dans les opérations du laboratoire. Au fil du
vieillissement de la population, les interventions médicales
et les tests de laboratoire se font de plus en plus nombreux.
De fait, la charge de travail au laboratoire grimpe de près de
5 % par an, et le coût et la complexité accrus des tests forcent
l’augmentation de l’enveloppe budgétaire du laboratoire. Le
laboratoire clinique affronte un dilemme de taille, celui de
satisfaire cette demande grandissante et de se perfectionner
pour composer avec l’aspect complexe des tests, tout en ne
débordant pas de son cadre budgétaire, toujours le même,
voire en faisant avec des compressions en raison du
financement à la baisse des soins de santé au Canada.
La viabilité de nos services de laboratoire relève notamment
de l’utilisation appropriée des tests afin d’offrir au patient le
test judicieux au moment opportun et de maintenir la
qualité des services. Les professionnels du domaine sont tout
à fait en mesure de contrôler l’utilisation des tests et ils
peuvent intervenir à maints égards, en participant à
l’éducation des médecins, en établissant des lignes directrices
sur la prescription des tests ou en limitant la prescription
des tests à certains groupes de médecins, par exemple.
Notre expérience à un grand établissement universitaire
canadien nous révèle que l’éducation médicale à propos des
indications et du caractère approprié des tests est efficace
lorsque le laboratoire est responsable de la mise en
application des lignes directrices sur la prescription des
tests2. Dans ses Lignes directrices de pratique clinique 2008,
l’Association canadienne du diabète recommande le dosage
de l’hémoglobine glyquée (HbA1c) tous les trois mois, pas
plus fréquemment3. Comme l’illustre la documentation4,
l’éducation médicale ne s’accompagne que d’une baisse
négligeable de la prescription. En revanche, l’application
d’une règle selon laquelle le laboratoire annulera le test si
son système d’information renferme le résultat du dosage
de l’HbA1c pour ce patient dans les 90 jours se traduit par
une diminution de 8 % des tests de dosage de l’hémoglobine
glyquée. Curieusement, le laboratoire reçoit toujours des
ordonnances de dosage de l’HbA1c inappropriées 18 mois
après l’entrée en vigueur de la règle, et le taux d’annulation
demeure le même. En théorie, le résultat escompté est celui
voulant que la prescription inappropriée cesse afin d’éviter
le prélèvement et son traitement. Pour y parvenir, il nous
faudra accentuer les initiatives d’éducation médicale et le
dialogue avec les cliniciens.
Dans les deux dernières années, nos laboratoires ont instauré
31 règles d’annulation fondées sur le même principe général.
Le taux d’annulation de la grande majorité des tests qui font
l’objet de ces règles va de 1 % à 8 %. Autrement dit, les règles
ont conduit à l’annulation de près de 61 000 tests par an. Le
coût estimatif des réactifs qui auraient été utilisés pour ces
tests s’élève à 160 000 $ environ chaque année, et la baisse
de la charge de travail a permis aux technologues de se
consacrer à d’autres tâches dont le volume s’accroît à juste
titre.
À noter que le laboratoire fait preuve de souplesse dans
l’application de ces règles d’utilisation. Le médecin a le loisir
de demander une exemption, justifiée par un motif clinique,
en l’indiquant sur l’ordonnance ou en communiquant avec
le pathologiste; mais, de concert avec les médecins, nous
nous efforçons de trouver des moyens de prévenir la
surutilisation de la demande d’exemption. Pour être certains
que le médecin connaît les résultats des derniers tests de son
patient, nous les indiquons dans l’avis d’annulation.
Espérons que cette mesure de diffusion accrue des résultats
amène une diminution des ordonnances du même test, ce
qui peut être nécessaire parfois, nous en convenons. L’un des
Winter 2012110 Canadian Journal of P athology
Conflits d’intérêts : aucun
ÉDITORIAL
Initiative fructueuse de gestion de l’utilisationdes tests dans un établissement canadien
Canadian Journal of P athology 111Winter 2012
SADEK
défis que pose cette façon de faire vient de ce que la
procédure d’annulation nécessite une main-d’œuvre
importante. Nous nous penchons sur cette question avec des
spécialistes de l’informatique en pathologie afin de
déterminer un mode d’application des règles plus efficient
et de traitement des exceptions par le système d’information
du laboratoire, plutôt qu’à la main.
Notre laboratoire est à la disposition de médecins des
milieux universitaire et communautaire; ils n’ont pas le
même mode de pratique, ce qui complique la gestion de
l’utilisation des tests. L’article des laboratoires Mayo propose
une autre façon de contrôler l’utilisation des tests, soit de
limiter la prescription des tests à certains groupes de
médecins. Nous avons choisi de limiter la possibilité de
prescrire le test HLA-B27, de ne l'offrir qu'à des spécialistes,
plus précisément les ophtalmologistes, les rhumatologues et
les chirurgiens orthopédistes. Nous avons observé une baisse
spectaculaire du nombre de tests, qui était auparavant de
2 500 par an et qui en est rendu à 200 par an, une situation
qui correspond mieux aux indications appropriées. En plus
de cinq ans, ce nombre n’a d’ailleurs pratiquement pas
bougé.
Nos initiatives fructueuses viennent souligner l’importance
et l’utilité d’un programme de gestion de l’utilisation des
tests au laboratoire dans un système de santé soucieux des
coûts. Nous constatons les retombées d’un tel programme
qui ne compromet en rien la qualité des soins de santé, à
savoir des économies de plusieurs centaines de dollars. Le
programme de gestion de l’utilisation ne sera pas le même
d’un établissement à un autre5,6, mais il constitue désormais
un passage obligé pour le laboratoire clinique. Nous avons
entrepris d’autres initiatives ayant trait à l’utilisation des
tests, qu’il s’agisse d’examiner avec les médecins leurs
tendances de prescription des tests, d’analyser le bien-fondé
des ordonnances de tests onéreux ou la nécessité d’aiguiller
des tests à un autre laboratoire (diagnostic cytogénétique ou
moléculaire, par exemple), mais il n’en demeure pas moins
que l’annulation de tests inappropriés de volume élevé se
traduit par les plus grandes économies sans nuire à la qualité
des soins.
Au fil des ans, notre expérience dans la gestion de
l’utilisation s’est approfondie. Nous avons incité des groupes
de médecins à remettre en question leur mode de
prescription. Nous nous employons à changer la culture de
prescription des médecins, à les convaincre d’abandonner la
pratique du pêcheur qui lance à la volée un vaste filet dans
l’espoir d’attraper tout ce qui passe au profit de celle du
chasseur qui vise juste en prescrivant les tests appropriés et
nécessaires.
Irene Sadek, M.D., MSC, FRCPCChef, Division d’hématopathologie Présidente, Comité de l’utilisation des services de laboratoireService de pathologie et de biologie médicaleCapital District Health Authority, Halifax (Nouvelle-Écosse)
Références 1. Hanson C, Plumhoff E. Test utilization and the clinical laboratory.
Communiqué 2012;37(3):1–5.
2. McHugh J, Afghan R, O’Brien E, et al. Impact of the introduction of guidelines
on vitamin B12 testing. Clin Chem 2012;58(2):471–5.
3. Association canadienne du diabète. Lignes directrices de pratique
clinique 2008 pour la prévention et le traitement du diabète au Canada.
Canadian Journal of Diabetes, septembre 2008, vol. 32, suppl. 1.
4. Axt-Adam P, van der Wouden JC, van der Does E. Influencing behavior of
physicians ordering laboratory tests: a literature study. Med Care
1993;31(9):784–94.
5. Kim JY, Dzik WH, Dighe AS, Lewandrowski KB. Utilization management in a
large urban academic medical center. Am J Clin Pathol 2011;135:108–18.
6. Bunting PS, Van Walraven C. Effect of a controlled feedback intervention on
laboratory test ordering by community physicians. Clin Chem
2004;50(2):321–6.
Winter 2012112 Canadian Journal of P athology
Dear CAP-ACP Members,
The Nominating Committee proposes the following Slate of
Officers for June 2013; the only new nominations are for
vice-president and members-at-large.
Executive:
• President – Martin Trotter
• Vice-president – Victor Tron
• Past president – Vina Alexopoulou
• Secretary treasurer – Brian Cummings
• Continuing professional development chair – Jason
Ford
• Annual meeting chair – Avrum Gotlieb
• Resource development chair – Alan Spatz
• Website editor – Tadaki Hiruki
• Journal editor-in-chief (ex-officio) – Godfrey
Heathcote
• Patient safety and quality assurance chair (ex-officio)
– Laurette Geldenhuys
• Member-at-large – Marciano Reis
• Member-at-large – Julianne Klein
Other:
• Membership chair – Bernard Tetu
If you would like to make an alternative nomination for the
positions of vice-president or member-at-large, please submit
your nomination to [email protected].
The nomination
• must be signed by five qualified ordinary members,
with membership dues paid;
• must be agreed to by the proposed nominee, who must
be a qualified ordinary member; and
• must be received at least 30 days prior to the Annual
General Meeting.
Laurette GeldenhuysPast PresidentChair, Nominating Committee
Message from the Nominating CommitteeCAP-ACP NEWS
Canadian Journal of P athology 113Winter 2012
This article has been reprinted from Mayo Medical Laboratories Communiqué, 2012, Volume 37, Number 3, by permissionof the Mayo Foundation for Medical Education and Research. All rights reserved.
Dr. Curtis Hanson and Elizabeth Plumhoff
ABSTRACTThe clinical laboratory has an important and expanding role in ensuring that laboratory tests
are appropriately utilized in clinical practice. Laboratories are discovering that they are well
positioned to provide medical guidance and direction for clinicians who are trying to maneuver
their way through the increasingly complex world of laboratory testing.
RÉSUMÉ Le rôle du laboratoire clinique dans l’utilisation appropriée des tests de laboratoire dans la
pratique clinique prend de l’ampleur. Le laboratoire constate de fait qu’il est en mesure de baliser
la prescription des tests, d’offrir un encadrement sur ce plan aux cliniciens qui s’efforcent de
trouver leur chemin dans l’univers de plus en plus complexe des analyses de laboratoire.
PRACTICE MATTERS
Test Utilization and the Clinical Laboratory
BackgroundThe clinical laboratory has an important and expanding role
in ensuring that laboratory tests are appropriately utilized in
clinical practice. Laboratories are discovering that they are
well positioned to provide medical guidance and direction
for clinicians who are trying to maneuver their way through
the increasingly complex world of laboratory testing,
including genetic-driven diagnostics and therapeutics. There
are literally thousands of laboratory tests that clinicians
might request as they evaluate a particular patient, but it is
difficult, if not impossible, for any one individual to be
proficient in all areas of medicine. Because of the number
and the complexity of these tests, physicians are realizing that
they have gaps in their knowledge and understanding of
these assays. In addition to providing guidance to clinicians,
test utilization efforts may also be driven by financial realities
as laboratories try to rein in laboratory costs or in response
to payer programs and policies that reduce payments to
providers. Whatever the underlying reasons, the clinical
laboratory needs to take the lead in developing a successful
test utilization initiative.
So, why the sudden interest and enthusiasm for test
utilization? Health care costs in the United States are thought
to approach $2.5 trillion per year, and laboratory and
pathology testing accounts for $60 billion or about 4% of
total health care costs. However, that percentage is increasing
rapidly, with some experts estimating that laboratory costs
are skyrocketing at a 15% to 25% annual increase. Molecular
and genetic assays are driving this escalation, as the explosion
of genomic knowledge has led to novel genetic assays for
almost any common, or even rare, disease process. This
financial burden will clearly become a focus for payers and
health care providers alike. It will be impossible to ignore the
realities associated with laboratory costs and the need for
defining appropriate test utilization.
Test Utilization DefinedTest utilization should be defined as a strategy for
performing appropriate laboratory and pathology testing
with the goal of providing high-quality, cost-effective patient
care. A test utilization program must be focused on patient
care, ultimately leading to a more efficient and cost-effective
laboratory diagnostic approach to answer the clinical
questions being asked. A test utilization initiative cannot be
driven as a pure cost-control process. If the primary motive
is financially instead of patient care driven, then any
Winter 2012114 Canadian Journal of P athology
TEST UTILIZATION AND THE CLINICAL LABORATORY
utilization program will either be short-lived or ineffective
in its outcome. High-quality medical practice must be the
driving force if a test utilization program is to be successful.
Mayo Clinic has defined the clinical value equation as: Value
= Quality/Cost with quality defined as Outcomes + Service
+ Safety. Clinical value increases when quality (ie, outcomes,
service, and safety) is improved and cost is decreased.
This is as relevant for the laboratory as it is for a clinical
practice. No matter how we define test utilization, the
clinical laboratory needs to understand the critical role it
must play in our changing health care environment.
