Breast Cancer Casting Type Calcifications. - Tabár

I
II
III
Breast Cancer
Early Detection with Mammography
Casting Type Calcifications:
Sign of a Subtype with Deceptive Features
László Tabár, MD
Professor and Director
Department of Mammography
Central Hospital
Falun, Sweden
University of Uppsala School of Medicine
Uppsala, Sweden
Tibor Tot, MD, PhD

Associate Professor of Pathology and Chairman
Department of Pathology and Clinical Cytology
Central Hospital
Falun, Sweden
University of Uppsala School of Medicine
Uppsala, Sweden
Peter B. Dean, MD
Professor
Department of Diagnostic Radiology
University of Turku
Turku, Finland
Visiting Professor
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA
With contributions by
Tony Hsiu-Hsi Chen, DDS, PhD; Stephen W. Duffy, MSc; Amy Ming-Fang Yen, PhD;
Sherry Yueh-Hsia Chiu, PhD
975 illustrations
Thieme
Stuttgart · New York
IV
Library of Congress Cataloging-in-Publication Data Important note: Medicine is an ever-changing science under-
is available from the publisher. going continual development. Research and clinical ex-
Tabár, László. perience are continually expanding our knowledge, in partic-
Breast cancer : the art and science of early detection with ular our knowledge of proper treatment and drug therapy. In-
mammography / László Tabár, Tibor Tot, Peter B. Dean. sofar as this book mentions any dosage or application, readers
p. ; cm may rest assured that the authors, editors, and publishers
ISBN 3-13-135371-6 (GTV : alk, paper) -- ISBN 1-58890-259-5 have made every effort to ensure that such references are in
(TNY : alk. paper) accordance with the state of knowledge at the time of pro-
1. Breast--Radiography--Atlases. 2. Breast--Cancer-Imaging-- duction of the book.
Atlases. Nevertheless, this does not involve, imply, or express any
[DNLM: 1. Breast Neoplasms--radiography. 2. Early Diagno- guarantee or responsibility on the part of the publishers in re-
sis. 3. Mammography--methods. 4. Radiographic Image Inter- spect to any dosage instructions and forms of applications
pretation, Computer-Assisted. WP 870 T112b 2005] I. Tot, stated in the book. Every user is requested to examine care-
Tibor. II. Dean, Peter B. III. Title. fully the manufacturers’ leaflets accompanying each drug and
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1 2 3 4 5 6
V
This book is dedicated to those physicians

who believe that greater knowledge
of the many subtypes of breast cancer
will lead to more individualized diagnosis
and therapy, to the ultimate benefit of their
patients.
VI
VII
Preface
Breast cancer is a heterogeneous disease in terms of his- that is associated with minimal invasion, although it may
tology, imaging, and outcome. Mammography as a screening behave like a very advanced cancer, much to the surprise of
examination has brought to light a new spectrum of breast all concerned.
cancer cases dominated by nonpalpable, preclinical tumors. Failure to recognize and single out this subtype, as well
The outcome of women with early stage disease is consider- as separate it from the other, truly early cases, has led to
ably better than that of women with late stage disease. The undertreatment of some women and overtreatment of
histologic and imaging findings in the early phase consist of many women with mammographically detected breast
a wide spectrum of minimal changes caused by early inva- cancer. We sincerely hope that greater knowledge and in-
sive and in situ disease, but the spectrum of imaging findings creased awareness of the breast cancer subtype present-
narrows as the disease advances. Our series of volumes on ing with casting type calcifications on the mammogram
the earliest manifestations of breast cancer is being written will serve two distinct purposes: to enable physicians to
to demonstrate and teach the importance of this phenome- prevent an even greater number of early deaths from breast
nal heterogeneity, which should affect the planning of surgi- cancer, while at the same time minimizing the need for
cal and adjuvant therapy. grueling and fatiguing therapy of most women with early
This volume seeks to uncover a deviant subtype of breast breast cancer.
cancer, easily recognizable by its mammographic and histo-
logic appearance, one that has yet to receive sufficient atten- 2007 László Tabár
tion despite its uniquely unpredictable nature. This subtype Tibor Tot
is generally considered to be a form of in situ disease or one Peter B. Dean
VIII
IX
List of contributors
Hsiu-Hsi Chen, DDS, PhD Ming-Fang Yen, PhD
Professor Institute of Preventive Medicine
Institute of Preventive Medicine College of Public Health
Division of Biostatistics National Taiwan University
Centre of Biostatistics Consultation Taiwan
College of Public Health
National Taiwan University Yueh-Hsia Chiu, PhD
Taiwan Institute of Preventive Medicine
College of Public Health
Stephen W. Duffy, MSc National Taiwan University
Professor of Cancer Screening Taiwan
Cancer Research Centre for Epidemiology,
Mathematics and Statistics
Wolfson Institute of Preventive Medicine
London, UK
X
XI
Contents
Chapter 1 Description of Calcifications Localized within the Ducts 1
General Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Characteristic Mammographic and Histological

Description of Calcifications localized within Presentation of Fragmented Casting Type
the Ducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Calcifications on the Mammogram . . . . . . . . . . . . . . 16
Anatomical Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Mammographic−Histological Correlation When
“Secretory Disease” Type, Plasma Cell Mastitis Type Both Fragmented Casting Type and Dotted
Calcifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Casting Type Calcifications Are Present . . . . . . . . . . 22
Casting Type Calcifications . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Casting Type Calcifications—Differential
Fragmented and Dotted Casting Type Diagnostic Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Calcifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Dotted Casting Type Calcifications . . . . . . . . . . . . . . . . 38
Fragmented Casting Type Calcifications Mammographic Display of Widespread Dotted
on the Mammogram . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Casting Type Calcifications in Five Separate
Dotted Casting Type Calcifications Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
on the Mammogram . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Mammographic−Histological Correlation
Fragmented Casting Type Calcifications . . . . . . . . . . . . 12 of Dotted Casting Type Calcifications
Mammographic Display of Widespread on the Mammogram . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Fragmented Casting Type Calcifications Mammographic−Histological Correlation
in Five Separate Cases . . . . . . . . . . . . . . . . . . . . . . . . . . 12 of Dotted Casting Type Calcifications Caused
Macroscopic and Subgross Histological by Grade 1 DCIS, a Rare Event . . . . . . . . . . . . . . . . . . 64
Correlation When Fragmented Casting Type
Calcifications Fill an Entire Lobe . . . . . . . . . . . . . . . . 14
Chapter 2 The Evolution of Casting Type Calcifications 73
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cluster of Calcifications as the Earliest Sign . . . . . . . . . . 80

No Apparent Abnormality on the Previous Subtle Casting Type Calcifications as the Earliest
Mammogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Sign . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Chapter 3 The Theory of Neoductgenesis 127
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 (C) Disorganized Architecture . . . . . . . . . . . . . . . . . . . . . 138

Comparison of Benign and Malignant Intraductal (D) Pathologic Ducts: Contorted and Crowded
Calcifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Closely Together . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
The Theory of Ductoneogenesis . . . . . . . . . . . . . . . . . . . . . 134 Histological Demonstration of Multiple Newly
Proposal of the Theory of Neoductgenesis . . . . . . . . . . . 135 Formed Ducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Morphological Demonstration of Neoductgenesis . . . . 135 (E) Tenascin Overexpression . . . . . . . . . . . . . . . . . . . . . . 154
(A) Unnaturally High Concentration of Ductlike Neoductgenesis with Asymmetric Density
Structures within a Limited Area . . . . . . . . . . . . . . . . . . 135 and Very Subtle, Associated Calcifications . . . . . . . . . . . 164
(B) Desmoplastic Reaction and Extensive Neoductgenesis without Associated Calcifications . . . . 172
Lymphocytic Infiltration . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Chapter 4 The Deviant Nature of the Breast Cancer Subtype with Castings 181
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Poor Correlation of Outcome with Mode of Therapy . . 204

The Use of Mammographic Tumor Features to Study Demonstration of Local Recurrence Following
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Relative Frequency of Breast Cancer Occurrence Axillary Node Status and Mammographic Tumor
by Mammographic Tumor Features . . . . . . . . . . . . . . . 185 Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Long-Term Outcome by Mammographic Tumor Histological Malignancy Grade and Mammographic
Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Tumor Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Proportion of Breast Cancer Death by Outcome of 1−14 mm Casting Cases Compared
Mammographic Tumor Features . . . . . . . . . . . . . . . . . . 192 with Advanced Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Demonstration of Fatal Cases with Casting Type
Calcifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
XII Contents
Chapter 5 Recognition of the Unpredictable, Often Fatal Nature of the Breast Cancer
Subtype Presenting with Casting Type Calcifications on the Mammogram 227
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Distant Metastases with Casting Type Calcifications . . 266

Examples with Fatal Outcome . . . . . . . . . . . . . . . . . . . . . . 230 Suggestion for Use of the Mammographic Prognostic
Frequent Recurrence with Casting Type Features in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . 270
Calcifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Chapter 6 Illustrative Cases with 3-Dimensional Stereoscopic Histological Images 273
Case 6.1 ........................................... 274 Case 6.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Case 6.2 ........................................... 277 Case 6.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Case 6.3 ........................................... 283 Case 6.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
Case 6.4 ........................................... 287
References 309
General Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Chapter 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

Chapter 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Chapter 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Chapter 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Chapter 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Subject Index 311

1
Chapter 1 Description of
Calcifications Localized
within the Ducts
2
3
General Introduction
Whenever calcifications are seen on the mammogram, the lowing aspects is provided to assist the reader in under-
radiologist should attempt to determine the anatomical cav- standing this complex breast cancer subtype:
ity within which the calcifications have been formed. The 1 Mammographic features
options are the following: 2 Mammographic−histological correlation using subgross
Within the ducts (secretory disease type and casting type (three-dimensional; 3D) large-section histology
calcifications) 3 Differential diagnosis
Within the TDLUs (crushed stone−like and powdery cal- 4 Clinical presentation
cifications) 5 Natural history: tendency for recurrence, therapeutic
Outside the glandular tissue (calcifications within the failures, long-term outcome
walls of blood vessels, within the stroma, around oil 6 A novel theory explaining the unexpectedly poor out-
cysts, or in the skin are characteristically benign) come of some cases with casting type calcifications
7 Practical implications for the management of patients
Knowledge of the cradle in which the calcifications have with casting type calcifications
been formed as well as analysis of their shape, density, and
distribution will facilitate an understanding of the underly- A unique collection of 3D mammographic/subgross 3D pa-
ing pathophysiological process. thology images for stereoscopic viewing with companion 2D
This volume deals with the most unpredictable entity conventional histology images is included at the end of this
among the breast cancer subtypes, which appears on the volume.
mammogram as casting type (BI-RADS® fine, linear, branch-
ing) calcifications.1−6 A detailed description of all of the fol-
4
Description of Calcifications localized

within the Ducts
Anatomical Background
The milk duct in the resting state is pleated and measures Accumulation of either fluid or cancer cells with necrotic de-
about 0.1−0.5 mm in width (Figs. 1.1 to 1.4). bris will greatly distend the duct system.1 Differentiating
these two entities from each other is a challenge faced by
the radiologist.
1.1 1.2
Fig. 1.1 Subgross histological image of milk ducts in the resting state.
1.3 1.4
Figs. 1.3 & 1.4 Subgross histological images of milk ducts, longitudinal and cross sections.
“Secretory Disease” Type, Plasma Cell Mastitis Type Calcifications 5
“Secretory Disease” Type,

Plasma Cell Mastitis Type Calcifications
An excessive amount of fluid produced by the TDLUs can
gradually accumulate within the ducts and their branches.
1.5 1.6
Figs. 1.5 & 1.6 Subgross histological images of milk ducts in the resting state and distended by fluid.
1.7 1.8
Figs. 1.7 & 1.8 Subgross histological images of milk ducts distended by inspissated fluid.
6 Description of Calcifications Localized within the Ducts
1.9 1.10
Figs. 1.9 & 1.10 Subgross histological images of milk ducts distended by inspissated fluid.
As water is resorbed from this fluid, the residual alkaline, 1 Long, needle-like calcifications (intraductal form)
proteinaceous material may calcify. These linear, often 2 Hollow, ringlike or tubelike calcifications (periductal
branching calcifications are localized within the preexisting form)
duct system and reflect its regular, harmonious structure.
This process, commonly called “secretory disease,” is bi- Intraductal form: The more commonly occurring long,
lateral, which explains the usual bilateral presentation of needle-like calcifications are merely calcified duct contents,
these typical calcifications. which assume the smooth, regular outline of the duct
There are two mammographic presentations of these cal- lumen. The mammographic image of these calcifications
cifications: will also have a homogeneously high density (Figs. 1.11 to
1.18).
1.11 1.12
Figs. 1.11 & 1.12 Detail images of CC projections with the intraductal form of “secretory disease” type calcifications.
1.13 1.14
Figs. 1.13 & 1.14 An asymptomatic woman, screening examination. The intraductal form of “secretory disease” type calcifications out-
lines the regular, harmonious structure of the preexisting duct system.
“Secretory Disease” Type, Plasma Cell Mastitis Type Calcifications 7
Periductal form: The hollow, ringlike or tubelike calcifica- scribe the mammographic finding: “plasma cell mastitis
tions occur when the proteinaceous fluid escapes through type calcifications.” These calcifications surround the duct,
the atrophic, porous duct wall and a sterile, asymptomatic so that the hollow center of the calcifications corresponds to
“mastitis” is initiated. This process is actually an immuno- the noncalcified duct lumen. This less common form is typi-
logical reaction with predominance of plasma cells and per- cally accompanied by the intraductal form.
iductal fibrosis. This explains the other term used to de-
1.15 1.16
Figs. 1.15 & 1.16 The periductal form of “secretory disease” or plasma cell mastitis type hollow calcifications
associated with fibrosis.
1.17 1.18
Figs. 1.17 & 1.18 MLO and CC projections demonstrate both the intraductal and periductal forms of “secretory
disease” or plasma cell mastitis type calcifications.
Casting Type Calcifications

these calcifications and their remarkable heterogeneity
Fragmented and Dotted Casting should resolve this deceptive appearance. (Examples 1.3 to
Type Calcifications 1.5). Microfocus magnification images will provide addi-
tional help in differential diagnosis because considerably
It is important to differentiate the plasma cell mastitis/ more calcifications will become evident if the lesion is
secretory disease type calcifications from the calcifications malignant, whereas magnification will not reveal additional
seen in a breast cancer subtype commonly called high nu- plasma cell mastitis type calcifications. Rarely, a partially
clear grade/poorly differentiated/Van Nuys Group 3/Grade 3 calcified fibroadenoma, traumatic fat necrosis, or benign in-
DCIS. traductal papilloma may contain focal branching calcifica-
The striking differences are the unilateral, lobar distribu- tions, which mimic casting type calcifications.
tion and the highly irregular, disharmonious appearance of When the dominant histological feature is the micropapil-
the malignant type calcifications. There are two mammo- lary growth pattern, the dotted casting type calcifications
graphic presentations: the fragmented casting type and are seen on the mammogram. In this type the duct lumen is
the dotted casting type, determined by the cellular growth filled with innumerable, separate, tiny, amorphous calcified
pattern of these two high-grade malignant processes. particles. The tips of the micropapillary tumor growth ex-
The solid growth pattern of high nuclear grade, poorly tensions break off and eventually calcify. These individual
differentiated cancer cells produces extensive intraluminal calcified particles accumulate to form the typical dotted
necrosis and amorphous calcifications, which correspond to casting image on the mammogram. (Fig. 1.24-1 to 3). There
the mammographic image of fragmented, elongated and is no benign pathological process localized within the ducts
branching calcifications (Figs. 1.22-1 to 3). The ductal lumen that produces a similar mammographic image.
is filled with cancer cells, necrotic debris, and amorphous An overview of the histological−mammographic correla-
calcifications that outline segments of the distended duct tion of these two subtypes of high-grade DCIS, seen on the
lumen in the form of solid, intermittent, cylindrical casts. mammogram as fragmented and dotted casting type calcifi-
These fragmented casting type calcifications form a par- cations, is presented in Figs. 1.21 to 1.24.
tial outline of the duct and its branches on the mammogram Although relatively infrequent, the casting type calcifica-
(Figs. 1.25 to 1.29). The origin of these calcifications can be tions represent the most reliable mammographic sign of
deduced from their typical mammographic appearance. Ini- malignancy, as 97 % of them will be malignant at histology
tially these calcifications will have an irregular contour but, (Fig. 1.19). The remaining 3 % are found in fibroadenomas,
as the necrotic process advances and the debris becomes benign papillomas, and rarely in traumatic fat necrosis.
more extensively calcified at the expense of the viable The distribution of malignant type calcifications is shown
malignant cells, the mammographic image will exhibit cal- in Fig. 1.20, based on 322 consecutive, histologically proven
cifications with a smoother outline and a more homo- breast cancer cases with calcifications on the mammogram
geneous density. This may occasionally cause differential di- as the only radiological abnormality. Casting type calcifica-
agnostic problems if the analysis is restricted to individual tions accounted for about 29 % of all malignant type calcifi-
calcifications. However, the localized, lobar distribution of cations.
Casting Type Calcifications 9
1.19
Fig. 1.19 The probability of malignancy is as high as 97 % when the finding on the mammogram
is casting type calcification(s) with or without an associated tumor mass. Women of all ages; pro-
spectively collected consecutive cases. These and subsequent patient material are all from the
Department of Mammography, Falun Central Hospital.
Casting Type (92/322)

29.0%
48.0% Powdery (74/322)
Crushed Stone–like
23.0% (156/322)
12-year total 1.20
Fig. 1.20 Relative frequency of malignant type calcifications without an associated tumor
mass. Women of all ages.
Fragmented Casting Type Calcifications

on the Mammogram
Characteristic histological features:

Large, polymorphic nuclei with frequent mitoses
Cell architecture: solid growth pattern
Extensive intraluminal necrosis
Amorphous calcifications filling segments of the ductal
lumen
Characteristic mammographic image:

Intermittent, elongated, branching, fragmented casting
type calcifications
The calcifications are usually scattered within a large part
of the lobe, where they are confined to the duct system.
Fig. 1.21 Schematic diagram representing fragmented casting

type calcifications. 1.21
1.22-1 1.22-3
Fig. 1.22-1 Mammogram. Fig. 1.22-2 Subgross, thick Fig. 1.22-3 Conventional histology.
section (3D) histology.
Fragmented and Dotted Casting Type Calcifications 11
Dotted Casting Type Calcifications

on the Mammogram
Characteristic histological features:

Large, polymorphic nuclei
Cell architecture: predominantly micropapillary, mixed
with solid growth pattern
Intraluminal necrosis
Numerous discrete amorphous calcifications within the
intraluminal necrosis
Characteristic mammographic image:

Dotted casting type, “snake skin”-like
Scattered, outlining most of the lobe
Fig. 1.23 Schematic diagram representing dotted casting type

1.23 calcifications.
1.24-1 1.24-3
Fig. 1.24-1 Mammogram. Fig. 1.24-2 Subgross, thick section (3D) histology Fig. 1.24-3 Conventional histology.
Fragmented Casting Type

Calcifications
Mammographic Display of Widespread
Fragmented Casting Type Calcifications in
Five Separate Cases
1.25 1.26
1.27 1.28
Fig. 1.25 to 1.28 Detail of MLO projections in four asymptomatic women showing a large number of casting type calcifica-
tions.
Fragmented Casting Type Calcifications 13
Fig. 1.29-1 Left breast, detail of

the CC projection with numerous
casting type calcifications without
an associated tumor mass.
1.29-1
Fig. 1.29-2 Operative specimen

radiograph of the case shown in
Fig. 1.29-1.
1.29-2
Macroscopic and Subgross Histological

Correlation When Fragmented Casting
Type Calcifications Fill an Entire Lobe
Fig. 1.30-1 Photograph of an operative specimen sliced at the

level of the nipple. 1.30-1
1.30-3
Fig. 1.30-3 Further magnification of the distended TDLUs and
their associated subsegmental duct.
Fig. 1.30-2 Subgross histological image covering much of the af-

fected lobe. The main duct, many of its branches and two TDLUs
1.30-2 (circle) are greatly expanded by the malignant process.
Fig. 1.30-5 & 6 Subgross histological−mammographic correla-

tion of the findings. The TDLUs contain the crushed stone−like cal-
cifications (circles), while the fragmented, casting type calcifica-
tions are localized in the ducts.
1.30-4 1.30-5
Fig. 1.30-4 A section of the retroareolar duct containing the
malignant process and the necrotic debris. Note the adjacent nor-
mal-sized pleated ducts.
1.30-6
The imprecise term “comedo” should be replaced by a de-

Comment
tailed description of:
The term “comedo carcinoma” has frequently been used to
describe the subtype of DCIS with extensive necrosis, solid cell The histological grade of the malignant cells
proliferation, and amorphous calcium. The duct contents are Their growth pattern
under pressure and tend to ooze out from a freshly cut surface The presence of central necrosis and calcifications
in a manner resembling “comedones” or “comedos” when
squeezed out from the skin of the face. These in turn are
named from their resemblance to maggots (grub or larvae of
flies and other insects), which are also termed “comedones” in
Latin. This term, when applied to describe breast cancer, has
the disadvantage of being variously interpreted by different
subspecialists. Its use tends to lead to confusion, since it fails
to accurately describe the underlying pathology.
Characteristic Mammographic and Example 1.1

Histological Presentation of Fragmented A 66-year-old asymptomatic woman, screening examina-
Casting Type Calcifications on the tion.
Mammogram
Ex. 1.1-1 Ex. 1.1-2

Ex. 1.1-1 & 2 Left breast, detail of the MLO and CC projections. There are branching calcifications without an associated tumor mass
extending to the retroareolar region.
Ex. 1.1-3 Ex. 1.1-4 Ex. 1.1-5

Ex. 1.1-3 to 5 Correlative subgross, thick section histological, microfocus mammographic and conventional histological images of the
region with casting type calcifications.
Ex. 1.1-6 Ex. 1.1-7
Ex. 1.1-8 Ex. 1.1-9

Ex. 1.1-6 to 9 Typical histological appearance of these mammographically detected fragmented casting type calcifications showing
large, polymorphic nuclei with frequent mitoses, solid cell proliferation, extensive intraluminal necrosis, and amorphous calcifications.
Example 1.1 continued
Ex. 1.1-10 Ex. 1.1-11 Ex. 1.1-12

Ex. 1.1-10 to 12 Histological examination of cases with extensive fragmented casting type calcifications often reveals ducts where
the necrosis encompasses the entire duct lumen, with few or no viable cancer cells remaining. These calcifications are of uniformly high
density on the mammogram.
Ex. 1.1-13 & 14 Comparative opera-

tive specimen radiograph and sub-
gross histology: the calcifications
within the ducts having extensive
necrosis and few viable cancer cells
will have a higher density and a de-
ceptively smooth contour.
Ex. 1.1-13 Ex. 1.1-14

Characteristic Mammographic and Histological Presentation of Fragmented Casting Type Calcifications on the Mammogram
Ex.
1.1-15 Ex. 1.1-16
Ex. 1.1-15 & 16 Conventional and subgross histological images of a cross section of a distended duct containing amorphous calcium
and surrounded by a desmoplastic reaction.
Ex.
1.1-17 Ex. 1.1-18
Ex. 1.1-17 & 18 Subgross and conventional histological images of ducts with extensive necrosis and a few remaining cancer cells.
The presence of fragmented casting type calcifications is a

highly reliable radiological sign of malignancy. Preoperative
microscopic diagnosis is necessary for optimum patient man-
agement. Histological−mammographic correlation helps us
understand that the regions containing calcifications with
high, even density and smooth contour will have the fewest
viable malignant cells. These are typically found in the more
central portion of the region with calcifications (Ex. 1.1-19).
Aiming at these regions with the larger-bore needle will
harvest calcifications, but few, if any, cancer cells.
Ex.
1.1-19
Ex. 1.1-19 to 21 Conventional and subgross histological images

of ducts from the regions outlined in the rectangles on the mam-
mogram below.
Ex.
1.1-20
Ex.
1.1-21
Ex. 1.1-22 The casting type calcifications

are of higher and uniform density; smooth-
contoured in the central portion of the
lesion (rectangles). Few viable cancer cells
accompany them.
Ex.
1.1-22
Characteristic Mammographic and

Histological Presentation of Fragmented
Casting Type Calcifications on the
Mammogram
The largest number of viable cancer

cells is usually found at the periphery of
the region with calcifications. Targeting
this area is more likely to provide diag-
nostic samples.
Ex. 1.1-23 to 25 Subgross and conven-

tional histological images of ducts from the
regions outlined in the rectangle on the
mammogram below, showing a large num-
ber of cancer cells.
Ex. 1.1-24
Ex. 1.1-23 Ex. 1.1-25
Ex. 1.1-26 The preferred site for larger-

bore needle biopsy is outlined by the rect-
angle.
Treatment and follow-up: In this case

the Grade 3 DCIS was spread over an
area measuring 5 cm × 3 cm. Because of
close margins, mastectomy was per-
formed. No evidence of recurrence was
found at the most recent follow-up
11 years after surgery Ex. 1.1-26
Mammographic−Histological Correlation Example 1.2

When Both Fragmented Casting Type and Twenty-one months following chemotherapy for carcinoma
Dotted Casting Type Calcifications Are of the cervix, this 29-year-old woman felt a “thickening” in
her left breast.
Present
Ex. 1.2-1 Ex. 1.2-2

Ex. 1.2-1 & 2 Left breast, MLO and detail of the MLO projections. The mammograms show innumerable calcifications without an
associated tumor mass.
Ex. 1.2-3 Left breast, detail of the CC pro-

jection.
Ex. 1.2-3
Ex. 1.2-4 & 5 Microfocus magnification mammography, MLO

and CC projections, demonstrating both types of casting calcifica-
tions, with a predominance of the fragmented casting type. The
rectangle with the dashed border outlines the dotted casting type
calcifications, and the rectangle with the solid border outlines
some of the fragmented casting type calcifications.
Ex. 1.2-4
Ex. 1.2-5
Ex. 1.2-6 Mastectomy specimen

radiograph.
Ex. 1.2-6
Ex. 1.2-7 Large-section histology (H&E

staining) shows an area measuring
70 mm × 35 mm with Grade 2 and 3 DCIS
with both micropapillary and solid cell pro-
liferation and a 3 mm focus of invasion.
Axillary dissection: no metastases found in
15 axillary lymph nodes.
Ex. 1.2-7
Ex. 1.2-8 Ex. 1.2-9

Ex. 1.2-8 & 9 Medium power magnification of the numerous cancerous ducts; some filled with mucin, some with necrosis and central
calcifications.
Mammographic−Histological Correlation When Both Fragmented Casting Type and Dotted Casting Type Calcifications Are Present
Ex. Ex.
1.2-10 1.2-11
Ex. 1.2-10 & 11 Detail of the mastectomy specimen radiograph. The malignant type calcifications can be seen along the resection
margin.
Ex. Ex.
1.2-12 1.2-13
Ex. 1.2-12 Large-section histology demonstrates the wide ex- Ex. 1.2-13 Subgross histological image showing
tent of the disease, with involved margins. the unnaturally high density of the cancerous ducts.
Ex. 1.2-14 Ex. 1.2-15

Ex. 1.2-14 & 15 Mammographic−histological correlation of a region with fragmented casting type calcifications.
Ex. 1.2-16 Ex. 1.2-17

Ex. 1.2-16 & 17 Mammographic−histological correlation of a region with the dotted casting type calcifications (circles).
Mammographic−Histological Correlation When Both Fragmented Casting Type and Dotted Casting Type Calcifications Are Present
Ex. 1.2-18 Ex. 1.2-19

Ex. 1.2-18 & 19 Conventional and subgross, thick section histology images of a duct distended by micropapillary DCIS,
necrosis, and calcifications.
Ex. 1.2-20 Subgross, thick-section

(3D) image demonstrating the rich
vascularization in this high grade
DCIS case.
Treatment and follow-up: Mast-

ectomy. Prophylactic mastectomy
of the contralateral breast re-
vealed LCIS. Follow-up: no recur-
rences found nine years after
operation. Ex. 1.2-20
Casting Type
Calcifications—
Differential Diagnostic
Problems
Fragmented Casting Type
Calcifications Which Bear a
Resemblance to Benign
Secretory Disease Type
Calcifications
Example 1.3
A 69-year-old asymptomatic
woman, screening examination.
Ex. 1.3-1 Right breast, detail of the

CC projection. Calcifications are
seen over a large area, without an Ex. 1.3-1
associated tumor mass.
Ex. 1.3-2 Microfocus magnification.

