Part 1 book “Breast cancer - Diagnostic imaging and therapeutic guidance” has contents: Development, anatomy, and physiology of the mammary gland, tumor formation, pathology of benign and malignant changes in the breast, nonimaging diagnostics, mammography,.. and other contents.
Trang 5Breast Cancer: Diagnostic Imaging and Therapeutic Guidance
Trang 6is available from the publisher.
This book is an authorized translation of the first German edition
published and copyrighted 2014 by Georg Thieme Verlag, Stuttgart Title
of the German edition: Diagnostik und Therapie des Mammakarzinoms
Translators: Elizabeth Crawford, Göttingen, Germany; Alan Wiser,
Ambler, PA, USA
Illustrator: Barbara Gay, Bremen, Germany
© 2018 Georg Thieme Verlag KG
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Trang 7Part 1: Anatomy, Physiology, and Pathology of the Breast
1 Development, Anatomy, and Physiology of the Mammary Gland 2
F Baum 1.1 Development 2
1.2 Anatomy 2
1.3 Physiology 2
Bibliography 3
2 Tumor Formation 4
F Baum 2.1 Mutation, Carcinogenesis, and Angiogenesis 4
2.2 Risk Factors 4
2.3 Genetic Risk Factors 5
2.4 Prevention 6
2.4.1 Primary Prevention 6
2.4.2 Secondary Prevention 6
2.4.3 Tertiary Prevention 6
2.5 Epidemiology, Incidence, and Mortality 6
Bibliography 7
3 Pathology of Benign and Malignant Changes in the Breast 9
J Rueschoff 3.1 Benign Changes 9
3.1.1 Histological Principles 9
3.1.2 Nonneoplastic, Nonproliferative Diseases of the Breast 9
3.1.3 Benign Tumor-Forming Diseases 11
3.2 Malignant Changes in the Breast 19
3.2.1 Classification of Malignant Breast Tumors (WHO Classification, B-Categories) 19
3.2.2 Prognostic and Predictive Factors 20
3.2.3 Papillary Lesions 24
3.2.4 Ductal Carcinoma In Situ 25
3.2.5 Microinvasive and Invasive Breast Carcinoma 26
3.2.6 Tumors of the Nipple 29
3.2.7 Malignant Mesenchymal Tumors and Lymphomas of the Breast 29
3.2.8 Metastatic Tumors 30
3.3 Acknowledgments 31
Bibliography 31
Part 2: Breast Diagnostics 4 Nonimaging Diagnostics 34
U Fischer 4.1 History 34
4.2 Informed Consent 34
4.3 Self-Examination 34
4.4 Inspection 34
4.5 Palpation 35
Bibliography 40
5 Mammography 41
U Fischer 5.1 Technique and Methods 41
5.1.1 Principles of X-ray Mammography 41
5.1.2 Components of a Mammography System 41
5.1.3 Exposure Parameters 43
5.1.4 Image Quality 43
5.1.5 Analog Mammography 44
5.1.6 Digital Mammography 45
5.1.7 Radiation Exposure 54
Trang 85.2 Parameters and Positioning 55
5.2.1 Standard Projections 55
5.2.2 Supplementary Views 57
5.2.3 Galactography 58
5.2.4 Mammography of the Male Breast 61
5.2.5 Quality Assurance in Parameters and Positioning 61 5.3 Interpretation of Mammograms 62
5.3.1 Terminology 62
5.3.2 Tissue Density in a Mammogram According to the ACR BI-RADS Atlas 63
5.3.3 Interpretation Criteria 64
5.3.4 BI-RADS Classification of Mammography 68
5.3.5 Normal Findings in the Mammogram 74
Bibliography 74
6 Breast Ultrasonography 77
S Luftner-Nagel 6.1 Technique and Methods 77
6.1.1 Basic Principles 77
6.1.2 Device Adjustments 79
6.1.3 Examination Technique 79
6.1.4 Ultrasound Techniques 81
6.1.5 Quality Assurance 84
6.2 Evaluation 84
6.2.1 Terminology 84
6.2.2 Tissue Type in Sonography 84
6.2.3 Evaluation Criteria 85
6.2.4 BI-RADS Classification of Breast Ultrasonography 89 6.2.5 Normal Findings in Sonography 92
Bibliography 93
7 Magnetic Resonance Imaging of the Breast 94
U Fischer 7.1 Technique and Methods 94
7.1.1 Basic Principles 94
7.1.2 Tumor Detection 95
7.1.3 Equipment 95
7.1.4 Timing of the Examination 95
7.1.5 Patient Positioning 96
7.1.6 Measurement Parameters 96
7.1.7 Image Postprocessing 97
7.1.8 Implant Evaluation 99
7.1.9 Nonestablished Examination Techniques 100
7.2 Evaluation 101
7.2.1 Terminology 101
7.2.2 Perfusion Pattern 101
7.2.3 Findings in the T1-Weighted Precontrast Image 101
7.2.4 Findings in the T2-Weighted Image 102
7.2.5 Findings in the T1-Weighted Contrast-Enhanced Image 102
7.2.6 Evaluation Criteria 103
7.2.7 BI-RADS Classification of MRI of the Breast 104
7.2.8 Normal Findings in MRI of the Breast 107
Bibliography 107
8 Imaging of Breast Lesions 110
U Fischer and S Luftner-Nagel 8.1 Benign Findings 110
8.1.1 Cysts 110
8.1.2 Inflamed Cysts 110
8.1.3 Complex Cysts 111
8.1.4 Myxoid Fibroadenoma 112
8.1.5 Fibrotic Fibroadenoma 114
8.1.6 Adenoma 116
8.1.7 Hamartoma 116
8.1.8 Lipoma 117
8.1.9 Mammary Fibrosis 119
8.1.10 Adenosis of the Breast 120
8.1.11 Fibrocystic Condition of the Breast 121
8.1.12 Adenomyoepithelioma 122
8.1.13 Acute Nonpuerperal Mastitis 124
8.1.14 Chronic Nonpuerperal Mastitis 125
8.1.15 Intramammary Lymph Nodes 125
8.1.16 Pseudoangiomatous Stromal Hyperplasia 126
8.1.17 Seroma 128
8.1.18 Hematoma 129
8.1.19 Fat Necrosis (Oil Cyst) 130
8.1.20 Abscess 131
8.1.21 Postoperative Scars 132
8.2 Findings with Ambiguous Biological Potential 133
8.2.1 Papillomas 133
8.2.2 Radial Scars 135
8.2.3 Atypical Ductal Hyperplasia 135
8.2.4 Phyllodes Tumors 136
8.2.5 Cysts with Intracystic Proliferation 138
8.2.6 Lobular Intraepithelial Neoplasia 139
8.3 Intraductal Carcinoma 141
8.3.1 Ductal Carcinoma In Situ (Low Grade) 141
Trang 98.3.2 Ductal Carcinoma In Situ (Intermediate Type) 141
8.3.3 Ductal Carcinoma In Situ (High Grade) 141
8.4 Invasive Tumors 143
8.4.1 Invasive Ductal Carcinoma 143
8.4.2 Invasive Lobular Carcinoma 145
8.4.3 Tubular Carcinoma 147
8.4.4 Medullary Carcinoma 147
8.4.5 Mucinous Carcinoma 148
8.4.6 Invasive Papillary Carcinoma 150
8.4.7 Sarcomas 152
8.4.8 Triple-Negative Carcinoma 152
8.4.9 Paget’s Disease of the Nipple 152
8.4.10 Inflammatory Carcinoma 154
8.4.11 Systemic Diseases Involving the Breast 155
9 Breast Intervention 158
F Baum 9.1 Biopsy 158
9.1.1 Objective of Percutaneous Tissue Sampling 158
9.1.2 Percutaneous Tissue Sampling Equipment and Implementation 158
9.1.3 Interventional Imaging 161
9.1.4 Classification of Findings 164
9.1.5 Tumor Seeding and Mechanical Tumor Induction 166
9.1.6 Quality Assurance 166
9.2 Localization 166
9.2.1 Objective of Pretherapeutic Localization 166
9.2.2 Equipment and Implementation 170
9.2.3 Quality Assurance 172
Bibliography 173
Part 3: Prevention and Therapy of Breast Cancer 10 Examination Concepts 176
U Fischer 10.1 Prevention 176
10.2 Early Breast Cancer Detection (Secondary Prevention) 176
10.2.1 Mammography Screening 177
10.2.2 Individualized Examination Concepts 180
10.2.3 Early Detection in Women with a High-Risk Profile 181 10.2.4 Future Concepts of Early Breast Cancer Detection 182 10.3 Diagnostic Work-up 183
10.4 Pretherapeutic Local Staging 183
10.5 Pretherapeutic Peripheral Staging 184
10.6 Follow-up Care 184
10.7 Implant Evaluation 185
10.8 Evaluation of the Male Breast 185
Bibliography 185
11 Surgical Treatment of Breast Carcinoma 187
T Kuehn 11.1 Significance of Surgery in the Context of Multimodal Treatment of Breast Carcinoma 187
11.2 Types of Breast Carcinoma 187
11.2.1 Lesions of Uncertain Biological Potential (B3 Lesions) 187
11.2.2 Preinvasive Carcinoma (Ductal Carcinoma in Situ; B5a) 187
11.2.3 Invasive Carcinoma (B5b) 187
11.3 Surgical Treatment of the Primary Lesion 189
11.3.1 Oncologic Aspects 189
11.3.2 Technical Aspects 189
11.4 Lymph Node Surgery 192
11.4.1 Procedure for Clinically Negative Node Status 195
11.4.2 Procedure for Clinically Positive Nodal Status 195
11.4.3 Procedure for Clinically Negative Node Status and Positive Sentinel Node 195
11.5 Secondary Breast Reconstruction 196
11.5.1 Timing the Reconstruction: Primary vs Secondary Reconstruction 196
11.5.2 Alloplastic Reconstruction (Implant Reconstruction) 197
11.5.3 Autologous Reconstruction (Reconstruction Using Endogenous Tissue) 197
11.5.4 Nipple Reconstruction 199
Bibliography 200
Contents
Trang 1012 Medical Treatment of Breast Cancer 201
M Hellriegel and G Emons 12.1 Basic Principles and Objectives 201
12.2 Adjuvant Drug Therapy 201
12.2.1 Adjuvant Chemotherapy 201
12.2.2 Neoadjuvant Therapy 202
12.2.3 Adjuvant Endocrine Therapy 204
12.2.4 Antibody Therapy 207
12.3 Medical Treatment in Locoregional Recurrence 207
12.4 Medical Treatment of Distant Metastases 208
12.4.1 Endocrine Therapy in Premenopausal Patients with Distant Metastases 208
12.4.2 Endocrine Therapy in Postmenopausal Patients with Distant Metastases 208
12.5 Endocrine Maintenance Therapy after Completing Chemotherapy 209
12.6 Chemotherapy of Metastatic Breast Cancer Combined with New Agents 209
Bibliography 210
13 Radiotherapy of Breast Cancer 212
C F Hess 13.1 Adjuvant Radiotherapy after Breast-Conserving Surgery 212
13.2 Adjuvant Radiotherapy after Mastectomy 212
13.3 Effectiveness of Adjuvant Radiation Therapy: Prognostic Factors 213
13.4 Integration of Adjuvant Radiotherapy into the Multimodal Treatment Concept 213
13.5 Target Volume and Dose Concept 213
13.5.1 Clinical Target Volume: Former Tumor Region, Mammary Gland, Chest Wall, and Regional Lymph Channels 214
13.5.2 Partial Breast Irradiation 215
13.5.3 Shortened Treatment Time: Alternative Fractionation Schemes 215
13.6 Acute Side Effects and Complications of Adjuvant Radiation Therapy 216
13.6.1 Acute Side Effects 216
13.6.2 Late Complications of Radiation Therapy 216
13.7 Planning and Implementing Radiation Therapy 217
13.8 Radiotherapy in Primarily Inoperable Tumors, Recurrences, and Metastatic Disease 218
13.9 Summary 218
Bibliography 218
14 Management of a Diagnostic Breast Center 220
F Baum 14.1 Expertise 220
14.2 Equipment 220
14.3 Facility Design 221
14.3.1 Doctor’s Consultation Room 221
14.3.2 Mammography and Sonography Rooms 221
14.3.3 Breast MRI Room 222
14.3.4 Rooms for a Second Ultrasound Unit and for Interventional Procedures 222
14.3.5 Recovery Room 223
14.4 Ambiance 223
14.5 Communication 223
15 Logistics in an Interdisciplinary Breast Center 225
G Emons 15.1 Background 225
15.2 Structure of a Certified Breast Center 225
15.3 Treatment Pathways in a Breast Center 225
15.4 Outlook 225
Bibliography 227
16 Counseling Techniques and Psychosocial Support 228
H Lorch, A Kuechemann, and J Rueschoff 16.1 Compliance 228 16.1.1 Quality of the Medical Services 228
Trang 1116.1.2 General and Personal Requirements 228
16.1.3 Structural, Organizational, and Procedural Components 228
16.1.4 Interactive and Communicative Competence 228
16.2 Communication 228
16.2.1 General Principles of Communication 229
16.2.2 Communication: Dealing with the Patient 229
16.2.3 Communicating Results to the Patient 230
16.3 The Patient’s Flow through the Department 230
16.3.1 Station 1: Registration 230
16.3.2 Station 2: History and Physical Examination 231
16.3.3 Station 3: The Diagnostic Procedure 232
16.3.4 Station 4: Communication of Results and Concluding Consultation 235
16.4 Summary 235
Bibliography 235
Index 237
Contents
Trang 12Carcinoma in the female breast is a frequent finding in routine
patient care, as it is the most common form of cancer in women
Breast cancer is a complex illness Physicians of various specialties
(e.g., radiology, gynecology, surgery, oncology) are involved with
its many different aspects and our knowledge of the disease is
presently growing at an incredible rate
Advances made in recent years in the diagnosis and therapy of
breast cancer pertain in large part to the study of etiological
factors that increase the likelihood of developing the disease
Most of what we know about inherited breast cancer risk, for
example, is based on research done in the past 10 to 15 years
There is no end in sight to the knowledge that can be gained
concerning the genetic predisposition to diseases Revolutionary
progress has also been made recently in the field of diagnostic
imaging Digital mammography and modified mammographic
techniques, improvements and innovations in ultrasound
diag-nostics, and, in particular, developments in breast MRI enabling
the acquisition of high-resolution images have broadened the
