Breast

Question 1

Classification of benign breast lumps

Answer 1

o Non proliferative breast lesions
▪ Simple cysts
▪ Papillary apocrine change
▪ Mild usual type hyperplasia

o Proliferative breast lesions
▪ Intraductal papilloma
▪ Usual type hyperplasia
▪ Sclerosing adenosis
▪ Radial scar
▪ Fibroadenoma

o Atypical hyperplasia
▪ ADH
▪ ALH

Question 2

Indications of breast MRI

Answer 2

• Breast implants
• Recurrent disease where conventional imaging inadequate
• Risk of multifocality in lobular cancer or occult cancer on mammography
• Assess response after neoadjuvant chemotherapy
- high risk breast screening (<50)

Question 3

Fibroadenoma

Answer 3

• Pathology
o Aberration of normal development
o Formed by a combination of connective tissue and proliferative epithelium
o Arises from hormone-dependent terminal duct lobular unit
o Influenced by hormones

• Classification
o Depends on stromal element
▪ Simple fibroadenoma – low cellularity stroma with regular cytology
▪ Phyllodes tumour
• Thought to arise from fibroadenoma • Marked cellularity and atypica with stroma

• Simple fibroadenoma
o Features
▪ Benign, mobile, discrete
▪ Rubbery masses

o Clinical
▪ Usually seen in late teens and early 20s
▪ Incidental finding on imaging or palpable lump
▪ Single or multiple

o Aetiology
▪ Unknown
▪ Links to OCP
▪ Links to EBV following immunosuppression

o Workup
▪ US guided core biopsy (patients >23)

o Pathology
▪ Rapid growth can occur in juvenile fibroadenoma or in perimenopausal group
▪ Tumours >5cm are considered ‘giant fibroadenoma’

▪ Macro
• Discrete, bosselated, white tumours that bulge when cut

• Management
o Core biopsy to confirm diagnosis
▪ If multiple, biopsy largest lesion
o <4cm with histological confirmation
▪ Reassurance and discharge
o Symptomatic, significant increase in size, distortion of breast
▪ Excision
o >4cm
▪ Excision
o Histological concern about stroma activity
▪ Excision

Question 4

Phyllodes tumour

Answer 4

o Definition
o Fibroepithelial tumour with a diverse range of biologic behaviours
▪ From phyllodes – leaf-like
▪ Papillary projections on pathology

o Epidemiology
▪ Rare, 4% of all breast neoplasms
▪ Women 42-45y
▪ older more likely to be malignant
▪ Present 15-20 years later than fibroadenoma
o Can be related to P53 gene mutation

o Clinical
▪ Breast mass
▪ Smooth, multinodular, mobile, painless
▪ 1-41cm
▪ Mass effect rare but can change breast contour
▪ Can have rapid growth
▪ Can produce marked distension and cutaneous venous engorgement
▪ Can have ulceration
▪ Incidental finding on biopsy for fibroadenoma
▪ LN mets very rare (usually haematogenous spread)

• Workup
o Mammogram/ ultrasound / biopsy
▪ Core → stromal overgrowth, mitoses, stromal cellularity
o Pathology
▪ Cauliflower-like appearance
▪ Pseudocapsule with stromal tongues protruding into breast tissue
▪ Brownish colour with areas of necrosis
▪ Not fixed to skin or muscle

o Classify (SAMSOM)
benign vs borderline vs malignant
▪ Stromal cellularity and atypia
▪ Mitotic activity • <4, 4-9, >9/10hpf
▪ Infiltration or circumscribed margins
▪ Stromal overgrowth – most important

o Management
▪ Excision with 1cm surgical margin, clear macroscopic margin
▪ RTX for borderline or malignant
▪ CTX for high risk malignant
▪ No role for hormonal treatment
▪ Metastatic disease
• poor response to radiation, hormone, chemotherapy

• Follow up
o 6 monthly for 2 years

o Prognosis
▪ Local recurrence in 20%
▪ Lymph node metastases are rare (5%)
• Metastasis usually haematogenous like sarcomas → lung most common
▪ Metastasis • <5% phylloides tumours metastasise
o 25% if malignant
o 5YS for malignant phyllodes → 60-80%

Question 5

Nipple discharge

Answer 5

• Epidemiology
o 5% of referrals of breast clinic
o 20% due to in situ or malignant disease

• Clinical assessment
o Single or multiple ducts
o Coloured or bloodstained
o Induced or spontaneous
o Unilateral or bilateral
o Frequency, colour, consistency of discharge

o Increased risk of cancer
▪ Blood stained (but sensitivity/specificity not high)
▪ Persistent discharge >2x/week
▪ Age
• 3% <40, 10% 40-60, 32% >60
▪ No blood, no mass, <1% cancer

• Aetiology
o Physiological discharge
▪ Coloured opalescent discharge from multiple ducts
o Galactorrhoea
▪ Bilateral, copious, pale milky discharge from multiple ducts
▪ Usually develops after ceasing breast feeding

▪ Causes
• Prolactin secreting pituitary adenoma
• Medications that influence esotrogen/progesterone/prolactin pathway
• Hypothyroidism
• Marijuana

▪ Workup
• Check prolactin level (if >1000mIU/L = elevated)

o Cause – pituitary tumour secondary to medication
o Duct ectasia
▪ Older women with thick yellow discharge
▪ Tortuous and dilated ducts predispose to fluid accumulation
• Results in multiduct discharge
o Benign breast changes (ANDI)
o Papilloma (80% of bloody discharge), cancer, epithelial hyperplasia, DCIS
▪ Serosanguineous, bloody discharge from a single duct
o Inflammatory cause
▪ Periductal mastitis/ abscess

