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Chapter 23 - The Breast
Susan C. Lester MD, PhD
• Chapter 23 - The Breast
– The Female Breast
• Normal
– Life Cycle Changes
• Pathology
– Disorders of Development
» Milkline Remnants.
» Accessory Axillary Breast Tissue.
» Congenital Nipple Inversion.
» Macromastia.
» Reconstruction or Augmentation.
– Clinical Presentations of Breast Disease
– Inflammations
» ACUTE MASTITIS
• Morphology.
» PERIDUCTAL MASTITIS
• Morphology.
» MAMMARY DUCT ECTASIA
• Morphology.
» FAT NECROSIS
• Morphology.
» LYMPHOCYTIC MASTOPATHY
(SCLEROSING LYMPHOCYTIC LOBULITIS)
» GRANULOMATOUS MASTITIS
– Benign Epithelial Lesions
» NONPROLIFERATIVE BREAST CHANGES
(FIBROCYSTIC CHANGES)
• Morphology.
» PROLIFERATIVE BREAST DISEASE
WITHOUT ATYPIA
• Morphology.
• Epithelial Hyperplasia.
• Sclerosing Adenosis.
• Complex Sclerosing Lesion (Radial Scar).
• Papillomas.
» PROLIFERATIVE BREAST DISEASE WITH
ATYPIA
• Morphology.
» CLINICAL SIGNIFICANCE OF BENIGN
EPITHELIAL CHANGES
– Carcinoma of the Breast
» INCIDENCE AND EPIDEMIOLOGY
• Risk Factors.
• Treatment of Women at High Risk for
Developing Breast Cancer.
» ETIOLOGY AND PATHOGENESIS
• Hereditary Breast Cancer
• Sporadic Breast Cancer
• Mechanisms of Carcinogenesis
» CLASSIFICATION OF BREAST CARCINOMA
• Carcinoma in Situ
• Ductal Carcinoma in Situ (DCIS; Intraductal
Carcinoma)
• Morphology.
• Lobular Carcinoma in Situ (LCIS)
• Morphology.
• Invasive (Infiltrating) Carcinoma
• Invasive Carcinoma, No Special Type (NST;
Invasive Ductal Carcinoma)
• Morphology.
• Invasive Lobular Carcinoma
• Morphology.
• Medullary Carcinoma
• Morphology.
• Mucinous (Colloid) Carcinoma
• Morphology.
• Tubular Carcinoma
• Morphology.
• Invasive Papillary Carcinoma
• Metaplastic Carcinoma
» PROGNOSTIC AND PREDICTIVE FACTORS
• Minor Prognostic Factors.
» STROMAL TUMORS
• Fibroadenoma
• Morphology.
• Phyllodes Tumor
• Morphology.
• Sarcomas
• Other Stromal Lesions
» OTHER MALIGNANT TUMORS OF THE
BREAST
– The Male Breast
• Pathology
– Gynecomastia
» Morphology.
– Carcinoma
1120
The Female Breast
Normal
The class Mammalia is remarkable for the evolution of modified skin appendages that
provide complete nourishment and immunologic protection for the young. In humans,
paired mammary glands rest on the pectoralis muscle on the upper chest wall. The breast
is composed of specialized epithelium and stroma that give rise to both benign and
malignant lesions specific to the organ ( Fig. 23-1 ).
Six to ten major ductal systems originate at the nipple. The keratinizing squamous
epithelium of the overlying skin continues into the ducts and then abruptly changes to a
double-layered cuboidal epithelium. A small keratin plug is often found at the duct
orifice. The surrounding areolar skin is pigmented and supported by smooth muscle.
Successive branching of the large ducts eventually leads to the terminal duct lobular unit
(TDLU). In the adult woman, the terminal duct branches into a grapelike cluster of small
acini to form a lobule ( Fig. 23-1 and Fig. 23-2B ). Each ductal system typically occupies
over a quarter of the breast, and the systems extensively overlap each other. In some
women, ducts extend into the subcutaneous tissue of the chest wall and into the axilla.
Figure 23-1 Normal breast anatomy and anatomical location of common breast lesions.
In the normal breast, ducts and lobules are lined by two cell types. A low, flattened
discontinuous layer of contractile cells containing myofilaments (myoepithelial cells) lies
on the basement membrane. These cells assist in milk ejection during lactation and have
an important role in maintenance of the normal structure and function of the lobule and
the basement membrane.[1] A second layer of epithelial cells lines the lumens. The luminal
cells of the terminal duct and the lobule produce milk, but those lining the large duct
system do not. A committed stem cell in the terminal duct is postulated to give rise to
both luminal and myoepithelial cells.[2]
The majority of breast stroma consists of dense fibrous connective tissue admixed with
adipose tissue (interlobular stroma). Lobules are enclosed by a breast-specific hormonally
responsive, delicate, myxomatous stroma that contains a scattering of lymphocytes
(intralobular stroma).
Life Cycle Changes
The breast is a unique organ in that it is not fully formed at birth, undergoes cyclic
changes during reproductive life, and starts to involute long before menopause.
1121
Figure 23-2 Lifecycle changes. A, Mammograms in young women are typically "dense" or white in
appearance. In this setting, mass-forming lesions or calcifications can be difficult to detect. (Courtesy of
Dr. Darrell Smith, Brigham and Women's Hospital, Boston, MA.) B, The density of a young woman's
breast is due to the predominance of fibrous interlobular stroma and the paucity of adipose tissue (normally
radiolucent or black). Prior to pregnancy, the terminal duct lobular units (TDLUs) are small and are
invested by loose cellular intralobular stroma. Larger ducts interconnect the TDLUs. C, During pregnancy,
branching of terminal ducts results in more numerous TDLUs, and the number of acini per TDLU
increases. Luminal cells within TDLUs (but not the large duct system) undergo lactational change in
preparation for milk production. D, With increasing age, the TDLUs decrease in size and number, and the
interlobular stroma is replaced by adipose tissue. An older woman's breast typically consists of small ducts
and atrophic lobules in adipose tissue. E, Mammograms become more radiolucent (darker) with age owing
to the increase in adipose tissue. Radio-dense mass-forming lesions, and calcifications become easier to
detect. (Courtesy of Dr. Darrell Smith, Brigham and Women's Hospital, Boston, MA.)
During midembryogenesis, the specialized mesenchyme of the breast fat pad condenses
around the epithelium of the breast bud. Via a complex interaction between stromal and
epithelial cells, cords of cells "invade" the stroma to form the rudimentary ductal system.
The continuing cross-talk between epithelium and stroma promotes normal tissue
structure and function throughout life.
The prepubertal breast in males and females consists of the large duct system ending in
terminal ducts with minimal lobule formation. At the beginning of menarche in women,
the terminal ducts give rise to lobules, and the interlobular stroma increases in volume.
There is a paucity of adipose tissue, and hence the breast appears radio-dense ( Fig. 23-
2A,B ). Just as the endometrium grows and ebbs with each menstrual cycle, so does the
breast.[3] In the first half, or follicular, phase of the menstrual cycle, the lobules are
relatively quiescent. After ovulation, under the influence of estrogen and rising
progesterone levels, cell proliferation increases, as does the number of acini per lobule,
and there is vacuolization of epithelial cells. Intralobular stroma becomes markedly
edamatous. This combined stimulatory effect of estrogen and progesterone on the breast
accounts for the sense of fullness commonly experienced by women during the
premenstrual phase of the cycle. When menstruation occurs, the fall in estrogen and
progesterone levels is followed by epithelial cell apoptosis, disappearance of the stromal
edema, and overall regression in the size of the lobules.
It is only with the onset of pregnancy that the breast assumes its complete morphologic
maturation and functional activity. Lobules increase both in number and in size. As a
consequence, there is a reversal of the usual stromal-epithelial relationship so that, by the
end of the pregnancy, the breast is composed almost entirely of lobules separated by a
relatively scant amount of stroma ( Fig. 23-2C ). Numerous dermal glands in the areola
(Montgomery tubercles) become more prominent and function in nipple lubrication. By
the third trimester, secretory vacuoles of lipid material are found within the epithelial
cells of the TDLU ( Fig. 23-2C ), but milk production is inhibited by the high levels of
progesterone.
Immediately after birth, the breast produces colostrum (high in protein), which changes to
milk (higher in fat and calories) within the first 10 days as progesterone levels drop. Just
as the health of the mother and that of the infant are intricately linked during pregnancy,
so too are they during breast-feeding. Breast milk not only provides complete
nourishment from birth until several years of age, but also provides protection against
infection and allergies. Maternal antibodies (chiefly secretory IgA), cells (neutrophils,
lymphocytes, and macrophages), and other mediators (e.g., cytokines, fibronectin, and
lysozyme) augment the infant's own developing defenses.[4] [5] Some drugs, radioactive
compounds given during diagnostic procedures, and viruses also pass into breast milk.[6]
Thus, the postpartum health of the nursing mother continues to influence that of her
infant.
After cessation of lactation, the lobules regress and atrophy, and the total breast size
diminishes markedly. However, complete regression to the appearance of the normal
nulliparous breast does not occur, and there is a permanent increase in the size and
number of lobules.
After the third decade, long before menopause, lobules and their specialized stroma start
to involute. The lobules may almost totally disappear in the very aged, leaving only ducts
to create a morphologic pattern that closely resembles that of the male breast ( Fig. 23-2D
). However, in most women, there is sufficient persistent estrogenic stimulation, possibly
of adrenal origin or from stores of body fat, to maintain the vestigial remnants of lobules
that differentiate even the very aged female breast from the male breast. The radio-dense
fibrous interlobular stroma of the young female breast ( Fig. 23-2A ) is progressively
replaced by radiolucent adipose tissue ( Fig. 23-2E ).
1122
Pathology
Disorders of Development
Milkline Remnants.
Supernumerary nipples or breasts result from the persistence of epidermal thickenings
along the milk line, extending from the axilla to the perineum, both below the adult breast
and above it in the anterior axillary fold. The disorders that affect the normally situated
breast may rarely arise in these heterotopic foci; occasionally, the cyclic changes of the
menstrual cycle cause painful premenstrual enlargements.
Accessory Axillary Breast Tissue.
In some women, the normal ductal system extends into subcutaneous tissue of the chest
wall and into the axillary fossa. A mastectomy might remove the entire breast but not
remove all breast epithelium. Therefore, prophylactic mastectomies markedly reduce but
do not completely eliminate the risk of developing breast cancer. Breast epithelium
outside of the breast proper might undergo lactational changes or give rise to tumors that
appear to be outside the breast and therefore might be misidentified as lesions of the
axillary lymph nodes or metastases from an occult breast cancer.
Congenital Nipple Inversion.
The failure of the nipple to evert during development is common and may be unilateral.
Inversion is usually spontaneously corrected during the growth activity of pregnancy, or
it can sometimes be corrected by simple traction on the nipples. Nipple inversion is of
clinical significance, since it may be confused with acquired retraction of the nipple,
which is sometimes associated with an invasive cancer or inflammatory diseases of the
nipple (e.g., recurrent subareolar abscess or duct ectasia).
Macromastia.
The appropriate breast size is subjective and influenced by cultural norms. However,
some women develop severe back pain and disability because of very large breasts. The
large size may be due to variations in body habitus or to an unusual tissue response to
hormonal changes during puberty resulting in massive rapid breast growth (juvenile
hypertrophy). Reduction mammoplasty removes breast tissue but preserves the nipple.
Reconstruction or Augmentation.
Breast tissue can be replaced or augmented by skin and muscle flaps or with synthetic
breast prostheses. In the past, numerous types of materials were injected directly into the
breast to increase volume but this was associated with a high incidence of complications
due to an inflammatory response and the shift of these materials within the breast tissue.
Silicone breast implants were developed in the early 1960s. Silicone, a polymer of silica,
oxygen, and hydrogen, can be produced in liquid, gel, and solid forms by varying the
length of the polymer. Silicone implants consist of a rubbery silicone shell filled with
either silicone gel or saline.
The most common complication associated with breast implants is the formation of a
thick fibrous capsule that causes cosmetic deformity. The typical histologic response is a
chronic inflammatory infiltrate of lymphocytes, macrophages, and giant cells with
associated fibrosis. Silicone gel seeps ("bleeds") through intact shells and is frequently
seen in the surrounding tissue. The fibrous capsule can limit the spread of silicone after
implant rupture. However, if the capsule is also ruptured, silicone gel can escape into
surrounding tissues and be transported into axillary lymph nodes. Migration to more
distant sites from implants has been demonstrated in animals but not definitively in
humans. After long periods of implantation, the outer shell can weaken and rupture.
Some implants become heavily calcified. The presence of implants, particularly if
calcified, complicates the mammographic examination of the breast. Special techniques
are necessary to visualize the breast tissue and avoid rupturing the implant.
Case reports have suggested linkage of implants to "human adjuvant disease," a proposed
autoimmune-like illness in response to foreign material. However, multiple large
epidemiologic studies have failed to show a connection between implants and objective
evidence of rheumatologic disease or cancer.[7] [8] Nevertheless, the very long-term
consequences of implants are unknown. There are approximately 2 million women in the
United States with implants, and the number of women bearing implants for more than 20
years will rapidly increase in the next three decades. Current information from the U.S.
Food and Drug Administration can be obtained at
http://www.fda.gov/cdrh/breastimplants/.
Clinical Presentations of Breast Disease
An overall perspective of the frequency of various breast problems can be gained from
analyzing a large series of patients with breast symptoms who were seen at a health
maintenance organization (HMO)[9] ( Fig. 23-3 ) and women undergoing diagnostic breast
biopsies ( Fig. 23-4 ). Three general points can be made. First, breast symptoms and signs
are common problems in clinical practice. In the first group, 16% of women enrolled in
the HMO presented with a breast symptom over a 10-year period. In the second group,
diagnostic breast biopsies made up 5% of all surgical pathology specimens. Second, it is
fortunate that the majority of breast symptoms or lesions will prove to have a benign
etiology. Only 4% of outpatient visits for breast symptoms resulted in a diagnosis of
breast cancer.[9] Of patients proceeding to surgery, only 26% proved to have cancer ( Fig.
23-4 ). Finally, the physical, psychological, and financial costs of investigating benign
breast disease, primarily to exclude malignancy, are substantial.
The most common symptoms reported by women are pain, a palpable mass, or nipple
discharge ( Fig. 23-3 ). In addition, women with abnormal findings on mammographic
screening require further evaluation but are, by definition, asymptomatic. All other
clinical presentations of breast disease are unusual. About 10% of the clinic visits in the
HMO study were for other findings (such as "lumpy" breasts) that were considered
normal by the doctor but had provoked enough concern for the woman to schedule an
appointment.[9] Inflammatory conditions, as a group, account for less than 1% of breast
symptoms.
Pain (mastalgia or mastodynia) is the most common breast symptom ( Fig. 23-3 ) and
may be cyclical with menses or noncyclical. Diffuse cyclical pain has no pathologic
correlate, and most effective treatments target hormone levels. Noncyclical pain is
usually associated with a focal site in the breast. Causes include ruptured cysts or areas of
prior injury or infections, but more often, no specific lesion can be identified. Although
1123
Figure 23-3 Common clinical presentations of breast disease. Over a 10-year period, 372 women over the
age of 40 made 539 visits to a health maintenance organization for the listed breast symptoms. [9] Some
women had more than one symptom and/or made more than one visit. In 10% of cases, the visit led to the
performance of a biopsy.
the great majority of painful masses are benign, about 10% of breast cancers present with
pain, and all masses need to be investigated. In the outpatient study, four of 221 (1.8%)
women presenting with breast pain were diagnosed with cancer.[9] Three of the four
women also had an associated palpable mass.