Although the calcifications are of
uniformly high density and smooth
contoured, as in plasma cell mastitis
type calcifications, they are oriented
in a number of different directions,
which should arouse suspicion
about a malignant process (neo-
ductgenesis).
Ex. 1.3-2
Ex. 1.3-3 Sliced specimen radio-

graph.
Ex. 1.3-3
Ex. 1.3-4 Large section histology:

Grade 3 DCIS found over an area
measuring 2.0 cm.
Ex. 1.3-4
Ex. 1.3-5 Microfocus magnification in the

MLO projection demonstrates that the
linear calcifications have an irregular orien-
tation, strengthening the suspicion of a
malignant process within the ducts.
Ex. 1.3-5
Ex. 1.3-6
Ex. 1.3-6 & 7 Subgross, thick-section (3D) histological image of a

long, distended duct containing cancer cells and calcifications. Ex. 1.3-7
Differential Diagnostic Problems
Ex. 1.3-8
Ex. 1.3-9
Ex. 1.3-8 to 10 These histological images show why the calcifica-

tions on the mammogram may have smooth borders and a uni-
form density. This happens after most of the cancer cells have
undergone necrosis and have calcified. However, in the immedi-
ate vicinity, there may be viable cancer cells with no necrosis. Ex. 1.3-10
Histological diagnosis: 20 mm × 20 mm Grade 3 DCIS, solid,

cribriform and clinging type. No metastases were found in
five axillary lymph nodes.
Treatment and follow-up: Sector resection with no addi-

tional treatment. No recurrences at the most recent follow-
up at 10 years.
Fragmented Casting Type Calcifications May Be Example 1.4

Deceptive, Particularly When Presenting as a Small A 66-year-old asymptomatic woman, screening examina-
Cluster tion.
Ex. 1.4-1 Ex. 1.4-2
Ex. 1.4-1 to 3 MLO (1) and CC (3) projec-

tion mammograms of the right breast.
Recalled for further work-up of a small
group of calcifications without a tumor
mass. Microfocus magnification mammo-
graphy (2) reveals malignant type linear,
branching calcifications and additional
irregular calcified particles. The rectangles
outline the cluster of calcifications.
Ex. 1.4-3
Ex. 1.4-4 Specimen radiograph shows that

the malignant type calcifications are dis-
tributed over a large area (rectangle).
40 mm
35 mm
Ex. 1.4-4
Ex. 1.4-5 & 6 Histology: 40 mm × 35 mm Grade 3 solid and mi-

cropapillary DCIS with signs of epithelial−stromal interaction (pe-
riductal desmoplastic reaction and lymphocytic infiltration).
Ex. 1.4-5
Ex. 1.4-6
Ex. 1.4-7 Histology: Images of the Grade

3 micropapillary “carcinoma in situ” com-
ponent with periductal desmoplastic reac-
tion and lymphocytic infiltration.
Ex. 1.4-7
Treatment and follow-up: Sector resection with no addi-

tional treatment. No recurrences at 16 years of follow-up.
Comment
When the fragmented casting type calcifications are localized
to a small area, are smooth contoured and have a high and
uniform density, it is more difficult to differentiate them from
secretory disease type calcifications. The differential diagnosis
is assisted by remembering the following:
1 The casting type calcifications occur unilaterally while se-
cretory disease type calcifications are typically bilateral.
2 Furthermore, microfocus magnification mammography
will always reveal additional malignant type calcifications,
while the number of benign type calcifications will not be
increased following magnification. This is because the ma-
lignant type calcifications are in various phases of develop-
ment, so that the increased resolution of microfocus mag-
nification will reveal the fainter calcifications that are more
highly fragmented, have a more irregular contour, and are
more typically malignant. On the other hand, since the
benign calcifications are of uniformly high density, they will
usually be already sufficiently visible on the standard mam-
mograms.
Example 1.5
A 68-year-old asymptomatic woman,
screening examination.
Ex. 1.5-1 & 2 Left breast, detail of the MLO

and CC projections. A small cluster of calci-
fications is outlined by rectangles.
Ex. 1.5-1
Ex. 1.5-2
Ex. 1.5-3 & 4 Microfocus magnification of the areas outlined by

the rectangles on Ex. 1.5-1 & 2, respectively. The linear, branching
calcification has a deceptively smooth contour and a uniformly
high density on both images. No associated tumor mass is seen.
Ex. 1.5-3
Ex. 1.5-4
Ex. 1.5-5 Specimen radiograph. The calcifications have been re-

moved with a good margin. No associated tumor mass is seen
(despite several small invasive foci found at histological examina-
tion).
Ex. 1.5-5
Ex. 1.5-6 Ex. 1.5-7

Ex. 1.5-6 Grade 3 DCIS on an area measuring 23 mm × 10 mm. Ex. 1.5-7 High-density intraductal calcification with no asso-
There is also an invasive ductal carcinoma measuring 3 mm in ciated cancer cells.
maximum diameter. Tumor-free margin: 8 mm.
Ex. 1.5-8 Ex. 1.5-9

Ex. 1.5-8 Tiny invasive carcinoma including DCIS with calcifica- Ex. 1.5-9 Mammographically occult, noncalcified in situ carci-
tion. noma with lymphocytic infiltration.
Treatment and follow-up: Sector resection and postopera-

tive irradiation. No signs of recurrence at follow-up exami-
nation 12 years after treatment.
Dotted Casting Type Calcifications

Mammographic Display of Widespread
Dotted Casting Type Calcifications in Five
Separate Cases
Figs. 1.31 to 1.35 Five separate examples of dotted casting type

calcifications. The main ducts and their branches are distended by
innumerable, dotlike calcifications, outlining the duct system.
1.31
Fig. 1.31 Image courtesy of Professor Gillian Newstead.
1.32 1.33
Dotted Casting Type Calcifications 39
1.34
Fig. 1.35 Image courtesy of Professor Peter J.

Dempsey.
1.35
Mammographic−Histological Correlation
of Dotted Casting Type Calcifications on
the Mammogram
Example 1.6
A 40-year-old asymptomatic woman with no family history
of breast cancer. First screening examination.
(see page 11 for comment)
Ex. 1.6-1 Ex. 1.6-2

Ex. 1.6-1 & 2 Right breast MLO and CC projections. There are innumerable calcifications spread throughout the upper half of the
breast, but they are restricted to a single lobe. No associated tumor mass is demonstrable.
Ex. 1.6-3 Cases with widely distributed

malignant type calcifications within a single
lobe, such as demonstrated in Ex. 1.6-1 & 2,
as well as those galactograms that outline
a single lobe arborizing over two or more
quadrants (as here) indicate that breast
cancer localized within a single diseased
lobe can occupy more than one quadrant
and still be unicentric.
Ex. 1.6-3
Ex. 1.6-4 to 6 CC projection, microfocus

magnification images over the retorareolar
area (4) and the central portion of the
breast (5), and low-power histology image
(6). The extremely large number of ducts
crowded closely together, as well as their
disorganized orientation, give a striking
pathological appearance. Compare Ex. 1.6-5
with the ductogram of a normal breast
shown in Ex. 1.6-3.
Ex. 1.6-4
Ex. 1.6-5
Ex. 1.6-6
Ex. 1.6-7 Right breast, MLO projec-

tion, microfocus magnification view.
The malignant type calcifications oc-
cupy a considerable portion of the
upper half of the breast. Note also
the high concentration of pathologi-
cal ducts in random orientation.
Ex. 1.6-7
Ex. 1.6-8 Large-section histology.

High-grade DCIS over a very large
area. No signs of invasion are de-
monstrable, although there were
seven axillary nodes with metas-
tases.
Ex. 1.6-8
Mammographic−Histological Correlation of Dotted Casting Type Calcifications on the Mammogram
Ex. 1.6-9 Ex. 1.6-10 Ex. 1.6-11
Ex. 1.6-13
Ex. 1.6-9 to 13 Microfocus magnification image of the nipple-

areola region (9 & 12). The dotted casting type calcifications fill
the main duct all the way to the nipple surface. The histological
Ex. images (11 & 13) of a distended duct show the micropapillary in-
1.6-12 situ carcinoma associated with the amorphous calcifications.
Ex. 1.6-14 Large-section histology of one

of the many slices showing the high con-
centration of cancerous ductlike structures.
Ex.
1.6-14
Ex. 1.6-15 Microfocus magnification mam-

mogram of the medial half of the breast.
Ex.
1.6-15
Ex. 1.6-16 Low-power histological image,

H&E and Alcian blue staining. Some of the
ducts have central necrosis with amorphous
calcifications; others contain micropapillary
cell proliferation and mucinous material
(blue).
Ex.
1.6-16
Treatment and outcome: Right mastectomy and Tamoxifen noma in the opposite breast. Left mastectomy. The patient
treatment. Eleven years following mastectomy, the patient also developed a primary lung cancer with brain metastases,
developed a 14 mm × 13 mm Grade 2 invasive ductal carci- of which she died at age 54 years.
Ex. Ex.
1.6-17 1.6-18
Ex. 1.6-17 & 18 Micropapillary DCIS with amorphous calcifications corresponding to the microcalcifications on the mammogram.
Ex. Ex.
1.6-19 1.6-20
Ex. 1.6-19 & 20 Histological examination reveals additional large areas with noncalcified micropapillary DCIS producing a mucinous
fluid.
Ex. Ex.
1.6-21 1.6-22
Ex. 1.6-21 Histological image of one of the metastatic axillary Ex. 1.6-22 14 × 13 mm Grade 2 invasive ductal carcinoma in the
lymph nodes. opposite breast.
Example 1.7
An asymptomatic woman, screening case.
Ex. 1.7-1 Ex. 1.7-2

Ex. 1.7-1 Left breast, CC and MLO mammograms (not ductograms!). The main duct of one
large lobe and all its branches are filled with calcifications from the nipple all the way to the
chest wall.
Ex. 1.7-2 Subgross, thick-section histological image of the nipple and central-retroareolar
region of the breast showing the pathologically dilated duct surrounded by normal ducts.
(Case courtesy of Dr. Melissa Trekell, Knoxville, TN, USA.)
Ex. 1.7-3 Ex. 1.7-4

Ex. 1.7-3 & 4 Left breast, detail of the MLO projection showing the outlining of a large lobe by calcifications.
Mammographic−Histological Correlation of Dotted Casting

Type Calcifications on the Mammogram
Ex. 1.7-5
Ex. 1.7-6
Ex. 1.7-7
Ex. 1.7-5 to 7 Mammographic−subgross histological correlation of the main duct and some
of its branches. This magnification demonstrates that the ducts are filled with dotted casting
type calcifications. The subgross, thick-section (3D) histology (Ex. 1.7-5) reveals the micro-
papillary cell growth pattern. The greatly distended lumen contains mostly necrotic material
and calcifications.
Ex. 1.7-8 to 10 Mammographic−histologi-

cal correlation of the diseased main duct
and comparison with the main ducts of the
adjacent normal lobes. The profound dis-
tension of the cancerous duct is striking
when compared to the pleated, normal
sized ducts (subgross histological images,
Ex. 1.7-9 & 10).
Ex.
1.7-8
Ex. Ex.
1.7-9 1.7-10
Ex. Ex.
1.7-11 1.7-12
Ex. 1.7-11 & 12 The extreme distension of the cancerous ducts is mainly caused by the necrotic, extensively calcified debris. The micro-
papillary cell proliferation can be followed along the basement membrane, while the von Kossa (silver nitrate) staining depicts the calci-
fications in black.
Ex. 1.7-13 Higher-magnification histologi-

cal image demonstrates the dispropor-
tionately small volume of the papillary cell
growth in relationship to the massive
volume of necrotic debris. The tips of the
continuously growing micropapillae break
off and eventually calcify in the lumen.
Ex.
1.7-13
Ex. 1.7-14 Ex. 1.7-15

Ex. 1.7-14 & 15 The saccular dilatation of one of the ducts is caused by extreme accumulation of calcified
debris. The thin rim of viable cancer cells can be seen along the inner wall of the duct.
Ex. 1.7-16 The subgross and conventional histological images

(Ex. 1.7-14 & 15) help make the mammographic appearance more
understandable.
Ex.
1.7-16
Ex. Ex.
1.7-17 1.7-18
Ex. 1.7-17 Subgross histological image of a duct with micropap- Ex. 1.7-18 to 20 These higher-power histological images show
illary DCIS. the micropapillary cell growth, the detached cancer cells within
the lumen, and the partially or entirely calcified cell clumps.
Ex. Ex.
1.7-19 1.7-20
Ex. 1.7-21 to 23 Mammographic−histologi-

cal correlation of the more distal ducts en-
croaching upon the chest wall.
Ex.
1.7-21
Ex. Ex.
1.7-22 1.7-23
Ex. 1.7-22 Histology (H&E and von Kossa staining). Micropapil- Fig. 1.7-23 Subgross histology demonstrating the large amount
lary DCIS with intraluminal calcifications. of intraluminal debris and calcium particles.
Mammographic−Histological Correlation
of Dotted Casting Type Calcifications on
the Mammogram
Ex. 1.7-24 to 26 Numerous cancerous

ducts containing few or no calcifications are
interspersed among the ducts filled with
calcifications, indicating that the disease ex-
tends beyond what is evident from the
mammogram. Ex. 1.7-24
Ex. 1.7-25
Treatment and follow-up: Mastectomy

patient lost to follow-up. Ex. 1.7-26
Example 1.8
A 32-year-old woman felt a lump in the lateral portion of her
right breast.
Ex. 1.8-1
Ex. 1.8-1 & 2 Microfocus magnification shows the ill-defined

circular tumor surrounded by a large number of dotted casting
type calcifications. Ex. 1.8-2: Microfocus magnification specimen
radiograph. The calcifications are seen both within the tumor and
in its surroundings. Ex. 1.8-2
Ex. 1.8-4
Ex. 1.8-3
Ex. 1.8-3 Large-section histology (H&E) images of the surgical
resection.
Figs. 1.8-4 & 5 High-power histological images of the surgical re-

section. The Grade 2 invasive ductal carcinoma measures 12 mm
and is surrounded by Grade 3 solid and cribriform DCIS measuring
35 mm. All nine resected axillary lymph nodes were free of dis-
ease. Ex. 1.8-5
Ex. 1.8-7
Ex. 1.8-6 Ex. 1.8-8

Ex. 1.8-6 to 8 Mammographic−histological correlation of the invasive tumor and the surrounding DCIS with dotted casting type calci-
fications.
Ex. 1.8-9 The extensive dotted casting

type calcifications outline the branching
ducts in exquisite detail.
Ex. 1.8-9
Ex.1.8-10 One duct containing

dotted casting type calcifications is
“entrapped” in the invasive tumor.
Ex.
1.8-10
Ex. 1.8-11 Mammographic−subgross, thick-section (3D) histo-

logical comparison of the portion of the invasive carcinoma that
envelops the dilated duct containing the dotted casting type calci-
fications (rectangle).
Ex.
1.8-11
Mammographic−Histological Correlation of
Dotted Casting Type Calcifications on the
Mammogram
Ex. 1.8-12 & 13 Subgross histological im-

ages. The enveloped duct with the calcified
particles is visualized on 3D histology at
progressively increasing magnification.
Ex. 1.8-12
Treatment and follow-up: The patient

received radiation therapy of the re-
maining right breast and was free of
disease 10 years after sector resection. Ex. 1.8-13
Ex.
1.8-14 Ex. 1.8-15
Ex. 1.8-14 & 15 Conventional histology images of micropapillary and solid DCIS.
Example 1.9
A 48-year-old asymptomatic woman
Ex. 1.9-1
Ex. 1.9-1 Screening examination. Detail of the
MLO projection, left breast. High in the axillary
tail, faint calcifications are seen in the accessory
breast tissue.
Ex. 1.9-2 Microfocus magnification images in

the MLO and CC projections: there is a region
containing crushed stone−like calcifications
associated with a dilated duct filled with dotted
casting type calcifications. No tumor mass is
seen. Ex. 1.9-2
Mammographic−Histological
Correlation of Dotted Casting Type
Calcifications on the Mammogram
Ex. 1.9-3 Microfocus magnification,

exaggerated CC projection.
Ex. 1.9-4 Corresponding histologi-

cal image: small invasive cancer
(oval) and DCIS.
Ex. 1.9-3 Ex. 1.9-4
Ex. 1.9-5 Ex. 1.9-6

Ex. 1.9-5 Breast ultrasound reveals a small invasive tumor within Ex. 1.9-6 A 5 mm invasive carcinoma (circle) and cribriform DCIS.
the aberrant tissue containing the calcifications.
Ex. 1.9-7 The invasive cancer is tubular carcinoma at histology. Ex. 1.9-7
Ex. 1.9-8 Operative specimen radiograph containing all of the

calcifications.
Ex. 1.9-8
Ex. 1.9-9 The operative specimen

was sliced by the pathologist. Con-
tact radiography of the two slices.
Ex. 1.9-9
Calcifications on the Mammogram
Ex. 1.9-10 Microfocus magnifica-

tion image of one of the two speci-
men slices demonstrating the dis-
tended duct, which is filled with the
dotted casting type calcifications.
Ex. 1.9-10
Ex. 1.9-11 Low-power histological

image of the duct dilated by cancer
cells, debris, and small calcium par-
ticles, corresponding to the dotted
casting type calcifications on the
mammogram.
Ex. 1.9-11
Ex. 1.9-14
Ex. 1.9-13
Ex. 1.9-13 to 17 Collage
of adjacent histological pic-
tures to better demon-
strate the cancerous ducts.
Ex. 1.9-15
Ex. 1.9-18 Microfocus

magnification image of
the second specimen slice
containing the crushed
Ex. 1.9-18 stone−like calcifications.
Ex. Ex.
1.9-19 1.9-20
Ex. 1.9-19 & 20 Low-power histology image of the Grade 2 cribriform carcinoma in situ associated with necrosis and central, amor-
phous calcifications. These calcifications correspond to the crushed stone−like calcifications on the mammogram. The area with DCIS
measured 30 mm × 20 mm and DCIS foci were seen close to the resection margin.
Dotted Casting Type Calcifications on the
Mammogram
Comment
This case is interesting because the axil-
lary breast tissue mimics a single diseased
lobe within the breast: the cancerous pro-
cess fills in and distends both the TDLUs
and the entire main duct within the acces-
sory breast. The disease becomes appa-
rent through the malignant type calcifica-
tions. The duct outlined by the dotted
casting type calcifications has the typical
shape of any major duct approaching the
nipple, but in this case there was no de-
tectable supernumerary nipple.
Treatment and follow-up: Sector resec-

tion and postoperative irradiation. There
was a local recurrence (DCIS) at the site of
surgery six years after treatment. Ex. 1.9-12
Ex. 1.9-16
Ex. 1.9-17
Mammographic−Histological Correlation Example 1.10

of Dotted Casting Type Calcifications A 68-year-old asymptomatic woman, screening examina-
Caused by Grade 1 DCIS, a Rare Event tion.
Ex. 1.10-1 Ex. 1.10-2
Ex. 1.10-3 Ex. 1.10-4

Ex. 1.10-1 to 4 Right breast, MLO projection (1) and with microfocus magnification (3). Adjacent to the hol-
low, benign type calcifications, there are linear, dotted casting type calcifications. Subgross, thick section
(3D) histology (2 & 4) shows that the tiny, psammoma body−like calcifications are localized within ducts dis-
tended by cribriform DCIS.
Ex. 1.10-5 Ex. 1.10-6
Ex. 1.10-7 Ex. 1.10-8

Ex. 1.10-5 to 8 Histological images (H&E) of this cribriform and micropapillary Grade 1 DCIS with psam-
moma body−like calcifications. These layered calcifications are localized in the small cavities surrounded by
the cancer cells. The faint dotted casting pattern is a summation image of large numbers of these tiny calcifi-
cations, which are too small to be individually perceptible on the mammogram.
Ex. 1.10-9 & 10 Subgross (9) and conven-

tional histological (10) images of the micro-
papillary component of this in situ carci-
noma. The malignant cells produce fluid
that distends the lumen.
Ex.
1.10-9
Ex.
1.10-10
Ex. 1.10-11 Subgross, thick-section (3D)

histological image of the cribriform com-
ponent of this DCIS.
Ex.
1.10-11
Dotted Casting Type Calcifications Caused
by Grade 1 DCIS, a Rare Event
Ex. 1.10-12 to 14 Three subgross, thick-

section (3D) histological images of the
cribriform component of this DCIS, with
and without associated calcifications.
Ex. 1.10-12
Ex. 1.10-13
Treatment and follow-up: Mastectomy.

No recurrence was observed at the most
recent follow-up at 15 years following
treatment. Ex. 1.10-14
Example 1.11
A 66-year-old asymptomatic
woman, screening examination.
Ex. 1.11-1 & 2 Left breast CC pro-

jection (1) and detail of the MLO
projection (2) show a small group
of calcifications in the central region
of the breast, with no associated
tumor mass.
Ex.
1.11-1
Ex.
1.11-2
Calcifications Caused by Grade 1
DCIS, a Rare Event
Ex. 1.11-3 & 4 Microfocus magni-

fication images reveal faint dotted
casting type calcifications.
Ex. 1.11-3
Ex. 1.11-4
Ex. 1.11-5 Histological examination

(H&E): micropapillary carcinoma in
situ with psammoma body−like cal-
cifications (circle).
Ex.
1.11-5
Ex. 1.11-6 Higher magnification of

the psammoma body−like calcifica-
tions.
Ex.
1.11-6
Comment
The psammoma body−like calcifications cannot be seen in-
dividually on the mammogram because they are too small.
The summation of many of these crystalline calcium particles
will result in faint, barely detectable microcalcifications. Grade
1 DCIS rarely occurs within the major ducts, but when it does,
the associated psammoma body−like calcifications can be
seen as dotted casting type calcifications on the mammo-
gram.
Dotted Casting Type Calcifications Caused
by Grade 1 DCIS, a Rare Event
Ex. 1.11-7 to 9 The mammographically vis-

ible microcalcifications do not reveal the full
extent of carcinoma in situ, especially when
it is Grade 1. Ex. 1.11-7 to 9 represent the non-
calcified micropapillary DCIS in this case.
Ex. 1.11-7
Ex. 1.11-8
Treatment and follow-up: Sector re-

section and postoperative irradiation.
No recurrence was observed at the most
recent follow-up at 10 years following
treatment. Ex. 1.11-9
73
Chapter 2 The Evolution of Casting

Type Calcifications
74
The Evolution of Casting Type Calcifications 75
Introduction
Consecutive series of mammograms provide the opportu- Magnetic resonance imaging can demonstrate the true
nity to observe the development of breast disease. Concern- extent of the disease earlier and far beyond the mam-
ing the specific breast cancer subtype presenting with cast- mographically detectable calcifications, because genetic
ing type calcifications on the mammogram, it appears that changes predisposing to malignant transformation appear
one breast lobe might have been genetically malconstructed to occur simultaneously throughout much of the lobe.
or damaged during intrauterine life. These genetic altera-
tions of the lobe may remain subclinical for decades. The
A Possible Biological Explanation for the Above
emergence of this specific breast cancer subtype may show
different patterns on the mammogram and on other imag- Observations
ing modalities, as follows: The development of the ductal system of the breast is in-
1 No apparent abnormality on the previous mammo- itiated in early embryological life, at which time the number
gram. In some cases the malignant type calcifications of main ducts is determined. The final arborization of the
seem to appear “suddenly” over a surprisingly large ducts takes place at puberty. While the number of TDLUs is
area on the mammogram although the previous exami- subject to continuous proliferation and involution during
nation showed no abnormalities. In these distressing the next few decades, the number of lobes, each with a main
cases the defective lobe with its numerous new duct, will remain constant. If one of the lobes becomes
branches due to “neoductgenesis” may appear on the genetically altered during embryological or adult life and ac-
mammogram in its entirety within a relatively short pe- quires a propensity for malignant change, this unique breast
riod, similarly to a submarine surfacing suddenly from cancer subtype can develop. It is characterized by both a
beneath the water (Example on pages 76−79). malignant transformation of the epithelial cells within
2 Cluster of calcifications as the earliest sign. In many of preexisting ducts and also by a rapid, disorderly formation of
the cases, a cluster of crushed stone−like calcifications new duct branches. This pattern is in stark contrast to that of
may be seen on the previous mammogram(s), often as- other breast cancer subtypes, which are characterized by
sociated with one or two linear calcifications, that pro- malignant transformation of the TDLUs involving only part
gress to extensive casting type calcifications on sub- of a lobe. The genetic changes predisposing to malignancy
sequent mammograms (Examples on pages 80−117). and the subsequent malignant process are both able to in-
3 Subtle casting type calcifications as the earliest sign. volve the duct system of an entire lobe (whatever its size).
In some cases, the earliest mammographically de- The result is a complex conglomerate of both preexisting
tectable phase of the casting cases may be subtle casting and newly formed neoplastic ducts. This suggested process
type calcification(s) that have been overlooked (Ex- may explain the seemingly sudden emergence of extensive
amples on pages 118−125). disease on the mammogram, although functional imaging
methods, such as contrast-enhanced MRI of the breast, may
When the initial, subtle sign of this already extensive dis- detect the presence of disease considerably earlier and over
ease is missed (or the patient is placed on short-term fol- a larger extent than does the mammogram.
low-up), the rapid development of this highly malignant In any case, the diagnostic and therapeutic team members
process may be manifest on the next mammogram by the need to be aware of the frequently extensive and highly fatal
appearance of innumerable casting type calcifications over a nature of this special subtype of breast cancer.1−9
surprisingly large region of the breast. To pursue the
analogy, the conning tower of a submarine will be visible
first, while the emergence of the body will follow later.
76 The Evolution of Casting Type Calcifications
No Apparent Abnormality on the Previous Mammogram

Only one case (Ex. 2.1) is presented here. The first group
Example 2.1
comprises cases in which no mammographic sign of the
presence of the disease was present at the time of the pre- A 69-year-old asymptomatic woman, screening examina-
vious examination. tion.
Ex. 2.1-1 Ex. 2.1-2

Ex. 2.1-1 & 2 Right and left breasts, MLO projections. No mammographic abnormality is seen.
Ex. 2.1-3 Ex. 2.1-4

Ex. 2.1-3&4 Nineteenmonthslaterthepatientfeltalumpintheupperouterquadrantofherrightbreast.Correspondingto
the clinically palpable lesion, the mammogram shows innumerable calcifications. Mammogram, MLO projection (Ex. 2.1-3)
and microfocus magnification (Ex. 2.1-4): de novo casting type calcifications with an associated nonspecific density.
No Apparent Abnormality on the Previous Mammogram 77
Ex. 2.1-5 Ex. 2.1-6

Ex. 2.1-5 Right breast, detail of the MLO projection, mi- Ex. 2.1-6 Preoperative localization: bracketing the patho-
crofocus magnification. logical lesions using multiple wires.
Ex. 2.1-7 Ex. 2.1-8

Ex. 2.1-7 & 8 Subgross, thick section 3D histological images demonstrate a large number of ducts packed tightly
together, distended by cancer cells, necrosis and amorphous calcifications.
Ex. 2.1-9 Specimen radio-

graph demonstrating the Ex.
calcifications. 2.1-9
Ex. 2.1-10 Large-section histology (H&E).
The calcifications within the contorted
cancerous ducts surrounded by desmoplas-
tic reaction correspond to the mammo-
graphic findings. The presence of an abnor-
mally high concentration of the pathologi-
cal ducts over a confined area makes it
highly unlikely that these could be pre-
existing ducts.
Ex.
2.1-10
Ex. 2.1-11 Higher-power large-section
histological image. The palpable lesion is
formed by the mass of abnormal ducts
surrounded by the desmoplastic reaction.
Ex.
2.1-11
No Apparent Abnormality on the Previous Mammogram 79
Ex. Ex.
2.1-12 2.1-13
Ex. 2.1-12 & 13 Comparative mammographic and thick-section histological images of this rapidly developing Grade 3 “in situ” process.
The millimeter scale shows that the individual ducts are extremely distended by the pathological process.
Ex. 2.1-14 Demonstration of the dense

desmoplastic reaction surrounding the
ducts and the extensive periductal lympho-
cytic infiltration. Histological diagnosis:
48 mm × 34 mm Grade 3 DCIS with a few
areas of microinvasion up to 1 mm. No
metastases were found in seven axillary
lymph nodes.
Ex. 2.1-14
Ex. 2.1-15 High-power magnification histo-

logical image (H&E): Grade 3 carcinoma in
situ with central necrosis.

