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Author
Jose Russo, MD
Section Editor
Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
Deputy Editor
Don S Dizon, MD, FACP
Disclosures: Jose Russo, MD Nothing to disclose. Anees B Chagpar, MD, MSc, MA,
MPH, MBA, FACS, FRCS(C) Nothing to disclose. Don S Dizon, MD, FACP Employee
of UpToDate, Inc.
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All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Sep 2014. | This topic last updated:
Jun 30, 2014.
NEWER VERSION OF TOPIC MESSAGE
INTRODUCTION The breast undergoes dramatic changes in size, shape, and
function in association with puberty, pregnancy, lactation, and menopause. It is
also the origin of the most common malignancy in women [1]. The risk of
developing breast cancer has been linked to both endogenous (eg,
nulliparity, early menarche, older age at first pregnancy) and exogenous
hormonal influences [2-5]. (See "Factors that modify breast cancer risk in
women" and "Menopausal hormone therapy: Benefits and risks".)
The molecular mechanisms underlying the development of breast cancer,
particularly estrogen-associated breast carcinogenesis, are incompletely
understood. Increasing evidence points to developmental differences in the
breast that may influence the risk of developing cancer. Thus, an
understanding of breast development and morphology, and the
biochemical factors that influence them, is pertinent to the study of both
premalignant and malignant conditions affecting the breast.
ANATOMY The mature adult breast lies between the second and sixth ribs
in the vertical axis, and between the sternal edge and the midaxillary line in
the horizontal axis. Breast tissue also projects into the axilla as the axillary
tail of Spence. The breast comprises three major structures: skin,
subcutaneous tissue, and breast tissue, which is composed of both
epithelial and stromal elements. The epithelial components are branching
ducts which connect the structural and functional units of the breast (the
lobules) to the nipple (picture 1). The stroma, which comprises the majority
of the breast volume in the non-lactating state, is composed of adipose
Lower outer quadrant (n = 88) 97.7 percent
Lesions in the inner quadrants of the breast were significantly more likely
to drain to IM lymph nodes compared with lesions in the outer quadrants
(37.4 versus 14.4 percent) [8]. Drainage to the IM lymph nodes based
upon location of the lesion includes:
process that is initiated during embryonic life (picture 3). Although puberty
marks the beginning of glandular maturation, full breast differentiation is
attained only with subsequent pregnancy and lactation.
At birth, the breast rudiment is formed by 10 to 12 primitive ductal
elements located beneath the nipple-areola complex. In the prepubertal
years, these ducts exhibit relatively slow but steady growth and branching,
with canalization into ductal structures. In boys, breast development
ceases at this stage.
Pubertal changes In girls, puberty usually begins around age 10 to 12 under
the influence of hypothalamic gonadotropin-releasing hormone. (See "Physiology
of gonadotropin-releasing hormone".) The cells of the anterior pituitary
gland release follicle-stimulating hormone (FSH) and luteinizing hormone
(LH), which promote maturation of the ovarian follicles, and their secretion
of estrogens, primarily in the form of 17-beta estradiol. (See "Molecular
biology and physiology of estrogen action".)
Breast development from puberty to adulthood is defined by several
parameters, including external appearance, volume, number of structures
present in the mammary gland, and the degree of branching or
differentiation of the individual structures (picture 2 and figure 2) [3]. The
external appearance of the breast from childhood to maturity has been
divided into five phases by Tanner (picture 4). (See "Normal puberty".)
Lobule formation From a microanatomic standpoint, puberty is marked by
increased growth and branching of the ducts to form club-shaped terminal end
buds; this is accompanied by an increase in the stromal component [3].
Growing terminal end buds form new branches, twigs, and small ductules
(termed alveolar buds). We use the term alveolar bud to identify those
structures that are morphologically more developed than the terminal end
bud, but more primitive than the terminal structure of the mature resting
breast, the acinus. With further branching, alveolar buds become smaller
and more numerous, and then they are called ductules.
Type 1 lobules When an average of 11 alveolar buds/ductules cluster around
a terminal duct, they form the type 1 (virginal) lobule (picture 5).
Lobule formation is apparent within one to two years after the onset of the
menses. Thereafter, glandular development is variable. Full differentiation
of the mammary gland to its maximal degree of branching and secretory
activity is a gradual process that takes many years (picture 6); it may never
be attained if pregnancy does not supervene.
