Breast Pathology

Normal Breast Structure

- Breast tissue contains a variable amount of fat and glandular tissue
o Ratio varies with age (older people = fattier
tissue, younger people = glandular tissue)
- Glandular tissue consists of ducts and lobules which
are surrounded by tissue
- Lobules have secretory functions and are lined by
epithelial cells with a peripheral layer of contractile
myoepithelial cells (composed of muscle filaments)
- Ducts can be intra- or extralobular
o Lactiferous ducts are those are those close to
the nipple
o Lactiferous sinuses are where breast milk is
stored

Clinical Presentations - Pain and Nipple Discharge

- Breast pain is most often cyclical, varying with menstruation (most common presentation)
- Nipple discharge can occur from a single duct or multiple ducts
o Can be clear, coloured, or blood-stained
- Breast ‘lump’ is the second most common presentation

Breast Pain
- Breast pain (cyclical mastalgia – no pathological change)
o Usually greatest pre-menstrually and resolves with period
o May be very severe, some response (primrose oil, simple analgesia)
o Important to reassure it is rarely associated with malignancy
▪ Unless it is advanced disease where the skin becomes ulcerated

Nipple Discharge
- Single or multiductal depends on clinical signs, discharge after…
o Pressing in one particular area → multiple ducts
o Pressing anywhere → single duct
- Can be clear, opaque, or blood-stained
o Clear discharge is physiological although rarely prolactinoma
▪ Prolactinoma is a prolactin-secreting tumour in the pituitary gland
- Multiple duct points towards duct ectasia
o Lactiferous duct widening and wall thickening → accumulation of greenish
fluid/discharge
- Single duct points towards a papillary lesion (e.g. papilloma) although rarely underlying
malignancy (e.g. DCIS)

Duct Ectasia
- Occurs in older women during their reproductive years (35-45yrs)
- Often associated with smoking and is very rare in non-smokers
o Elastic tissue defect, pulling secretions into the duct
- Treatment is not often necessary, but duct excision may be considered if profuse or
uncomfortable for the patient
- No increased risk of malignancy
Intraductal Papilloma
- Single duct discharge, may be intermittently blood-stained
o Happens when the papilloma twists, causing
infarct/ulceration
- On occasions, a malignancy may be found arising within the
papilloma (rare)

Clinical Presentations – Breast Lumps

- Breast lumps require triple clinical assessment involving:
o Clinical history and examination
o Radiology – Mammography (older women) and ultrasound (younger women)
o Needle Biopsy – fine needle aspiration and/or core needle biopsy

Clinical History
- Duration of lump
- Increasing or decreasing in size
- Cyclical (unlikely pathological) or constant
- Pain or skin changes (inflammation and tethering point towards underlying malignancy)

Clinical Examination
- Location: most lumps are found in the upper outer quadrant
o Benign lesions are less frequent in the medial aspect of the breast (caution)
- Size
- Consistency
o Soft lesions are typically fatty
o Firm lesions can be benign (fibroadenomas) or cystic (depending on fluid)
o Hard lesions are typically malignant or cystic (depending on fluid)
- Character: can be a focal lesion, have vague or smooth boundaries (benign), or irregular
- Skin changes: ask patient to raise arms, the breast moves which can show dimpling or peau
d’orange (signs of malignancy)
- Axilla and axillary tail: palpable enlarged lymph glands
o If thickened, the mass may be a metastasis