The patient was recurrence-free at
the most recent follow-up examination
seven years after surgery. Ex. 2.1-15
Cluster of Calcifications as the Earliest Sign

The second group comprises cases in which very subtle early
Example 2.2
signs of the presence of the disease have not been fully
appreciated. The crushed stone−like calcifications may rep- A 43-year-old asymptomatic woman, screening examina-
resent a precursor of castings. We can speculate from the tion. A single cluster of calcifications was not perceived at
underlying histology that if the malignant process produc- screening.
ing crushed stone−like calcifications is not removed surgi-
cally, it could progress to widespread disease producing
casting type calcifications. Judging from the underlying his-
tology, these would have developed to casting type calcifica-
tions over a large area had they not been removed surgically.
Ex. 2.2-1 Detail of the left MLO screening

mammogram. The circle outlines the tiny
cluster of calcifications.
Ex. 2.2-1
Ex. 2.2-2 Photographic magnification of the cluster of crushed

stone−like calcifications.
Ex. 2.2-2
Cluster of Calcifications as the Earliest Sign 81
Ex. 2.2-3 & 4 Twenty-five months later, still asymptomatic,

screening examination. Left MLO (3) and CC (4) projections. In-
numerable casting type calcifications have appeared since the
previous examination, and are spread over two-thirds of the
breast. No associated tumor mass is visible.
Although the first visible calcification cluster was localized in the
upper outer quadrant, the calcifications are now found not only in
the upper half of the breast but also fill part of the lower half of
the breast, with the corresponding main duct being also filled
with malignant type calcifications (rectangle).
Ex. 2.2-3
Ex. 2.2-4
Ex. 2.2-8 Ex. 2.2-9

Ex. 2.2-8 & 9 Subgross (8) and low-power conventional (9) histo-
logical images of ducts containing micropapillary DCIS and calcifi-
cations.
Ex. 2.2-5 Ex. 2.2-5 Detail of the lateromedial horizontal projection.
Ex. 2.2-6 Ex. 2.2-7

Ex. 2.2-6 & 7 Microfocus magnification images demonstrate the presence of both types of casting type
calcifications, fragmented and dotted.
Ex. 2.2-10 The calcifications demonstrate

a plethora of ducts containing both types of
casting type calcifications.
Ex. 2.2-10
Ex. 2.2-11 Large-section histological

image. The cancerous ducts occupy a large
area (rectangle).
Ex. 2.2-11
Ex.
2.2-12 Ex. 2.2-13
Ex. 2.2-12 & 13 Medium-power histological images of solid and micropapillary DCIS with intraluminal necrosis and central calcifica-
tions.
Ex. 2.2-14 Additional magnification image

of this case.
Ex.
2.2-14
Ex. 2.2-15 & 16 Histological diagnosis:

120 mm × 60 mm area with Grade 3 DCIS.
No metastases were found in the nine axil-
lary lymph nodes removed at surgery.
Ex.
2.2-15
Ex.
2.2-16
Ex. 2.2-17 & 18 Histological slides demon-

strating the localization of some of the dot-
ted casting type calcifications.
Ex. 2.2-17
Ex. 2.2-18
Treatment and follow-up: mastectomy without adjunctive

treatment. The patient was recurrence-free at the most re-
cent follow-up examination 16 years after surgery.
Example 2.3
A 51-year-old asymptomatic woman, screening examina-
tion.
Ex. 2.3-1 Ex. 2.3-2

Ex. 2.3-1 & 2 Left breast, detailed images in the MLO and CC projections. The tiny cluster of calcifications in the lower inner quadrant
was not perceived.
Ex. 2.3-3 Ex. 2.3-4

Ex. 2.3-3 & 4 Photographic magnification of the area with the calcifications.
Ex. 2.3-5 Ex. 2.3-6

Ex. 2.3-5 & 6 Two years later, at the next screening examination, the woman is now aged 53 and is still asymptomatic. Detail of the
MLO projection (5) and with microfocus magnification (6). A large number of casting type calcifications occupy the entire lower inner
breast.
Ex. 2.3-7 CC projection demonstrating

the extensive calcifications and a tiny stellate
lesion.
Ex. 2.3-7
Ex. 2.3-8 & 9 Microfocus magnification

images of the medial and mid portions of
the left breast in the CC projection.
Ex. 2.3-8
Ex. 2.3-9
Ex. 2.3-10 Ultrasound Ex. 2.3-11 Specimen radiograph Ex. 2.3-12 Ex. 2.3-13
image of the stellate lesion. of an ultrasound guided 14G core Ex. 2.3-12 & 13 Histology of the core sample: Grade 2 invasive
biopsy sample. ductal carcinoma.
Ex. 2.3-14 & 15

Microfocus magnifica-
tion radiographs of
5-mm thick specimen
slices.
Ex.
Ex. 2.3-14 2.3-15
Ex. 2.3-16 & 17

Subgross, thick-section
(3D) histological images
of the extensive in situ
carcinoma with calcifi-
cations.
Ex.
Ex. 2.3-16 2.3-17
Ex.
2.3-18 Ex. 2.3-19
Ex. 2.3-18 One of the specimen slices reveals four tiny stellate Ex. 2.3-19 The subgross histological image demonstrates one of
lesions. the lesions, associated with intraductal tumor growth.
Ex. 2.3-21
Ex. 2.3-21 The largest of the four inva-
sive cancer foci (3 mm × 3 mm).
Ex. 2.3-20 Subgross, large-section his-

tology showing one invasive focus and
numerous DCIS foci. DCIS was seen over
Ex. an area of 60 mm × 45 mm (Grade 1−3,
2.3-20 solid, micropapillary and cribriform).
Ex.
2.3-22 Ex. 2.3-23
Ex. 2.3-22 & 23 Subgross, thick-section (3D) (22) and conventional thin section (23) histological images of the micropapillary DCIS.
Treatment and follow-up: Mastectomy. No recurrence was

demonstrable at her most recent follow-up at 9 years and
6 months after treatment.
Example 2.4
A 58-year-old woman presented
with a palpable, hard lump in the
upper outer quadrant of her right
breast. Her previous screening
mammogram taken 16 months
earlier had been interpreted as
normal.
Ex. 2.4-1 Right breast, CC projec-

tion, previous screening examina-
tion at age 56 years. Ex. 2.4-1
Ex. 2.4-2 Photographic magnification of the re-

gions outlined in Ex. 2.4-1. The upper rectangle
shows one nonspecific calcification; the lower
rectangle outlines a small cluster of calcifications
without an associated tumor mass.
Ex. 2.4-2
Ex. 2.4-3 Right breast, CC projec-

tion, 16 months after the previous
mammographic examination, now
aged 58.
Ex. 2.4-3
Ex. 2.4-4 Photographic magnification of the re-

gions outlined in Ex. 2.4-3. The upper rectangle
shows predominantly crushed stone−like calcifica-
tions, while in the lower rectangle there is a mix-
ture of crushed stone−like and casting type calcifi-
cations.
Ex. 2.4-4
Ex. 2.4-5 & 6 Right and left breasts, MLO

projections. Multiple clusters of calcifica-
tions are seen outlined by the rectangle.
Ex. 2.4-5 Ex. 2.4-6
Ex. 2.4-8
Ex. 2.4-8 Fine-needle aspiration biopsy of
the palpable tumor: malignant cells.
Ex. 2.4-7
Ex. 2.4-7 Microfocus magnification: a mixture of crushed stone−
like and casting type calcifications are grouped in multiple
clusters.
Ex. 2.4-9 Operative specimen radiograph

with multiple clusters of calcifications.
Ex. 2.4-9
Ex. 2.4-10 Large-section histology, H&E

staining. The area containing the calcifica-
tions is encircled.
Ex. 2.4-10
Ex. 2.4-11 Radiographs of the specimen

slices demonstrating the clusters of calcifi-
cations.
Ex.
2.4-11
Ex. Ex.
2.4-12 2.4-13
Ex. 2.4-12 & 13 Microfocus magnification of the areas with the malignant type calcifications in the specimen slices. These are a mixture
of crushed stone−like and casting type calcifications; but there is no demonstrable tumor mass.
Ex. 2.4-14 Large-section histological image

of a slice containing some of the calcifica-
tions and surrounding tissue. Combined
H&E and von Kossa staining. The clusters of
calcifications, stained in black, are encircled.
Ex. 2.4-14
Ex. 2.4-15 Radiograph of one of the speci-

men slices with a cluster of calcifications.
Ex. 2.4-15

(H&E stain) of a slice containing the calci-
fications. The smaller rectangle outlines
the area with calcified DCIS; the larger
rectangle shows the area containing non-
calcified DCIS, measuring together
50 mm × 30 mm.
Ex.
2.4-16
Ex. 2.4-17 Detail image of the histological

slide (combined H&E and von Kossa stain-
ing). The dark dots represent the calcifica-
tions.
Ex.
2.4-17
Ex. 2.4-18 Further magnification of the cal-

cified area on the histological slide (com-
bined H&E and von Kossa staining). The
silver nitrate staining (von Kossa) selectively
marks the calcifications.
Ex.
2.4-18
Ex. 2.4-19 Calcified and noncalcified DCIS

foci side by side.
Ex. 2.4-19
Ex. 2.4-20 Low-power histological image

showing solid cell proliferation, central ne-
crosis, and amorphous calcification.
Ex. 2.4-20
Ex. 2.4-21 High-power histological image

demonstrates the Grade 3 cancer cells with
large nuclei and nucleoli.
Ex. 2.4-21
Ex. 2.4-22 Large-section histology (H&E

stain). The rectangle outlines the area with
noncalcified DCIS.
Ex.
2.4-22
Ex. 2.4-23 Large-section histology, com-

bined H&E and von Kossa staining. The rect-
angle outlines the area with noncalcified
DCIS.
Ex.
2.4-23
Ex. 2.4-24 Low-power histological image

shows the solid cell proliferation and central
necrosis without amorphous calcification.
The absence of calcifications explains why
this area was occult on the mammogram.
Ex.
2.4-24

(H&E stain). The part of the image outlined
by the oval mark contains a tiny focus of
Grade 2 invasive ductal carcinoma (detail
image in Ex. 2.4-26). An additional 8 mm
focus was found in another histologic sec-
tion. The rectangle outlines lymph vessel in-
vasion (see Ex. 2.4-27).
Ex. 2.4-25
Ex. 2.4-26 Higher-magnification of the area

within the oval-shaped mark in Ex. 2.4-25,
showing a 2 mm Grade 2 invasive ductal
carcinoma.
Ex. 2.4-26
Ex. 2.4-27 The Grade 3 cancer cells are

seen within two lymph vessels (LVI, lymph
vessel invasion). Also, micrometastases
were found in one of 10 axillary lymph
nodes.

The patient was free from recurrence
at the most recent follow-up, four years
after treatment. Ex. 2.4-27
Example 2.5
tion.
Ex. 2.5-1 Ex. 2.5-2

Ex. 2.5-1 & 2 Right breast, MLO projection and microfocus magnification over the area with calcifications detected at screening.
Ex. 2.5-3 Microfocus magnification in the

CC projection. The crushed stone−like calci-
fications have irregular density, size, and
shape. Instead of further work-up with
needle biopsy, six-month follow-up was er-
roneously chosen.
Ex. 2.5-3
The patient returned after six months

with an obvious, palpable tumor.
Ex. 2.5-5
Ex. 2.5-4
Ex. 2.5-4 & 5 Right breast, MLO and CC projections showing an
ill-defined malignant tumor, corresponding to the palpable lesion.
Ex. 2.5-6 Ultrasound examination demonstrates a large invasive

carcinoma that had developed during the six month follow-up
period. Ex. 2.5-6
Ex. 2.5-7
Ex. 2.5-7 & 8 Microfocus magnification images in the MLO and
CC projections demonstrate the evolution of casting type calcifi-
cations within and surrounding the tumor.
Case courtesy: Dr. D.N.
Treatment and follow-up: Mastectomy. The patient moved

and was lost to follow-up. Ex. 2.5-8
Example 2.6
Screening examination of a 64-year-old asymptomatic wo-
man.
Ex. 2.6-1 Ex. 2.6-2

Ex. 2.6-1 & 2 Screening mammograms, detail of the MLO and CC projections. There are scattered, nonspecific microcalcifications in
the upper portion of the breast, without an associated tumor mass.
Ex. 2.6-3 Microfocus magnification, CC

projection. Although the calcifications ap-
pear to be nonspecific, their location in
the retroglandular clear space should have
indicated further work-up with large-bore
needle biopsy.
Ex. 2.6-3
Ex. 2.6-4 Screening examination two years later, still asympto-

matic. Right breast, detail of the MLO projection. The calcifica-
tions now occupy a larger area.
Ex. 2.6-4
Ex. 2.6-5 Microfocus magnification view,

right MLO projection. The calcifications are
now clearly of the casting type.
Ex. 2.6-5
Ex. 2.6-6 Right breast, CC projection.
Ex. 2.6-6
Ex. 2.6-7 Right breast, microfocus magni-

fication. The casting type calcifications have
evolved over the very same area where
the nonspecific calcifications were previously
localized.
Ex. 2.6-7
Ex. 2.6-8 Fine-needle aspiration biopsy:

atypical cells.
Ex. 2.6-8
Ex. 2.6-9 Specimen radiograph. The calcifi-

cations are seen on the surgical margin.
Ex. 2.6-9
Ex. 2.6-10 Large, thin-section (3−4 μm)

histology: 55 mm Grade 3 DCIS.
Ex. 2.6-10
Ex. 2.6-11 Large, thick-section, subgross

(about 1000 μm) histology, showing the
malignant ductal proliferation extending to
the surgical margin.
Ex. 2.6-11
Ex. 2.6-12 Detail of a microfocus specimen

radiograph.
Ex.
2.6-12
Ex. 2.6-13 & 14 Details of a subgross his-

tology specimen showing the amorphous
calcifications associated with the neoplasm.
Ex.
2.6-13
Ex.
2.6-14
Ex. 2.6-15 Large, thin-section histology

showing the extent of the disease.
Ex. 2.6-15
Ex. 2.6-16 Medium-power magnification

(H&E stain). Longitudinal section of the
cancerous duct filled with necrotic debris
and calcifications. Only a few viable cancer
cells can be demonstrated. There is periduc-
tal desmoplastic reaction and lymphocytic
infiltration.
Ex. 2.6-16
Ex. 2.6-17 High-power magnification

showing the Grade 3 cancer cells.

The histological examination showed an
additional 40 mm focus of DCIS. The
patient was symptom-free at the most
recent follow-up examination seven
years after treatment. Ex. 2.6-17
Example 2.7
(Case courtesy of Dr. Angela Sie, M.D., Long Beach, CA, USA)
tion. A single cluster of calcifications was detected at screen-
ing.
Ex. 2.7-1 Ex. 2.7-2

Ex. 2.7-1 & 2 Right breast, MLO and CC projections demonstrate the tiny cluster of crushed stone−like
calcifications (encircled) with no associated tumor mass.
Ex. 2.7-3 Microfocus magnification view:

Mammographically malignant type calcifi-
cations.
Ex.
2.7-3
Ex. 2.7-4 Preoperative large-bore needle biopsy

showing a representative sample of calcifications
contained in the specimen. Histology: Grade 2 & 3
DCIS.
Ex. 2.7-4
Ex. 2.7-5 & 6 Axial breast contrast

MRI shows a much greater extent of
the disease than can be appreciated
from the mammogram.
Ex. 2.7-5
Ex. 2.7-6
Treatment and follow-up: Mastectomy. The histological ex-

amination showed Grade 2 and Grade 3 DCIS with multiple
foci of Grade 2 invasive cancers ( 10 mm). The patient was
symptom-free at the most recent follow-up examination
two years after treatment.
Example 2.8
A 53-year-old asymptomatic woman, screening examination.
Ex. 2.8-1 Left breast, detail of the MLO projection showing a small cluster
of non-specific calcifications. The tiny cluster of non-specific calcifications Ex.
were not perceived. 2.8-1
Ex.
2.8-2
Ex. 2.8-2 & 3 Screening examination two years later, still asymptomatic.
Left breast, detail of the MLO (2) and CC (3) projections, photographic
magnification. The cluster of punctate calcifications was considered to be Ex.
of the “benign type” and “unchanged” since the previous examination. 2.8-3
Ex. 2.8-4
Ex. 2.8-4 & 5 An additional two years later the patient was still asymptomatic. The
individual calcifications have become larger and coarser. No associated tumor mass
is seen. Ex. 2.8-5
Ex. 2.8-6
Ex. 2.8-6 & 7 An additional three years later, the patient is still asymptomatic. The
calcifications have increased in number. Furthermore, a second cluster of calcifica-
tions and an associated tumor mass have developed. The importance of these
changes was not recognized. Ex. 2.8-7
Ex. 2.8-8 Ex. 2.8-9

Ex. 2.8-8 & 9 Two years after her last screening examination the patient felt a lump in the upper outer quadrant of her left
breast. Detail of the MLO and CC projections. There has been a dramatic change during the past two years, in contrast to the
gradual changes over the previous seven years.
Ex. 2.8-10 Ex. 2.8-11

Ex. 2.8-10 Microfocus magnification image of the pal- Ex. 2.8-11 Microfocus magnification radiograph of the
pable tumor, MLO projection. A cluster of coarse calcifica- paraffin block showing the cluster of coarse calcifications
tions is seen within the ill-defined, mammographically and the fragmented, casting type calcifications.
malignant tumor. In addition, fragmented, rodlike calcifi-
cations have developed.

of the tumor and its immediate surround-
ings (H&E).
Ex. 2.8-12
Ex. 2.8-13 Intermediate magnification,

demonstrating the area with the cluster
of coarse calcifications (H&E).
Ex. 2.8-13
Ex. Ex.
2.8-14 2.8-15
Ex. 2.8-14 High-power histological image (H&E). Ex. 2.8-15 The calcifications are surrounded by invasive and in
situ carcinoma (H&E).
Histology: 15 mm × 11 mm Grade 2 in-

vasive ductal carcinoma. Grade 2 DCIS
was found both inside the invasive com-
ponent and also in an area measuring
15 mm surrounding the invasive tumor.
pN0/16.
Ex. 2.8-16 Specimen radiograph of the Ex.

paraffin block containing the calcifications. 2.8-16
Ex. 2.8-17 Conventional histology (H&E). The casting type calci-

fications are localized to the in situ component adjacent to the
invasive tumor (within the rectangle on the mammogram).
Ex.
2.8-17
Ex. 2.8-18 Conventional histology (H&E).

Higher magnification of the in situ com-
ponent with calcification.
Ex. 2.8-18
Ex. 2.8-19 Histological (H&E) detail of the

in-situ carcinoma.
Ex. 2.8-19
Ex. 2.8-20 Specimen radiograph of the ax-

illary specimen containing 16 lymph nodes.
Ex. 2.8-20
Follow-up: The patient was alive and well at the most re-
cent examination, nine years following mastectomy.
Example 2.9
(Case courtesy of Michael Vendrell, M.D., Saint Paul, MN,
USA)
A 49-year-old asymptomatic patient had mammography
and breast MRI because her sister had a breast cancer.
Ex. 2.9-1 Ex. 2.9-2

Ex. 2.9-1 & 2 Right breast CC projection (1) and microfocus magnification (2): nonspecific calcifications are seen in the lower
inner quadrant without an associated tumor mass.
Ex. 2.9-3 Ex. 2.9-4

Ex. 2.9-3 & 4 Right breast MLO projection (1) and microfocus magnification (2): the nonspecific calcifications seem to form
small clusters.
Ex. 2.9-5 Ex. 2.9-6

Ex. 2.9-5 & 6 Breast MRI, sagittal (5) and axial (6) planes, water excitation, post-gadolinium contrast shows irregular, ductlike enhance-
ment in the lower inner quadrant of the right breast.
Ex. 2.9-7 Breast MRI. Use of a

lower threshold value for determina-
tion of contrast enhancement re-
sults in a larger volume of abnor-
mal-appearing tissue (in blue). The
red areas in the left axilla represent
enhancement of normal lymph
nodes.
Ex. 2.9-7
Ex. 2.9-8 Breast MRI, coronal projec-

tion, same parameters as Ex. 2.9-7.
The pathological enhancement is
encircled.
Histology of 14G core biopsy:

Grade 3 DCIS without sizable
areas of necrosis. No invasive foci
were found.
Comment
These images demonstrate the
ability of breast MRI to detect
the disease much earlier and to
a greater extent than mammog-
raphy.
Ex. 2.9-8
Subtle Casting Type Calcifications as the Earliest Sign

The third group comprises cases in which the earliest sign of
the presence of the disease is a few casting type calcifica-
Example 2.10
tions visible on the mammogram, but not appreciated. A 55-year-old asymptomatic woman, screening examina-
tion. Called back for further assessment of the fragmented,
rodlike calcifications in the upper portion of the left breast.
Ex. Ex.
2.10-1 2.10-2
Ex. 2.10-1 & 2 Left breast, MLO projection and microfocus magnification view. There are a few fragmented, rodlike calcifications
among the numerous dotlike and lucent-centered skin calcifications.
Ex. 2.10-3 Left breast, CC projection,

microfocus magnification view. The frag-
mented, rodlike calcifications have been
erroneously underdiagnosed.
Ex.
2.10-3
Subtle Casting Type Calcifications as the Earliest Sign 119
Ex. 2.10-4 Screening examination four years later, still asympto-

matic, age now 59. Left breast, MLO projection. The fragmented,
rodlike calcifications have increased in number and give the im-
pression that they are filling the duct lumen more completely.
Ex. 2.10-4
Ex. 2.10-5 Left breast, CC projec-

tion. Compared with the image four
years earlier (Ex. 2.9-3), one of the
linear, fragmented calcifications is
no longer seen. The remaining calci-
fications were not appreciated.
Ex. 2.10-5
Ex. 2.10-6 & 7 Subsequent screening examination two years

later, age now 61. Left breast, detail of the MLO and CC projec-
tions, photographic magnification. The fragmented, rodlike calci-
fications have become longer and more contiguous. No tumor
mass is seen associated with the developing calcifications. The im-
portance of the changes was not appreciated.
Ex.
2.10-6
Ex.
2.10-7
Ex. 2.10-8 & 9 Screening examination after an additional two

years, still asymptomatic, age now 63. Left MLO and CC projec-
tions. The patient was called back for further examination of the
developing density adjacent to the calcifications (magnification
views on the next page).
Ex.
2.10-8
Ex.
2.10-9
Ex. 2.10-10 & 11 Microfocus magnification views in the MLO and

CC projections, same examination date as in Ex. 2.10-8 & 9 on the
previous page. The calcifications are of the fragmented casting
type. The associated small tumor mass is ill-defined. Both the cal-
cifications and the tumor mass are mammographically malignant.
Ex.
2.10-10
Ex.
2.10-11
Ex. Ex.
2.10-12 2.10-13
Ex. 2.10-12 & 13 The tiny (7 × 5 mm) invasive component is a poorly differentiated ductal carcinoma.
Ex. Ex.
2.10-14 2.10-15
Ex. 2.10-14 & 15 Low-magnification histological images (H&E) of both the invasive and the in-situ components.
Ex. Ex.
2.10-16 2.10-17
Ex. 2.10-16 & 17 Low-power histology (H&E) of the area with calcified Grade 3 DCIS. Few viable cancer cells are seen in the immediate
vicinity of the casting type calcifications.
Treatment and follow-up: Mastectomy. The patient was

free from recurrence at her follow-up examination 14 years
after treatment.
Example 2.11
A 56-year-old asymptomatic woman underwent a series of with the development of an invasive tumor. This evolution
screening examinations. This case demonstrates both the can be studied because of a series of oversights. The authors
development of crushed stone−like and casting type calcifi- are grateful to B. L., MD, for donating this case for teaching.
cations and their subsequent disappearance concurrent
Ex. 2.11-1 Ex. 2.11-2 Ex. 2.11-3

Ex. 2.11-1 to 3 Detail of three successive MLO mammograms of the right breast. The first examination shows no abnormality (Ex. 2.11-1).
Two years later (at age 58) a solitary cluster of crushed stone−like, malignant type calcifications has appeared (Ex. 2.11-2). Oversight. At the
third examination one year later (at age 59), considerable change is seen (Ex. 2.11-3).
Ex. Ex.
2.11-4 2.11-5
Ex. 2.11-4 & 5 Photographic magnification of the second and third screening mammograms shows that some of the calcifications have
disappeared, but new, casting type calcifications have developed.
Ex. 2.11-6 Two years later (at age 61) Ex. 2.11-7 After another two years (age Ex. 2.11-8 After an additional year (at
more of the calcifications have disap- now 63) there is further disappearance age 64) the woman presents with a
peared. of the calcifications with the concurrent palpable tumor, manifested on the mam-
development of a faint density. mogram by two malignant tumors having
a dumbbell shape.
Ex. Ex.
2.11-9 2.11-10
Ex. 2.11-9 to 11 Histology (H&E). Poorly differentiated invasive ductal carcinoma with a high-grade DCIS component.
Treatment and follow-up: Mastectomy. The patient had no

recurrence at the most recent follow-up examination five
years after treatment.
Ex.
2.11-11
126 The Evolution of CastingType Calcifications
127
Chapter 3 The Theory of

Neoductgenesis
A proposal to explain the divergent nature
of a special subtype of breast cancer
presenting with casting type calcifications
and/or an asymmetric density with
architectural distortion on the mammogram.
128
129
Introduction
The branching, rodlike calcifications on the mammogram and haphazard manner (Fig. 3.2). The discrepancy on the
outline the ducts and their branches. If the calcifications mammogram between the petrified fluid within the pre-
were localized within the preexisting duct system (“in situ” existing ducts (“secretory disease type” calcifications, a
in its literal meaning), they would point toward the nipple, benign process) and the casting type calcifications (a malig-
resulting in a harmonious image, as the plasma-cell mastitis nant entity) is so striking that the distinction can be made
type calcifications do (Fig. 3.1). “Casting type calcifications,” with a high degree of accuracy by analyzing the mammo-
on the other hand, point in random directions in a disorderly grams.
3.2-1
3.1 3.2
Fig. 3.1 “Secretory disease” type calcifications fol- Fig. 3.2 Casting-type calcifications point in random directions,
low the preexisting, orderly duct pattern, pointing in producing a disorderly, haphazard pattern.
the direction of the nipple.
130 The Theory of Neoductgenesis
Comparison of Benign and Malignant Intraductal

Calcifications
3.3-1 3.3-2
Fig. 3.3-1 Left breast, MLO projection showing the early phase Fig. 3.3-2 The same case six years later. The orderly pattern of
of “secretory disease” type calcifications. these benign intraductal calcifications is considerably different
from the disorganized pattern seen in casting type (malignant) in-
traductal calcifications shown in Figs. 3.4 to 3.7.
3.4
Comparison of Benign and Malignant Intraductal Calcifications 131
3.5
3.6
3.7
3.8-1 3.8-2
Figs. 3.8-1 & 2 Mammographic−conventional histological comparison of casting type calcifications in high-grade DCIS.
3.9-1 3.9-2
Figs. 3.9-1 & 2 Mammographic demonstration of “secretory disease” type calcifications. The subgross histological image shows the
underlying pathophysiological process leading to the calcifications.
3.10-1 3.10-2
Figs. 3.10-1 & 2 Mammographic−subgross histological comparison of casting type calcifications in Grade 3 DCIS.
Comparison of Benign and Malignant Intraductal Calcifications 133
3.11-1 3.12-1
3.11-2
3.12-2
3.11-3
Fig. 3.11-1 to 3 Subgross histological image
of the inspissated fluid within distended ducts 3.12-3
(2). Calcification of this fluid leads to the for- Fig. 3.12-1 to 3.12-3 Casting type calcifica-
mation of “plasma cell mastitis type calcifications (1 & 3) with histological comparison (2).
tions” (1 & 3).
The Theory of Ductoneogenesis

Comparison of benign and malignant intraductal calcifica-
tions:
3.13 3.14
Figs. 3.13 & 3.14 Additional cases of malignant, casting type calcifications (Figs. 3.13, 3.14,
3.16-1) compared to “secretory disease” type (benign) calcifications on Fig. 3.15.
3.15
3.16-1 3.16-2
Fig. 3.16-2 Medium-power
histological image of dis-
tended ducts with solid cell
proliferation of malignant
cells, central necrosis, and
amorphous calcifications.
Morphological Demonstration of Neoductgenesis 135
Proposal of the Theory of Neoductgenesis

The failure of the casting type calcifications to follow the well. In this breast cancer subtype the dominant feature ap-
orderly ductal pattern can lead to the conclusion that many of pears to be the formation of new ducts or ductlike structures.
them are localized within tubelike/ductlike structures that We propose that this process be called “neoductgenesis.”
have been formed by the disease itself, although some of This theory helps explain many features of this breast cancer
them may be localized within the preexisting duct system as subtype which might otherwise seem contradictory.
Morphological Demonstration of Neoductgenesis

(A) Unnaturally High Concentration of Ductlike Structures within a
Limited Area
The prominent feature of neoductgenesis is an unnaturally
high concentration of ductlike structures within a lim-
ited area. These are greatly distended by malignant cells,
central necrosis, and occasional amorphous calcifications.
3.17-1 3.17-2 3.17-3

Fig. 3.17-1 Microfocus magnification Figs. 3.17-2 & 3 Subgross (2) and conventional large-section (3) histological images
showing innumerable casting type calci- demonstrate the densely packed, distended cancerous ducts, desmoplastic reaction, and
fications surrounded by an asymmetric, extensive lymphocytic infiltration.
nonspecific density.
(B) Desmoplastic Reaction and Extensive Lymphocytic Infiltration

Many of these densely packed, ductlike structures are sur-
rounded by desmoplastic reaction and extensive lympho-
cytic infiltration.
3.18-1 3.18-2
Figs. 3.18-1 & 2 Subgross and conventional histological images demonstrate the extensive desmoplastic
reaction and lymphocytic infiltration surrounding the neoducts.
Further examples demonstrate

the abnormally high concentra-
tion of pathological ductal struc-
tures containing high-grade
malignant cells, central necrosis,
and amorphous calcifications.
The periductal desmoplastic re-
action and extensive lymphocytic
infiltration surround the newly
formed ductal structures and are
most likely the result of an im-
munological reaction.
3.18-3
Figs. 3.18-3 & 4 Histological de-

monstration of the large number of
closely spaced ducts surrounded by
desmoplastic reaction and extensive
lymphocytic infiltration.
3.18-4
Fig. 3.18-5 Subgross, thick-section

histological image of the dilated,
cancerous ducts with intraluminal
amorphous calcifications and peri-
ductal lymphocytic infiltration.
3.18-5
Figs. 3.18-6 & 8 The large number of

tightly packed ductlike structures can be
better appreciated on these lower-power
images.
3.18-6
Fig. 3.18-7 Higher-magnification histologi-
cal image demonstrating the desmoplastic
reaction and lymphocytic infiltration.
3.18-7
3.18-8
(C) Disorganized Architecture

