Anatomic Structure and Lifecycle Changes
 The adult female breast is located on the anterior chest wall, overlying the pectoralis muscles. The normal nipple-areolar complex  is positioned slightly inferior to center. |
 The major breast structures are the nipple-areolar complex  , the large duct system  , the terminal duct lobular units  , which are supported by intralobular stroma, and the interlobular stroma  . |
NORMAL BREAST
Introduction
Highly evolved modified skin appendage
Defining feature of class Mammalia
Provides source of nourishment and immunologic protection for newborn
Unlike other organs, changes over the lifecycle in response to menarche, pregnancy, lactation, and menopause
Embryologic Development
Stroma differentiates first and induces downgrowth of overlying epithelium
Milkline extends from axilla to groin
In primates, bats, elephants, and manatees, only 2 pectoral breasts normally develop
In rare cases, supernumerary nipples &/or breast tissue can develop in other areas along milkline
Can enlarge and produce milk during pregnancy and lactation
Gross Anatomy
Breasts rest on anterior chest wall overlying pectoralis major and minor muscles
Borders of breast
Superior border approximately at 2nd rib; inferior at 6th rib; lateral at mid axillary line; medial at edge of sternum
Breast tissue often extends into axilla (tail of Spence)
Lesions occurring in this tissue may be difficult to distinguish from diseases involving nodes
Deep margin of breast rests on fascia of pectoralis major muscle
In some women, breast tissue is present in subcutaneous tissue and can extend beyond grossly evident breast borders
Mastectomies remove majority of breast tissue but may not remove all epithelial cells
Suspensory (Cooper) ligaments are fascial attachments to skin and chest wall
Attached to both fascia of skin and pectoralis major muscle
Provide support and allow for mobility
Swelling of breast tissue around these ligaments causes orange peel appearance of skin (“peau d’orange”)
Carcinoma involving these ligaments results in skin retraction &/or dimpling
Lymphatic drainage
Majority of lymphatic drainage (˜ 75%) passes to axilla and initially flows to 1 or 2 sentinel nodes
Injection of dye or radioactive tracer to identify these nodes can be performed either adjacent to the carcinoma or more superficially in the breast
For women with metastases to nodes, sentinel node is 1st to be involved in > 90% of patients
Intramammary nodes can also be involved by metastases but are rarely the sentinel node
Less commonly, flow goes to lymphatics, penetrating pectoralis muscles and chest wall
Internal mammary nodes or other nodal basins can harbor the sentinel node
Abnormal flow patterns may occur when axilla is obstructed by disease
Breast lymphatics are present preferentially in superficial location
Some, but not all, lymphatics connect with plexus of lymphatics at areola (“Sappey plexus”)
Dermal lymph-vascular invasion is seen most commonly close to nipple
Cutaneous lymphatic anastomoses may account for rare cases of metastases to contralateral breast in absence of distant metastases
Microscopic Anatomy: Introduction
Nipple
Positioned slightly medial and inferior to center of breast
Located at 4th intercostal space in nonpendulous breast
Cone-shaped, average height 10-12 mm
Covered by pigmented squamous epithelium
May contain cytologically benign cells with clear or pale cytoplasm
Toker cells are similar to luminal cells in appearance and immunophenotype
Present in majority of nipples if identified by cytokeratin 7 studies
Most common next to nipple orifices
Must be distinguished from DCIS involving nipple skin (Paget disease)
Occasional squamous cells can also have cytoplasmic clearing
Intercellular bridges are usually evident
Keratin-producing squamous cells extend into ducts 1-2 mm
Outside of lactation, keratin plug may be present in nipple orifice
Abrupt transition from squamous cells to normal luminal/myoepithelial lining of ducts
If keratin-producing cells extend deeper into duct (squamous metaplasia of lactiferous ducts [SMOLD]), keratin can be trapped, creating an epidermal inclusion cyst
If ruptured, subareolar abscesses may result due to intense inflammatory response to keratin spilled into stroma
Basement membrane of ducts is continuous with basement membrane of skin
Surrounds entire ductal/lobular system; separates epithelial cells from breast stroma
Consists of type IV collagen and laminin
In Paget disease, tumor cells can cross from ductal system into nipple skin without crossing basement membrane
Elastic fibers are normally present in varying amounts around mammary ducts, but not lobules
With age, supporting structures of major ducts can weaken and allow extravasation of nipple contents
Resulting chronic inflammation may cause nipple discharge and periductal fibrosis (“duct ectasia”)