spectrum of available imaging procedures and dramatically
improved the accuracy of breast cancer diagnosis In addition to
individualized and risk-adapted early diagnosis concepts,
nation-wide, population-based early diagnosis programs have been
introduced Moreover, there are now image-guided techniques
available for all imaging modalities that enable the performance
of reliable, low-risk, outpatient biopsies This has sharply reduced
the rate of unnecessary operations undertaken for diagnostic
excision In the field of surgery, too, there have been numerous
changes and improvements One of the greatest new advances in
recent years has been the introduction of the sentinel lymph
node biopsy technique, which spares many patients the burden of
an unnecessary extensive lymphadenectomy, with its potential
for complications In addition, an increased range of
breast-conserving operations and improved plastic-reconstructive
sur-gical techniques are available to today’s patients
As might be expected, the approaches used in adjuvant
medication and radiation therapy for treatment of breast cancer
have changed and developed as well The continual integration of
new research and study results effects a constant modification
and optimization of the relevant treatment concepts
Conse-quently, it becomes more difficult all the time for practitioners
who are not directly involved in the diagnostics or treatment of
breast diseases to keep up with the latest information on the
topic of breast cancer
Our aim in publishing this book is to create a reference work
for physicians who are not directly involved with breast health, as
well as for interested specialists and students It gives a
comprehensive overview of the most important aspects of breast
cancer diagnosis and therapy, so that any unfamiliar aspects or
terms can be looked up easily and understood rapidly Theemphasis here is on a succinct presentation of the facts,guidelines, and recommendations as we know them today.Because guidelines and recommendations vary betweendifferent countries and continents, the authors have agreed inthis book to present European—i.e., German—recommendations
as appropriate In general, we have deliberately chosen not toprovide lengthy explications of background information
In preparing the chapters on diagnostics and therapy of breastcancer, we were particularly pleased to have the privilege ofworking with Professor Clemens F Hess, radiotherapist andradiation oncologist; Professor Guenther Emons and his leadingsenior physician, Dr Martin Hellriegel, gynecologist and gyneco-logical oncologist; Dr K P Hermann, physicist specializing inmammography; and all of the participating staff at the Women’sHealth Care Center in Göttingen, to create what is in essence a
“Göttingen Breast Book.” This is significant because Göttingen’sown university medical center has for decades now made thediagnosis and treatment of breast cancer a high priority in bothresearch and patient care
Our particular thanks also go out to the“external” colleagueswho worked with professionalism and passionate commitment tohelp make this book a success First of all there is Dr Heike Lorch,who, together with Ms Jutta Rueschof and Ms Anke Kuechemann,did such excellent work in preparing the chapter on counselingtechniques and psychosocial guidance for women with breastcancer Their wealth of experience and empathy shine throughunmistakably Furthermore, we extend our heartfelt thanks toProfessor Thorsten Kuehn, who unfortunately no longer works inthe vicinity of Göttingen His extensive experience and pragmaticapproach to breast surgery have given this book—like our previousbook on breast intervention—a special additional value We alsowish to thank Professor Josef Rueschof most heartily for bringingstructure and a clear overview, in his inimitable style, to thehistopathological intricacies and details of breast pathology.His manner of combining text and images makes it possible forthe reader to quickly grasp the morphological aspects of breastdisease In conclusion, a word to our own department: We havethoroughly enjoyed writing another book with you, Susi (a.k.a Dr.Luftner-Nagel); discussing, critiquing, and modifying the contents,and ultimately agreeing on the final version Thank you so much
We hope our readers enjoy this“breast book,” and wish themevery success in the rapid clarification of questions on the topic ofthe breast
Prof Uwe Fischer, MDFriedemann Baum, MD
Trang 13Certified Breast Center of the
University of Medicine Göttingen
Department of Obstetrics and Gynecology
Certified Breast Center of the
University of Medicine Göttingen
Department of Obstetrics and Gynecology
Göttingen, Germany
Clemens-Friedrich Hess, MD, PhD
Professor
Certified Breast Center of the
University of Medicine Göttingen
Department of Radiation Therapy and Radiation Oncology
Göttingen, Germany
Anke Kuechemann, MAWomen’s Health Care CenterGöttingen, Germany
Thorsten Kuehn, MDProfessor
Esslingen HospitalDepartment of Obstetrics and GynecologyEsslingen, Germany
Heike Lorch, MD, MAAssociate ProfessorAschaffenburg, Germany
Susanne Luftner-Nagel, MDWomen’s Health Care CenterGöttingen, Germany
Jutta RueschoffWomen’s Health Care CenterGöttingen, Germany
Josef Rueschoff, MDProfessor
Nordhessen PathologyKassel, Germany
Contributors
Trang 14ABVS automated breast volume scanner
ACR American College of Radiology
ADH atypical ductal hyperplasia
AFIP Armed Forces Institute of Pathology
AGD average glandular dose
AGO Arbeitsgemeinschaft für gynäkologische
Onkologie (Working Group forGynecological Oncology)ALD axillary lymph node dissection
AJCC American Joint Committee on Cancer
ALH atypical lobular hyperplasia
ARNO 95 Arimidex-Nolvadex 95
ATAC study Anastrozole, Tamoxifen Alone or in
CombinationBCT breast-conserving therapy,
breast-conserving surgeryBIG Breast International Group
BI-RADS breast imaging reporting and data system
BRCA genes breast cancer genes
BSA body surface area
BW body weight
BZG Diagnostisches Brustzentrum Göttingen
(Women's Health Care Center Göttingen)CAD computer-aided diagnostic system;
computer-assisted detection;
computer-aided diagnosticsCCC comprehensive cancer center
CCD detector charge-coupled device detector
CC projection craniocaudal projection
CT computerized tomography, ~ tomogram
CTV clinical target volume
DBT breast tomosynthesis
DCIS ductal carcinoma in situ
DEGUM Deutsche Gesellschaft für Ultraschall in der
Medizin (German Society for Ultrasound inMedicine)
DGS Deutsche Gesellschaft für Senologie
(German Society of Senology)DIEP flap deep inferior epigastric perforator flap
DIN ductal intraepithelial neoplasia
DIN Deutsches Institut für Normung (German
Institute for Standardization)DKG Deutsche Krebsgesellschaft (German Cancer
Society)DNA deoxyribonucleic acid
EBCTCG Early Breast Cancer Trialists' Collaborative
GroupeDQE effective detective quantum efficiency
EIC extensive intraductal components
EMA epithelial membrane antigen
EORTC European Organization for the Research and
HER human epidermal growth factor receptorHPF high power field: field of vision on
enlargementHRT hormone replacement theapryIBCSG International Breast Cancer Study Group
IC infraclavicularIDC invasive ductal carcinomaIGAP flap inferior gluteal artery perforator flapILC invasive lobular carcinoma
IPC invasive papillary carcinoma
IR inversion recoveryISO International Organization for
StandardizationKi-67 proliferation indexLCIS lobular carcinoma in situ
LH luteinizing hormoneLIN lobular intraepithelial neoplasia
LM projection lateromedial projection with medially
applied detectorLVEF left ventricular ejection fractionMLO projection mediolateral oblique projection
ML projection mediolateral projection with laterally
applied detectorMRM modified radical mastectomyMRM density magnetic resonance mammographic
densityMRI magnetic resonance imagingMRS magnetic resonance spectroscopyMQRA Mammography Quality Standards
Reauthorization ActmTOR kinase Mammalian target of rapamycin kinaseNHSBSP National Health Service Breast Screening
ProgramNOS not otherwise specifiedNSABP National Surgical Adjuvant Breast and Bowel
ProjectNST no special typePAS publicly available specificationPAS stain periodic acid–Schiff stainPASH pseudoangiomatous stromal hyperplasiapCR pathologically confirmed complete
remissionpathological complete remissionpathological complete responsePGMI quality rating perfect/good/moderate/inadequate
(mammogram quality scoring system)PgR progesterone receptor
PIC predominant intraductal componentsPTV planning target volume
ROI region of interest
SC supraclavicular
Trang 15SE spin echo
SERM selective estrogen receptor modulator
SGAP flap superior gluteal artery perforator flap
SIC small intraductal components
SISH silver in-situ hybridization
SLN sentinel lymph node
SLNB sentinel lymph node biopsy
SMA smooth-muscle actin
T1W T1-weighted
T2W T2-weighted
TDLU terminal duct lobular unit
TE echo time
TGC time gain compensation
TIC time–signal intensity curve
TR repetition time
TRAM flap transverse rectus
abdominis-musculocutaneus flapTSE turbo spin echo
UDH usual ductal hyperplasia
UICC Union for International Cancer Control/
Union internationale contre le cancerVEGF vascular endothelial growth factor
WHO World Health Organization
Abbreviations
Trang 17Part 1
Anatomy, Physiology, and
Pathology of the Breast
Trang 181 Development, Anatomy, and Physiology of the Mammary Gland
F Baum
1.1 Development
Mammals (from the Latin Mammalia) are named for the fact that
they feed their young on milk produced in the mammary gland
The various species of mammals have developed different numbers
of mammary glands along the genetically determined milk line
Mammalian breasts generally occur in pairs, as is the case in
humans Normally, humans have one breast on each side of the
chest At the prepubescent stage, both girls and boys have
mam-mary buds With the onset of puberty, the production of estrogen
increases in the female body, causing changes in the mammary
gland: the breast buds enlarge and the breast exhibits an
increased build-up of adipose tissue Milk is secreted in the
mam-mary gland even when there is no pregnancy, but the volume of
this basic secretion varies widely from one individual to the next,
and often goes unnoticed
1.2 Anatomy
The network of lactiferous ducts resembles a coral bush
(▶Fig 1.1) From the point of exit at the nipple (mammilla), the
milk ducts branch out within the breast, with a smaller duct
diameter after each divergence At the periphery, the smallest
milk ducts originate from the lobules of the gland, where the milk
is secreted Some 30 of these milk ducts, leading from all four
quadrants of the breast, open out into the mammilla and thus
form the functional unit of the mammary gland
The lobules are embedded in a network of connective tissue
that permeates the breast, extending outward in an arc from
somewhere in the deep fascia Known as Cooper’s ligaments, thistissue helps to provide structural integrity, supporting bothlobules and adipose tissue The ratio of fat to glandular tissue inthe human breast varies widely between individuals, from almost100% fat to almost 100% glandular tissue In mammography, this
is referred to as a lipomatous or an extremely dense parenchymaltype, respectively
In addition to the secretory unit, made up of lobules and milkducts, the mammary gland also contains lymph nodes that pro-tect the body from bacterial incursion Bacteria can enter throughthe milk duct openings at the nipple The lymph nodes are com-monly located in the upper outer quadrants, but have also beendetected in the other three quadrants Lymph flow is chieflytoward the underarm (axilla), first to the sentinel lymph nodeand from there to the other axillary lymph nodes Only a verysmall portion enters the thoracic cavity via the parasternal lymphnodes The arterial blood supply to the breast is carried mainly bythe medial mammary branches of the internal thoracic artery(ca 60%) and by the lateral mammary branches of the lateralthoracic artery (ca 30%) Venous drainage is through the corre-sponding veins
