Session 11: The Breast Flashcards
Describe the structure of the normal breast including its topography
The breasts consist of glandular and supporting fibrous tissue embedded within a fatty matrix, together with blood vessels, lymphatics and nerves. Both men and women have breasts, but they are normally only well developed in women. In the non-pregnant, non-lactating woman mammary tissue is a relatively small part of the breast tissue.
Mammary glands are in the subcutaneous tissue overlying the pectoralis major and minor muscles. They consist of 15-20 lobublated masses of tissues, with fibrous tissue connecting the lobes and adipose tissue between them. The adipose tissue is oestrogen sensitive.
Each lobe is made up of lobules of Alveoli, blood vessels and Lactiferous ducts. The alveoli are the site of milk synthesis. Myoepithelial cells, smooth muscle cells responsible for milk let down surround the alveoli.
Mammary glands are modified sebaceous glands – blind at one end (alveoli) and open at the other (lactiferous ducts).
The amount of fat surrounding the glandular tissue determines the size of non-lactating breasts. The roughly circular body of the breast rests of a bed that extends from:
- Lateral Sternal Edge à Midaxillary Line
- 2nd Rib à 6th Rib
What are the constituents of Colostrum?
Milk is secreted in significant quantities from soon after birth. The composition varies with time.
Colostrum
In the first week after birth, up to 40ml/day of Colostrum is secreted. Colostrium contains less water soluble vitamins, fat and sugar than later milk, but much more protein, fat soluble vitamins and particularly immunoglobulins. So Colostrum is not particularly nutritious but essential in conferring passive immunity to the baby. The neonatal gut is still open – capable of absorbing immunoglobulins whole.
Over the follows 2 – 3 weeks, IgG and total protein declines, whilst fat and sugar rises to produce Mature Milk.
What are the constituents of Mature Milk?
Mature milk is produced for as long as the baby suckles.
Composition of Mature Milk:
- Water – 90%
- Lactose – 7% (Galactose and Glucose disaccharide) (sugar)
- Fat – 2%
- Proteins found in mature milk:
Lactoglobulin (maternal IgG)
Lactalbumin (broken to provide amino acids)
- Minerals: Ca2+, Fe, Mg, K, Na, P, S (in particular calcium is needed to support ossification of the growing baby)
- Vitamins: A, B, B2, C, D, E, K,
pH = 7.0
Energy value = 27MJ.l-1
Where does synthesis of milk take place?
Synthesis of milk takes place in Alveolar Cells
Fats
- Synthesised in Smooth Endoplasmic Reticulum
- Passes in membrane bound droplets towards the lumen
Protein
- Passes through Golgi Apparatus
- Secreted by exocytosis
Sugar
- Synthesised and secreted
Describe the development of the breast from birth to puberty
At birth only a few lactiferous ducts are present, and the breast remains this way until puberty.
At puberty, Oestrogens cause the ducts to sprout and branch and the ends form masses of cells that later become alveoli (Alveoli begin development).
With each menstrual cycle there are cyclic changes in breast tissue with changes in the levels of oestrogen and progesterone. As progesterone rises, mammary tissue rises in the luteal phase. Human mammary glands are relatively more developed in the non-pregnant state than most other mammals.
Describe the development of the breast during pregnancy
Most development of mammary tissue occurs during pregnancy. During pregnancy the high Progesterone : Oestrogen ratio favours the development of alveoli, but not secretion.
Rising titres of oestrogen and progesterone in early pregnancy, secreted by the corpus luteum and placenta stimulate substantial development and hypertrophy of the ductular-lobular-alveolar system and prominent lobules form. The lumina of alveoli become dilated. Alveolar cells differentiate in mid-pregnancy to be capable of milk production but milk is not secreted in significant quantities. There is significant growth of breast tissue.
Describe the hormonal control of milk production
During pregnancy, a high progesterone/oestrogen ratio favours development of alveoli, but not secretion. At birth the levels of Progesterone fall sharply, along with a less sharp fall in Oestrogen. These changes lead to the breast becoming responsive to Prolactin. Milk secretion is allowed by the fall in steroids to a very low level once the placenta is delivered (disinhibition).