Type 2 and 3 lobules The breast tissue of adult women contains two other
identifiable types of lobules in addition to the type 1 lobule. The changing levels
of estrogen and progesterone during menstrual cycles stimulate the type 1 lobule
to sprout new alveolar buds and gradually evolve to more mature
structures called type 2 and type 3 lobules (picture 7 and picture 8). The
number of alveolar buds per lobule increases from approximately 11 in the
proliferation of the distal elements of the ductal tree marks the progression
from type 3 lobule to a type 4 lobule (picture 10). In these newly formed
lobules, the epithelial cells composing each acinus not only increase
greatly in number due to active cell division but they also increase in size
mainly because of cytoplasmic enlargement [3].
In mid-pregnancy, the lobules further enlarge and increase in number.
They surround the duct from which their central branch proceeds so thickly
that the chief duct, the terminal or intralobular terminal duct, can no longer
be recognized. The transition between the terminal ducts and the budding
acini is gradual, making the histological distinction between the two of
them difficult; both show evidence of early secretory activity.
Later pregnancy Mammary changes during the second half of pregnancy are
chiefly a continuation and accentuation of secretory activity. Further progressive
branching continues with less prominent bud formation. The formation of fully
differentiated secretory units or acini becomes increasingly evident.
Proliferation of new acini is reduced, and the lumen of already formed units
becomes distended by the accumulation of secretory material or
colostrum.
Just before and during parturition, there is a new wave of mitotic activity
within the mammary gland. At this time, and during lactation, the process
of further growth and differentiation may be observed in the same lobule
type, side by side with the process of milk secretion [3]. At this point, the
glandular component of the breast has increased to the point where the
breast is composed primarily of epithelial elements, with very little stroma.
These changes persist throughout lactation.
Lobular involution (regression)
Postlactation The postlactational breast requires a combination of lactogenic
hormone deprivation and local signals to undergo glandular involution (regression
or atrophy), a process characterized by apoptotic cell death and tissue
remodeling. The factors that trigger apoptosis have not been clearly
defined. Certain gene products are upregulated during mammary
involution, as are local extracellular proteases that are involved in tissue
remodeling [11,12].
Menopause Menopause supervenes as a consequence of ovarian follicular
atresia, resulting in an ovary completely devoid of follicles. This is characterized
clinically by the absence of ovarian estradiol and progesterone secretion,
resulting in amenorrhea. (See "Ovarian development and failure
(menopause) in normal women".)
After menopause, the breast undergoes regression, with atrophy of the
glandular elements, and a marked decrease in the number of lobules
(picture 11). This process differs greatly from postlactational involution
(regression or atrophy). In some areas, the lobules disappear completely,
and only the ducts remain. Concurrently, the fibrous connective tissue
fold in the type 2 lobules, and 10-fold in the type 3 lobules (table 2) [30,34].
The content of ER-alpha and PR in the lobular structures of the breast is
directly proportional to the rate of cellular proliferation [34]. Type 1 lobules
consistently contain a higher percentage of ER and PR-positive cells than
do type 2 or 3 lobules, indicating a progressive decease in the number of
receptor-positive cells as the structures become more differentiated (table
2).
These biologic differences may have profound implications for cancer risk.
The fact that the highest proliferative capacity and the highest percentage
of ER-alpha- and PR-positive cells are present in type 1 lobules provides a
mechanistic explanation for the greater susceptibility of these structures to
be transformed by chemical carcinogens in vitro and in experimental
animals [2,35-41], and supports the observation that type 1 lobules are the
site of origin of ductal carcinomas (see 'Cancer risk' below). The
proliferating cells differ from those that are receptor-positive, suggesting
that the proliferative influence of estrogen on the breast epithelium is
indirect [34].
PARITY, LOBULAR DIFFERENTIATION AND BREAST CANCER
RISK By the end of the fifth decade, the breast of both nulliparous and parous
women is composed predominantly of type 1 lobules [10]. However, despite
their architectural similarity, there are important differences between the
type 1 lobules of the nulliparous woman, and the regressed type 1 lobules
of the parous woman. Type 1 lobules of nulliparous women have a very
active intralobular stroma, whereas those of the parous woman are more
hyalinized, and indicative of a regressed structure (picture 11). Another
important difference is the higher proliferative activity in the type 1 lobules
of nulliparous as compared to parous women. The cells of both type 1 and
type 3 lobules in the parous breast are predominantly in the G0 phase or
resting phase, while in type 1 lobules of the nulliparous breast, proliferating
cells predominate, and the fraction of cells in G0 is quite low. Thus, parity,
in addition to exerting an important influence on the lobular composition of
the breast, profoundly influences its proliferative activity.
These biologic differences may provide some explanation for the increased
susceptibility of the breast of nulliparous women to develop breast cancer.