Discrete palpable masses are the second most common breast symptom ( Fig. 23-3 ) and
must be distinguished from the normal nodularity of the breast. A breast mass usually
does not become palpable until it is about 2 cm in diameter ( Table 23-1 ). These masses
are most common in premenopausal women and become less frequent with age ( Fig. 23-
4 ). However, the likelihood that a palpable mass is malignant increases with the age of
the patient. For example, only 10% of breast masses in women under age 40 proved to be
malignant
TABLE 23-1 -- Characteristics of Breast Carcinomas by Clinical Presentation
Carcinomas
Invasive Average with
Carcinoma Size of Lymph
Clinical (% of Invasive Node DCIS (% of LCIS (% of
Presentation Carcinomas) Carcinomas Metastases Carcinomas) Carcinomas)
Palpable mass 94% 2.4 cm 58% 2% 4%
Mammographic 94% 1.1 cm 14% 4% 2%
density
Mammographic 26% 0.6 cm 6% 71% 3%
calcifications
Based on the results of 235 carcinomas diagnosed in 914 women undergoing diagnostic
biopsies at Brigham and Women's Hospital over a 6-month period in 2001.
Mammographic lesions were nonpalpable.
DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ.
compared to 60% of masses in women over age 50 ( Fig. 23-4 ). The most commonly
encountered lesions are invasive carcinomas, fibroadenomas, and cysts. Approximately
50% of carcinomas arise in the upper outer quadrant, 10% in each of the remaining
quadrants, and about 20% in the central or subareolar region.
Nipple discharge is a less common presenting symptom but is of concern when it is
spontaneous and unilateral. A discharge produced by manipulating the breast is normal
and unlikely to be associated with a pathologic lesion. A milky discharge (galactorrhea)
is associated with increased production of prolactin (e.g., by a pituitary adenoma),
hypothyroidism, or endocrine anovulatory syndromes. It can also occur in patients taking
oral contraceptives, tricyclic antidepressants, methyldopa, or phenothiazines. Repeated
nipple stimulation can also induce lactation (e.g., this method is sometimes used by
women who wish to breast-feed adopted infants). Milky discharge has not been
associated with malignancy. Bloody or serous discharges are most commonly associated
with benign lesions but, rarely, can be due to a malignancy. A normal bloody discharge
can also occur during pregnancy, possibly due to the rapid formation of new lobules. The
risk of malignancy with discharge increases with age. Discharge is associated with
carcinoma in 7% of women younger than 60 years and in 30% of women older than 60
years. The most common etiologies for discharge are a solitary large duct papilloma,
cysts, or carcinoma ( Fig. 23-4 ). Carcinomas presenting as nipple discharge not
associated with a palpable mass are equally divided between invasive and in situ
carcinomas.[10] There is considerable interest in developing the cytologic examination of
induced nipple discharge into a screening test for breast cancer.
Mammographic screening was introduced in the 1980s as a means to detect small,
nonpalpable breast carcinomas not associated with breast symptoms. The sensitivity and
specificity of mammography increase with age. As the dense, fibrous interlobular tissue
of the young woman is replaced by the fatty tissue of the older woman, it becomes easier
to detect small masses and calcifications. Also, with increasing age, benign lesions
become less frequent and malignant lesions become more frequent. Screening is
generally recommended to start at age 40. Younger women usually undergo
mammography only if they are at high risk for developing carcinoma, owing either to a
prior palpable cancer or to a strong family history. Despite the screening of women at
high risk of breast cancer, only 12% of mammographic lesions in women
1124
Figure 23-4 Frequency of benign and malignant breast lesions diagnosed after biopsy by clinical
presentation and age. (Based on 914 women who underwent diagnostic breast surgery at Brigham and
Women's Hospital, Boston, from January to June 2001.)
under age 40 proved malignant compared to 30% of lesions in women over age 50 ( Fig.
23-4 ). The principal mammographic signs of breast carcinoma are densities and
calcifications:
• Densities. Most neoplasms grow as solid masses and are radiologically denser
than the intermingled connective and adipose tissue of the normal breast.
Mammography can detect masses before they become palpable. For example, the
average size of an invasive carcinoma that is detected as a mammographic density
is only half that of carcinomas detected by palpation ( Table 23-1 ). The most
common lesions that are detected as densities are invasive carcinomas,
fibroadenomas, and cysts ( Fig. 23-4 ). Ductal carcinoma in situ (DCIS, or
carcinoma limited to the ductal system) rarely presents as a density ( Table 23-1 ).
• Calcifications. Calcifications are associated with secretory material, necrotic
debris, and hyalinized stroma. Calcifications associated with malignancy are
commonly small, irregular, numerous, and clustered or linear and branching.
DCIS is the most common malignancy associated with calcifications ( Table 23-1
). Invasive carcinomas presenting as calcifications are quite small and are rarely
associated with lymph node metastases. Benign calcifications are usually
associated with clusters of apocrine cysts, hyalinized fibroadenomas, and
sclerosing adenosis.
About 10% of carcinomas, even if they are palpable, are not detectable by
mammography. The principal reasons are surrounding dense tissue (especially in younger
women), absence of calcifications, small size, or location close to the chest wall or in the
periphery of the breast. The inability to image a palpable mass does not indicate
benignity, and all palpable masses require further investigation.
Other imaging modalities are useful adjuncts. Ultrasonography can distinguish solid and
cystic lesions and can define more precisely the borders of solid lesions. Most palpable
masses that cannot be imaged by mammography are detectable by ultrasound. Magnetic
resonance imaging (MRI) detects cancers by the rapid uptake of contrast agents due to
increased tumor vascularity. It has been most useful in detecting cancer in women with
dense breasts, in determining the extent of chest wall invasion in locally advanced
cancers, for detection of mammographically occult cancers, and for the evaluation of
breast implant rupture.
Inflammations
Inflammatory diseases of the breast are rare; they often present as an erythematous
swollen painful breast. Of these, the most important is acute mastitis, which is virtually
confined to the lactating period. "Inflammatory breast cancer" mimics inflammation by
obstructing dermal vasculature with tumor emboli, resulting in an enlarged erythematous
breast, and should always be suspected in a nonlactating woman with the clinical
appearance of mastitis.
1125
ACUTE MASTITIS
Almost all cases of acute mastitis occur during lactation; most of these arise during the
first month of nursing. During the early weeks of nursing, the breast is vulnerable to
bacterial infection because of the development of cracks and fissures in the nipples. From
this portal of entry, usually Staphylococcus aureus or, less commonly, streptococci
invade the breast tissue. Women present with an erythematous painful breast, usually
accompanied by fever. At the outset, only one duct system or sector of the breast is
involved. If not treated, the infection may spread to the entire breast.
Morphology.
Staphylococcal infections tend to produce a localized area of acute inflammation that
may progress to the formation of single or multiple abscesses. Streptococcal infections
tend to cause, as they do in all tissues, a diffuse spreading infection that eventually
involves the entire breast. The involved breast tissue may be necrotic and is infiltrated by
neutrophils.
Most cases of lactational mastitis are easily treated with appropriate antibiotics and
complete drainage of milk from the breast. Rarely, surgical drainage may be required.
PERIDUCTAL MASTITIS
In this condition, known by a variety of names (recurrent subareolar abscess, squamous
metaplasia of lactiferous ducts, Zuska disease), women, as well as men, present with a
painful erythematous subareolar mass, which is usually clinically thought to be an
infectious process.[11] More than 90% of patients with periductal mastitis are smokers.[12]
This condition
Figure 23-5 Recurrent subareolar abscess. When squamous metaplasia extends deep into a duct, keratin
becomes trapped and accumulates. If the duct ruptures, the ensuing intense inflammatory response to
keratin results in an erythematous painful mass. A fistula tract may burrow beneath the smooth muscle of
the nipple to open at the edge of the areola.
is not associated with lactation, a specific reproductive history, or age. In recurrent cases,
a fistula tract often tunnels under the smooth muscle of the nipple and opens onto the skin
at the edge of the areola. Many women with this condition have an inverted nipple
secondary to fibrosis and scarring, and it has been suggested that this condition might
contribute to the squamous metaplasia of the ducts. However, in most women, the
inversion is more likely a secondary phenomenon due to the inflammatory response. The
strong association with cigarette smoking is intriguing. It has been suggested that the
vitamin A deficiency associated with smoking or toxic substances in tobacco smoke alter
the differentiation of the ductal epithelium.[12]
Morphology.
The main histologic feature is keratinizing squamous epithelium extending to an
abnormal depth into the orifices of the nipple ducts ( Fig. 23-5 ). Keratin is trapped within
the ductal system and causes dilation and eventually rupture of the duct. An intense
chronic and granulomatous inflammatory response develops to keratin spilled into
periductal tissue. If secondary infections with skin bacteria or with mixed anaerobes
occur, acute inflammation is also present.
Appropriate clinical management requires removing the involved duct and fistula tract in
continuity, which, in most cases, is curative.[12] Incision drains the abscess cavity, but the
offending keratinizing epithelium remains and recurrences are common. If a
superimposed infection is present, antibiotic therapy must be directed toward the bacteria
present, as standard staphylococcal therapy is usually ineffective.
1126
MAMMARY DUCT ECTASIA
This disorder tends to occur in the fifth or sixth decade of life, usually in multiparous
women, and, unlike periductal mastitis, is not associated with cigarette smoking. Patients
present with a poorly defined palpable periareolar mass, sometimes with skin retraction,
often accompanied by thick, white nipple secretions. Pain and erythema are uncommon.
Morphology.
This lesion is characterized chiefly by dilation of ducts, inspissation of breast secretions,
and a marked periductal and interstitial chronic granulomatous inflammatory reaction (
Fig. 23-6 ). The dilated ducts are filled by granular debris that contains principally lipid-
laden macrophages. The periductal and interductal inflammation is manifested by heavy
infiltrates of lymphocytes and macrophages, with a striking predominance of plasma cells
in some cases. On occasion, granulomatous inflammation forms around cholesterol
deposits. Fibrosis may eventually produce skin and nipple retraction. Squamous
metaplasia of nipple ducts is not a feature of this disorder.
This lesion is of clinical significance because the formation of an irregular mass can be
mistaken for a carcinoma by palpation and by mammographic examination.
FAT NECROSIS
Fat necrosis can present as a painless palpable mass, skin thickening or retraction, a
mammographic density, or mammographic calcifications. The majority of women will
give a history of trauma or prior surgery.
Figure 23-6 Mammary duct ectasia. Chronic inflammation and fibrosis surround an ectatic duct filled with
inspissated debris. The fibrotic response can mimic the irregular shape of malignant carcinomas on
palpation or mammogram.
Morphology.
Grossly, the lesion may consist of hemorrhage in the early stages and, later, central
liquefactive necrosis of fat. Still later, it may appear as an ill-defined nodule of gray-
white, firm tissue containing small foci of chalky white or hemorrhagic debris. The
central focus of necrotic fat cells is initially surrounded by macrophages and an intense
neutrophilic infiltration. Then, during the next few days, progressive fibroblastic
proliferation, increased vascularization, and lymphocytic and histiocytic infiltration wall
off the focus. Subsequently, foreign body giant cells, calcifications, and hemosiderin
make their appearance, and eventually, the focus is replaced by scar tissue or is encysted
and walled off by collagenous tissue.
The major clinical significance of the condition is its possible confusion with breast
carcinoma as a palpable mass or mammographic calcifications.
LYMPHOCYTIC MASTOPATHY (SCLEROSING LYMPHOCYTIC LOBULITIS)
This condition presents with single or multiple hard palpable masses. In some cases, the
masses are bilateral or are detected as mammographic densities. The lesions are so hard
that it can be difficult to obtain tissue with a needle biopsy. Microscopically, they show
collagenized stroma surrounding atrophic ducts and lobules. The epithelial basement
membrane is often thickened. A prominent lymphocytic infiltrate surrounds epithelium
and blood vessels. This condition is most common in women with type 1 (insulin-
dependent) diabetes or autoimmune thyroid disease. Therefore, it is hypothesized that this
is an autoimmune disease of the breast. The only clinical significance is to distinguish
this condition from carcinoma.
GRANULOMATOUS MASTITIS
Granulomas in the breast are caused by a wide variety of diseases, all of them rare, and
are present in fewer than 1% of all breast biopsies. Systemic granulomatous diseases
(e.g., Wegener granulomatosis, sarcoidosis) may involve the breast; on occasion, the
breast may be the presenting site of involvement. Infections (mycobacterial, fungal)
occur, most commonly in immunocompromised patients or in the setting of a breast
prosthesis or nipple piercing. Granulomatous lobular mastitis is an uncommon breast-
limited disease distinguished by granulomas involving lobular epithelium. Only parous
women are affected, and it is hypothesized that the disease is a hypersensitivity reaction
mediated by prior alterations in lobular epithelium during lactation.
Benign Epithelial Lesions
A wide variety of benign alterations in ducts and lobules are observed in the breast. Most
present as mammographic lesions or as incidental findings. Less commonly, they present
as palpable masses. These changes have been divided into three groups, according to the
subsequent risk of developing
1127
breast cancer: (1) nonproliferative breast changes, (2) proliferative breast disease, and (3)
atypical hyperplasia.
NONPROLIFERATIVE BREAST CHANGES (FIBROCYSTIC CHANGES)
This group includes a miscellany of alterations in the female breast that are often grouped
under the term "fibrocystic changes." To the clinician, the term might mean "lumpy
bumpy" breasts on palpation; to the radiologist, a dense breast with cysts; and to the
pathologist, benign morphologic changes. These changes are termed "nonproliferative" to
distinguish them from the "proliferative" changes associated with an increased risk of
breast cancer.
These lesions might come to clinical attention when they mimic carcinoma by producing
palpable lumps, mammographic densities or calcifications, or nipple discharge. The
involved areas, by palpation, may have an ill-defined diffuse increase in consistency as
well as discrete nodularities that can make detection of other breast masses more difficult.
Cysts are the most common cause of a palpable mass and are alarming when they are
solitary, firm, and unyielding. They can usually be diagnosed by disappearance of the
mass after fine-needle aspiration of the contents. Calcifications are commonly found in
cysts and adenosis and often form mammographically suspicious clusters. Cystic changes
can also be associated with spontaneous unilateral nipple discharge.
Morphology.
There are three principal patterns of morphologic change: (1) cyst formation, often with
apocrine metaplasia; (2) fibrosis; and (3) adenosis.
• Cysts. Small cysts form by the dilation and unfolding of lobules. When cystic
lobules coalesce, larger cysts are formed. Unopened cysts are brown to blue (blue-
dome cysts) owing to the contained semitranslucent, turbid fluid. Cysts are lined
either by a flattened atrophic epithelium or by cells altered by apocrine
metaplasia. Metaplastic cells have an abundant granular, eosinophilic cytoplasm,
with round nuclei, resembling the apocrine epithelium of sweat glands ( Fig. 23-7
). Papillary projections may be present in cysts and calcifications are common.
"Milk of calcium" is a term radiologists use to describe calcifications in large
cysts that look as if they are lining the bottom of a rounded cyst on
mammography.
• Fibrosis. Cysts frequently rupture, with release of secretory material into the
adjacent stroma. The resulting chronic inflammation and fibrous scarring
contribute to the palpable firmness of the breast.
• Adenosis. Adenosis is defined as an increase in the number of acini per lobule.
A normal physiologic adenosis occurs during pregnancy throughout the breast. In
nonpregnant women, adenosis can occur as a focal change. The acini are often
enlarged (blunt duct adenosis) and are not distorted as is seen in sclerosing
adenosis, described later. Calcifications are occasionally present within lumens.
Lactational adenomas present as palpable masses in pregnant or lactating women. They
are formed by normal-appearing breast tissue with physiologic adenosis and epithelial
lactational changes. These
Figure 23-7 Apocrine cysts. Cells with round nuclei and abundant granular eosinophilic cytoplasm,
resembling the cells of normal apocrine sweat glands, line the walls of a cluster of small cysts. Secretory
debris, frequently with calcifications, is often present. Groups of cysts are common findings associated with
clustered mammographic calcifications.
lesions are probably not true neoplasms but an exaggerated focal response to hormonal
influences.