1.3 Physiology
The physiology of the mammary gland is controlled entirely byhormones Metabolic activity in the mammary gland varies underthe influence of estrogen Even in childhood, hormonal fluctua-tions can occasionally cause swelling of the mammary bud Butthis is usually a temporary phenomenon that reverts within ashort time
From the onset of menses, or menarche, many women observechanges in the mammary gland that recur every month Follow-ing ovulation and approximately one week prior to menstruation,there is sometimes tenderness or a painful sensation of pressure
in the breast, in some cases accompanied by swelling These nomena are triggered by the temporary gestagen production inthe fallopian tubes, which usually abates when menstruationbegins
phe-When pregnancy occurs and the fertilized egg implants in theuterine wall, the placenta begins producing chorionic gonadotro-pin This stimulates the corpus luteum, which in turn triggerscontinuous secretion of progesterone, essential for maintainingthe placenta in the uterus The continuing production of proges-terone during pregnancy also triggers further differentiation
in the mammary gland and considerable growth of the secreting lobules The stimulation due to sucking, in the nursingphase, increases the secretion of the hormones prolactin andoxytocin by the pituitary gland It is the interaction of these hor-mones which triggers the production of milk in the mammarygland, or lactation
milk-The effects of progesterone and prolactin on the mammarygland are reversible: the breast returns to its inactive state oncebreast feeding has ended After weaning, the stimulation of the
Fig 1.1 The course of a milk duct A mammary duct divides
numerous times from the nipple The smallest milk ducts originate
from the lobules of the gland at the periphery and the milk is
conducted from many lobules to the mammilla
1
Trang 19mammary gland by prolactin and oxytocin is reduced, causing
the gland lobules to become smaller and fewer The changes in
the breast that occurred with lactation are thus completely
undone
In menopause, the hormonal stimulation of the glandular
tis-sue decreases considerably Normally, there is also a reduction of
glandular tissue in this phase, which increases the transparency
of the mammary gland in mammography
Bibliography
[1] Kaufmann M, Costa SD, Scharl A Die Gynäkologie 3 Aufl Berlin: Springer;
2012 [2] Keidel WD Kurzgefasstes Lehrbuch der Physiologie 2 Aufl Stuttgart: Thieme;
1970 [3] Netter FH Atlas der Anatomie des Menschen 3 Aufl Stuttgart: Thieme; 2003
1.3 Physiology
1
Trang 202 Tumor Formation
F Baum
2.1 Mutation, Carcinogenesis, and
Angiogenesis
Life on earth is based on genes that are passed on from one
gene-ration to the next Genetic material is transmitted in the form of
nucleic acids (DNA) contained within the chromosome, which is
in the nucleus of the cell Each time a cell divides, it creates a
complete copy of itself Any errors that occur while the genetic
information is being replicated are termed mutations
Consider-ing the extensive amount of data contained within DNA, such
errors are unavoidable For the most part, these small mutations
have no physiologically significant effect, but in some cases the
resulting change is incompatible with the cell’s life processes In
very rare cases, the mutation actually increases the new cell’s
chances of survival over those of the original cell Throughout
many millions of years and countless generations, this process
has cumulatively led to a huge diversity of species
Seen over the course of generations, mutation is what drives
evolution—but in an individual it can endanger health and even
life A genetic mutation that changes the physiological properties
of an organism may have any of a number of effects If the
modi-fied cell continues to“play by the rules” of the organism then the
mutation generally presents no danger
If a cell loses its characteristic property of living within a
com-munity of cells, however, then it has become what we call a
can-cer cell Generally, a series of six to eight mutations is required
before this point is reached Specifically, cancer cells lack the
property of“contact inhibition,” the trait that inhibits cell
migra-tion into other cells and organs (▶Fig 2.1) In a manner of
speak-ing, contact inhibition is what regulates the different “territories”
in multicellular organisms It prevents cells from spreading into
organs in which they do not belong
The loss of contact inhibition makes it possible for a cancer cell
to infiltrate foreign tissue This process is aided by certainenzymes that dissolve connective tissue and other structures.Furthermore, cancer cells can leave their point of origin and movevia lymph vessels and blood vessels These processes are termedlymphatic spread and hematogenous spread, respectively, andcan lead to the formation of metastases
Cancer cells are characterized by an accelerated metabolismand an exceedingly rapid cell cycle They thus have particularlyhigh nutritional requirements To meet their extensive needs,these cells secrete enzymes that stimulate the surrounding tissue
to rapidly form a system of capillaries, a process termed genesis or tumor angiogenesis These new capillaries are mor-phologically simple endothelial tubes that lack the complexstructure of normal blood vessels but suffice to enable the devel-opment of carcinoma cells and to supply them This capillary net-work drains energy and nutrients from the surrounding organs,and consequently from the overall organism Sometimes, how-ever, cancer cells grow so rapidly that even the dedicated bloodsupply cannot feed all parts of the tumor, and cancer cells begin
angio-to die, usually in the center of the tumor
2.2 Risk Factors
The probability that a woman will develop breast cancer at somepoint in her life depends on a number of different factors(▶Table 2.1,▶Table 2.2) Oncogenes and tumor suppressor genesplay an important role in the regulation of healthy cell growthand tumor development Oncogenes accelerate cell growth, whiletumor suppressor genes slow it down
On average, a woman in Europe has an 11% chance of oping breast cancer In industrialized countries, the incidence
Fig 2.1 Tumor development (a) A mutated cell clone (gray) has evolved within a milk duct from the epithelium (white) (b) Over time, a second(green) and a third (orange) mutation occur (c) Further mutations in the course of time; e.g., up to a sixth mutation (red) (d) This cell clone has lostits contact inhibition and thus supplants the surrounding cells (e) With further time, the cell clone has penetrated the boundaries of anatomicalstructures: it has become an invasive tumor
Table 2.1 Absolute breast cancer risk by age (from Royal New Zealand College of General Practitioners [RNZCGP] Early detection of breast cancer
1999 Wellington, New Zealand: RNZCGP;1999:1–61)
Risk of disease Age group (years)
Absolute 5-year risk (%) < 0.5 0.5–1 1–1.5 1.5–2
2
Trang 21of breast cancer is rising and the average age of initial illness
is dropping In Asia and Africa, this risk is significantly lower,
which suggests that certain lifestyle factors may play a
signif-icant role In those parts of China, for example, where
West-ern standards of living have been introduced, the incidence
of breast cancer is increasing accordingly One possible
explanation for this is the decreased bodily production of
melatonin as a result of the use of artificial light, which
shortens the night phase This results in an increased risk of
breast cancer A lower risk of breast cancer is seen among
women who have late menarche or early menopause, and
among those who bear and breast-feed children The risk is
increased, on the other hand, by such factors as obesity,
alco-hol consumption, and lack of physical exercise Female
hor-mone replacement therapy—in particular if hormones are
taken for long periods—increases the risk of breast cancer
1.5-to 3-fold
Take Home Points
●Age and breast cancer risk: The most important
population-based risk factor for breast cancer is increasing age
●Mammographic density and breast cancer risk: A high
mam-mographic density (ACR III or IV) is one of the greatest
individ-ual risk factors
2.3 Genetic Risk Factors
In addition to lifestyle-related factors, genetic factors can also
affect a woman’s risk of breast cancer In families with a high
incidence of breast cancer, an individual’s lifetime risk of ing breast cancer can be as high as 80% In these families there isalso an increased incidence of ovarian carcinoma
develop-The high incidence of these cancers in high-risk families is due todefects in repair enzymes, which play an important role in cell divi-sion in both organs These enzymes are proteins that check andcorrect the double-stranded DNA during the cell division process,normally reducing the number of mutations If the genes codingfor these repair enzymes are altered, then these enzymes can loseeither the ability to detect replication errors or the ability to correctdetected replication errors These defective enzyme genes are calledbreast cancer (or BRCA) genes (▶Table 2.3) Other genes associatedwith breast/ovarian cancer are RAD51C and RAD51D It has alsolong been known that persons who have ataxia telangiectasia or
Li–Fraumeni syndrome have a higher risk of breast cancer
BRCA mutations are inherited in an autosomal dominant itance pattern: they can be inherited from father or mother Ifone parent carries this mutated gene, each child has a 50% chance
inher-of inheriting it
Note
It can be assumed that some 5 to 10% of all women who havebreast carcinoma have an autosomal dominant geneticpredisposition
The presence of an autosomal dominant inheritable germlinemutation with a probability of more than 10% may be assumed ifone of the following constellations exists within the family:
●At least three women with breast cancer, regardless of age
●At least two women with breast cancer, one of them before age
50 years
●At least two women with ovarian cancer
●At least one woman with breast cancer and one woman withovarian cancer
●At least one woman with both breast cancer and ovarian cancer
●At least one woman with breast cancer diagnosed before age 36years
●At least one woman with bilateral breast cancer diagnosedbefore age 51 years
●At least one man with breast cancer and one woman withbreast or ovarian cancer
Some cancer societies see a high-risk constellation in families inwhich women develop breast or ovarian cancer at an early age:
●Two women with breast and/or ovarian cancer diagnosedbefore age 50 years
Table 2.2 Relevant risk factors for developing breast cancer, in
descending order of significance (from Deutsche Gesellschaft für
Senologie e.V., Deutsche Krebshilfe e.V S3-Leitlinie
“Brustkrebs-Früherkennung in Deutschland” 1 Aktualisierung München:
Type ACR IV tissue density 3.8–5.2
Status post surgery for contralateral carcinoma:
●Age < 45 years 5.0–9.0
●Age 45–59 years 3.7–4.1
●Age≥ 60 years 1.8–3.0
Status post surgery for DCIS (premenopause) 5
Status post surgery for ADH 2.0–4.0
Menarche at age < 11 years 3
Menopause at age > 54 years 2
Abbreviations: ACR, American College of Radiology; ADH, atypical
ductal hyperplasia; DCIS, ductal carcinoma in situ
Table 2.3 High-risk genes with known germline mutations and ated lifetime risk of breast or ovarian carcinoma
associ-Gene Percent lifetime risk of
Breast carcinoma Ovarian carcinomaBRCA1 (detectable) 80 45
BRCA2 (detectable) 80 20BRCA3 (detectable) ? ?