Nipple-areolar complex is supported by a subdermal layer of circumferential smooth muscle
Facilitates nipple erection and function during nursing
Very rare leiomyomas can arise from this muscle
Milk secretion occurs through 10-15 major duct orifices opening on surface of nipple
Arranged radially in nipple crevices
Some major ducts may bifurcate beneath nipple
Ducts dilate to form lactiferous (milk) sinuses
Serve as reservoir for subareolar milk during nursing
Sinuses have serrated contour and are supported by smooth muscle, collagen, and elastic fibers
Some lesions are specific to nipple
Large duct papillomas
Duct ectasia
Squamous metaplasia of lactiferous ducts (SMOLD)
Paget disease of nipple
Syringomatous adenoma
Areola
Lacks pilosebaceous units and hair except at periphery
Contains numerous sebaceous glands
Open through small prominences at periphery of areola and are associated with lactiferous ducts (Montgomery tubercles)
Numerous sensory nerve endings are present
Large Duct System
15-20 major ductal systems emptying at nipple
Additional smaller ductal systems open onto areola
Ducts ramify until they form terminal duct lobular units (TDLUs)
Ductal systems vary considerably in size and extent
Often overlap
Rarely confined to single quadrant
Size and extent vary greatly in different individuals; location of ductal system cannot be predicted
Some large ducts branch and fill widely separated areas of breast
Cannot be recognized grossly; requires duct injection or serial section reconstruction in 3 dimensions
Anastomoses between ductal systems were reported in 1 study
Significance for carcinoma
DCIS is clonal population that involves a single ductal system
Distribution of DCIS generally follows the system
e.g., fan-shaped with apex toward nipple
Multiple duct systems could be involved in the following situations
2 separate clonal populations of DCIS are present
DCIS grows into a 2nd ductal system via one of the reported anastomoses
DCIS grows into a 2nd ductal system by crossing into another duct orifice at the nipple
Lobules
Formed when terminal duct branches into multiple rounded acini
Functional unit of breast for milk production
Lobulocentric architecture (duct surrounded by multiple acini) is important in distinguishing benign lesions that maintain this structure from malignant lesions that do not
Majority of breast lesions referred to as “ductal” arise from TDLU
TDLU can unfold with coalescence of acini to form structures resembling ducts
Cysts, epithelial hyperplasia, sclerosing adenosis, and majority of carcinomas are thought to arise from TDLU
Epithelial Cell Types
2 types of epithelial cells are present in both ducts and lobules: Luminal cells and myoepithelial cells
Precursor or stem cells may be present, but special techniques are required for recognition
Precursor cell is thought to give rise to both cell types
Supported by occurrence of benign and malignant tumors composed of both cell types
Normal ducts and lobules are lined by epithelium that consists of 2-cell layer
Recognition of normal 2-cell layer is important feature to distinguish benign lesions from invasive carcinoma
Luminal cells form innermost cell layer
Produce milk in TDLU
Luminal cells in large ducts do not undergo lactational changes and do not produce milk
Some luminal cells extend to basement membrane
Cuboidal to columnar in shape
Nuclei are small, round to oval, and usually have inconspicuous nucleoli
Cells have moderate amount of eosinophilic cytoplasm
Usually express “luminal” low molecular weight keratins 7, 8, 18, 19
May also express “basal” keratins
Some, but not all, luminal cells are positive for ER-α &/or PR at any given time
Receptors are not expressed in proliferating cells
Positive cells are present in both large duct system and TDLU but may be more frequent in latter
Express E-cadherin and other catenins
Some cells are positive for mammaglobin &/or gross cystic disease fluid protein 15 (GCDFP-15)
Thought to be precursor cell for majority of carcinomas
Myoepithelial cells form outer layer on basement membrane
Cells form a contractile meshwork that does not cover entire basement membrane
In cross section, myoepithelial cell layer is incomplete
These cells have multiple functions
Contract for milk ejection during breastfeeding
Help maintain basement membrane
Aid in luminal cell polarity
Inhibit angiogenesis
Cells are often flattened with small, round, condensed nuclei
Cytoplasm can be more abundant and clear; may mimic lobular neoplasia
With age, cells can become prominent and spindled in shape (“myoepithelial atrophy”)
Usually express “basal” high molecular weight keratins 5/6, 14, and 17
May also express “luminal” keratins
Express contractile proteins: Actin-sm, calponin, SMHC
Also express p63, CD10, P-cadherin, mapsin, as well as other proteins not expressed by luminal cells
Do not express ER or PR