The Clinical Laboratory’s RoleLaboratory professionals need to be fully engaged with the
clinical practice in any test utilization process. It is not easy
and requires interactions with clinical colleagues that may
not always be comfortable. We need to be able to question
test requests that come from our clinical colleagues, suggest
appropriate tests to answer the clinical question being asked,
and cancel test orders when they are inappropriate for the
question at hand. Laboratorians must become comfortable
and confident in these interactions. Our clinical colleagues
have few incentives to order fewer tests, and they certainly
are not being trained with that intent in mind. So it becomes
the laboratory’s responsibility to identify utilization issues,
implement a program that will achieve more effective
laboratory testing, and establish processes from the
beginning to the end of the testing cycle that lead to a
successful laboratory test utilization program.
Test Utilization Control Process The biggest questions that laboratories usually encounter
when trying to develop a test utilization program are simple:
“How do we do it?” and “Where do we start?” That we have
these very basic questions emphasizes that no simple
answers exist. A successful solution requires a multipronged
approach that must involve the clinician, the laboratory, and
clinically engaged pathologists and laboratory directors. The
key is to understand how the clinical laboratory test cycle
works, the roadblocks that invariably exist, and how the
laboratory can integrate into these processes and overcome
the roadblocks.
A utilization control process actually starts when the
clinician begins to consider what tests are needed to evaluate
his or her patient—whether for diagnosis, follow-up,
therapeutics, or exclusion of disease. Appropriate ordering
depends on the clinician having the correct core knowledge
to make that decision. The laboratory enters the process
early on as it provides that clinician with the tools to order
the correct test. A test-ordering process often varies. The
process for ordering clinical tests may be designed to make
it easy for the physician to request any and all tests, or it may
include prerequisites, requirements, or permissions that the
clinician must fulfill prior to placing that order.
After the test order or specimen is received in the laboratory,
the laboratory professional can play a more active role in the
test decision process. Clinical laboratories are beginning to
explore how to use algorithms, test guidelines, and test
formularies to put appropriate medical and utilization
reviews in place. Instead of taking the easier and passive role,
“if the doctor orders it, we do it,” clinical laboratories are
beginning to explore how to use algorithms, test guidelines,
and test formularies to put appropriate medical and
utilization reviews in place.
An overall test utilization control process might look
something like this:
1. Important test information (clinical indications, overall
value of that test, test indications, etc) that is readily
available is the first step for the laboratory engaging the
clinician in a test utilization effort. This information
should be available in an easy electronic format—
whether it is linked to the electronic medical record, the
electronic ordering system, other available electronic
tools, or via smart phone applications. If that is not
possible, a current laboratory test catalog may
substitute. Electronic information is preferable as it is
current and accurately represents recent changes.
2. Algorithms and test-ordering guidelines are the next
step necessary to guide the clinician through a
utilization process (Figure 1). While they are a small
Value=(Outcomes, Safety, Service)
Quality
Cost
Canadian Journal of P athology 115Winter 2012
HANSON AND PLUMHOFF
piece of the puzzle, testing algorithms and guidelines are
essential tools in guiding both the clinician and
laboratory toward appropriate test selection. The success
of test-ordering algorithms and guidelines, however,
depends on the clinician making the effort to seek out
that information, and a busy clinician may lack the time
or willingness to do so. It may be necessary to actively
engage the clinician in discussions surrounding the use
of algorithms using educational tools such as recorded
videos, Grand Round presentations, publications, etc.
3. Other tools are available to assist in a utilization process.
Some laboratories have implemented a test formulary
patterned after the pharmaceutical model. The
laboratory test formulary is used to limit access to
certain tests and often requires authorization from a
pathologist, subspecialist, or laboratory committee
before a particular test can be ordered. Laboratories may
use a tiered approach, with some tests available to all
physicians, some complex tests available to only a
subspecialty group of physicians, and other complex
tests requiring written justification and committee
authorization. Another approach that has been used to
control test utilization is mandating that some tests can
only be ordered after discussion with the laboratory
pathologist. Whatever the process, test formulary
restrictions may be driven by cost and reimbursement
issues, known situations of test misutilization, or
whether the test is performed in-house versus sent to a
reference laboratory. Regardless of the underlying
rationale, a test formulary by itself will have little
impact, but appropriate test utilization requires active
engagement with the clinical practice by the laboratory
to ensure that the most effective testing strategy is being
used to answer the clinical question.
4. Sometimes it may be necessary to use a “send and hold”
process where a test may be sent to a testing laboratory
(or even held within the ordering laboratory), but
testing is not performed by the receiving laboratory
until the sender notifies the receiving laboratory to
perform or cancel the test. This strategy is utilized when
an initial laboratory result is required to determine the
need for the follow-up test, but delaying the shipment
could impact specimen integrity. In this manner, the
specimen is available for testing as soon as the initial
result is released. For example, it is very appropriate that
flow cytometry, molecular-based studies, and
cytogenetic studies in hematologic disease be held until
the bone marrow aspirate and biopsy are reviewed by
the pathologist or until the initial round of testing is
complete. A decision can then be made regarding if or
what subsequent testing is necessary.
5. Reports must be clear and should integrate all the
findings associated with an episode of care.
Unfortunately, laboratory information systems do not
always effectively transmit the intended information to
the clinician. Laboratory reports are often just lists of
results with no or minimal correlative interpretation.
This can make it difficult, if not impossible, for the
clinician to get the information he or she needs. The
pathologist in particular needs to be engaged in this
process to ensure that the reporting system is working
as intended.
6. Finally, auditing results is a critical step in the utilization
process. The laboratory generates a tremendous amount
of data. When analyzed, these data can tell you how a
test is being used, whether the intended outcome of a
utilization process is being achieved, and where
problems exist. The audit process can also identify
which guidelines are not working as planned or need
modifications or revisions.
Where Can the Laboratory Influence Test Utilization?At several points along the test-ordering continuum
laboratories can influence and change the ordering process.
Preanalytic: Clinician Test Ordering1. Modify test order requisition forms, whether electronic
or paper, and keep them current. Remove obsolete tests
and limit the inclusion of esoteric tests on the general
requisition. Establish a process to destroy old forms,
remembering to remove hard copies from outlying
areas.
2. Organize tests by disease state or by ordering patterns,
rather than the more typical alphabetical approach.
3. Review and minimize the process where tests are
bundled together for ease of physician ordering.
Winter 2012116 Canadian Journal of P athology
TEST UTILIZATION AND THE CLINICAL LABORATORY
12/11
Reactive: regardless of S/CO ratio*
HCPCR/60707 Hepatitis C VirusAntibody Screen with Re�ex to HCV RNA by PCR, SerumReactive antibody screen automatically re�exes to PCR
Type of Patient Abnormal liver enzyme levels with or without symptoms Recipient of blood or blood products prior to 1991 Hemophiliac Injection drug user
HCVQU/83142 Hepatitis C Virus (HCV) RNA Detection and Quanti�cation by Real-Time Reverse Transcription PCR, Serum
Additional testing is recommended to rule-out recovery from recent acute hepatitis C or ongoing (chronic) HCV infection with intermittent viremia.
Repeat PCR testing in 1 to 3 months, if clinically indicated.
Active HCV infection follow-up and treatment decisions depend on patient risk group.
Type of Patient Acute hepatitis Immunocompromised
Any viral load
Antibody result
Go to HCV Treatment Algorithm
STOPThis result and a reactive antibody screen suggest a false-reactive screen.
Indeterminate or unreadable
Negative Positive
STOPRepeat testing is recommended in 1 to 2 months.
STOPResolved (past) HCV infection
Negative Any viral load
Active HCV infection
Possible resolved/ past infection. Repeat HCVQU/83142 in 1 to 3 months.
Hepatitis C Virus (HCV) RNA Detection and Quanti�cation by Real Time ReverseTranscription PCR (RT-PCR), Serum
This result and a reactive antibody screen suggest either a false-reactive screen or a resolved (past) infection.
Recommend testing with RIBA/80181 Hepatitis C Virus Antibody Con�rmation, Serum to distinguish between these 2 conditions.
* S/CO ratio = signal-to-cutoff ratio
Negative Any viral load
Negative
Recommended Approach to the Diagnosis of Hepatitis C
© Mayo Foundation for Medical Education and Research (MFMER). All rights reserved. MAYO, Mayo Medical Laboratories and the triple-shield Mayo logo are trademarks and/or service marks of MFMER.
Figure 1. This is an example of an algorithm that was developed by Mayo Clinic Department of Laboratory Medicine and Pathology,Division of Clinical Microbiology and Mayo Medical Laboratories to guide the diagnosis of hepatitis C. Algorithms are available onlineat www.mayomedicallaboratories.com
Canadian Journal of P athology 117Winter 2012
HANSON AND PLUMHOFF
4. Review standing orders and how they are used in the
clinical practice.
5. Establish a process to review any new tests that are
requested.
6. Include necessary educational material – algorithms,
practice guidelines, publications, etc – to help close the
knowledge gap.
Laboratory Processing1. Establish an approval and cancel process for certain
tests. If it is a low-volume test, this process can be
undertaken by knowledgeable individuals and reviewed
manually. For higher-volume tests, an information
system-based process and intervention may need to be
developed.
2. Review those tests the laboratory sends to reference
laboratory partners using a test formulary-like or a
utilization review process. Some requests may need
laboratory director approval before processing.
PostanalyticLaboratory reports may not be easy to read or understand,
leaving the clinician with more questions than answers.
While there will be differences in format and presentation,
all laboratory reports must contain certain elements as
mandated by the Clinical Laboratory Improvement
Amendments (CLIA). The report may also need to contain
additional items not specifically required, but that can assist
the clinician in the interpretation of laboratory test results.
ConclusionTest utilization management is not a new concept to most
laboratories, but few have taken the steps necessary to truly
initiate a utilization control process. Every laboratory needs
to design its own strategy for test utilization and find what
best fits the structure and culture of its institution.
Laboratory professionals can position themselves as
utilization experts who can assist clinicians with test
ordering and ultimately improve the quality and efficiency
of patient care. The task is not easy. Conversations with
clinical colleagues to gain information, cancel a test, or
suggest ordering a different test can be uncomfortable, but
these interactions are necessary to build a successful
laboratory utilization program that leads to high-quality,
cost-effective patient care.
Winter 2012118 Canadian Journal of P athology
Mixed Encapsulated Papillary Carcinoma/Invasive Ductal Carcinoma of the Male Breast
with Metastasis to Lymph Node
Zhongchuan Will Chen, MDCM, and Pauline Henry, MD, are members of the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario. Anna Marie Mulligan, MBBCh, and Vladimir Iakovlev, MD, are membersof the Department of Laboratory Medicine and the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University ofToronto. Correspondence may be directed to [email protected] article has been peer reviewed.Competing interests: None declared
Zhongchuan Will Chen, MDCM, Anna Marie Mulligan, MBBCh, Pauline Henry, MD, Vladimir Iakovlev, MD
ABSTRACTEncapsulated papillary carcinoma (EPC) of the breast is a controversial entity with features and
behaviour overlapping between ductal carcinoma in situ and invasive carcinoma. At present,
its metastatic potential is not clearly understood. The authors report the novel case of an EPC
in a man with nodal metastasis.
This 61-year-old man underwent total mastectomy with axillary dissection. The specimen
contained an EPC with an area of conventional invasive ductal carcinoma (IDC) at the
periphery. One of eight lymph nodes in the axillary dissection contained a metastasis. Of note,
the metastasis consisted mainly of a tumour with an encapsulated architecture replacing the
node and with capsular penetration; there was also a focus of IDC, recapitulating the primary
tumour.
The encapsulated component of EPC may have the ability to metastasize concurrently with the
invasive component. This case is remarkable due to the previously unreported finding of a
mixed EPC/IDC metastasizing to a lymph node in a male.
RÉSUMÉ Le carcinome papillaire encapsulé du sein est une entité controversée dont les caractéristiques
et l’évolution rappellent celles du carcinome canalaire in situ pour certaines et celles du
carcinome invasif pour d’autres. Son potentiel métastatique demeure largement méconnu
encore. Les auteurs examinent le cas inédit d’un homme présentant un carcinome papillaire
encapsulé avec métastase ganglionnaire.
L’homme de 61 ans a subi une mastectomie totale accompagnée d’un évidement ganglionnaire
axillaire. À l’analyse histologique, on dénote un carcinome papillaire encapsulé ainsi qu’une
zone caractéristique d’un carcinome canalaire invasif en périphérie. Une métastase s’est logée
dans l’un des huit ganglions excisés à l’évidement ganglionnaire. À souligner que la métastase
en question est formée principalement d’une tumeur d’architecture encapsulée qui se substitue
au ganglion et qu’il y a pénétration de la capsule; on observe également un foyer de carcinome
canalaire invasif à l’image de la tumeur primitive. La composante encapsulée du carcinome
peut métastaser en même temps que la composante invasive. Ce cas est remarquable en ce qu’il
est le premier cas rapporté chez un homme d’une tumeur mixte disséminée dans un ganglion
lymphatique, où cohabitent un carcinome papillaire encapsulé et un carcinome invasif.