2.3 Genetic Risk Factors
2
Trang 22●One woman with unilateral breast cancer diagnosed before age
30 years
●One woman with bilateral breast cancer diagnosed before age
40 years
●One woman with ovarian cancer diagnosed before age 40 years
Consultation at a specialized and interdisciplinary facility is
rec-ommended for individuals from families with a potentially
high-risk constellation These facilities provide counseling and can
check whether the inclusion criteria indicate that genetic testing
is advisable
2.4 Prevention
2.4.1 Primary Prevention
Primary prevention refers to the prevention of the development
of disease in the first place The removal of benign polyps during
a colonoscopy can, for example, prevent the development of
malignant colorectal tumors In the case of breast cancer, primary
prevention consists in removing both breasts (bilateral
mastectomy)
2.4.2 Secondary Prevention
The aim of secondary prevention is to detect the disease in the
earliest possible stage The three imaging modalities most
com-monly used for the detection of breast cancer are mammography,
ultrasound, and magnetic resonance imaging (MRI) The aim of
using these procedures is to detect changes in the breast that are
characteristic of carcinomas Each method has its own particular
strengths and the detectability of alteration in tissues depends on
factors such as the size of a tumor and, in particular, the ability to
distinguish tissue with breast cancer changes from the
surround-ing normal structures
The standard method used in early detection of breast cancer is
X-ray mammography: the breast radiograph The sensitivity of
mammography is approximately 70%, with a specificity (i.e.,
accuracy) of about 90% The same figures are obtained with breast
ultrasonography for the early detection of breast carcinomas
However, both methods show considerably lower values for both
sensitivity and specificity in detecting tumors of 5 to 10 mm
diameter The most reliable technique for the early detection of
breast carcinoma is MRI of the breast Available study data cate that both the sensitivity and the specificity of this examina-tion are greater than 90% This also applies for tumors between 5and 10 mm in size, but only when stringent quality control stand-ards are applied
indi-Early-detection diagnostics are not the same as a diagnosticwork-up The latter is applied when symptoms such as pain, pal-pable lumps, retractions, discoloration, or bleeding are reported
Some 72,000 new cases of breast carcinoma are diagnosed eachyear in Germany In many other regions around the world, therisk is much lower The incidence of a disease is defined as thenumber of new cases diagnosed per 100,000 women per year InGermany, breast carcinoma incidence is about 120 per 100,000women per year
Breast cancer also has the highest mortality rate for women,accounting for some 17.3% of cancer deaths among women Themortality rate is defined as the number of deaths caused per100,000 women per year In Germany, the mortality rate forbreast cancer is about 40 per 100,000 per year Some 17,000patients per year die in Germany as a result of breast cancer(▶Fig 2.2,▶Fig 2.3)
2
Trang 23[1] Adami HO, Bergström R, Hansen J Age at first primary as a determinant of
the incidence of bilateral breast cancer Cumulative and relative risks in a
population-based case-control study Cancer 1985; 55(3):643 –647
[2] Aranda FI, Laforga JB Microvessel quantitation in breast ductal invasive
carci-noma Correlation with proliferative activity, hormonal receptors and lymph
node metastases Pathol Res Pract 1996; 192(2):124 –129
[3] Bhatia S, Robison LL, Oberlin O, et al Breast cancer and other second
neoplasms after childhood Hodgkin ’s disease N Engl J Med 1996; 334
(12):745 –751
[4] Bicknell R, Harris AL Mechanisms and therapeutic implications of
angiogene-sis Curr Opin Oncol 1996; 8(1):60 –65
[5] Brinck U, Fischer U, Korabiowska M, Jutrowski M, Schauer A, Grabbe E The variability of fibroadenoma in contrast-enhanced dynamic MR mammogra- phy AJR Am J Roentgenol 1997; 168(5):1331 –1334
[6] Buadu LD, Murakami J, Murayama S, et al Breast lesions: correlation of trast medium enhancement patterns on MR images with histopathologic findings and tumor angiogenesis Radiology 1996; 200(3):639 –649 [7] Buckley DL, Drew PJ, Mussurakis S, Monson JR, Horsman A Microvessel den- sity of invasive breast cancer assessed by dynamic Gd-DTPA enhanced MRI.
con-J Magn Reson Imaging 1997; 7(3):461 –464 [8] Byrne C, Schairer C, Wolfe J, et al Mammographic features and breast cancer risk: e ffects with time, age, and menopause status J Natl Cancer Inst 1995;
87(21):1622 –1629 [9] Eckart WU 100 Jahre organisierte Krebsforschung; Thieme, Stuttgart; 2000
Fig 2.3 Relative percentages of the mostcommon tumor locations among all cancerdeaths in men and women in the USA in
2015 (American Cancer Society https://
www.cancer.org/search.html?q=Cancer%
20Fact%20and%20Statistics%202011)
Fig 2.2 Relative percentages of the mostcommon tumor locations among all newcancer cases in men and women in the USA
in 2015 (from American Cancer Societyhttps://www.cancer.org/search.html?
q=Cancer%20Fact%20and%20Statistics%
202011)
2.5 Epidemiology, Incidence, and Mortality
2
Trang 24[10] Folkman J, Klagsbrun M Angiogenic factors Science 1987; 235
(4787):442 –447
[11] Folkman J Seminars in Medicine of the Beth Israel Hospital, Boston
Clin-ical applications of research on angiogenesis N Engl J Med 1995; 333
(26):1757 –1763
[12] Frouge C, Guinebretière JM, Contesso G, Di Paola R, Bléry M Correlation
between contrast enhancement in dynamic magnetic resonance imaging of
the breast and tumor angiogenesis Invest Radiol 1994; 29(12):1043 –1049
[13] Hancock SL, Tucker MA, Hoppe RT Breast cancer after treatment of Hodgkin ’s
disease J Natl Cancer Inst 1993; 85(1):25 –31
[14] Hulka CA, Edmister WB, Smith BL, et al Dynamic echo-planar imaging of the
breast: experience in diagnosing breast carcinoma and correlation with tumor
angiogenesis Radiology 1997; 205(3):837 –842
[15] Kaste SC, Hudson MM, Jones DJ, et al Breast masses in women treated for
childhood cancer: incidence and screening guidelines Cancer 1998; 82
(4):784 –792
[16] Leitlinienprogramm Onkologie der AWMF, Deutschen Krebsgesellschaft eV
und Deutschen Krebshilfe eV Leitlinienreport der S 3 Leitlinie fur die
Diag-nostik,Therapie und Nachsorge des Mammakarzinoms AWMF Register-Nr.
032 –045OL München: W Zuckschwerdt Verlag GmbH 2012
[17] London SJ, Connolly JL, Schnitt SJ, Colditz GA A prospective study of benign
breast disease and the risk of breast cancer JAMA 1992; 267(7):941 –944
[18] Collaborative Group on Hormonal Factors in Breast Cancer Familial breast
cancer: collaborative reanalysis of individual data from 52 epidemiological
studies including 58,209 women with breast cancer and 101,986 women
without the disease Lancet 2001; 358(9291):1389 –1399
[19] Peer PG, van Dijck JA, Hendriks JH, Holland R, Verbeek AL Age-dependent
growth rate of primary breast cancer Cancer 1993; 71(11):3547 –3551
[20] Pluda JM Tumor-associated angiogenesis: mechanisms, clinical implications,
and therapeutic strategies Semin Oncol 1997; 24(2):203 –218
[21] Robert K-I Gesellschaft der epidemiologischen Krebsregister in Deutschland
e.V., Krebs in Deutschland 2007/2008 8 Ausgabe Berlin: Robert
Koch-Institut; 2012
[22] Royal New Zealand College of General Parctitioners (RNZCGP) Early Detection
of Breast Cancer 1999 Wellington, New Zealand: RNZCGP; 1999: 1 –61 [23] Schmoll HJ, Hö ffken K, Possinger K Kompendium Internistische Onkologie 4 Aufl Berlin: Springer; 2005
[24] Spero ff L The meaning of mammographic breast density in users of nopausal hormone therapy Maturitas 2002; 41(3):171 –175
postme-[25] Stomper PC, Herman S, Klippenstein DL, Winston JS, Budnick RM, Stewart CC Invasive breast carcinoma: analysis of dynamic magnetic resonance imaging enhancement features and cell proliferative activity determined by DNA S-phase percentage Cancer 1996; 77(9):1844 –1849
[26] Szabó BK, Aspelin P, Kristo ffersen Wiberg M, Tot T, Boné B Invasive breast cancer: correlation of dynamic MR features with prognostic factors Eur Radiol 2003; 13(11):2425 –2435
[27] Talamini R, Franceschi S, La Vecchia C, et al The role of reproductive and strual factors in cancer of the breast before and after menopause Eur J Cancer 1996; 32A(2):303 –310
men-[28] Teifke A, Behr O, Schmidt M, et al Dynamic MR imaging of breast lesions: relation with microvessel distribution pattern and histologic characteristics of prognosis Radiology 2006; 239(2):351 –360
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[30] Weidner N, Semple JP, Welch WR, Folkman J Tumor angiogenesis and metastasis —correlation in invasive breast carcinoma N Engl J Med 1991; 324(1):1 –8
[31] Weidner N, Folkman J, Pozza F, et al Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma J Natl Cancer Inst 1992; 84(24):1875 –1887
[32] Yarbro JW, Page DL, Fielding LP, Partridge EE, Murphy GP American Joint Committee on Cancer prognostic factors consensus conference Cancer 1999; 86(11):2436 –2446
2
Trang 253 Pathology of Benign and Malignant Changes in the Breast
J Rueschoff
3.1 Benign Changes
3.1.1 Histological Principles
The breast is made up of 15 to 25 glands (lobules or segments)
(▶Fig 3.1a) These glands comprise a dense system of bifurcating
ducts and ductules ending in the milk-secreting lobules (acini;
▶Fig 3.1b) The large majority of breast diseases originate in the
epithelial cells that line the ducts and lobules The most frequent
point of origin is at the ends of the glandular“tree,” the terminal
duct lobular unit (TDLU) (▶Fig 3.1c, d)
Immunhistochemically, the luminal cell layer (both glandular
and ductal) and the basal myoepithelial cell layer develop from a
progenitor cell expressing basal (high molecular weight)
cytoker-atins (CK5/6 or CK5/14) The mature myoepithelial cell may
revert to being CK5/6 negative, though myofilaments with
anti-bodies for smooth muscle actin (SMA) and CD1032 can be
detected Mature luminal duct and gland cells are positive for the
low molecular weight cytokeratin CK8/18, but negative for CK5/6
(progenitor cell model1,7)
3.1.2 Nonneoplastic, Nonproliferative
Diseases of the Breast
Diseases of the breast are among the most common disorders of
organs in women and are often associated with the formation of
a palpable lump In principle breast diseases can also develop inmen It is important to distinguish between palpable lumpscaused by true new tissue growth (tumor or neoplasia) and thosethat do not exhibit uncontrolled, progressive growth (nonneo-plastic, pseudotumorous) Because breast tissue is hormone-responsive, changes occur particularly during the menstrual cyclebut also during pregnancy and lactation, which can sometimespromote changes such as the formation of cysts (mastopathy), orinflammatory processes (mastitis) In individual cases it can be