• Examination
o Breast examination for mass
o Pressure around areola to identify any dilated duct (will produce discharge)

o Testing of discharge
▪ Haemoglobin

Investigations
o Ductoscopy
▪ Microendoscope passed into offending duct to directly visualize lumen
▪ Can assist in directing duct excision at surgery and detecting deeper lesions missed by blint centlra excision

o Ductal lavage
▪ Cannulation of duct then irrigation and cytology on subsequent discharge
▪ Role has been questioned due to low sensitivity/specificity

o Ductography
▪ Can identify intraductal lesions
• Filling defect or duct cut off has high PPV for papilloma or carcinoma
▪ Painful therefore limited use
▪ Not widely practiced

o Cytology
▪ Poor sensitivity, limited use

o Mammogram
▪ If patient >35

o Ultrasound
▪ Can occasionally identify papillomas and malignant lesions in ducts close to nipple
• Next steps

o Single duct spontaneous discharge
▪ → surgery to determine cause if
• Blood stained discharge
• Persistent >2x/week
• Associated with a mass
• New serosanguineous discharge in postmenopausal women

Question 6

Mastalgia

Answer 6

• Symptoms
o Main consideration is referred pain vs breast pain
▪ Referred pain is unilateral, associated with activity, reproduced with pressure on chest wall
• NSAIDs relieve symptoms
o True mastalgia is associated with swelling and nodularity of breasts
▪ Resolves spontaneously in 20-40%, but can recur
▪ Worse before and relieved after menstruation
▪ Exacerbated by perimenopausal state, exogenous hormones (HRT, OCP)

• Aetiology
o Cyclical mastalgia thought to be related to excess prolactin, excess estrogen or lack of progesterone, or increased sensitivity of receptors in breast tissue

• Workup
o History as above
o Examine chest wall
▪ Roll patient and palpate chest wall
o Mammography if patient >40 years
▪ 5% of women with breast cancer complain of pain
▪ 2.7% women complaining of pain are diagnosed with cancer

• Management
o Exclude worrisome diagnoses
o Reassurance
o Analgesia
o Firm bra 24h/day
o Gentle stretching exercises, swimming
o Evening primrose oil not shown to be of benefit in RCA
o Phytoestrogens (soy milk, agnus castus – a fruit extract) – have been shown to have a mild benefit
o Reducing dietary fat intake (<15% dietary calories) – some benefit
o Severe symptoms
▪ Tamoxifen 10mg daily or danazol during luteal phase

Question 7

Sclerosing adenosis

Answer 7

o Present with palpable mass and breast pain
o Mammogram
▪ Microcalcifications
o Histology
▪ Fibrosis with excessive myoepithelial proliferation

Management
Excisional biopsy

Question 8

Radial scar and complex sclerosing lesions

Answer 8

o Radial scar <1cm, CSL>1cm
o Usually asymptomatic, found on mammogram
▪ Occasionally present as palpable mass
o Pathology
▪ Can serve as background for formation of ADH, CIS
o Can appear like malignancy mammographically, macro/histo
• Management
o High volume core biopsy or excision biopsy to exclude malignancy

Question 9

Pseudoangiomatous stromal hyperplasia of the breast

Answer 9

• Benign myofibroblastic proliferation of non-specialised mammary stroma
o Often incidental finding on biopsies
o Can be confused histologically with mammary angiosarcoma – needs IHC to distinguish

• Management
o Excision biopsy

Question 10

Fibromatosis

Answer 10

• Aka desmoid tumour of breast
• Features
o Infiltrative fibroblastic and myofibroblastic proliferation
o Risk of local recurrence but not metastases
o Rare, <0.2% all primary breast lesions
o Most likely arises from chest wall muscles

• Workup
o Biopsy – often core or vacuum assisted needle biopsies required
▪ If this insufficient, open excision biopsy required

• Management
o Observation only if confirmed diagnosis
o If becomes symptomatic (by invading chest wall and intercostal nerves) → pain → excision
o If recurs after excision, consider excision with 1cm margins

Question 11

Periductal mastitis

Answer 11

▪ Young women
▪ associated with smoking – toxic metabolites (lipid peroxidase, epoxides, nicotine, cotinine) accumulate
• Gram negative bacteria (smoking inhibits gram positive bacteria) or anaerobes/mixed
• Local ischaemia contributes due to microvascular changes from smoking
▪ May present with mass or abscess
• Often anaerobes
• High rate of recurrence

Treatment
o As for other abscesses (aspiration)
 30% get mammary duct fistula after incision & drainage
o Aim for excision 6 weeks after resolution of infection

Question 12

Mammary duct fistula

Answer 12

• Fistula between damaged / infected duct and skin
• Occurs in 1/3 patients after I+D periareolar abscess

• Management
o Fistulotomy – cut onto a probe into fistula and allow healing by secondary intention
▪ Painful, scarring is worse
o OR Fistula excision and primary closure
▪ Use circumareolar incision if possible for best cosmetic outcome
▪ Need to completely excise granulation tissue-lined tract and affected ducts under nipple

Question 13

Granulomatous mastitis

Answer 13

o Noncaseating granulomas and microabscesses within a breast lobule

o Epidemiology
▪ Rare
▪ Usually young women, not associated with smoking

o Presentation
▪ Firm irregular mass (may be suspicious for cancer)
▪ Multiple recurrent abscesses

o Aetiology
▪ Thought to be related to Corynebacterium but treatment of these infections does not seem to resolve infection

o Management
▪ Confirm diagnosis on biopsy
▪ Avoid excision of mass
• Usually has persistent wound discharge and failure of wound healing
▪ Steroids and immunosuppressants have variable efficacy
• Does improve symptoms but does not alter course of condition
• Controversial whether useful
▪ Treat superimposed infections as they appear and supportive therapy only
• Usually resolves spontaneously after 6-18 months

Question 14

Mondor’s disease

Answer 14

o Spontaneous superficial thrombophlebitis of a breast vein
▪ Thoracoepigastric vein
▪ Lateral thoracic vein
▪ Superior epigastric vein

o Thickened palpable cord with surrounding erythema
▪ Never involves upper inner part of breast
o Resolves spontaneously with NSAIDs and massage