The architecture bears little resemblance to that of a nor- ducts have a haphazard pattern with ducts pointing in ran-
mal duct system. While the normal ducts have a regular pat- dom directions. There is also a remarkable lack of TDLUs on
tern of arborization terminating in TDLUs, the pathological the newly formed ducts.
3.19-1 3.19-2
3.19-3 3.19-4
3.19-5 3.19-6
Figs. 3.19-1 to 6 Comparative subgross histological images of normal (left) and pathological (right) duct systems. The normal duct
may be distended by fluid. The inner surface of the duct wall is smooth and there are TDLUs branching from the duct. The newly formed
ducts containing micropapillary cancer cell proliferation do not show normal duct architecture, lack TDLUs, and are associated with ex-
tensive periductal lymphocytic infiltration.
(D) Pathologic
Ducts: Contorted
and Crowded
Closely Together
On subgross histology, these
pathological ducts are contorted,
are crowded closely together,
and may have numerous small
buds surrounded by a lympho-
cytic reaction. The subgross his-
tological images strongly support
the theory that new ducts are
being formed. The term coated
infiltration may appropriately
convey that the newly formed
duct retains the ability to pro-
duce a basement membrane
while simultaneously penetrating
the surrounding tissues. Neo-
ductgenesis can also explain the
lack of TDLUs attached to these 3.20-1
long, contorted, abnormal “ducts,” Figs. 3.20-1 Subgross histological image showing the haphazard distribution of the cancer-
since the process of neoduct- ous ducts (lower two-third of image) compared to evenly distributed and widely spaced nor-
genesis does not appear to have mal ducts (upper third of image).
the ability to produce TDLUs.
3.20-2 3.20-3
Figs. 3.20-2 & 3 Higher-power subgross histological images of the area outlined by the dashed and solid rectangles in Fig. 3.20-1.
Histological Demonstration
of Multiple Newly Formed
Ducts
Figs. 3.20-4 to 6 Subgross (4 & 5) and

conventional (6) histological images of ab-
normally shaped ducts lined with micro-
papillary carcinoma in situ. The fingerlike
extensions lack TDLUs and are most likely
manifestations of neoductgenesis. 3.20-4
3.20-5
3.20-6
Fig. 3.20-7 Subgross image of normal breast tissue demonstrat-

ing the normal milk duct configuration and distribution. The ducts
are narrow and widely spaced.
3.20-7
3.20-8 3.20-9
Figs. 3.20-8 & 9 Subgross image of a duct containing micropapillary DCIS. This long, distended duct shows several small budding duc-
tal extensions, but lacks TDLUs.
3.20-10 3.20-11
Figs. 3.20-10 & 11 Microfocus magnification specimen radiograph (10) and subgross pathology (11) showing closely spaced, newly
formed ducts containing casting type calcifications.
Figs. 3.20-12 to 14 Subgross (12 & 13) and

conventional (14) histological images of the
contorted ducts containing micropapillary
in situ carcinoma.
3.20-12
3.20-13 3.20-14
3.20-15 3.20-16
Figs. 3.20-15 & 16 Mammographic−subgross histological correlation. The innumerable calcifications on the mammogram demon-
strate the closely spaced ducts.
Histological Demonstration of
Multiple Newly Formed Ducts
The subgross, thick section (3D)

histology images provide further
insight into the configuration of
these newly formed, abnormal
ducts while enabling us to make
a direct comparison with the
surrounding normal breast struc-
ture.
Ex. 3.1-1 Ex. 3.1-2

Ex. 3.1-1 The galactographic contrast Ex. 3.1-2 Magnification of the specimen radio-
medium outlines the ducts of a lobe graph shows the malignant type calcifications
with numerous microcalcifications. with no associated tumor mass.
Example 3.1
A 36-year-old woman with bloody
secretion from the right nipple.
Ex. 3.1-3 Large-section histology:

45 mm × 32 mm area with Grade 3 DCIS.
Involved margin. Ex. 3.1-3
Ex. 3.1-4 Subgross histology. The abnor-

mally high concentration of cancerous duct-
like structures packed tightly together is
striking in comparison with the neighbor-
ing, sparsely distributed normal glandular
tissue. Ex. 3.1-4
Ex. 3.1-5 The thick-section, sub-

gross histology technique makes it
possible to directly compare the dis-
tribution and architecture of normal
ducts and TDLUs with the cancer-
ous, ductlike structures. These do
not resemble preexisting ducts in
terms of orientation, size, shape, or
architecture.
Ex. 3.1-5
Ex. 3.1-6 Large-section histology

demonstrates the abnormally high
concentration of the cancerous
ducts.
Ex. 3.1-6
Histological Demonstration of Multiple Newly Formed Ducts
Ex. 3.1-7 to 12 Subgross, thick section and conventional histo- Treatment and follow-up: Mastectomy, no adjunctive
logical images of the pathological ducts distended by cancer cells, treatment. The patient was recurrence-free at her most re-
necrotic debris, and amorphous calcifications. cent follow-up examination, seven years after her treat-
ment.
Ex. 3.1-7 Ex. 3.1-8

Ex. 3.1-7 Subgross histological image. Ex. 3.1-8 A distended duct with solid cell proliferation
and central necrosis.
Ex. 3.1-9 Ex. 3.1-10

Ex. 3.1-9 & 10 The cancerous ducts contain amorphous calcifications within the central necrosis.
Ex. 3.1-11 Ex. 3.1-12

Ex. 3.1-11 Grade 3 cancer cells with necrosis. Ex. 3.1-12 Extensive periductal lymphocytic infiltration.
Example 3.2
A 59-year-old asymptomatic woman,
screening examination. Her mother died
from breast cancer.
Ex. 3.2-1 Left breast, detail of the CC pro-

jection. A large number of calcifications are
seen in the lateral portion of the breast,
surrounded by a nonspecific density.
Ex. 3.2-1
Ex. 3.2-2 Microfocus magnification view

showing mammographically malignant
type, crushed stone−like and casting type
calcifications.
Ex. 3.2-2
Ex. 3.2-3 Subgross, 3D histological image

of the area with calcifications. Dilated,
cancer-filled ductlike structures are densely
packed into an area of several cm2. Note
the normal distribution of the atrophic
ducts and TDLUs in the vicinity of the
cancer.
Ex. 3.2-3
Ex. 3.2-4 Ex. 3.2-5

Ex. 3.2-4 & 5 Microfocus magnification view over the area with calcifications, MLO projection (4) and large-section histology (5). Mam-
mographic−large section histological comparison documents the abnormal accumulation of the ductlike, cancerous structures within
a confined area.
Ex. 3.2-6 Ex. 3.2-7

Ex. 3.2-6 & 7 Subgross histological images of the dilated, tortuous, ductlike structures filled with cancer cells having a solid growth
pattern, intraluminal necrotic debris, and occasional amorphous calcification. Normal, atrophic glandular elements are seen in close
proximity (within the rectangle).
Ex. 3.2-8 to 11 This series of subgross, 3D histological images

demonstrates the random distribution and spatial arrangement of
atrophic, normal ducts and TDLUs surrounded by fibrous tissue in
close proximity to the distended, cancerous ductlike structures,
which are tightly packed and are confined over an area of several
cm2. This area, which stains a dark purple with hematoxylin, corre-
sponds to the area with the malignant type calcifications on the
mammogram.
Ex.
3.2-8
Ex.
3.2-9
Ex.
3.2-10
Ex.
3.2-11
Ex. 3.2-12 to 15 Higher-magnification images of the pathologi-

cal ducts distended by cancer cell proliferation, central necrosis,
and amorphous calcification. Comparative subgross (12, 13 & 15)
and conventional histological (14) images.
Ex.
3.2-12
Ex.
3.2-13
Ex.
3.2-14
Final histology: Grade 2 DCIS spread over an area measur-

ing 40 mm in diameter. No signs of invasion. No metastases
were found in the 14 surgically removed axillary lymph
nodes.
Treatment and follow-up: Radical excision. No signs of re- Ex.

currence were demonstrable during 14 years of follow-up. 3.2-15
Example 3.3
tion.
Ex. 3.3-1 The axillary tail of the left breast, detail of the MLO pro-
jection.
Ex. 3.3-1
Ex. 3.3-2 Microfocus magnification image of the region within

the rectangle in Ex. 3.3-1. Numerous crushed stone−like and short
casting type calcifications are seen with no associated tumor
mass.
Ex. 3.3-2
Ex. 3.3-3 Left breast, detail of the CC projection. The region

within the rectangle is magnified in Ex. 3.3-4.
Ex. 3.3-3
Ex. 3.3-4. Left breast, detail of the

CC projection, microfocus magnifi-
cation. The malignant type calcifica-
tions appear to have a lobar dis-
tribution. The circular lesion within
the dashed rectangle is an enlarged
sentinel node (“reactive nodes” are
often seen in casting type calcifica-
tion cases).
Ex. 3.3-4
Ex. 3.3-5 Large-section histology (H&E).

Grade 3 DCIS over an area of 40 mm × 20 mm.
No signs of invasion.
Ex. 3.3-5
Ex. 3.3-6 & 7 Medium-power histological

images demonstrate the abnormally large
number of ducts tightly spaced in the axil-
lary tail. No TDLUs are seen.
Ex. 3.3-6
Ex. 3.3-7
Histological Demonstration of
Multiple Newly Formed Ducts
Ex. 3.3-8 to 10 Increasingly higher

magnification images of this Grade 3
“DCIS.” The ductlike structures are
greatly dilated by highly malignant
cells, central necrosis, and amor-
phous calcifications.
Ex. 3.3-8
Ex. 3.3-9
Treatment and follow-up: Mas-

tectomy and breast reconstruc-
tion were performed one year
after segmentectomy. No recur-
rences were found through 81/2
years of follow-up. Ex. 3.3-10
(E) Tenascin Overexpression tion.1−4 Figures 3.21-1 to 3 illustrate a newly formed, cancer-
ous duct containing malignant cells expressing the HER2/
Once we realize that some of the ducts are newly formed, we neu oncogene, indicating a high-grade tumor. The duct is
can also assume that the ducts grow by penetrating the sur- surrounded by a thick layer of tenascin. The myoepithelial
rounding tissue. That this intrusion is an “invasive” process cell layer is still present, as indicated by the p63 nuclear
is supported by the presence of tenascin overexpression positivity. This special type of breast cancer may retain the
around the newly formed ducts. The beta-glycoprotein, myoepithelial cell layer while also evoking a strong stromal
tenascin, is produced at sites of epithelial−stromal interac- response, which is characteristic of invasive tumors.
Figs. 3.21-1 to 3 Longitudinal sec-

tion of a newly formed duct stained
immunohistochemically with HER2/
neu (red), Tenascin C (brown) and
p63 (dark brown color showing in-
tense nuclear staining in the myo-
epithelial layer).
3.21-1
3.21-2
3.21-3
The presence of extensive periductal

desmoplastic reaction and periductal
lymphocytic infiltration on conventional
H&E histological staining distinguishes
the newly formed ducts from the pre-
existing ducts. Also, overexpression of
tenascin immunohistochemical staining
highlights the newly formed ducts. In
invasive carcinoma both desmoplastic
reaction and tenascin overexpression as
well as lymphocytic infiltration may be
present, but the infiltrating epithelial
structures lack myoepithelium and nor-
mal basement membrane. Figs. 3.22-1
to 3 demonstrate a newly formed duct
with Grade 3 in-situ carcinoma and an
associated invasive carcinoma, both of
them overexpressing HER2/neu onco- 3.22-1
gene.
Fig. 3.22-1 Demonstration of a newly

formed duct with Grade 3 in-situ carcinoma
and an associated invasive carcinoma, both
of them overexpressing HER2/neu onco-
gene.
Fig. 3.22-2 Detail image at higher magni-

fication of the area of the rectangle in Fig.
3.22-1. 3.22-2
Fig. 3.22-3 Smooth-muscle actin staining

demonstrates the myoepithelial cell layer
surrounding the “in situ” component. 3.22-3
Example 3.4
A 53-year-old woman felt a lump in her left breast above the
nipple.
Ex. 3.4-1 Ex. 3.4-2

Ex. 3.4-1 Left breast, MLO projection. The area with the palpable Ex. 3.4-2 Microfocus magnification reveals multiple clusters of
lesion is marked with a metal pellet. calcifications associated with nonspecific densities.
Ex. 3.4-4
Ex. 3.4-4 Histology (H&E) of a 14G core biopsy specimen. Multi-
ple foci of in situ carcinoma.
Ex. 3.4-3 Microfocus magnification view, CC projection. Mam-

mographically malignant type, crushed stone−like and casting
type calcifications are surrounded by a nonspecific, ill-defined
Ex. 3.4-3 density.
Ex. 3.4-5 Specimen slice radiograph with the malignant type cal-
cifications and a surrounding density.
Ex. 3.4-5
Ex. 3.4-6 Large-section histology (H&E): a

large concentration of cancerous ducts is
associated with a strong desmoplastic reac-
tion, accounting for the mammographic
findings.
Ex. 3.4-6
Ex. 3.4-7 Ex. 3.4-8

Ex. 3.4-7 & 8 Tenascin C stain. Periductal tenascin overexpression is demonstrable in the region containing abnormal ductlike, cancer-
ous structures.
Ex. 3.4-9 Cross section of a cancerous duct with extensive peri-

ductal desmoplastic reaction and lymphocytic infiltration.
Ex.
3.4-9
Ex. 3.4-10 An abnormally high concentration of cancer-filled

ductlike structures surrounded by adipose tissue.
Ex.
3.4-10
Ex. 3.4-11 Histological image of large, amorphous calcifications

seen on the mammograms.
Ex.
3.4-11
Ex. 3.4-12 The Grade 3 cancer cells show a solid growth pattern.
Ex.
3.4-12
Ex. 3.4-13 Medium-power histological image of ducts distended

by cancer cells. The strong desmoplastic reaction is striking.
Ex.
3.4-13
Ex. 3.4-14 to 16 Three images demonstrate periductal tenascin

overexpression associated with new ductlike formations. These
budlike protrusions do not have the shape or architecture of nor-
mal ducts and are devoid of TDLUs.
Ex.
3.4-14
Ex.
3.4-15
Treatment and follow-up: Mastectomy. No recurrence was

demonstrable at the most recent follow-up five years and Ex.
eight months after treatment. 3.4-16
Example 3.5
tion.
Ex. 3.5-1 & 2 Screening mammograms, detail images, MLO and
CC projections. A cluster of microcalcifications can be seen with
no associated tumor mass.
Ex. 3.5-1 Ex. 3.5-2
Ex. 3.5-3 Ex. 3.5-4

Ex. 3.5-3 & 4 Microfocus magnification images over the areas with calcifications showing a mixture of crushed stone−like and casting
type calcifications, indicating a malignant process.
Ex. Ex.
3.5-5 3.5-6
Ex. 3.5-5 Subgross, 3D histological image of a duct and its branches distended by cancer Ex. 3.5-6 Tenascin overexpression
cells, necrotic debris, and calcifications. Extensive periductal lymphocytic infiltration and surrounding the cancerous duct.
neoangiogenesis are present.
Ex. Ex.
3.5-7 3.5-8
Ex. 3.5-7 & 8 Conventional and subgross histological images of a duct distended by cancer cells and necrotic debris, surrounded by a
thick desmoplastic reaction. The side branch is associated with extensive lymphocytic infiltration.
Ex. 3.5-9 An unusual, ductlike

structure with branches, filled with
cancer cells and surrounded by a
thick, fibrous, desmoplastic tissue
layer.
Ex.
3.5-9
Ex. 3.5-10 Specimen radiograph

with the fragmented casting type
calcifications.
Ex.
3.5-10
Ex. Ex.
3.5-11 3.5-12
Ex. 3.5-11 & 12 Details of the magnified specimen radiographs.
Ex. Ex.
3.5-13 3.5-14
Ex. 3.5-13 Medium-power histological image of ducts distended Ex. 3.5-14 Subgross, thick-section (3D) histology image showing
by cancer cells and amorphous calcifications. The periductal the very extensive desmoplastic reaction around the duct.
desmoplastic reaction is extensive.
Ex. Ex.
3.5-15 3.5-16
Ex. 3.5-15 A distended duct containing cancer cells, central ne- Ex. 3.5-16 A long, cancer−filled duct attached to an uninvolved
crosis, and amorphous calcium. TDLU.
Ex. Ex.
3.5-17 3.5-18
Ex. 3.5-17 & 18 Low- and higher-power histological images of a long, cancer-filled duct with no attached TDLUs or duct branches.
Ex. Ex.
3.5-19 3.5-20
Ex. 3.5-19 Subgross, 3D histological images of a long duct with Ex. 3.5-20 Conventional histological image of the ductlike struc-
solid cell proliferation of cancer cells. The associated branches ture seen in Ex. 3.5-19.
have an unusual appearance.
Final histology: 30 × 30 mm area with apocrine type Grade 3 Treatment and follow-up: Segmentectomy, no additional
DCIS. Solid and cribriform growth pattern. No invasive com- treatment. No sign of recurrence 11 years after treatment.
ponent demonstrable. The malignant process was excised
with adequate margins.
Neoductgenesis with Asymmetric Density and Very Subtle,

Associated Calcifications
Example 3.6
tion.
Ex. 3.6-1 Ex. 3.6-2
Ex. 3.6-3 Ex. 3.6-4

Ex. 3.6-1 to 4 Right and left breasts, MLO and CC projections of her screening examination. A subtle asym-
metric density associated with a few nonspecific calcifications has led to callback for further examination.
Neoductgenesis with Asymmetric Density and Very Subtle, Associated Calcifications 165
Ex. 3.6-5 Ex. 3.6-6

Ex. 3.6-5 & 6 Microfocus magnification view of the area outlined on the left CC projection (Ex. 3.6-4). The
calcifications within the small cluster are mammographically suspicious for malignancy.
Ex. 3.6-7 Ex. 3.6-8

Ex. 3.6-7 & 8 Histological examination of the 14G core biopsy shows Grade 3 micropapillary DCIS with necrosis.
Ex. 3.6-9 Specimen radiograph

(10 cm × 7 cm × 3 cm) showing the
excised asymmetric density and
the associated calcifications.
Ex. 3.6-9
Ex. 3.6-10 Radiograph of the specimen

slices. The removed asymmetric density is
mammographically nonspecific.
Ex.
3.6-10
Ex. 3.6-11 At large-section histology, the

tumor is composed of a large number
of cancerous ducts with their associated
desmoplastic reaction.
Ex.
3.6-11
Ex. Ex.
3.6-12 3.6-13
Ex. 3.6-12 & 13 Subgross histological comparison of normal duct structure containing many TDLUs (12) as opposed to the haphazard,
disorderly arrangement of the cancerous, newly formed ductlike structures that are surrounded by a desmoplastic reaction and lympho-
cytic infiltration (13).
Ex. 3.6-14 to 17 Histology (H&E) shows an 85 mm × 65 mm area

of DCIS with predominantly micropapillary architecture, contain-
ing intraductal necrotic debris. Extensive periductal fibrosis and
lymphocytic infiltration are seen. No invasion is demonstrable.
“Close” margin.
Ex. 3.6-14
Ex. 3.6-15
Ex. 3.6-16
Ex. 3.6-17
The patient had declined further treatment. Two years later

she felt a lump behind her left nipple.
Ex. Ex.
3.6-18 3.6-19
Ex. 3.6-18 & 19 Detail of the MLO and CC projections two years after operation. Mammography shows a large region with architectural
distortion that has developed since the previous follow-up examination.
Ex. Ex.
3.6-20 3.6-21
Ex. 3.6-20 Histology of the 14G core biopsy: Grade 3 DCIS with Ex. 3.6-21 Large-section histological examination following mas-
micropapillary cell proliferation. tectomy.
Ex. Ex.
3.6-22 3.6-23
Ex. 3.6-22 & 23 Subgross histological comparison of a dilated, normal duct (22) and the ducts formed by neoductgenesis (23).
Ex.
3.6-24
Ex. 3.6-24 Subgross histological demonstration of both cross sections and longitudinal sections of contorted ducts distended by
extensive necrosis and a thin layer of cancer cells. The periductal desmoplastic reaction (light ring and layer) and the lymphocytic infiltra-
tion (dark, ill-defined, flamelike appearance) serve as evidence that these ducts are the product of neoductgenesis.
Ex. 3.6-25 & 26 Further thick-sec-

tion (25) and conventional (26) his-
tological images with the bizarre
appearance of newly formed, abnor-
mal ducts accompanied by a strong
periductal desmoplastic and
Ex.
3.6-25
Ex.
3.6-26
Ex. 3.6-27 & 28 Due to the lack of

extensive calcifications or the pre-
sence of a tumor mass, this exten-
sive disease produced only very sub-
tle mammographic findings.
Ex.
3.6-27
Treatment and follow-up: The

patient underwent segmentec-
tomy and declined postoperative
irradiation. Two years later mas-
tectomy was performed due to
recurrence on a large area. The
patient was free of recurrence at
the most recent follow-up ex-
amination eight years after her
first surgery.
Comment
When a large number of densely
packed ductlike structures sur-
rounded by a desmoplastic reac-
tion become palpable, the phe-
nomenon is sometimes referred
to as “tumor forming DCIS.”
However, we consider this to
be another example of neoduct-
genesis, rather than “in-situ”
Ex.
disease.
3.6-28
Neoductgenesis without Associated Calcifications

Three-fourths (76 %) of the classic DCIS cases are detected by pected from their mammographic presentation. The lesion
finding calcifications on the mammogram, while the re- is composed of an aggregation of tightly packed ductal
maining fourth (24 %) are detected either by finding a domi- structures distended by carcinoma cells, which are sur-
nant mass, such as intracystic papillary carcinoma (8 %), at rounded by a basement membrane and an accompanying
galactography (6 %), or as an asymmetric density with archi- desmoplastic reaction. Although there is necrosis, there are
tectural distortion (10 %).5 The asymmetric density repre- few or no calcifications. The presence of fibrous tissue with
senting “DCIS” poses a considerable challenge for the breast its ill-defined borders or even spiculations accounts for the
imager, since it may appear as a very nonspecific finding mammographic and ultrasound findings of an ill-defined
both at screening and also at work-up. Occasionally, the tumorlike mass.
patient may feel a “thickening” in her breast. The breast im- According to conventional histological criteria, the pre-
ager may be further surprised by the discrepancy between sence of a basement membrane classifies them as an in situ
the mammographic and ultrasound findings showing the process, “DCIS.” However, the dense and disorganized duct-
characteristic features of an invasive carcinoma, while the like structures bear little resemblance to the normal, pre-
lesion may have the histological features of “ductal carci- existing ductal architecture. These structures are tightly
noma in situ.” One reason why this entity is seldom de- spaced, forming a tumorlike conglomerate, accounting for
scribed is the infrequent use of large-section histology, the term “tumor forming DCIS.” The process of neoduct-
without which the relationship of the lesion to its surround- genesis provides a logical explanation for the pathogenesis
ings may not be fully appreciated. of this process and for its appearance at mammography,
These lesions have a very characteristic appearance at subgross histology, and large-section histology.
subgross and large-section histological examination, as ex-
Example 3.7
A 62-year-old woman with a palpable lesion in the medial
portion of her right breast, close to the sternum.
Ex. 3.7-1 Ex. 3.7-2

Ex. 3.7-1 & 2 Right breast, MLO and CC projections. The region with the palpable lesion is marked with a lead pellet (BB).
Neoductgenesis without Associated Calcifications 173
Example 3.7
Ex. 3.7-3 Ex. 3.7-4

Ex. 3.7-3 Microfocus magnification, CC projection. The palpable Ex. 3.7-4 The breast ultrasound image shows the characteristics
lesion is ill-defined and of high density, mammographically malig- of invasive carcinoma.
nant.
Ex. 3.7-5 Ex. 3.7-6

Ex. 3.7-5 & 6 The low- and medium-power images of large-section histology demonstrate the abnormal concentration of pathologic
ductlike structures confined to a limited area, while there are no ducts at all in the surroundings. The conglomerate consists of these
distended structures filled with malignant cells surrounded by dense fibrosis, which accounts for its mammographic and ultrasound
appearance.
Ex. 3.7-7 Ex. 3.7-8

Ex. 3.7-7 & 8 Histological images (H&E) with increasing magnification. Diagnosis: in-situ carcinoma measuring 17 mm × 12 mm.
Ex. 3.7-9 & 10 Histological images (H&E)

with further magnification.
Ex.
3.7-9
Treatment and follow-up: Sector resec-

tion and postoperative irradiation. No
recurrence was demonstrable at the fol-
low-up examination seven years after
treatment.
Comment
The histological diagnosis is “ductal car-
cinoma in situ.” Although the histologi-
cal criteria for a ductal carcinoma in situ
are present, it is unlikely that the cancer
cells are within preexisting ducts. Again,
the process of neoductgenesis explains
these seemingly contradictory findings. Ex.
3.7-10
Example 3.8
This 84-year-old woman felt a lump in her left breast and

consulted her physician. Physical examination confirmed
the presence of a hard, palpable tumor. No nipple discharge,
no skin changes.
Ex. 3.8-1 Ex. 3.8-2

Ex. 3.8-1 & 2 Left breast MLO (1) and lateromedial horizontal (2) projections: against the background of adipose tissue, there is a large
nonspecific asymmetric density having a lobar distribution in the lateral portion of the breast. No associated calcifications are dem-
onstrable. The density changes its appearance from projection to projection.
Ex. 3.8-3 Left breast CC projection show-

ing the asymmetric density extending from
the nipple to the chest wall.
Ex. 3.8-3
Ex. 3.8-4 Microfocus magnifica-

tion of the density with architec-
tural distortion.
Ex. 3.8-4
Ex. 3.8-5 Ex. 3.8-6
Ex. 3.8-7 Ex. 3.8-8

Ex. 3.8-5 to 8 Low-power histological images (H&E): within a background of fibrosis, cross sections of numerous cancer-filled ducts are
surrounded by a desmoplastic reaction and lymphocytic infiltration.
Treatment: Sector resection. No postoperative irradiation.