difficult, not only clinically and in breast imaging, but also logically, to distinguish nonneoplastic benign changes from neo-plastic malignant lesions Indeed, a reliable evaluation ofpathological findings in the breast can be a challenge even forpathologists In the following subsections, the typically diffusechanges in breast tissue are described and distinguished fromthose lesions that typically lead to tumor formation
patho-Defects and Supernumerary Structures
Congenital abnormalities of the breast are relatively rare and aredivided into defects and supernumerary structures:
●Defects: These range from the complete absence of breast tissueand nipple (amastia) to isolated abnormalities of the nipple(athelia, microthelia) or the breast (amatia, aplasia) and to bilat-eral or unilateral underdevelopment of the breast (micromastia,anisomastia)
Gland cellsTerminal duct
d c
Gland duct
Acinus
b a
Lactiferous
sinus
Areola
Pectoral muscle
Fig 3.1 Anatomy of the breast (a, b) matic diagrams (c, d) histology and immuno-histology (a) Mammary gland with ca 15 to 25individual lobes, each ending at the nippleorifice (b) Detail from (a): The branching ductslead into terminal ducts (ductules) and end inthe secretory lobes (acini) (c) Terminal ductlobular unit (TDLU) (d) TDLU with a luminal(blue nuclei) and a basal myoepithelial cell layer(brown represents CD10)
Sche-3.1 Benign Changes
3
Trang 26●Supernumerary structures: Supernumerary nipples (polythelia)
and/or breasts (polymastia) develop in the milk line and are
found in approximately 3% of the population, with no gender
preference The most common localizations of such formations
are in the axilla (45% of cases), near the breast (25%), and in the
medioclavicular line of the chest wall (12%) Carcinomas in a
mamma aberrata (dystopic carcinomas) are rare and are
prognostically unfavorable.40
Macromastia
The term “macromastia” (diffuse hypertrophy of the breast)
refers both to premature (infantile) breast development and to
excessive growth of the breast beyond what is age-appropriate
Macromastia occurs most frequently in adolescence, with
prolif-eration of ductal epithelia and fibrosis of breast tissue being the
most prominent histological features Most commonly there is an
increase in fatty tissue (lipomatous macromastia) In the
differen-tial diagnosis, the following secondary forms must be
distin-guished from primary macromastia:
●Paraneoplastic: in the case of endocrine-active tumors
(hypo-physeal adenoma, small-cell bronchial carcinoma, Cushing’s
disease, acromegaly, dysgerminoma)
●Drug related (digitalis)
●Tumor-related: by infiltration of the breast tissue (malignant
lymphomas)
Fibrocystic Mastopathy
Characteristic features of a simple fibrocystic breast condition are
morphological changes in which fibrosis of the mammary tissue
with duct ectasia is predominant but not epithelial proliferation
Such changes can be detected in ca 50% of women age 30 years
and over and are considered by some authors to be a variant of
the norm with no pathological significance There is no associated
increased risk of breast cancer.1
Typical histological findings include the following changes:
●Cysts and duct ectasia: The lactiferous ducts are noticeablyenlarged but generally show an intact epithelial lining(▶Fig 3.2), although solitary cysts (larger than 1 cm) may form
●Fibrosis: This is an intralobular or perilobular collagen fiberproliferation in the breast stroma
●Metaplasia: This is usually an apocrine metaplasia with drical, red eosin-stained epithelia (similar to sweat glands)
cylin-Mastitis
Inflammations of the breast are either acute (usually bacterialinfection) or mainly chronic (usually resulting from retention ofsecretion) Reactive specific and granulomatous inflammatorychanges are rare.2
Acute Mastitis
Acute inflammations (thelitis, areolitis) are usually caused bycontact infection during breastfeeding and can lead to a canalicu-lar transmission of the inflammation to the glandular tissue(puerperal mastitis) The most frequent pathogen (95% of cases)
is Staphylococcus aureus from the nasopharyngeal cavity of thechild, the mother, or the nursing staff Purulent inflammations ofthe mammary gland (nonpuerperal mastitis) are rare after thepostnatal period These develop due to displacement of the lactif-erous duct by nipple calluses, scars, or tumors with subsequentretention of secretions Secondary colonization can then lead toformation of a suppurating abscess Histologically, there is a leu-kocytic infiltration of the milk ducts and lobules with invasion ofthe mantle and supporting tissue Healing of abscesses and fistu-las can leave scarring and deformation of the breast
Chronic Periductal Mastitis (Retention Syndrome)
About one-third of nonpuerperal mastitis cases are nonbacterial,chemically induced inflammations caused by intraductal secre-tion retention (▶Fig 3.3a) Histological features include ectatic
Fig 3.2 Fibrocystic mastopathy (a) Cystic duct ectasia (b) Fibrocystic tissue transformation with ectatic ductules, partly lined by (reddish) apocrinemetaplastic epithelium (A), and incipient focal lobule sclerosis (S) (From Bock K, Ramaswamy A, Köhler H Fortbildungskurs zur Aufrechterhaltungund Weiterentwicklung der fachlichen Befähigung für Pathologen [6.10.2012]—Referenzzentrum Mammographie Südwest am UniversitätsklinikumGießen-Marburg am Standort Marburg [Course text].)
3
Trang 27ducts filled with thickened secretion and foam cells
(galactosta-sis) and periductal lymphocytes and plasma cells (periductal
mastitis) The ductal epithelium is usually flattened or replaced
by granulation tissue The final stage, obliterative galactophoritis,
is characterized by periductal fibrosis and scarred duct
obli-teration Occasionally there are granulomatous inflammatory
changes, which must then be distinguished from nonpathogenic,
idiopathic granulomatous mastitis (the histological features
being lobulocentric, noncaseating granulomas) as well as from
a pathogen-specific mastitis
Pathogen-Specific Mastitis
Pathogen-specific inflammations of the breast are rare, and
include tuberculous mastitis (hematogenic), syphilis (chancre of
the nipple), and the extremely rare actinomycosis, or other
mycotic pseudotumors (blastomycosis, cryptococcosis) Histology
typically shows an inflammatory response accompanied by
cen-tral acellular (“caseating”) necrosis Substantiation is provided by
microscopic, bacteriologic, or molecular genetic pathogen
verifi-cation Sarcoidosis rarely affects the breast Histomorphological
findings of noncaseating granulomas must therefore be
inter-preted within the scope of the clinical picture
Panniculitis-Associated Fat Necrosis
Necroses of the mammary adipose tissue often occur as tumorlike
changes in patients between 50 and 70 years of age In up to 50%
of cases, the patient’s history includes trauma, such as postsurgical
status (ca 1 in 200 operations) Clinical findings include a
circum-scribed, painful lump that is difficult to distinguish from a
carci-noma, even on mammography Microscopy shows fat necrosis
with a lipophagic inflammatory response (foam cells, Touton giant
cells) partially displaying cystlike, confluent fat-cell necroses (oil
cysts; ▶Fig 3.3b) Pronounced accompanying hemorrhages can
occur if the patient is undergoing anticoagulant therapy The
dif-ferential diagnosis includes abscesses and carcinomas
Inflammatory Response to Breast Implants
Foam cell–rich and scarring inflammatory changes can also occur
as a reaction to a prosthesis (breast implant) This occurs in 22 to
58% of cases 3 to 9 months after implantation In 4 to 6% of cases,implants may rupture and cause tumorlike silicone granulomas
to form These contain nonbirefringent silicone components rounded by histiocytes and giant cells.1
sur-3.1.3 Benign Tumor-Forming Diseases
In the current classification of the World Health Organization(WHO), breast lesions that typically manifest as circumscribed,sometimes palpable tumors are divided into epithelial, mesen-chymal, and fibroepithelial tumors; growths in nipple tissue;
malignant lymphomas; metastatic tumors; and tumors of themale breast.24This section describes primarily the benign, non-carcinomatous lesions (▶Table 3.1; for malignant lesions, seeChapter 3.2)
Epithelial Proliferations
There are a number of distinct proliferating epithelial lesionsoriginating in the lobules that can occasionally be difficult to dis-tinguish from carcinomas, both radiologically and histologically
These lesions do not generally present an increased risk of breastcancer Exceptions are the rare forms of microglandular adenosisand the complex sclerosing lesions (radial scar), which are oftenfound in conjunction with in situ or invasive, usually lobular,carcinoma.4
in signet-ring cells
Fig 3.3 Breast inflammation (a) Galactophoritis obliterans with cystic ductal ectasia (Z) and wall thickening in a duct that was displaced by a
papilloma (P); known as retention syndrome (b) Fat necrosis with scarred-cystic degradation of the necrotic adipose tissue (so-called oil cysts; lower
right, regular adipose cells)
3.1 Benign Changes
3
Trang 28Sclerosing Adenosis
Sclerosing adenosis is a compact proliferation of glandular
epithelium and especially myoepithelium in a lobulelike
arrange-ment (▶Fig 3.4b) The basal membrane is intact and
microcalcifi-cations are commonly found within the gland lumen Actin-sm
(SMA)-positive or CK5/6-positive myoepithelium is seen between
the glands and forms an important differential diagnostic
crite-rion for the differentiation of adenosis from scirrhous and tubular
carcinomas Invasion of the nerve sheath or vessels is seen
occa-sionally (up to 2% of cases), but should not be interpreted as a
sign of malignancy
Radial Scar
The radial scar is a special form of adenosis with central elastotic scarring that encloses individual glands and radiatestoward the periphery, where it passes into an adenosis(▶Fig 3.4c) Lesions larger than 0.5 cm with ductal ectasia, meta-plasia, and epithelial hyperplasia are also called complex scleros-ing lesions The absence of fatty tissue invasion and the presence
hyaline-of primarily double-row tubules with intact epithelia andmyoepithelia are generally considered to exclude carcinoma(▶Fig 3.4d) In case of doubt, this can be immunohistologicallyconfirmed (CK5/6, SMA-positive)
Microglandular Adenosis
A characteristic sign of microglandular adenosis is irregularand indistinctly circumscribed groups of proliferated, rela-tively uniform gland tubules that are lined with cubic epithe-lium and, in contrast to the other forms of adenosis, show nomyoepithelium (i.e., are SMA negative) An eosinophilic, PAS-positive secretion is commonly seen in the lumen Clinicallyand histologically these lesions have the appearance of a tub-ular carcinoma Unlike the tubular carcinoma, however, thecells of the microglandular adenosis express S100 but no hor-mone receptors, and are always negative for epithelial mem-brane antigen (EMA) and for GCDFP-15 (gross cystic diseasefluid protein) The basal membrane around the newly formedglands is intact.5