Question 15

Gynaecomastia

Answer 15

• Definitions and epidemiology
o Hyperplasia of stromal and ductal tissue of male breast
▪ Pseudogynaecomastia → similar appearance but is related to excess adipose tissue not hyperplasia or stromal or ductal tissue
o Any age
o Common – 35% men
o Painful concentric swelling
o Benign and reversible

o Differential diagnosis is primary breast cancer
▪ Usually painless eccentric masses

• Aetiology
o Associated with Klinefelter syndrome
▪ Increased risk of male breast cancer
o Relative hyperestrogenism
▪ Decreased androgen production, increased estrogen production
▪ increased peripheral aromatization, reduced androgen receptors

o cause
▪ physiological
• neonatal, puberty, elderly
o usually self-limiting

▪ pathological
• → Klinfelter’s syndrome, hyperprolactinaemia, bilateral cryptochidism, testicular tumour, lung Ca, chronic liver disease, thyrotoxicosis, adrenal disease

▪ pharmacological
• increased beer or cannabis intake – phytoestrogens present in beer
• antiandrogens (spironolactone), gonadotrophin disturbance (H2 antagonists (cimetidine), antipsychotics, methyldopa), estrogen receptor competitors (digoxin, cannabis, griseofulvin), anabolic steroids
• antiretrovirals for HIV

▪ idiopathic

Clinical
o History to identify cause as above
o Examination of breast, axilla, testis, abdomen
o Investigations – aim to identify pathological cause or and exclude primary breast cancer
▪ Bloods – if rapidly growing gynaecomastia
• LFTs, renal function
• Prolactin, AFP, bHCG, total testosterone, TFTs
▪ Imaging – if indeterminate cause, suspicious for cancer or considering surgery
• Mammography / US +/- FNA or core needle biopsy
• US testis/abdo

• Treatment
o Reassurance
▪ 80% resolve in 2 years without treatment
o Stop drug if drug related
o Address underlying cause if pathological
o Medical management
▪ Tamoxifen 10mg daily or danazol 100mg BD for 1 week, TDS for 5 weeks
o Surgical management
▪ If medical failure or if large (class IIa/III)
▪ Technical aspects
• Periareolar incision
• Leave disc of breast tissue behind nipple with intact pectoral fascia and overlying fat to prevent retraction and fixation to muscle (saucer deformity)
• Keep thick skin flaps thick to reduce risk of skin necrosis
• If large consider free nipple grafts , excision of excess skin
▪ Risks
• Nipple necrosis, sensory changes, cosmesis

Question 16

FNA vs core biopsy

Answer 16

• FNA previous standard of care
o Easy to perform, rapid diagnosis
o No architectural information
o ER but no PR/HER2

• Core biopsy
o Improved sens and spec
o Architectural information
o ER/PR/HER2 receptor status

• FNA still useful for assessment of suspicious lymph nodes

Question 17

ADH

Answer 17

• Indicator of risk rather than a precursor lesion
• Diagnosis
o Found on core needle biopsy of mammographic microcalcifications

• Histology
o Proliferation of uniform epithelial cells with monomorphic round nuclei
▪ Fill part but not all of duct
o Similar to low grade DCIS but only involves <2mm

• Management
o Wire-localised excision biopsy to exclude associated malignant lesion
▪ 10-20% get upgraded to DCIS or cancer
o No need for re-excision if positive margins
▪ Unless positive only at margins which suggests missed lesion

Question 18

ALH

Answer 18

• Diagnosis
o Incidental finding on breast biopsy

• Histology
o Proliferation of monomorphic, evenly spaced dyshesive cells that fill but don’t expand a lobule
▪ Can also involve ducts

o Has same cytological and architectural features of LCIS, but is less quantitatively

• Management
o Concordant lesion, incidental ALH → no further treatment
▪ Upgrade to DCIS or cancer is <3% after biopsy

Question 19

DCIS

Answer 19

• Definition
o Clonal proliferation of malignant epithelial cells confined within basement membrane of mammary ducts, precursor lesion for invasive Ca

• Classification
o Subtype
▪ Comedo
• Central necrosis, multiple mitotic figures, large pleomorphic nuclei
▪ Non-comedo
• Absence of necrosis, no mitotic figures
• Solid, papillary, micropapillary or cibriform, flat (clinging) architecture

o Grade
▪ Low/intermediate/high
• Nuclear morphology
• Mitotic index

▪ High grade
• Necrosis, aggressive biologic characteristics
• High local recurrence rates

▪ I: irregular nuclei, small, no necrosis
▪ II: some necrosis, small nuclei
▪ III: pleomorphic nuclei, commedo necrosis

• Scoring system Van Nuys (Size, Margin, Age, Pathology) – for risk of local recurrence
o Lumpectomy alone for scores 4, 5, 6, lumpectomy and radiation for scores 7, 8, 9. Mastectomy for 10, 11, 12

• Clinical
o 90% asymptomatic
▪ Detected as pleomorphic or linear microcalcifications on mammogram
• Indeterminant calcifications can be examined using magnification views
▪ Incidental calcifications on mammogram that end up being malignant → • 65% pure DCIS • 32% DCIS with cancer • 4% breast cancer
▪ Sterotactic core needle biopsy shows diagnosis
o 10%
▪ Palpable mass
▪ Pagets
▪ Nipple discharge

Question 20

Indication of mastectomy in DCIS

Answer 20

• Preferred if:
o Multicentric DCIs
o Large lesions
o Centrally located disease
o Inadequate margins after re-excision after BCS
o Patient preference
o Adjuvant radiotherapy contraindicated

• Should have immediate breast reconstruction

Question 21

Margins for DCIS

Answer 21

2mm margin

Question 22

SLNB in DCIS

Answer 22

• Nodal metastasis in DCIS <3%

• Consider SLNB if
o Large DCIS >4cm
o Palpable breast lesion, ie mass forming DCIS
o High grade disease
o Microinvasive disease
o Suspicious nodes on examination of ultrasound o → these high risk features increase risk of invasive cancer to 20%)
o Mastectomy

