Diagnostic Problems in Breast Pathology: Expert Consult: Online and Print

362 Pages·2008·234.07 MB·English

by  Frederick C. Koerner MD

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DIAGNOSTICPROBLEMSINBREASTPATHOLOGY ISBN:978-1-4160-2612-9
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Diagnosticproblemsinbreastpathology/FrederickC.Koerner.–1sted.
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Includesbibliographicreferences.
ISBN978-1-4160-2612-9
1. Breast–Cancer–Diagnosis.2. Breast–Diseases. I.Title.
[DNLM:1. Breast–pathology.2. BreastDiseases–pathology. WP815K78d2009]
RC280.B8K642009
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2008038309
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To my wife,
Doris Dewing,
whose belief in the value of this endeavor
never wavered
vii
Preface
Readerswillfindthefollowingworkmodestinitsscope.Itdoesnotencompassthefullrangeof
clinical, pathological, andinvestigational information concerningdiseasesofthebreast inency-
clopedic detail,nordoesitdiscusstheentirerangeofdisorders thatafflictthemammarygland.
Severalexcellenttextsofthistypealreadyexist,andIcannotimproveuponthem.Instead,Ihave
set out three limited objectives. First, I have tried to record in both verbal and photographic
format the morphologic characteristics of those mammary lesions commonly encountered in
thepracticeofdiagnosticsurgicalpathology.Second,Ihaveendeavoredtoconceptualizelesions
according to fundamental biologic processes and, in so far as possible, to categorize lesions
according to these concepts. Identifying the underlying nature of a pathologic abnormality
servestwopurposes:ithelpsthediagnosticiantoshapethedifferentialdiagnosis,anditprovides
thecontextrequiredtounderstandtheoriginandthesignificanceofthemorphologiccharacter-
istics. The analysis of these morphologic findings sometimes represents the most challenging
element of the diagnostic process; therefore, I have set out a third objective: to offer a few lines
of reasoning and points of general advice in the hope that they will assist pathologists when
analyzing problematic cases. Drawn from the common wisdom and from personal experience,
which includes occasional painful mistakes, these suggestions should serve as generalizations
only, pertinent in certain situations but to be disregarded in others. I acknowledge that I have
notmetanyofmygoalscompletely.Nevertheless,Iferventlyhopethattheinformationcontained
within these pages will make it easier for practicing pathologists to resolve certain of the diag-
nostic problems in breast pathology with confidence.
Manypersonscontributedtothecreationofthisbook.IwishthatIcouldacknowledgeeachof
them by name and that I could recount the help that each of them offered, but space does not
allowmethisluxury.Nevertheless,withgreatpleasureandmuchappreciationIgivecredittothe
following colleagues and collaborators.
Three eminent surgical pathologists of the latter part of the twentieth century inspired my
study of mammary pathology. Dr. Robert E. Scully, Emeritus Professor of Pathology at Harvard
MedicalSchooland,untilrecently,theseniorpathologistattheMassachusettsGeneralHospital,
showed me the intellectual elegance and beauty inherent in the practice of academic surgical
pathology. Dr. John G. Azzopardi, Emeritus Professor of Oncology at the Royal Postgraduate
Medical School and formerly an Honorary Consultant in Pathology at the Hammersmith
Hospital, demonstrated the power of detailed morphologic observation in the characterization
of mammary lesions. Dr. Paul Peter Rosen, Professor of Pathology at Weill Medical College of
Cornell University and Chief of Breast Pathology at New York Presbyterian Hospital-Cornell
Medical Center, taught me the specific features of many mammary lesions and inspired me to
try to discern the biologic mechanisms giving rise to these entities. From all three pathologists,
I learned the importance of clear thinking and the need for critical reflection when evaluating
boththecommonwisdomandone’spersonalobservations,for,asProfessorAzzopardiwarned,
‘‘Experiencecanbemerelytherepetitionofthesameerroroftenenough.’’Itwastheintellectual
rigor in the pursuit of an understanding of mammary diseases shown by these scholars that
inspired this young and callowpathologist tofollow their lead.
The motivation to put these thoughts on paper came from many sources. Friends, family
members, students, clinical colleagues, fellow pathologists, and trainees in the Department of
Pathology atthe Massachusetts General Hospital all encouraged me in manyways and at many
times. Among the latter, Dr. Paula M. Arnell deserves special mention for her consistent and
enthusiastic encouragement. Many ideas in these pages evolved during conversations with col-
leagues. Drs. Horacio M. Maluf and Melinda F. Lerwill listened to many off-beat ideas and
unconventional notions with more patience and open-mindedness than one should expect
even from friends. I must express my gratitude to these two intellectual companions for their
viii PREFACE
interest, patience, generosity of spirit, and refusal to despair during our many exploratory
discussions.