Adenomas of the Breast
As a rule, adenomas are circumscribed, rounded, and well-definedlumps in the breast, comprising tubular proliferations withtwo-layered glandular epithelium and myoepithelium (tubularadenoma or adenoma purum) These account for approximately1% of all benign breast lesions and typically develop in youngwomen after menarche Radiologically they have the appearance
of fibroadenomas During pregnancy there are also signs of tion (lactating adenoma) Furthermore, apocrine epithelial meta-plasia may be present (apocrine adenoma), or polypoid adenomasmay be seen bulging into ectatic ducts (ductal adenoma) A rareform of adenoma is the pleomorphic adenoma, which has a mor-phology comparable to that of the corresponding salivary glandtumor It consists of epithelial and clear myoepithelial cell prolifer-ations, mixed with chondroid components All of these lesions arebenign, show no recurrence after complete removal, and are notlinked to an increased risk of cancer in any way However, theymust be distinguished from the very rare myoepithelial andepithelial-myoepithelial lesions that look similar to the tubularadenoma and may be associated with atypias.24,25
secre-Intraductal Proliferative Lesions and Precursor Lesions of Invasive Breast Cancer
Intraductal epithelial cell proliferations occur in the followingforms:
●UDH: usual (or simple) ductal hyperplasia
●FEA: flat epithelial atypia (arising from a columnar cell lesion)
●ADH: atypical ductal hyperplasia
●DCIS: ductal carcinoma in situ
Table 3.1 WHO classification of breast tumors, part 1 (primarily benign
lesions; as per Lakhani et al24)
Tumor group Entity
Epithelial tumors Benign epithelial proliferations
(Sclerosing) adenoses and variantsRadial scar and complex sclerosing lesionAdenomas of the breast
Intraductal proliferative lesionsUDH
Columnar cell lesionsFEA
ADHEpithelial-myoepithelial tumorsPleomorphic adenomaAdenomyoepithelioma (with/withoutcarcinoma)
Fibroepithelial tumors Fibroadenoma
Phyllodes tumorHamartomaMesenchymal tumors Nodular fasciitis
MyofibroblastomaDesmoid-type fibromatosisInflammatory myofibroblastic tumorBenign vascular lesions (hemangioma,angiomatosis)
Pseudoangiomatous stromal hyperplasiaGranular cell tumor
Benign peripheral nerve sheath tumor(neurofibroma, schwannoma)Lipoma and angiolipomaLeiomyoma
Tumors of the nipple Adenoma
Syringomatous tumorTumors of the male breast Gynecomastia
Abbreviations: ADH, atypical ductal hyperplasia FEA, flat epithelial
atypia UDH, usual ductal hyperplasia
3
Trang 29The risk of malignancy associated with these lesions depends
on the degree of atypia and the extent of breast tissue
involve-ment The latest WHO classification no longer uses the so-called
DIN terminology (ductal intraepithelial neoplasia), originally
introduced by the Armed Forces Institute of Pathology (AFIP),43
for the classification of intraductal proliferating lesions
Usual Ductal Hyperplasia
Benign proliferative lesions of the ductal epithelia without
mor-phological signs of atypia are called “usual [or “simple”] ductal
hyperplasia” (▶Fig 3.5a) The remarkable histopathological
fea-ture is in the terminal ducts of the TDLU, where the duct lumina
are filled by epithelial proliferations more than four cell layers
wide These form irregular, usually slitlike lumina adapted to the
ducts (peripheral fenestrations) with thin epithelial bridges The
cells are often arranged in lines (streaming) and are
morphologi-cally made up of different cell types, some with elongated and
nonround nuclei, as well as focal apocrine metaplasia The basalmyoepithelial layer is typically intact Unlike in DCIS, the cells inUDH predominantly express cytokeratin CK5/6 (▶Fig 3.5c),which is why they are also called progenitor cell lesions or stemcell lesions.5Women with UDH have a slightly (1.5-fold to 2-fold)increased risk of developing breast cancer
Columnar Cell Lesions and Flat Epithelial Atypia
With the introduction of systematic radiographic screening forbreast cancer, findings referred to as columnar or cylindrical celllesions have gained in significance The following forms are histo-pathologically distinguished:
●Columnar cell metaplasia: The normally double-layered lium of the lobules and terminal intra-acinar ducts is replaced
epithe-by a single layer of cylindrical epithelium with apical apocrinecytoplasmic constrictions (“apical snouts”) The abnormal
Fig 3.4 Types of adenosis (a) Ductal adenosis (blunt duct adenosis, A) with slightly ectatic lobules lined by a single-layer cylindrical epithelium
(columnar cell metaplasia) with granular (often calcified) secretion in the lumen (N, normal lobule) (b) Sclerosing adenosis with tumorlike gland
proliferation and typically intact myoepithelial layer Insert: nuclei of the gland lumen epithelia (blue), bordered by p63-positive myoepithelium
(brown) (c) Radial scar with glandular and ductal proliferation radiating from a hyaline-elastotic center (✩) Peripheral adenosis (d) Tubular
carcinoma is the most important differential diagnosis There is a comparable central elastotic fibrosis (✩) Unlike the radial scar, however, the gland
here does not have an intact myoepithelial layer (cf inserts: myoepithelial imaging with cytokeratin CK5 is positive in [c] and negative in [d])
(Figures [c] and [d] from Bock K, Ramaswamy A, Köhler H Fortbildungskurs zur Aufrechterhaltung und Weiterentwicklung der fachlichen
Befähigung für Pathologen [6.10.2012]—Referenzzentrum Mammographie Südwest am Universitätsklinikum Gießen-Marburg am Standort Marburg
[Course text].)
3.1 Benign Changes
3
Trang 30apocrine secretion causes ectasia of the lobular lumina
Secre-tory calcifications, which may appear as slightly polymorphic,
grouped calcifications on mammography, are not rare One
form of columnar cell metaplasia is the blunt duct adenosis, in
which multiple lobules are lined with ductlike columnar cells
●Columnar cell hyperplasia: This form is characterized by focal
overlapping of the cylindrical cells (crowding) without signs of
cytologic atypia
●FEA: Lobules are lined by a relatively uniform cell population
with monotonically enlarged and rounded nuclei, in which the
chromatin is usually lighter in the center and one or two
prom-inent nucleoli are seen (▶Fig 3.5b) The epithelium is
fre-quently single-layered along the duct contour If the lobule
boundary is overpassed and there is expansion to the
interlobu-lar ducts, then it corresponds to the monomorphic-type
cling-ing carcinoma (low-grade DCIS) The breast cancer risk
associated with columnar cell lesions is considered to be low,
and has been overestimated (in small-scale studies) even when
an FEA was verified An increased cancer risk is only certain
once an ADH has been verified
Atypical Ductal Hyperplasia
The characteristic feature of ADH that distinguishes it from FEA isthe verifiable formation of micropapillae and cell bridges (so-called secondary architectures; ▶Fig 3.5d) It is distinguishedfrom low grade DCIS by the number and size of ducts affectedeither a maximum of two affected ducts (as per Page) or one le-sion smaller than 2 mm (as per Tavassoli) Strictly speaking, theADH lesion is limited to one lobule The transition to a DCIS isindicated when multiple lobules are affected or if the atypiaencroaches upon interlobular ducts ADH increases the risk ofdeveloping breast cancer 3-fold to 5-fold.46
Lobular Neoplasia
Cell proliferations in the terminal lobules (▶Fig 3.6 and
▶Table 3.2) are called lobular neoplasia and include atypical ular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) Anal-ogous to intraductal neoplasia, these lesions are also referred totogether using the term“lobular intraepithelial neoplasia” (LIN).Together with other histologically benign breast findings, they
Fig 3.5 Intraductal proliferative lesions (a) Usual ductal hyperplasia (UDH) with slitlike residual lumina in one duct (lower right; H) and anotherduct (upper left; K) with a single layer lining of cylindrical epithelium (columnar cell metaplasia; both B2 lesions) (b) Flat epithelial atypia (FEA): thegland is lined with partially overlapping epithelium with enlarged nuclei and a number of visible nucleoli; one mitosis is visible between 1 and 2 hours(B3 lesion) (c) Immunohistochemically, the UDH shows CK5/6-positive myoepithelia with mosaiclike distribution throughout the epithelia (d) Inatypical ductal hyperplasia (ADH), these CK5/6-positive myoepithelia are nearly or entirely absent (Figures [a] and [b] from Bock K, Ramaswamy A,Köhler H Fortbildungskurs zur Aufrechterhaltung und Weiterentwicklung der fachlichen Befähigung für Pathologen [6.10.2012]—ReferenzzentrumMammographie Südwest am Universitätsklinikum Gießen-Marburg am Standort Marburg [Course text].)
3
Trang 31a b
Fig 3.6 Types of lobular neoplasia (a) Atypical lobular hyperplasia (ALH) with uniform, atypical cells filling the lobules that do not cause significant
ectasia Some of the gland lumina are still visible to some extent, and the myoepithelial layer is essentially intact (cytokeratin CK5/6
immunostaining) (b) Classic lobular carcinoma in situ (LCIS) with ectatic and deformed acini (c) Pleomorphic lobular carcinoma with pronounced
ectatic glands that are filled with atypical pleomorphic tumor cells and central necroses (d) Extension of LCIS into neighboring ducts (below),
partially with so-called pagetoid spread, interfusing the ductal epithelia with single cells or small cell groups (arrows) Immunostaining for the cell
adhesion molecule E-cadherin (strong brown staining) is present in ductal epithelia but is absent from the lobular neoplasia (tumor cells shown only
blue nuclei using haemalum as counterstain) (From Bock K, Ramaswamy A, Köhler H Fortbildungskurs zur Aufrechterhaltung und
Weiterentwicklung der fachlichen Befähigung für Pathologen [6.10.2012]—Referenzzentrum Mammographie Südwest am Universitätsklinikum
Gießen-Marburg am Standort Marburg [Course text].)
Table 3.2 Classification of lobular neoplasia (according to Lakhani et al26and Sinn et al48)
Spectrum of lobular
neoplasia (WHO 2012)
LIN classification(WHO 2003)
Definition Associated DCIS Associated IDC (NST) Associated ILC
ALH LIN 1 Less than 50% of TDLU
filled, not distended
in 7.7% in 12.3% in 1.5%
LCIS LIN 2 More than 50% of
TDLU affected, tended
dis-in 14.7% in 9.4% in 8.2%
Pleomorphic LCIS LIN 3 Maximum distention of
TDLU, pleomorphicwith necroses
in 18.5% in 3.3% in 19.6%
Abbreviations: IDC, invasive ductal carcinoma ILC, invasive lobular carcinoma NST, no special type TDLU, terminal duct lobular unit
3.1 Benign Changes
3
Trang 32are usually found incidentally in approximately 0.5 to 5% of cases.