Follow-up mammography 23 months later: A large num-

ber of casting type calcifications are present at the biopsy
site.
Ex. 3.8-9 Ex. 3.8-10

Ex. 3.8-9 & 10 Detail images of the left CC projection demonstrating the de novo calcifications near the biopsy scar.
Ex. 3.8-12
Ex.
3.8-11
Ex. 3.8-11 Microfocus magnification radiograph of a specimen
slice demonstrates the casting type calcifications.
Ex. 3.8-13
Ex. 3.8-12 & 13 Higher-magnification histology (H&E) shows the
cellular details of this Grade 3 in situ carcinoma with central necro-
sis.
Ex. 3.8-14 Specimen radiograph containing the calcifications.
Ex.
3.8-14
Ex. 3.8-15 Microfocus magnification of one of the specimen

slices.
Ex.
3.8-15
Ex. 3.8-16 Large-section histology (H&E): the recurrence mea-

sures 20 mm × 10 mm.
Ex.
3.8-16
Ex. Ex.
3.8-17 3.8-18
Ex. Ex.
3.8-19 3.8-20
Treatment and follow-up: The patient was well at her most

recent follow-up one year after her second operation, a mas-
tectomy.
Comment
This malignant growth first presented as a nonspecific density
without calcifications arising within an involuted breast of
this 84-year-old woman. Within two years the same disease
recurred, but the central necrotic tissue was now partially cal-
cified, producing the typical mammographic appearance of
casting type calcifications. The histological features of neo-
ductgenesis are present in the initial and in the recurrent le-
sion. This and other similar cases indicate that the process
of neoductgenesis may progress for some years before the
calcifications are mammographically demonstrable.
181
Chapter 4 The Deviant Nature of

the Breast Cancer Subtype
with Castings
182
Introduction 183
Introduction
Breast cancer presenting with casting type calcifications on
the mammogram is one of the most unpredictable of all
breast cancer subtypes.
Figs. 4.1-1 & 2 Examples of fragmented casting type calcifica-

tions.
4.1-1
4.1-2
Figs. 4.1-3 & 4 Dotted casting type calcifications without and

with microfocus magnification.
4.1-3
4.1-4
184 The Deviant Nature of the Breast Cancer Subtype with Castings
The Use of Mammographic Tumor Features

to Study Breast Cancer
The development of an effective method of early detection The goal of mammographic screening is to prevent death
combined with surgical removal of the disease has enabled from breast cancer. To achieve this, we have to prevent the
the present generation of physicians to make a significant disease from developing to an advanced stage by detecting
improvement in the outcome of breast cancer patients. and removing it while it is still in the 1−14 mm size range
Evaluation of both randomized controlled mammography and localized to the breast (node negative). Mammographic
screening trials and organized service screening programs screening can accomplish a significant change in the spec-
has demonstrated a substantial and significant decrease in trum of the disease, which is called downward stage shift-
mortality from breast cancer as a result of diagnosis and ing.8 The mortality benefit is primarily achieved by down-
treatment in the preclinical detectable phase.1−6 Breast staging the larger invasive cancers to smaller-sized invasive
cancer should be treated in its preclinical phase if we are to carcinomas. A detailed description of a systematic strategy
save women from dying of breast cancer. The decisive factor for finding breast cancer in its earliest detectable stages is
is whether the treatment is given early or late in the natural described in the first volume of this series.9
history of the disease, rather than which treatment choice is The mammographic tumor features of 1−14 mm invasive
offered to breast cancer patients.7 carcinomas can be classified into five distinct categories
(Fig. 4.2).
2)
Stellate Circular/oval Powdery Crushed stone– Casting type

like
Tumor with no associated calcifications

Calcifications with or without a tumor mass
4.2
All have histologically proven 1–14 mm invasive breast cancer
Fig. 4-2 The 1−14 mm breast cancers according to their mammographic tumor features.
The Use of Mammographic Tumor Features to Study Breast Cancer 185
Relative Frequency of Breast

Cancer Occurrence by
Mammographic Tumor Features
Stellate tumors without associated calcifications are by far
the most frequently occurring mammographic subtype, fol-
lowed by the circular/oval, noncalcified tumors. Casting
type calcifications associated with 1−14 mm invasive carci-
noma account for 7 % of these tumors.
1.1% Stellate (185/376)

10.9%
Circular (82/376)
10.6%
Powdery calcifications ± tumor mass
49.2% (24/376)
6.4%
Casting type calcifications ± tumor mass
(40/376)
Crushed stone–like calcifications ± tumor

mass (41/376)
21.8% Other (4/376) 4.3-1
Fig. 4.3-1 Relative frequency of occurrence of the five distinct mammographic tumor subtypes of 1−9 mm breast cancer.
Stellate (316/495)
2.0
2.0% 5.9%
4.7% 0.2%
Circular (116/495)
Powdery calcifications ± tumor mass (10/495)

63.8%
23.4% Casting type calcifications ± tumor mass (23/495)
Crushed stone–like calcifications ± tumor mass (29/495)
4.3-2
Other (1/495)
Fig. 4.3-2 Relative frequency of occurrence of the five distinct mammographic tumor subtypes of 10−14 mm breast cancer.
tumors presenting with casting type calcifications, stands

Long-Term Outcome by out in stark contrast in terms of distribution of histologi-
Mammographic Tumor Features cal prognostic factors, poor response to therapy and unex-
pectedly dismal prognosis. When all subtypes are lumped
One might expect that when these different subtypes are de- together, the 24-year breast cancer specific survival of 376
tected at the earliest possible phase (1−9 mm and also women with 1−9 mm invasive carcinoma is 93 % (Fig. 4.4-1).
10−14 mm invasive tumors), each subtype would have a simi- However, the summation of divergent outcomes is mislead-
lar, equally excellent prognosis. This is indeed the case in four ing, since it includes the subtype that deviates considerably
out of the five mammographic subtypes. The fifth subtype, from the others in the same size group.
1.0
0.9
93.0%
Stellate (185/376)
0.8
0.7 10.9% Circular (82/376)

Cumulative Survival
0.6
10.6% 49.2% Powdery calcifications ± tumor mass
0.5 (24/376)
6.4%
0.4 Casting type calcifications ± tumor mass
21.8% (40/376)
0.3
Crushed stone–like calcifications ± tumor
0.2 mass (41/376)
0.1 1–9 mm (12/376) Other (4/376)
0
4.4-1 0 2 4 6 8 10 12 14 16 18 20 22 24
Years since diagnosis
Fig. 4.4-1 Cumulative breast cancer specific survival of women with 1−9 mm breast cancer, all mammographic subtypes combined.
1.0
0.9
89.0 %
0.2
0.8 Stellate (316/495)
4.7 5.9
0.7 2.0 Circular (116/495)
Cumulative Survival
0.6
Powdery calcifications ± tumor mass
0.5 63.8
23.4 (10/495)
0.4 Casting type calcifications ± tumor mass

(23/495)
0.3 Crushed stone–like calcifications ± tumor mass
(29/495)
0.2
Other (1/495)
0.1
10–14 mm (31/495)
0
4.4-2 0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.4-2 Cumulative breast cancer specific survival of women with 10−14 mm breast cancer, all mammographic subtypes combined.
It would be a mistake to plan uniform treatment for all of are separated from the rest, it is apparent that the long-
these distinct subtypes based on their average survival val- term outcome curves are remarkably different (Figs. 4.5-1 &
ue. When only the tumors with casting type calcifications 4.5-2).
1.0
0.9 95.0 %
0.8
0.7
72.0 %
0.6
Survival rate
0.5
0.4
0.3
0.2 All the others (6/336) RR=1.0

0.1 Casting (6/40) RR=9.55 (3.07–29.66)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Years since diagnosis 4.5-1
Fig. 4.5-1 Cumulative survival of women with 1−9 mm invasive breast cancer, separating the cases with casting type calcifications
from all the rest.
1.0
91.0 %
0.9
0.8
0.7
Cumulative survival
0.6
52.0 %
0.5
0.4
0.3

0.1 RR=10.28 (4.72–22.42)
Casting (9/23)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.5-2 Cumulative survival of women with 10−14 mm invasive breast cancer, separating the cases with casting type calcifications
from all the rest.
The survival of the noncasting cases compares favorably casting type calcifications have survival curves similar to
with the 24-year survival of 357 patients with DCIS, while those of large, advanced cancers (Figs. 4.6-1 & 2).
the 1−9 mm and 10−14 mm invasive cancers associated with
1.0
95.0%
0.9 94.0%
0.8
0.7
72.0%
Survival rate
0.6
0.5
0.4
0.3
DCIS (6/357)
0.2
Noncasting, 1–9 mm (6/336)
0.1
Casting type calcifications, 1–9 mm (6/40)
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
4.6-1 Years since diagnosis
Fig. 4.6-1 Comparative cumulative survival of women with DCIS and with 1−9 mm invasive breast cancers. The invasive cases with
casting type calcifications are plotted separately.
94.0%
1.0
0.9
0.8
91.0%
0.7
Survival rate
0.6
0.5
52.0%
0.4
0.3
DCIS (6/357)
0.2
Noncasting, 10–14mm (22/472)
0.1 Casting type calcifications, 10–14 mm (9/23)
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Fig. 4.6-2 Comparative cumulative survival of women with DCIS and with 10−14 mm invasive breast cancers. The invasive cases with
casting type calcifications are plotted separately.
Long-Term Outcome by Mammographic Tumor Features
The long-term prognosis is excellent for each invasive breast

cancer subtype (excluding casting), whether it is expressed
as disease specific survival/case fatality rate or as proportion
of breast cancer death, in both the 1−9 mm and 10−14 mm
size ranges (Figs. 4.7-1 & 2).
Frequency: 21.8% 49.2% 6.4% 10.9% Other:

Proportion (2/82) (1/185) (0/24) (2/41) (1/4)
of breast 3.0% 0.6% -
– 4.9%
cancer death:
1.8%
Breast cancer death (all others

combined) 6/336 31.3%
No breast cancer death (all others
combined) 330/336 98.2%
4.7-1
Fig. 4.7-1 Proportion of breast cancer death in women with 1−9 mm noncasting invasive breast cancers.
Frequency: 23.4% 63.8% 2.0% 5.9% Other: 0.2%

Proportion (9/116) (13
(13/316) (0/10) (0/29) (0/1)
of breast 7.8% 4.1% -
– -
–
cancer death:
4.7%
Breast cancer death (all noncasting

combined) 22/472 31.3%
No breast cancer death 95.3%
(all noncasting combined) 450/472
4.7-2
Fig. 4.7-2 Proportion of breast cancer death in women with 10−14 mm noncasting invasive breast cancers.
At one extreme, the subgroup of stellate tumors comprising therapeutic regimens may offer little or no demonstrable
half of the 1−9 mm invasive carcinoma cases has a 99 % benefit to this group.12
24-year disease specific survival (Fig. 4.8-1).10,11 Adjuvant
99.0%
1.0
0.9
Stellate (185/376)
Cumulative survival
0.8
0.7
Circular (82/376)
0.6 Powdery calcifications ± tumor mass

49.2% (24/376)
0.5
Casting type calcifications ± tumor mass
0.4
(40/376)
0.3 Crushed stone–like calcifications ± tumor
mass (41/376)
0.2
Other (4/376)
Stellate (1/185)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.8-1 Cumulative disease specific survival of women with 1−9 mm invasive breast cancers presenting as stellate tumors without
associated calcifications on the mammogram.
1.0
92.0 %
0.9
0.8
0.7 Stellate (316/495)

Cumulative survival
0.6 Circular (116/495)

63.8%
0.5 Powdery calcifications ± tumor mass (10/495)
0.4 Casting type calcifications ± tumor mass (23/495)
0.3 Crushed stone–like calcifications +/- tumor mass (29/495)
0.2 Other (1/495)
0.1 Stellate without calcifications (13/316)

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.8-2 Cumulative disease specific survival of women with 10−14 mm invasive breast cancers presenting as stellate tumors without
associated calcifications on the mammogram.
Long-Term Outcome by Mammographic Tumor Features the 1−9 mm and 10−14 mm invasive cancers show 99−100 %
and 92−100 % 24-year breast cancer specific survival, re-
At the other extreme, the outcome of the casting cases respectively. In contrast, the cases with casting type calcifica-
sembles that of advanced cancers. When the long-term out- tions show a 72 % and 52 % 24-year breast cancer specific
come of each subgroup is plotted separately, the majority of survival, respectively (Figs. 4.9-1 & 2).
100.0% 99.0%
1.0
0.9
0.8
92.0% 88.0%
0.7
72.0%
Cumulative survival
0.6
0.5
Stellate without calcifications (1/185)
0.4 RR=1.00
Circular/oval without calcifications (2/82)
0.3 RR=5.03 (0.46–55.50)
Powdery calcifications ± tumor mass (0/24)
0.2 Crushed stone–like calcifications ± tumor mass (2/41) RR=9.39 (0.85 –103.81)
0.1 Casting type calcifications ± tumor mass (6/40) RR=33.14 (3.99–275.48)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.9-1 Cumulative disease specific survival of women with 1−9 mm invasive breast cancer according to the five distinct mammo-
graphic tumor subtypes.
1.0
100.0%
92.0 %
0.9
0.8 85.0 %
0.7
Cumulative survival
0.6
52.0 %
0.5
0.4
Stellate without calcifications (13/316) RR=1.0
0.3 Circular/oval without calcifications (9/116) RR=1.81 (0.77–4.23)
Powdery calcifications ± tumor mass (0/10) –
0.2
Crushed stone–like calcifications ± tumor mass (0/29) –
0.1
Casting type calcifications ± tumor mass (9/23 RR=11.64 (4.96–27.32)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.9-2 Cumulative disease specific survival of women with 10−14 mm invasive breast cancer according to the five distinct mammo-
graphic tumor subtypes.
breast cancer death occurs in this subgroup. No other tumor

Proportion of Breast Cancer Death characteristic is able to discriminate the fatal cancers in
these size ranges so effectively and within such a small sub-
by Mammographic Tumor group as is accomplished by detecting casting type calcifica-
Features tions on the mammogram.
No matter how the long-term outcome of women with
Casting type calcifications associated with invasive breast 1−9 mm or 10−14 mm invasive breast cancer is measured,
cancers account for only a small fraction of the total number tumors associated with casting type calcifications on the
of tumors in the 1−9 mm (10.6 %) and 10−14 mm (4.7 %) size mammogram stand out as by far the most lethal sub-
ranges (Figs. 4.10-1 & 2), yet a disproportionately high rate of group.
Frequency Breast cancer death rate

Casting
40/376 10.6%
All others
combined 50.0%
336/376 50.0% Cases
89.4% with
casting
Breast cancer death:

4.10-1 cases with casting 6/12
Fig. 4.10-1 Frequency of occurrence of invasive tumors asso-

ciated with casting type calcifications in the 1−9 mm size range Breast cancer death:
and their contribution to all breast cancer death. all others combined 6/12
Frequency Breast cancer death rate

4.7%
Casting
23/495
All others
combined 29.0%
472/495
95.3% 71.0%
Breast cancer death:

4.10-2 cases with casting 9/31
Fig. 4.10-2 Frequency of occurrence of invasive tumors asso- Breast cancer death:
ciated with casting type calcifications in the 10−14 mm size range all others combined 22/31
and their contribution to all breast cancer death.
3.2%
Frequency: 21.8% 49.2% 6.4% 10.9% 10.6%
Proportion of (2/82) (1/185) (0/24) (2/41) (6/40)
breast cancer 2.4% 0.5% -
– 4.9% 15.0%
death:
Other: 1.1%
(1/4)
96.8%
Breast cancer death 12/376

Other cause or alive 364/376
4.11-1
Fig. 4.11-1 Proportion of breast cancer death in women with 1−9 mm invasive cancer (3.2 %). Frequency of occurrence and proportion
of breast cancer death by mammographic tumor subtypes in 1−9 mm invasive breast cancers; 24-year follow-up of 376 cases.
Frequency: 23.4% 63.8% 2.0% 5.9% 4.7%

7.0% Proportion of (9/116) (13/316)
(13 (0/4) (0/29) (9/23)
breast cancer 7.8% 4.1% -
– -
– 39.1%
death:
Other:
(0/1)
93.0% Breast cancer death 31/495

Death from other cause or
alive 464/495
4.11-2
Fig. 4.11-2 Proportion of breast cancer death in women with 10−14 mm invasive cancer (7.0 %). Frequency of occurrence and propor-
tion of breast cancer death by mammographic tumor subtypes in 10−14 mm invasive breast cancers; 24 year follow-up of 495 cases.
Demonstration of Fatal Cases

with Casting Type Calcifications
Example 4.1
tion. She was called back for evaluation of the extensive cal-
cifications appearing since the previous screening examina-
tion.
Ex. 4.1-1 Ex. 4.1-2

Ex. 4.1-1 & 2 Right breast, MLO projection, consecutive screening examinations at ages 40 and 42 years. No
calcifications can be detected in Ex. 4.1-1. Innumerable malignant, casting type calcifications are present in
Ex. 4.1-2.
Ex. 4.1-3 Large-section histology image. A

5 cm × 4 cm area contains a high concentra-
tion of cancerous ducts with necrosis and
Ex. 4.1-3
Demonstration of Fatal Cases with Casting Type Calcifications 195
Ex. 4.1-4 Microfocus magnification radio-

graph of a mastectomy specimen slice
demonstrates innumerable dotted casting
type calcifications within the closely packed
ductal structures.
Ex. 4.1-4
Ex. 4.1-5 Histological demonstration of

the large number of ducts, closely spaced
and surrounded by a desmoplastic reaction
and extensive lymphocytic infiltration.
Ex. 4.1-5
Ex. 4.1-6 Higher magnification shows the

amorphous intraluminal calcifications corre-
sponding to the dotted casting type calcifi-
cations seen on the mammogram.
Ex. 4.1-6
Ex. 4.1-7 Histological demonstra-

tion of the abnormally large number
of closely spaced ductal structures
with periductal desmoplastic reac-
tion and lymphocytic infiltration.
Ex. 4.1-7
Ex. 4.1-8 Low-power image of this

node-negative 10 mm Grade 2 inva-
sive ductal carcinoma.
Ex. 4.1-8
Ex. 4.1-9 Medium-power histologi-

cal image of cancerous ducts with
periductal reaction.
Ex. 4.1-9
Mammographic, subgross/thick section and conventional

histological comparison of the findings in this case:
Ex. 4.1-10 Ex. 4.1-11

Ex. 4.1-10 & 11 The amorphous calcifications as seen at mammography and subgross, thick-section his-
tology.
Ex. 4.1-12 Ex. 4.1-13

Ex. 4.1-12 & 13 The nipple and retroareolar region also contain numerous cancerous ducts.
Ex. 4.1-14 Ex. 4.1-15

Ex. 4.1-14 & 15 The dotted casting type calcifications are produced by micropapillary cell proliferation, here
demonstrated by subgross, thick-section histology and by medium-power histology.
Ex. 4.1-16 Ex. 4.1-17

Ex. 4.1-16 & 17 Intermediate- and low-power magnification of the area with neoductgenesis.
Treatment and outcome: Mastectomy. The patient died
from metastatic breast cancer 4 years and 5 months after the
operation.
calcifications localized in the upper outer quadrant of the

Example 4.2
right breast. This occurred in 1979 when the malignant
A 46-year-old asymptomatic woman, first screening exami- potential of powdery calcifications was not fully appre-
nation. She was called back for evaluation of the powdery ciated.
Ex. 4.2-1 Ex. 4.2-2

Ex. 4.2-1 & 2 Detail of the right MLO projection and microfocus magnification image. The powdery calcifications have a triangular, lobar
distribution. No tumor mass is seen. The calcifications were evaluated as benign type and the patient returned to routine screening.
Ex. 4.2-3 Ex. 4.2-4

Ex. 4.2-3 & 4 Detail of the right MLO projection at subsequent screening examinations two years and seven years later. No apparent
change is seen at two years (Ex. 4.2-3), but at seven years, at age 53 (Ex. 4.2-4), the calcifications appear to be diminishing in density and
extent.
Ex. 4.2-5 Ex. 4.2-6

Ex. 4.2-5 & 6 Detail of the right MLO projection and microfocus magnification image at age 55. The powdery calcifications have been
entirely replaced on the mammogram by a large number of casting type calcifications in exactly the same part of the breast.
Ex. 4.2-7 Ex. 4.2-8

Ex. 4.2-7 & 8 Histological examination still shows the psammoma body-like calcifications. These correspond to the mammographic
appearance of powdery calcifications that are associated with sclerosing adenosis.
Ex. 4.2-9 Ex. 4.2-10

Ex. 4.2-9 & 10 The casting type calcifications correspond to large amorphous calcifications surrounded by central necrosis and Grade 3
carcinoma cells with solid cell architecture.
Ex. Ex.
4.2-11 4.2-12
Ex. 4.2-11 Histological image (H&E) of a TDLU distended by Ex. 4.2-12 The crystalline calcified structures are seen as bright
malignant cells, amorphous calcifications and necrosis. spots with polarized light.
Ex. Ex.
4.2-13 4.2-14
Ex. 4.2-13 & 14 Occasional psammoma body-like calcifications are scattered among the cancer cells.
Ex. Ex.
4.2-15 4.2-16
Ex. 4.2-15 & 16 Higher-power histological images (H&E): most of the areas show solid cell proliferation, central necrosis, and amor-
phous calcifications, accounting for the mammographic finding.
Ex. 4.2-17 & 18 Low- and intermediate-

magnification histology of the 10 mm
Grade 2 invasive ductal carcinoma.
Ex. 4.2-17
Ex. 4.2-18
Ex. 4.2-19 The axillary lymph node con-

tained micrometastases.
Treatment and outcome: Mastectomy.

One year later the patient felt a hard
lump medial to the mastectomy scar.
Histology showed recurrence of the dis-
ease with extensive lymph vessel infil-
tration. The patient died from breast
cancer 31/2 years after mastectomy. Ex. 4.2-19
Example 4.3
A 45-year-old woman felt a lump in the upper half of her
right breast. Mammographic examination shows casting
type calcifications extending over a region measuring 8 cm.
Ex. 4.3-1 Ex. 4.3-2

Ex. 4.3-1 to 3 Detail of the right MLO projection and microfocus magnification images in the MLO and CC projections. There are in-
numerable casting type calcifications extending over much of the upper half of the breast.
Ex. 4.3-3
Ex. 4.3-4 Ex. 4.3-5

Ex. 4.3-4 & 5 The cancerous ducts seen in cross section (4) and longitudinal section (5) containing the amorphous calcifications
accounting for the mammographic finding.
Ex. 4.3-6 Ex. 4.3-7

Ex. 4.3-6 Ducts containing casting type calcifications (van Gie- Ex. 4.3-7 High-power histology (van Gieson stain): Grade 3 in-
son stain). situ carcinoma.
Ex. 4.3-8 Ex. 4.3-9

Ex. 4.3-8 There are numerous lymph vessels containing me- Ex. 4.3-9 Histological examination revealed metastases in two
tastases (lymph vessel invasion, LVI), although the invasive com- axillary nodes. Histologic image courtesy of Prof. Hans Nordgren,
ponent measured only 2 mm in diameter. Dept. of Clinical Pathology, Uppsala University, Sweden.
Treatment and outcome: Mastectomy. Five years later the

patient developed bone and liver metastases. The patient un-
derwent chemotherapy and bone marrow transplantation.
She died from breast cancer 51/2 years after mastectomy.
Poor Correlation of Outcome with Mode of Therapy

It is disappointing but not surprising that the selection of breast cancer subtype is very similar to that of advanced, stage
treatment appears to have little effect upon the outcome of II−IV breast cancers (Fig. 4.18, p. 226), and there is sufficient
women with casting type calcifications associated with evidence showing that therapeutic regimens have a limited
1−14 mm invasive breast cancers. The clinical outcome of this impact upon the final outcome of such breast cancer cases.13−14
1.0
0.9
0.8
70.0 % 71.0 %
0.7
Cumulative survival
0.6
0.5
0.4
0.3 Breast conserving surgery (2/13)
0.2
Mastectomy (9/35)
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.12-1 Disease specific survival of 1−14 mm invasive breast cancers associated with casting type calcifications according to choice
of surgical procedure.
1.0
0.9
0.8
76.8 %
0.7
62.1 %
Cumulative survival
0.6
0.5
0.4
0.3
0.2 With radiotherapy (4/ 22), HR= 0.91 ( 0.29, 2.80)

0.1 Without treatment of radiotherapy (13/ 47), HR=1.00
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
4.12-2
Fig. 4.12-2 Disease specific survival of 1−14 mm invasive breast cancers associated with casting type calcifications according to choice
of radiotherapy vs. no radiotherapy.
Poor Correlation of Outcome with Mode of Therapy 205
Women with 1−14 mm invasive breast cancers not as- In particular, the largest group of women with 1−14 mm in-
sociated with casting type calcifications have excellent 26- vasive breast cancers, those with stellate tumors not as-
year disease specific survival irrespective of postoperative sociated with calcifications, appear to receive no survival
irradiation. benefit from postoperative radiation.
Excluding Casting
1.0
92.0%
0.9
92.0%
0.8
0.7
Cumulative survival
0.6
0.5
0.4
0.3
0.2 Without postop irradiation (17/ 362) With postop irradiation (18/ 557)
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Fig. 4.12-3 Disease specific survival of 1−14 mm invasive breast cancers (cases associated with casting type calcifications excluded)
without and with postoperative radiotherapy.
1.0
95.0%
0.9
92.0%
0.8
0.7
Cumulative survival
0.6
0.5
0.4
0.3
Postop irradiation (11/ 353) No radiotherapy (8/216)
0.2
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Fig. 4.12-4 Twenty-six-year disease specific survival of women with 1−14 mm invasive breast cancers appearing as stellate tumors
without associated calcifications on the mammogram, by choice of postoperative radiotherapy or no postoperative radiotherapy.
Demonstration of Local Recurrence Following

Radiotherapy
Example 4.4-4 to 8
A 59-year old asymptomatic woman, screening examina-
tion. A small cluster of calcifications, which was overlooked,
is seen retrospectively in the lower inner quadrant of the left
breast.
The next screening examination was at age 60, still
asymptomatic. The calcifications are more prominent and
are now of the casting type.
Ex. 4.4-1 to 3 Left MLO projection (1) and detail of the left MLO
(2) and CC (3) projections showing a group of calcifications in the
lower inner quadrant with no associated tumor mass. Ex. 4.4-1
Ex. 4.4-2 Ex. 4.4-3

Demonstration of Local Recurrence Following Radiotherapy 207
Ex. 4.4-4 Detail of the left MLO

and CC projections one year later.
Casting type calcifications are local-
ized in the lower inner quadrant in
an area measuring at least 4 cm in
diameter.
Ex. 4.4-4
Ex. 4.4-5 Microfocus magnification

image: fragmented casting type
calcifications without an associated
tumor mass.
Ex. 4.4-5
Ex. 4.4-6 Specimen radiograph (8 cm × 8 cm surgical specimen)

without microfocus magnification: the calcifications have been
removed with a good margin.
Ex.
4.4-6
Ex.
4.4-7
Ex. 4.4-7 & 8 Microfocus magnification of specimen slices containing Ex.

the casting type calcifications. 4.4-8
Ex. Ex.
4.4-9 4.4-10
Ex. 4.4-9 & 10 Histology (H&E): 40 mm × 30 mm Grade 3 DCIS. No sign of invasion.
Ex. 4.4-11
Ex. 4.4-11 Histology (H&E): low-power longitudinal section of a duct with extensive periductal fibrosis and
Ex. Ex.
4.4-12 4.4-13
Ex. 4.4-12 Higher-power histological image (H&E) of a duct Ex. 4.4-13 The ductal lumen is nearly completely obstructed by
cross section. No cancer cells are demonstrable. The entire lumen extensive fibrosis. The periductal lymphocytic infiltration is strik-
is filled with an amorphous calcification. ing.
Ex. 4.4-14 The patient received postoperative irradiation. Fol-

low-up mammography two years after segmentectomy and post-
operative irradiation: a new cluster of casting type calcifications is
seen in the subcutaneous retroareolar region, at the upper border
of the areola, distant to the site of operation.
Ex. 4.4-14
Ex. 4.4-14 & 15 Detail of the left MLO and

CC projections two years following surgery
and postoperative irradiation. The new cal-
cifications are located at the upper border
of the areola.
Ex.
4.4-15
Ex. 4.4-16 Radiograph of a specimen slice

from the mastectomy. Numerous casting
type calcifications are seen at the tissue
margin.
Ex.
4.4-16
Ex. 4.4-17 Large-section histology showing

the cancerous ducts with intraluminal calci-
fications on the specimen margin.
Ex. 4.4-17
Ex. 4.4-18 & 19 Low- and

medium-power histological
images of one duct with
solid cell proliferation, intra-
luminal necrosis, and amor-
phous calcification.
Ex. 4.4-18 Ex. 4.4-19
Ex. 4.4-20 High-power histological image

(H&E) of the area within the rectangle on
Ex. 4.4-19. Grade 3 in-situ carcinoma.
Follow-up: Five years after the initial

operation and radiotherapy and three
years after recurrence and mastectomy,
the patient is alive and well. Ex. 4.4-20
Example 4.5
(Case courtesy of Urpo Saari, M.D., Tyräskylä, Finland)
This case also represents a recurrence after segmentectomy
and postoperative radiotherapy.
Ex. 4.5-1 Ex. 4.5-2

Ex. 4.5-1 & 2 Left breast, detail of the MLO projection. The area with calcifications is encircled. Microfocus magnification image shows
the cluster containing both crushed stone-like and casting type calcifications. No tumor mass is seen.
Ex. 4.5-3 Ex. 4.5-4

Ex. 4.5-3 Specimen radiograph. The calcifications described on Ex. 4.5-4 Follow-up examination two years later: there is an egg-
the mammogram are close to the tissue margin. Postoperative ir- shell-like calcification (due to traumatic fat necrosis) in the upper
radiation was given after this sector resection. portion of the breast; otherwise no abnormality is demonstrable.
Ex. 4.5-5 After an additional two years (four years after surgery
and postoperative irradiation), a large group of casting type calci-
fications recurred at the site of surgical excision.
Treatment and follow-up: Mastectomy. The patient is lost

to follow-up. Ex. 4.5-5
Axillary Node Status and Mammographic Tumor Features

There is a remarkable difference in axillary node positivity pared with 20 % node positivity in tumors associated with
according to mammographic tumor features (Figs. 4.13-1 & casting type calcifications, of whom 15 % (6/40) died from
2). Only 4.3 % of women with 1−9 mm stellate cancers had breast cancer.
positive axillary nodes (and 0.5 % died of breast cancer) com-
4.3%
31.4%
Positive 8/185
64.3% Negative 119/185
Unknown 58/185
4.13-1
Fig. 4.13-1 Axillary node status in women with 1−9 mm invasive breast cancers pre-
senting as stellate tumors without associated calcifications on the mammogram.
7.5%
20.0%
72.5% Positive 8/40

Negative 29/40
Unknown 3/40
4.13-2
senting with casting type calcifications on the mammogram.
Axillary Node Status and Mammographic Tumor Features 215
As the stellate tumor size increases to 10−14 mm, the node expectedly high rate of node positivity (43.5 %) emphasizes
positivity rate increases to 15.2 %. In the tumors of similar the deviant nature of these tumors (Figs. 4.13-3 & 4).
size, but associated with casting type calcifications, the un-
5.1%
15.2%
Positive 48/316
Negative 252/316
79.7% Unknown 16/316
4.13-3
senting as stellate tumors without associated calcifications on the mammogram.
8.7%
43.5%
47.8% Positive 10/23

Negative 11/23
Unknown 2/23
4.13-4
senting with casting type calcifications on the mammogram.
Surprisingly, the conventional prognostic factors of axillary 1−14 mm invasive breast cancers will have excellent long-
node status and histological malignancy grade do not pre- term survival, even those few with node-positive 1−9 mm
dict the long-term outcome of 1−14 mm invasive breast invasive tumors. A surprising finding is the consistently
cancers associated with casting type calcifications. The un- poor outcome of women with 1−14 mm invasive cancer as-
reliability of the axillary node status in predicting the long- sociated with casting type calcifications, regardless of node
term survival of women with 1−9 mm and 10−14 mm inva- status (Fig. 4.14-5). These findings demonstrate that the
sive breast cancers is demonstrated in terms of the mammo- node status in 1−14 mm invasive breast cancers is a much
graphic tumor features in Figs. 4.14-1 to 5. In the absence of less reliable prognostic factor than it is for larger tumors.
casting type calcifications, the vast majority of women with
1.0
0.9
94.3%
0.8
0.7
76.1%
Cumulative survival
0.6
0.5
0.4
0.3
All the others (6/221) RR=1.0
0.2
0.1 Casting (4/29) RR=6.10 (1.72–21.65)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.14-1 Cumulative 24-year disease specific survival of women with node-negative 1−9 mm inva-
sive breast cancer by mammographic tumor features.
1.0
93.0 %
0.9
0.8
0.7
Cumulative survival
0.6
53.0 %
0.5
0.4
0.3 All the others (14/376) Casting (4/11)

0.2
RR=1.0 RR=12.73 (4.15–38.99)
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.14-2 Cumulative 24-year disease specific survival of women with node-negative 10−14 mm inva-
sive breast cancer by mammographic tumor features.
Axillary Node Status and Mammographic Tumor Features 217
Fig. 4.14-3 Cumulative 24-year

disease specific survival of women
1.0
100.0%
with node-positive 1−9 mm inva-
sive breast cancer by mammo- 0.9
graphic tumor features.
0.8
0.7
66.7%
Cumulative survival
0.6
0.5
0.4
0.3
0.2 All the others (0/14)
0.1 Casting (1/8)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.14-4 Cumulative 24-year 1.0

disease specific survival of women
with node-positive 10−14 mm inva- 0.9
sive breast cancer by mammo- 80.0%
graphic tumor features. 0.8
0.7
Cumulative survival
0.6
50.0%
0.5
0.4
0.3
All the others (7/73) Casting (4/10)
0.2
RR=1.0 RR=5.49 (1.59–19.01)
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
1.0
Fig. 4.14-5 Cumulative 24-year
disease specific survival of women 0.9
with 1−14 mm invasive breast
cancers associated with casting 0.8
type calcifications according to 0.7
68.4%
Cumulative survival
axillary node status.