The text would never have materialized had Dr. Robert H. Young, Robert E. Scully Professor
ofPathologyatHarvardMedicalSchoolandDirectorofGynecologicandUrologicPathologyat
the Massachusetts General Hospital, not introduced me to the publishing staff at Elsevier and
encouragedmeatmanypointsduringmyseveralyearsofwriting.Mr.WilliamSchmittgraciously
butforcefullypriedthemanuscriptfrommyhands,andMsKatieDeFrancescoandMr.Norman
Stellanderoversaweverydetailofitstransformationintothefinaltext.Toall,Iexpressmyheartfelt
thanks.
FREDERICK C. KOERNER, MD
1
1
Introduction to the Diagnosis of
Diseases of the Breast
Although diseases of the breast number relatively chronic inflammatory cells. The presence of blue-
fewer than those affecting many organs, the field of gray myxoid material or a few unexpected cells
mammary pathology challenges the histopathologist within this stroma may represent the only clues to
asmuch asany discipline in surgical pathology. The the presence of aninvasive carcinoma.
patient’s signs and symptoms and the other clinical Knowledgeofmammaryanatomyalsoallowsone
details of the case do not give the pathologist much tounderstandthepathogenesisofcertainlesions.For
more than general guidance regarding the nature of example,familiaritywiththedistributionoftheglan-
the lesion. The macroscopic examination might sug- dular tissue and the organization of the glandular
gestadiagnosisincertaincases,butmanyofthemost and stromal components make recognition of most
troublesomelesionscannotbeseenwiththeunaided hamartomas straightforward, and an understanding
eye. Thus, it falls to the microscopist, and to the ofthetopologicrelationshipsofthenormalnonspe-
microscopist alone, to establish the diagnosis of the cializedstromaallowsonetocomprehendtheorigin
patient’s disease. Guided primarily by one’s knowl- of the morphologic features of tumors derived from
edge of histopathology, one must distinguish the this tissue. Finally, once one understands the struc-
artifactual from the genuine, the reactive from the tureofthebreast, onecanappreciatethepersistence
neoplastic, and the trivial from the life-threatening. of the normal organization in many benign altera-
Thistaskrequiresathoroughgoing understandingof tions such as sclerosing and the obliteration of the
the microanatomic structure of the mammary gland normal relationships by malignant lesions such as
and the morphologic manifestations of mammary cancers. Thus, the structures of the breast serve as a
diseases. It takes patience, experience, and careful frame of reference that allows the pathologist to
thought to develop this body of knowledge, but detect abnormalities, understand their development,
pathologists who undertake this endeavor will find and differentiate them from others showing superfi-
themselvesrewardedbyanenhancedappreciationof cial similarities.
thesubtleties of mammarypathology. Besides learning the anatomy of the gland, the
One should begin one’s study of diseases of the pathologist must study the ways in which the
breastbymasteringthemicroanatomyofthenormal normal gland changes with age. With the onset of
mammary gland. The author would encourage the ovulation,simplelobulessproutfromsmallductules,
reader toconsult anystandard textbook of histology and each of these so-called type I lobules consists of
toreviewthefundamentalsofterminologyandtissue little more than a coiled tubule with a few short
organization. Neither poses much complexity, and stubby branches. Familiarity with the characteristics
experienced students will find them second-nature; of these primitive lobules allows one to recognize
yet even such basic principles as these play critical themasthetypeofglandulartissuefoundinectopic
roles in the pathologist’s study of breast tissue. locations, such as the axilla and supernumerary nip-
Without knowledge of the composition of the ples,aswellasthevarietyoflobulesthatoccasionally
breast,onewillneverdetectthestructuralalterations form in cases of gynecomastia. As the reproductive
that indicate the presence of a lesion. The nonspe- years come to an end and the menopause ensues,
cialized stroma, for instance, usually consists of eo- theglandulartissueshrinks,andthefibrousconnec-
sinophilic collagen, just a few fibroblasts, and rare tive tissue turns to fat. These alterations leave acini
2 INTRODUCTION TO THEDIAGNOSIS OF DISEASES OF THEBREAST
embedded in adipose tissue in a pattern that structure contribute critical diagnostic information.