- Prolactin is secreted from the Anterior Pituitary, under the control of the hypothalamus. It is a polypeptide, produced by lactotrophs which make prolactin spontaneously. Therefore they are controlled by inhibition (by dopamine). Factors promoting secretion of prolactin reduce dopamine secretion.
If the infant does not suckle, prolactin levels fall after birth. Suckling initiates and maintains secretion by a neuro-endocrine reflex by mechanically stimulating receptors in the nipple. The more mechanical stimulation there, the more prolactin is secreted.
Impulses pass up to the brain stem, and to the hypothalamus to reduce the secretion of dopamine and vaso-active intestinal peptide, so promoting prolactin secretion.
The amount of milk produced before the next feed depends upon the suckling stimulus. Suckling at one feed promotes prolactin which causes production of next feed. Milk is produced continuously between feeds and accumulates in alveoli and the ducts, increasing the turgor (rigidity) of the breast – the breasts expand.
What is meant by Milk Let-down?
When the infant next suckles, a second reflex promotes milk ‘let-down’. Milk ‘let down’ is caused by a dramatic increase in the secretion of Oxytocin from the Posterior Pituitary Gland.
Oxytocin causes the myoepithelial cells surrounding the alveoli to contract and compression of the lactiferous ducts, ejecting the milk. Infants do not suck milk out of the breast and so have to learn how to suck milk from a bottle. As it causes the release of oxytocin, suckling is also important in keeping the uterus clamped down on open placenta blood vessels.
The ‘let down’ neuro-endocrine reflex can be conditioned and often begins before the baby reaches the nipple. Anticipation of feed promotes the release of baby. This ensures the baby gets nutritious diet in appropriate quantities.
So babies do not suck milk out of the breast – it is ejected by a let-down reflex.
Describe the mechanisms which produce cessation of lactation
- Maintenance of lactation depends on regular and sufficient suckling at each feed, to promote prolactin secretion to produce and oxytocin secretion to remove milk.
- If suckling stops the production of milk will also stop. This is in part due to lower prolactin levels and in part due to turgor-induced damage to the breast (compression of the blood vessels supporting the alveoli => secretion stops).
- Milk production can be suppressed with steroids. Prolactin secretion also reduces fertility, making a new pregnancy less likely until the infant stops suckling.
- Breast feeding is good – leads to fewer infections, good for bonding and encouragement is needed to persist.
Describe the range of common breast diseases
Inflammatory conditions
Benign epithelial lesions
Stromal tumours
Breast carcinoma
What is meant by Physiological and Pathological Breast Changes?
Physiological Breast Changes – Changes or symptoms that come about due to normal breast physiology.
Pathological Breast Changes – Changes or symptoms that come about due to underlying breast pathology.
inner cells = alveoli, outer layer (contractile function)
Describe normal physiological breast changes
Prepubertal breast
- Few lobules
Menarche (First menstrual cycle / onset of puberty)
- Increase in number of lobules
- Increased volume of interlobular stroma
Menstrual cycle
- Follicular phase – lobules inactive (quiescent)
- After ovulation, in luteal phase – Cell proliferation and stromal oedema ( can cause pre-menstrual pain)
- Menstruation – Decrease in size of lobules
Pregnancy (See above)
- Increase in size and number of lobules
- Decrease in stroma
- Secretory changes in epithelium
Cessation of Lactation
- Atrophy of lobules but not to former levels
Increasing Age
- Terminal duct lobular units (TDLUs) decrease in number and size
- Interlobular stroma replaced by adipose tissue (mammograms easier to interpret). This is the reason why mammograms aren’t very useful in young women.
Give examples of pathological breast changes. What is meant by polythelia?