0.6 54.5%
0.5
0.4
0.3
0.2 Negative (8/35)
0.1 Positive (5/12)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Histological Malignancy Grade and Mammographic

Tumor Features
Additionally, there is a considerable difference in the dis- of Grade 2 and 3 in our consecutive series of cases diagnosed
tribution of histological malignancy grade according to from 1977 to 2001. Although the casting type calcifica-
mammographic tumor features (Figs. 4.15-1 & 2): 38 % of the tions represent a Grade 3 intraductal malignant process,
1−9 mm stellate cancers were Grade 2 and 3, whereas 88 % of note that the majority of the associated 1−9 mm invasive
the tumors associated with casting type calcifications were carcinomas are Grade 2.
3.2%
7.0%
30.8% 58.9% Grade 1 (109/185)

Grade 2 (57/185)
Grade 3 (13/185)
Grade Unknown (6/185)
4.15-1
Fig. 4.15-1 Distribution of histological malignancy grade in 1−9 mm invasive breast cancers presenting as
stellate tumors without associated calcifications on the mammogram.
5.0%
7.5%
30.0%
Grade 1 (3/40)
57.5% Grade 2 (23/40)
Grade 3 (12/40)
Grade unknown (2/40)
4.15-2
Fig. 4.15-2 Distribution of histological malignancy grade in 1−9 mm invasive breast cancers presenting
with casting type calcifications on the mammogram.
Histological Malignancy Grade and Mammographic Tumor Features 219
As the stellate tumor size range increases to 10−14 mm, the essentially unchanged (88 % vs. 83 %) (Figs. 4.15-3 & 4). The
frequency of Grade 2 and 3 tumors also increases (from 38 % most important finding is that the majority of the
to 53 %) at the expense of the Grade 1 tumors. In the tumors 10−14 mm invasive carcinomas associated with casting
of similar size, but associated with casting type calcifica- type calcifications are Grade 2.
tions, the very high rate of Grade 2 and 3 tumors remains
2.5%
8.5%
45.0% Grade 1 (142/316)

44.0%
Grade 2 (139/316)
Grade 3 (27/316)
Grade Unknown (8/316)
4.15-3
as stellate tumors without associated calcifications on the mammogram.
4.3%
13.0%
26.1%
Grade 1 (3/23)
Grade 2 (13/23)
56.6% Grade 3 (6/23)
Grade unknown (1/23)
4.15-4
with casting type calcifications on the mammogram. Note that 56.6 % of the associated invasive
10−14 mm cancers are Grade 2.
Unfortunately, the histological malignancy grade also come, but there was a 100 % disease specific survival in the
loses its reliability in predicting the long term outcome of 1−9 mm tumor size range. Even in the size range of 10−
women with 1−9 mm and 10−14 mm invasive breast can- 14 mm, the Grade 3 tumors had a better outcome than the
cers15,16 (Figs. 4.16-1 to 4). One would expect that women 1−9 mm Grade 2 tumors.
with Grade 3 tumors would have a poorer long-term out-
1.0 100.0%
0.9
0.8
0.7
Cumulative survival
0.6
0.5
0.4
0.3
0.2
0.1 1–9 mm (0/42)

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.16-1 Cumulative survival of women with 1−9 mm Grade 3 invasive breast cancer.
1.0
0.9
89.3%
0.8
0.7
Cumulative survival
0.6
0.5
0.4
0.3
0.2
0.1 10–14 mm (4/63)

0
0 2 4 6 8 10 12 14 16 18 20 22 24
The surprising discrepancy between the outcome of women Figs. 4.16-3&4 show the surprisingly poorer long-term outcome
with 1−14 mm Grade 3 and Grade 2 invasive breast cancers of women with 1−9 mm and 10−14 mm Grade 2 invasive breast
can be explained using the mammographic prognostic fea- cancers compared to those with Grade 3 tumors (Figs. 4.16-1 &2).
tures (following pages 222−225). These observations should cause us to critically examine the value
of the histological malignancy grade as a prognostic factor.
1.0
0.9
0.8 85.3%
0.7
Cumulative survival
0.6
0.5
0.4
0.3
0.2
1–9 mm (8/136)
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
0.9
83.0%
Cumulative Surviva
0.8
0.7
0.6
0.5
0.4
0.3
35.0%
0.2
0.1
RR=1.0 RR=11.05 (4.44 – 27.51)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
4.16-4
When plotting the survival curves of 1−9 mm Grade 3 type calcifications (93.5 % 24-year survival), and also 2
tumors (Fig. 4.17-1), the absence of breast cancer death in breast cancer deaths among only 6 women with invasive
any of the subgroups precludes further division. In the size tumors of identical size and histological grade but as-
group of 10−14 mm (Fig. 4.17-2), one observes 2 breast sociated with casting type calcifications (50.0 % 24-year sur-
cancer deaths among the 57 cases not containing casting vival).
100.0%
1.0
0.9
0.8
0.7
Cumulative survival
0.6
0.5
0.4 Stellate (0/13)

Circular / oval (0/11)
0.3
1 or 2 + nonspecific Calcification (0/0)
0.2
Casting type calcification (0/12)
0.1
Crushed stone-like calcification (0/6)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.17-1 Cumulative survival of women with 1−9 mm Grade 3 invasive breast cancers by mammo-
1.0
0.9
93.5%
0.8
0.7
0.6
Cumulative survival
0.5 50.0%
0.4
0.3
0.2 All the others (2/57) Casting (2/6)

0.1 RR=1.0 RR=12.71 (1.75–92.12)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
4.17-2
Fig. 4.17-2 Cumulative survival of women with 10−14 mm Grade 3 invasive breast cancers by mammo-
When plotting the survival curves of 1−9 mm Grade 2 deaths among only 23 women with invasive tumors of iden-
tumors by separating out the cancers with casting type cal- tical size and histological grade but associated with casting
cifications from the rest, one observes 4 breast cancer type calcifications (69.0 % 24-year survival). By whatever
deaths among the 113 cases not containing casting type cal- measure we choose, the outcome is poorer for the Grade 2
cifications (88.7 % 24-year survival), and also 4 breast cancer tumors than for the Grade 3 tumors in the same size range.
1.0
0.9
88.7%
0.8
0.7
Cumulative survival
0.6 69.0%
0.5
0.4
0.3

0.1 Casting (4/23) RR=4.69 (1.17–18.83)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.17-3 Cumulative survival of women with 1−9 mm Grade 2 invasive breast cancers by
mammographic tumor features.
0.9
83.0%
Cumulative Surviva
0.8
0.7
0.6
0.5
0.4
0.3
35.0%
0.2
0.1
RR=1.0 RR=11.05 (4.44 – 27.51)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
4.17-4
Fig. 4.17-4 Cumulative survival of women with 10−14 mm Grade 2 invasive breast cancers by
mammographic tumor features.
The divergent behavior of the 1−9 mm and 10−14 mm Grade While axillary node status and malignancy grade are well-
2 tumors associated with casting type calcifications demon- established and reliable prognostic factors in tumors
strated in Figs. 4.17-3 & 4 (previous page) is further empha- 20 mm, their prognostic reliability appears to diminish
sized when comparing the outcome of the largest subgroup, with decreasing tumor size.
stellate tumors without associated calcifications, against the
outcome of tumors associated with casting type calcifica-
tions.
1.0
100.0%
0.9
0.8
0.7
69.0%
Cumulative survival
0.6
0.5
0.4
0.3
Stellate without calcifications (0/57)
0.2
0.1
Casting type calcifications ± tumor mass (4/23)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.17-5 Cumulative survival in the 1−9 mm size range of women with Grade 2 stellate invasive
breast cancers compared with Grade 2 invasive tumors associated with casting type calcifications.
1.0
0.9
89.0%
0.8
0.7
Cumulative survival
0.6
0.5
0.4 35.0%
0.3
0.2 Stellate without calcifications (10/139)

0.1
Casting type calcifications ± tumor mass (7/13)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Fig. 4.17-6 Cumulative survival in the 10−14 mm size range of women with Grade 2 stellate invasive
breast cancers compared with Grade 2 invasive tumors associated with casting type calcifications.
Our interpretation of the above findings can explain much 6 It is generally accepted that the patient outcome is de-
of the confusing discrepancy between the outcome of termined by the histological features of the small inva-
women with 1−14 mm Grade 3 and Grade 2 invasive breast sive tumor, regardless of whether there is an associated
cancers. in-situ component. This assumption leads to confusion
1 Women with 1−9 mm Grade 2 stellate invasive carci- concerning this particular breast cancer subtype, where
nomas without associated casting type calcifications the in-situ component is characterized by casting type
have excellent 24-year survival (Figs. 4.17-5 & 6). calcifications. This is because in the majority of the
2 Since women with tumors of the same size category and cases the invasive component is a 1−14 mm Grade 2
histological grade associated with casting type calcifica- tumor, which should otherwise have an excellent prog-
tions have a dismal prognosis, the associated Grade 2 nosis in the absence of casting type calcifications. The
invasive component cannot by itself be responsible for surprisingly poor outcome of these cases cannot be at-
the poor outcome. The same conclusion applies to the tributed to the histological features of the small, Grade 2
10−14 mm size category. invasive component.
3 The large tumor burden contained within the region of 7 One consequence of attributing the poor outcome to the
several centimeters size with casting type calcifications small, nonpalpable invasive component, while under-
must therefore be responsible for the poor outcome in estimating the true nature of the complex conglomerate
these cases, even if it is currently classified as an in-situ consisting of Grade 3 DCIS and duct forming high-grade
component. invasive carcinoma shown on the mammogram as cast-
4 We propose that the casting type calcifications repre- ing type calcifications, is frequent recurrence and poor
sent both an in-situ carcinoma (when the cancer cells outcome despite adjuvant therapeutic regimens. An-
are confined within the preexisting duct system) and other consequence of this assumption is the currently
also a “duct forming high-grade invasive carcinoma,” inappropriate TNM classification, whereby breast can-
where the cancer cells are situated within the newly cer death is considered to have been caused by, for ex-
formed ducts, mimicking the adjacent in-situ process. ample, a T1a Grade 2 invasive tumor. This in turn gives
This process of neoductgenesis appears to account for the mistaken impression that some “small” breast can-
the significant, potentially harmful portion of the tumor cers are systemic from their inception.17
burden. 8 The failure to discriminate between the two extremes
5 The discrepancy between the long-term survival of of outcome within the 1−14 mm invasive breast cancer
women with 1−14 mm Grade 3 and Grade 2 invasive group has lead to overtreatment of the majority of
breast cancers can be explained by the fact that most 1−14 mm breast cancers, since the therapeutic guide-
1−14 mm invasive breast cancer cases with associated lines are based on the aggregated outcome data, com-
casting type calcifications are histological Grade 2, and bining cancers having truly excellent long-term survival
include most of the fatal cases (Figs. 4.15-1 to 4, 4.16-1 (the majority) with cancers having a high short-term
to 4, 4.17-1 to 6). This may give the false impression that fatality rate (the minority).18
the histological Grade 2 is a more fatal disease than
Grade 3. However, it is the duct forming high-grade
malignant process that must be responsible for the high
fatality rate.
Outcome of 1−14 mm Casting Cases Compared with

Advanced Cancers
There is a striking similarity between the breast cancer group in the same size category has a long-term outcome in-
specific survival curves of the 1−9 mm and 10−14 mm inva- distinguishable from that of advanced cancers, the ines-
sive tumors associated with casting type calcifications and capable conclusion must be that we are dealing with a dis-
the outcome curves of much larger, advanced breast cancers ease subgroup that in reality acts like an advanced cancer.
(Fig. 4.18). The similarity in outcome of tumors that have Because this tumor behaves like an advanced cancer, the
been classified as T1a and T1b to the outcome of advanced policy of calling it a 1−9 mm or 10−14 mm invasive cancer
cancers should prompt us to resolve this discrepancy. Re- must be in error. After all, it is the long-term clinical be-
ports confirming the poor outcome of small invasive cancers havior of a tumor subgroup that reveals its true nature,
associated with casting type calcifications give further cre- which should also determine its place in the TNM staging
dence to the importance of this topic.10,16−22 If the vast ma- classification. Unfortunately, the present classification sys-
jority of women with 1−9 mm and 10−14 mm breast cancers tem fails to provide an accurate match between the charac-
have excellent long-term survival, as demonstrated in pre- teristics of this tumor subtype and the eventual patient out-
vious figures (pages 220−224), yet one well-defined sub- come.
1.0
0.9
0.8
0.7
Cumulative survival
0.6
0.5
0.4
1–14 mm (21/84) casting
0.3 1–9 mm (10/53) casting
1–14 mm (11/31) casting
0.2 15–19 mm (8/34) node-positive Grade 3 NOS
20–29 mm (12/76) node-negative Grade 3 NOS
0.1 20–29 mm (12/66) node-positive Grade 2 NOS
30–49 mm (7/25) node-negative Grade 2 NOS
0
0 5 10 15 20 25
4.18 Years since diagnosis
Fig. 4.18 The breast cancer specific survival of 1−9 mm and 10−14 mm invasive breast cancers associated with casting
type calcifications closely follows the survival curves of 15−19 mm node-positive Grade 3 invasive ductal carcinoma,
20−29 mm node-negative Grade 3 and node-positive Grade 2 invasive ductal carcinoma, and 30−49 mm node-negative
Grade 2 invasive breast cancer.
227
Chapter 5 Recognition of the

Unpredictable, Often Fatal
Nature of the Breast
Cancer Subtype Presenting
with Casting Type
Calcifications on the
Mammogram
228
229
Introduction
In summary, it appears that the tumor-filled ducts are a mix- ability to disseminate both hematogenous and lymphatic
ture of both cancer-filled preexisting ducts (in situ) and metastases even in the absence of demonstrable “classic” in-
newly formed ducts (neoductgenesis) in this special subtype vasive foci. The large, high-grade invasive tumor burden ac-
of breast cancer. The result is a conglomerate of “comedo counts for the poor long-term outcome, which is similar to
carcinoma in situ” or Grade 3 DCIS combined with “high- that of the large and high-grade classical invasive tumors.
grade duct forming invasive carcinoma”/“neoductgene- An additional problem is that the associated small focus
sis.” Both will have central necrosis and often amorphous (foci) of classical invasive, generally Grade 2 carcinoma is
calcifications with solid or micropapillary cell architecture currently considered to be the determining component for
surrounded by a basement membrane. The new, cancerous the TNM classification of this breast cancer subtype. The
branches of the ducts also have a distinct desmoplastic reac- small, often Grade 2 invasive foci fail to account for the
tion and extensive lymphocytic infiltration and are often as- frequent extensive lymph vessel invasion. Occasionally the
sociated with neoangiogenesis. lymph vessels contain cancer cells resembling the Grade 3
The unique subgross histologic presentation of this breast cells seen in the “DCIS” component, although the invasive
cancer subtype helps us understand that this disease has the focus is Grade 2.
230 The Unpredictable Nature of the Breast Cancer Subtype with Castings
Examples with Fatal Outcome

Example 5.1
tion. She was called back for assessment of the microcalcifi-
cations found on the screening mammograms of the right
breast.
Ex. 5.1-1 & 2 MLO and CC projections. Crushed stone−like and

casting type calcifications without an associated tumor mass are
seen in the upper portion of the breast. Ex. 5.1-1
Ex. 5.1-2
Examples with Fatal Outcome 231
Example 5.1
Ex. 5.1-3 Ex. 5.1-4

Ex. 5.1-3 & 4 Microfocus magnification views of the areas in the rectangles in Ex. 5.1-1 & 2, MLO and CC projections. The mammo-
graphically malignant type calcifications are a mixture of crushed stone−like and casting type calcifications.
Ex. 5.1-5 Ex. 5.1-6

Ex. 5.1-5 & 6 Preoperative FNAB under stereotactic guidance shows malignant cells.
Ex. 5.1-7 Specimen radiograph: the micro-

calcifications have been removed with a
good margin.
Ex.
5.1-7
Ex. 5.1-8 & 9 Comparative large, thin

(4 μm) (8) and subgross, thick section
(about 1000 μm) (9) histology:
36 mm × 12 mm Grade 3 DCIS. The lesion
has been removed with a 15 mm free
margin.
Ex.
5.1-8
Ex.
5.1-9
Ex. 5.1-10 & 11 Medium-power histological

image. Cross section of a large number of
cancerous ducts, which are spaced unusu-
ally close together, surrounded by a desmo-
plastic reaction and lymphatic infiltration.
Ex.
5.1-10
Ex.
5.1-11
Ex. 5.1-12 Subgross histological image

showing an unnaturally high concentration
of ducts that are greatly distended by
malignant cells, central necrosis, and oc-
casional amorphous calcifications.
Ex.
5.1-12
Ex. Ex.
5.1-13 5.1-14
Ex. 5.1-13 A strong lymphocytic reaction surrounds the cancer- Ex. 5.1-14 Grade 3 cancer cells, solid cell architecture.
ous process.
Ex. Ex.
5.1-15 5.1-16
Ex. 5.1-15 & 16 The pathological ducts are contorted and have numerous small buds surrounded by a strong lymphocytic reaction, but
lack any TDLUs.
Ex.
5.1-18
Ex.
5.1-17
Ex. 5.1-17 & 18 The pathological ducts are crowded closely together. The strong lymphocytic reaction identifies the small buds corre-
sponding to the formation of new, ductlike structures.
Ex. Ex.
5.1-19 5.1-20
Ex.
5.1-22
Ex.
5.1-21
Ex.
5.1-24
Ex.
5.1-23
Ex. 5.1-19 to 24 Comparative subgross, 3D histological images (19, 21, 23) and conventional histology (20, 22, 24), demonstrating the
abnormal ductlike structures distended by cancer cells, necrosis, and occasional amorphous calcifications.
Interpretation: According to conventional histological cri- penetrate into the surrounding tissue. Our interpretation is
teria, the presence of a basement membrane classifies these that Grade 3 “DCIS” with castings over a large area has inva-
malignancies as an in-situ process, “DCIS.” However, many sive properties (neoductgenesis), which can account for the
of the ducts have a dense and disorganized architecture and fatal outcome in this case, since we must assume that classic
show tenascin overexpression, lymphocytic infiltration, and in-situ carcinoma, if it be truly in situ, could not have been
a desmoplastic reaction, all of which indicate that these par- the cause of death.
ticular ducts are newly produced during tumor growth and
Follow up: Yearly follow-up with clinical breast examina-

tion and mammography showed no abnormality until six
and one-half years after sector resection and radiotherapy,
when the patient was hospitalized because of histologically
proven breast cancer metastases to the lungs and skeleton
(Ex. 5.1-25 to 30).
Ex. 5.1-25
Ex. 5.1-25 Chest radiograph showing densities suspicious for
metastases.
Ex. 5.1-26 Ex. 5.1-27

Ex. 5.1-26 & 27 Bone scan. Multiple areas of increased uptake
consistent with metastases.
Ex. 5.1-28 Ex. 5.1-29 Ex. 5.1-30

Ex. 5.1-28 to 30 Chest CT, bone window. Destruction of the left anterior third rib.
Ex. Ex.
5.1-31 5.1-32
Ex. 5.1-31 & 32 CT-guided large-core needle biopsy of the chest wall metastases.
Ex. Ex.
5.1-33 5.1-34
Ex. 5.1-33 & 34 CT showing destruction of the sphenoid sinus.
Ex. Ex.
5.1-35 5.1-36
Ex. 5.1-35 & 36 Abdominal CT, bone window. Lumbar vertebral destruction.
Treatment: Sector resection and postoperative irradiation.

Comment
This case clearly demonstrates the disturbing discrepancy be-
Outcome: The patient died 7 years and 1 month following tween a so-called in situ carcinoma and a fatal outcome, a dis-
treatment. Autopsy revealed metastatic breast cancer as the crepancy which can be explained by the process of neoduct-
cause of death. genesis.
Example 5.2
tion.
Ex. 5.2-2
Ex. 5.2-1 & 2 Left breast, MLO and CC projections. Retrospective
review of the films shows a small, superficial, branching calcifica-
tion and some nonspecific calcifications in the upper outer quad-
rant. The subtle finding was not appreciated at this screening.
Ex. 5.2-1
Ex. 5.2-4
Ex. 5.2-3 & 4 Photographic magnification of the area with the
findings on the MLO (3) and CC (4) projections.
Ex. 5.2-3
Ex. 5.2-5 Two years after her pre-

vious screening examination the
patient felt a thickening in the
lateral portion of her left breast.
Detail of the left CC microfocus
magnification view demonstrates in-
numerable casting type calcifica-
tions filling most of the quadrant.
Ex. 5.2-5

Grade 3 DCIS with microinvasion
covering an area measuring
60 mm × 50 mm.
Ex. 5.2-6
Comparative subgross, thick-section

(3D) histology and medium-power con-
ventional histology demonstrate the
dense aggregate of abnormal ducts.
Ex. 5.2-7 Subgross, thick section (3D)

histology.
Ex. 5.2-7
Ex. 5.2-8 & 9 Details of the large-section

histology slide.
Ex. 5.2-8
Ex. 5.2-9
Ex. Ex.
5.2-10 5.2-11
Ex. 5.2-10 & 11 Medium-power histological images (H&E). Ducts in cross section demonstrating solid cell proliferation with extensive
central necrosis and amorphous calcification.
Ex. Ex.
5.2-12 5.2-13
Ex. 5.2-12 & 13 Subgross, thick-section (3D) and conventional histological images of ducts in cross section containing amorphous
calcifications.
Ex.
5.2-15
Ex. Ex. 5.2-14 & 15 Higher-power histological images show the cel-
5.2-14 lular details of this Grade 3 in-situ carcinoma.
Outcome: The patient died of metastatic breast cancer.

Comment
Again, we find an obvious discrepancy between the so-called
in-situ carcinoma and the fatal outcome. Examination of both
the large-section subgross (3D) histology and the low-power
view of the large thin-section histology specimen reveals the
same phenomenon as seen in the previous case, which is an
abnormally high concentration of cancerous ducts packed
tightly together. These do not resemble preexisting ducts in
terms of orientation, size, shape, architecture, desmoplastic
reaction or lymphocytic infiltration, or lack of TDLUs, but they
are surrounded by a basement membrane.
Example 5.3
tion.
Ex. 5.3-1 Ex. 5.3-2
Ex. 5.3-3 Ex. 5.3-4

Ex. 5.3-1 to 4 Right and left breasts, MLO and CC projections. No calcifications or tumor mass are seen.
Twenty months after her screening mammogram, the

patient felt a “thickening” in the upper outer quadrant of her
right breast.
Ex. 5.3-5 Ex. 5.3-6

Ex. 5.3-5 & 6 Right breast, MLO and CC projections. The entire upper outer quadrant is filled with calcifications that have
developed since the last examination.
Ex. 5.3-7 Right breast, MLO projection, microfocus

magnification view over the area with the calcifica-
tions. These are a mixture of casting type and
crushed stone−like, malignant type calcifications.
No associated tumor mass is seen.
Ex. 5.3-7
Ex. 5.3-8 Right breast, CC projection, microfocus

magnification view, demonstrating the extent and
type of the calcifications.
Ex.
Initial treatment: Sector resection. 5.3-8
Ex.
5.3-10
Ex. Ex.
5.3-9 5.3-11
Ex. 5.3-9 & 10 Further magnification of the right upper outer quadrant (9) Ex. 5.3-11 Fine-needle aspiration biopsy: malig-
and breast ultrasound image (10). Neither mammography nor ultrasound nant cells.
shows any obvious tumor mass.
Ex. 5.3-12 Specimen radiograph of

the surgical specimen after sector
resection shows malignant type cal-
cifications along the resection margin
(specimen size 8 cm × 7 cm × 2 cm).
Ex. 5.3-12

70 mm × 60 mm Grade 3 DCIS ex-
tending to the surgical margin.
There is no histological evidence of
invasion.
Ex. 5.3-13
Ex. 5.3-14 Subgross large-section

histological image demonstrating
numerous cancer-filled, distended
ducts in the vicinity of entirely nor-
mal glandular structures.
Ex.
5.3-14
Ex. Ex.
5.3-15 5.3-16
Ex. Ex.
5.3-17 5.3-18
Ex. 5.3-15 to 18 Medium- and high-power histological images show solid cell proliferation of Grade 3 cancer cells, central necrosis, and
Ex. 5.3-19 Subgross, thick-section

(3D) histological image covering
several centimeters of this speci-
men. The cancerous ducts measure
more than 1 mm in diameter,
approximately 10 times the size of
normal ducts.
Ex. 5.3-19
Ex. 5.3-20 Higher-magnification 3D

histological image showing the large
number of ductlike structures dis-
tended by cancer cells, necrotic de-
bris, and amorphous calcification.
Ex. 5.3-20
Ex. Ex.
5.3-21 5.3-22
Ex. 5.3-21 & 22 Desmoplastic reaction and lymphocytic infiltration are seen surrounding some of the ducts (21), where tenascin over-
expression can also be demonstrated (22).
Ex. Ex.
5.3-23 5.3-24
Ex. 5.3-23 & 24 Ducts distended by proliferating cancer cells. Tenascin overexpression (wide brown layer surrounding the duct), indi-
cating that these may be the result of neoductgenesis.
Ex. Ex.
5.3-25 5.3-26
Ex. 5.3-25 & 26 Smooth-muscle actin staining demonstrates the myoepithelial cell layer, supporting the diagnosis of “in-situ carci-
noma.”
Further treatment: Subcutaneous mastectomy. Breast re- Two years later the patient felt a large lump in her ipsilateral
construction with a saline implant. axilla.
Ex.
5.3-28
Ex. 5.3-28 Specimen radiograph of 12 surgically removed axillary nodes. There
are casting type calcifications within the lymph nodes, and also in the axillary
adipose tissue surrounding the lymph nodes.
Ex. Ex.
5.3-27 5.3-29
Ex. 5.3-27 Right MLO projection. There are sev- Ex. 5.3-29 Fine-needle aspiration of one of the pathological axil-
eral pathological axillary nodes containing calcifi- lary nodes: malignant cells.
cations.
Ex. Ex.
5.3-30 5.3-31
Ex. 5.3-30 & 31 Histological examination of the axillary adipose tissue, H&E (30) and actin staining (31). There are ductlike structures in
the loose connective tissue surrounding the axillary nodes, mimicking in-situ carcinoma.
Ex. Ex.
5.3-32 5.3-33
Ex. 5.3-32 & 33 Smooth-muscle staining shows the lack of myoepithelial cell layer around the ductlike structures in the axillary fat.
These structures are independent of the lymph nodes and are located in the axillary adipose tissue.
Ex. Ex.
5.3-34 5.3-35
Ex. 5.3-34 & 35 Basement membrane staining (Collagen IV) of the ductlike structures containing cancer cells in the axillary adipose
tissue does not demonstrate a distinct membrane.
Ex. Ex.
5.3-36 5.3-37
Ex. 5.3-36 & 37 Tenascin overexpression around the cancerous, ductlike structures in the axillary adipose tissue suggests neoduct-
genesis.
Ex. 5.3-38 Low-power histology

image of one of the 12 resected
lymph nodes.
Ex.
5.3-38
Ex. Ex.
5.3-39 5.3-40
Ex. Ex.
5.3-41 5.3-42
Ex. 5.3-39 to 42 Medium-power histology (H&E) images of one of the axillary lymph nodes show numerous pathological ductlike struc-
tures in cross section. These are similar in appearance to that of ductal carcinoma in situ within the breast. The ductlike structures are
distended by Grade 3 malignant cells with solid architecture, central necrosis, and amorphous calcifications, and are surrounded by a
desmoplastic reaction and lymphocytic infiltration. Ex. 5.3-40 is a magnified image of the area within the rectangle in Ex. 5.3-38.
Adjuvant treatment: Chemotherapy with FEC (fluorouracil tases to the lungs appearing during treatment. Further dis-
[5FU], epirubicin, and cyclophosphamide). Progression of ease progression during Herceptin, Taxol and other adjuvant
the disease with core biopsy-proven breast cancer metas- therapy.
Ex. 5.3-43 Detailed image of the axillary

specimen radiograph, showing that both
the axillary lymph nodes and the surround-
ing adipose tissue contain a large number
of casting type calcifications.
Ex.
5.3-43
Ex. Ex.
5.3-44 5.3-45
Ex. 5.3-44 & 45 These ductlike structures are filled with cancer cells, necrosis, and amorphous calcifications, and are inside the axillary
lymph nodes. Obviously, there are no preexisting ducts within axillary lymph nodes. These must be newly formed ducts (neoductgene-
sis), an interpretation supported by tenascin overexpression.
Outcome: The patient died from breast cancer metastases

six years following initial surgery.
Comments orientation, size, and architecture and the presence of lym-

This is an even more complex case than the previous ones, al- phocytic infiltration and desmoplastic reaction distinguish
though there are many common features. Similarities include them from normal ducts, although they are still surrounded by
the contradiction of a diagnosis of in-situ carcinoma causing a basement membrane.
systemic dissemination and the lack of response to adjunctive The differences include the regional metastases to a large num-
treatment regimens, including chemotherapy and treatment ber of axillary nodes and even metastases to the axillary
with Herceptin. There is also the phenomenon of an abnor- adipose tissue. These metastases are strikingly similar in ap-
mally high density of cancerous ducts distributed over a large pearance to the “in-situ” component in the breast.
volume of tissue. Again, these ducts lack TDLUs, and their
Frequent Recurrence with Casting Type Calcifications 253
Frequent Recurrence with Casting Type Calcifications

The breast cancer subtype presenting with casting type cal-
Example 5.4
cifications recurs frequently, despite postoperative irradia-
tion or chemotherapy. It is also the subtype commonly as- Screening examination of a 62-year-old woman.
sociated with Paget disease of the nipple.
Ex. 5.4-1 Ex. 5.4-2

Ex. 5.4-1 Right breast, MLO projection. A tiny cluster of Ex. 5.4-2 Microfocus magnification view, MLO projection.
microcalcifications is seen without an associated tumor
mass.
Ex. 5.4-3 Microfocus magnification

view, CC projection. The mammo-
graphically malignant type calcifica-
tions are a mixture of the crushed
stone−like and casting type calcifica-
tions.
Ex. 5.4-3
Ex. 5.4-4 Specimen radiograph. The mammo-

graphically detected calcifications have been re-
moved with a close margin.
Ex. 5.4-4
Ex. 5.4-5 Microfocus magnification of the speci-

men radiograph. The calcifications are associated
with an ill-defined density, corresponding to a con-
glomerate of cancerous ducts and desmoplastic
reaction.
Ex. 5.4-5
Ex. 5.4-6 Histology: Typical Paget cells in the skin

of the nipple. There were also two foci of Grade 3
DCIS, measuring 10 mm × 6 mm and 6 mm × 4 mm.
Treatment and follow-up: Sector resection.