The lesions are usually multicentric (85% of cases) and often
bilat-eral (30–67%) With few exceptions, there are no clinical or
mam-mographic findings that can be called typical.26
The histological findings include a solid epithelial proliferation
originating in the lobules, with relatively small, monomorphic
cells and nuclei with no prominent nucleoli The lobules are
ectatic, but the architecture remains intact If the lobules are not
ectatic, or if only few acini (less than 50%) are filled with solid,
atypical cell proliferations, then the lesion is an ALH The
charac-teristic and not uncommon feature of lobular neoplasia is
page-toid growth in the terminal ductules, with growth undermining
the still intact luminal ductal cell layer The classic cell type (A),
with only slight cell atypia, must be distinguished from cell type
B, which has prominent nucleoli and coarse chromatin If there is
a preponderance of cell type B, the lesion is a pleomorphic
lobu-lar neoplasia, which may be accompanied by necrosis and
increased mitosis (also called LIN 3) Immunohistochemical
methods are used to distinguish lobular neoplasia, particularly
the LIN 3 lesion, from lobule cancerization as seen in DCIS Unlike
DCIS, lobular neoplasias are E-cadherin negative in the majority
of cases.26
Note
Although the presence of lobular neoplasia increases the risk of
developing cancer by a factor of 7 to 12, it is not invariably a
precancerous lesion
The risk of developing a subsequent invasive carcinoma is
approximately 20% in 10 years (20% ipsilateral, 10%
contrala-teral); if more than five lobules are affected, or if there is a family
history of cancer, then the risk is even higher Approximately 35%
of women with a lobular neoplasia develop an invasive
carci-noma after 35 years Lifelong aftercare and monitoring, with and
without tamoxifen treatment, is recommended In the case of
LIN 3, the risk of cancer is significantly higher (▶Table 3.2) If this
type of lesion is found, the aim of surgery should be complete
excision of the lesion with clear lesion borders.5
Fibroepithelial Tumors
Fibroadenomas and phyllodes tumors are biphasic tumors that
consist of an epithelial component and a dominant mesenchymal
(or stromal) tissue component A breast hamartoma is a
pseudo-tumor that also falls into this category
Fibroadenoma
Fibroadenoma is the third most common form of breast disease
(ca 20% of cases), after mastopathy and carcinoma
Fibroadeno-mas develop in patients between the ages of 20 and 40 years
(peak frequency at ages 20–24 years.) Most fibroadenomas are
solitary, and form in the upper outer quadrants; approximately
20% are multiple, and 3 to 5% are bilateral
The vast majority (ca 90%) of fibroadenomas are less than 4 cm
in diameter, are grayish-white in appearance, and are easily
demarcated from the surrounding glandular tissue (▶Fig 3.7a)
Histological features include a hypocellular myxoid stroma with
enclosed, fissurelike lumina lined with flat, double-row epithelia
(▶Fig 3.7b) The juvenile fibroadenoma that occurs in cents (11 to 18 years) must be distinguished from these and ischaracterized by pseudopapillary epithelial proliferation withdense, hypercellular stroma The rapid growth of this tumor canlead to what is termed a giant fibroadenoma
adoles-A fibroadenoma can also develop into a phyllodes tumor or astromal sarcoma Atypical epithelial proliferations are detected in
a
b
Fig 3.7 Fibroadenoma (a) Sharply defined, ca 2.2 cm, firm-elastictumor with grayish-white, whorllike cross section (b) Histology showsfissurelike ducts, compressed by bulging mantle tissue The epithelium
is flattened (pressure atrophy)
3
Trang 331 to 2% of cases, of which approximately 70% are of LCIS type
(usually in women over 40 years of age).40
Phyllodes Tumor
The phyllodes tumor (WHO classification24) or cystosarcoma
phylloides (older nomenclature) probably develops from a
fibroa-denoma, and is characterized by stromal overgrowth with wide
fissures and epithelial and mesenchymal metaplasia (▶Fig 3.8a)
The mean age of patients is some 10 to 20 years older than for
fibroadenoma, but it is sometimes seen as early as puberty and
as late as postmenopause
Phyllodes tumors have been described with a diameter of
30 cm and weighing 5,000 g Histology shows a hypercellularstroma, often made up of spindle cells, with a myxoid matrix
Metaplasias of cartilage, bone, adipose tissue, and squamousepithelia are common The presence of fewer than 4 mitosesper 10 high-power fields [HPF], a lack of cell atypia, andsharply defined tumor margins indicate benignity Approxi-mately 65% of phyllodes tumors are benign Roughly 15% ofphyllodes tumors are malignant (stromal sarcoma), which pri-marily metastasize hematogenously The verification ofincreased numbers of mitoses (over 10 per 10 HPF), atypical,hypercellular stroma, and invasive growth at the tumor mar-gin are together considered to be reliable criteria for deter-mining malignancy (▶Fig 3.8b) The rate of recurrence isquite high (ca 30%)
Breast Hamartoma
Hamartomas (also termed fibroadenolipomas) are well-definedpseudotumors of the breast that have a surrounding connectivetissue pseudocapsule These range from 1 to 20 cm in size and aremade up histologically of all breast tissue types The interstitialtissue contains lobules and a large amount of fibrolipomatous tis-sue Macroscopically, these easily enucleated lumps appear likenormal breast tissue (“breast within a breast” impression) or like
a lipoma This hamartomatous neoplasm arises from a local differentiation and is rare (0.16% of all lumps detected in mam-mography) It shows no age preference and has no malignantpotential
mal-Mesenchymal (Nonsarcomatous) Tumors
Changes originating in the mesenchyme of the breast essentiallycorrespond to those found in extramammary soft tissue; they aretherefore described only briefly here
Hemangioma
The hemangioma is a circumscribed tumor (0.6–2.5 cm in ter) with grouped, dilated (cavernous) or narrow-lumened (capil-lary), blood-filled vessels (▶Fig 3.9a) Complete excision isrecommended for reliable differentiation from an angiosarcoma.6
diame-Diffuse angiomatoses are rare
Pseudoangiomatous Stromal Hyperplasia
Pseudoangiomatous stromal hyperplasia (PASH) is a relativelycommon, angiomalike connective tissue reaction (CD34 positive,CD31 negative) that may be microscopically small (in up to 25%
of breast biopsies) or tumorlike in appearance (▶Fig 3.9b) Thelesion can recidivate but is benign
Pubertal gynecomastia is relatively common (50–70% of cent males) It begins with unilateral accentuation and regressesspontaneously within 2 to 3 years
adoles-Lipoma
Lipomas are benign proliferations of adipose tissue that manifestbetween the ages of 40 and 60 years as circumscribed, usuallyencapsulated, asymptomatic lumps of 2 to 10 cm diameter Theyare always benign
a
b
Fig 3.8 Phyllodes tumor (a) Phyllodes tumor with clover leaf–like,
lobed structure (b) The phyllodes tumor has a widened epithelial layer
with, in this example, pleomorphic nuclei, and a hypercellular stromal
base (indicators of malignancy are the verification of increased
mitoses, necroses, and invasive growth)
3.1 Benign Changes
3
Trang 34Fibromatosis (Extra-abdominal Desmoid
Tumor)
This is a locally aggressive lesion made up of myofibroblasts that
radiate in an aligned manner into the surrounding adipose and
lobule tissue The lesion commonly originates from the pectoral
fascia and has indistinct borders (▶Fig 3.9c) Possible causes
include prior trauma (surgery) and familial adenomatosis coli
There is recurrence if surgical excision is incomplete
The following lesions must be differentiated:
●Scars (macrophages and siderin inclusions, absence of the
nuclearβ-catenin staining typical of desmoid tumors12)
●Spindle cell carcinoma (cytokeratin positive)
●Nodular fasciitis (fast subcutaneous growth, spontaneous
healing)
●Myofibroblastoma (CD34 and desmin positive)
●Inflammatory myofibroblastic tumor (interspersed plasma
cells, 50% positive for alkaline phosphatase)
●Benign tumors made up of cells from the peripheral nervesheaths:
○Granular cell tumor (PAS and S 100 positive, foam cell–likeSchwann cells;▶Fig 3.9d)
to that of an intraductal papilloma, but infiltration of the millary stroma must not be misinterpreted as a sign of
Fig 3.9 Benign mesenchymal tumors (a) Hemangioma with clustered blood-filled capillary sprouts in the mammary stroma (left) located betweenthe normal glands (right) (b) Pseudoangiomatous stromal hyperplasia (PASH; see text) with fissured, angiomalike connective tissue reaction (but,unlike hemangioma, CD31 negative) (c) Fibromatosis (extra-abdominal desmoid tumor) with spindlelike fibroblasts arranged in alignment, typicallyindistinctly circumscribed at the margins (high recurrence rate) Unlike scar tissue (insert), fibromatosis displays a positive nuclearβ-catenin staining.(d) Granular cell tumor with granular, foam cell–like proliferation of S 100-positive (Schwann) cells (insert) (Figures [c] and [d] from Bock K,Ramaswamy A, Köhler H Fortbildungskurs zur Aufrechterhaltung und Weiterentwicklung der fachlichen Befähigung für Pathologen [6.10.2012]—Referenzzentrum Mammographie Südwest am Universitätsklinikum Gießen-Marburg am Standort Marburg [Course text].)
3
Trang 35malignancy Solid, papillary, and/or tubular formations may be
observed, generally preserving an intact double-row of
epithe-lium Apocrine metaplasias may occur, while necroses and
mito-ses are absent Clinical findings include a bulging, secreting, and
painful, pressure-sensitive nipple that bleeds easily on contact.40
Tumors of the Male Breast
Unilateral or bilateral enlargement of the male breast due to
abnormal growth of the mammary gland is called gynecomastia
It is commonly seen during puberty and between 60 and 80 years
of age Pseudogynecomastia is distinguished from gynecomastia
by an increase in adipose cell inclusions
Note
In elderly patients with gynecomastia, it is important to rule out
male climacteric with its relative increase in estrogen levels, as
well as a secretory testicular (Leydig cell) tumor, and cirrhosis of
the liver Gynecomastia can also be associated with certain
medications (including estrogens, corticosteroids, digitalis,
spironolactone, cimetidine, and others) or may be seen as a
symptom of a paraneoplastic syndrome
Macroscopically, the breast diameter is enlarged by 2 to 4 cm Inapproximately 70% of cases, histological features include intra-ductal, pseudopapillary epithelial proliferations (tubular gyneco-mastia; ▶Fig 3.10) Secretion and the formation of typicallobules are characteristic features of lobular gynecomastia (10–50% of cases) Precancerous epithelial hyperplasias are rare andpresent a morphological picture that largely corresponds to that
of carcinoma in situ and, ultimately, invasive carcinoma (seeChapter 3.2).37,40
3.2 Malignant Changes in the Breast
3.2.1 Classification of Malignant Breast Tumors (WHO Classification, B-Categories)
With the publication of the latest WHO classification of breasttumors in a separate volume,24several changes have been intro-duced both in the classification of certain lesions and in theirdesignations (▶Table 3.3)
Fig 3.10 Gynecomastia (a) Proliferated ductal structures without epithelial atypias embedded in a myxoid stroma (b) Enlarged detail from (a)
Table 3.3 WHO classification of breast tumors, part 2 (malignant and potentially malignant lesions; according to Lakhani et al24)
Epithelial tumors Papillary lesions:
●Intraductal papilloma with and without atypias 8503/0(2)
●Intraductal papillary carcinoma 8503/2
●Encapsulated papillary carcinoma 8504/2 (13)
●Solid papillary carcinoma 8509/2 (13)Intraductal proliferations:
Trang 36DCIS is no longer listed under the proliferative lesions; DCIS, LCIS,
and ALH are now classified together under precursor lesions
Furthermore, ductal breast carcinoma is now classified as invasive
breast carcinoma NST (no special type) to emphasize that not all
so-called ductal carcinomas necessarily originate in the ducts
The origin is usually in the TDLU, from which various di
fferenti-ated carcinomas with different phenotypes and genotypes can
develop Terms such as ductal carcinoma NST or NOS (not
other-wise specified), as well as IDC (invasive ductal carcinoma), are
still accepted as alternative designations, however.15
With the introduction of mammographic breast cancer
scree-ning, the (early) diagnosis of breast cancer is increasingly verified
histologically by use of minimally invasive biopsy procedures
The main techniques used in this context are core needle biopsy
(for mass lesions) and vacuum-assisted biopsy (for suspicious