ORIGINAL ARTICLE
Canadian Journal of P athology 119Winter 2012
CHEN ET AL.
Encapsulated papillary carcinoma (EPC) of the breast is
an unusual neoplasm characterized by a circumscribed
expansile mass consisting of an arborizing network of
papillae covered by malignant epithelial cells. The papillae
are frequently compact, forming cribriform and solid areas;
however, fibrovascular cores, albeit sometimes
inconspicuous, are retained. A fibrous rim typically
surrounds the tumour, and morphological evidence of
stromal invasion is lacking. Despite the morphological
impression of an in situ process, myoepithelial cells are
typically absent from the periphery of the lesion, leading
certain authors to postulate that EPC is an indolent form of
invasive carcinoma.1,2 On the other hand, others have
proposed that EPC is a variant of ductal carcinoma in situ
since type IV collagen can be identified around the
periphery of the tumour.3 As is the case for all breast cancers,
it is rarer in men, with fewer than 50 cases reported in the
literature to date. We describe the first case in a man of a
mixed EPC/invasive ductal carcinoma (IDC) with metastasis
to a lymph node in which the metastatic deposit had the
same architectural pattern as the primary, containing
predominantly the encapsulated and focally the IDC
component.
Case ReportA previously healthy 61-year-old man presented with a self-
identified left breast mass. A needle-core biopsy was
performed, and the lesion was diagnosed as EPC with IDC,
of no special type (NST). He subsequently underwent a total
mastectomy with axillary dissection, which, on pathological
examination, revealed EPC with IDC and metastasis to one
of eight lymph nodes. The patient received adjuvant
chemotherapy on the FEC-D protocol (5-fluorouracil,
epirubicin, and cyclophosphamide followed by docetaxel).
He was then started on tamoxifen and completed 5 weeks
of adjuvant radiation therapy, with no evidence of recurrent
or metastatic disease 18 months after surgery.
Materials and MethodsThe surgical specimen was fixed in 10% neutral buffered
formalin. Paraffin-embedded tissue sections of 4 µm were
cut and stained with hematoxylin and eosin.
Immunohistochemistry was also performed on these
sections according to established protocols on a Ventana
Benchmark XT automated stainer (Ventana Medical
Systems, Tucson, Arizona). The antibodies used included
p63 (clone BC4A4, Biocare Medical, Concord, California),
smooth muscle myosin heavy chain (clone SMMS1,
BioGenex, Fremont, California), estrogen receptor (ER)
(clone SP1, Ventana Medical Systems), progesterone
receptor (PR) (clone 1E2, Ventana Medical Systems), and
HER2 (clone A0485, Dako, Carpinteria, California; and
clone 4B5, Ventana Medical Systems). Fluorescent in situ
hybridization for HER2 (PathVysion HER-2 DNA probe kit,
Abbott [www.abbottmolecular.com]) was also performed
on paraffin sections according to standard protocols.
ResultsGross examination of the surgical specimen showed a 2.2 ×
2.2 × 1.6 cm retro-areolar, well-circumscribed, solid mass
with an eccentric cystic area containing serosanguineous
fluid. Microscopic examination revealed the mass to consist
of a dilated, cystic space containing a compact papillary
growth with fibrovascular cores, surrounded by a thick
fibrous capsule (Figure 1). Immunostaining for
myoepithelial cells with antibodies to p63 and smooth
muscle myosin–heavy chain (SMM-HC) was negative at the
periphery of the tumour (Figure 2). The findings were in
keeping with a diagnosis of EPC. At one edge of the
encapsulated component, there were several foci showing
histological evidence of stromal invasion. The invasive
component was an IDC-NST (see Figure 1). The largest
dimension of the EPC was 2.2 cm, and the IDC extended 1.7
cm along the EPC edge. In the axillary dissection, eight
lymph nodes were identified, the largest of which harbored
a 2.4 cm metastasis with extranodal extension (Figure 3).
Interestingly, this metastasis recapitulated the EPC pattern
of the primary tumour and almost completely replaced the
node. Focally, there was penetration of the nodal capsule by
the EPC as well as by an area of IDC-NST (see Figure 3).
The invasive components at the primary and metastatic sites
also had similar morphology and histological grade: no
tubular differentiation, moderate nuclear pleomorphism,
and low mitotic counts. A final diagnosis of IDC-NST (1.7
cm, Nottingham grade II/III) arising on a background of
EPC was made. Lymphovascular invasion was not identified
Winter 2012120 Canadian Journal of P athology
MIXED EPC/IDC OF THE MALE BREAST WITH METASTASIS
and all margins were negative. Immunoreactivity for ER was
100% and for PR 80% in both the primary tumour and
metastasis. HER2 immunostaining was equivocal (2+), and
testing by fluorescence in situ hybridization showed non-
amplification in both the primary tumour and metastasis.
Of note, both EPC and IDC components at the primary and
metastatic sites showed equivalent staining for ER, PR, and
HER2.
DiscussionEPC usually presents as a subareolar mass with nipple
discharge in elderly women, but has been reported to occur
in men. In the largest series to date of 917 EPCs from the
California Cancer Registry, the median age was 69.5 years
and only 32 cases (3.5%) involved males.4 EPC is typically
considered an indolent tumour with a prognosis similar to
ductal carcinoma in situ (DCIS) despite the absence of a
myoepithelial cell layer. In the same series of 917 EPCs, the
relative cumulative survival for EPC compared with age-
Figure 1. Encapsulated papillary carcinoma with cystic spacescontaining compact papillary proliferations with fibrovascularcores and surrounded by a thick fibrous capsule (thick arrows); afocus of invasive ductal carcinoma, no special type is present atthe periphery (double arrows). (Hematoxylin and eosin)
Figure 2. Smooth muscle myosin–heavy chain immunostaininghighlights the absence of myoepithelial cells around theencapsulated (thick arrows) and invasive (double arrows)components, while blood vessels and a normal duct on the left ofthe image serve as internal controls. Note the vascular networkwithin the encapsulated papillary carcinoma component.(Immunoperoxidase)
Figure 3. A, The lymph node metastasis recapitulates thehistopathology of the primary encapsulated papillary carcinoma(EPC). B and C, The node is extensively replaced by an almostexclusively EPC component with foci of invasive carcinoma at theperiphery. Note the penetration of the nodal capsule by theencapsulated component at two sites. D, A focus of invasive ductalcarcinoma of no special type is seen between them. (Hematoxylinand eosin)
C A
B
D
Canadian Journal of P athology 121Winter 2012
CHEN ET AL.
matched controls was 97.3% after 5 years and 95.6% after
10 years. In addition, only 39 of 917 cases (4.3%) showed
direct extension into adjacent tissue or metastasis to lymph
nodes, illustrating the tumour’s low propensity for
metastasis.4 Similarly, a recent series containing 208 cases of
EPCs described clinicopathological findings consistent with
previous studies.5
Histologically, EPC consists of dilated ducts or spaces
occupied by a proliferation of neoplastic cells supported by
fibrovascular cores, or papillae. Myoepithelial cells are
typically not present within or at the periphery of the
tumour. EPC must be differentiated from other papillary
lesions of the breast, including benign papilloma and
papillary DCIS. The main distinguishing feature between
DCIS and EPC is the absence, or presence, of myoepithelial
cells around the periphery of the tumour, which are absent
from EPC and present in papillary DCIS. EPC can be
distinguished from papilloma by the preservation of
myoepithelial cells in the fibrovascular cores and the absence
of a neoplastic epithelial component in the latter.
Histological evidence of stromal invasion may be seen with
EPC and should be distinguished from pseudo-invasion in
which neoplastic epithelium becomes entrapped within the
fibrous capsule. Invasive carcinoma should be clearly located
beyond the fibrous capsule and should show features of
infiltrative malignancy: stromal infiltration with possible
desmoplasia, cytological atypia, and mitoses. When stromal
invasion occurs in this setting, it is typically an invasive
ductal carcinoma of no special type; it is extremely rare for
the invasive component to be an invasive papillary
carcinoma. When an invasive carcinoma is present in
association with EPC, the current convention is that only
the unequivocally invasive component should be used to
determine the size of tumour for staging.1 If there is no
invasive component, the size of the EPC should not be used
to determine the T stage, and a comment on the indolent
nature and prognosis of EPC should be provided to the
clinician in order to avoid overtreatment of the patient.1
To our knowledge, this report is the first of EPC/IDC with
lymph node metastasis in a male. To date, there are seven
literature reports of EPC with clearly documented lymph
node sampling in males, but none had lymph node
involvement.6–12 The metastatic potential of pure EPC in
women has been documented and is presumed to be very
low, but exact numbers have not been defined. It is believed
that some metastases from EPC actually represent
metastases from an occult invasive stromal component
missed as a result of inadequate sampling, or mechanical
transport of tumour to a lymph node.13 Nevertheless, one
case report described two patients with adequately sampled
EPCs without stromal invasion that developed lymph node
micrometastases.14 In both patients, the micrometastases
showed morphological features similar to the primary EPCs
and had no features suggesting mechanical transport, such
as the presence of foreign body giant cells, altered red blood
cells, lymphocytes, or hemosiderin-laden macrophages
adjacent to the transported epithelium.14 In our case, the
lymph node metastasis consisted predominantly of tumour
with morphological features identical to the breast EPC as
well as showing a minor, invasive component with features
of the primary IDC-NST. The most plausible explanation
for this is that the EPC component of the primary tumour
has metastatic potential distinct from the IDC component.
Alternatively, the possibility of mechanical transport to a
lymph node during needle biopsy of the primary tumour
exists. However, the lack of histological evidence of
mechanical transport and the requirement that the
transported epithelium grew to be bigger than the primary
in the 1-month interval between biopsy and mastectomy
render this hypothesis less likely. A third explanation could
include the development of an EPC with subsequent stromal
invasion arising in an epithelial rest within the lymph node.
The fact that both the breast and lymph node tumours
showed identical morphology makes this scenario unlikely.
If further studies can definitively demonstrate that EPC
indeed has metastatic potential independent of a coexisting
IDC component, then the current convention of not
including the size of the EPC component in the T stage may
need to be reconsidered. Perhaps a separate T stage category
could be devised for EPC and other tumours with uncertain
malignant potential. Such a category could reflect the
prognosis of these tumours, which is significantly better
than that of IDC.
This previously undescribed case of mixed EPC-IDC with
lymph node metastasis reiterating the primary mixed
pattern in a man provides further insight into the biology
Winter 2012122 Canadian Journal of P athology
MIXED EPC/IDC OF THE MALEBREAST WITH METASTASIS
and behaviour of this peculiar tumour. Since the metastasis
contained not only the IDC component but also the EPC
component of the primary, it suggests that EPC itself may
have metastatic potential and supports the view that this
entity occupies an intermediate position in a spectrum of
disease from in situ to invasive carcinoma.2
References1. Collins LC, Schnitt SJ. Papillary lesions of the breast: selected diagnostic and
management issues. Histopathology 2008;52(1):20–9.
2. Hill CB, Yeh IT. Myoepithelial cell staining patterns of papillary breast lesions:
from intraductal papillomas to invasive papillary carcinomas. Am J Clin Pathol
2005;123(1):36–44.
3. Esposito NN, Dabbs DJ, Bhargava R. Are encapsulated papillary carcinomas
of the breast in situ or invasive? A basement membrane study of 27 cases. Am
J Clin Pathol 2009;131(2):228–42.
4. Grabowski J, Salzstein SL, Sadler GR, Blair S. Intracystic papillary carcinoma:
a review of 917 cases. Cancer 2008;113(5):916–20.
5. Rakha EA, Gandhi N, Climent F, et al. Encapsulated papillary carcinoma of
the breast: an invasive tumor with excellent prognosis. Am J Surg Pathol
2011;35(8):1093–103.
6. Brahmi SA, El M’rabet FZ, Akesbi Y, et al. Intracystic papillary carcinoma
associated with ductal carcinoma in situ in a male breast: a case report. Cases
J 2009;2:7260.
7. De Cicco C, Baio SM, Veronesi P, et al. Sentinel node biopsy in male breast
cancer. Nucl Med Commun 2004;25(2):139–43.
8. Dragoumis DM, Tsiftsoglou AP. Intracystic papillary carcinoma associated
with ductal carcinoma in situ in a male breast. J Postgrad Med 2008;54(1):39–
40.
9. Hussain A, Sweeney KJ, Salman R, et al. Intracystic papillary carcinoma of the
male breast: a case report and review of the literature. Ir J Med Sci 2012
Sep;181(3):329–31. Epub 2009 Jul 9.
10. Imoto S, Hasebe T. Intracystic papillary carcinoma of the breast in male: case
report and review of the Japanese literature. Jpn J Clin Oncol 1998;28(8):517–
20.
11. Romics L Jr., O’Brien ME, Relihan N, et al. Intracystic papillary carcinoma in
a male as a rare presentation of breast cancer: a case report and literature
review. J Med Case Reports 2009;3:13.