Myoepithelial cells associated with carcinomas can diminish in number, become displaced from basement membrane, and fail to express some cell-specific markers
Complete loss of myoepithelial cells is useful diagnostic feature to recognize invasive carcinomas
Microglandular adenosis is only “benign” lesion lacking myoepithelial cells
Likely a nonmetastasizing form of invasive carcinoma
Stroma
Composition depends on patient age, menstrual status, and history of pregnancy and lactation
Composed of varying amounts of fibroglandular breast tissue and adipose tissue
Interlobular stroma surrounds large ducts and TDLUs
Responsible for majority of breast volume
1/2 of fibroglandular tissue is located in upper outer quadrant
Nearly 1/2 of all cancers occur in this area
Ratio of ductal/fibrous breast tissue to adipose tissue varies between individuals and changes over time
Determines mammographic density of breast tissue
Increased density makes detection of abnormalities during clinical exam and mammography more difficult
Relative proportion of adipose tissue increases with age
Increase in breast size at puberty is primarily due to increase in interlobular stroma
Therefore, there are hormonal influences on this stroma that are not well understood
Juvenile hypertrophy is bilateral enlargement of breasts; possibly due to hormonal imbalance
Cellular components include fibroblasts, myofibroblasts, adipocytes, blood vessels, and lymphatics
Majority of fibroblasts and myofibroblasts are CD34 positive
Some myofibroblasts are positive for ER &/or PR
Large multinucleated stromal cells may be due to degenerative changes
Some lesions of this stroma also occur outside of breast
Lipomas and angiolipomas
Myofibroblastomas (but most common in breast)
Nodular fasciitis (less common in breast)
Desmoid fibromatosis
Angiosarcomas (most common in breast, other types of sarcomas very rare)
Other stromal lesions are specific to breast
Pseudoangiomatous stromal hyperplasia (PASH)
Intralobular stroma surrounds acini in TDLU
Looser, more cellular appearance compared to interlobular stroma
Often has scattering of lymphocytes and plasma cells
May be myxoid in appearance
Lesions of this stroma are biphasic (include both stroma and epithelial cells)
Fibroadenomas
Phyllodes tumors
BREAST DEVELOPMENTAL CHANGES
Childhood and Puberty
At birth, breast consists of nipple and large ducts
Infants, especially breastfed infants, can transiently produce milk under influence of maternal hormones (“witch’s milk”)
At puberty in females, main mammary ducts branch, giving rise to terminal duct buds
Precursors of future TDLUs
Connective tissue elements proliferate
Adipose cells proliferate and extend into subcutaneous tissue
Periductal stromal tissue and vascular supply proliferates
Tanner phases of pubertal breast development
Phase 1
Nipple elevation but no palpable glandular tissue
Phase 2
Mound of nipple and breast tissue projects from chest wall
Palpable tissue present in subareolar region
Phase 3
Increased glandular tissue elements
Increased areolar size with development of pigmentation
Phase 4
Development of separate nipple-areolar complex and secondary mound anterior to breast tissue
Phase 5
Final adolescent development, smooth breast contour
At puberty in males, breast usually does not develop beyond a rudimentary large duct system
Lobules are only very rarely present
2/3 of males may experience some degree of breast enlargement (gynecomastia) that does not persist
Menstrual Cycle Changes
Proliferative phase of menstrual cycle
Early breast changes prior to ovulation (days 3-14)
Increased in ovarian estrogen production
Mammary lobules are relatively quiescent
Decreased stromal density
Decreased breast volume and water content
Breast MR examination should be scheduled during early phase of cycle
Secretory phase of menstrual cycle
Later breast changes after ovulation (days 15-28)
Due to estrogen production with increased progesterone levels (luteal phase)
Proliferation of mammary ductal epithelium, increased number of acini
Increased stromal density (edema)
Increased breast volume and water content
Some women may experience symptoms due to increased interlobular fluid and epithelial proliferation
Menstruation
Decreasing estrogen and progesterone levels
Regression of lobules and disappearance of stromal edema
Pregnancy-related Changes
With onset of pregnancy, breast tissue becomes fully mature and functional
Lobules progressively increase in number and size
Early pregnancy changes
Generalized breast enlargement
Marked ductal and lobular proliferation
Increase in number of lobules and acinar units within each lobule
Increased nipple-areolar complex pigmentation
Montgomery tubercles (sebaceous glands of areola) become prominent; appear as rounded papules on skin surface
Function in nipple lubrication during breastfeeding
Later pregnancy changes
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