Question 23

Indication of adjuvant radiotherapy for DCIS

Answer 23

• Indicated after BCS – reduces local recurrence (50%) but does not improve survival
• To chest wall if re-excision for local recurrence or positive margins
• 45-50G over 5 weeks

Question 24

Indication of hormonal therapy after DCIS surgery

Answer 24

Hormonal therapy (tamoxifen – NSABP-B24 trial)

• Recommended in patients with high risk of developing breast cancer, especially ER+ DCIS
• ER neg – no role

Question 25

LCIS

Answer 25

• Epidemiology o Usually presents in 40s ▪ Median age 44-46 (10 years younger than DCIS) ▪ 10% post menopausal o Increased risk of IBC (7-18x) ▪ 0.5-1% / year ▪ Cumulative risk 7.1% at 10 years = lifetime risk 30-40% ▪ 3x more likely in ipsilateral breast than contralateral breast • Pathology o LCIS subtypes ▪ Classic • Monomorphic population of small, round, polygonal/cuboidal cells • Thin rim of cytoplasm • High N:C ratio • Regular spaced, loosely cohesive • Fill and distend acini • Small nucleoli and a few mitotic figures • Pagetoid spread – neoplastic cells spread along adjacent ducts ▪ Pleomorphic (treat like DCIS as high risk) • Larger nuclei with prominent nucleoli and mitotic figures • Central necrosis, calcification within lobules o Diagnosis pathologically ▪ LCIS → 50% of acini in an involved lobular unit is filled and distended by LCIS cells • Therefore no central lumina ▪ ALH → cells fill <50% acini or no distension of lobule • Lumina visible 0.5-3.8% of otherwise benign breast biopsies • Clinical o Usually incidental finding after breast biopsy ▪ No specific symptoms, incidence in population therefore unknown o Often multifocal and bilateral ▪ 50% have multiple foci in same breast ▪ 30% have LCIS in contralateral breast • Management o Treat as risk factor for invasive breast cancer o Excision biopsy recommended to rule out malignancy ▪ Further resection required if pathology/imaging are discordant o Risk reduction ▪ BRCA1/2 – bilateral mastectomy ▪ Tamoxifen in high risk patients o Surveillance ▪ 6-12 monthly breast examination ▪ Annual mammogram

Question 26

Genes involved in breast cancer.

Answer 26

BRCA 1, BRCA 2, p53, STK 11, CDH1, PALB2, PTEN, ATM

Question 27

Pathophysiology of breast cancer.

Answer 27

o 95% sporadic, 5% hereditary o Sporadic tumours are related to estrogen exposure - early menarche - late menopause - nulliparity - COCP/HRT o Cyclical proliferation of glandular cells within breast related to oestrogen result in increased risk of DNA damage

Question 28

Morphology of breast cancer.

Answer 28

- ductal carcinoma - 80% - lobular carcinoma - 10% - tubular/cribriform - 5% - mucinous, medullary, micropapillary, metaplastic (5%)

Question 29

Features of invasive lobular cancer

Answer 29

- 5-10%  Presentation o often presents as an ill-defined thickening. o Calcification uncommon, mammogram may be normal or show asymmetry o FNA error-prone - ~50% false -ve o Tend to be larger at Dx, but biochemical/genetic features more favourable o If multicentric in 1 breast, 24% have +ve contralateral biopsy  Pathology o small cells, "Indian filing", multicentric. May have co-existing ductal component o Other pathological types - solid, alveolar, mixed o Cells are monotonous, -> grading is difficult o Pleomorphic type has nuclear pleomorphism and has poorer prognosis o Most show loss of expression of CDH1 which encodes E-cadherin - ER/PR positive, HER 2 negative Prognosis o As larger and can be multicentric, more often need mastectomy compared with IDC o patients with ILC tended to be older and have lower grade tumours, hormone-receptor positive, of larger size and with absence of vascular invasion.  ILC showed indolent but progressive characteristics with nearly linear survival curves that crossed those of IDC after approximately 10 years of follow-up, thus eventually exhibiting a worse long-term outcome.  Secondaries to meninges, serosa, GIT, genital tract, adrenal, other unusual sites

Question 30

Grading of breast cancer.

Answer 30

- Bloom-Richardson grade (TNM). - Tubule formation (majority, moderate, little or none) - Nuclear size/pleomorphism (small, moderate, marked variation) - Mitotic rate ( 0-5, 6-10, >11) Grade 1 - 3-5 Grade 2 - 6-7 Grade 3 - 8-9

Question 31

ER/PR

Answer 31

- Both ER & PR are steroid receptors located in the cell nucleus  Measured using IHC (immunohistochemistry) - recognition of receptor by Ab  Only nuclear (not cytoplasmic) staining indicates a +ve result  Include in report: o an estimate of the % of nuclei stained o the predominant intensity of staining (low, intermediate or high) o a conclusion as to whether the assay is positive or negative  e.g. ≥1% nuclei staining at any intensity (low, intermediate or high)  What percentage of patients respond to hormonal treatment? o 30% of all comers o 50-60% of oestrogen receptor positive tumours o up to 80% of oestrogen/ progesterone receptor positive tumours

Question 32

HER 2

Answer 32

 Human Epidermal Growth Factor Receptor 2  Encoded by ERBB2, a proto-oncogene on chromosome 17  Can heterodimerise with any of the other 3 receptors o Results in autophosphorylation of tyrosine residues -> signalling pathways -> increased cell proliferation -> decreased apoptosis  HER-2 is over-expressed in 25-30% of breast cancers (gene amplification & up-regulation, not mutation)  HER2 status predicts the response to specific antibody therapy, and several other systemic therapies (e.g. good response to anthracycline chemo, poor response to endocrine Rx), as well as being a general prognostic marker  HER2 assays - currently available techniques for routinely evaluating HER2 status include o immunohistochemistry for detecting protein overexpression and  A positive HER2 result is 3+, uniform, intense membrane staining of > 30% of invasive carcinoma cells.  A negative result is 0 or 1+ staining.  An equivocal result is 2+. (In this case, in situ hybridisation testing is required.) o in situ hybridisation for detecting gene amplification.  E.g. chromogenic in situ hybridization (CISH), fluorescence in situ hybridisation (FISH)  FISH measures number of copies of HER2 gene on CH17 (>2 = +ve)

