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Histology of the Breast

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Title: Histology of the Breast


1
Histology of the Breast Rebecca Cook Ph.D. Cancer
Biology Department April 21, 2003
2
Embryonic development
Compared to other stages of breast development,
fetal development of breast tissue is relatively
independent of sex steroid hormones Week
4--Mammary ridges appear as thickened lines of
epidermis that extend from the axilla to the
medial thigh. Weeks 5-7--Proliferation of the
mammary ridge ectoderm results in primary bud
formation which grows down into the dermis. Weeks
10-12--The primary bud branches to form secondary
buds. 3 mo.-birth--The buds lengthen and branch.
During the last 3 months of gestation the buds
canalize to form the lactiferous ducts.
3
  • Breast development during puberty
  • Female breast development is reinitiated to
    produce the stuctures that will allow for
    lactation later in life (regulated by steroid and
    peptide hormones and growth factors).
  • The male breast remains a rudimentary system of
    simple ducts within a small amount of
    fibrocollagenous tissue.
  • The growth regulatory and differentiation
    mechanisms involved in development, maintenance,
    and function of the mammary glands beginning at
    puberty include systemic, local, cell surface and
    intracellular controls.

4
Hormonal regulation and characteristics of breast
development at puberty The onset of cyclic
production of estrogen and progesterone at
puberty leads to the characteristic anatomical
and histological changes of mature
breasts. Anatomical changes include 1. Breast
enlargement due to an increase in adipose tissue
(estrogen-dependent) and breast parenchyma. 2.
Full pigmentation of the areola and nipple
(dependent on estrogen, progesterone, and
pituitary peptide hormones).
5
Enlarging Pubescent Breast
Ducts
Adipose tissue
Dense CT septa
6
Branching ductal tree of prepubescent breast
Convergence of major ducts
Early formation of terminal ductal lobular units
(TDLU)
Whole mount preparation
7
  • Histological changes occurring in the breast at
    puberty
  • Estrogen, progesterone, growth hormone and
    prolactin are the major hormones involved in
    breast development during puberty. Histological
    changes occurring in response to these hormones
    include
  • Ductal elongation and thickening of the ductal
    epithelium (Progesterone is not required for
    ductal growth during puberty)
  • Increased connective tissue density surrounding
    the ducts
  • Formation of Terminal ductal lobular units
    (TDLU, functional units of the breast) which is
    dependent on both estrogen and progesterone.
  • TDLU are also referred to as lobulo-alveoli,
    acini, and lobules.

8
Young adult breast
9
Multiple lobular units radiate from a single duct
10
Appearance of ducts and alveoli in the immature
breast
Ducts and alveoli consist of 2 cell layers 1.
Basally localized myoepithelial cells that are
flattened and have pale cytoplasm 2. Luminal
cuboidal epithelial cells In comparison to
alveolar epithelial cells, ductal epithelial
cells contain few mitochondria and sparse ER
Changes occurring in the ducts and alveoli
during the menstrual cycle 1. Early in the cycle
lumens of the ducts arent clearly evident 2.
Later in the cycle ductal lumens become apparent
and may contain eosinophilic secretion.
11
Early pubescent breast
TDLU
Adipose tissue
Duct
Dense CT
12
Characteristics of mature breasts
  • Breast size ranges from 500g. Size
    varies with body weight since breast is a major
    repository of adipose tissue.
  • 15-25 lobes, each empties into terminal duct at
    nipple
  • Dense CT septa divide lobes
  • Each lobe is divided into many TDLU

13
Nipple
  • Ectodermally derived
  • 15-25 milk ducts enter the base of the nipple
    where they dilate to form the milk sinuses
  • Milk sinuses terminate into cone shaped ampullae
    (milk repositories) below the nipple surface
  • Ampullae of non-lactating women are plugged with
    keratin to prevent infection of the breast
    through the nipple
  • Nipple erection and emptying of the milk sinuses
    is controlled by circular and longitudinal smooth
    muscle fibers, collagen and elastic CT
  • Areola contains sebaceous glands of Montgomery
    whose secretions are thought to protect the
    areola and nipple during suckling

14
Non-lactating nipple and areola
Keratin Plugs
15
Non-lactating nipple with keratin plug
16
Glands of Montgomery
17
Convergence of the major lactiferous ducts at the
nipple
18
Terminal duct lobular unit
19
Mature TDLU form after several menstrual cycles
20
Diagram of inactive mammary gland
21
Higher magnification of a lobule
BM surrounds each alveolus
Interlobular Dense CT
IntralobularLoose CT
22
Alveolar cell types in the mature breast
Alveolar epithelium is specialized into type A, B
and myoepithelial cells. Type A Luminally
located, columnar cells, basophilic because they
are rich in ribosomes. Synthesize and secrete
milk components. Type B Thought to be the
precursors of Type A and myoepithelial cells.
Basally located with clear cytoplasm and round
nuclei. Myoepithelial cells Basal cells with
dense nuclei that are in close contact with the
luminal secretory cells. Glycogen production
gives cells a clear cytoplasm when stained with
HE. Contain myofibrils that allow the cells to
contract to help in milk secretion.
23
Cell types found in alveoli
Columnar secretory cells
BM
24
IHC staining of actin demonstrates the presence
of myoepithelial cells
25
The appearance of secretory epithelial cells
varies with duct and lobule size
Smaller ducts/lobules
Larger ducts/lobules
26
EM of a single lobular unit
Lumen
27
Normal variations in the breast associated with
hormonal changes during the menstrual cycle
  • Cyclic progesterone and estrogen associated with
    a full ovulatory cycle drive development of TDLU
    and connective tissue growth into a womans 30s.
    In the absence of pregnancy, apoptosis of the
    expanded epithelium within the TDLU occurs.
  • Differentiation effects of progesterone
  • Myoepithelial cells accumulate glycogen
  • Epithelial cells develop more prominent nucleoli
    and secretion
  • Stromal changes occur with an increase in intra
    and inter-lobular edema
  • Several anovulatory menstrual cycles can lead to
    increased accumulation of secretions, edema, and
    mononuclear cell infiltrates resulting in
    transiently cystic structures.