In a study of normal breasts in unselected forensic postmortem cases, grossly evident
cysts and fibrosis were found in 20% and histologic changes were present in 59% of
women.[13] Therefore, nonproliferative changes are most likely part of the spectrum of
histologic features that can be observed in the normal breast.
PROLIFERATIVE BREAST DISEASE WITHOUT ATYPIA
These changes rarely form palpable masses. More commonly, they are detected as
mammographic densities (e.g., complex sclerosing lesions or sclerosing adenosis), as
calcifications (e.g., sclerosing adenosis), or as incidental findings in biopsies performed
for other reasons (e.g., hyperplasia). More than 80% of large duct papillomas present as
nipple discharge, the remainder as small palpable masses or mammographic densities. A
large papilloma can spontaneously infarct, possibly because of torsion on the stalk,
resulting in a bloody discharge. Non-bloody discharge probably results from intermittent
blockage and release of normal breast secretions or irritation of the duct by the papilloma.
Small papillomas occur deep within the breast and are usually incidental findings
although they can be associated with calcifications. Although each of these lesions can be
found in isolation, more commonly, more than one lesion is present, not infrequently in
association with nonproliferative breast changes.
This group of disorders is characterized by proliferation of ductal epithelium and/or
stroma without cellular abnormalities suggestive of malignancy. The following entities
are included in this category: (1) moderate or florid epithelial hyperplasia, (2) sclerosing
adenosis, (3) complex sclerosing
1128
Figure 23-8 A, Normal. A normal duct or acinus has a single basally located myoepithelial cell layer (cells
with dark, compact nuclei and scant cytoplasm) and a single luminal cell layer (cells with larger open
nuclei, small nucleoli, and more abundant cytoplasm). B, Epithelial hyperplasia. The lumen is filled with a
heterogeneous population of cells of different morphologies, often including both luminal and
myoepithelial cell types. Irregular slitlike fenestrations are prominent at the periphary.
lesions, (4) papillomas, and (5) fibroadenoma with complex features.
Morphology.
Epithelial Hyperplasia.
In the normal breast, only myoepithelial cells and a single layer of luminal cells are
present above the basement membrane ( Fig. 23-8A ). Epithelial hyperplasia is defined by
the presence of more than two cell layers. Hyperplasia is moderate to florid when there
are more than four cell layers. The proliferating epithelium, often including both luminal
and myoepithelial cells, fills and distends the ducts and lobules. Irregular lumens
(fenestrations) can usually be discerned at the periphery of the cellular masses ( Fig. 23-
8B ).
Sclerosing Adenosis.
The number of acini per terminal duct is increased to at least twice the number found in
uninvolved lobules. The normal lobular arrangement is maintained. The acini are
compressed and distorted in the central portions of the lesion but characteristically dilated
at the periphery. Myoepithelial cells are usually prominent. On occasion, stromal fibrosis
may completely compress the lumens to create the appearance of solid cords or double
strands of cells lying within dense stroma, a histologic pattern that at times closely
mimics the appearance of invasive carcinoma ( Fig. 23-9 ). Calcifications are frequently
present within the lumens of the acini.
Complex Sclerosing Lesion (Radial Scar).
Radial scars are stellate lesions characterized by a central nidus of entrapped glands in a
hyalinized stroma ( Fig. 23-10 ). These lesions can resemble irregular invasive
carcinomas mammographically or on gross examination. The term "scar" refers to the
morphologic appearance, as these lesions are not associated with prior trauma or surgery.
A more general term is "complex sclerosing lesion," which includes not only radial scars
but also related lesions with components of sclerosing adenosis, papilloma formation, and
epithelial hyperplasia.
Papillomas.
Papillomas are composed of multiple branching fibrovascular cores, each having a
connective tissue axis lined by luminal and myoepithelial cells ( Fig. 23-11 ). Growth
occurs within a dilated duct. Epithelial hyperplasia and apocrine metaplasia are
Figure 23-9 Sclerosing adenosis. The involved terminal duct lobular unit is enlarged, and the acini are
compressed and distorted by the surrounding dense stroma. Calcifications are often present within the
lumens. Although this lesion is frequently mistaken for an invasive carcinoma, unlike carcinomas, the acini
are arranged in a swirling pattern, and the outer border is usually well circumscribed.
1129
Figure 23-10 Complex sclerosing lesion (radial scar). There is a central nidus consisting of small tubules
entrapped in a densely fibrotic stroma surrounded by radiating arms of epithelium with varying degrees of
cyst formation and hyperplasia. These lesions typically present as an irregular mammographic density and
closely mimic an invasive carcinoma.
frequently present. Large duct papillomas are usually solitary and situated in the
lactiferous sinuses of the nipple. Small duct papillomas are commonly multiple and
located deeper within the ductal system.
Small duct papillomas have been shown to be a component of proliferative breast disease
and increase the risk of subsequent carcinoma. It is less clear whether or not large duct
papillomas carry the same risk.
Figure 23-11 Intraductal papilloma. A central fibrovascular core extends from the wall of a duct. The
papillae arborize within the lumen and are lined by myoepithelial and luminal cells.
Fibroadenomas will be discussed in the section devoted to stromal lesions.
PROLIFERATIVE BREAST DISEASE WITH ATYPIA
Proliferative disease with atypia includes atypical ductal hyperplasia (ADH) and atypical
lobular hyperplasia (ALH). ADH is present in 5% to 17% of biopsies performed for
calcifications and is found less frequently in biopsies for mammographic densities or
palpable masses. Occasionally, ADH is associated with radiologic calcifications; more
commonly, it is adjacent to another calcifying lesion. ALH is an incidental finding and is
found in fewer than 5% of biopsies done for any reason.
Morphology.
Atypical hyperplasia is a cellular proliferation resembling ductal carcinoma in situ
(DCIS) or lobular carcinoma in situ (LCIS) but lacking sufficient qualitative or
quantitative features for a diagnosis of carcinoma in situ.
ADH is recognized by its histologic resemblance to ductal carcinoma in situ, including a
monomorphic cell population, regular cell placement, and round lumina. However, the
lesions are characteristically limited in extent, and the cells are not completely
monomorphic in type or they fail to completely fill ductal spaces ( Fig. 23-12A ).
ALH refers to a proliferation of cells identical to those of LCIS (described later), but the
cells do not fill or distend more than 50% of the acini within a lobule ( Fig. 23-12B ).
ALH can also extend into ducts, and this finding is associated with an increased risk of
developing invasive carcinoma.
CLINICAL SIGNIFICANCE OF BENIGN EPITHELIAL CHANGES
Multiple epidemiologic studies have classified benign histologic changes in the breast
and determined the subsequent risk these changes confer for the later development of
invasive cancer ( Table 23-2 ).[14] [15] [16] Nonproliferative changes do not increase the risk of
cancer. Proliferative disease is associated with a mild increase in risk. Proliferative
disease with atypia (ADH and ALH) confers a moderate increase in risk. Carcinoma in
situ (DCIS and LCIS) is associated with a substantial risk if untreated and will be
discussed later. The magnitude of risk may be modified by the woman's menopausal
status, family history, and time since the biopsy ( Table 23-2 ).
Carcinoma of the Breast
Carcinoma is the most common malignancy of the breast, and breast cancer is the most
common non-skin malignancy in women. A woman who lives to age 90 has a one in eight
chance of developing breast cancer. In 2001, almost 240,000 women were diagnosed
with breast cancer, and over 40,000 died of the disease. As the demographic bulge of the
"baby boomers" continues to grow older, the absolute number of women with breast
cancer is expected to increase by about a third over the
1130
Figure 23-12 A, Atypical ductal hyperplasia. A duct is filled with a mixed population of cells consisting of
oriented columnar cells at the periphery and more rounded cells within the central portion. Although some
of the spaces are round and regular, the peripheral spaces are irregular and slitlike. These features are
highly atypical but fall short of a diagnosis of DCIS. B, Atypical lobular hyperplasia. A population of
monomorphic small, rounded, loosely cohesive cells partially fill a lobule. Some intracellular lumina can be
seen. Although the cells are morphologically identical to the cells of LCIS, the extent of involvement is not
sufficient for this diagnosis.
next 20 years, just because of the effect of the aging of the population. It is both ironic
and tragic that a neoplasm arising in an exposed organ, readily accessible to self-
examination and clinical diagnosis, continues to exact such a heavy toll. Only lung cancer
causes more cancer deaths in women living in the United States.
TABLE 23-2 -- Breast Lesions and Relative Risk of Developing Invasive Carcinoma
Relative Risk
of Developing
Invasive Breast at
Pathologic Lesion Carcinoma Risk Modifiers of Risk
Nonproliferative Breast 1.0 Neither
Changes
Duct ectasia
Cysts
Apocrine change
Mild hyperplasia
Adenosis
Fibroadenoma without
complex features
Proliferative Disease 1.5–2.0 Both Increased risk if there is a
Without Atypia breasts family history of breast
carcinoma
Moderate or florid Decreased risk 10 years after
hyperplasia biopsy
Sclerosing adenosis
Papilloma
Complex sclerosing lesion
(radial scar)
Fibroadenoma with complex
features
Proliferative Disease with 4.0–5.0 Both Increased risk if there is a
Atypia breasts family history of breast
carcinoma
Atypical ductal hyperplasia Increased risk if
premenopausal
Atypical lobular hyperplasia Decreased risk 10 years after
biopsy for ALH
Carcinoma in Situ 8.0–10.0
Lobular carcinoma in situ Both Treatment (tamoxifen,
breasts bilateral mastectomy)
TABLE 23-2 -- Breast Lesions and Relative Risk of Developing Invasive Carcinoma
Relative Risk
of Developing
Invasive Breast at
Pathologic Lesion Carcinoma Risk Modifiers of Risk
Ductal carcinoma in situ * Ipsilateral Treatment (tamoxifen,
breast surgery to eradicate the
lesion, radiation therapy)
*This risk applies to low-grade DCIS originally misdiagnosed as benign disease and followed without
treatment. The risk for progression of high-grade DCIS is presumed to be greater than this.
INCIDENCE AND EPIDEMIOLOGY
After remaining constant for many years (except for a transient rise in 1974 attributed to
increased awareness after the publicity surrounding Betty Ford and Happy Rockefeller
developing breast cancer), the incidence of breast cancer
1131
Figure 23-13 Breast cancer incidence and mortality rates for women over 50 years of age. Rates are per
100,000 women and are age-adjusted to the 2000 U.S. standard million population. (SEER Cancer
Statistics Review 1973–1999; http://seer.cancer.gov/.)
began to increase in older women, raising concern that there was an unidentified
environmental cause ( Fig. 23-13 ). During this same period of time, starting in the early
1980s, mammographic screening was introduced, and the number of women of
appropriate age undergoing screening increased steadily to current reported rates of 60%
to 80%.[18] Screening results in the increased detection of small invasive carcinomas and in
situ carcinomas. Since DCIS is almost exclusively detected by mammography ( Table 23-
1 ), this effect is shown by the accompanying increase in in situ carcinomas in this group
of women ( Fig. 23-13 ). During this period, the number of women presenting with large
or locally advanced carcinomas decreased, whereas the number of women with only in
situ carcinoma or small node-negative carcinomas markedly
Figure 23-14 Change in stage of breast cancer at presentation from 1983 to 1996. (SEER Cancer Statistics
Review, http://seer.cancer.gov/.)
increased ( Fig. 23-14 ). Over the same time period, the incidence of breast carcinoma in
younger women, who have a much lower risk of breast cancer and for whom screening is
not recommended, did not increase. In retrospect, the increase in incidence in older
women can be explained primarily by the influence of screening.
Until recently, about one third of women diagnosed with breast cancer eventually
succumbed to the disease. During the 1980s, the number of women dying of breast cancer
remained constant, despite the increase in the incidence of breast cancer ( Fig. 23-13 ).
One possible explanation is that screening was detecting clinically insignificant cancers.
In 1994, after a lag time of about 10 years, the mortality rate started to decline ( Fig. 23-
13 ). If screening is detecting clinically significant cancers at a curable stage, this
downward trend will continue. Better treatment modalities should also contribute to this
hopeful trend. Currently, only 20% of women with breast cancer are expected to die of
the disease.
The frequency of this disease in women has prompted an intensive study of risk factors
for developing breast cancer to gain clues as to its etiology as well as to identify
modifiable risk factors that would be helpful for prevention strategies.
Risk Factors.
The most common risk factors for the development of breast cancer, identified by
epidemiologic studies, have been combined into a statistical model to calculate the
absolute risk of an individual woman developing cancer within the next 5 years or by age
90.[19] A modified interactive version of this model is available at
http://bcra.nci.nih.gov/brc/. It is designed for women over the age of 35 without a prior
diagnosis of LCIS or DCIS and without a family history suggestive of a single gene
mutation.[20] The model incorporates the following risk factors.
• Age. Breast cancer is rarely found before the age of 25 years except in certain
familial cases. The incidence rises throughout a woman's lifetime. Seventy-seven
per cent of cases occur in women over 50 years of age. The average age at
diagnosis is 64 years.
• Age at Menarche. Women who reach menarche when younger than 11 years of
age have a 20% increased risk
1132
compared to women who reach menarche when more than 14 years of age. Late
menopause also increases risk, but the magnitude of the risk has not been
quantified.
• First Live Birth. Women with a first full-term pregnancy at younger than 20
years of age have half the risk of nulliparous women or women over the age of 35
at their first birth. It is hypothesized that pregnancy results in terminal
differentiation of epithelial cells, removing them from the potential pool of cancer
precursors. However, the biologic basis of such differentiation has not been
determined. This effect might be overshadowed in pregnancies in older women by
the proliferation early in pregnancy of cells that might have already undergone
preneoplastic changes.
• First-Degree Relatives with Breast Cancer. The risk of breast cancer increases
with the number of affected first-degree relatives (mother, sister, or daughter).
However, the majority of cancers occur in women without such a history, as only
13% of women with breast cancer have one affected first-degree relative, and
only 1% have two or more.[21] In turn, over 87% of women with a family history
will not develop breast cancer. This model is not designed to calculate the risk for
women in families with a high likelihood of a single gene mutation such as
BRCA1 or BRCA2 (see the section on hereditary breast cancer below).
• Breast Biopsies. Increased risk is associated with prior breast biopsies showing
atypical hyperplasia. This model does not adjust for the mild increase in risk
associated with proliferative breast changes without atypia ( Table 23-2 ).
• Race. Although the overall incidence of breast cancer is lower in women of
African-American ancestry, women in this group present at a more advanced
stage and have an increased mortality rate compared with white women.[22] [23]
Social factors such as decreased access to health care and lower use of
mammography account for some of the difference, but genetic factors also play a
role. A greater number of breast cancers are diagnosed in black women than in
white women younger than 40 years of age, and breast carcinomas in black
women have a higher nuclear grade, more frequently lack hormone receptors, and
have different types of sporadic p53 mutations. Caucasian women generally have
the highest rates of breast cancer. The risk of developing an invasive carcinoma
within the next 20 years at age 50 is 1 in 15 for Caucasians, 1 in 20 for African
Americans, 1 in 26 for Asian/Pacific Islanders, and 1 in 27 for Hispanics.[24]
Absolute risk for individual women, either for the next 5 years or lifetime risk, can be
calculated by using this model. For example, a 60-year-old woman who first gave birth
when she was more than 30 years of age (but with no other factors that would increase
her risk) has a 2% risk of developing breast cancer over the next 5 years, compared to the
1% risk for a similar 60-year-old woman who had her first child when she was under the
age of 20. Although all women are at high enough risk to undergo breast examination and
screening mammography at the appropriate age, certain very high-risk women can
consider other interventions such as chemoprevention or prophylactic mastectomy
(discussed below). A risk of 1.7% of developing breast cancer in the next 5 years was
used as the entry criterion for the chemoprevention trials.