superficially resembles the appearance of invasive Theauthorcannothelpthereaderdevelopanunder-
well-differentiatedcarcinoma.Knowledgeofthephe- standing of these sophisticated aspects of mammary
nomenonofatrophyanditshistologicfeatureshelps anatomy except to emphasize that such knowledge
the pathologist from mistaking this age-related does not originate in a textbook. It comes only
change asa carcinoma. from untold hours at the microscope coupled with
During the reproductive years, the breast under- aconstantreferencetonormaltissueandaconscious
goes a series of changes with each menstrual cycle, effort tonurture the growthof this understanding.
and pathologists will find it useful to become Althoughalterationsinthestructureofthebreast
acquainted with these cytologic variations. The indicate the presence of an abnormality, these ana-
lutealphasebringsaboutchangesinscatteredtermi- tomic deviations do not themselves provide much
nal duct(cid:2)lobular units. The nuclei of the acinar diagnostic information. An increase in the number
luminal cells enlarge, and their nucleoli become of cells in the epithelium of a duct, for instance,
especially prominent. A burst of mitotic activity could reflect an inflammatory process, a reaction to
takes place in the latter portion of the cycle, and a injury,aprimaryhyperplasiaofductalcells,oraneo-
few days later, most of the newly created cells die. plasticepithelialproliferation.Tomakespecificdiag-
Pathologists can easily misinterpret the large nuclei noses, pathologists must study the morphologic
and nucleoli, the increased nuclear-to-cytoplasm attributes of the cells in question. Because the reso-
ratio, the division figures, and the apoptotic cells as lutionofmanyofthemostdifficultdiagnosticprob-
evidence of carcinoma. The hormonal fluctuations lems requires an appreciation of subtle cellular
that bring about these alterations of the normal characteristics, pathologists must work slowly and
cells also seem to affect other types of epithelial patiently and must make frequent use of high mag-
cells. Hyperplastic ductal cells and the epithelial nification. Diagnosticians attuned to the nuances of
cells of papillomas, for instance, can show unex- cytopathologywillfindthemselvesathomestudying
pected nuclear enlargement, nucleolar prominence, breast specimens. The remaining chapters of this
and mitotic activity at this time of the cycle. One work set out many of the specific cellular character-
wouldhaveadifficulttimedisentanglingthefindings istics that serve as diagnostic criteria for certain
created by the superimposition of hormonal effects common lesions; however, as a prelude, the author
onotherlesionswithoutasecureappreciationofthe wouldremindthereaderofafewwell-knowngeneral
appearanceof the mammary epithelium atall stages points.
ofthe menstrual cycle. First, the comparison of pathologic structures or
The information presented in histology texts cellswiththeirnormalcounterpartsinthesamespec-
servesthebeginningpathologistwell,buttheexperi- imen often makes subtle features, which might first
enced diagnostician requires a more detailed and appearminimalorperhapsevenimaginary,standout
nuanced understanding of the structure of the clearly. Most pathologists find it especially challen-
breast. Features such as the density of the glandular gingtoappreciatetheslightenlargementofcellsand
tissue, the ratio of ducts to lobules, the branching theirnucleiandthechangesinchromatintexturethat
pattern and contour of the ducts, the size and characterize neoplastic cells, but comparing the sus-
shape of lobules, the cellularity of the stroma, the pectcellswithnormalonesusuallymakessuchfind-
nature of the extracellular matrix, and the arrange- ings clearer. The estimations of acinar size, lobular
ment of the components of the gland, among size, and glandular density all become easy if one
others, serve as points of reference for the seasoned follows this approach.
pathologist.Evensubtledisturbancesintheexpected Second,pathologistsmustremainalerttotheillu-
appearance of these attributes often signal the pres- sions created by off-center planes of section and by
ence of an abnormality. For instance, an overly inti- thestructuraldisturbancescausedbypathologicpro-
matepositioningofepithelialcellsandadipocytesor cesses. As the intricately branching glands of the
capillariessometimesindicatesthepresenceofanin- breast curve in and out of the tissue section, they
vasive carcinoma. Columns of malignant cells that can create the impression of epithelial stratification
looklikedistendedductsbutbranchinnonanatomic where none exists. Most pathologists have become
configurations probably represent invasive carci- so familiar with this artifact that they overlook it
noma, and fragmentation of collagen bundles or a without noticing it, but the same phenomenon
disturbance in the pattern of their flow usually complicates the evaluation of the epithelium of
reflects the destructive growth of malignant cells. fibroadenomas and papillomas. Disturbances of the
The discussions of diagnostic problems in the ensu- stromaoftendistortthearchitectureofnearbyglands,
ing pages illustrate many examples of the way in and alterations of glands can entrap stroma in ways
which alterations in the fine points of mammary that mimic the appearances of unrelated lesions.