12. Yoshida M, Mouri Y, Yamamoto S, et al. Intracystic invasive papillary
carcinoma of the male breast with analyses of loss of heterozygosity on
chromosome 16q. Breast Cancer 2010;17(2):146–50.
13. Carter BA, Jensen RA, Simpson JF, Page DL. Benign transport of breast
epithelium into axillary lymph nodes after biopsy. Am J Clin Pathol
2000;113(2):259–65.
14. Mulligan AM, O’Malley FP. Metastatic potential of encapsulated (intracystic)
papillary carcinoma of the breast: a report of 2 cases with axillary lymph node
micrometastases. Int J Surg Pathol 2007;15(2):143–7.
DISPLAY CLASSIFIED
Cytopathology Review CourseApril 27 – 30, 2013
Montréal, Québec, Canada
Course Director: Dr. Manon Auger
For further information
contact:
Email: [email protected]
McGill University Health Centre
Continuing Education Office
Tel: (514) 934-8253
Fax: (514) 934-1779
www.muhc-cme.mcgill.ca
Canadian Journal of P athology 123Winter 2012
A Case of Confused Identity: Which CancerDoes the Lymphatic Metastasis Belong To?
Ali Cadili, BA, MSc, MD, and Kelly Dabbs, MSc, MD, FRCSC, are members of the Department of Surgery, Misericordia Hos-pital and University of Alberta, in Edmonton, Alberta. Hanin Musbah is a student at the University of Alberta. Correspondence may be directed to [email protected] article has been peer reviewed.Competing interests: None declared
Ali Cadili, BA, MSc, MD, Hanin Musbah, Kelly Dabbs, MSc, MD, FRCSC
ABSTRACTA 64-year-old woman developed a malignant melanoma of the upper arm, and metastatic
melanoma was confirmed in one sentinel axillary node by immunohistochemistry. She
underwent further axillary node dissection, and metastatic tumour was identified in six of 14
nodes. Immunohistochemistry was not performed at that time. Two years later, a screening
mammogram revealed a lesion that was proven to be a primary breast carcinoma on needle
core biopsy; the patient underwent simple mastectomy. Pathological review of the lymph nodes
from the axillary dissection indicated that they contained metastatic breast carcinoma and not,
as had been assumed, metastatic melanoma. The patient’s prognosis was upgraded.
RÉSUMÉ Une femme de 64 ans présente un mélanome malin au bras; l’immunohistochimie révèle la
présence d’une métastase dans un ganglion axillaire sentinelle. La patiente subit un évidement
ganglionnaire axillaire, et l’analyse détecte une tumeur métastatique dans 6 des 14 ganglions
prélevés. Il n’y a pas eu d’analyse immunohistochimique à ce moment-là. Deux ans plus tard,
une mammographie de dépistage décèle une lésion qui s’avère un carcinome du sein primitif
à la biopsie par aspiration; la patiente subit une mastectomie simple. L’examen pathologique
des ganglions lymphatiques excisés à l’évidement axillaire indique la présence de métastases
d’un carcinome du sein, non pas du mélanome comme on l’a supposé d’abord. Le pronostic a
été modifié en conséquence.
ORIGINAL ARTICLE
Case ReportA 64-year-old woman presented to her family physician with
a changing mole on the upper outer aspect of her left arm.
An excisional biopsy was performed, and it revealed
malignant melanoma. The Breslow thickness was 5 mm,
Clark level IV, and there was no evidence of ulceration. The
patient was referred to a surgeon for a wide excision of the
biopsy area and a sentinel lymph node (SLN) biopsy. The
SLN biopsy result revealed that one node was positive for
tumour cells expressing HMB-45 and MART1, consistent
with metastatic melanoma (Figure 1). Several clusters of
melanoma cells were identified by immunohistochemistry
in the positive node, the largest of which measured 5 mm in
greatest diameter. The patient thereafter underwent a
completion lymph node dissection (CLND) of the left axilla,
and six positive lymph nodes, out of 14 lymph nodes
examined, were identified. In accordance with the hospital’s
protocol for handling CLND specimens following positive
SLN results, the nodes were not examined with
immunohistochemistry. Based on these results, the patient
Winter 2012124 Canadian Journal of P athology
A CASE OF CONFUSED IDENTITY
was prescribed a 1-year course of adjuvant interferon
treatment. The interferon treatment was halted after 8
months because of worsening syncopal episodes thought to
be the result of intolerance.
Two years after the initial melanoma diagnosis, the patient
was referred back to the surgeon because of an abnormal
result on screening mammography. This showed changes in
the left breast suspicious for cancer, which had not been
present on her last mammogram 2 years previously. The
patient reported no specific symptoms other than a slightly
indrawn nipple present for the past few years. Her family
history included breast cancer in one maternal aunt
diagnosed in old age. The patient reached menarche at the
age of 13 years, had her first pregnancy at the age of 31,
breastfed two term infants, and reported prior use of oral
contraceptives for a total of 4 years. She had reached
menopause at the age of 52 and had no history of radiation
or other risk factors for breast cancer. The patient’s medical
history was notable for hypertension (controlled for years
with hydrochlorothiazide) and hypothyroidism, for which
the patient was on medication. Her only previous surgery
was a hysterectomy (without oophorectomy) for
leiomyomas.
An ultrasonography of the left breast confirmed the lesion
and a subsequent ultrasound-guided core-needle biopsy
revealed infiltrating carcinoma. A metastatic workup,
including blood tests, chest radiography, computed
tomography of the abdomen, and a bone scan, did not reveal
any metastatic spread. The patient underwent a simple
mastectomy with no lymph node sampling, given the prior
left axillary lymph node dissection. Pathological
examination of the mastectomy specimen revealed
multifocal, invasive pleomorphic lobular carcinoma, with
the largest lesion measuring 4.1 cm in greatest dimension.
In addition, pleomorphic lobular carcinoma in situ was also
identified within the specimen. The carcinoma showed
Figure 1. Malignant melanoma cells in a sentinel lymph node.(Hematoxylin and eosin; insets, immunoperoxidase)
Figure 2. Metastatic lobular carcinoma in an axillary lymph node.(Immunoperoxidase; inset, hematoxylin and eosin)
Figure 3. Lobular carcinoma of breast in an axillary lymph node.(Hematoxylin and eosin)
Canadian Journal of P athology 125Winter 2012
CADILI ET AL.
lymphovascular and perineural invasion and expressed both
estrogen and progesterone receptors. The HER2/Neu status
was negative and, of note, one intramammary lymph node
was identified as harboring metastatic carcinoma. All
margins were clear of carcinoma, the closest margin being
the deep margin that was 4 mm away from tumour.
Given the patient’s history of melanoma with nodal
dissection on the same side as the breast carcinoma, a full
pathological review of the previously excised axillary lymph
nodes was undertaken. The review concluded that the six
positive lymph nodes in the axillary node dissection
exhibited a pattern of metastasis that was characteristic of
lobular carcinoma but unusual for metastatic melanoma.
The positive nodes were strongly positive for cytokeratin 7
on immunohistochemistry and negative for HMB-45 and
MART1 (Figures 2 and 3). The axillary nodes also exhibited
widespread extranodal extension. Based on these findings,
the patient was put on adjuvant chemotherapy. She
completed three cycles of docetaxel and cyclophosphamide
therapy and, at the time of this writing, was set to undergo
three cycles of FEC (5-fluorouracil, epirubicin,
cyclophosphamide) treatment.
DiscussionThat the sentinel lymph node was positive for melanoma
metastasis was confirmed by immunohistochemistry.
However, the cancer identified in the subsequent axillary
lymph node dissection actually represented metastasis from
an occult primary breast carcinoma rather than the
melanoma. The standard procedure for dealing with a
CLND specimen following a positive SLN does not involve
detailed immunohistochemistry, since it is assumed that any
cancer found is of the same type as that in the SLN. In this
particular case, had immunohistochemical staining been
carried out on the CLND specimen, the metastatic cancer
would most likely have been identified as originating from
a breast primary. This would not have altered the decision
to put the patient on a course of adjuvant interferon therapy;
the characteristics of the primary melanoma, as well as the
positive SLN, are sufficient to warrant this course of action.
Rather, that determination would have triggered a diligent
search for the occult breast primary carcinoma which, in
turn, would have resulted in earlier treatment of that cancer.
The revised assessment actually places the patient in an
improved risk/survival category. Had the lymph node
metastases represented metastatic melanoma, as originally
thought, the patient would have had a stage IIIC melanoma.1
The estimated 5-year survival rate for patients with stage
IIIC melanoma has been found to range from 24 to 29%.2,3
On the other hand, the estimated 5-year survival for our
patient with a stage IIB breast cancer is 76%.4With this new
information, the patient has been re-classified as having
stage IIIA melanoma, which carries a survival of up to
70%.2,3
References1. American Joint Committee on Cancer. Melanoma of the skin. In: AJCC Cancer
Staging Manual, 6th edition. New York: Springer; 2002: 209–20.
2. Ries LAG, Eisner MP, Kosary CL, et al., eds. SEER Cancer Statistics Review,
1975–2000. Bethesda (MD): National Cancer Institute; 2003: Tables XVI-1-9.
3. Balch CM, HSoong SJ, Gershenwald JE, et al. Prognostic factors analysis of
17,600 melanoma patients: validation of the American Joint Committee on
Cancer melanoma staging system. J Clin Oncol 2001;19(16):3622–34.
4. Woodward WA, Strom EA, Tucker SL, et al. Changes in the 2003 American
Joint Committee on Cancer staging for breast cancer dramatically affect stage-
specific survival. J Clin Oncol 2003;21(17):3244–48.
Winter 2012126 Canadian Journal of P athology
Uterine Tumour Resembling Ovarian Sex-CordTumour with True Sex-Cord Differentiation
Manjula Jain, MD, Neha Kawatra Madan, MD, Smita Singh, MD, are members of the Department of Pathology with LadyHardinge Medical College, in New Delhi, India. Correspondence may be directed to [email protected]. This article has been peer reviewed.Competing interests: None declared
Manjula Jain, MD, Neha Kawatra Madan, MD, Smita Singh, MD
ABSTRACTUterine tumours are diagnosed in the majority of cases using light microscopy. In some cases,
extensive immunohistochemical analysis is needed to properly categorize these tumours. The
authors present a rare case in a 50-year-old woman who had a submucosal polypoid growth in
the uterine fundus that showed a circumscribed tumour arranged in sheets and nests of small
oval to plump spindle cells. In places, tumour cells were more round to cuboidal, arranged in
tubules, anastomosing cords, and trabeculae. Immunohistochemically, the cells showed diffuse
and strong cytoplasmic positivity for calretinin, CD99, and vimentin and diffuse nuclear
positivity for progesterone receptor. Focal positivity for cytokeratin and estrogen receptor and
focal weak positivity for inhibin and CD10 were noted, whereas epithelial membrane antigen,
carcinoembryonic antigen, smooth muscle actin, and desmin were not expressed. The findings
provided strong evidence of true sex-cord differentiation. The final diagnosis was uterine
tumour resembling ovarian sex-cord tumour (with true sex-cord differentiation), infiltrating
less than half of the myometrium.
RÉSUMÉ Habituellement, l’examen au microscope optique est suffisant pour déterminer la nature de la
tumeur utérine. Dans certains cas, l’analyse immunohistochimique approfondie est nécessaire
pour classer la tumeur avec précision. Les auteurs examinent le cas rare d’une femme de 50 ans
présentant une croissance polypoïde sous-muqueuse dans le fonds de l’utérus; il s’agit d’une
tumeur circonscrite déployée en plages et en nids de petites cellules fusiformes ovales ou
ventrues. Par endroits, les cellules tumorales sont plutôt rondes ou cubiques, formant des
tubules, des filons anastomosés ou des trabécules. L’analyse immunohistochimique révèle la
présence cytoplasmique diffuse et intense de calrétinine, de CD99 et de vimentine, et de
récepteurs de la progestérone dans le noyau. Il indique également la présence localisée de
cytokératine et de récepteurs oestrogéniques et la faible présence localisée d’inhibine et de CD10,
alors qu’il n’y a pas d’expression de l’antigène de la membrane épithéliale, de l’antigène
carcinoembryonnaire, d’actine du muscle lisse ni de desmine. Les constatations pointent avec
insistance dans la direction d’une véritable différenciation des cordons sexuels. Le diagnostic
définitif est celui d’une tumeur utérine à l’allure d’une tumeur ovarienne des cordons sexuels
(différenciation des cordons sexuels sans équivoque) se propageant à moins de la moitié du
myomètre.
ORIGINAL ARTICLE
Canadian Journal of P athology 127Winter 2012
JAIN ET AL.
UTROSCT refers to a uterine tumour resembling an ovarian
sex-cord tumour, the true nature of which remains unclear.