Additional risk factors are recognized but have not been incorporated into the model
owing to their rarity, difficulties in quantifying the risk, or lack of definitive studies.
• Estrogen Exposure. Postmenopausal hormone replacement therapy slightly
increases the risk of breast cancer in current users but might not increase the risk
of death.[25] [26] Estrogen and progesterone together increase the risk more than does
estrogen alone. Invasive lobular carcinomas and other estrogen receptor (ER)-
positive carcinomas are reported to be increased in this group does. Oral
contraceptives are unlikely to increase the risk of breast cancer[27] and can decrease
the risk of other malignancies such as ovarian carcinoma. Reducing endogenous
estrogens by oophorectomy decreases the risk of developing breast cancer by up
to 75%.
• Radiation Exposure. Women who have been exposed to therapeutic radiation or
radiation after atom bomb exposure have a higher rate of breast cancer. Risk
increases with younger age and higher radiation doses. Women in their teens and
twenties (but not at older ages) undergoing mantle radiation for Hodgkin disease
have a 20% to 30% risk of developing breast cancer 10 to 30 years after
treatment.[28] Modern mammographic screening uses low doses of radiation and is
unlikely to have an effect on the risk of breast cancer.
• Carcinoma of the Contralateral Breast or Endometrium. Increased risk is
associated with carcinoma of the contralateral breast or endometrium, probably
owing to the share hormonal risk factors for these tumors.
• Geographic Influence. Breast cancer incidence rates in the United States and
Europe are four to seven times higher than those in other countries. The risk of
breast cancer increases in immigrants to the United States during several
generations. The specific factors have not been identified but have received
considerable attention in the attempt to identify modifiable risk factors. Diet,
physical activity, breast-feeding, and environmental factors have been
investigated.
• Diet. Various items in diet, in particular dietary fat, have been suggested to
increase risk, but large studies have failed to find a strong correlation. Some
studies have shown a reduced risk with increased β-carotene intake. Coffee
addicts will be pleased to know that there is no substantial evidence that caffeine
consumption increases the risk, but studies do show that moderate or heavy
alcohol consumption confers an increased risk of breast cancer.[29] Higher estrogen
levels and lower folate levels associated with alcohol consumption may be
mechanisms underlying this association.
• Obesity. There is decreased risk in obese women younger than 40 years owing to
the association with anovulatory cycles and lower progesterone levels late in the
cycle. There is increased risk in postmenopausal obese women, which is
attributed to synthesis of estrogens in fat depots.
• Exercise. Studies have been inconsistent, but some have shown a decreased risk
of breast cancer in premenopausal women who exercise.
• Breast-Feeding. The longer women breast-feed, the greater is the reduction in
the risk of breast cancer.[30] The lower incidence of breast cancer in developing
countries may be largely explained by the more frequent and longer nursing of
infants.
1133
• Environmental Toxins. There is concern that environmental contaminants such
as organochlorine pesticides could have estrogenic effects on humans. The
possible effect of environmental toxins on breast cancer risk is being intensively
investigated. No specific substances have been definitively associated with an
increased risk.
• Tabacco. Cigarette smoking is not associated with breast cancer but is
associated with the development of periductal mastitis or a subareolar abscess
(discussed earlier).
Treatment of Women at High Risk for Developing Breast Cancer.
With the exception of DCIS, all other risk factors for the development of invasive breast
cancer affect both breasts equally. Therefore, strategies to prevent cancer must treat both
breasts.
Bilateral prophylactic mastectomy can prevent the development of 89% of breast cancers
in women who are at moderate risk for the disease owing to a family history. However,
prevention can come at a high cost. In one study, at least 12 women who were at risk
owing to their family history underwent the procedure for every one case of cancer
prevented.[31]
Chemoprevention is another option for women who are at risk for developing invasive
breast cancer. Tamoxifen is a drug that competes for binding to the ER and has both
estrogenic and antiestrogenic effects. It is the most widely used endocrine therapy for the
treatment of breast cancer. In selected groups of women, tamoxifen has been shown to
reduce the incidence of breast cancer.[32] However, tamoxifen also increased the risk of
venous thromboembolism, endometrial
TABLE 23-3 -- BRCA1 and BRCA2
BRCA1 BRCA2
Chromosome 17q21 13q12.3
Gene size 81 kb 84 kb
Protein size 1863 amino acids 3418 amino acids
Function Tumor suppressor Tumor suppressor
Transcriptional Transcriptional regulation
regulation
Role in DNA repair Role in DNA repair
Mutations >500 identified >300 identified
Mutations in population about 0.1% about 0.1%
Risk of breast cancer 60–80% 60–80%
Age at onset Younger age (40s to 50 years
50s)
Families with breast cancer due to 52% 32%
a single gene (%)
Families with breast and ovarian 81% (20–40% risk) 14% (10–20% risk)
cancer (%)
Families with male and female <20% 76%
breast cancer
Risk of other tumors (varies with Prostate, colon, Prostate, pancreas, stomach,
TABLE 23-3 -- BRCA1 and BRCA2
BRCA1 BRCA2
specific mutation) pancreas melanoma, colon
Mutations in sporadic breast Very rare (<5%) Very rare (<5%)
cancer
Epidemiology Specific mutations Specific mutations are found
are found in certain in certain ethnic groups
ethnic groups
Pathology of breast cancers Greater incidence of Similar to sporadic breast
medullary cancers
carcinomas (13%),
poorly differentiated
carcinomas, ER-,
PR-, and Her2/neu-
negative carcinomas,
carcinomas with p53
mutations
Additional information about these genes can be found at http://www.ncbi.nlm.nih.gov/.
cancer, and cataracts. Current clinical trials are attempting to identify other selective
estrogen receptor modulators (SERMs) that have the same benefit but fewer side effects.
ETIOLOGY AND PATHOGENESIS
The major risk factors for the development of breast cancer are hormonal and genetic
(family history). Breast carcinomas can, therefore, be divided into sporadic cases,
possibly related to hormonal exposure, and hereditary cases, associated with family
history or germ-line mutations. Hereditary carcinoma has received intense scrutiny in the
hopes that the specific genetic mutations can be identified and that these alterations will
illuminate the causes of all breast cancer. Recent studies have borne out these hopes. We
begin our discussion with hereditary breast cancer and follow with sporadic breast
cancer.
Hereditary Breast Cancer
A family history of breast cancer in a first-degree relative is reported in 13% of women
with the disease.[21] However, only 1% of women have multiple affected relatives, a
history suggestive of a highly penetrant germ-line mutation.
About 25% of familial cancers (or around 3% of all breast cancers) can be attributed to
two highly penetrant autosomaldominant genes: BRCA1 and BRCA2 ( Table 23-3 ). The
probability of breast cancer associated with a mutation in these genes increases if there
are multiple affected first-degree relatives, if individuals are affected before menopause
and/or
1134
have multiple cancers, if there is a case of male breast cancer, or if family members also
develop ovarian cancer. The general lifetime breast cancer risk for female carriers is 60%
to 85%, and the median age at diagnosis is about 20 years earlier compared to women
without these mutations. The penetrance (i.e., the number of carriers who actually
develop breast cancer) can vary with the specific type of mutation present. Mutated
BRCA1 also markedly increases the risk of developing ovarian carcinoma, which is as
high as 20% to 40%. BRCA2 confers a smaller risk for ovarian carcinoma (10% to 20%)
but is associated more frequently with male breast cancer. BRCA1 and BRCA2 carriers
are also susceptible to other cancers, such as colon, prostate, and pancreas, but to a lesser
extent.
Although BRCA1 and BRCA2 do not show sequence homology, they function in similar
pathways and interact with the same multiprotein complexes. Both act as tumor
suppressors, as it is a loss of function that confers the risk of malignancy. A wide variety
of functions have been suggested for these proteins, including transcriptional regulation,
cell-cycle control, ubiquitin-mediated protein degradation pathways, and chromatin
remodeling. A key function for both appears to be their role in protecting the genome
from damage by halting the cell cycle and promoting DNA damage repair in a complex
process that is not yet fully understood. BRCA1 is phosphorylated in response to damage
and may transduce DNA damage signals from checkpoint kinases to effector proteins.
BRCA1 is also bound with BRCA2 and RAD51 in a nuclear dot complex—presumably
the site of DNA repair.[33] BRCA2 can bind directly to DNA and functions in homologous
recombination for the error-free repair of double-strand DNA breaks.[34] Why loss of these
functions specifically affects the breast is unclear. Perhaps the intermittent proliferation
of breast epithelium (as opposed to the constitutive proliferation of other epithelia such as
colon or skin) makes this organ more susceptible to the accumulation of genetic damage,
or possibly, other cell types have additional mechanisms for DNA repair that the breast
lacks. BRCA1, but not BRCA2, interacts with the ER and is involved in X chromosome
inactivation—two features that may be related to its gender-specific risk.[35] Interestingly,
male breast cancers are markedly increased only in families carrying BRCA2 mutations.
Both genes have a total length of over 80 kb, and hundreds of different mutations
distributed throughout the coding region have been reported for each one. The frequency
of mutations is only 0.1% to 0.2% in the general population. Some mutations diminish
the function of the genes and increase cancer risk, whereas others might be unimportant
sequence variants. Genetic testing is difficult and often inconclusive unless several family
members are affected or unless the individual belongs to an ethnic group with a known
high incidence of specific mutations.[36] For example, people of Ashkenazi Jewish descent
have a 2% to 3% risk of three specific mutations. Identification of carriers of clinically
significant mutations is important, as prophylactic mastectomy and/or oophorectomy can
reduce the risk of cancer mortality. [31] [37] [38]
In hereditary carcinomas, one mutant BRCA allele is inherited, and the second allele is
inactivated by somatic mutation. Although BRCA1 and BRCA2 mutations are rarely
found in sporadic tumors, about 50% of such tumors have decreased or absent expression
of BRCA1. In most cases, this is accomplished by a combination of loss of
heterozygosity (LOH) and methylation of the promoter to inactivate both alleles. [39]
Hypermethylation of the promoter is detected in 13% of unselected carcinomas but is
more common in medullary carcinomas (67% of tumors) and mucinous carcinomas (55%
of tumors)—histologic subtypes that are more commonly found in BRCA1 carriers. A
similar mechanism has not yet been described for BRCA2.
BRCA1-associated breast cancers are more commonly poorly differentiated, have a
syncytial growth pattern with pushing margins, have a lymphocytic response, and do not
express hormone receptors or overexpress HER2/neu (an epidermal growth factor
receptor that is commonly overexpressed in breast cancer, to be discussed later), as
compared to sporadic breast carcinomas. BRCA2-associated breast carcinomas do not
have a distinct morphologic appearance. Initial results using gene expression RNA
profiling have revealed that BRCA1, BRCA2, and subtypes of sporadic cancers can be
recognized by their gene expression patterns[40] [41] ( Box 23-1 ). Sporadic carcinomas with
an mRNA profile similar to BRCA1 carcinomas have been termed "basal-like"
carcinomas owing to the expression of genes that are characteristic of myoepithelial or
possible breast progenitor cells. These results demonstrate that a subset of sporadic
carcinomas have biologic similarities to hereditary carcinomas.
Genetic susceptibility due to other known genes is much less common, and together this
group accounts for fewer than 10% of hereditary breast carcinomas. [42] Only five have
been studied sufficiently to be worth noting. Mutations in the cell-cycle checkpoint
kinase gene (CHEK2), which is an important component of the recognition and repair of
DNA damage and which activates BRCA1, may account for 5% of familial cases. [43] The
risk for a mutation carrier may be as low as 20%. Women with the Li-Fraumeni
syndrome (due to a germ-line mutation in the p53 gene) have an 18-fold higher risk of
developing breast cancer before the age of 45. Mutations in p53 also occur in 19% to
57% of sporadic breast carcinomas. Cowden syndrome ("multiple hamartoma syndrome"
due to a mutation of the PTEN gene on chromosome 10q) confers a 25% to 50% lifetime
risk of breast cancer in affected women. Mutations in the PTEN gene are rare in sporadic
carcinomas, but LOH is found in 11% to 41%. Further studies will be necessary to
determine whether the function of the other allele is altered (e.g., by methylation).
Women with Peutz-Jeghers syndrome (caused by truncating mutations in the LKBI gene)
are at increased risk for breast cancer. There is, as yet, no evidence that this gene plays a
role in sporadic carcinoma. The role of the ATM gene in breast cancer susceptibility in
ataxia telangiectasia carriers has been intensively studied owing to the high frequency of
carriers in the population (approximately 7%) and the increased sensitivity to radiation
exposure leading to concerns about screening mammography. Studies have had mixed
results, some showing an increased risk and others not showing an association. The risk
might be dependent on the type of germ-line mutation (e.g., truncating versus missense).
Mutations in the ATM gene in sporadic carcinomas are rare.
All of these genes considered together still leave at least two-thirds of familial risk
unexplained. The search for a putative "BRCA3" gene of high penetrance has, as yet, been
unsuccessful, and such a gene might not exist.[44] A polygenic model
1135
in which many weakly penetrant genes (perhaps dozens or hundreds) act in combination
to create a spectrum of risk could explain the majority of familial breast cancers, as well
as risk in the general population.[45] [46] [47] This model suggests that most breast cancers
arise in a minority of women carrying combinations of these susceptibility genes. The
identification of these genes might allow better stratification of women into low-risk and
high-risk groups, which would help to focus efforts toward prevention and early detection
in these women. Yet to be determined are the number of genes that could be involved, the
nature of interactions among these genes (e.g., additive or multiplicative), the interaction
with environmental factors, and the possible role of protective alleles. Candidates for
such genes have been identified by their ability to modify the expression of known genes
such as BRCA1.
Genome-wide approaches (e.g., microarray technology; Box 23-1 ) could play an
important role in identifying this potentially very large group of susceptibility genes. One
current approach classifies hereditary cancers by mRNA profiling in the hopes that
cancers arising due to the same germline mutation (or mutations) will have similar
patterns, as has been demonstrated with BRCA1 and BRCA2. [48] If true, this would
simplify linkage analysis by identifying groups of families likely to carry similar
mutations.
Many studies have confirmed that some of the genes involved in hereditary breast cancer
(e.g., BRCA1 and p53) are also important in many sporadic cancers. It is hoped that the
continued investigation of the wide variety of naturally occurring mutations and
combinations of mutations will provide important clues to breast cancer pathogenesis.
Sporadic Breast Cancer
The major risk factors for sporadic breast cancer are related to hormone exposure:
gender, age at menarche and menopause, reproductive history, breast-feeding, and
exogenous estrogens. The majority of these cancers occur in postmenopausal women and
overexpress ER. Estrogen itself has at least two major roles in the development of breast
cancer. Metabolites of estrogen can cause mutations or generate DNA-damaging free
radicals.[49] Via its hormonal actions, estrogens drive the proliferation of premalignant
lesions as well as cancers. However, other mechanisms also undoubtedly play a role, as a
significant subset of breast carcinomas are ER-negative or occur in women without
increased estrogen exposure.
Mechanisms of Carcinogenesis
The vast array of histologic appearances of proliferative and atypical breast disease, as
well as carcinomas, are the outward manifestations of the dozens or hundreds of biologic
changes taking place within these lesions and point to the complex and variable pathways
to carcinogenesis. Indeed, not one common genetic or functional change can be found in
every breast cancer. Most reported changes occur in only a subset of carcinomas and
usually in highly variable combinations with other changes.