It is hypothesized that unlike parous women, the type 1 lobule found in the
breast of nulliparous women never went through the process of
differentiation, seldom reaching the type 3 lobule, and never the type 4
stages [10]. Although the lobules of parous women regress at menopause
to type 1, they are permanently genetically imprinted by the differentiation
process in some way that protects them from neoplastic transformation,
even though these changes are no longer morphologically observable.
Thus, they are biologically different from the type 1 lobule of nulliparous
women.
There was an interaction with family history as well; women with a weak or
no family history of breast cancer who had complete involution had a risk
for breast cancer that was five-fold lower than the risk of those with a
strong family history and no involution (RR 0.59 versus 2.77, respectively).
Among nulliparous women, and those whose age at first birth was over the
age of 30, the absence of involution significantly increased the risk of
breast cancer (RR 2.41 versus 2.74, respectively). In contrast; for both
groups, there was no excess risk if involution was complete.
Subsequent studies confirm that the degree of lobular involution is
inversely associated with breast cancer risk [48,49]. A nested case-control
study of lobule involution used the number of acini per lobule as a
reflection of the degree of involution and compared acinar counts in
women who did or did not go on to develop breast cancer [48]. Women
with no involution had a higher mean acinar count (32 acini/lobule) than
women with partial (19.7 acini/lobule) or complete involution (7.7
acini/lobule). There was a step-wise increase in breast cancer risk with
increasing numbers of acini and decreasing degree of involution per
lobule. Another study assessed lobule type rather than the degree of
involution but arrived at a similar conclusion; women with more type 1
lobules, with more complete involution, have a lower breast cancer risk
[48].
Taken together, these data suggest that breast cancer risk is decreased in
women with more type 1 lobules and more complete involution
(regression) of lobular structures. This reflects parity and terminal
differentiation of lobules and helps to explain why pregnancy and lactation
seem to decrease the risk of breast cancer [45]. This data also raises
concerns that reactivation of type 1 lobules, as has been described in
women receiving postmenopausal hormone therapy who develop dense
breasts, may increase the risk of developing breast cancer [50].
ARCHITECTURAL PATTERNS AND BREAST PATHOLOGY The fact
that the mature breast exhibits variations in development, proliferative activity,
and hormone receptor content raises the question of whether benign,
premalignant, and/or malignant breast lesions develop as a reflection of
these variations. A clinical overview of benign, high-risk, and malignant
breast lesions are reviewed elsewhere. (See "Overview of benign breast
disease" and "Breast cysts: Clinical manifestations, diagnosis, and
management" and "Atypia and lobular carcinoma in situ: High risk lesions
In DH, type 1 lobules are the most frequent structures present, and they
have the highest proliferative rate, supporting the postulate that this lesion
arises from type 1 lobules. In contrast, type 2 and 3 lobules are more
prominently represented, and have a higher proliferative rate in more
differentiated lesions, such as BDA and SAD.
Cancer risk Several lines of evidence support the type 1 lobule as being
the equivalent of the terminal ductal lobular unit [52,53], and the site of
origin of ductal carcinomas (picture 13 and picture 14 and picture 15 and
picture 16):
Although the breast tissue from parous women in the general population
contains predominantly type 3 lobule, and a very low percentage of type 1
lobules, the nontumoral breast tissue of parous women who have
developed breast cancer (all of whom had a late first pregnancy or a family
history of breast cancer in our studies) consist of predominantly type 1
lobules [46,54].
Particularly in view of the fact that the terminal ductal lobular units are
thought to represent the site of origin of mammary carcinomas, partial or
incomplete menopausal breast involution (or reactivation of type 1 lobules
under the influence of postmenopausal hormone therapy) may also
interact with other risk factors such as parity, age at first birth, the
presence of benign breast disease, and family history to influence the risk
of breast cancer [45,47]. (See 'Parity, lobular differentiation and breast
cancer risk' above.)
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SUMMARY
The principal blood supply of the breast is derived from the internal
mammary artery. Approximately one-third of the blood supply (mainly to
the upper outer quadrant) is provided by the lateral thoracic arteries. (See
'Anatomy' above.)
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All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Sep 2014. | This topic last updated:
Mar 06, 2013.
NEWER VERSION OF TOPIC MESSAGE
INTRODUCTION Benign breast disease represents a spectrum of disorders
that come to clinical attention as imaging abnormalities or as palpable
lesions found on physical examination. Following establishment of a
benign diagnosis, treatment in general is aimed at symptomatic relief and
patient education.
Some benign breast diseases, such as atypical hyperplasia, confer an
increase in the patient's future risk of developing breast cancer, and should
lead to counseling about screening recommendations and risk reduction
ductal carcinoma in situ (DCIS) [5]. (See "Breast ductal carcinoma in situ:
Epidemiology, clinical manifestations, and diagnosis".)