Some authors believe that they are of epithelial nature, others
suggest that they have a myoid phenotype or are of
endometrial stromal origin, and still others conclude that the
immunophenotype is consistent with true sex-cord
differentiation.1,2
The term UTROSCT was first used by Morehead and Bowman
in 1945. Clement and Scully performed a detailed evaluation
of 14 such cases in 1976 and divided them into two groups
based on the predominance of the stromal or epithelial
component. Endometrial stromal tumours with minor sex-
cord-like elements (ESTSCLE) were put into group 1, and
uterine tumours resembling ovarian sex-cord tumour
(UTROSCT) with predominance of the sex-cord-like
component were put into group 2.3 We present a case of
UTROSCT in a 50-year-old woman.
Case ReportA 50-year-old woman with a G4, P3, A1 obstetrical history was
admitted to the gynecology ward with complaints of bleeding
per vaginam and lower abdominal pain of 1 month’s duration.
On pelvic examination, the uterus was found to be the size it
would be at 12 week’s pregnancy, retroverted, and mobile, and
no adnexal mass was palpable. Pelvic ultrasonography showed
an echogenic polypoid intracavitary uterine mass measuring
4 × 3 × 3 cm, suggesting the presence of a myoma. Both ovaries
appeared normal. Results of a cervical Papanicolaou smear
were unremarkable. A preoperative diagnosis of uterine
myoma was made, and a vaginal hysterectomy was performed.
The gross specimen consisted of the uterus with the cervix but
without adnexa. The endometrial cavity was expanded and
occupied by a submucosal polypoid growth measuring 3.5 ×
2.5 × 2 cm, arising from the fundus. On section, the polyp
appeared well circumscribed, soft, and grey-white with focal
yellow-tan areas (Figure 1). The cervix was unremarkable.
Sections from the polypoidal mass showed a circumscribed
submucosal tumour predominantly arranged in sheets and
nests, containing numerous small arterioles and extending into
the superficial myometrium (Figure 2A and B). Tumour cells
were small, oval to plump, and spindled, exhibiting mild
anisocytosis with a moderate amount of eosinophilic
cytoplasm, round to oval nuclei, fine granular chromatin, and
inconspicuous nucleoli. In places, the tumour cells were
arranged in tubules, anastomosing cords, and trabeculae (see
Figure 2C and D). In these areas, the cells appeared more
round to cuboidal and showed mild nuclear atypia. Mitotic
activity was low, with zero to two mitotic figures per high-
power field. There were no areas of hemorrhage or necrosis,
and no lymphovascular invasion was noted.
At this stage, a differential diagnosis of ESTSCLE, UTROSCT,
and low-grade endometrial adenocarcinoma with spindled
stroma and focal sex-cord-like structures was considered.
Immunohistochemistry was subsequently performed with a
panel of markers including cytokeratin (CK), epithelial
membrane antigen (EMA), carcinoembryonic antigen (CEA),
estrogen receptor (ER), progesterone receptor (PR), CD10,
vimentin, calretinin, inhibin, CD99, smooth muscle actin, and
desmin. The cells showed diffuse and strong cytoplasmic
positivity for calretinin, CD99, and vimentin, suggesting sex-
cord differentiation, and diffuse nuclear positivity for PR
(Figure 3). Focal positivity for CK and ER and focal weak
positivity for inhibin and CD10 were also noted (Figure 4),
whereas EMA, CEA, smooth muscle actin, and desmin were
not expressed, thus ruling out ESTSCLE and endometrial
adenocarcinoma with spindled stroma and focal sex-cord-like
structures.
The final diagnosis was UTROSCT, infiltrating less than half
Figure 1. Gross specimen showing a submucosal polypoid growththat is soft and grey-white, with focal yellow-tan areas.
Winter 2012128 Canadian Journal of P athology
UTERINE TUMOUR RESEMBLING OVARIAN SEX-CORD TUMOUR
of the myometrial wall. The patient was closely
followed up for 6 months. No postoperative
complications or recurrence was noted.
DiscussionUTROSCTs are an unusual group of uterine
tumours that exhibit ovarian sex-cord-like
epithelial structures. They are placed in the
miscellaneous category in the recent World Health
Organization classification of tumours of the
uterine corpus.4 Clinically, UTROSCTs
predominate in middle-aged women, with an
average age at presentation of 50 years. The main
presenting features include abnormal vaginal
bleeding and lower abdominal pain, sometimes
with a palpable uterine mass. Preoperative
diagnosis of these tumours is difficult as they are
rare, and no specific signs are seen on imaging
studies. No serum marker has yet been found for
these mysterious neoplasms.
Grossly, the majority of UTROSCTs are
circumscribed solid intramural masses.
Sometimes, they are polypoidal and submucosal,
as in our case. The cut surface is soft and yellow-
tan, unlike the firm and whorled pattern of a
leiomyoma. They show a diverse histology with a
variety of stromal and epithelial patterns
resembling ovarian sex-cord tumours.
Occasionally, diffuse sheets of uniform cells
resembling a granulosa cell tumour may be seen.
The tumour cells show mild atypia, and mitoses
are scanty.
The histogenesis of UTROSCT has been a matter
of controversy. Czernobilsky has stated that they
most likely arise from pluripotent mesenchymal
cells that express a predominant immuno-
phenotype of sex-cord tumours.5 Variable
positivity for a number of immunohistochemical
markers has been shown by various workers.2,6,7
Three studies have all demonstrated that
UTROSCT is a polyphenotypic neoplasm
expressing markers of epithelial, sex-cord, and
endometrial stromal differentiation.2,6,7 They
Figure 2. A, Circumscribed tumour predominantly arranged in sheets and nests,permeating into the superficial myometrium. B, Tumour tissue showingnumerous small arterioles. C and D, Round to cuboidal cells arranged in tubules,anastomosing cords, and trabeculae. (Hematoxylin and eosin)
A
C D
B
A
C D
B
Figure 3. Tumour cells showing diffuse and strong cytoplasmic positivity forcalretinin (A), CD99 (B), and vimentin (C) and diffuse nuclear positivity forprogesterone receptor (D). (Immunoperoxidase)
Canadian Journal of P athology 129Winter 2012
JAIN ET AL.
concluded that the most reliable immuno-
histochemical markers in UTROSCT are
calretinin, inhibin, CD99, and melan-A. They also
remarked that positivity for calretinin and for at
least one of the other three markers is highly
suggestive of UTROSCT. Although the staining
pattern of UTROSCT does not indicate any single
path of differentiation, it seems to be unique and
can be useful in differentiating it from other more
common tumours.
The differential diagnosis includes ESTSCLE,
endometrial adenocarcinoma with spindled
stroma and sertoliform sex-cord-like areas,
leiomyoma with epithelioid features, and
metastasis of ovarian Sertoli-Leydig cell tumour
(Table 1). ESTSCLE contains areas of conventional
endometrial stromal sarcoma composed of small
spindle cells and numerous arterioles, in addition
to focal sex-cord-like areas. It shows diffuse
positivity for ER, PR, and, most importantly,
CD10. It may show focal positivity for one of the
sex-cord markers, mostly calretinin, but it is never
strong and diffuse, as seen in our case. Endometrial
adenocarcinoma with sex-cord-like areas shows
strong immunoreactivity for CK, EMA, and CEA
but usually lacks positivity for the sex-cord
markers. Leiomyomas, especially the epithelioid
variant, may show sex-cord-like structures but lack
positivity for sex-cord markers. Metastatic ovarian
Sertoli-Leydig cell tumour can be differentiated on
the basis of the clinical picture, finding a primary
in the ovary, and expression of the sex-cord
markers (inhibin, calretinin, WT1, and melan-A).
UTROSCTs were initially considered benign;
however, occasional cases have shown malignant
transformation.8 Recurrences have been reported
in 15% of cases 2–12 years after hysterectomy. It is
currently suggested that UTROSCTs should be
considered neoplasms of uncertain malignant
potential. Vaginal hysterectomy is usually
performed for small tumours, whereas radical
surgery is undertaken for larger ones. These
tumours are extremely rare. Their clinical,
A
C D
B
Figure 4. Tumour cells showing focal positivity for CK (A) and estrogen receptor(B) and focal weak positivity for inhibin (C) and CD10 (D). (Immunoperoxidase)
Table 1. Comparison of Immunophenotype of the Various Differential Diagnoses
Endometrial Leiomyoma Adenocarcinoma with with Sertoliform Epithelioid
UTROSCT ESTSCLE Sex-Cord-Like Areas FeaturesCalretinin + ER + CK + SMA +Inhibin + PR + EMA + Desmin +CD99 + CD10 + CEA + Vimentin +Melan-A + Inhibin +/-CD56 + CD99 +/-Vimentin +ER +/-PR +/- �CD10 +/-�CK +/-�
CEA = carcinoembryonic antigen; CK = cytokeratin; EMA = epithelial membrane antigen; ER = estro-gen receptor; ESTSCLE = endometrial stromal tumours with minor sex-cord-like elements; PR = prog-esterone receptor; SMA = smooth muscle actin; UTROSCT = uterine tumour resembling an ovariansex-cord tumour.
DISPLAY CLASSIFIED
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Our main referral centre, University Hospital of Northern BC, includes a catchment population of 350,000 and is
articipation in medical student and resident teaching through the Northern Medical P
Our main referral centre, University Hospital of Northern BC, includes a catchment population of 350,000 and is
rogram, University ofarticipation in medical student and resident teaching through the Northern Medical P
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rogram, University of
articipation in medical student and resident teaching through the Northern Medical PNorthern British Columbia, and University of British Columbia
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articipation in medical student and resident teaching through the Northern Medical PNorthern British Columbia, and University of British Columbia
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Winter 2012130 Canadian Journal of P athology
UTERINE TUMOUR RESEMBLING OVARIAN SEX-CORD TUMOUR
pathological, and immunohistochemical features are
extremely varied. Thus, there is no standard approach to such
cases.
More extensive studies must be performed on these tumours
in future. Recent studies have shown that UTROSCTs lack the
JAZF1–JJAZ1 translocation suggesting that this tumour may
be distinct from other endometrial stromal tumours, including
ECTSCLE, at least 50% of which show this translocation.9
References1. McCluggage WG. Uterine tumors resembling ovarian sex-cord tumors:
immunohistochemical evidence for true sex-cord differentiation. Histopathology
1999;34:375–6.
2. de Leval L, Lim GS, Waltregny D, Oliva E. Diverse phenotypic profile of uterine
tumors resembling ovarian sex cord tumors: an immunohistochemical study of
12 cases. Am J Surg Pathol 2010;34(12):1749–61.
3. Clement PB, Scully RE. Uterine tumors resembling ovarian sex-cord tumors. A
clinicopathologic analysis of fourteen cases. Am J Clin Pathol 1976;66:512.
4. Nogales F, Tavassoli FA. Tumours of the uterine corpus. In: Tavassoli FA, Devilee
P, eds. Pathology and Genetics of Tumours of the Breast and Female Genital
Organs. Lyon, France: IARC Press; 2003:217–57.
5. Czernobilsky B. Uterine tumors resembling ovarian sex-cord tumors: an update.
Int J Gynecol Pathol 2008;27:229–35.
6. Irving JA, Carinelli S, Prat J. Uterine tumors resembling ovarian sex-cord tumors
are polyphenotypic neoplasms with true sex-cord differentiation. Mod Pathol
2006;19:17–24.
7. Hurrell DP, McCluggage WG. Uterine tumour resembling ovarian sex cord
tumour is an immunohistochemically polyphenotypic neoplasm which exhibits
coexpression of epithelial, myoid and sex cord markers. J Clin Pathol
2007;60(10):1148–54.
8. Biermann K, Heukamp LC, Büttner R, Zhou H. Uterine tumor resembling an
ovarian sex cord tumor associated with metastasis. Int J Gynecol Pathol
2008;27:58–60.
9. Staats PN, Garcia JJ, Dias-Santagata DC, et al. Uterine tumors resembling ovarian
sex cord tumors (UTROSCT) lack the JAZF1-JJAZ1 translocation frequently seen
in endometrial stromal tumors. Am J Surg Pathol 2009;33(8):1206–12.
Canadian Journal of P athology 131Winter 2012
Conflict and Resolution: William Boyd’s Appointment to the Department of Pathology
of the Winnipeg General Hospital
Guillermo Quinonez, MD, MS, MA, FRCPC, is with the Department of Pathology, University of Manitoba, Winnipeg, Manitoba,and the Department of Social Medicine, University of North Carolina, Chapel Hill, North Carolina; he also has an office inAncaster, Ontario. Correspondence can be directed to [email protected] article has been peer reviewed.Competing interests: None declared
Guillermo Quinonez, MD, MS, MA, FRCPC
ABSTRACTThe appointment of William Boyd as professor at the University of Manitoba in 1915 illustrates
the conflict that exists between two visions of pathology: the view that the main responsibility
of a pathologist lies in research and teaching, with patient care as an ancillary activity; and the
opposing view that the main activities of a pathologist should be patient centred, with teaching
and research as only ancillary activities. The dean of medicine, Harvey H. Chown, supported
the former, while the practising physicians at the Winnipeg General Hospital supported the
latter. A comprehensive explanation for the dean’s reasons for the appointment has not been
specifically addressed in the literature. This essay describes the events and concludes that,
although Boyd became the leading pathologist in English Canada, Chown’s vision succeeded
only partially because Boyd excelled in teaching but not in basic science research.