A general model for carcinogenesis postulates that a normal cell must achieve seven new
capabilities, including genetic instability, to become malignant [50] [51] (see Chapter 7 ) (
Fig. 23-15 ). In hereditary carcinoma, one or more of these alterations is facilitated by the
inheritance of germ-line mutations. Each of the new capabilities can be achieved by a
change in one of many genes. For example, changes in ER, EGF-R, RAS, or HER2/neu
may result in self-sufficiency in growth signals. On the other hand, one cellular alteration
(e.g., a change in a gene such as p53 that has a central role in controlling the cell cycle,
DNA repair, and apoptosis) can affect more than one of these capabilities.
The morphologic changes in the breast associated with the smallest increased risk of
cancer are lesions with increased numbers of epithelial cells (proliferative changes). This
suggests that these early changes are related to evasion of growth-inhibiting signals,
evasion of apoptosis, and self-sufficiency in growth signals. There is evidence that even
at this early stage, there is abnormal expression of hormone receptors and abnormal
regulation of proliferation in association with hormone receptor positivity. [52]
Genetic instability, in the form of LOH, appears to be a later change, as it is rarely
detected in proliferative changes but becomes more frequent in atypical hyperplasias and
is almost universally present in carcinoma in situ. Frank aneuploidy, as observed by
nuclear enlargement, irregularity, and hyperchromasia, or image analysis to measure
DNA content, is seen only in high-grade DCIS and some invasive carcinomas. Limitless
replicative potential is suggested by the ability of clonal populations of the cells of DCIS
to completely fill a ductal system in the breast. Increased angiogenesis is evident
surrounding the basement membrane of some ducts that are involved by some types of
DCIS. This might be due to direct stimulation by the malignant cells, secondary
stimulatory effects on stromal cells, or the loss of inhibition of angiogenesis by
myoepithelial cells.
The morphologic and biologic features of carcinomas are usually established at the in situ
stage, as in the majority of cases, the in situ lesion closely resembles the accompanying
invasive carcinoma. For example, lobular carcinomas are associated with LCIS, well-
differentiated carcinomas with low-grade DCIS, and high-grade carcinomas with high-
grade DCIS. Recurrent carcinomas generally have the appearance of the original
carcinoma. Breast carcinomas do not generally "dedifferentiate," or become more poorly
differentiated over time.
This view of oncogenesis focuses on the malignant epithelial cell and does not take into
account the other tissue components. The structure and function of the normal breast
require complex interactions between luminal cells, myoepithelial cells, and stromal
cells. The same functions that allow for normal formation of new ductal branch points
and lobules during puberty and pregnancy—abrogation of the basement membrane,
increased proliferation, escape from growth inhibition, angiogenesis, and invasion of
stroma—can be co-opted during carcinogenesis by abnormal epithelial cells, stromal
cells, or both.[53] While the changes described above are accumulating in the luminal cells
(or, less commonly, myoepithelial cells), parallel changes also occur due to mutation or
epigenetic changes (e.g., DNA methylation) or via abnormal signaling pathways in these
other cell types, resulting in the loss of normal cellular interactions and tissue structure. [54]
Loss of these normal functions also occurs with age, and this loss might contribute to the
increased risk of breast cancer in older women.
The final step of carcinogenesis, the transition of carcinoma limited by the basement
membrane to ducts and lobules (carcinoma
1136
Box 23-1. GENE EXPRESSION PORTRAITS OF BREAST CARCINOMAS
Until recently, changes occurring in cancer cells were studied one at a time or in small
groups in small sets of tumors. New microarray technologies ("gene chips") have enabled
investigators to simultaneously detect and quantify the expression of large numbers of
genes (potentially all genes) in different tumors (see Box 7-1 , Chapter 7).
A major advantage of gene arrays is the ability to analyze a multitude of changes in
cancer cells (i.e., a "molecular portrait") to discern overall patterns that would not be
possible to detect by conventional techniques. An example of the type of data that may be
generated from such assays is illustrated in a simplified form in the figure on the facing
page. The results for 26 breast carcinomas (each corresponding to one column) for 28
genes (represented by each row) are displayed. A relative increased quantity of mRNA
(relative to a reference standard) is shown by red, a relative decreased quantity by green,
and an average amount by black. Also shown in the figure are the histology of the
different tumor types and the expression of selected proteins detected by
immunohistochemistry (ER, HER2, e-cadherin, and basal keratin).
Microarray studies, such as this one and others, have identified breast cancer subtypes
previously identified by morphology (e.g., lobular carcinomas), by protein expression
(e.g., ER-positive and HER2/neu-positive carcinomas), and by germ-line mutations (e.g.,
BRCA1 and BRCA2 carcinomas). In addition, new subtypes that were not previously well
defined have been identified (e.g., the basal-like carcinomas). In the figure, results are not
shown for many other tumor subtypes, such as tubular, mucinous, and medullary
carcinomas, because these are relatively rare and too few cases have been examined to
allow firm conclusions.
mRNA levels do not always correspond to changes in protein expression. The quantity of
protein within a cell depends not only on the amount and rate of transcription and
translation, but also on protein degradation and the rate of transport out of the cell.
Therefore, other assays are necessary to determine actual protein content.
Immunohistochemistry (IHC) uses antibodies to detect proteins on tissue sections.
Whereas tissue used for mRNA profiling may include both tumor and stromal cells, IHC
has the advantage of being able to identify the cell type expressing the protein and the
specific cellular location of the protein.
Estrogen Receptor-Positive Carcinomas. Seventy per cent to 80% of breast carcinomas
express ER and are thought to arise from intrinsically ER-positive luminal cells. ER-
positive ductal carcinomas ("no special type") are usually well to moderately
differentiated and often show tubule formation. Most special types of breast cancer (i.e.
lobular, tubular, mucinous, and papillary) are also ER-positive. In the microarray data
illustrated, the group of ductal carcinomas, in general, show normal or overexpression of
the ER-related gene cluster and luminal keratins, and exhibit low levels of mRNAs from
the groups of genes characteristic of the other tumor types. In the lower part of the figure,
IHC on one representative ductal carcinoma demonstrates that ER is present in the
nucleus, e-cadherin on the cell membrane, and that HER2/neu and basal keratins are
undetectable.
In contrast to traditional IHC assays that determine the expression of only ER and a
single gene under its regulation, PR, mRNA profiling provides information about many
other ER-regulated genes. Using this type of assay, it might be possible to identify the
cancers that express ER but fail to respond to hormonal treatments due to disruption of
the signaling pathway, resulting in low expression of other ER-regulated genes.
Lobular carcinomas can be identified by the distinctive morphologic pattern of
infiltration as single cells or loosely cohesive cell clusters. This appearance has been
linked to the loss of the normal cell adhesion molecule e-cadherin, which is retained in
most other carcinomas within the ER-positive group. By expression profiling, the lobular
carcinomas cluster together and are most closely related to the other ER-positive
carcinomas. The absence of e-cadherin can be seen by both diminished mRNA and the
absence of the protein by IHC.
Estrogen Receptor-Negative Carcinomas. These carcinomas may arise owing to loss of
ER expression or from normally ER-negative cells. Expression profiling identifies two
major types of ER-negative carcinomas.
HER2-Positive Carcinomas. This group of carcinomas was previously identified by
overexpression of the HER2/neu protein. In the majority of carcinomas, the mechanism
of over-expression is amplification of the gene resulting in increased transcription into
mRNA and protein translation. Breast cancers are routinely assayed for HER2/neu gene
and protein using FISH or IHC ( Figs. 23-27C and B , respectively) in order to predict
clinical responses to antibodies targeted to the protein. These carcinomas tend to be
poorly differentiated.
The expression profile reveals not only increased copies of HER2/neu mRNA, but also
increased transcription of other adjacent genes that are amplified within this segment of
DNA. These carcinomas do not overexpress the genes that are characteristic of the other
subtypes of cancers in this array (e.g. ER and basal keratins), but do express e-cadherin.
Basal-like Carcinomas. This group of carcinomas is distinguished by the expression of
keratins that are more typical of myoepithelial cells or potential breast progenitor cells; it
has not been previously well characterized. Because the myoepithelial cell is located in
the basal area of the lobules and ducts, in the absence of knowing the specific cell of
origin, this group of carcinomas was termed basal-like. In addition to the expression of
specific keratins, they also show expression of other genes in common with myoepithelial
cells (e.g., p-cadherin) as well as numerous genes related to cell proliferation. This group
of carcinomas does not express ER or ER-related genes or HER2/neu, as can be seen by
the array data and by IHC.
Carcinomas arising in women with BRCA1 mutations also cluster with this group.
BRCA1 carcinomas are similar to basal-like carcinomas in being poorly differentiated,
lacking ER and HER2/neu expression, and expressing basal-like keratins. However, most
women with basal-like carcinomas do not have germ-line BRCA1 mutations.
Conclusions. mRNA expression profiling is a powerful tool for investigating breast
carcinomas. Analogous arrays to analyze DNA and protein expression profiles are under
development. In addition to identifying tumor types, as in this example, mRNA arrays
have been used for predicting prognosis and response to therapy, examining tumor
changes after therapy, and classifying hereditary carcinomas. Although it might not be
feasible to perform transcriptional profiling on every clinical case of breast cancer, these
studies will generate information that will lead to better diagnostic, prognostic, and
therapeutic tests that are applicable to all patients.
1137
Figure 23- Selected data from mRNA expression profiling (26 carcinomas and 28 genes) are shown in the
top half of the figure. Each vertical column represents one carcinoma (and shows information acquired
from one "gene chip") and each horizontal row represents the data for a gene (identified at the left). Red
indicates an increase, green a decrease, and black no change in mRNA relative to a standard. Cluster
analysis was used to group carcinomas with similar expression patterns and the groups are identified as
basal-like, HER2 positive, and the ER-positive lobular and ductal carcinomas. The most important gene
clusters are identified on the right. These carcinomas have typical morphologic appearances as shown in
the middle row of images (H&E). In the lower half of the figure, mRNA expression patterns are correlated
with changes in protein expression by using antibodies to detect antigens within tissues. The presence of a
protein is indicated by a brown reaction product within the tumor cells and can be localized to a subcellular
site (estrogen receptor-nuclear; HER2/neu and e-cadherin-membrane; basal keratin-cytoplasmic). The
array data are courtesy of Dr. Andrea Richardson, Brigham and Women's Hospital, Boston, MA, as
modified from Signoretti S, Di Marcotullio L, Richardson A, et al.: Oncogenic role of the ubiquitin ligase
subunit Skp2 in human breast cancer, J Clin Invest 110:633–641, 2002.
1138
Figure 23-15 The normal breast is maintained by a complex set of interactions among luminal cells,
myoepithelial cells, the basement membrane, and stromal cells (illustrated to the left of the figure).
Morphologic changes are displayed according to the risk for subsequent invasive carcinoma (top row of
pictures). The seven categories of changes in biologic functions that must occur in successful malignant
cells are shown in colored boxes. The changes need not occur in a specific order but accumulate until cells
acquire malignant potential. The association of these changes with premalignant breast lesions suggests that
the earliest events are related to evasion of growth-inhibiting signals, evasion of apoptosis, and self-
sufficiency in growth signals. Hereditary carcinomas arise from cells that have germ line mutations that
alter DNA repair and/or normal signals for apoptosis and therefore require fewer acquired changes.
Luminal cells likely give rise to the majority of cancers, but myoepithelial cells can also undergo malignant
transformation. Changes in the malignant cells are accompanied by alterations in the supporting
myoepithelial and stromal cells due to a combination of genetic and epigenetic events and disruption of the
normal intercellular signaling pathways. The final alteration, invasion of stroma, is the least well
understood. It has been difficult to identify biologic changes that are specific to invasive carcinomas. It is
possible that invasion is a result of the loss of the ability of myoepithelial and stromal cells to maintain the
basement membrane rather than a gain of function by the malignant cells.
in situ) to invasive carcinoma, is the least understood. Specific gene functions necessary
for invasion have been difficult to identify.[55] It is possible that this transition is primarily
due to the loss of the basement membrane and tissue integrity caused by the abnormal
function of myoepithelial and stromal cells rather than to the gain of the ability of
malignant cells to invade through the basement membrane and into stroma ( Fig. 23-15 ).
New techniques that survey hundreds to thousands of changes in the DNA, RNA, and
proteins of carcinomas have provided the first glimpses of the overall biologic diversity
of invasive breast carcinomas[40] [41] [56] [57] ( Box 23-1 ). Not surprisingly, ER-positive and
negative carcinomas segregate into separate groups. Dozens to hundreds of genes may be
under transcriptional control by ER, and this is reflected by a set of common genes
showing increased transcription in these carcinomas. In fact, the expression of these
downstream genes in ER-positive tumors might ultimately be more predictive of tumor
behavior and response to estrogen blocking agents than is the presence of the receptor
itself. ER-positive carcinomas without this pattern have gene expression profiles that are
more like the profiles of ER-negative carcinomas. ER-positive carcinomas also show
increased transcription of so-called luminal type genes, thought to be characteristic of
normal luminal cells and possibly related to the overall better differentiation seen in these
carcinomas. The ER-negative tumors fall into two major groups. The basal-like
carcinomas have features suggestive of myoepithelial cell differentiation (e.g., basal
keratins, p-cadherin, and laminin expression). BRCA1 carcinomas cluster with this group.
A second ER-negative group is characterized by amplification of Her2/neu. Additional
subgroups have also been identified.
Some of the important components of these gene expression profiles are thought to be
derived from stromal cells intermingled with the cancer cells, again supporting the
importance of nonepithelial cells in the overall behavior of cancer.
CLASSIFICATION OF BREAST CARCINOMA
Almost all breast malignancies are adenocarcinomas, all other types (i.e., squamous cell
carcinomas, phyllodes tumors, sarcomas, and lymphomas) making up fewer than 5% of
the total.
Carcinomas are divided into in situ carcinomas and invasive carcinomas. Carcinoma in
situ refers to a neoplastic population of cells limited to ducts and lobules by the basement
1139
membrane. In some cases, the cells can extend to the overlying skin without crossing the
basement membrane and appear clinically as Paget disease. However, carcinoma in situ
does not invade into lymphatics and blood vessels and cannot metastasize. Invasive
carcinoma (synonymous with "infiltrating" carcinoma) has invaded beyond the basement
membrane into stroma. Here, the cells might also invade into the vasculature and thereby
reach regional lymph nodes and distant sites. Even the smallest invasive breast
carcinomas have some capacity to metastasize.
Carcinoma in situ was originally classified as ductal or lobular on the basis of the
resemblance of the involved spaces to ducts and lobules. Invasive ductal and lobular
carcinomas were named by their association with the characteristic in situ component.
Although these descriptive terms are still used, all carcinomas are thought to arise from
the terminal duct lobular unit, and the terms "ductal" and "lobular" do not imply a site or
cell type of origin.[58]
Carcinoma in Situ
Ductal Carcinoma in Situ (DCIS; Intraductal Carcinoma)
The number of cases of DCIS has rapidly increased in the past two decades from fewer
than 5% of all carcinomas before mammographic screening to 15% to 30% of carcinomas
in well-screened populations ( Fig. 23-13 ). Among mammographically detected cancers,
almost half are DCIS. DCIS most
Figure 23-16 A, This mammogram reveals multiple clusters of small, irregular calcifications in a segmental
distribution. Suspicious calcifications must be biopsied, as 20% to 30% will prove to be due to DCIS. B,
Comedo DCIS fills several adjacent ducts (or completely replaced lobules) and is characterized by large
central zones of necrosis with calcified debris. This type of DCIS is most frequently detected as radiologic
calcifications. Less commonly, the surrounding desmoplastic response results in an ill-defined palpable
mass or a mammographic density.
frequently presents as mammographic calcifications ( Fig. 23-16A ). Less typically, DCIS
presents as a mammographic density or a vaguely palpable mass or nipple discharge or is
incidental in a biopsy for another lesion.