28
Breast development during early pregnancy
  • Extensive epithelial cell proliferation and
    expansion of lobular alveolar/TDLU at the expense
    of the adipose and connective tissue.
  • Requires estrogen, progesterone, prolactin,
    growth hormone, and insulin.
  • Colostrum secretion begins around the 3rd month
    of pregnancy.

29
Breast development during the 2nd trimester of
pregnancy
  • Rate of epithelial proliferation begins to
    decline.
  • Alveoli epithelium appears monolayered and
    flattened while ductal epithelium maintains
    appearance of 2 cell layers.
  • Alveolar epithelium begins to differentiate and
    assume a presecretory function.
  • Requires prolactin, human placental lactogen,
    growth hormone, insulin and glucocorticoid.
  • Milk proteins and lipids are actively
    synthesized, but only small amounts are released.
  • Prolactin regulates secretion and its levels
    increase throughout pregnancy. Luteal and
    placental hormones (progesterone) antagonize
    prolactin activity preventing lactation until
    parturition.

30
Structural changes of the breast occurring during
pregnancy
31
Proliferation of TDLU at 5 months of pregnancy
32
Diagram of mammary gland during first half of
pregnancy
33
Extensive lobular proliferation occurs during
pregnancy
34
Diagram of mammary gland during the 7th month of
pregnancy
35
Colostrum secretion increases during the later
stages of pregnancy
36
Diagram of mammary gland during lactation
37
Low power view of lactating breast
38
Higher magnification of lactating breast
Epithelium appears squamous
39
Both apocrine and merocrine secretion patterns
are involved in milk secretion
Merocrine secretion Lactose and
proteins Apocrine secretion Lipids
40
EM of lactating breast
41
Hormonal control of lactation
  • Milk secretion is controlled by prolactin,
    glucocorticoid, growth hormone, insulin, and
    thyroid hormone.
  • Prior to parturition the pro-secretory effect of
    prolactin is antagonized, mainly by progesterone.
  • Suckling maintains continued milk production by
    releasing prolactin and adrenocorticotropic
    hormone.
  • Suckling also stimulates oxytocin release from
    the posterior pituitary which induces
    myoepithelial cell contraction and ejection of
    milk from the alveoli into the ductal system.

42
The composition of milk varies during lactation
  • Colostrum is the first secretion following
    parturition
  • Antibody rich, especially in IgA-produced by
    plasma cells in the loose CT around the alveoli.
    Confers passive immunity to infant.
  • Typically richer in protein and much lower in fat
    than mature milk.
  • Available for the first few days after birth and
    is then replaced by mature milk.
  • Mature milk
  • Contains water, Na K Cl- Ca2 and PO43,
    protein (lactalbumin and casein), carbohydrates
    (lactose), lipids (mainly triglycerides),
    vitamins and antibodies (mainly IgA).
  • Approximately 1-2 ml of milk/g of breast tissue
    per day is produced.

43
Cessation of lactation causes glandular involution
  • Involution is the process by which in the absence
    of lactation, the alveoli are reduced in number
    and size due to apoptosis of the expanded
    secretory epithelium.
  • Remaining alveolar epithelium returns to a
    non-secretory 2 cell layered epithelium.
  • Breast returns to a more ductular system
    characteristic of the inactive mature breast.
  • New connective and adipose tissues form between
    the involuted mammary alveolar structures.
  • Complete regression of the glands takes about 3
    months.

44
Post-menopausal breast
  • Involution is dependent upon declining levels of
    estrogen and progesterone. Little else is known
    about which factors control this process.
  • In contrast to post-lactational involution during
    which the number and size of alveoli is reduced,
    post-menopausal breast involution is
    characterized by regression of the parenchymal
    TDLU.
  • Deposition of adipose tissue and connective
    tissue increases.
  • At completion of involution only small islands of
    the ductal system remain embedded in dense
    fibrous connective tissue.
  • Normal histology of postmenopausal breast varies.

45
The remaining ductal tree in a post-menopausal
breast
46
Higher magnification of branching ductal tree in
aging breast
47
Appearance of the ductal tree and TDLU in a 59
year old woman
Distended ductal tree
Moderately atrophic lobules
48
Young adult breast
49
Normal lobule from non-cancerous breast of an 83
year old woman
Fewer lobules
Increased density of intralobular CT
50
Higher magnification of a lobule
BM surrounds each alveolus
Interlobular Dense CT
IntralobularLoose CT
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