Question 33

Ki6

Answer 33

▪ Marker of proliferation -MIB-1 monoclonal antibody staining

Question 34

Mollecular profiling/subtypes

Answer 34

 Luminal A: 50%. Low grade. ER+, PR+, HER2 – [Ki67<14%]  Luminal B: 10%. Higher grade. ER+, PR+/-, HER2 +/- [Ki67>14%]  HER2 enriched: 5-10%. High grade. P53 mutation, ER-, PR-, HER2+  Basal: 30%. Mostly “triple negative”, high grade. ER-, PR-, HER2-

Question 35

Oncotyping for breast cancer

Answer 35

-Clinical gene expression assays: eg Oncotype DX. -21 gene reverse transcription PCR assay on tissue provides indepedent prognostic information (individualised risk estimate/recurrence score (0-100) -low<18, inter 18-30, high >30

Question 36

Breast screening.

Answer 36

o 2 yearly mammogram (sensitivity 80%, specificity 90%) for patients aged 50-74 years ▪ Women 40-49 or >75 can also access screening program - asymptomatic - ADH, LCIS, ALH -> annual screening - hx of breast cancer >5 years since diagnosis -> annual screening - 200 women, 100 screened, 5 women recalled (4 further imaging, 1 biopsied), 1 cancer. - early detection benefits -> increased survival, increased treatment options, improved quality of life. - reduction in breast cancer mortality highest in 50-69yo (21-28%).

Question 37

WHO principles of screening.

Answer 37

1) important health problem 2) recognisable latent or early symptomatic stage 3) disease process well understood 4) acceptable treatment for patients with disease 5) test with high level of accuracy 6) test accceptable to the population 7) facilities for diagnosis and treatment 8) agreed policy on whom to treat as patients 9) cost should be economical 10) screening should be a continuining process

Question 38

Managing risk -> average or slighly higher risk (1.5x)

Answer 38

95% population Criteria  - No FHx of breast cancer  - One FDR diagnosed with breast cancer ≥50yo  - One SDR diagnosed with breast cancer at any age  - 2 SDRs on the same side of the family diagnosed with breast cancer ≥50yo  - 2 FDRs or SDRs diagnosed with breast cancer ≥50yo, but on different side of the family  Management  Usual screening 

Question 39

(Managing risk breast cancer) Moderately increased risk 1.5-3x (<4% of the female population) 

Answer 39

Criteria  -One FDR diagnosed with breast cancer <50yo  -2 FDRs on the same side of the family diagnosed with breast cancer  -2 SDRs on the same side of the family, at least one <50yo  Management  At least 2 yearly MMG from 50-74yo  Annual MMG from 40yo if FDR diagnosed <50yo  Consider tamoxifen for risk reduction 

Question 40

(Managing risk breast cancer) High risk >3x, or carrying a mutation (<1% female population) 

Answer 40

Criteria  -Women at potentially high risk of ovarian cancer  -3 or more FDRs or SDRs on the same side of the family with breast or ovarian cancer  -2 or more FDRs or SDRs on one side of the family diagnosed with breast or ovarian cancer if any of the following applies to at least one of the relatives:  -Breast cancer <40yo  -Ovarian cancer <50yo  -Bilateral breast cancer  -Breast and ovarian cancer in the same woman  -Ashkenazi Jewish ancestry  -Male breast cancer  -One FDR or SDR diagnosed <45yo plus another FDR or SDR on the same side of the family with sarcoma <45yo  -Member of family in which presence of a high risk breast cancer gene mutation has been established  Management  -Individualised surveillance program - may include regular clinical examination and annual breast imaging with MMG, MRI or U/S  -MRI screening rebated by Medicare for screening of asymptomatic women <50yo who are high risk due to strong family hx or genetic mutation  -Referral to cancer specialist of family cancer clinic for risk assessment, possible genetic testing  Risk reduction strategies  -Bilateral mastectomies (>30yo)  -Aim to reduce risk as close to 0% as possible  -4% recurrence at 10 years  -BSO (>40yo)  -Lifetime ovarian ca risk  -BRCA1 - 40-50%  -BRCA2 - 10-20%  -96% risk reduction  Reduces breast cancer incidence 30-45%  Early BSO not recommended  Average age ovarian ca 51yo  Premature menopause -> require HRT -> increased cancer risk again 

Question 41

What is BIRADS classification?

Answer 41

- Breast imaging, reporting, and data system. - 7 categories. 0 - incomplete (needs further imaging) 1 - negative (routine screening) 2 - benign (routine screening) 3 - probably benign (risk of Ca <2%, short interval f/up) 4 - suspicious (risk of Ca 2-95%, biopsy) 5 - highly suggestive of malignancy (risk of Ca >95%) 6 - biopsy proven Ca

Question 42

Types of biopsy on a breast lesion.

Answer 42

o Core needle biopsy is preferred ▪ Sensitivity 95-99% vs FNA 70-90% ▪ Provides histological and architectural information rather than just cytology o Image guided ▪ Ultrasound preferred if lesion visible on ultrasound or palpable ▪ Alternative is stereotactic using mammography-guidance o If unable to safely biopsy lesion ▪ Can place guidewire and perform surgical excision biopsy o Discordance ▪ Imaging suggestive of malignant but biopsy is benign → excision biopsy to exclude malignancy

Question 43

Staging for breast cancer

Answer 43

-TNM staging. T stage - Tis: carcinoma in situ - T1: <2cm - T2: 2-5cm - T3: >5cm - T4a: chest wall - T4b: satellite - T4c: a+b - T4d: inflammatory breast cancer N stage - N1: 1-3 LN (axillary) - N2: 4-9 LN or internal mammary without axillary - N3: 10+ LN or infraclavicular, int mammary, supraclavicular with axillary M stage - M1: distant mets

Question 44

Breast conserving: WLE + RTx.