RÉSUMÉLa nomination de William Boyd à un poste de professeur à l’Université du Manitoba en 1915
illustre le conflit entre deux visions opposées de la pathologie : celle voulant que les principales
fonctions du pathologiste relèvent de la recherche et de l’enseignement, la prestation de services
destinés au patient étant une tâche accessoire, l’autre selon laquelle les principales activités du
pathologiste sont centrées sur le patient, tandis que l’enseignement et la recherche ne sont que
des tâches secondaires. S’affrontent alors deux camps, les tenants de la première vision avec à
leur tête Harvey H. Chown, doyen de la faculté de médecine, à l’origine de la nomination de
William Boyd, et les adeptes de la seconde, les médecins exerçant à l’Hôpital général de
Winnipeg. La documentation ne s’étend pas vraiment sur les motifs du doyen. L’article passe
en revue cette période en examinant ces deux écoles de pensée et se conclut par le constat
voulant que, bien que William Boyd soit devenu la figure de proue en pathologie dans le Canada
anglais, la vision de M. Chown ne se soit pas concrétisée tout à fait, car son protégé a excellé en
enseignement, mais pas en recherche fondamentale.
ORIGINAL ARTICLE
Winter 2012132 Canadian Journal of P athology
CONFLICT AND RESOLUTION: WILLIAM BOYD’S APPOINTMENT TO WGH
Conflict between clinicians and basic science scientists
has been a driving force in the development of
pathology in certain periods of the specialty’s history.1–3
Conflict resulting from a struggle between distinct views of
the specialty was illustrated in 1914 with the appointment of
William Boyd as professor of pathology and bacteriology at
the University of Manitoba and as director of the laboratories
of the Winnipeg General Hospital (WGH). Hoogstraten, in
a presentation given to the Manitoba Medicine History
Club,4 and Carr, in a biography of Boyd,5 have amply
documented the event. Both authors presented an objective
narrative but, while Carr was sympathetic to Boyd,
Hoogstraten, a clinician, was not. The conflict resulted from
two perspectives: the view that the main responsibility of a
pathologist lies in research and teaching, with patient care as
an ancillary activity, and the perspective that the main
activities of a pathologist should be patient-centred, with
teaching and research as only ancillary activities. The conflict
was clearly expressed in Boyd’s appointment made by the
dean of the Manitoba Medical College, Harvey Havelock
Chown. A comprehensive explanation of the events demands
additional research on the contextual conditions that were
evolving at the Manitoba Medical College and the WGH in
those years, which influenced the dean’s decision.
AntecedentsThe root of the conflict can be understood in terms of the
inadequate conditions of medical education in North
America at the beginning of the 20th century, the same
period in which Chown was dean. The conditions in
Winnipeg were no different from those in the United States.
To address the problem, in 1902 the American Medical
Association (AMA) appointed the AMA Council on Medical
Education, which in 1905 set the minimum standards for
medical education: 4 years of high school for admission, a 4-
year medical course, and satisfactory performance in a state
licensing examination. Based on medical school inspections
in the United States, the council also categorized the
institutions as classes A, B, and C. Around the same time, the
Carnegie Foundation for the Advancement of Teaching was
created (1906). Both organizations joined forces, and
Abraham Flexner from the Carnegie Foundation and Nathan
P. Colwell from AMA inspected American and Canadian
medical schools. The basis for their report, a bulletin
published in 1910, was the Johns Hopkins educational model
that included full-time staff, laboratories, and hospital
facilities.6 The model responded to a new vision of medicine
closer to the German one and distinct from the French model
of clinical-pathological correlation based on the autopsy. The
new approach introduced experiment and laboratory into
the everyday practice of medicine and considered medical
education a university function. The Carnegie Foundation
was ready to provide monetary subsidies for schools’
infrastructure, for fostering relationships between medical
schools and hospitals, and for establishing salaried
professorships.7
Flexner’s report on the Manitoba Medical College and the
WGH was satisfactory.6 Flexner visited Winnipeg in May of
1909 and reported that the Medical College had 115 students
and a teaching staff of 41. The only source of income for the
college was students’ fees, which amounted to $14,000 per
year. Using this criterion alone, the Medical College was a
proprietary school. When referring to pathology, Flexner
mentioned that the University of Manitoba competently gave
instruction in that subject and that there was a well-kept
collection of several hundred wet specimens. He stated that
the hospital was “excellent.” The school faculty formed the
staff of the wards, and the relationship between both
institutions was “admirable.” Students worked at the
hospital’s installations. He categorized the college not as A,
B, or C (he never used this system), but grouped it with
Kingston, below the University of Toronto and McGill but
above Laval and Halifax.6
Dean Chown was a leader, and he therefore made difficult
decisions. In spite of Flexner’s comments about the situation
in Winnipeg, he had to have known the real conditions of the
college in relation to the direction that medical education
was taking in North America. He knew that he had to
reinforce the basic sciences as part of the medical school
curriculum, since that was the future. Chown followed the
general recommendations given by Flexner in his report and
took the initiative of creating basic science departments
directed by full-time university professors. The decision was
understandable, and the action not completely unexpected,
for an individual with a somewhat authoritarian personality,
according to his son.8 These were Dean Chown’s realities.
Canadian Journal of P athology 133Winter 2012
QUINONEZ
The AppointmentA notification in the Manitoba Medical College Annual
Announcement for the session 1914–1915 heralded the
beginning of William Boyd’s tenure. It read, “The University
has decided to appoint a Professor of Pathology, who will
devote his whole time to this department. As the various
hospitals furnish abundant material for the study of
Pathology, this will give every opportunity for research as well
as for didactic work.” The notification indicated that a
decision to appoint a professor of pathology and
bacteriology, who will do research and teach, had been taken
by the authorities. The decision was made in a faculty
meeting in May 1913.4,5 However, a determining factor was
that in the same year the college had been rated as class B by
AMA, in part due to inadequate physical facilities and only a
few full-time professors.9 This event likely precipitated the
decision. The notice, interestingly, brought attention to the
fact that WGH was not the only focus and that the future
professor would control the pathological material generated
in all Winnipeg hospitals. In practice, however, WGH became
the only institution under the proposed structure. Future
events resulting from this decision highlighted the first-ever
conflict in determining the vision for the role of a
department of pathology in a university-affiliated hospital in
Winnipeg.
As an Edinburgh-trained surgeon and a citizen of the
Empire, Dean Chown looked to Great Britain for recruits to
create the basic science faculty. The first one was R.J. Evatt, a
graduate from Durham, England, who became full-time
professor of anatomy. Alexander Gibson, a graduate from
Edinburgh, eventually replaced him in 1913.9 The next
recruit was William Boyd. It became evident that Sidney J.S.
Peirce, the director of the laboratories and a practitioner at
WGH, did not fit Chown’s vision. On June 9, 1914, Gibson,
a classmate and close friend of Boyd who had arrived in
Winnipeg 6 months earlier, wrote to Boyd inviting and
encouraging him to apply for the professorship.4,5 Even Boyd
himself, in a presentation in Winnipeg years later, cited
Gibson’s intervention as the reason for his appointment. On
August 18, 2 months later, Dean Chown reported to the
faculty on the negotiations and, on September 11, 1914, he
reported that the university had appointed William Boyd as
professor of pathology and bacteriology.
Consequences of the AppointmentBoyd’s appointment was met with the expected negative
reactions. In the faculty meeting on October 8, 1915, it was
revealed that Peirce had presented his resignation as lecturer
in pathology. Peirce was the recognized pathologist at WGH
and at the provincial level. Before becoming director of the
laboratories, he had spent 1 year of training with Gordon
Bell, the first professor of pathology and bacteriology and the
founder of the department, and 2 more years at the Mayo
Clinic with Louis B. Wilson, one of the leading pathologists
and medical educators in the United States. Furthermore,
Director Peirce had spent one winter with Professor Aschoff
in Germany. He had also published several papers in
bacteriology and pathology, and had done an excellent job
directing the department. His autopsies were well written
with the scientific language of a trained pathologist. It is only
natural to conclude that the resignation was the result of his
frustration at not being appointed professor. The response
to his resignation by the faculty council was to appoint a
committee to consult with Peirce and the hospital
administration about the work and the pathological material,
but it did not deal with the issue of his resignation. However,
the result was that Peirce withdrew his resignation and
continued working in the hospital and at the college.4,5
The outcome of Boyd’s appointment also had consequences
for the dean. Chown resigned as dean in November 1915, the
month following Peirce’s resignation, but was convinced to
withdraw his resignation in December.4 There is no record
of the reasons for this sudden and unexpected action.
However, the negative reaction by the medical staff of the
hospital, of which Chown was a member and a successful
surgeon, is the most likely explanation. Peirce was also a
member of the staff and worked closely with clinicians as a
consultant. This conclusion about the dean’s resignation is
supported by events in the following years. Peirce’s daily
autopsy presentations were well attended, but the same
cannot be said of Boyd’s. At the beginning of Boyd’s tenure,
no one attended his autopsies except, occasionally, Chown.
Peirce was clearly a popular figure at the hospital.
The plan to restructure pathology as one of the fundamental
basic sciences continued to be implemented by Chown and
the authorities of the college. In January 1916, a committee
formed by Chown, Boyd, and Prowse (the future dean of
Winter 2012134 Canadian Journal of P athology
CONFLICT AND RESOLUTION: WILLIAM BOYD’S APPOINTMENT TO WGH
medicine) was appointed to integrate the Department of
Pathology of WGH with that of the college under the control
of the professor of pathology. In another meeting of the
faculty council a month later, a motion addressing the same
issue was introduced.4 The motion also recognized that,
before Boyd’s arrival, the departments of pathology in both
institutions were separate entities. The motion was
elaborated in more detail in a memo attached to the faculty
council minutes and dated March 10, 1916. In it, both
departments were amalgamated under the authority of the
professor of pathology (i.e., Boyd), and the responsibilities
of the hospital and the college were clearly spelled out.4
The Ensuing YearsThe impact of the Flexner report in the United States is very
well known.7 But, what was the impact of the decisions taken
by the faculty council under Chown’s leadership that
followed Flexner’s philosophy? In the first 3 years of Boyd’s
tenure, the department became consolidated. As part of the
support given by the hospital administration, the
department was moved to new facilities, new equipment was
added, and the budget was increased.10 It is clear that the
hospital’s board of directors had agreed to the takeover of
the department by the Medical College since, by this time,
the board had three members representing the university.11
It is also curious to find that in the 1917 annual report, in
the same paragraph in which Boyd praises the use of the
laboratory facilities for teaching by Peirce and emphasizes
the need for close collaboration between the hospital and
the college, he added, “When the normal conditions of peace
again prevail it is intended to develop this aspect of the
work.”10
Teaching pathology to undergraduate students was
expanded by increasing hours of instruction and by
separately identifying the teaching of clinical pathology. This
distribution followed the Hopkins model but, curiously, also
followed the Edinburgh curriculum.5 Pathology and
histology were also segregated from bacteriology. Pathology
was divided into general pathology and special (anatomical)
pathology. In the Faculty of Medicine’s Annual
Announcement of 1917–1918, information on an
anatomical and pathological museum under the direction
of Professors Gibson and Boyd appeared for the first time.
It indicated that there was already a museum in existence
(one developed by Peirce before Boyd’s arrival) and that it
had been reorganized. Specimens were now systematically
grouped and carefully classified and identified.
In the hospital’s annual reports, Boyd was listed as
“Pathologist” and “Director of Laboratories.” Peirce
appeared in the annual report of 1916, but in the next 2 years
his name did not show up again; he was mentioned only in
the corresponding reports of the department written by
Boyd and in the annual announcements of the college.
Peirce’s activities, as described by Boyd, were focused in the
areas of clinical (general) pathology and teaching. He
stopped performing autopsies except during Boyd’s
absences, did some clinical research, and taught medical
students at the hospital. It may be that Boyd’s intentions
were to assign clinical pathology to Peirce, keeping
anatomical pathology for himself. At the college, Peirce was
promoted from lecturer to associate professor.
One important event at the college was the discussion about
conversion of the college into the Faculty of Medicine of the
University of Manitoba. This change was an aspiration of
the faculty and became possible when the provincial
government passed the University of Manitoba Amendment
Act in 1917. It was in this year that Dean Chown resigned as
dean and as chief surgeon of WGH to become a member of
the new board of governors of the university.