Imaging
- Mammography is an x-ray of breast tissue, where the breast is
placed between two plates
o Taken at two angles cranio-caudal and oblique to see as
much tissue as possible
o Composite shadowing when mixing tissue can make it
look irregular
o More effective in older patients because tissue is fattier, and
therefore lumps/masses are more apparent
o It is impossible to get all the breast (i.e. medial aspect) with
mammography
- Ultrasound is not as useful as a screening tool (labour-intensive and
carries many false positives) but is very helpful when a lump is present
o Can tell is a lesion is cystic (usually benign) or solid
o Can show the outline of a lesion (smooth = benign, irregular =
malignant)
o Useful for image-guided biopsy
Benign Breast Lumps
- Make up the majority of presentations, consisting of:
o Simple cysts
o Fibrocystic change
o Fibroepithelial lesions
o Papilloma
o and fat necrosis
- Simple cysts are either near the skin surface (epidermal inclusion cyst) or,
more commonly, in breast parenchyma (as a dilated duct or lobule)
o Near the skin surface:
▪ Can arise anywhere in the skin
▪ There’s an infolding of squamous cells, with trapped keratin
o Breast parenchyma:
▪ More deep-seeded
▪ Developed abnormally, or as a result of entrapped secretions
▪ Lined by metaplastic apocrine epithelium
▪ Attenuated as a result of pressure within the cyst
- Fibrocystic change is very common (occurring in half of women) but does not usually produce
signs or symptoms
o Clinically may present with lumps, bumps, or thickening
o Often detected (calcification) in breast screening programme
o A form of non-proliferative abnormality
▪ Differing from proliferative ones (those with characteristics leading towards
malignant transformation)
o Three components:
▪ Cyst formation: normal development of breast
tissue but a duct blockage leads to secretion
build-up in turn dilating epithelium
▪ Fibrosis (less frequently): cyst rupture leads to
chronic inflammation and fibrosis
▪ Adenosis: increased acini in the lobule without
epithelial proliferation
- Fibroepithelial lesions consist of fibroadenomas and Phyllodes tumour
o Pathology: fibroadenoma → benign phyllodes tumour → malignant phyllodes tumour
o Difference depends on balance of epithelial and stromal proliferation
▪ Fibroadenomas have a balance of epithelial and stromal tissue
▪ Phyllodes tumours have an overgrowth of stroma
• Usually benign – tendency for local recurrence
• Can be malignant and sarcomadous
▪ All of which have similar histologies, making it difficult to diagnose especially
with needle core biopsies
- Fibroadenomas are very common
o Present as painless palpable and mobile mass in younger
patients (<30 years) of as a mammographic abnormality in
older patients
o Contains both epithelial and stromal elements
▪ Interlobular dense stroma
▪ Intralobular loose stroma (fibroadenomas thought to
arise from this – although can contain fat, smooth muscle, and bone)
o Hormonally responsive, size alters with menstrual cycle and more marked during
pregnancy
 o Needle core biopsy – if benign, likely no excision
o No increased risk of breast malignancy
o Fibroadenoma histology has no nuclear pleomorphisms, no mitotic figures, no necrosis,
and no increased cellularity
- Papilloma’s consist of benign epithelium covering a fibrovascular core
o Exhibit a branching pattern on histology
o Typically grow within the duct wall causing blockage and widening (palpable lump)
▪ Present with lump or nipple discharge (particularly close to the nipple)
• Discharge can be bloody (highly vascular) and can twist/traumatise
causing infarct
o Can be solitary or multiple
▪ Solitary papilloma’s are easily discharged – found in large ducts and are located
near the nipple
• Have a lower risk of malignancy
▪ Multiple papilloma’s are found in terminal ducts and are located in deep tissue
• Have a higher risk of malignancy
▪ All of them require histological assessment due to possible malignant change
• Papilloma without epithelial atypia → <10% risk to malignancy
• Papilloma with epithelial atypia → >35% risk to malignancy

- Fat necrosis is a common finding, can

resemble malignancy
o Usually presents with a painless lump which can well circumscribed and discrete or
vaguely thickened
o Often secondary to trauma
▪ Seatbelt (bruising and a deeper lump formation)
• Damage to fatty tissue of the breast →
inflammatory response of macrophage
infiltrate (mop up released lipid) taking
foamy appearance
• Lesion persists for months, form oily
cyst or can calcify
▪ Surgery or biopsy
o Picked up during screening (calcification)

Breast Cancer

- Most commonly diagnosed cancer in women (25% of all cancers)

 o 55 000 cases a year are diagnosed, plus 8 000 cases of in situ per year
o ~1.7 million cases per year worldwide
- Incidence rises with age
o ~50% diagnosed in women aged 65 and over
o Invasive carcinoma diagnosis increased by 20% (over last 25 yrs)
o In situ diagnosis have tripled (over last 25 yrs)
▪ As a result of breast screening programmes
o Male breast cancer approximately 400 cases per year
- 2nd most common cause of death
o ~11 500 women die per year
o Mortality rates are decreasing (earlier diagnosis & earlier treatment)
- Survival is greatest amongst women diagnosed in their 60s (screening age)
o Picked up earlier, more amenable to treatment
o 90% 5YS, 80% 10YS, 65% 20YS
o Younger women tend to have more aggressive cancers that don’t respond as well to
treatment
- Risk factors include:
o Increasing age, family history
▪ 1st degree relative: 2x risk (only 15% actually get cancer)
o Genetics
▪ BRCA1 and BRCA2 gene abnormalities
• 50/50 chance of developing breast cancer by age 70
o Previous history
o Increased breast density
▪ Increased proportion of glandular tissue in the breast compared to fat
▪ More difficult to detect subtle abnormalities, increased risk of false negative
screening
o Obesity, alcohol, smoking, ionising radiation
▪ Adipocytes produce oestrogen, increasing your risk
o Unopposed oestrogen
▪ Exogenous oestrogen (OCP), early menarche, late menopause, nulliparity (and
older age at first childbirth)
▪ Breastfeeding has protective effects
- Clinical presentation includes symptomatic patients, or patients found positive in screening
o Symptomatic – most common presentation is a lump. Skin abnormalities (tethering,
dimpling) and nipple discharge can also be brought up
▪ Patients with metastatic disease also fall under this category
o Screening – hasn’t noticed any lumps, typically by mammographic abnormality on x-
ray or cluster of calcifications that is being investigated further
- NHS Breast Screening Programme
o 1988 – 3 yearly cycle, women aged 50-70
o 4% of all women are recalled for a screening assessment clinic due to abnormalities
▪ Majority are benign or are done due to technical reasons
▪ 1/4 recalled will get a diagnosis of cancer
- Diagnosis requires a triple assessment – including clinical, radiological, and pathological
assessments
- Clinical assessment
o Assessment of lumps and bumps
o Skin changes (dimpling, peau d’orange, tethering) and nipple discharge
o Axilla palpation (metastatic spread)
o Systemic questioning:
 ▪ Weight loss, fatigue, lethargy, anaemia
o Family history (and if indicated, genetic screening)
- Radiological assessment
o Mammography (older patients, >50 years)
o Ultrasound (younger patients)
o MRI to define lesions better, younger patients
o Younger patients have denser breast tissue (increased glandular:adipose ratio)
o May or may not identify a suspicious lesion and decide to biopsy
- Pathological assessment
o Either by fine-needle aspiration or core biopsy
o Fine needle aspirate (cytology)
▪ Quick, very minimal technical difficulty, cheap process & painless for patient
(fewer complications, no requirement of LA)
▪ Difficult to subtype benign and malignant lesions (cytology), can’t give a
positive benign diagnosis. Can’t differentiate between invasive carcinoma and
in situ carcinoma – high equivocal rate, can’t sample calcifications