DCIS consists of a malignant population of cells limited to ducts and lobules by the
basement membrane. The myoepithelial cells are preserved, although they may be
diminished in number. DCIS is a clonal proliferation and usually involves only a single
ductal system. However, the cells can spread throughout ducts and lobules and produce
extensive lesions involving an entire sector of a breast. When DCIS involves lobules, the
acini are often distorted and unfolded and take on the appearance of small ducts.
Morphology.
Historically, DCIS has been divided into five architectural subtypes: comedocarcinoma,
solid, cribriform, papillary, and micropapillary. Some cases of DCIS will have a single
growth pattern, but the majority have a mixture of patterns.
Comedocarcinoma is characterized by solid sheets of pleomorphic cells with high-grade
nuclei and central necrosis ( Fig. 23-16B ). The necrotic cell membranes commonly
calcify and are detected on mammography as clusters or linear and branching
microcalcifications ( Fig. 23-16A ). Periductal concentric fibrosis and chronic
inflammation are common, and extensive lesions are sometimes palpable as an area of
vague nodularity.
1140
Noncomedo DCIS consists of a monomorphic population of cells with nuclear grades
ranging from low to high. In cribriform DCIS, intraepithelial spaces are evenly
distributed and regular in shape (cookie cutter-like) ( Fig. 23-17A ). Solid DCIS
completely fills the involved spaces ( Fig. 23-17B ). Papillary DCIS grows into spaces
and lines fibrovascular cores typically lacking the normal myoepithelial cell layer ( Fig.
23-18A ). Micropapillary DCIS is recognized by bulbous protrusions without a
fibrovascular core, often forming complex intraductal patterns ( Fig. 23-18B ).
Calcifications may be associated with central necrosis but more commonly form in
intraluminal secretions ( Fig. 23-17A ).
Paget disease of the nipple is a rare manifestation of breast cancer (1% to 2% of cases)
and presents as a unilateral erythematous eruption with a scale crust. Pruritus is common,
and the lesion might be mistaken for eczema. Malignant cells, referred to as Paget cells,
extend from DCIS within the ductal system into nipple skin without crossing the
basement membrane ( Fig. 23-19 ). The tumor cells disrupt the normal epithelial barrier,
and this allows extracellular fluid to seep out onto the nipple surface. The Paget cells are
easily detected by nipple biopsy or cytologic preparations of the exudate.
A palpable mass is present in 50% to 60% of women with Paget disease, and almost all of
these women will have an underlying invasive carcinoma. In contrast, fewer than half of
women without a palpable mass will have invasive carcinoma. The carcinomas are
usually poorly differentiated and overexpress HER2/neu. The production by keratinocytes
of heregulin-α, which acts via the HER2/neu receptor, may play a role in the
pathogenesis of this disease.[59]
Prognosis depends on the extent of the underlying carcinoma and is not affected by the
presence or absence of DCIS involving the skin when matched for age, tumor size, grade,
HER2/neu status, and nodal status.[60]
Figure 23-17 Noncomedo DCIS. A, Cribriform DCIS comprises cells forming round, regular ("cookie
cutter") spaces. The lumens are often filled with calcifying secretory material. B, This solid DCIS has
almost completely filled and distorted this lobule with only a few remaining luminal cells visible. This type
of DCIS is not usually associated with calcifications and may be clinically occult.
DCIS with microinvasion is defined by foci of tumor cells less than 0.1 cm in diameter
invading the stroma. Microinvasion is most commonly seen in association with
comedocarcinoma.
The majority of cases of DCIS cannot be detected by either palpation or visual inspection
of the involved tissue. Occasional cases of comedocarcinoma are associated with
sufficient periductal fibrosis to produce a thickening of the tissue, and punctate areas of
necrosis ("comedone"-like) can be seen grossly.
The natural history of DCIS has been difficult to determine because in the past, all
women were treated with mastectomy, and the current practice of surgical excision
usually followed by radiation is largely curative. The consensus seems to be that many
cases of small, low-grade DCIS, and probably most cases of high-grade and extensive
DCIS, progress to invasive carcinoma,[61] emphasizing the importance of proper diagnosis
and appropriate therapy for this condition.
Mastectomy for DCIS is curative in over 95% of cases. Rare recurrence and/or death are
usually due to residual DCIS in ducts in subcutaneous adipose tissue that was not
removed during surgery, or occult foci of invasion that were not detected at the time of
diagnosis.
Breast conservation is appropriate for most women with DCIS but results in a slightly
higher risk of recurrence and therefore death from breast cancer. The major risk factors
for recurrence are (1) grade, (2) size, and (3) margins.
Details of algorithms based on these features are beyond our scope. Suffice it to say that
these three risk factors were combined to create a prognostic index that can be used to
divide women with DCIS treated with breast conservation into three groups.[62] DCIS with
the lowest scores rarely recurred, and radiation therapy did not appear to have an
additional effect. DCIS with the highest scores recurred in over half of women despite
radiation. In the intermediate group, about 20% of women had a recurrence, but radiation
1141
Figure 23-18 Noncomedo DCIS. A, Papillary DCIS. Delicate fibrovascular cores extend into a duct and are
lined by a monomorphic population of tall columnar cells. Myoepithelial cells are absent. B, Micropapillary
DCIS. The papillae are connected to the duct wall by a narrow base and often have bulbous or complex
outgrowths. The papillae are solid and do not have fibrovascular cores.
appeared to reduce the risk. Although this index requires validation in prospective
studies, it does suggest that pathologic features can be used to select women who can be
safely treated with breast conservation. Tamoxifen also reduces the risk of local and
distant recurrence, but the benefit is probably restricted to women with ER-positive
DCIS.[63] Deaths from breast cancer in women with treated DCIS are very rare (<2% of
women with DCIS), even when the breast is preserved.
Figure 23-19 Paget disease of the nipple. DCIS arising within the ductal system of the breast can extend up
the lactiferous ducts into nipple skin without crossing the basement membrane. The malignant cells disrupt
the normally tight squamous epithelial cell barrier, allowing extracellular fluid to seep out and form an
oozing scaly crust over the nipple skin.
Lobular Carcinoma in Situ (LCIS)
LCIS is always an incidental finding in a biopsy performed for another reason, as LCIS is
not associated with calcifications or a stromal reaction that would form a density.
Therefore, it remains infrequent (1% to 6% of all carcinomas) with or without
mammographic screening ( Table 23-1 ). LCIS is bilateral in 20% to 40% of women
when both breasts are biopsied,
1142
compared to 10% to 20% of cases of DCIS. LCIS is more common in young women,
80% to 90% of cases occurring prior to menopause.
Because LCIS is frequently multicentric and bilateral and subsequent carcinomas occur at
equal frequency in both breasts, it has been suggested that LCIS is not a true neoplasm
but rather is a marker of breast cancer risk. However, the cells of LCIS and invasive
lobular carcinoma are identical in appearance, and both lack expression of e-cadherin, the
transmembrane protein that is responsible for epithelial cell adhesion.[64] The loss of
expression correlates with the histologic appearance of lobular carcinomas as single
detached cells. LCIS can have the same genetic changes (such as LOH on 16q, the site of
the gene for e-cadherin) as an adjacent area of invasive carcinoma, supporting its role as a
true precursor of invasive carcinoma in some cases.[65]
Morphology.
The abnormal cells of atypical lobular hyperplasia (ALH), LCIS, and invasive lobular
carcinoma are identical and consist of small cells that have oval or round nuclei with
small nucleoli that do not adhere to one another ( Fig. 23-20 ). Signet-ring cells
containing mucin are present commonly. LCIS rarely distorts the underlying architecture,
and the involved acini remain recognizable as lobules. LCIS almost always expresses
estrogen and progesterone receptors, and overexpression of HER2/neu is not observed.
Women with LCIS develop invasive carcinomas at a frequency similar to that of women
with untreated DCIS. In patients observed for more than 20 years, invasive carcinoma
develops in 25% to 35%, or at about 1% per year. Older studies indicated that both
breasts were at equal risk, but a recent report suggests that the ipsilateral breast may be at
greater risk in women with lobular neoplasia.[17] Invasive carcinomas developing in
women after a diagnosis of LCIS are threefold more likely to be of lobular type compared
with carcinomas overall, but the majority do not show specific lobular morphology.
Treatment choices include bilateral prophylactic mastectomy,
Figure 23-20 Lobular carcinoma in situ. A monomorphic population of small, rounded, loosely cohesive
cells fills and expands the acini of a lobule. The underlying lobular architecture can still be recognized.
tamoxifen, or, more typically, close clinical follow-up and mammographic screening.
Invasive (Infiltrating) Carcinoma
In young women or in older women not undergoing mammographic screening, invasive
carcinoma almost always presents as a palpable mass. By the time a cancer becomes
palpable, over half the patients will have axillary lymph node metastases ( Table 23-1 ).
Larger carcinomas may be fixed to the chest wall or cause dimpling of the skin.
Lymphatics may become so involved as to block the local area of skin drainage and cause
lymphedema and thickening of the skin, a change referred to as peau d'orange. Tethering
of the skin to the breast by Cooper ligaments mimics the appearance of an orange peel.
When the tumor involves the central portion of the breast, retraction of the nipple may
develop.
In older women undergoing mammography, invasive carcinomas most commonly present
as a density ( Fig. 23-21A ) and are, on average, half the size of a palpable cancer ( Table
23-1 ). Fewer than 20% will have nodal metastases. Invasive carcinomas presenting as
mammographic calcifications without an associated density are very small in size, and
metastases are unusual ( Table 23-1 ).
The term "inflammatory carcinoma" refers to the clinical presentation of a carcinoma
extensively involving dermal lymphatics, resulting in an enlarged erythematous breast.
The underlying carcinoma usually has a diffuse infiltrative pattern and typically does not
form a discrete palpable mass. This can result in confusion with inflammatory conditions
and delay in diagnosis. The diagnosis is made on clinical grounds and does not correlate
with a specific histologic type of carcinoma.
Rarely, breast cancer presents as an axillary nodal metastasis or distant metastasis. In
most cases, the primary carcinoma is either small or obscured by dense breast tissue. The
number of primary carcinomas that remain occult in such cases is small with the use of
mammography, ultrasound, and MRI to examine the breast.
The most common histologic types of breast adenocarcinoma are listed in Table 23-4 .
These types are important to recognize owing to their specific clinical associations. Other
rare types of adenocarcinoma (e.g., apocrine carcinomas, carcinomas with
neuroendocrine differentiation, and clear cell carcinomas) are similar to carcinomas of no
special type in behavior and prognosis.
Invasive Carcinoma, No Special Type (NST; Invasive Ductal Carcinoma)
Invasive carcinomas of no special type include the majority of carcinomas (70% to 80%)
that cannot be classified as any other subtype.
Morphology.
On gross examination, most carcinomas are firm to hard and have an irregular border (
Fig. 23-21B ). Within the center of the carcinoma, there are small pinpoint foci or streaks
of chalky white elastotic stroma and occasionally small foci of calcification. There is a
characteristic grating sound (similar to cutting a water chestnut) when cut or scraped.
Less
1143
Figure 23-21 Invasive ductal carcinoma. A, This mammogram shows a density with an irregular border.
There is a small, superimposed, incidental calcification. (Courtesy of Dr. Jack Meyer, Brigham and
Women's Hospital, Boston, MA.) Over 90% of such masses will prove to be invasive carcinomas. Rarely,
complex sclerosing lesions, prior surgical scars, and fibromatosis may present in this fashion. B, An
irregular dense white mass is present within yellow adipose tissue. The pathologic gross differential
diagnosis is the same as the radiologic differential diagnosis.
frequently, carcinomas have a well-circumscribed border and may be soft to firm in
consistency.
These carcinomas display a wide spectrum of appearances. Well-differentiated tumors
consist of tubules lined by minimally atypical cells and can occasionally be difficult to
distinguish from benign sclerosing lesions ( Fig. 23-22A ). Such cancers
TABLE 23-4 -- Distribution of Histologic Types of Breast Cancer
Total Cancers Per Cent
In Situ Carcinoma * 15–30
Ductal carcinoma in situ 80
Lobular carcinoma in situ 20
Invasive Carcinoma 70–85
No special type carcinoma ("ductal") 79
Lobular carcinoma 10
Tubular/cribriform carcinoma 6
Mucinous (colloid) carcinoma 2
Medullary carcinoma 2
Papillary carcinoma 1
Metaplastic carcinoma <1
The data on invasive carcinomas are modified from Dixon JM, et al: Long-term
survivors after breast cancer. Br J Surg 72:445, 1985.
*The proportion of in situ carcinomas detected depends on the number of women undergoing
mammographic screening and ranges from less than 5% in unscreened populations to almost 50% in
patients with screen-detected cancers. Current observed numbers are between these two extremes.
typically express hormone receptors and do not overexpress HER2/neu. Others are
composed of anastomosing sheets of pleomorphic cells ( Fig. 23-22B ) and are less likely
to express hormone receptors and more likely to overexpress HER2/neu. The majority of
invasive ductal carcinomas lie between these two extremes. Most carcinomas induce a
marked increase in dense, fibrous desmoplastic stroma, giving the tumor a hard
consistency on palpation and replace fat, resulting in a mammographic density (scirrhous
carcinoma).
Carcinomas of NST are accompanied by varying amounts of DCIS. The grade of the
DCIS usually correlates with the grade of the invasive carcinoma. For example, comedo
DCIS is usually associated with poorly differentiated carcinomas, and low-grade DCIS is
usually associated with well-differentiated carcinomas. Carcinomas associated with a
large amount of DCIS require large excisions with wide margins to reduce local
recurrences.
Morphologic analysis of this large group of carcinomas has not identified tumor types of
significant clinical relevance beyond the specialized types to be described below. Recent
studies using microarrays to analyze the transcriptional profile of these cancers have
identified additional subgroups. ( Box 23-1 )[41] [56] [57] The challenge of future studies will
be to show the clinical relevance of subtypes identified by gene expression profiling (e.g.,
with respect to etiology, presentation, prognosis, or response to treatment) and, if found,
to determine whether these carcinomas can be recognized by more widely
1144
Figure 23-22 A, Well-differentiated invasive carcinoma of no special type. Well-formed tubules and nests
of cells with small monomorphic nuclei invade into the stroma with a surrounding desmoplastic response.
B, Poorly differentiated invasive carcinoma of no special type. Ragged sheets of pleomorphic cells without
tubule formation infiltrate into the adjacent stroma.
available means of evaluation (e.g., by refined morphologic criteria or immunoperoxidase
studies for protein expression).
Invasive Lobular Carcinoma
Invasive lobular carcinomas usually present like carcinomas of NST as a palpable mass
or mammographic density. However, about one-fourth of cases have a diffuse pattern of
invasion without prominent desmoplasia and might produce only a vaguely thickened
area of the breast or subtle architectural changes on mammography. Metastases can also
be difficult to detect clinically and radiologically owing to this type of invasion.
Lobular carcinomas have been reported to have a greater incidence of bilaterality.
However, many studies have been biased owing to the greater likelihood of performing
contralateral surgery in women with lobular carcinoma. The actual number of women
who develop subsequent clinically detected invasive carcinomas is only 5% to 10%,
similar to the number of women with NST carcinomas.
The incidence of lobular carcinomas has been reported to be increasing among
postmenopausal women.[66] It has been suggested that this increase may be related to the
use of postmenopausal hormone replacement therapy.[67]
Morphology.
Grossly, most tumors are firm to hard with an irregular margin. Occasionally, the tissue
may feel diffusely thickened and a discrete tumor mass cannot be defined. The histologic
hallmark of lobular carcinomas is the pattern of single infiltrating tumor cells, often only
one cell in width (in the form of a single file) or in loose clusters or sheets ( Fig. 23-23 ).
The desmoplastic response may be minimal or absent. The cells have the same cytologic
features as LCIS and lack cohesion, without formation of tubules or papillae. Signet-ring
cells are common. Tumor cells are frequently arranged in concentric rings surrounding
normal ducts. Several variants, including tumors with large nests of cells and a high
degree of pleomorphism, have been described.