Peirce left for Brandon, Manitoba, in March of 1918,
apparently with bitterness.12 When he departed, there was
no one who could teach clinical pathology. However, Peirce
left a legacy that cannot be easily ignored, and two of his
contributions are worthy of mention. One was the
transformation of the laboratories into a significant hospital
institution. The other was his effort in collecting and
preserving anatomical specimens that represented the
groundwork on which Boyd created the Pathology Museum,
one of his legacies to pathology. Boyd himself recognized
Peirce’s contributions when, in the departmental annual
report of 1918, he wrote, “It is unnecessary to remark that
the development of the Laboratory from its very beginning,
and of the Pathological work of the Hospital generally, is
entirely due to Dr. Peirce’s energy and scientific
attainments.” With Peirce gone, Boyd was now free to stamp
his vision on the department.
Canadian Journal of P athology 135Winter 2012
QUINONEZ
ConclusionDid Dean Chown make the right decision by selecting Boyd,
an external candidate, instead of Peirce, an internal one?
Chown’s position and action were determined by three
events. The first and essential reason was a consequence of
the Flexner report. Although the report itself had been kind
to the Medical College and to WGH, by its calling attention
to the conditions of medical education in North America,
Chown knew that, in reality, the Manitoba Medical College
was not an exception to Flexner’s criticisms. The institution
lacked strong basic sciences and full-time professors, one of
the main demands of the new vision introduced by Flexner.
A second and less important reason was Chown’s
background as a citizen of the British Empire and a surgeon
trained in Edinburgh. It was only natural that he looked there
for a candidate. Finally, a less important reason was the direct
influence of the anatomist Gibson, who originally referred
Boyd. Because the dean was evidently looking for
suggestions, he could not ignore the advice. These three
conditions together may explain Chown’s decision to appoint
Boyd over Peirce. Judging by the end results of the conflict,
we can only admit that Chown made the right decision. Boyd
became not only the leader of pathology in English Canada
but also brought fame to the department and, consequently,
to the Medical School. However, he only implemented the
teaching component of Chown’s vision since his contribution
to research was limited.13 The latter was perhaps not Boyd’s
flaw alone. Basic research was not on the agenda in Winnipeg
and most university hospitals in those years.14
This article is dedicated to Ian Carr, historian of Manitoba medicine.
References1. Foster WD. Pathology as a Profession in Great Britain and The Early History
of the Royal College of Pathologists. London: The Royal College of
Pathologists; n.d.
2. Rosai J, ed. Guiding the Surgeon’s Hand: The History of American Surgical
Pathology. Washington (DC): American Registry of Pathology; 1997.
3. Long ER. A History of American Pathology. Springfield (IL): Charles C.
Thomas Pub; 1962.
4. Hoogstraten J. Untitled presentation to the Manitoba Medicine History Club.
Winnipeg (MB): University of Manitoba, Neil John Maclean Health Sciences
Library Archives; 1987.
5. Carr I. William Boyd: Silver Tongue and Golden Pen. Toronto (ON):
Associated Medical Services & Fitzhenry & Whiteside; 1993.
6. Flexner A. Medical Education in the United States and Canada. A Report to
the Carnegie Foundation for the Advancement of Teaching (Bulletin Number
Four). New York: The Foundation; 1910.
7. Stevens R. American Medicine and the Public Interest. New Haven (CT): Yale
University Press; 1973.
8. Chown B. The story of the medical college. Univ Man Med J 1933;5:28–34.
9. Faculty of Medicine, University of Manitoba. Centennial Program. Winnipeg
(MB): The Faculty; 1983.
10. Winnipeg General Hospital. Department of Pathology: Annual Report.
Winnipeg (MB): The Hospital; 1917.
11. Winnipeg General Hospital. Department of Pathology: Annual Report.
Winnipeg (MB): The Hospital; 1916.
12. Bigelow WA. Forceps, Fin and Feather. Altona (MB): Friesen & Sons; 1969.
13. Carr I, Beamish RE. Manitoba Medicine: A Brief History. Winnipeg (MB): The
University of Manitoba Press; 1999.
14. Bowden D. Pathology 100, 1890–1990. Man Med 1990;60:55–7.
Winter 2012136 Canadian Journal of P athology
CAP-ACP William Boyd Lecture, 2012: Going Viral
Richard G. Hegele, MD, PhD, FRCPC, is a member of the Department of Laboratory Medicine and Pathobiology, Universityof Toronto, in Toronto, Ontario. Correspondence may be directed to [email protected] article was peer reviewed.Competing interests: Dr. Hegele has received payment as a consultant for Gilead Sciences, Inc.
Richard G. Hegele, MD, PhD, FRCPC
ABSTRACTFor a country that has a comparatively small population, Canada has a long-standing tradition
of internationally recognized excellence and leadership in pathology education and research.
In this presentation, the author reviews two areas of respiratory syncytial virus lung infection,
viral persistence and receptor discovery, to illustrate how pathologists have relevant expertise
that can be used to contribute to the creation of new knowledge and change paradigms about
disease etiology and pathogenesis, and to inform the design of innovative strategies for
treatment and prophylaxis.
RÉSUMÉ Pays dont la population est relativement peu nombreuse, le Canada jouit néanmoins depuis
longtemps d’une réputation mondiale d’excellence et de chef de file en éducation et en recherche
dans le domaine de la pathologie. L’auteur examine deux aspects de l’infection pulmonaire due
au virus respiratoire syncytial, la persistance virale et la découverte du récepteur, pour illustrer
l’expertise pertinente du pathologiste susceptible de contribuer à l’acquisition de nouvelles
connaissances, donc à la création d’un savoir nouveau, et à la transformation des paradigmes
au sujet de l’étiologie et de la pathogenèse de la maladie, et d’éclairer la conception de stratégies
thérapeutiques et prophylactiques novatrices.
ORIGINAL ARTICLE
It is a privilege to present the 2012 William Boyd Lecture
of the Canadian Association of Pathologists-Association
canadienne des pathologistes (CAP-ACP). William Boyd was
a pioneer of Canadian pathology, having emigrated from
Scotland to Winnipeg after having completed his training
and serving in the First World War. He was professor of
pathology at the University of Manitoba from 1915 to 1937
and at the University of Toronto from 1937 to 1951, and was
the inaugural professor of pathology of a brand new medical
school in Vancouver at the University of British Columbia
(UBC, 1951–1954). Professor Boyd published several
textbooks, including Surgical Pathology (1925; later called
Pathology for the Surgeon); Pathology of Internal Disease
(1931; later called Pathology for the Physician), Textbook of
Pathology (1932), and An Introduction to Medical Science
(1937). These books were extremely popular all over the
world, going through many editions and translation into
multiple foreign languages. Professor Boyd, of “silver tongue
and golden pen”1 was lauded for his “clarity, fine prose and
infectious enthusiasm for the subject matter.” Several
generations of medical students and physicians owe their
understanding of the causes and mechanisms of disease to
Dr. Boyd’s books and lectures, and one cannot underestimate
his influence on our country’s long-standing track record of
productivity and impact in pathology-related research and
practice. One little known fact about Dr. Boyd is that in
Canadian Journal of P athology 137Winter 2012
HEGELE
addition to being a pathologist, he was trained as a
neurologist and a psychiatrist and held a diploma in
psychiatry. It is tempting to speculate how this latter
credential could have given him an extra edge that enabled
him to leave such a profound legacy, in the face of having to
deal with the daily rigours and distractions of academic
leadership.
In some ways, my professional and scientific career
development can be traced to the memory of Dr. Boyd. It was
because of the William Boyd Lecture I attended in Winnipeg
in 1988, during my residency training, that I first met Dr.
James C. Hogg, professor of pathology at the University of
British Columbia (UBC). I knew of Dr. Hogg’s reputation as
an accomplished experimental lung pathologist and a
formidable presence on the world stage, recognized for his
many fundamental contributions to our understanding of
pulmonary structure-function relationships, particularly in
the context of obstructive lung diseases.2 Dr. Hogg delivered
the 1988 William Boyd Lecture when he was literally on his
way home to Vancouver after completing a sabbatical at the
University of Oxford. At Oxford he learned this “highfalutin”
technique called in situ hybridization3 and witnessed first-
hand early iterations of a new method called polymerase
chain reaction (PCR). As a result of this sabbatical
experience, Dr. Hogg almost single-handedly ushered in the
era of molecular biology to the study of lung disease. At the
coffee break following the Boyd lecture, I introduced myself
to Dr. Hogg and we talked at length about the implications
and exciting possibilities of applying molecular biological
approaches to the study of lung diseases. The next year, Dr.
Hogg became my PhD supervisor and introduced me to
respiratory viruses and asthma. I did my graduate degree in
experimental pathology, working in the UBC Pulmonary
Research Laboratory at St. Paul’s Hospital on the role of
respiratory syncytial virus (RSV) in the onset of pediatric
asthma. To this day, Dr. Hogg remains a dear colleague and
friend – we are even working on a paper together at this
moment. I owe great debt of gratitude to the CAP-ACP –
through the vehicle of the William Boyd Lecture – for
enabling me to have a chance encounter with Dr. Hogg and
literally change my life.
My presentation will focus on two major projects that
illustrate how I believe my background as an anatomical
pathologist proved invaluable to success. Firstly, I will review
work done while I was at UBC that defined a new paradigm
of RSV persistence in the lungs, and effects of persistent
infection on chronic airway inflammation, a hallmark of
asthma that has been recognized since Osler’s time.4
Secondly, I will recount the story of work done in Vancouver
and Toronto concerning our group’s discovery of nucleolin
as a cellular receptor to RSV, and share with you the feeling
of trepidation and excitement that came with delving into
the unknown. I will then close with a brief personal
perspective about how the expertise of pathologists can be
used in the creation of new knowledge concerning the causes
and mechanisms of disease.
Role of RSV in the Onset of Pediatric AsthmaAlthough relatively underappreciated in the area of surgical
pathology because it is not a common source of biopsy or
resection specimens, asthma is the most common chronic
disease in children and puts a huge burden on society, with
approximately 8–10% of the general population affected and
costs to the Canadian health care system of more than $1
billion annually.5,6 Asthma is a heterogeneous condition that
is defined by phenomena of reversible airflow obstruction,
airway hyper-responsiveness to bronchoconstrictor agents,
and chronic airway inflammation and remodelling.
Attempting to understand the pathobiology of asthma is
difficult owing to the heterogeneity of patients and the
potentially unrelated mechanisms producing the disease
phenotype. For this reason, investigators have focused on
particular subgroups of asthmatic patients so that any new
advances can be specifically targeted to these individuals. One
subgroup of asthmatic patients is those children whose onset
of disease occurs after an episode of RSV bronchiolitis, an
association first reported in the late 1950s.7 The mechanisms
of post-bronchiolitis asthma are not well understood,
although a relationship to a genetic predisposition to allergy
seems to be involved. In the absence of a safe, effective RSV
vaccine or good antiviral therapy, post-bronchiolitis asthma
will continue to be a problem for the foreseeable future.
Viral respiratory infections have traditionally been
considered to be of acute onset and of short clinical course,
characterized by the recovery of the infected patient with
clearance of the virus from the respiratory tract or, in
Winter 2012138 Canadian Journal of P athology
WILLIAM BOYD LECTURE, 2012: GOING VIRAL
unfortunate circumstances, by patient death.8When I began
my PhD studies with Dr. Hogg, after completion of my
anatomical pathology residency training, it was unknown
whether viruses could chronically persist9 in the lungs and
act to stimulate chronic airway inflammation. Given the
difficulties of testing the “working hypothesis” of RSV
persistence in the lungs of the natural hosts of RSV (humans,
primates, and cows),10 we elected to develop a small animal
model of experimental lung infection of guinea pigs with
human virus. The guinea pig was chosen because this species
was an established animal model of allergic sensitization and
airway hyper-responsiveness in the laboratory at St. Paul’s
Hospital.11 Sure enough, with the use of sensitive PCR-based
detection techniques for detection of RSV-associated nucleic
acid in guinea pig lung specimens, we documented RSV
persistence for as long as we studied the animals (for at least
60–100 days post-RSV inoculation) and noted virus-
associated airway inflammation with T cells and eosinophils,
airway hyper-responsiveness to inhalational acetylcholine
challenge,12–14 features of human asthma.15 This body of work
was very satisfying: RSV causes persistent lung infection and
is associated with structural and functional changes of
asthma, thus implicating a direct viral role in pathogenesis –
end of story.
Or was it? Nature has a way of being far more interesting than
any brilliant hypothesis one could ever conceive. Moving
from animal models to humans, we did a study in which
cores of human lung tissue and secretions from the lower
airways were tested for the presence of nucleic acid from
common respiratory viruses by using a PCR panel that we
developed.16,17 In contrast to the prevailing view that the
human lung is a sterile environment, at least in health,18,19
our results suggested that the lungs are actually a reservoir of
all sorts of pathogens. What made things particularly
confusing was the lack of an obvious relationship between
the presence of any given virus and a specific lung disease.