The patient declined postoperative irradiation.
Eight months later the patient presented with
an eczema-like change on her right nipple. Ex. 5.4-6
Ex. 5.4-8
Ex. 5.4-8 Medium-power histological image of the nipple. Typi-
cal Paget cells confirming the diagnosis: Paget disease of the
nipple.
Ex. 5.4-7 Right nipple showing changes that are consistent with
Ex. 5.4-7 Paget disease (preoperative photograph including skin marking).
Ex. 5.4-9 Double immunohistochemical

staining (HER2/neu and p63) demonstrating
nests of HER2/neu and positive tumor cells
(red membranous staining) in the back-
ground of the squamous cells of the epider-
mis (brown nuclear staining).
Ex. 5.4-9
Treatment and follow-up: Surgical removal of the nipple−

areola complex. Her latest follow-up examination eight
years after the second operation showed no evidence of re-
currence.
below demonstrate the variety of appearances this disease

Example 5.5
can produce (Ex. 5.5-1 to 11). The radiological technologists
When the high-grade intraductal malignant process extends should be trained to recognize nipple abnormalities that
to the nipple, the clinical manifestation is termed Paget dis- may have been caused by Paget disease, since the underly-
ease of the nipple. The 10 examples of Paget disease shown ing breast cancer may not be evident on the mammogram.
Ex. 5.5-1 Ex. 5.5-2
Ex. 5.5-3 Ex. 5.5-4
Ex. 5.5-5 Ex. 5.5-6

Ex. 5.5-1 to 6 Six examples of Paget disease.
Ex. 5.5-7 Ex. 5.5-8
Ex. 5.5-9 Ex. 5.5-10
Ex. 5.5-7 to 11 Four additional examples of Paget disease.
Ex. 5.5-11 Case courtesy of Martii Pamilo, M.D., Helsinki,

Finland. Ex. 5.5-11
Example 5.6
A 55-year-old woman felt a lump under her left areola. Fine-
needle aspiration by the surgeon showed malignant cells.
Ex. 5.6-1 Ex. 5.6-2

Ex. 5.6-1 & 2 Left breast, MLO projection (1) and microfocus magnification (2) of the lower half of the left breast show a large number
of malignant type calcifications surrounded by a nonspecific density.
Ex. 5.6-3 Ex. 5.6-4
Ex. 5.6-5 Ex. 5.6-6

Ex. 5.6-3 to 6 Medium-power conventional histological images (3 & 5) and subgross, 3D histological images (4 & 6) demonstrate an
unnaturally high concentration of ductlike structures filled with malignant cells and central necrosis.
Ex. 5.6-7 & 8 Comparative sub-

gross (7) and large-section histologi-
cal (8) images of the mastectomy
specimen show an area measuring
33 mm of high grade DCIS with
signs of neoductgenesis and neo-
angiogenesis.
Ex. 5.6-7
Treatment: Mastectomy. Ex. 5.6-8
Ex. 5.6-9 Ex. 5.6-10

Ex. 5.6-9 & 10 Higher-magnification histology images (H&E). Both solid and micropapillary cell proliferation with necrosis are present.
Ex. 5.6-11 & 12 Subgross, thick-

section (3D) histological images
show a large number of tortuous,
newly formed blood vessels (most
probably neoangiogenesis) supply-
ing the newly formed, cancerous
ducts (neoductgenesis).
Ex.
5.6-11
Ex.
5.6-12
Ex. 5.6-13 & 14 First follow up ex-

amination one year after mastec-
tomy. A cluster of malignant type
calcifications and an ill-defined den-
sity are the signs of recurrence on
the mastectomy side.
Ex. 5.6-13 Ex. 5.6-14
Ex. 5.6-15 & 16 Specimen radio-

graph (15) and microfocus magnifi-
cation (16) of the cluster of casting
type calcifications.
Ex. 5.6-17 & 18 At histology, high-

grade DCIS was seen in an area Ex. 5.6-16
measuring 35 mm × 35 mm. The
periductal desmoplastic reaction
caused the nonspecific density on
the mammogram.
Ex. 5.6-15
Further treatment and follow-

up: Surgical removal of the re-
currence followed by postopera-
tive irradiation to the mastec-
tomy side. No signs of recurrence
11 years after the first operation.
Ex. 5.6-17 Ex. 5.6-18

Example 5.7
A 72-year-old asymptomatic woman, screening mammo-
gram.
Ex. 5.7-1 Ex. 5.7-2

Ex. 5.7-1 & 2 Detail of the right MLO projection and microfocus magnification image show a large number of malignant
type (both crushed stone−like and casting type) calcifications spread over a large area.
Treatment: Mastectomy.
Ex. 5.7-3 Ex. 5.7-4

Ex. 5.7-3 & 4 Histology of the mastectomy specimen (H&E). The cancer cells show solid and micropapillary cell architecture within the
numerous, tightly packed ducts distended by necrosis and amorphous calcifications.
Follow-up: Five annual clinical and mammographic exami- cations were demonstrable in the subcutaneous tissue on
nations including an MLO view of the mastectomy side were the mastectomy side.
normal. Six years after mastectomy, malignant type calcifi-
Ex. 5.7-5 Ex. 5.7-6

Ex. 5.7-5 & 6 Higher-magnification histological images (H&E) of cross sections of ductlike structures.
Ex. 5.7-7 Ex. 5.7-8

Ex. 5.7-7 MLO view of the mastectomy site with calcifications. Ex. 5.7-8 Microfocus magnification: the calcifications are
crushed stone−like and casting type, similar in appearance to
those seen preoperatively.
Ex.
5.7-10
Ex. 5.7-10 Large-section histology.
Ex. Ex. 5.7-9 Microfocus magnification image of the specimen fol-

5.7-9 lowing reoperation.
Ex. 5.7-11 The ductlike cancerous

structures have the morphological
features of neoductgenesis. This in-
dicates that these ducts have re-
cently developed in the subcuta-
neous tissue in a location that did
not previously contain normal ducts.
Ex.
5.7-11
Ex. 5.7-12 to 15 Von Kossa (silver nitrate) staining of the ducts

from the mastectomy site. Cancer cells, necrosis, and intraluminal
amorphous calcifications distend the ductlike structures, which
are also surrounded by desmoplastic reaction. It appears that
neoductgenesis is not restricted to the glandular tissue, but can
also occur within the axillary lymph nodes and in the subcuta-
neous tissue and muscle.
Ex. 5.7-12
Ex. 5.7-13
Ex. 5.7-14
Treatment and outcome: Surgical removal of the recur-

rence on the chest wall followed by postoperative irradia-
tion to the mastectomy side. The patient died of a myo-
cardial infarction 14 years after her mastectomy. No autopsy
was performed. Ex. 5.7-15
Distant Metastases with Casting Type Calcifications

A 22-year old woman with no family history of breast cancer
Example 5.8
felt a hard lump in the upper outer quadrant of her right
(Case courtesy of Bruce A. Porter, M.D., FACR, First Hill Diag- breast. The diagnostic work-up included mammography,
nostic Imaging, Seattle, WA, USA) breast ultrasound and breast MRI, 14G core needle biopsy,
and whole body MRI for staging.
Ex. 5.8-1 Ex. 5.8-2

Ex. 5.8-1 & 2 Right breast, MLO and CC projections. There is a large area containing casting type calcifications in the upper half of the
breast with no associated tumor mass.
Distant Metastases with Casting Type Calcifications 267
Ex. 5.8-3 & 4 Microfocus magnifi-

cation images in the MLO (3) and
CC (4) projections. The calcifications
are of the casting type and crushed
stone−like, mammographically
malignant.
Ex. 5.8-3
Ex. 5.8-4
Ex. 5.8-5 Transverse 60-second MIP (maxi-

mum intensity projection). Mixed pattern of
enhancement involves most of the lateral
right breast with a discrete dominant mass
(infiltrating cancer) and surrounding diffuse
enhancement (DCIS). The left breast is nor-
mal.
Ex. 5.8-5
Ex. 5.8-6 CAD (computer-aided detection)

color parametric enhancement map. The in-
vasive ductal cancer is labeled intensely red,
indicating rapid wash-in and wash-out, i. e.,
a malignant pattern on CAD. The surround-
ing DCIS is less intense, but very abnormal.
Ex. 5.8-6
Ex. 5.8-7 Ex. 5.8-8

Ex. 5.8-7 Right oblique MIP. Ex. 5.8-8 Histology of the 14G core biopsy specimen of the invasive com-
ponent shows Grade 2 invasive ductal carcinoma.
Distant Metastases with Casting Type Calcifications 269
Ex. 5.8-9 Ex. 5.8-10

Ex. 5.8-9 & 10 Sagittal InterVIEWS, right breast (0.64 mm × 0.5 mm × 0.5 mm voxels).
Note the serpiginous, abnormal neoduct proliferation (DCIS).
Ex. Ex.
5.8-11 5.8-12
Ex. 5.8-11 & 12. Chest coronal short T1 inversion recovery (STIR). The right axillary and paraclavicular adenopathy is subtle but asym-
metrical compared to the left-side lymph nodes. Additional pulmonary nodules are seen on this more posterior slice. A PET-CT examina-
tion confirmed the pulmonary metastases: multiple hypermetabolic lung lesions were seen.
Treatment: The patient is currently undergoing treatment.
Comment
Functional imaging methods, such as breast MRI, play a crucial
role in detecting and staging this cancer subtype, especially in
high-risk women with dense breasts.
Suggestion for Use of the Mammographic Prognostic

Features in Clinical Practice
Breast cancers are detected in ever-increasing numbers at This discrepancy should alert us to the possibility that the
ever-smaller sizes, often nonpalpable, due to the wide- current breast cancer classification system is not adequately
spread application of screening mammography. Access to a serving its purpose. This group of fatal cancers is characterized
large number of breast cancer cases in their earliest de- by the combination of a 1−14 mm typically Grade 2 invasive
tectable phase of development has allowed us to study the cancer and a much larger, high-grade intraductal malignant
morphology and natural history of the individual subtypes. component with casting type calcifications on the mammo-
These detailed studies have produced some observations gram. The theory of neoductgenesis raises the possibility that
that conflict with the current diagnostic and therapeutic a portion of the large volume containing Grade 3 “DCIS” may
concepts concerning small, 1−9 mm and 10−14 mm, invasive act as large, poorly differentiated duct-forming invasive carci-
breast cancers. The purpose of this series of books is to bring noma. This would explain the high fatality rate among these
attention to these conflicts and to propose possible explana- cases. The primary characteristic feature of this breast cancer
tions that may help to resolve them. The use of mammo- subtype is its pathognomonic mammographic appearance.
graphic tumor features as a method for prognostic classifi- Separating 1−14 mm invasive breast cancers into these
cation has a central role in this process. two categories with a high degree of accuracy would have
For example, the vast majority of women with 1−14 mm two advantages: the group with excellent outcome after
invasive breast cancer have excellent long-term disease surgery alone could be spared much adjuvant therapy, while
specific survival without adjuvant therapy.1−4 However, the group with poor prognosis could be selected for more
there is a small, well-defined group of breast cancers, appropriate treatment. Analysis of the 24-year follow up re-
characterized by casting type calcifications on the mammo- sults of 871 consecutive 1−14 mm invasive breast cancers
gram, which frequently has a fatal outcome despite adju- leads us to suggest a modification of the current TNM cancer
vant therapy.5−6 This group has been customarily relegated staging system. This modification would incorporate the five
to the T1a−T1b category, although its outcome is uncharac- specific mammographic tumor features into the classifica-
teristically poor for the 1−14 mm size range, being instead tion of 1−14 mm invasive breast cancers to form distinct,
similar to the outcome of cancers 30−50 mm in diameter easily identifiable subgroups with either very good or very
(Fig. 4.18 on page 226). The long-term survival curves of this poor prognosis. Management of 1−14 mm invasive breast
particular subgroup of T1a−T1b cancers indicate that we are cancers should be more appropriate when mammographic
dealing with a much larger tumor burden than one would tumor features are taken into account to distinguish be-
anticipate from the size range of 1−14 mm. tween breast cancers with significantly different prognosis.
Suggestion for Use of the Mammographic Prognostic Features in Clinical Practice 271
The following practical suggestions are based on our cur- However, the term Grade 3 DCIS includes other breast
rent understanding of the breast cancer subtype presenting cancer subtypes as well, each having a strikingly different
with casting type calcifications: imaging appearance. We can best discriminate among
1 For the radiologist: MRI examination of the breast will the individual subgroups of Grade 3 DCIS by combining
help assess the true extent of the disease in casting type the diagnostic information available from both histology
calcification cases. Also, breast MRI examination should and radiology (mammography, galactography, breast ul-
be performed preoperatively on each patient with trasound and MRI).
clusters/multiple clusters of crushed stone−like, malig- 3 For the oncologist: The high fatality rate of this breast
nant type calcifications in order to distinguish between cancer subtype, even in the era of modern adjuvant ther-
cases with Grade 2 in-situ carcinoma localized to the apy, indicates its poor sensitivity to currently available
TDLU(s) and the high-grade, extensive malignant process adjuvant therapeutic agents. An entirely new approach to
occupying the whole lobe. A thorough preoperative im- developing more potent therapy is needed for this partic-
aging work-up, careful evaluation of the specimen radio- ular breast cancer subtype.
graph, and detailed comparison with modern, large-sec- 4 For scientists studying the genetic abnormalities as-
tion histology will help in treatment planning. sociated with breast cancer: This specific subtype can
2 For the pathologist: it is strongly suggested to use large- be pinpointed by the radiologist with a high degree of ac-
section histology in routine practice because of its super- curacy. Concentrated effort in mapping the genetic aber-
ior ability to document the extensive involvement of the rations characteristic of this subgroup of breast cancers
entire duct system of the lobe. This accurate documenta- should help in elucidating its specific biological features.
tion is a precondition for adequate radiological−histo- The goal is to develop effective therapeutic agents
logical correlation and communication with the breast tailored to this breast cancer subtype.
team. The morphology can be best appreciated when
comparing the magnified specimen slice radiograph with The current TNM classification fails to distinguish these two
the large-section histology techniques.7 The limited field groups from each other because the present clinical practice
of view of the standard microscopic slide compromises of classifying and predicting the long-term outcome of
evaluation of a process extending over much of the 1−14 mm invasive breast cancers uses morphological cri-
breast. This book deals with one particular breast cancer teria based solely on histopathological examination.
subtype, which is described at histology as Grade 3 DCIS.
273
Chapter 6 Illustrative Cases with

3-Dimensional
Stereoscopic Histological
Images
274 Illustrative Cases with 3-Dimensional Histological Images
Case 6.1
tion.
6.1-4
6.1-2
Figs. 6.1-1 & 2 Left breast, MLO (1) and
microfocus magnification (2) views show
a combination of casting type and
crushed stone−like calcifications sur-
rounded by an ill-defined density.
6.1-5
Figs. 6.1-4 & 5 Histology (H&E): in-situ
carcinoma with central necrosis. No signs
6.1-1 of invasion.
6.1-3
Fig. 6.1-3 Large-section histology (H&E).
The cancerous area has been marked by
the pathologist.
3D Image
Figs. 6.1-6 & 7 Subgross, thick-section (3D) histological images of this in-situ carcinoma.
Case 6.1 275
At age 64 years, recurrence was detected beside the surgical

scar.
6.1-9
Figs. 6.1-8 to 10 Left breast MLO (8), CC projections (9) and microfocus magnification
view (10): malignant type calcifications are seen (recurrence) at the site of the surgical ex-
cision. The calcifications have a similar appearance to those seen eight years earlier,
before treatment.
6.1-8
6.1-11 6.1-12 6.1-13

Fig. 6.1-11 14G core Figs. 6.1-12 & 13 Medium-power (12) and higher-power his-
biopsy specimen con- tology (13; H&E) of the 14G core biopsy: cancer in situ with
taining calcifications. solid cell proliferation and central necrosis (12). The recurrent
carcinoma is a combination of in situ and invasive ductal carci-
noma.
6.1-10
3D Image
Figs. 6.1-14 & 15 Subgross, thick-section (3D) histology. The contorted, distended ducts filled with carcinoma are spread over a
region measuring 22 mm × 10 mm.
Case 6.1 continued
6.1-16 6.1-17
Fig. 6.1-16 Microfocus magnification of one of the specimen Fig. 6.1-17 Large-section histology (H&E): the pathological ducts
slices showing the casting type calcifications surrounded by an ill- and the surrounding density have been removed with a good
defined density. margin.
6.1-18 6.1-19 6.1-20

Figs. 6.1-18 to 20 Histology (H&E): in-situ carcinoma (18, 20) associated with Grade 2 invasive cancer (19).
3D Image
Fig. 6.1-21 & 22 Subgross, thick-section (3D) histology: the distended ducts containing cancer cells, central necrosis and amor-
phous calcifications are closely spaced.
Case 6.2 277
Case 6.2
A 66-year-old woman, operated for cancer in her left breast moxifen. At her fourth annual follow-up examination a
four years before this examination. Her treatment included cancer was detected in the lower-inner quadrant of her right
surgery, postoperative irradiation and treatment with ta- breast.
6.2-1 6.2-2
Figs. 6.2-1 & 2 Right breast, MLO projection (1) and microfocus magnification (2). There is a stellate tumor with asso-
ciated casting type calcifications within and surroundings of the mammographically malignant tumor.
3D Image
Figs. 6.2-3 & 4 Subgross, thick-section (3D) histology shows an overview of both the invasive and intraductal carcinoma.
6.2-5 6.2-6
Fig. 6.2-5 Further magnification of the malignant tumor asso-
ciated with casting type calcifications.
6.2-7
Figs. 6.2-6 & 7 Microfocus magnification of two surgical speci-
men slices.
3D Image
Fig. 6.2-8 & 9 Subgross, thick-section (3D) histology. The invasive tumor also has in-situ components and a rich net of tumor
vessels.
Case 6.2 279
6.2-10 6.2-11
Figs. 6.2-10 & 11 Microfocus magnification images of two surgical specimen slices containing the casting type calcifications.
3D Image
Figs. 6.2-12 & 13 Subgross, thick-section (3D) histology. On this lower-magnification image the invasive tumor and the sur-
rounding in-situ components are seen.
3D Image
Figs. 6.2-14 & 15 Subgross, thick-section (3D) histology. The long ducts are filled with cancer cells and lack TDLUs. Occasional
amorphous calcifications are seen.
3D Image
Figs. 6.2-16 & 17 Subgross, thick-section (3D) histology. Higher magnification of the cancerous ducts also shows central necro-
sis and casting type calcifications.
Case 6.2 281
3D Image
Figs. 6.2-18 & 19 Subgross, thick-section (3D) histology. These abnormal, cancer-filled ducts and their branches do not contain
calcifications.
3D Image
Figs. 6.2-20 & 21 Subgross, thick-section (3D) histology. The lower magnification makes it possible to compare the discre-
pancy in size and shape between the atrophic ducts and the cancer-filled ducts.
3D Image
Figs. 6.2-22 & 23 Subgross, thick-section (3D) histology. Closer view of the abnormal, cancerous ducts which have no asso-
ciated TDLUs.
The patient died from disseminated breast cancer two years

after diagnosis and treatment.
Case 6.3 283
Case 6.3
A 36-year-old woman with bloody discharge from the right
nipple. There is no palpable tumor at physical examination.
Fig. 6.3-1 Right breast, CC pro- Fig. 6.3-2 Specimen radiograph showing Fig. 6.3-3 Large-section histology (H&E):
jection, detail of galactogram. The innumerable crushed stone−like and a few there is an abnormal concentration of the
slightly dilated duct and its branch- casting type calcifications. cancerous ducts over a large area, correspond-
es drain an area with multiple ing to the region with the malignant type cal-
cluster calcifications. No tumor cifications.
mass is demonstrable.
3D Image
Figs. 6.3-4 & 5 Subgross, thick-section (3D) histology: direct comparison of the distribution and architecture of normal ducts
and associated TDLUs (on the left-hand side of the image pair) with the cancerous, ductlike structures, which we consider to be
the product of neoductgenesis (on the right-hand side of the image pair). These pathological structures do not resemble pre-
existing ducts in terms of orientation, size, shape, or architecture.
3D Image
Figs. 6.3-6 & 7 Subgross, thick-section (3D) histology: The architecture of the normal breast is demonstrated here, showing
the subsegmental ducts and the associated TDLUs.
Fig. 6.3-8 Galactogram, detail of the MLO projection. The

bloody nipple discharge originated from the region containing
the malignant type calcifications.
6.3-8
Case 6.3 285
3D Image
Figs. 6.3-9 & 10 Subgross, thick-section (3D) histological image of the area with calcifications: Dilated, cancer-filled ductlike
structures are densely packed into a region several centimeters in size. Note the normal distribution of the atrophic ducts and
TDLUs in the vicinity of the cancer.
6.3-11 6.3-12
Figs. 6.3-11 & 12 Histology (H&E): the ducts are distended by Grade 3 cancer cells, central necrosis and amorphous calcifications.
Case 6.3 continued
3D Image
Figs. 6.3-13 & 14 Subgross, thick-section (3D) histological image of the area with calcifications: The distended, cancer-filled
ductlike structures are tightly packed together.
3D Image
Fig. 6.3-15 & 16 Subgross, thick-section (3D) histological image: The cancer-filled ductlike structures are extremely distended,
measuring 1.0 mm or more in diameter. The normal, resting duct has a diameter of about 0.1 mm.
Case 6.4 287
Case 6.4
tion. Her mother died from breast cancer.
6.4-1 6.4-2
Figs. 6.4-1 & 2 Details of the MLO (1) and CC (2) projections, microfocus magnification views, showing a mixture of crushed stone−like
and casting type calcifications. These are mammographically malignant type calcifications.
Fig. 6.4-3 Large-section histology shows

an abnormal accumulation of the duct-
like, cancerous structures within a con-
fined area.
Fig. 6.4-4 Medium-power magnification

histological image (H&E). Cross section of
a duct distended by cancer cells with
solid cell architecture, central necrosis,
and amorphous calcification. No signs of
invasion.
6.4-3 6.4-4
3D Image
Figs. 6.4-5 & 6 Subgross, thick-section (3D) image of the area with calcifications. The dilated, cancer-filled ducts have diameters
that are 10−15 times that of normal ducts. The ductlike structures are densely packed into a confined region several centimeters
in diameter.
3D Image
Figs. 6.4-7 & 8 Subgross, thick-section (3D) histology demonstrates the normal distribution and spatial arrangement of
atrophic, normal ducts and TDLUs surrounded by fibrous tissue in contrast to the distended, cancerous ductlike structures,
which are tightly packed with little intervening connective tissue.
3D Image
Figs. 6.4-9 & 10 Subgross, thick-section (3D) histology: the atrophic, normal ducts and TDLUs and the extremely distended,
cancer-filled ducts are seen side by side.
Case 6.4 289
3D Image
Figs. 6.4-11 & 12 Subgross, thick-section (3D) of the area with calcifications. The pathological ducts can be compared with the
normal ducts in close proximity.
3D Image
Figs. 6.4-13 & 14 Subgross, thick-section (3D) of the area with calcifications: higher magnification of the pathological ducts.
Case 6.4 continued
3D Image
Figs. 6.4-15 & 16 Subgross, thick-section (3D) histology demonstrates the individual ducts with solid cell proliferation, central
necrosis, and amorphous calcifications.
Case 6.5 291
Case 6.5
A 55-year-old woman felt a lump under her left areola.
6.5-1 6.5-2
Figs. 6.5-1 & 2 Left breast, MLO projection (1) and microfocus magnification (2) of the lower half of the left
breast show a large number of malignant type calcifications surrounded by a nonspecific density.
3D Image
Figs. 6.5-3 & 4 Subgross, thick-section (3D) histology demonstrates an unnaturally high concentration of ductlike structures
filled with malignant cells and central necrosis. A large number of tumor vessels supply this poorly differentiated conglomera-
tion.
3D Image
Figs. 6.5-5 & 6 Subgross, thick-section (3D) histology: at higher magnification the relationship between the distended, cancer-
ous ducts and the tumor vessels is better appreciated.
3D Image
Figs. 6.5-7 & 8 Subgross, thick-section (3D) histology demonstrates the intimate relationship of the pathological ducts with
the surrounding tumor vessels.
Case 6.5 293
3D Image
Figs. 6.5-9 & 10 Subgross, thick-section (3D) histology: high magnification of the tortuous tumor vessels.
3D Image
Figs. 6.5-11 & 12 Subgross, thick-section (3D) histology shows the haphazard architecture of the tumor vessels.
Case 6.5 continued
3D Image
Figs. 6.5-13 & 14 Subgross, thick-section (3D) histology: the pathological ducts are distended by tumor cells, necrosis, and
amorphous calcifications to a size more than 10 times the diameter of normal ducts (see millimeter scale).
Case 6.6 295
Case 6.6
A 31-year-old lactating woman presented with a palpable cal examination confirmed a hard tumor larger than 2.0 cm,
lump in the upper outer quadrant of her right breast. Physi- suspicious for malignancy.
6.6-1 6.6-2 6.6-3 6.6-4

Figs. 6.6-1 to 4 Right and left breasts, MLO (1 & 2) and CC (3 & 4) projections. Corresponding to the palpable tumor, an asymmetric
density with architectural distortion is seen covering a region 6 cm × 7 cm filling the upper outer quadrant. No associated calcifications
are demonstrable.
3D Image
Figs. 6.6-5 & 6 Subgross, thick-section (3D) histology: normal TDLUs; some of them show changes typically seen in lactation.
6.6-7 6.6-8 6.6-9