Well-differentiated and moderately differentiated invasive lobular carcinomas are usually
diploid, express hormone receptors, and are associated with LCIS in the majority of
cases. HER2/neu overexpression is very rare. In contrast, poorly differentiated lobular
carcinomas are usually aneuploid, often lack hormone receptors, and may overexpress
Figure 23-23 Invasive lobular carcinoma. Parallel arrays of small, regular cells with scant cytoplasm
infiltrate singly in linear arrays or as small clusters of cells. There is often associated LCIS.
1145
HER2/neu. If matched by grade and stage, lobular carcinomas have the same prognosis as
carcinomas of NST.
Most lobular carcinomas show a loss of a region on chromosome 16 (16q22.1) that
includes a cluster of at least eight genes responsible for cell adhesion, including e-
cadherin and β-catenin.[68] The gene for e-cadherin on the opposite chromosome is
inactivated by mutations, methylation of the promoter, or decreased expression of
transcription factors. These changes are also found in LCIS.
Lobular carcinomas have a different pattern of metastasis compared to other breast
cancers. Metastases to the peritoneum and retroperitoneum, the leptomeninges
(carcinomatous meningitis), the gastrointestinal tract, and the ovaries and uterus are more
frequently observed. These carcinomas are less likely to metastasize to the lungs and
pleura.
Medullary Carcinoma
Medullary carcinoma presents as a well-circumscribed mass and may be mistaken
clinically and radiologically for a fibroadenoma (described later). There is sometimes a
history of rapid, almost explosive, growth.
Morphology.
These tumors do not have the striking desmoplasia of the usual carcinoma and therefore
are distinctly more yielding on external palpation and on cut section. The tumor has a
soft, fleshy consistency (medulla is Latin for "marrow") and is well circumscribed. The
carcinoma is characterized by (1) solid, syncytium-like sheets (occupying more than 75%
of the tumor) of large cells with vesicular, pleomorphic nuclei, containing prominent
nucleoli and frequent mitoses; (2) a moderate to marked lymphoplasmacytic infiltrate
surrounding and within the tumor; and (3) a pushing (noninfiltrative) border ( Fig. 23-24
). All medullary carcinomas are poorly differentiated. DCIS is minimal or absent.
Lymphatic or vascular invasion is never seen.
Figure 23-24 Medullary carcinoma. The cells are highly pleomorphic with frequent mitoses and grow as
sheets of cohesive cells. A lymphoplasmacytic infiltrate is prominent.
Medullary carcinomas have a slightly better prognosis than do carcinomas of no special
type, despite the almost universal presence of poor prognostic factors, including high
nuclear grade, aneuploidy, absence of hormone receptors, and high proliferative rates.
However, HER2/neu overexpression is not observed. Lymph node metastases are
infrequent and rarely involve multiple nodes. The syncytial growth pattern and pushing
borders may reflect retention or overexpression of adhesion molecules that could
potentially limit metastatic potential.
Among women carrying the BRCA1 gene, 13% of cancers are reported to be of this type (
Table 23-4 ). However, the majority of medullary carcinomas (or medullary-like
carcinomas) are not associated with germ-line BRCA1 mutations. Interestingly,
hypermethylation of the BRCA1 promoter is observed in 67% of medullary carcinomas,
suggesting an association of this morphology with underlying gene expression.
Mucinous (Colloid) Carcinoma
This unusual type (1% to 6% of all breast carcinomas) also commonly presents as a
circumscribed mass. It tends to occur in older women and may grow slowly during the
course of many years.
Morphology.
The tumor is extremely soft and has the consistency and appearance of pale gray-blue
gelatin. The tumor cells are seen as clusters and small islands of cells within large lakes
of mucin that push into the adjacent stroma ( Fig. 23-25 ).
Mucinous carcinomas are usually diploid, and the majority express hormone receptors.
The overall prognosis is slightly better than that of carcinomas of no special type.
The incidence of mucinous carcinomas is also slightly higher in women with BRCA1
mutations. Similar to the observations in medullary carcinoma, hypermethylation of
Figure 23-25 Mucinous (colloid) carcinoma. The tumor cells are present as small clusters within large
pools of mucin. The borders are typically well circumscribed, and these cancers often mimic benign
masses.
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the BRCA1 promoter has been observed in 55% of mucinous carcinomas not associated
with BRCA1 germ line mutations.
Tubular Carcinoma
Tubular carcinomas accounted for only 2% of all breast carcinomas before
mammographic screening but have increased in frequency and represent up to 10% of
carcinomas less than 1 cm in diameter. Tubular carcinomas are typically detected as
irregular mammographic densities. Women usually present in their late forties. Tumors
are multifocal within one breast in 10% to 56% of cases and bilateral in 9% to 38%.
Morphology.
These tumors consist exclusively of well-formed tubules and are sometimes mistaken for
benign sclerosing lesions ( Fig. 23-26 ). However, a myoepithelial cell layer is absent,
and tumor cells are in direct contact with stroma. Cribriform spaces may also be present.
Apocrine snouts are typical, and calcifications may be present within the lumens. LCIS is
frequently present, but this association has not been explained.
More than 95% of all tubular carcinomas are diploid and express hormone receptors. By
definition, all are well differentiated. Axillary metastases occur in fewer than 10% of
cases unless multiple foci of invasion are present. This subtype is important to recognize
because of its excellent prognosis.
Invasive Papillary Carcinoma
Invasive carcinomas with a papillary architecture are rare and represent 1% or fewer of
all invasive cancers. Papillary architecture is more commonly seen in DCIS. The clinical
presentation is similar to that of carcinomas of NST, but the overall prognosis is better.
Metaplastic Carcinoma
"Metaplastic carcinoma" includes a wide variety of rare types of breast cancer (<1% of
all cases), including conventional
Figure 23-26 Tubular carcinoma. The carcinoma must be completely composed of well-formed tubules
lined by a single layer of well-differentiated cells.
adenocarcinomas with a chondroid stroma, squamous cell carcinomas, and carcinomas
with a prominent spindle cell component that might be difficult to distinguish from
sarcomas. Some of these carcinomas express genes in common with myoepithelial cells
and likely arise from this cell type.[69] Given the heterogeneity of tumor types and their
rarity, little is firmly established with regard to clinical features and prognosis.
PROGNOSTIC AND PREDICTIVE FACTORS
The outcome for women with breast cancer varies widely. Some women have the same
life expectancy as women without breast cancer. Other women have only a 13% chance
of being alive in 5 years. Except for the few women (<10%) with distant metastases at
presentation or with inflammatory carcinoma, prognosis is determined by the pathologic
examination of the primary carcinoma and the axillary lymph nodes. This information is
important for counseling patients about the likely outcome of their disease, for choosing
appropriate treatment, and for accurately classifying groups of similar patients for clinical
trials (e.g., see http://www.nci.nih.gov/search/clinical_trials/ for information about
ongoing protocols for women with cancer at different stages).
Major prognostic factors are the strongest predictors of death from breast cancer and are
incorporated into the American Joint Committee on Cancer (AJCC) staging system.[70]
Predictive factors are used to determine the likelihood of response to a particular therapy.
The major prognostic factors are as follows:
1. Invasive carcinoma or in situ disease. By definition, in situ carcinoma is
confined to the ductal system and cannot metastasize. Breast cancer deaths
associated with DCIS are due to the subsequent development of invasive
carcinoma or areas of invasion undetected at the time of diagnosis. The great
majority of women with adequately treated DCIS will be cured. In contrast, at
least half of invasive carcinomas will have metastasized locally or distantly at the
time of diagnosis.
2. Distant metastases. Once distant metastases are present, cure is unlikely,
although long-term remissions and palliation can be achieved, especially for
women with hormonally responsive tumors. Favored sites for dissemination are
the lungs, bones, liver, adrenals, brain, and meninges. The potential for metastasis
can be reflected by gene expression patterns in the primary carcinoma.[71] The
pattern associated with axillary lymph node metastasis may be different from that
associated with distant metastasis. [72] The metastatic cells may be directed to
specific sites by the expression of chemokine receptors in the cancer cells and the
respective chemokines in target organs.[73]
3. Lymph node metastases. Axillary lymph node status is the most important
prognostic factor for invasive carcinoma in the absence of distant metastases. The
clinical assessment of nodal involvement is very inaccurate, with both false-
positive findings (e.g., palpable reactive nodes) and false-negative findings (e.g.,
lymph nodes with small metastatic deposits). Therefore, biopsy is necessary for
accurate assessment.
With no involvement, the 10-year disease-free survival rate is close to 70% to
80%; the rate falls to 35% to 40%
1147
with one to three positive nodes and 10% to 15% in the presence of more than 10
positive nodes.
Most breast carcinomas drain to one or two sentinel nodes that can be identified
by radiotracer, colored dye, or both. The sentinel node is highly predictive of the
status of the remaining nodes. Sentinel node biopsy can spare women the
increased morbidity of a complete axillary dissection. In some women,
particularly those with medial tumors, the sentinel node may be an internal
mammary node. These nodes are generally not biopsied owing to the morbidity
associated with the procedure.
Macrometastases (>0.2 cm) are of proven prognostic importance. Because
sentinel nodes often undergo more intense scrutiny with additional sections
through the tissue, and immunohistochemistry or reverse transcriptase-polymerase
chain reaction (RT-PCR) to detect rare tumor cells, increased numbers of women
with minute metastatic deposits in lymph nodes are being identified. The clinical
significance of small micrometastases is unclear and is being addressed by current
clinical trials.
4. Tumor size. The size of the carcinoma is the second most important prognostic
factor and is independent from lymph node status. However, the risk of axillary
lymph node metastases does increase with the size of the carcinoma. Women with
node-negative carcinomas under 1 cm in diameter have a prognosis approaching
that of women without breast cancer. The 10-year survival rate of such women
without treatment is approximately 90%. On the other hand, over half of women
with cancers over 2 cm in diameter present with lymph node metastases, and
many of these women will eventually succumb to breast cancer.
5. Locally advanced disease. Tumors invading into skin or skeletal muscle are
frequently associated with concurrent or subsequent distant disease. With
increased awareness of breast cancer detection, such cases have fortunately
decreased in frequency and are now rare at initial presentation.
6. Inflammatory carcinoma. Women presenting with the clinical appearance of
breast swelling and skin thickening have a particularly poor prognosis with a 3-
year survival rate of only 3% to 10%.
The major prognostic factors are used by the American Joint Committee on Cancer to
divide breast carcinomas into clinical stages as follows:[70]
• Stage 0. DCIS or LCIS (5-year survival rate: 92%).
• Stage I. Invasive carcinoma 2 cm or less in diameter (including carcinoma in
situ with microinvasion) without nodal involvement (or only metastases < 0.02
cm diameter) (5-year survival rate: 87%).
• Stage II. Invasive carcinoma 5 cm or less in diameter with up to three involved
axillary nodes or invasive carcinoma greater than 5 cm without nodal involvement
(5-year survival rate: 75%).
• Stage III. Invasive carcinoma 5 cm or less in diameter with four or more
involved axillary nodes; invasive carcinoma greater than 5 cm in diameter with
nodal involvement; invasive carcinoma with 10 or more involved axillary nodes;
invasive carcinoma with involvement of the ipsilateral internal mammary lymph
nodes; or invasive carcinoma with skin involvement (edema, ulceration, or
satellite skin nodules), chest wall fixation, or clinical inflammatory carcinoma (5-
year survival rate: 46%).
• Stage IV. Any breast cancer with distant metastases (5-year survival rate: 13%).
Minor Prognostic Factors.
Most women with nodal involvement and/or carcinomas over 1 cm in diameter will
benefit from some form of systemic therapy. In this group, minor prognostic factors can
be used to decide among chemotherapy regimens and/or hormonal therapies. For node-
negative women with small carcinomas, minor prognostic factors are used to identify the
women most likely to benefit from systemic therapy and those who might not need any
additional treatment.[74] Three of these factors—estrogen receptor, progesterone receptor,
and HER2/neu—are most useful as predictive factors for response to specific therapeutic
agents.
1. Histologic subtypes. The 30-year survival rate of women with special types of
invasive carcinomas (tubular, mucinous, medullary, lobular, and papillary) is
greater than 60%, compared with less than 20% for women with cancers of no
special type.[75]
2. Tumor grade. The most commonly used grading system to assess the degree of
tumor differentiation (Scarff Bloom Richardson) combines nuclear grade, tubule
formation, and mitotic rate. Eighty-five per cent of women with well-
differentiated grade I tumors, 60% of women with moderately differentiated grade
II tumors, and 15% of women with poorly differentiated grade III tumors survive
for 10 years.
3. Estrogen and progesterone receptors. Current assays use
immunohistochemistry to detect the receptors in the nucleus ( Fig. 23-27A ). Fifty
per cent to 85% of carcinomas express estrogen receptors, and such tumors are
more common in postmenopausal women. Women with hormone receptor-
positive cancers have a slightly better prognosis than do women with hormone
receptor-negative carcinomas. The evaluation of hormone receptors is most
valuable to predict response to therapy. Eighty per cent of tumors with estrogen
receptors and progesterone receptors respond to hormonal manipulation, whereas
only about 40% of those with only one type of receptor respond. Tumors with
neither estrogen nor progesterone receptors have a less than 10% likelihood of
responding.
4. HER2/neu. HER2 (human epidermal growth factor receptor 2 or c-erb B2 or neu)
is a transmembrane glycoprotein involved in cell growth control.[76] [77] It does not
appear to have a specific ligand but acts as a coreceptor for multiple growth
factors. HER2/neu is overexpressed in 20% to 30% of breast carcinomas. In over
90% of cases, overexpression is associated with amplification of the gene on
17q21, and this can be determined either by evaluating protein content using
immunohistochemistry or by determining gene copy number by using FISH (
Figs. 23-27B and C ). Although not all studies have come to the same conclusion,
many have shown that overexpression of HER2/neu is associated with a poor
prognosis. In addition, ongoing studies are addressing the possibility that
HER2/neu-over-expressing tumors respond differently to hormonal or
anthracycline chemotherapy regimens. However, evaluation of HER2/neu is most
important to determine response to therapy targeted to this protein.
1148
Trastuzumab (Herceptin) is a humanized monoclonal antibody to HER2/neu
developed to specifically target tumor cells and, it is hoped, spare normal cells. In
clinical trials, the combination of Trastuzumab with chemotherapy improved
response in patients with carcinomas overexpressing HER2/neu. Unfortunately,
cardiac toxicity, due to an unknown mechanism, could limit its usefulness.
However, as the first gene-targeted therapeutic agent for a solid tumor, the results
have been very promising.
5. Lymphovascular invasion (LVI). Tumor cells may be seen within vascular
spaces (either lymphatics or small capillaries) surrounding tumors. This finding is
strongly associated with the presence of lymph node metastases and is a poor
prognostic factor in women without lymph node metastases. The presence of
tumor cells in lymphatics of the dermis is strongly associated with the clinical
appearance of inflammatory cancer and bodes a very poor prognosis. LVI must be
strictly defined to have prognostic significance.
6. Proliferative rate. Proliferation can be measured by flow cytometry (as the S-
phase fraction), by thymidine labeling index, by mitotic counts, or by
immunohistochemical detection of cellular proteins (e.g., cyclins, Ki-67)
produced during the cell cycle. Cyclin E content, when both full-length and low-
molecular-weight isoforms are detected, is a very strong predictor of survival. [78]
Tumors with high proliferation rates have a worse prognosis, but the most reliable
method to assess proliferation has not yet been established. Mitotic counts are
included as part of the standard grading system.
7. DNA content. The amount of DNA per tumor cell can be determined by flow
cytometric analysis or by image analysis of tissue sections. Tumors with a DNA
index of 1 have the same total amount of DNA as normal diploid cells, although
marked karyotypic changes may be present. Aneuploid tumors are those with
abnormal DNA indices and have a slightly worse prognosis.