Disorders of development
- Milk line remnants - polythelia (3rd nipples) may occur with or without accessory axillary breast tissue (so can get cancer in axillae or labia)
Inflammatory conditions
- Acute mastitis, duct ectasia, fat necrosis
Benign epithelial lesions
- Fibrocystic change, epithelial hyperplasia, papilloma
Stromal tumours
- Fibroadenoma, phyllodes tumours, lipoma, hamartoma (disorder of development, usually benign but can be malignant)
Gynaecomastia
Breast carcinoma
Describe the Clinical Presentation of Breast Conditions
Pain
- Cyclical and diffuse – Often physiological
- Non-cyclical and focal – Ruptured cysts, injury, inflammation
- Occasionally the presenting complaint in breast cancer
Palpable mass
- May represent normal nodularity
- Worrying if it is hard, craggy and fixed
- Invasive carcinomas, fibroadenomas, cysts
- No women should be allowed to have a lump in the breast without a firm diagnosis
Nipple discharge
- Most concerning if spontaneous and unilateral
- Milky – Endocrine disorders (e.g. pituitary adenoma), side effect of medication (e.g. Oral Contraceptive Pill)
- Bloody or serous – benign lesions e.g. papilloma, duct ectasia (lactiferous ducts et shorter and wider with age, secretions can collect leading to the epithelium becoming irritated); occasionally malignant lesions
Skin changes
Lumpiness
What are the types of mammographic abnormalities?
Found during breast screening program
Easier to detect lesions in the breasts of older women
Women between 47-73years invited every 3 years.
- 2 view mammograms every 3 years
- Aim is to detect small impalpable cancers and pre-invasive cancer (incidence of DCIS has increased from 5% of breast cancers to 25% in screened populations).
- Assess abnormalities using further imaging, FNAC and core biopsy
Worrying findings include densities (asymmetric?), parenchymal deformities and calcifications
- Densities – Invasive carcinomas, fibroadenomas, cysts
- Calcifications – Ductal Carcinoma In Situ (DCIS), benign changes
Describe the incidence of breast conditions in general
Breast symptoms and signs are common
Most breast symptoms and signs will be benign
Fibroadenoma most common benign tumour
Breast cancer most common non-skin malignancy in women
Mammographic screening increases detection of small invasive tumours and in situ carcinomas
What is meant by the triple approach with regard to investigations and diagnosis?
Clinical
- History, family history, examination
Radiographic Imaging
- Mammogram and ultrasound scan, sometimes MRI
Pathology
- Fine needle aspiration cytology (FNAC) and core biopsy
Describe Duct Ectasia
- Dilation and inflammation of lactiferous duct
- Often patients are in their 50’s and 60’s
- May have a peri-areolar mass and/or nipple discharge
- Can mimic carcinoma clinically
Describe Fat Necrosis
- Presents as a mass, skin changes or mammographic abnormality
- Often history of trauma or surgery e.g. seatbelt injury
- Can mimic carcinoma clinically and mammographically
What is meant by Fibrocystic Change?
- Benign Epithelial Lesions
- Commonest breast lesion
- May present as a mass or mammographic abnormality
- Mass often disappears after fine needle aspiration (FNA)
- Histology – Cyst formation, fibrosis and apocrine metaplasia
- Can mimic carcinoma clinically and mammographically
Describe Epithelial Hyperplasia
- Benign Epithelial Lesions
- Proliferation of epithelial cells which fill and distend ducts and lobules
- Associated with a slight increased risk of carcinoma
- If atypical, there is a higher increased risk of carcinoma
Describe Papilloma
- Benign Epithelial Lesions
- Benign tumours, growing finger-like projections outwards.
- Large duct papillomata are usually in lactiferous ducts, near the nipple
- Smaller duct papillomata are situated deeper in the breast
- Associated with slight increased risk of carcinoma
- May present with nipple discharge (may be bloody) or small, palpable mass
- Histology – Intraduct lesion consisting of multiple branching fibrovascular cores covered by myoepithelial and epithelial cells
What is meant by a Fibroadenoma?