microcalcifications) The samples taken are small; their tion requires specialized knowledge—and usually years of experi-ence—in breast pathology As diagnostic certainty on the basis ofsuch biopsy material can be limited (in ca 10% of cases no defini-tive diagnosis is possible), the B-categories were introduced forminimally invasive breast diagnostics to define further diagnosticand therapeutic procedures (▶Table 3.4) Today, the conclusiveinterpretation of all findings (clinical, radiological, pathological)
evalua-is determined in an interdevalua-isciplinary case conference to decidewhich further therapeutic procedures are indicated
3.2.2 Prognostic and Predictive Factors
The tumor stage is defined by the Union for International CancerControl (UICC) on the basis of tumor size, lymph node status, anddegree of histological tumor differentiation (tumor grade), whichare generally considered the strongest prognostic factors for
Table 3.3 continued
Invasive carcinoma precursor lesionsa:
Invasive breast carcinomab:
●Invasive carcinomas (NST); possibly mixed withpleomorphic, osteoclastic, choriocarcinomatous ormelanocytic components
○Carcinoma with medullary features (classic) 8510/3 < 1
○Metaplastic carcinoma (NOS) 8575/3 1
○Carcinoma with apocrine differentiation (frequently + NST) 8507/3 4
Tumors of the nipple Paget’s disease of the nipple 8540/3 1–4
Malignant mesenchymal tumors
and lymphomas
Leiomyosarcoma, liposarcoma, angiosarcoma,rhabdomyosarcoma, osteosarcoma, Hodgkin’s lymphomaand non-Hodgkin’s lymphoma
Trang 37breast cancer These are referenced in deriving the risks of
recur-rence and fatality (i.e., the prognosis;▶Table 3.5).3,13
The degree of histological differentiation is classified by grade
(G1, G2, G3) and is based on three histological criteria:
●Percentage of glandlike, i.e., tubular, differentiation in the
tumor
●Degree of nuclear pleomorphism
●Mitosis rate
A score of 1 to 3 is given in accordance with the extent of each
factor, and these scores are then added together A total score of
3 to 5 corresponds to G1; 6 or 7 corresponds to G2; and 8 or 9
corresponds to G3 The tumor grade is a highly relevant
prognos-tic parameter.16
Determination of the hormone receptor status and human
epi-dermal growth factor 2 (HER2) receptor status is also essential
for making decisions about therapy These factors are
fundamen-tal in determining the indication for hormone replacement
ther-apy, as well as for therapies targeting the HER2/neu growth
factor receptor.41At the 12th International St Gallen Breast
Can-cer Conference (2011),18 a new molecular subtyping of breast
cancer based on these markers was recommended that
subse-quently forms the basis for decisions regarding breast cancer
therapy This subtyping is founded on the progenitor or stem cell
concept of breast cancer development,7,23 which relates to the
different cytokeratin patterns in the basal and luminal epithelial
layers (see▶Fig 3.1)
Note
Using gene expression profiles and cluster analysis, Perou et al35
were able to show that there are four molecular subtypes ofbreast cancer that exhibit highly significant differences in thecourse of the disease (occurrence of metastases):
deci-Mib-1 proliferation rate This categorization of breast cancer
is the foundation for further decisions regarding the therapy
of early breast cancers without distant metastases(▶Fig 3.11,▶Fig 3.12)
The extent to which gene expression profiles will one day findtheir way into the routine diagnostic examination of tumor tissuedepends upon the results gained from randomized clinical trials
Ultimately, their adoption will also depend on whether the value
of the information thus gained justifies the additional costs,which can be considerable.13
Table 3.4 Classification of histological findings (B classification after percutaneous breast biopsy; according to NHSBSP33)
Category Relative incidencea
(%)
B1 7 Normal tissue or not interpretable Findings that are not compatible
with image findings or cannot be represented in images (e.g.,microcalcification < 100μm); samples that cannot be evaluated
Repeat biopsy
B2 34 Benign lesions Definitely benign finding on histology, compatible
with image findings: benign tumors, nontumorous proliferativelesions, inflammatory and reactive processes
Normal screening intervals
B3 12 Lesions with uncertain malignant potential Findings with increased
risk of synchronous malignancy indicating the possibility of anonrepresentative biopsy: heterogeneous lesions with only benigncomponents in the biopsy (papillary, complex sclerosing lesions,phyllodes tumor); lesions often associated with carcinoma (lobularneoplasia, atypical columnar cell lesions (FEA), atypical ductalproliferation in the sense of ADH)
Further diagnostic work-up (surgicalbiopsy)
B4 1 Lesions highly suspicious of malignancy Scattered, definitely atypical
cells (in the stroma, in the duct); non–high-grade DCIS versus UDH;
comedo material and atypical cells outside of ducts (do not classifylobular neoplasia as B4)
Open biopsy
B5a Intraductal carcinomas (including Paget’s disease, pleomorphic
subtype of LCIS with intraductal spread and necroses)B5b Invasive carcinomas
B5c Uncertain invasion
B5d Nonepithelial malignancies, metastases
Abbreviations: ADH, atypical ductal hyperplasia DCIS, ductal carcinoma in situ FEA, flat epithelial atypia UDH, usual ductal hyperplasia
aRelative incidence in screening (North Rhine-Westphalia, Germany).13
bNot an absolute directive for action, but rather a point to be discussed in the interdisciplinary planning of further procedures
3.2 Malignant Changes in the Breast
3
Trang 38In recent years inoperable, locally advanced, and inflammatory
breast cancers have been treated systemically in the preoperative
setting (neoadjuvant therapy).28A good response to neoadjuvant
therapies (chemotherapy, endocrine therapy, and/or targetedmedications) can thus enable breast-conserving surgical proce-dures, even for large tumors Furthermore, patients with
Table 3.5 TNM classification and UICC staging (according to Wittekind and Meyer52)
Stage T category N category M category 10-year survival ratea(%)
cN1a: 1–3 axillary lymph nodes (1 lymph node > 2 mm); N1b: along the internal thoracic artery (internal mammary artery); N1c: N1a + N1b
dN2a: 4–9 axillary lymph nodes (1 lymph node > 2 mm); N2b: along the internal thoracic artery without axillary lymph node involvement
eT4a: chest wall/skin involvement; T4b: skin edema/ulceration, satellite nodules of the skin; T4c: T4a + T4b; T4d: inflammatory carcinoma
fN3a:≥ 10 axillary lymph nodes (> 2 mm) or ipsilateral infraclavicular lymph nodes; N3b: along the internal thoracic artery with ≥ 1 axillary lymphnodes; N3c: lymph node metastases in ipsilateral supraclavicular lymph nodes
Progenitor/
stem cell
EGFR amplification p53 mutation,
BRCA defect
Triple-negative (HER2/ER/PR)
50% ER/
PR-negative
positive
ER/PR-(ER+/PR+ and Ki67 <14%)
(• HER2/ER+ or PR+
• ER+ or PR+ and Ki67 increased)
Basal program (15%)
(Adeno-)Myoepithelial carcinoma
(B) Moderate/poor: chemotherapy + anti-HER2
(B) Moderate:
endocrine + therapy + anti-HER2
chemo-(B) Good/moderate: endocrine
+ chemotherapy
(A) Very good:
endocrine only
• Invasive (ductal) carcinoma NST G3
• Invasive (ductal) carcinoma NST G2-3
• Invasive (lobular) carcinoma G2
• NST carcinoma G1
• Tubular carcinoma G2
HER2 program (15%)
Luminal program (70%) B
A
Intermediate
cell
HER2 amplification
3
Trang 39histopathologically verified complete response (pCR) have a
sig-nificantly better prognosis (overall survival).22 In this context,
pCR means an absence of invasive tumor residues in breast and
lymph nodes; DCIS residues apparently have no effect on
long-term survival As a rule, poorly differentiated carcinomas (G3; ER
or PgR [estrogen receptor negative or progesterone receptor gative] and/or triple-negative) respond better to chemotherapythan well-differentiated tumors In the case of HER2-positive
Fig 3.12 Biomarker findings in invasive breast carcinoma (NST) (a) Positive ER (estrogen receptor) findings with intense (brown) immunoreaction
in almost all tumor cell nuclei (≥ 1% immunoreactive tumor cell nuclei signifies a positive test result19) (b) NST carcinoma with ca 10% Ki67-positive
tumor cell nuclei, corresponding to a low proliferative activity (but the threshold of < 14% according to the St Gallen Consensus18is questionable
due to limited reproducibility14) (c) HER2-positive breast cancer with intense, ring-shaped appearance of the tumor cell membranes
(immunohistological-score: 3 +) (d) Verification of HER2 gene amplification with SISH (silver in-situ hybridization: multiple silver-black signals in the
tumor cell nuclei significantly outnumber the red chromosome 17 signals; a ratio≥ 2.0 corresponds to a positive SISH53) (e) Normal findings without
HER2 gene amplification: approximately equal numbers of black gene and red chromosome 17 signals
3.2 Malignant Changes in the Breast
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Trang 40tumors, there is also the option of using targeted therapy.50
Veri-fication of pCR in patients after neoadjuvant therapy is a
favor-able prognostic factor on its own within various classification
systems.25In Germany, the extent of tumor regression is usually
measured using the grading described by Sinn (▶Table 3.6)
3.2.3 Papillary Lesions
There are several different breast lesions that are termed
“papil-lary.” They range from benign (papilloma; M8503/0) to benign
with atypia (DCIS/LCIS M8503/2) to intraductal (M8503/2),
encap-sulated (M8504/2, and M8504/3 in the case of focal invasion), and
(coarse) invasive papillary carcinoma (M8503/3) These must be
distinguished from invasive-micropapillary carcinomas (M8507/3)
and solid papillary carcinomas (M8509/2 and M8509/3)
Due to the partially overlapping terminology, exact frequency
data regarding the individual lesion types are not available On
the whole, however, papillomas are considerably more prevalent
(5% of benign breast lesions) than papillary carcinomas (ca 1–2%
of breast cancers)
Intraductal Papilloma with and without
Atypias
Formal pathology characterizes a papillary proliferation as
fin-gerlike epithelial protrusions on a core of connective tissue In
benign lesions, the typical double-layer characteristic of mantleepithelium with an intact basal cell layer (S100, CK5/6 positive)can be demonstrated (▶Fig 3.13) These lesions are usuallycentrally located as isolated tumors in the cystically ectatic retro-mammillary section of the excretory duct.34The more peripher-ally located papillary lesions represent a greater problem as theycan be associated with atypical epithelial proliferations in or nearthe papillary lesion in up to 43% of cases Due to this heterogene-ity of papillomas, even lesions that appear to be benign in thecore needle biopsy sample are classified as B3 (uncertain malig-nant potential) (see▶Table 3.4)
Intraductal, Encapsulated, and Invasive Papillary Carcinoma
In these cases one finds a circumscribed papillary lesion confined
to the milk ducts, which—unlike a papilloma—is characterized by
a monomorphic (“clonal”) cell population; in other words, it haslost the characteristic double-layer with basal myoepithelium(CK5/6 negative;▶Fig 3.14) One variant is the intracystic papil-lary carcinoma, in which the papillary proliferation may formwithin cysts up to 10 cm in size The prognosis with this type oflesion is comparable to that of DCIS (see Chapter 3.2.4) providedthat invasive growth has been ruled out.29The prognosis is simi-larly favorable in the case of a so-called encapsulated papillarycarcinoma, which is separated from surrounding tissue by a thick,fibrous wall.11By contrast, invasive papillary carcinoma (IPC) is agrossly-invasive neoplasia with predominantly papillary architec-ture (more than 90%) The prognosis corresponds to that for inva-sive carcinomas (NST)
Micropapillary and Solid Papillary Carcinomas
These are two rare forms of invasive carcinoma (less than 1–2% ofcases):
●Micropapillary carcinomas: These are tumors in which thetumor cells seem to be located in cavities (usually due toshrinkage artifacts) and which are made up of small cell prolif-erations that may form central lumina (micropapillae withoutconnective tissue stroma) These tumors commonly show
Fig 3.13 Intraductal papilloma (a) The epithelial proliferation on fingerlike, branching stroma papillae fills the milk duct (b) The epithelialproliferation shows—as seen for normal duct epithelia—a myoepithelial layer (brown) located below the luminal epithelium (CK5/6 positive)
Table 3.6 Grading of tumor regression according to Sinn et al47
Grade Histological findings
0 No effect
1 Increased tumor sclerosis with focal resorptive
inflam-mation and/or pronounced cytopathic effects
2 Extensive tumor sclerosis with only focal, possibly
multifocal, detection of minimally invasive tumorresidue (≤ 0.5 cm); frequently extensive DCIS
3 No invasive tumor residue
4 No residual tumor (neither invasive nor in situ)
Abbreviation: DCIS, ductal carcinoma in situ
3