INTRODUCTION TO THEDIAGNOSIS OF DISEASES OF THEBREAST 3
Theprocessofcollagenousspherulosiscanconverta mammary cells and well-characterized lesions.
lobule to a ductlike structure, and the distention Assuming that all varieties of adenosis contain myo-
of the peripheral acini of a lobule can reconfigure epithelial cells, one would misinterpret the absence
the intralobular stroma so that the focus looks ofthesecellsintheglandsofmicroglandularadeno-
like a papillary tumor growing in a small duct. sis as proof of malignancy. On the other hand, the
Pathologistsmustnotpermittheseillusionstointer- malignant cells of low-grade adenosquamous carci-
ferewith theiranalysis ofthe pathologic changes. nomas typically express proteins present in myoepi-
Third,whenstudyingcytologiccharacteristics,one thelialcells,andignoranceofthischaracteristiccould
must pay particular attention to the attributes of the leadtoanerroneousbenigndiagnosisinsuchacase.
nucleus,becausenoothersubcellularstructureoffers Pathologists may find that the use of panels of
a clearer insight into the nature of the cell. One immunohistochemical stains permits more secure
should make note of the size and shape of the conclusions than staining for a single marker. When
nuclei,theircontours,thetextureandstainingquali- searching for myoepithelial cells, one might use a
ties of their chromatin, the thickness of the nuclear nuclear marker such as p63 protein in parallel with
membranes, and the characteristics of their nucleoli. acytoplasmicmarkerlikemyosinheavychain;simi-
These features vary somewhat from cell to cell, of larly, staining for keratin in conjunction with CD68
course, so one must also study the variation of would allow one to distinguish invasive carcinoma
these properties within the population. Determining cells from histiocytes.
the average size of the nuclei and the range of their Wise pathologists always integrate the results of
shapes elucidates important properties of an epithe- immunohistochemical staining with the features
lialproliferation. observed in the conventional hematoxylin and
Fourth, the appreciation of subtle findings takes eosin(cid:2)stained sections, and the diagnosis suggested
patientstudy.Itsometimesrequirestheexamination bytheformermustsquarewiththeinterpretationof
ofmanycellsbeforeonecanconcludethatthecyto- the latter. Immunohistochemical findings that seem
logic aberrations of a population of epithelial cells topointinunexpecteddirectionsmayrepresentspu-
suffice for the diagnosis of malignancy, and the rious results or yet-undescribed phenomena. When
destructive relationship between the malignant cells the immunohistochemical features do not jibe with
ofaninvasivecarcinomaandtheunderlyingcollagen the conventional ones, this author bases his diagno-
may become evident only after the inspection of sis onthe traditional characteristics.
many clusters. Pathologists should not hesitate to After detecting an abnormality and determining
examine additional sections of a suspicious focus, its characteristics, the pathologist must integrate the
to submit additional tissue for histologic study, or morphologicinformationtoreachadiagnosis.When
to set aside uninterrupted time to study problematic allthefeaturesofacasepointinthesamedirection,
cases. Furthermore, the fresh perspective that comes their interpretation does not cause a problem; how-
from a good night’s sleep often helps clarify ambig- ever, many specimens have inconclusive or conflict-
uouscases. ing findings, which bedevil even the most seasoned
Finally, immunohistochemical staining can pro- observer. Well-considered experience provides the
vide critical information, but one must use this best guide for resolving the ambiguous situations
technique only in well-defined settings and one that so often arise in the practice of mammary
mustinterprettheresultscarefully. Antibodiestocy- pathology. Besides emphasizing the importance of
tokeratin 5/6, for instance, have proved helpful in experience, the author cannot do more than offer a
distinguishing conventional ductal hyperplasia from fewspecificsuggestions.Forexample,oneshouldnot
ductalcarcinomainsitu,butoneshouldrestricttheir expectallregionsofalesiontoillustrateitsdiagnostic
usetofociinwhichthecellsappeartypicalandgrow features equally. Ambiguous findingsin one portion
inmanylayers.Especiallyfloridformsofhyperplasia do not nullify convincing findings present in
composed of large immature cells and flat prolifera- another, and one’s diagnosis must rest on the char-
tions of benign ductal cells both fail to express acteristics of the most distinctive regions of the
the protein. Staining with these antibodies in either lesion. Moreover, cytologic features should probably
situation invites an erroneous interpretation. carry more weight than structural or architectural
Furthermore,pathologistsmustbasetheirinterpreta- ones. As a rule, malignant mammary cells display
tionofimmunohistochemicalstainingonexperience cytologic atypia, and one should usually refrain
rather than on expectation, no matter how well rea- from making the diagnosis of malignancy unless
soned thelatter. one observes these aberrations. Developmental
Before relying on staining results to guide one defects, pathologic processes, and iatrogenic forces
in a difficult case, one must accumulate firsthand can all displace benign epithelial cells into locations
experience with the staining properties of normal usually associated with carcinomas. One must not
4 INTRODUCTION TO THEDIAGNOSIS OF DISEASES OF THEBREAST
allow the unexpected position of these cells to over- represent random alterations of tissue and cellular
ruletheir benign cellularattributes. structure. These features develop because the patho-
Pathologists must also keep their eyes on the logicprocessesthatdefinethelesionsalterthetissue
entire context of the case, including the clinical in specific and characteristic ways. One can use the
details. The diagnosis of a small atypical ductal pro- histologic findings to identify the underlying pro-
liferation in an excision specimen might become cesses, and pathologists who master this ability will
obvious when compared with the remainder of the find that an appreciation of the fundamental nature
atypical population removed in a prior surgical pro- of a lesion usually points to the proper diagnosis
cedure. Marked nuclear enlargement and pleomor- even in the presence of unexpected or conflicting
phism of the type seen in high-grade carcinomas evidence.