Figure 23-27 Predictive markers. A, Estrogen receptor is detected in the nucleus by immunohistochemical
studies. Progesterone receptor has the same appearance. B, HER2/neu overexpression is detected on the cell
membrane by immunohistochemistry. C, Amplification of the HER2/neu gene can be detected by FISH
analysis with a fluorescent probe for the gene. A normal cell has two copies of the gene. These tumor cells
have over 25 signals, indicating amplification of the gene for HER2/neu. (Courtesy of Dr. Jonathan
Fletcher, Brigham and Women's Hospital, Boston, MA.)
A new approach to prognosis, mentioned previously, is gene expression profiling. For
example, changes in 70 marker genes were used to classify tumors according to a good or
poor prognosis signature and were shown to be more predictive of outcome than the use
of traditional indicators.[79] Currently, this method requires the use of rapidly frozen tissue
and therefore cannot be used to evaluate most breast cancers. However, techniques for
gene expression profiling on paraffin-embedded tissues are being developed.
Despite the numerous prognostic indicators currently in use or under investigation, it is
impossible in an individual case to predict the outcome. Sadly, only time tells this story.
For this reason, there are continuing searches for better or more refined biologic markers
of prognosis and more effective treatment modalities.
A diagnosis of breast cancer is not a medical emergency. Most cancers have been present
for many years prior to detection, and survival time, even for advanced cancer, is usually
measured in years. Women can take the necessary time to make informed choices among
the many, often equivalent, treatment options.
Current therapeutic approaches include local and regional control, using combinations of
surgery (mastectomy or breast conservation) and postoperative radiation, and systemic
control, using hormonal treatment or chemotherapy or both. Axillary node dissection or
sentinel node sampling is performed for prognostic purposes, but the axilla can also be
treated with radiation alone. Newer therapeutic strategies include inhibition (by
pharmacologic agents or specific antibodies) of membrane-bound growth factor receptors
(e.g., HER2/neu), stromal proteases, and angiogenesis.
Such therapies are based on models of breast cancer dissemination that have evolved as
our understanding of its biology has changed. Earlier models proposed that breast cancer
spreads in a contiguous fashion by direct extension from breast to nodes and could
therefore be cured by en bloc
1149
surgical resection. However, radical surgery, including mastectomies with removal of
pectoralis muscles, internal mammary nodes, and even supraclavicular nodes, failed to
decrease mortality. A subsequent model, based on studies demonstrating that
lumpectomy (removal of the breast mass) and radiation were equivalent to mastectomy,
postulated that all cancers had spread systemically by the time of diagnosis and that local
or regional treatment was unimportant for overall survival. In the current era of increased
detection of early-stage carcinomas by mammography, a third model that combines the
first two is thought to be more appropriate to guide therapy.[80] Although some women
already have systemic involvement at first presentation and cannot be cured by local and
regional control, in situ and small invasive carcinomas, especially those detected by
mammography, are often limited to the breast, and local and regional treatment with
intent to cure must be the goal for such cancers.[81] For more advanced cancers that have
metastasized beyond the breast, newer therapies, such as Herceptin, and better hormonal
therapies hold out the hope of sustained remission and longer survival.
STROMAL TUMORS
The two types of stroma in the breast, intralobular and interlobular (see the section on the
normal breast), give rise to distinct types of neoplasms. The breast-specific biphasic
tumors fibroadenoma and phyllodes tumor arise in the interlobular stroma. This
specialized stroma may elaborate growth factors for epithelial cells, resulting in the
proliferation of the non-neoplastic epithelial component of these tumors. Interlobular
stroma is the source of the same types of tumors found
Figure 23-28 A, This mammogram shows a well-circumscribed mass. (Courtesy of Dr. Jack Meyer,
Brigham and Women's Hospital, Boston, MA.) Although the most common lesion would be a
fibroadenoma, other benign (e.g., fibrous lesions or PASH) and malignant (e.g., medullary or mucinous
carcinomas) lesions can also have this appearance. B, Fibroadenoma. A rubbery, white, well-circumscribed
mass is clearly demarcated from the surrounding yellow adipose tissue. The fibroadenoma does not contain
adipose tissue and therefore appears denser than the surrounding normal tissue on mammogram.
in connective tissue in other sites of the body (e.g., lipomas and angiosarcomas) as well
as tumors arising more commonly in the breast (e.g., pseudoangiomatous stromal
hyperplasia and fibrous tumors).
Fibroadenoma
This is the most common benign tumor of the female breast. Occurring at any age within
the reproductive period of life, fibroadenomas are somewhat more common before age
30. They are frequently multiple and bilateral. Young women usually present with a
palpable mass and older women with a mammographic density ( Fig. 23-28A ) or
mammographic calcifications. The epithelium of the fibroadenoma is hormonally
responsive, and a slight increase in size may occur during the late phase of each
menstrual cycle. An increase in size due to lactational changes or, not uncommonly,
infarction and inflammation may lead to a fibroadenoma mimicking carcinoma during
pregnancy. Regression usually occurs after menopause. The stroma often becomes
densely hyalinized and may calcify. Large lobulated ("popcorn") calcifications have a
characteristic mammographic appearance, but small calcifications may appear clustered
and require biopsy to exclude carcinoma.
Morphology.
Fibroadenomas grow as spherical nodules that are usually sharply circumscribed and
freely movable in the surrounding breast substance. They vary in size from less than 1 cm
in diameter to large tumors that can replace most of the breast. Grossly, the tumors are
well-circumscribed, rubbery,
1150
grayish white nodules that bulge above the surrounding tissue and often contain slitlike
spaces ( Fig. 23-28B ).
The stroma is usually delicate, cellular, and often myxoid, resembling intralobular
stroma, enclosing glandular and cystic spaces lined by epithelium. The epithelium may be
surrounded by stroma or compressed and distorted by it ( Fig. 23-29 ). In older women,
the stroma typically becomes densely hyalinized and the epithelium atrophic.
Some fibroadenomas are polyclonal in origin and are probably due to focal hyperplasia of
lobular stroma. For example, almost half of women receiving cyclosporin A after renal
transplantation develop fibroadenomas.[82] The tumors are frequently multiple and bilateral
and are likely to be due to drug-related growth stimulation. On the other hand, there is a
subset of fibroadenomas that are benign neoplasms of stromal cells. Multiple studies have
shown that in some tumors, the fibrous (stromal) component is clonal and may have
cytogenetic aberrations, but the epithelial component is polyclonal. No consistent
cytogenetic changes have been found.[83] [84]
Fibroadenomas were originally grouped with other "proliferative changes without atypia"
in conferring a mild increase in the risk of subsequent cancer. However, in one study,
only fibroadenomas associated with cysts larger than 0.3 cm, sclerosing adenosis,
epithelial calcifications, or papillary apocrine change ("complex fibroadenomas")
conferred a mild increase in the risk of subsequent breast cancer[85] ( Table 23-2 ). It is
hoped that future studies will better define the risk associated with these lesions.
Phyllodes Tumor
Phyllodes tumors, like fibroadenomas, arise from intralobular stroma. Although they can
occur at any age, most present in the sixth decade, 10 to 20 years later than the average
presentation of a fibroadenoma.[86] Most present as palpable masses, but a few are detected
mammographically. The term "cystosarcoma phyllodes" is sometimes used for these
lesions. However,
Figure 23-29 Fibroadenoma. The lesion consists of a proliferation of intralobular stroma surrounding and
often pushing and distorting the associated epithelium. The border is sharply delimited from the
surrounding tissue.
the term "phyllodes tumor" is preferred, as the majority of these tumors behave in a
relatively benign fashion, and most are not cystic.
Morphology.
The tumors vary in size from a few centimeters in diameter to massive lesions involving
the entire breast. The larger lesions often have bulbous protrusions (phyllodes is Greek
for "leaflike") due to the presence of nodules of proliferating stroma covered by
epithelium ( Fig. 23-30 ). In some tumors, these protrusions extend into a cystic space.
This growth pattern can also occasionally be seen in larger fibroadenomas and is not an
indication of malignancy. Phyllodes tumors are distinguished from the more common
fibroadenomas on the basis of cellularity, mitotic rate, nuclear pleomorphism, stromal
overgrowth, and infiltrative borders. Low-grade lesions resemble fibroadenomas but with
increased cellularity and mitotic figures. High-grade lesions may be difficult to
distinguish from other types of soft tissue sarcomas and may have foci of mesenchymal
differentiation (e.g., rhabdomyosarcoma or liposarcoma). These tumors not uncommonly
recur with a higher grade.
Phyllodes tumors must be excised with wide margins or by mastectomy to avoid the high
risk of local recurrences. Axillary lymph node dissection is not indicated because the
incidence of nodal metastases, as for other stromal malignancies, is exceedingly small.
The majority are low-grade tumors that may recur locally but only rarely metastasize.
Rare high-grade lesions behave aggressively, with frequent local recurrences and distant
hematogenous metastases in about one third of cases. [87] Only the stromal component
metastasizes.
Sarcomas
Tumors of the extrinsic connective tissue of the breast include the same types of benign
and malignant lesions that are seen elsewhere in the body. Malignant lesions include
Figure 23-30 Phyllodes tumor. Compared to a fibroadenoma, there is increased stromal cellularity,
cytologic atypia, and stromal overgrowth, giving rise to the typical leaflike architecture.
1151
angiosarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, chondrosarcoma, and
osteosarcoma. Sarcomatous differentiation also occurs in phyllodes tumors and in
carcinomas ("metaplastic carcinomas"). Sarcomas usually present as bulky palpable
masses. Lymph node metastases are rare; hematogenous spread to the lung is commonly
seen.
Angiosarcomas of the breast arise spontaneously or as a complication of radiation
therapy.[88] There is a 0.3% to 4% risk of angiosarcoma after radiation therapy for breast
cancer, most cases arising 5 to 10 years after treatment. Most of these tumors arise in the
skin of the breast. Angiosarcomas can also arise in the skin of a chronically edematous
arm after mastectomy (Stewart-Treves syndrome), but this complication has become
much less common with greater attention to surgical techniques and more limited axillary
dissections.
Other Stromal Lesions
Pseudoangiomatous stromal hyperplasia (PASH) and fibrous tumors commonly present
as circumscribed palpable masses or mammographic densities in premenopausal women
or older women on hormone replacement therapy. Histologically, they are benign
proliferations of interlobular stroma. Lipomas and hamartomas are often palpable but can
also be detected mammographically as fat-containing lesions. All are benign and require
diagnosis only to distinguish them from malignancies.
Fibromatosis is due to a clonal proliferation of fibroblasts and myofibroblasts. It presents
as an irregular mass that can involve both skin and muscle and closely mimics invasive
carcinoma. Wide excision is mandatory, as recurrences are common and may be difficult
to control. Although locally aggressive, this lesion does not metastasize. Most cases are
sporadic, but some occur as part of familial adenomatous polyposis (FAP), hereditary
desmoid syndrome, and Gardner syndrome. Mutations in the adenomatosis polyposis coli
(APC) gene are found in patients with FAP as well as in sporadic cases of breast
fibromatosis.[89]
OTHER MALIGNANT TUMORS OF THE BREAST
Malignant tumors may arise from the skin of the breast, sweat glands, sebaceous glands,
and hair shafts; these tumors are identical to their counterparts found in other sites of the
body. Lymphomas may arise primarily in the breast, or the breasts may be secondarily
involved by a systemic lymphoma. Most are of large cell type of B-cell origin. Young
women with Burkitt lymphoma may present with massive bilateral breast involvement
and are often pregnant or lactating. Metastases to the breast are rare and most commonly
arise from a contralateral breast carcinoma. The most frequent nonmammary metastases
are from melanomas and lung cancers.
The Male Breast
Pathology
The normal male breast consists of the nipple and a rudimentary duct system ending in
terminal buds without lobule formation. Only two processes occur with sufficient
frequency to merit consideration.
Gynecomastia
Gynecomastia (enlargement of the male breast) may be unilateral or bilateral and presents
as a button-like subareolar enlargement. In advanced cases, the swelling can simulate the
adolescent female breast. The lesion must be differentiated only from the rare carcinoma
of the male breast. Gynecomastia is chiefly of importance as an indicator of
hyperestrinism, suggesting cirrhosis of the liver or the possible existence of a functioning
testicular tumor.
Morphology.
There is proliferation of a dense collagenous connective tissue, but more striking are the
changes in the epithelium of the ducts. Marked micropapillary hyperplasia of the ductal
linings occurs ( Fig. 23-31 ). The individual cells are fairly regular, columnar to cuboidal
cells with regular nuclei. Lobule formation is rare.
Like the female breast, the male breast is subject to hormonal influences, and
gynecomastia may occur as a result of an imbalance between estrogens, which stimulate
breast tissue, and androgens, which counteract these effects. It is encountered under a
variety of normal and abnormal circumstances. It may be found at the time of puberty, in
the very aged, or at any time during adult life when there is cause for hyperestrinism. The
most important of these is cirrhosis of the liver, since the liver is responsible for
metabolizing estrogen. In older males, gynecomastia may occur owing to a relative
increase in adrenal estrogens as the androgenic function
1152
Figure 23-31 Gynecomastia. Terminal ducts (without lobule formation) are lined by a multilayered
epithelium with small papillary tufts. There is typically surrounding periductal hyalinization and fibrosis.
of the testis fails. Drugs such as alcohol, marijuana, heroin, antiretroviral therapy,
anabolic steroids used by some athletes and body builders, and some psychoactive agents
have also been associated with gynecomastia.[90] Rarely, gynecomastia may occur as part
of Klinefelter syndrome (XXY karyotype) or in association with functioning testicular
neoplasms, such as Leydig cell and, rarely, Sertoli cell tumors.
Carcinoma
Carcinoma arising in the male breast is a rare occurrence, with a frequency ratio to breast
cancer in the female of less than 1:100 or a lifetime risk of 0.11% compared to about 13%
in women.[91] There are about 1500 cases and 400 deaths each year. Risk factors are
similar to those in women and include first-degree relatives with breast cancer, decreased
testicular function (e.g., Klinefelter syndrome), exposure to exogenous estrogens,
increasing age, infertility, obesity, prior benign breast disease, exposure to ionizing
radiation, and residency in Western countries. Gynecomastia does not appear to be a risk
factor. Four per cent to 14% of cases in males are attributed to germ line BRCA2
mutations. A breast cancer family with at least one affected male has a 60% to 76%
chance of having a BRCA2 mutation. Male breast cancer is less commonly observed in
BRCA1 families. Three per cent to 8% of cases are associated with Klinefelter syndrome.
The pathology of male breast cancer is remarkably similar to that of cancers seen in
women. The same histologic subtypes of invasive cancer are present, although papillary
carcinomas (both invasive and in situ) are more common and lobular carcinomas are less
common. The expression of molecular markers is similar with the one exception that ER
positivity is more common in male breast cancer (81% of tumors). Unlike in women, the
incidence of ER-positive tumors does not increase with age. Prognostic factors are
similar in men and women.
Because breast epithelium in men is limited to large ducts near the nipple, carcinomas
usually present as a palpable subareolar mass, 2 to 3 cm in diameter. Nipple discharge is
a common symptom. The carcinoma is situated close to the overlying skin and underlying
thoracic wall, and even small carcinomas can invade these structures. Ulceration through
the skin is more common than in women. Dissemination follows the same pattern as in
women, and axillary lymph node involvement is present in about half of cases at the time
of discovery of the lesion. Distant metastases to the lungs, brain, bone, and liver are
common. Although men present at higher stages, prognosis is similar in men and women
when they are matched by stage. Most cancers are treated locally with mastectomy and
axillary node dissection. The same systemic treatment guidelines are used for men and
women, and response rates are similar.
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