Histology of the Breast

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Histology of the Breast Rebecca Cook Ph.D. Cancer
Biology Department April 21 2003
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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.
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• 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.

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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).
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Enlarging Pubescent Breast
Ducts
Adipose tissue
Dense CT septa
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Branching ductal tree of prepubescent breast
Convergence of major ducts
Early formation of terminal ductal lobular units
(TDLU)
Whole mount preparation
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• 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.

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Young adult breast
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Multiple lobular units radiate from a single duct
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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.
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Early pubescent breast
TDLU
Adipose tissue
Duct
Dense CT
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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

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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

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Non-lactating nipple and areola
Keratin Plugs
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Non-lactating nipple with keratin plug
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Glands of Montgomery
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Convergence of the major lactiferous ducts at the
nipple
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Terminal duct lobular unit
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Mature TDLU form after several menstrual cycles
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Diagram of inactive mammary gland
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Higher magnification of a lobule
BM surrounds each alveolus
Interlobular Dense CT
IntralobularLoose CT
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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.
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Cell types found in alveoli
Columnar secretory cells
BM
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IHC staining of actin demonstrates the presence
of myoepithelial cells
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The appearance of secretory epithelial cells
varies with duct and lobule size
Smaller ducts/lobules
Larger ducts/lobules
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EM of a single lobular unit
Lumen
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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.

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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.

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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.

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Structural changes of the breast occurring during
pregnancy
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Proliferation of TDLU at 5 months of pregnancy
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Diagram of mammary gland during first half of
pregnancy
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Extensive lobular proliferation occurs during
pregnancy
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Diagram of mammary gland during the 7th month of
pregnancy
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Colostrum secretion increases during the later
stages of pregnancy
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Diagram of mammary gland during lactation
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Low power view of lactating breast
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Higher magnification of lactating breast
Epithelium appears squamous
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Both apocrine and merocrine secretion patterns
are involved in milk secretion
Merocrine secretion Lactose and
proteins Apocrine secretion Lipids
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EM of lactating breast
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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.

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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.

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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.

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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.
  

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