Answer 44

o Survival equivalence to mastectomy. LR rates ~14% BCS + RT vs 10% Mastec. (LR 35% without RT) o Contraindications: muticentric/multifocal, extensive DCIS or indeterminant calcs, locally advanced or inflammatory br ca, tumour to breast ratio >20%, relative contra in BRCA. o Localisation: palpation, image guided HWL (US, stereo), radionucleotide seed implant, Bx clip, carbon o Procedure: Incision over tumour (curvilineal skin tension lines or radial in inf/medial breast), excise with adequate margins (>2mm microscopically clear), orientate, specimen imaging

Question 45

Contraindication of nipple areolar complex sparing mastectomy.

Answer 45

- extensive DCIS - tumour >4cm - <2cm from NAC - inflammatory breast ca

Question 46

Indications for axillary clearance.

Answer 46

- palpable lymphadenopathy - FNA pos node - T4/inflamm tumour - Pos SNBx (>3 nodes, [consider in 1-2 macromets], T3 tumour, mastectomy, no breast radiation)

Question 47

Indications for radiotherapy as adjuvant treatment.

Answer 47

o Post WLE: 6/52 whole breast external beam radiation + boost to tumour bed o Post mastectomy: positive margins, nodal disease >3 or 2 (with 15yr life expectancy), T3/4 tumour

Question 48

Locally Invasive Breast Cancer Definition

Answer 48

 <5cm  impalpable or palpable but not fixed nodes  no mets  T1-2, N0-1, M0

Question 49

Risk of breast cancer with benign breast disease.

Answer 49

- no proliferative aspect - no increased risk o proliferative -

Question 50

Staging in breast cancer

Answer 50

clinical stage III disease further investigation is warranted (staging). o CA 15.3 o Bone scan o CT CAP

Question 51

ITC vs micro vs macromets

Answer 51

ITC -> <0.2mm micrometastases - 0.2mm - 2mm macrometastases - >2mm

Question 52

Synoptic report for breast cancer

Answer 52

 Site o E.g location in mastectomy, distance from margins  Tumour type  Invasive carcinoma size & lesion size o E.g. 3mm invasive in 10mm DCIS  Grading (Bloom & Richardson -> Tubular formation, Nuclear size/score, Mitotic rate; grade 1 3-5, grade 2 6-7, grade 3 8-9) - LVI - resection margins (invasive Ca -> no tumour on ink, DCIS -> 2mm) - receptors (ER/PR/HER 2) - DCIS - other findings (ALH/ADH) - axillary findings (SLNBx vs ALND; no of pos nodes; no of nodes harvested; ITC vs micro vs macromets; extranodal extension)

Question 53

Trastuzumab (Herceptin)

Answer 53

 Humanised monoclonal Ab to EC domain of HER2 protein  Patients with early breast cancer are eligible for immunotherapy with trastuzumab only if HER2 gene amplification has been demonstrated by in situ hybridization (41% of FISH +ve respond to herceptin, 5% of FISH -ve)  Patients with metastatic disease are eligible for trastuzumab therapy if a 3+ positive result has been demonstrated by immunohistochemistry or HER2 gene amplification has been demonstrated by in situ hybridisation.

Question 54

Contraindications of WLE

Answer 54

o T4, N2 or M1 o Patient choice o Clinically/radiologically evident multifocal/multicentric disease o Large/central tumours in small breasts o High risk women (FHx, BRCA) o Contraindication to XRT  Pregnancy  Previous XRT  Collagen vascular diseases

Question 55

Types of breast reconstruction

Answer 55

Immediate vs delayed Autologous vs implant

Question 56

Immediate breast reconstruction

Answer 56

 Advantages o No loss of ‘breast’ o Single operation & hospital stay o Preservation of skin & inframammary fold o Skin-sparing & subcutaneous mastectomy techniques can lead to better cosmetic result  Disadvantages o Limited time for decision-making o increased operating time o difficulties of co-ordinating two surgical teams  does not compromise adjuvant treatment o although complications could result in delay in starting adjuvant treatment  Adjuvant radiotherapy o Can have detrimental effects on breast reconstructions o These can be decreased by choosing autologous over implant o Consider delayed-immediate reconstruction

Question 57

Delayed breast reconstruction

Answer 57

 Advantages o Unlimited time for decision-making -> Full pathology available o Avoids any potential delay of adjuvant treatment o Avoids detrimental effects of adjuvant therapy on reconstruction  Disadvantages o Skin-sparing mastectomy techniques can’t be used (poor aesthetic outcomes of contracted skin envelope)  larger skin paddle required o needs 2nd operation/hospitalisation

Question 58

Implant based reconstruction

Answer 58

 Tissue expansion o Serial expansion of chest-wall to replace skin lost with mastectomy o ± replacement with silicon implant o difficult to create ptosis  best result with bilateral procedures  Indications o Small, non-ptotic breasts o Bilateral reconstruction o Unwilling/unfit to undergo autologous  Contraindications o Very thin chest-wall tissues o Mastectomy skin flaps threatened o Absent pec major o Radiotherapy significantly increases risk of complications & decreases aesthetic result  Surgical techniques o Tissue expander under pec major o Weekly serial expansion after 2-4 weeks o 1-3 months after maximal expansion – expander removed, capsulectomy & definitive implant o 30% will need further surgery within 1st 5yrs to optimise aesthetic appearance o long-term aesthetic results decrease with time (ptosis of contralateral breast -> asymmetry)  Complications o Early: haematoma, infection, skin flap necrosis, wound dehiscence o Late: implant rupture, malposition, extrusion, capsular contracture (increased after XRT), breast implant associated - anaplastic large cell lymphoma)