o Core biopsy (histology)

▪ Specific benign diagnosis, very low false positive rate, distinguishes in situ
from invasive carcinoma (can identify basement membrane), identify invasive
subtypes and provide provisional grades (ER status, HER2 status)
▪ More technically complex, more training required, radiology required, LA
required (skin is cut), higher complication rate (haematoma), more expensive

- Breast cancer classification is done based off cell type (ductal/lobular), grade, and stage
o Classification can also be done via hormone receptor expressions (ER)and
molecular classifications (gene profiles)
- In situ carcinoma
o Neoplastic cells are confined to a duct
o Intact basement membrane (no potential for metastasis)
 ▪ Therefore, will not need lymph node assessment
o Progress to invasive carcinoma if untreated, requiring excision
- Invasive carcinoma
o Neoplastic cells, but breach of the basement membrane
o Can metastasise to lymph nodes, requiring Sentinel Node Biopsy
- Cell-type used to differentiate, difference between ductal and lobular carcinoma is there
is a loss of a cell-surface protein (e-cadherin) in lobular carcinoma, resulting in
malignancy to be less cohesive
o Ductal carcinoma tends to form well-defined lumps/circumscribed mass (on
radiology), clearly outlined tumour with abnormal glandular structures on
histology (adenocarcinoma)
o Lobular carcinoma has a vague, diffuse infiltrative pattern (vague thickening),
with less distinct radiological findings (requiring MRI), non-distinct edges,
meaning wider infiltration (infiltrative single cells on histology)

- Grade assesses tubule formation, mitotic activity, and nuclear pleomorphism

o Each get a score out of 3
o Grade 1: score 3-5
o Grade 2: score 6-7
o Grade 3: score 8-9
- TNM staging is also done
o T – increasing tumour size, skin/chest wall involvement
o N – increasing lymph node involvement, particularly axillary lymph nodes
o M – presence or absence of distant metastatic disease

Prognostic Factors

- Prognostic factors in breast cancer include tumour type, histological

grade, size, nodal involvement (*), hormone receptor status, and some
other factors
- Tumour type
o Favourable prognoses: tubular, lobular, mucinous, and medullary
carcinomas
o Poor prognoses: most ductal carcinomas, other rare aggressive
types
- Tumour grade
 o Tubule formation, pleomorphism, mitotic activity (# of mitotic figures)
- TNM staging is also done
o T – increasing tumour size, skin/chest wall involvement
▪ T1 – 20mm or less
▪ T2 – 20-50mm
▪ T3 – 50-100mm or <50mm with infiltration to underlying muscle
▪ T4 - >100mm
o N – increasing lymph node involvement, particularly axillary lymph nodes
▪ N0 – Node negative
▪ N1 – Nodes involved, mobile
▪ N2 – Nodes involved, fixed
▪ N3 – Supraclavicular nodes or oedema (lymphatic obstruction)
o M – presence or absence of distant metastatic disease
▪ M0 – No metastases
▪ M1 – Metastases present
- Predictive test for specific therapeutic approaches depending on
tumour features
o Oestrogen receptor status
▪ Benefit from hormonal therapy
• Tamoxifen, rumadex
▪ ER+ provides a better prognosis
o HER-2 (Human Epidermal Growth Factor)
▪ 50% of cases are positive
▪ Respond to Herceptin
▪ Improved short-term prognosis
- Early detection is one of the main hopes to reduce mortality
o Women aged 50-70 routinely screened
o Need to identify younger patients who are at higher risk (e.g. family history)
▪ May benefit from careful clinical/radiological follow up or prophylactic
surgery
- Risk factors
o BRCA1 and BRCA2 mutations (tumour suppressor genes)
▪ Tested 10 years prior to paternal/maternal index age of diagnosis
▪ Prophylactic surgery? Breast/ovaries
▪ Ovarian cancer risk at 40 years
o Family history without mutations
▪ First degree relatives (especially if pre-menopausal)
o Pre-existing breast conditions
▪ Breast cancer
▪ Atypical duct hyperplasia (4x lifetime risk)
▪ Hyperplasia of usual type (2x lifetime risk)
▪ LCIS (4x risk)
▪ DCIS (6-8x risk)
o Potential for tamoxifen prophylaxis