Figs. 6.6-7 to 9 14-g core biopsy: poorly differentiated in-situ carcinoma.
6.6-10 6.6-11
Fig. 6.6-10 Radiographs of the sliced surgical specimen. Fig. 6.6-11 Large-section histology: the in-situ process measures
10 cm.
3D Image
Figs. 6.6-12 & 13 Subgross, thick-section (3D) histology: There is a large number of distended, cancerous ducts on the left side
of the image, while entirely normal breast parenchyma is seen on the right side of the image.
Case 6.6 297
6.6-14 6.6-15
Figs. 6.6-14 & 15 Several large-section histological slices are needed to cover the area with the pathological ducts.
3D Image
Figs. 6.6-16 & 17 Subgross, thick-section (3D) histology: longitudinal and cross sections of several pathological ducts dis-
tended by cancer and intraluminal necrosis.
6.6-18 6.6-19
Figs. 6.6-18 & 19 Medium-power histology images of the large section (H&E). The pathological ducts are seen against a dense fibrous
background. The ducts are tightly packed and are surrounded by a desmoplastic reaction and lymphocytic infiltration.
Fig. 6.6-20 Higher-magnification histological image of this poor-

ly differentiated in-situ carcinoma.
6.6-20
3D Image
Figs. 6.6-21 & 22 Subgross, thick-section (3D) histology: higher magnification of one of the pathological ducts. Two side
branches (one in cross section, the other in longitudinal section) are surrounded by a desmoplastic reaction and lymphocytic
infiltration, giving the impression that this represents neoductgenesis.
Case 6.6 299
6.6-23 6.6-24
Figs. 6.6-23 & 24 Tenascin overexpression can be seen around the longitudinal duct and its branches, indicating that these are the re-
sult of neoductgenesis.
6.6-25 6.6-26
Figs. 6.6-25 & 26 Histological examination revealed an area 10 cm × 6 cm with poorly differentiated in-situ associated carcinoma with
a 2 mm Grade 2 invasive cancer. These images show the invasive component.
3D Image
Figs. 6.6-27 & 28 Subgross, thick-section (3D) histology: Overview of the large number of contorted, cancerous ducts tightly
packed over a large area.
Case 6.7
Screening examination of a 51-year-old asymptomatic
woman. She was called back for further examination be-
cause of the findings on her screening mammograms.
6.7-1 6.7-2
Figs. 6.7-1 & 2 Right breast, detail of MLO projection (1) and microfocus magnification (2) projection. Several groups of crushed stone−
like and also casting type calcifications are seen with no associated tumor mass in the upper portion of the breast.
3D Image
Figs. 6.7-3 & 4 Subgross, thick-section (3D) histology: normal ducts and TDLUs.
Case 6.7 301
6.7-5
Figs. 6.7-5 & 6 Right breast, CC (5) and microfocus magnification (6) im-
ages demonstrating the malignant type calcifications. 6.7-6
3D Image
Figs. 6.7-7 & 8 Subgross, thick-section (3D) histology: corresponding to the calcifications on the mammogram, there is an
accumulation of pathological ducts (the dark area in the center of the image) surrounded by normal ducts and TDLUs, fibrosis,
and adipose tissue.
Fig. 6.7-9 Large thin-section histology (H&E): the Fig. 6.7-10 Specimen radio- Fig. 6.7-11 Medium-power mag-
area with the poorly differentiated DCIS measures graph. The calcifications have nification of one of the cancerous
36 mm × 12 mm. The closest margin is 15 mm. been surgically removed with an ducts distended by the poorly
adequate margin. differentiated cancer cells and
central necrosis.
3D Image
Figs. 6.7-12 & 13 Subgross, thick-section (3D) histology: higher magnification of the abnormal, cancerous ducts. The patho-
logical ducts are 1−2 mm in diameter, many times the diameter of the normal ducts appearing in the background.
Case 6.7 303
3D Image
Figs. 6.7-14 & 15 Subgross, thick-section (3D) histology: photographs of areas with normal breast tissue, for comparison.
3D Image
Figs. 6.7-16 & 17 Subgross, thick-section (3D) histology: photographs of areas with normal breast tissue and a few cystically
dilated TDLUs.
3D Image
Figs. 6.7-18 & 19 Subgross, thick-section (3D) histology: higher magnification of the abnormal ducts and tumor vessels. The
pathological ducts can be compared with the normal ducts in the lower right-hand corner. There is a preparation artifact (white
circle).
3D Image
Case 6.7 305
3D Image
3D Image
Figs. 6.7-24 & 25 Subgross, thick-section (3D) histology: photographs of areas with the pathological ducts.
3D Image
3D Image
Case 6.7 307
3D Image
308
References 309
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risk factors for the development of local recurrence in breast 5 Otto SJ, Fracheboud J, Looman CW, et al. National Evaluation
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4 Thurfjell E, Thurfjell MG, Lindgren A. Mammographic finding based mammography screening in Dutch municipalities and
as a predictor of survival in 1−9 mm invasive breast cancers, effect on breast-cancer mortality: a systematic review. Lancet.
worse prognosis for cases presenting as calcifications alone. 2003;361:1411−7.
Breast Cancer Res Treat. 2001;67(2):177−80. 6 Tabár L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mam-
5 Zunzunegui RG, Chung MA, Oruwari J, Golding D, Marchant DJ, mography service screening and mortality in breast cancer
Cady B. Casting-type calcifications with invasion and high- patients: 20-year follow-up before and after introduction of
grade ductal carcinoma in situ: a more aggressive disease? screening. Lancet. 2003;361:1405−10.
Arch Surg. 2003;138(5):537−40. 7 Tabár L, Dean PB. Mammography and breast cancer: the new
6 Yagata H, Harigaya K, Suzuki M, et al. Comedonecrosis is an un- era. Int J Gynaecol Obstet. 2003;82(3):319−26.
favorable marker in node-negative invasive breast carcinoma. 8 Duffy SW, Tabár L, Vitak B, et al. The relative contributions of
Pathol Int. 2003;53(8):501−6. screen-detected in situ and invasive breast carcinomas in re-
7 Peacock C, Given-Wilson RM, Duffy SW. Mammographic cast- ducing mortality from the disease. Eur J Cancer. 2003;39:
ing-type calcification associated with small screen-detected 1755−60.
invasive breast cancers: is this a reliable prognostic indicator? 9 Tabár L, Tot T, Dean PB. Breast Cancer: The Art and Science of
Clin Radiol. 2004;59(2):165−70. Early Detection with Mammography. Volume I. Perception, In-
8 Tabár L, Chen Tony HH, Yen Amy MF, et al. Mammographic terpretation, Histopathologic Correlation. Stuttgart: Thieme;
tumor features can predict long-term outcomes reliably in wo- 2005:259−404.
men with 1−14-mm invasive breast carcinoma. Cancer. 2004; 10 Tabár L, Chen Tony HH, Yen Amy MF, et al. Mammographic
101(8):1745−59. tumor features can predict long-term outcomes reliably in
9 Kahán Z, Ormándi K, Gaál S, Hajnal-Papp R, Boda K, Thurzó L. women with 1−14-mm invasive breast carcinoma. Cancer.
Casting-type calcification indicates a higher probability of 2004;101(8):1745−59.
early relapse and death among operable high-risk breast can- 11 Alexander MC, Yankaskas BC, Biesemier KW. Association of
cer patients. European Association for Cancer Research, Buda- stellate mammographic pattern with survival in small inva-
pest, 1−4 July 2006. Poster 334 (Page 202). sive breast tumors. AJR Am J Roentgenol. 2006;187(1):29−37.
310 References
12 Tabár L, Dean PB. Preventing premature death from breast 23 Peacock C, Given-Wilson RM, Duffy SW. Mammographic cast-
cancer. Eur. Oncol. Rev. 2005:2−4. ing-type calcification associated with small screen-detected
13 Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, invasive breast cancers: is this a reliable prognostic indicator?
Fisher ER, et al. Twenty-year follow-up of a randomized trial Clin Radiol. 2004;59(2):165−70.
comparing total mastectomy, lumpectomy, and lumpectomy 24 Kahán Z, Ormándi K, Gaál S, Hajnal-Papp R, Boda K, Thurzó L.
plus irradiation for the treatment of invasive breast cancer. Casting-type calcification indicates a higher probability of
N Engl J Med. 2002;347:1233−41. early relapse and death among operable high-risk breast
14 Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. cancer patients. European Association for Cancer Research,
Twenty-five-year follow-up of a randomized trial comparing Budapest, 1−4 July 2006. Poster 334 (Page 202).
radical mastectomy, total mastectomy, and total mastectomy
followed by irradiation. N Engl J Med. 2002;347:567−75.
15 Tot T. The limited prognostic value of measuring and grading Chapter 5
small invasive breast carcinomas: The whole sick lobe versus
the details within it. Med Sci Monit. 2006;12(8):RA170−5. 1 Cady B, Michaelson JS. The life-sparing potential of mammo-
16 Fisher B. Laboratory and clinical research in breast cancer—a graphic screening. Cancer. 2001;91:1699−703.
personal adventure: the David A. Karnofsky memorial lec- 2 Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus
ture. Cancer Res. 1980;40(11):3863−74. tamoxifen with or without irradiation in women 70 years of
17 Fisher B, Jeong JH, Dignam J, et al. Findings from recent age or older with early breast cancer. N Engl J Med. 2004;
National Surgical Adjuvant Breast and Bowel Project adjuvant 351(10):971−7.
studies in stage I breast cancer. J Natl Cancer Inst Monogr. 2001; 3 Tabár L, Dean PB. Preventing premature death from breast
(30):62−6. cancer. Eur. Oncol. Rev. 2005:2−4.
18 Tabár L, Chen HH, Duffy SW, et al. A novel method for predic- 4 Tabár L, Chen THH, Yen AMF, Dean PB. Detection, diagnosis, and
tion of long-term outcome of women with T1a, T1b, and 10− treatment of early breast cancer requires creative interdiscipli-
14 mm invasive breast cancers: a prospective study. Lancet. nary teamwork. Semin Breast Dis. 2005;8(1):4−9.
2000;355(9202):429−33. 5 Zunzunegui RG, Chung MA, Oruwari J, Golding D, Marchant DJ,
19 Malik HZ, Wilkinson L, George WD, Purushotham AD. Pre- Cady B. Casting-type calcifications with invasion and high-
operative mammographic features predict clinicopathologi- grade ductal carcinoma in situ: a more aggressive disease?
cal risk factors for the development of local recurrence in Arch Surg. 2003;138(5):537−40.
breast cancer. Breast. 2000;9(6):329−33. 6 Tabár L, Chen Tony HH, Yen Amy MF, et al. Mammographic
20 Thurfjell E, Thurfjell MG, Lindgren A. Mammographic finding tumor features can predict long-term outcomes reliably in
as a predictor of survival in 1−9 mm invasive breast cancers, women with 1−14-mm invasive breast carcinoma. Cancer.
worse prognosis for cases presenting as calcifications alone. 2004;101(8):1745−59.
Breast Cancer Res Treat. 2001;67(2):177−80. 7 Tabár L, Tot T, Dean PB. Breast Cancer: The Art and Science of
21 Zunzunegui RG, Chung MA, Oruwari J, Golding D, Marchant Early Detection with Mammography. Volume I. Perception, Inter-
DJ, Cady B. Casting-type calcifications with invasion and high- pretation, Histopathologic Correlation. Stuttgart: Thieme; 2005:
grade ductal carcinoma in situ: a more aggressive disease? 405−38.
Arch Surg. 2003;138(5):537−40.
22 Yagata H, Harigaya K, Suzuki M, et al. Comedonecrosis is an
unfavorable marker in node-negative invasive breast carci-
noma. Pathol Int. 2003;53(8):501−6.
311
Subject Index
A no abnormality on previous mammogram 76 replacing powdery-type 199

nonspecific 110 stellate lesion 87−88, 89
adjuvant therapy 190, 270 casting type calcification evolution 104 subtle 75
axillary lymph nodes clusters 116 earliest sign of disease 118−125
adenopathy 269 periductal 6, 7 survival 187−188, 204−205, 216, 224, 225
casting type calcifications 249, 252 plasma cell mastitis type 7, 129, 133 cancer cells
distant metastases 269 powdery 9, 184, 198 ductal 30, 53
duct-like structures 249, 250, 251, 252 psammoma body-like 64, 70, 199, 200 Grade 2 276
metastases 203, 249−252 punctate 110 Grade 3 285
distant with casting type calcifications 269 recurrence 275 necrosis 31
dotted casting type calcifications 42, 45 rodlike 112, 118−123 c-erb-B 2
micrometastases 99, 201 secretory disease type 34, 129, 130, 132, 134 oncogene 154
neoductgenesis 252 silver nitrate stain 96 staining 255
status and mammographic tumor features subtle in neoductgenesis 164−171 chemotherapy 252
214−217 wide distribution 33 metastatic disease 251
calcifications, casting type 184 comedo carcinoma 15, 229
axillary lymph nodes 252
B status 214, 215, 249
case study 300 D
breast tissue, accessory
cluster as earliest sign 80−103
calcifications 58
crushed stone-like mix 91, 92, 94, 146, 150, DCIS
main duct distension 63
156, 160 calcified 96, 97
case study 287 casting type calcifications 225
C distant metastases 267 central necrosis 274, 275
fatal outcome 243−244 cribriform 59, 62, 64, 65−67, 89
calcifications ill-defined density 274 foci 89
amorphous 17, 19, 44, 45, 77, 158 recurrence 253, 262, 263 Grade 1 65, 89
cancerous duct-like structures 145, 147, without tumor mass 230−231 Grade 2 and 3 89, 109, 114, 149
149, 153, 162, 247 de novo 76, 177−179 Grade 3 21, 31, 37, 79, 84, 89
case study 285, 290, 294 development 124 apocrine-type 163
casting type calcifications 194, 197, 200, differential diagnosis problems 28−37 calcification cluster 105, 107
203, 209, 211, 233, 241, 246, 262 disorganized pattern 130, 133−134 calcified 123
clusters of calcification 97 distant metastases 266−269 cancer cell solid growth pattern 158
cribriform DCIS 62 dotted 8, 38−71 cancerous duct-like structures 145, 153
distended ducts 134 cluster 82−83 casting type calcifications 132, 203, 211,
intraluminal 195, 265 LCIS 27 241, 245
neoplasm association 106 localization 85 genetic aberrations 271
with periductal lymphocytic infiltration 136 mammographic−histological correlation 26, high-grade duct-forming invasive carci-
recurrence 276, 280 40−63, 64−71 noma/neoductgenesis 229
associated tumor mass 111−115 single lobe 40 histology 152
asymmetric density 165 widespread 38−39 invasive ductal carcinoma 97, 99, 155
benign-type 34 evolution 75−125 microinvasion 239
branching 16 fatal cases 194−203, 230−252 micropapillary proliferation 168
clusters fragmented 8, 10−37, 112, 183 nuclei/nucleoli 97
coarse 112, 113 benign secretory disease resemblance outcome 225
multiple 156, 283 28−31 recurrence with casting subtype 254
crushed stone-like 9, 15, 58, 62, 184 cluster 82−83 solid cribriform 54, 55, 56
case study 300 with dotted 22−27 solid micropapillary 33, 34, 166
casting precursor 80 filling entire lobe 14−15 subgroup distinction 271
casting type mixed (see calcifications, follow-up 21 subtle calcifications 165
casting type) histological presentation 10, 11, 16−21 without sizable necrosis 117
cluster 75, 80, 108 histological−mammographic correlation high-grade
development 124 20−27 casting type calcifications 132
irregular density/size/shape 100 LCIS 27 invasive ductal carcinoma 125
recurrence 212, 283 malignant cell numbers 20, 21 recurrence with casting type calcifications
de novo 177−179 mammographic presentation 10, 11, 16−21 261
densely packed ducts 142 orientation 28, 30 micropapillary 27, 43, 45, 65, 66, 70
density development adjacent 121 radiograph 161 central calcification 83
disappearance 124, 125 rodlike 118−123 duct 51
eggshell-like 213 small cluster presentation 32−37 duct histology 82
intraductal 6, 7 small tumor mass association 121 ducts containing 142
benign 130, 132 treatment 21 intraluminal calcifications 52
high-density 37 widespread 11−13 intraluminal necrosis 83
intraluminal 52, 211 histological malignancy grade 218, 219 lining ducts 140
irregular particles 32 ill-defined density 276 necrotic debris 167
linear branching 32, 36 innumerable 135 noncalcified 71
lucent-centered skin 118 invasive ductal carcinoma 114 solid 89
malignant-type 25, 34, 108, 130−134, 143, 148 lethality 192 subtle calcifications 165
case study 291, 301 neoductgenesis 248, 250 multiple foci 156
fatal outcome 245 random pointing direction 129 noncalcified 37, 96, 97, 98
lobar distribution 151 recurrence 277, 278, 279, 280 poorly differentiated 296, 299, 302
main duct 81 following segmentectomy and postopera- recurrence 274−276
recurrence with casting type calcifications tive radiation 210 local 63
261 frequent 253−265 solid micropapillary 33, 34
surrounding density 157 local following radiotherapy 206−213 tumor-forming 171, 172
312 Subject Index
deaths casting type calcifications 196, 201, 268 L

DCIS Grade 3 271 with DCIS Grade 2 and 3 109
mammographic tumor features 192−193 distant metastases with casting type calcifi- lobe
noncasting invasive breast cancers 189 cations 268 genetic alteration 75
density small foci 99 number 75
architectural distortion 295 invasive 37, 59 lobular carcinoma in situ (LCIS) 27
asymmetric 165, 175−176 casting type calcifications 101 lymph node
subtle calcifications 164−171 cluster of coarse calcifications 113 enlarged sentinel/reactive 151
calcifications adjacent 121, 157, 165 crushed stone-like calcifications 101 see also axillary lymph nodes
case study 291 with DCIS Grade 3 97, 99, 155 lymphocytic infiltration 33, 37, 135
ill-defined 274, 276 high-grade 225 neoductgenesis 135−137, 166, 167, 169−170,
desmoplastic reactions 19, 78, 79, 135 high-grade DCIS component 125 179
cancerous ducts 157, 248 high-grade with neoductgenesis 229 periductal 79, 107, 138, 145, 155, 158
ducts distended by cancer cells 159 poorly differentiated 270 case study 298
neoductgenesis 135−137, 166, 179, 265 poorly differentiated 123 casting type calcifications 195−196, 209,
periductal 33, 107, 136, 155, 158 tubular 59 233, 234, 248
case study 298 ductal carcinoma in situ see DCIS neoangiogenesis 161
casting type calcifications 195−196, 233, ductal system development 75 without calcifications 176
254 duct-like structures, cancerous
extensive 162 abnormal accumulation 147
neoductgenesis 169−170, 171 axillary nodes 249, 250, 251, 252
M
without calcifications 176 branches 161
magnetic resonance imaging (MRI)
thick 161 calcium 161
casting type calcifications 271
duct(s) cancer cells 147, 149, 153, 162, 173, 265
disease detection 75
arborization 75 case study 283−286, 287, 291, 292, 294, 301,
early 117
pattern 138 304−307
malignancy
branching 55 densely packed 135, 137, 142, 143, 146, 148
casting type calcifications 8, 9
duct(s) axillary tail region 152
histological grade 218−225
cancer cells 30, 53 case study 287, 288, 291, 298, 299
radiological sign 20
cancerous 139 cast-type calcifications 234−235, 262
see also calcifications, malignant-type
high density 25 necrosis 291
mammography
casting type calcifications 15, 30, 46 disease recurrence with casting type calcifi-
no previous sign 76−79
fragmented 18, 19, 24 cations 258−261, 264
tumor features
necrosis 18, 19, 24, 194, 233, 241, 246 distended 145, 161, 162, 235, 247
axillary node status 214−217
central calcification 83 case study 286−289, 291, 292, 296, 297, 302
breast cancer study 184−193
crowded 41, 139 proliferating cancer cells 248
mastectomy
densely packed 77, 233, 234, 283 haphazard appearance 166
cancerous duct-like structures 145
disorganized orientation 41, 42 high concentration 144
DCIS
distended 19, 30, 48, 49 long 163
high-grade with invasive ductal carcinoma
dotted casting type calcifications 56, 61 necrosis 153, 235, 247, 294, 297
125
fluid 5, 138 disease recurrence with casting type calci-
micropapillary 45
inspissated fluid 133 fications 258−261, 265
DCIS Grade 1 67
malignant cells 233, 246 necrotic debris 145, 147, 149, 161
DCIS Grade 1−3 89
recurrence 275, 276 neoductgenesis 169−170, 171, 264
DCIS Grade 2 and 3 109
saccular dilatation 50 normal duct comparison 144
DCIS Grade 3 79, 85, 107, 153
solid cell proliferation 134, 246 size 247
casting type calcifications 203
dotted casting type calcifications 43, 44, solid cell proliferation 290
with invasive ductal carcinoma 99
47, 58 unnaturally high concentration 135
ductal carcinoma
dilated 56, 61
invasive 101, 201
necrosis 47, 49
encroachment on chest wall 52
E poorly differentiated 123
prophylactic of contralateral breast 27
entrapped in invasive tumor 56
epithelial−stromal interaction 33 recurrence 259, 263, 265
expansion with malignancy 14
sites 154 survival 204
genetic change 75
mastitis 7
haphazard organization 139
metastases
histology 27 F
axillary lymph nodes 42, 45, 203, 249−252,
malignant-type calcifications 81, 105
fatality rate 269
micropapillary DCIS 140, 142
DCIS Grade 3 271 micrometastases 99, 201
mucin 24, 44, 45
see also deaths; survival distant with casting type calcifications
necrosis 77
fibrosis, periductal 167, 173, 176, 209 266−269
casting type calcifications 18, 19, 24, 194,
fine-needle aspiration biopsy fatal 241
233, 241, 246
casting type calcification evolution 104 lung 236−237
central 97, 98, 134, 280, 285
crushed-stone/casting type calcification mix pulmonary 269
debris 107
92 skeletal 236−237
dotted casting type calcification 47, 49
microcalcifications 71
fragmented casting type calcification 18,
cluster 160, 253
19, 24 G lobar 143
intraluminal 83, 211
scattered 102
neoplastic 75 galactograms 40 micrometastases, axillary lymph nodes 99, 201
normal configuration/distribution 141, 146, genetic aberrations 75, 271 micropapillary proliferation 24, 44, 47, 49, 138
148
calcification in lumen 49, 51
pathological system 138
H casting type calcifications 197, 257
recurrence 280−282
DCIS Grade 3 168
resting state 4, 5−6
HER2 staining 154, 255 disease recurrence 262
solid cell proliferation 211, 241, 246
HER2/neu oncogene 155 casting type calcifications 259
see also desmoplastic reactions; duct-like
Herceptin 251, 252 tip breaking 49
structures, cancerous; lymphocytic infiltra-
histology, large-section 271 mitoses, frequent 17
tion; neoductgenesis
mucin, ductal 24, 44, 45
ductal carcinoma
myoepithelial cell layer 155, 248, 250
Grade 2 invasive 45, 54, 88, 99, 114
Subject Index 313
N nipple treatment modality 204−205

bloody secretions 143, 283, 284 tumor subtypes 186−191
necrosis Paget disease 255, 256−257
cancerous duct-like structures 145, 147, 149, recurrence of casting subtype 255
nuclei, polymorphic 17
T
153, 161, 235, 247
disease recurrence with casting type calci- TDLU
fications 258−261, 265
O absence with neoductgenesis 139, 140
neoductgenesis 169 architecture 283
casting type calcifications 15, 194, 200, 246 outcome 225 case study 295
comedo carcinoma 15 axillary node status unpredictability 216 crushed stone-like calcifications 15
ductal 18, 19, 24, 31, 47, 77 casting type calcifications 216, 226 cystic dilatation 303
casting type calcifications 194, 233, 241 mode of therapy poor correlation 204−205 distended 14, 63, 200
central 97, 98, 134 distribution 283, 285, 288
cribriform DCIS 62 duct arborization termination 138
debris 107 P duct connections 138
intraluminal 83, 211 malignant transformation 75
histology 27 p63 staining 154, 255
normal configuration/distribution 146, 148
intraluminal 17 Paget disease of nipple 255, 256−257
number 75
needle biopsy, large-bore paraclavicular adenopathy 269
subsegmental duct 14
calcifications 109 Tenascin C staining 154, 157
site 21 R tenascin overexpression 154−163, 248
neoangiogenesis 161 axillary adipose tissue 250
disease recurrence with casting type calcifi- radiotherapy 204−205 axillary lymph nodes 252
cations 259, 260 Grade 3 DCIS with Grade 2 invasive ductal periductal 157, 159, 299
neoductgenesis 28, 75 carcinoma 57 terminal duct lobular unit see TDLU
with asymmetric density and subtle calcifica- local recurrence 206−213 TNM classification 225, 226, 229, 270, 271
tions 164−171 postoperative 210 treatment outcome 204−205
axillary lymph nodes 252 survival 204 tumor vessels 293
cancer classification 270 retroareolar duct, malignant process 15 tumors
case study 283, 298, 299 retroareolar region, dotted casting type calcifi- circular 184, 185
casting type calcifications 197, 248, 250 cations 41, 46 classification 270
de novo calcifications 177 local recurrence following radiotherapy
desmoplastic reactions 135−137, 166 206−213
disease recurrence with casting type calcifi- S
mammographic features 184−193
cations 259, 260 deaths 192−193
sclerosing adenosis 199
disorganized architecture 138 histological malignancy grade 218−225
secretory disease 6−7
distant metastases with casting type calcifica- survival 222−223
benign 28−31
tions 269 oval 184
segmentectomy
duct histology 169 size range 270
Grade 3 DCIS 163
high-grade duct-forming invasive carcinoma stellate 87−88, 89, 184, 185, 277
postoperative radiotherapy 210, 212−213
229 axillary node status 214, 215
silver nitrate stain 96, 265
histological demonstration 140−153 histological malignancy grade 218, 219
solid cell proliferation 17, 24, 97, 98, 134
lymphocytic infiltration 135−137, 166, 167, survival 224, 225
surgery, breast-conserving 204
169−170, 179 without calcifications 190, 225
survival 225
morphological demonstration 135−163 subtypes 184
adjuvant therapy 270
pathologic ducts contorted and crowded 139 occurrence 185
axillary node status unpredictability 216
in situ carcinoma/fatal outcome discrepancy survival 186−191
casting type calcifications 187−188, 204−205,
237, 241 see also TNM classification
216, 224, 225, 226
theory 135
cumulative disease-specific 191
tissues 265
histological malignancy grade 220−221 V
unnaturally high concentration of ductlike
invasive tumors 226
structures 135
mammographic tumor features 222−223 vascularization 27, 293
without associated calcifications 172−179
stellate tumors 224, 225
see also tenascin overexpression
without calcifications 190, 225
314

Breast Cancer Casting Type Calcifications. - Tabár

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I

Tibor Tot, MD, PhD

Some of the product names, patents, and registered designs

ISBN 978-3-13-135391-7 (TPS, Rest of World)

This book is dedicated to those physicians

Chapter 1 Description of Calcifications Localized within the Ducts 1

General Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Characteristic Mammographic and Histological

Chapter 2 The Evolution of Casting Type Calcifications 73

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cluster of Calcifications as the Earliest Sign . . . . . . . . . . 80

Chapter 3 The Theory of Neoductgenesis 127

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 (C) Disorganized Architecture . . . . . . . . . . . . . . . . . . . . . 138

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Poor Correlation of Outcome with Mode of Therapy . . 204

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Distant Metastases with Casting Type Calcifications . . 266

Chapter 6 Illustrative Cases with 3-Dimensional Stereoscopic Histological Images 273

Case 6.1 ........................................... 274 Case 6.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

General Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Chapter 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

Subject Index 311

Description of Calcifications localized

“Secretory Disease” Type,

Casting Type Calcifications

Casting Type (92/322)

12-year total 1.20

Fragmented Casting Type Calcifications

Characteristic histological features:

Characteristic mammographic image:

Fig. 1.21 Schematic diagram representing fragmented casting

Dotted Casting Type Calcifications

Characteristic histological features:

Characteristic mammographic image:

Fig. 1.23 Schematic diagram representing dotted casting type

Fragmented Casting Type

Fig. 1.29-1 Left breast, detail of

Fig. 1.29-2 Operative specimen

Macroscopic and Subgross Histological

Fig. 1.30-1 Photograph of an operative specimen sliced at the

Fig. 1.30-2 Subgross histological image covering much of the af-

Fig. 1.30-5 & 6 Subgross histological−mammographic correla-

The imprecise term “comedo” should be replaced by a de-

Characteristic Mammographic and Example 1.1

Ex. 1.1-1 Ex. 1.1-2

Ex. 1.1-3 Ex. 1.1-4 Ex. 1.1-5

Ex. 1.1-6 Ex. 1.1-7

Ex. 1.1-8 Ex. 1.1-9

Example 1.1 continued

Ex. 1.1-10 Ex. 1.1-11 Ex. 1.1-12

Ex. 1.1-13 & 14 Comparative opera-

Ex. 1.1-13 Ex. 1.1-14

Example 1.1 continued

The presence of fragmented casting type calcifications is a

Ex. 1.1-19 to 21 Conventional and subgross histological images

Ex. 1.1-22 The casting type calcifications

Characteristic Mammographic and

The largest number of viable cancer

Ex. 1.1-23 to 25 Subgross and conven-

Ex. 1.1-23 Ex. 1.1-25

Ex. 1.1-26 The preferred site for larger-

Treatment and follow-up: In this case

Mammographic−Histological Correlation Example 1.2

Ex. 1.2-1 Ex. 1.2-2

Ex. 1.2-3 Left breast, detail of the CC pro-

Ex. 1.2-4 & 5 Microfocus magnification mammography, MLO

Example 1.2 continued

Ex. 1.2-6 Mastectomy specimen