Question 59

Autologous breast reconstruction

Answer 59

 Indications o Immediate reconstruction when adjuvant radiotherapy planned o Delayed reconstruction following adjuvant XRT o Large ptotic breasts o Failure of previous implant reconstruction  Pedicled Latissimus dorsi flap o Usually combined with an implant o Lowest flap failure rate o Indications  High risk for autologous reconstruction  Abdomen unsuitable as donor site o Disadvantages  Scar on back  Shoulder stiffness & impairment of upper limb function o Complications  Early: haematoma, infection, breast skin necrosis, partial/complete flap failure  Late: seroma, implant Cx - Lower abdominal flaps o Contraindications  Absolute  Previous ligation of flap pedicle  Previous abdominoplasty  Relative  Multiple abdominal scars  Previous abdominal liposuction o Surgical techniques  Transverse rectus abdominus myocutaneous (TRAM) flap -> Pedicled or free  Deep inferior epigastric perforator (DIEP) flap o Complications  Early: Thrombosis of arterial or venous anastomosis, Haematoma, Partial or total flap loss, Fat necrosis, Wound breakdown  Late: Donor-site bulge or hernia, decreased abdominal strength

Question 60

SNAC (SN bx vs AC)

Answer 60

o Multicentre randomised controlled trial o SNAC 1  Is SNB associated with less morbidity and equivalent cancer-related outcomes than AC in early breast cancer?  Yes (decreased arm swelling & functional problems) o SNAC 2  Extended eligibility  1o tumours >3cm, multiple tumours in same breast  endpoints: local axillary recurrence, diagnostic accuracy of SNB

Question 61

Management of breast cancer in pregnancy.

Answer 61

 Local o Risk of spontaneous abortion highest in 1st trimester o Mastectomy is procedure of choice, especially if 1st trimester (delay to XRT) o Breast conserving surgery is feasible in 2nd & 3rd trimesters  Axilla o SLNB  can be performed with lymphoscintigraphy, effect of blue dye (& risk anaphylacxis)  Systemic o Chemo contraindicated in 1st trimester but can be given safely in 2nd & 3rd  Recommended in node +ve disease (within 6 weeks of surgery) - If using trastuzumab – monitor for oligohydramnios  Should be stopped 3 weeks before delivery to avoid myelosuppression & septic complications in mother & baby o Endocrine Rx not recommended  Locally advanced & inflammatory cancer o 3 strategies  termination of pregnancy  chemo with acceptance of foetal risks  delay cancer Rx with acceptance of cancer risks  Future pregnancy o Counselling re effect of chemo o Should wait at least 6 months after completion of treatment  Prognosis o Tends to be Dx at more advanced stage o More likely to have large tumours, LVI & mets

Question 62

Indications for neoadjuvant chemotherapy in breast cancer.

Answer 62

▪ Downstaging to facilitate BCS rather than mastectomy ▪ Unresectable / locally advanced tumours ▪ Node positive disease ▪ Inflammatory breast cancer ▪ Delay to surgery (pregnant, recent AMI) ▪ Consider in triple negative or HER2 enriched

Question 63

Work up pre neoadjuvant chemotherapy and post neoadjuvant management.

Answer 63

▪ Needs extensive workup before starting treatment • Core biopsy of breast • Mark tumour and positive axillary nodes • Axillary imaging • Breast MRI to assess radiological response pre and post treatment • Formal staging o Bloods o CT chest abdo pelvis o Bone scan o +/- PET CT ▪ Assess response after 2-4 cycles • If responsive, continue for 8 cycles and then assess suitability for surgery • If unresponsive, change chemotherapy regimen or use RTX and reassess ▪ Managing axilla • If clinically negative, perform SLNB after neoadjuvant chemotherapy • If clinically positive, restage axilla after neoadjuvant chemotherapy o If remains positive → axillary dissection o If becomes negative → targeted biopsy + SLNB in select cases or ALND

Question 64

Add axilla RTX after ALND.

Answer 64

o ECE, perinodal fat invasion, large number of +ve nodes, <10 axillary nodes dissected

Question 65

Adjuvant endocrine treatment

Answer 65

Treat all ER positive tumours using SERM (tamoxifen) or aromatase inhibitor (anastrozole) ▪ SERMs - Selective oestrogen receptor modulators (SERMs) are competitive ER antagonists with partial agonist activity. - tamoxifen 20mg/d. • For premenopausal women • Recommended treatment for 5 years o Decreases risk of death by 1/3 • Small increased risk of uterine carcinoma and venous thrombosis ▪ AIs - block conversion of adrenally synthesized androgens to oestrogen - Exemestane, anastrazole, letrozole • For post menopausal women • Slightly kore efficacious • Duration is unclear, some advocate for lifelong if high risk. Otherwise 5-10 years is a good start • Side effects o Osteoporosis, vaginal dryness and atrophy, dyspareunia - Zoladex - oophorectomy

Question 66

Adjuvant chemotherapy

Answer 66

AC followed by T – 3-4 cycles AC x2-3 weeks then 3-4 cycles T x 2-3 weeks = 12-24 weeks ▪ Anthracycline (Doxorubicin) • Cardiotoxicity ▪ + Cyclophosphamide, • Haemorrhagic cystitis ▪ Followed by Taxane (Paclitaxel) • Peripheral neuropathy

Question 67

Indications for referral to genetics

Answer 67

1) Pathogenic variant identified in the family. 2) Tumour pathology - TNBC <=50 years 3) Personal hx of cancer - male breast cancer - breast cancer and Jewish ancestry - Two primary breast cancers in the same person (where the first <60 years) - Two or more different but associated cancers in the same person (breast and ovarian Ca) - breast cancer <=40years - lobular breast cancer + family hx of lobular breast/diffuse type gastric Ca - breast Ca Dx <50 years with limited family structure/knowledge - breast Ca + family hx of Peutz-Jegher/Cowden/Li Fraumeni 4) For those with family hx of cancer - Two 1st or 2nd degree relatives diagnosed with breast or ovarian cancer plus one or more of the following on the same side of the family:* + additional relative(s) with breast or ovarian cancer +breast cancer diagnosed <50 years +more than one primary breast cancer in the same woman +breast and ovarian cancer in the same woman +Jewish ancestry +breast cancer in a male +pancreatic cancer +high grade (> Gleason 7) prostate cancer