Undeterred, we decided to go back to the guinea pig model
and did a new series of experiments designed to compare the
effects of experimental RSV lung infection on airway
inflammation and airway hyper-responsiveness in two
different strains of guinea pig. One strain was genetically
predisposed toward developing allergy, and the other strain
was genetically resistant to becoming allergic. Given the
association between post-bronchiolitis asthma and allergy,
our working hypothesis was that RSV would persist in the
“allergy-susceptible” guinea pigs and be cleared by the
“allergy-resistant” strain, according to predictions of the Th1-
Th2 paradigm of CD4+ T lymphocytes.20 [Briefly, Th1
responses are involved in delayed-type hypersensivity
responses and are considered to be effective in antiviral
immunity, while Th2 responses are involved in allergic
responses and are less effective in antiviral immunity.]
Instead, what we found was that RSV persisted in the lungs
of all animals tested, regardless of their genetic predisposition
to allergy, but only the Th2-skewed, allergy-susceptible
guinea pigs developed RSV-associated airway inflammation
and hyper-responsiveness.21 The Th1-skewed, allergy-
resistant animals were spared the deleterious effects of RSV
on airway inflammation and lung function. We concluded
that the presence of virus within the lungs was by itself
insufficient to produce the structural and functional changes
of an asthmatic phenotype; instead, the host’s genetic
background for allergy appears to be important. These
findings emphasized the importance of virus-host
interactions in the genesis of a disease phenotype, not the
simple presence or absence of virus in lesional tissue.
Overall, I believe my background as a pathologist provided
me with important requisite knowledge and skills to apply
existing experimental techniques – and develop new ones –
to answer specific questions in a comprehensive, integrated
manner. As an epilogue to this body of work, the issue of
whether or not the lung is sterile has been resolved
definitively by the application of next-generation sequencing
technologies. The existence of a lung “microbiome” has now
been established unequivocally,22 and there is also emerging
evidence of a human lung “virome.”23,24 Overall, the concept
of the human lung being a sterile environment has been put
to rest once and for all. The new challenge is to understand
how this “garden” of microorganisms interacts with the host
to produce various disease phenotypes.
Discovery of a Cellular Receptor for RSV Continuing on the theme of virus-host interactions, our
group became interested in what can be considered as the
ultimate RSV-host interaction – namely, how the virus
interacts with the host cell surface to initiate infection. One
Canadian Journal of P athology 139Winter 2012
HEGELE
of the long-standing mysteries of RSV pathobiology is just
exactly what the virus binds to on the cell surface at the
beginning of infection, something that has perplexed even
experienced virologists for over half a century. All sorts of
candidate RSV receptors have been proposed over the years
since the discovery of RSV in 1956,25 but no candidate
molecule has fulfilled the functional criteria for a receptor,
that is, decreased cellular infection after the implementation
of interventions designed to decrease virus-receptor binding
and the converse situation whereby there is increased
infection of a resistant cell type after ectopic expression of
the candidate receptor molecule on the cell surface. Our
group sought to identify functional RSV receptors, the
rationale for pursuing this program of research being that
RSV receptors could provide new targets for the development
of novel antiviral prophylaxis and therapy, something much
needed in the field.
A courageous PhD student, Farnoosh Tayyari, went into this
area without any prior expertise in membrane biology. This
was probably a good thing, as neither she nor anyone else
working in the laboratory had any preconceived notion as to
what a receptor for RSV might be. We went back to first
principles and elected to chemically characterize the RSV
receptor(s). This approach consisted of pretreating cultured
cells with enzymes that digest the main components of the
cell surface (protein, lipid, carbohydrate) and seeing what
effects these enzyme treatments had on subsequent RSV
infection. Results showed that only protease digestion of the
cell surface resulted in decreased infection of cell cultures,
and this was seen in cells originating from various species,
including human, dog, and hamster. With this information,
a virus overlay protein binding assay (VOPBA) on protein
extracts from cell cultures was performed. VOPBA is a
technique similar to a Western blot, but for which the
infectious virus serves as the “primary antibody” and anti-
RSV antibody is the secondary antibody. Results of
numerous experiments reproducibly identified a signal of
molecular weight ~100 kDa, which on mass spectrometry
yielded nucleolin as a common “hit” among different RSV-
permissive cell types. This was not what any of us expected:
nucleolin was discovered and described as an intranuclear
molecule, and the idea of it being expressed on the cell
surface was puzzling. A literature search revealed that various
investigators have documented nucleolin expression on the
cell surface.26,27 We also showed that RSV could co-localize
with nucleolin on the cell surface using confocal microscopy
and antibody blocking approaches.
To validate nucleolin as a functional RSV receptor,
Dr. Tayyari and Dr. David Marchant, a post-doctoral fellow,
performed a large number of inhibition experiments
(blocking antibodies, competition with soluble nucleolin,
RNA interference of nucleolin expression), and results
showed significant decreases of RSV cellular infection
through these interventions. The issue of reconstitution,
whereby a resistant cell line becomes permissive to RSV via
ectopic expression of nucleolin, proved challenging. After
considerable detective work, Dr. Tayyari found that a type of
insect cell (Sf9) was reported as being RSV resistant.28
Dr. Marchant transfected the human nucleolin gene into Sf9
cells, and human nucleolin protein was expressed on the cell
surface. Nucleolin-transfected Sf9 cells were permissive to
RSV. This latter finding represented one of those “eureka
moments” that words cannot adequately express. Overall,
seeing the RSV signal in the nucleolin-transfected Sf9 cells
more than compensated for all of the challenges and
hardships we had experienced along the way.
While these were very impressive findings in a cell culture
dish, ultimate validation required confirmation of nucleolin
being a functional receptor for RSV in vivo. We established a
new collaboration with Dr. Theo Moraes at the Hospital for
Sick Children, in Toronto, whose laboratory had developed
a mouse model of experimental RSV lung infection. RNA
interference was used as a strategy to knockdown nucleolin
expression in the murine lung: this was an exciting time in
which my research associate, Peter Mastrangelo, worked with
Dr. Moraes, his technician Wenming Duan and David
Marchant, who came to Toronto from Vancouver expressly
to help set up in vivo experiments. RNA interference was
associated with decreased RSV infection of the murine lung,
thereby confirming nucleolin’s functional role in vivo. Our
paper on the discovery of nucleolin as a functional RSV
receptor was published last year.29 Our current work focuses
on understanding cell surface nucleolin expression in
different disease states, and testing compounds that can
interfere with RSV-nucleolin binding as potential agents for
prophylactic or therapeutic use.
Winter 2012140 Canadian Journal of P athology
WILLIAM BOYD LECTURE, 2012: GOING VIRAL
Overall, what enabled us to solve this 50+-year-old mystery?
I contend that a pathologist’s extensive knowledge of
phenotypes, high comfort level with using whatever
techniques are available to be directed at answering specific
questions, and going into the area without a preconceived
bias as to what the RSV receptor might be, proved crucial to
the success of this project.
ConclusionPathology is traditionally considered as a “bridge” specialty
between basic science and clinical care. As such, pathologists
can play a crucial role in working toward improving health
care by being involved in investigations of the causes and
mechanisms of disease. Pathologists can work in various roles
as principal investigators and collaborators: our expertise in
disease phenotyping at the tissue, cellular, and molecular
levels is arguably unmatched by any other discipline. I was
fortunate to have the opportunity to pursue investigative
pathology of viral lung disease just at the time that molecular
biological techniques were making their way into our arena.
It has been extremely gratifying to have the opportunity to
work with so many dedicated and talented individuals who
share a common goal to create new knowledge about disease
etiology and pathogenesis that has the potential to be
translated into improved health. In contrast to the era of
molecular biology as a dominant force for basic biomedical
research, in which I completed my scientific training, we now
live in an “-omics” and informatics age, where the ability to
interrogate biological systems comprehensively is
unprecedented in both breadth and depth. We have powerful
tools – and more are being developed – to be able to
understand the relationships of the various components
comprising a biological system. More than ever, we have the
ability to definitively determine which specific viral and host
factors are important to the development of airway
inflammation and hyper-responsiveness in the setting of
persistent RSV infection, and how to manufacture “designer”
molecules as novel RSV treatments. These things would be
been a pipedream only a few short years ago.
As a closing thought, in a previous issue of Canadian Journal
of Pathology, I wrote about the concept of “consilience,”
defined as a jumping or linking together of knowledge for
the purpose of forming new perspectives.30 In my opinion,
pathologists are particularly well placed to be leaders in
medical and scientific consilience, from a mindset that is
conducive to the effective management and integration of
large amounts of information obtained from different
sources. Our profession has a strong tradition of being able
to navigate through data and synthesize them to make sense
of the world around us, for the betterment of patients and
populations. Even with this expertise, we will need to
continually develop new skill sets to remain a relevant and
thriving discipline. Let us not forget how privileged we are
to have such opportunities before us: it is our obligation to
make the most of them, and in the process we have the
potential to derive considerable personal satisfaction and
fulfillment.
AcknowledgementsI have had the pleasure and privilege to work with many fine
individuals over the years. Special thanks to Drs. J. C. Hogg,
S. Hayashi, P. D. Pare, R. R. Schellenberg, A. Dakhama, A.
Bramley, N. Chan, V. Macek, T. Vitalis, T. Sutton, F. Tayyari,
D. Marchant, P. Mastrangelo, T. Moraes, W. Duan, M. A.
Khan, B. Wiggs and H.E. Manson.
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The Department of Pathology and Molecular Medicine in the Queen’s University Faculty of Health Sciences and its affiliated teaching hospitals is recruiting an academic Forensic Pathologist. We are seeking someone with subspecialty training/expertise in forensic pathology. Expertise in another area, such as cardiac pathology or neuropathology or another area in anatomical pathology would be an asset. We are a very collegial department, with a strong culture of scholarship. The successful candidate would be the Director of the Kingston Regional Forensic Pathology Unit and Clinical Director of the Kingston General Hospital autopsy service and would be provided protected time to establish a research program. The applicant would also be expected to contribute to the department’s undergraduate, graduate and residency training programs in the area of forensic sciences. The compensation package is very competitive, and includes an attractive benefits package.
Candidates must be eligible for medical licensure in the province of Ontario and must hold postgraduate qualifications in Pathology, and, possess or be eligible to obtain certification in pathology from the Royal College of Physicians and Surgeons of Canada or the American Board of Specialities. This is an interna-tional search and the University invites applications from all qualified individuals. Appointment will be at the academic rank commensurate with experience.
Evaluation of applications will begin January 1, 2013 and will continue until the position is filled. Applicants should submit a letter of interest and a curriculum vita to: Victor A. Tron, Head, Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6 (Tel): (613) 533-2850; (Fax): (613) 533-2907; E-mail: [email protected] (electronic submission preferred). URL: www.path.queensu.ca
One of Canada’s leading universities, Queen’s has a long-standing reputation for academic excellence, research and a diverse and vibrant learning environment. With its strong tradition of public service, the University has helped to shape Canadian values and policies, educating notable political and cultural figures. Queen’s University is located on the shore of Lake Ontario, in the heart of historic Kingston, midpoint between Montreal, Toronto, and the nation’s capital.
Queen’s is committed to employment equity and diversity in the workplace and welcomes applications from women, visible minorities, Aboriginal people, persons with disabilities, and persons of any sexual orientation or gender identity. All qualified candidates are encouraged to apply; however, Canadian citizens and permanent residents will be given priority.
ACADEMIC FORENSIC PATHOLOGIST
QUEEN’S UNIVERSITY
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Winter 2012142 Canadian Journal of P athology
BOOK REVIEW
Biomarkers of Kidney Disease
Biomarkers of Kidney Disease is a thorough review of the
contemporary literature of biomarkers in renal disease. The
text focuses on potential biomarkers of kidney disease that can
be used for early diagnosis, assessment of severity, and long-term
prognosis. The book begins with a description of the
characteristics of an ideal biomarker in kidney disease, statistical
considerations of biomarker research, and comprehensive
chapters describing the role of metabolomics and proteomics in
the study of biological markers in kidney disease. The text then
proceeds to detailed descriptions of the current literature for
biomarkers in acute kidney injury, renal cancer, diabetic
nephropathy, glomerular disease, preeclampsia, and cystatin C
in renal disease.
The strength of the book lies in its early introductory chapters
focusing on taking biomarkers from the bench to the bedside.
The weakness of the text is that it is somewhat descriptive and
lacks figures other than tables listing identified biomarkers. The
field of biomarker research is rapidly evolving; nevertheless, this
comprehensive text provides an excellent introduction to the
topic based on the literature available at the time of publication.
This book would be valuable to clinicians with an interest in
renal disease and translational research in the field.
Dawn L. MacLellan, MD, FRCSCDepartments of Urology and PathologyDalhousie UniversityHalifax, Nova Scotia
Charles L. Edelstein, EditorAcademic Press, 2011ISBN: 978-0-12-375672-5426 pages
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