would not have the same significance in a patient With these suggestions in mind, pathologists
whohadundergoneirradiation.Finally,pathologists shouldfeelwellpreparedtotacklethecommondiag-
learn a great deal from consultations with their col- nostic problems of mammarypathology.
leagues and discussions of difficult cases. Although
pathologists base their diagnoses on more or less
Selected Readings
standardized criteria, they weight these observations
differentlyandincorporatemanyotherfinepointsof Mills SE: Sternberg’s Histology for Pathologists, 3rd ed.
morphologyderivedfromtheirownexperiencesinto Philadelphia,LippincottWilliams&Wilkins,2006.
theiranalysis.Thuscomparingthoughtprocessesand Potten CS, Watson RJ, Williams GT, et al: The effect of
sharingpersonal wisdom aboutdiagnostic problems age and menstrual cycle upon proliferative activity
willdo more toenhance apathologist’s understand- of the normal human breast. Br J Cancer 1988;58:
ing of mammary pathology than any other single 163-170.
RussoJ,RiveraR,RussoIH:Influenceofageandparity
educational endeavor.
on the development of the human breast. Breast
Asafinalpoint,theauthorwouldremindpathol-
CancerResTreat1992;23:211-218.
ogists that the histologic attributes of lesions do not
Part
I
EPITHELIAL
PROLIFERATIONS
Chapter2 CONCEPTS BASIC TO THEANALYSISOF EPITHELIAL PROLIFERATIONS 7
Cellular Proliferation 7
Intercellular Cohesion 8
Cellular Polarization 10
Cytologic Atypia 10
Architectural Atypia 12
Chapter3 CONVENTIONAL DUCTAL PROLIFERATIONS 15
Definitions and ClinicopathologicCharacteristics 15
Usual Ductal Hyperplasia 15
Ductal Carcinoma InSitu 15
Relationship between DuctalHyperplasia andDuctalCarcinoma InSitu 15
Histologic Characteristics 16
Usual Ductal Hyperplasia 16
Low-Grade DuctalCarcinoma InSitu 26
High-Grade DuctalCarcinoma InSitu 33
Intermediate-Grade DuctalCarcinoma InSitu 33
Atypical Ductal Hyperplasia 33
Flat Epithelial Atypia 36
Immunohistochemical Characteristics ofDuctal Proliferations 45
Approach to theDiagnosis ofConventionalDuctal Proliferations 45
Problems inthe DiagnosisofConventional DuctalHyperplasia 46
Ductal Hyperplasia withHyperchromatic Nuclei 47
Ductal Hyperplasia inPerimenopausal Women 47
Immature Hyperplasia 49
Unusual Forms ofCytologic Atypia 54
Atypia in theAdolescent 60
Problems inthe DiagnosisofDuctalCarcinoma InSitu 61
Distinction ofIntermediate-Grade DuctalCarcinoma InSitufromConventional
DuctalHyperplasia 61
Dimorphic DuctalCarcinoma 62
Clinging Carcinoma 63
Recognition of StromalInvasion 67
DistinctionbetweenDuctalCarcinomaInSituandCarcinomainLymphaticVessels 75
Interpretation ofImmunohistochemical Stains forMyoepithelial Cells 77
Recognition of DuctalCarcinoma InSituinthe Irradiated Breast 79
Ductal Carcinoma InSituinGynecomastia 81