- Stromal tumour
- Presents with a mass, usually mobile, or mammographic abnormality
- ‘breast mouse’ – mobile and elusive
- Can be multiple and bilateral
- Can grow very large and replace most of the breast
- Macroscopically – Well defined boundaries, rubbery, greyish/white
- Histology – Composed of a mixture of stromal and epithelial elements
- Can minic carcinoma clinically and mammographically
- Probably localised hyperplasia rather than true neoplasm
Describe a Phyllodes Tumour
- Stromal tumour
- Rare before 40 years old
- Present as masses or as mammographic abnormalities
- Benign, borderline and malignant types
- Most are benign
- Can be very large and involve the entire breast
- Generally softer than fibroadenomas
- Histology – Nodules of proliferating stroma covered by epithelium (phullon = leaf) – leaf-like architecture. Stroma is more cellular and atypical than in fibroadenomas. Mitotic figures seen.
- Need to be excised with a wide margin (rim of normal tissue) or may recur
- Malignant type behaves aggressively, recur locally and metastasise via the bloodstream (like sarcomas).
Describe an In Situ Carcinoma
- Neoplastic population of cells limited to ducts and lobules by basement membrane
- Myoepithelial cells are preserved
- Does not invade into vessels and therefore cannot metastasise
- Cells can extend to nipple skin without crossing basement membrane
- Paget’s Disease
- Unilateral red and crusting nipple
- Eczematous or inflammatory conditions of the nipple should be regarded as suspicious and biopsy should be performed to exclude Paget’s disease, particularly in an older lady
Describe a Ductal Carcinoma In Situ
Most often presents as mammographic calcifications
Clusters or linear and branching
Can also present as a mass
Can spread through ducts and lobules and be very extensive
Histologically often shows central (comedo) necrosis with calcification – with dead cells in the middle
Can progress to invasive carcinoma
What are the types of invasive carcinoma?
Invasive Ductal Carcinoma, no specific type (IDC-NST)
- 70-80% of invasive carcinomas
- Well-differentiated type – tubules lined by atypical cells
- Poorly differentiated type – sheets of pleomorphic cells
- 35-50% 10 year survival
Invasive Lobular Carcinoma
- 5-15%
- Infiltrating cells in a single file, cells lack cohesion (lost adhesion molecules e.g. E-cadherin)
Other types of Invasive Carcinoma
- Tubular (1-2% - excellent prognosis)
- Mucinous (1-6%, excellent prognosis, often older women)
- Medullary
- Papillary
What are the patterns of metastases of breast cancer?
Lymph Nodes
- Via lymphatics
- Usually in the ipsilateral axilla
Distant Metastases
- Via blood vessels
- Lungs, bones (most frequent site), liver, brain
Invasive lobular carcinoma can spread to odd sites, e.g. peritoneum, retroperitoneum, leptomeninges (could possibly lead to presentation of meningitis), gastrointestinal tract, ovaries, uterus
What are the factors in determining breast cancer?
- In situ disease or invasive carcinoma
- Histological subtype – IDC NST has poorer prognosis
- Tumour grade
- Tumour stage
- TMN
- Tumour size
- Locally advanced disease – invading into skin or skeletal muscle
- Lymph node metastases
- Distant metastases
- Gene expression profile
Microarrays have been used to examine the expression patterns of some 25,000 genes in tissues from breast cancer patients.
Computer cluster analysis of the patterns led to the identification of about 17 marker genes that can correctly identify about 90% of women who would eventually develop metastases.
Describe Systemic Control
Chemotherapy – if benefits thought to outweigh the risks, if given before surgery = neoadjuvant (to quickly treat someone or shrink down a tumour to offer conserving surgery rather than metastases)
Hormonal Treatment
- Tamoxifen if a high amount of oestrogen receptors found on assessment (approximately 80% of cancers are oestrogen positive)
Herceptin Treatment
- Depends on amount of Her2 receptors found on assessment (approximately 20% of cancers are HER2 positive)
- HER2 is a member of the human epidermal growth factor receptor family
- Encodes a transmembrane tyrosine kinase receptor
- Herceptin = trastuzumab = humanised monoclonal antibodies against the HER2 protein