Question 68

Indication to test for BRCA 1 and 2 pathogenic variant

Answer 68

Manchester score >= 15 (10% probability) The scoring system includes information of the Age Dx of cancer, breast cancer histology, grade and receptors, ovarian cancer pathology, lack of family hx

Question 69

Paget's disease of breast

Answer 69

- Definition Malignant intraepithelial adenocarcinoma of the nipple-areolar complex (pagetoid cells) - Pathology o Pagetoid cells ▪ Large round or oval cells with large pleomorphic, hyperchromatic nuclei ▪ Prominent nucleoli ▪ Clear, pale cytoplasm o Reactive epidermis/dermis changes with lymphocytic infiltration and angiogenesis ▪ Hyperaemic, exudative appearance • Pathogenesis – 2 theories o 1- in situ transformation theory: pagetoid cells are keratinocytes that have undergone malignant transformation o 2 – epidermotropic theory: cells migrate along basement membranes and enter epidermis and nipple-areola complex from ducts - Workup o Biopsy if not clearly contact dermatitis ▪ Punch biopsy • If non-diagnostic → excision biopsy ▪ Histology shows • → pagetoid cells, IHC positive for CK7, CAM-5.2, AE1/AE3, S100 o Note HMB-45, keratinins are negative (melanoma) • 90% are HER2 positive o Bilateral mammography, and ultrasound ▪ Standard investigation of lesion if found ▪ Consider MRI if select patients – mammogram can miss many underlying cancers in pagets • Management o Nipple areolar complex involvement only ▪ Treat as DCIS ▪ Resection of nipple areolar complex + adjuvant radiotherapy • OR mastectomy with SLNB ▪ Adjuvant hormonal treatment • Recommended if ER+ o Underlying tumour ▪ Total mastectomy or central lumpectomy (if centrally located) with radiotherapy • Mastectomy if underlying tumour is distant from nipple areolar complex ▪ SLNB

Question 70

Pathogenesis of duct ectasia

Answer 70

Theories o ?aberration of processes of normal duct involution o Hormonal  Endocrine-induced relaxation of contractile, myoepithelial elements of duct wall  However Dexon et al found no relation between parity/breastfeeding & duct ectasia o Obstruction & stagnation  Terminal portion of duct often blocked with squamous cells o 2o inflammation o Lymphatic blockage

Question 71

Lactational mastitis

Answer 71

 Epidemiology o Most common type of infectious mastitis o 2-10% of breastfeeding women  Aeitiology o Usually associated with breastfeeding problems o Risk factors:  Mastitis with previous child  Severe prolonged unilateral engorgement  Nipple cracking  Investigations o Milk culture may help if hospital-acquired or not responding to Abx o U/S to exclude abscess o MRI if inflammatory breast cancer is suspected  DDx o Blocked lactiferous duct – tender, palpable lump without systemic un-wellness o Galactoceles – milk retention cysts. Not tender or systemically unwell o Inflammatory breast cancer – peau d’orange  Microbiology o Staphylococcus aureus o increasing incidence of MRSA o less frequent: S. pyogenes, E. coli, bacteroides, Corynebacterium spp, coagulase negative staphylococci  Treatment o Symptomatic relief o Breast emptying (improve breastfeeding techniques) o Antibiotics (cephalexin, clindamycin if suspect MRSA) o U/S if no improvement in 48-72hrs

Question 72

Post-irradiation mastitis

Answer 72

o related to obstructed lymphatic flow & responds to manual lymphatic drainage

Question 73

Male breast cancer

Answer 73

• Epidemiology o 1% all breast cancer o 0.1% cancer death in men o Male breast cancer belt → Atlantic to Indian oceans in sub-Saharan Africa (Tanzania 6% of breast cancers) • Pathology o 90% are invasive ▪ 10% DCIS o 80% ductal 5% papillary 1% lobular ▪ Similar proportions to breast cancer in female o Hormone status ▪ ER+/PR+ more likely in males ▪ HER2 data inconclusive • Clinical o Increasing incidence with age ▪ Age of diagnosis 10 years later in men than women o Painless mass ▪ 85% of presentations o Usually centrally located with nipple retraction, discharge, pain, ulceration ▪ 50% of presentations o Often delayed diagnosis ▪ 22 months average from symptoms to diagnosis o Risk factors ▪ Hormonal misbalance • Obesity, cirrhosis (hyperestrogenic milieu) ▪ Klinefelters – 50x increased risk • 47XXY karyotype • Small testes • Gynaecomastia ▪ Family history • 15-20% male breast cancer has family history o Probably related to BRCA1 and BRCA2 carriage ▪ Radiation exposure ▪ Obesity ▪ Gynaecomastia is not a risk factor - Treatment o Early breast cancer ▪ Mastectomy • Resect part of pectoralis major to get negative margin if required o Locally advanced disease ▪ Neoadjuvant therapy then surgery as for female breast cancer o Axillary staging ▪ As for female breast cancer o Adjuvant therapy ▪ As for females • Treatment of metastatic disease o Hormone receptor positive ▪ Tamoxifen is drug of choice • Aromatase inhibitors less effective because o only partially block production (80% peripheral, 20% testis) o decreased estrogen stimulates testicular production by feedback to hypothalamus • aromatase inhibitors therefore should only be used in conjunction with orchidectomy (medical or surgical) o HR negative ▪ Chemotherapy

Question 74

US features of abnormal LN

Answer 74

 Round  Loss of fatty hilum  Thickened cortex (>3mm)

Question 75

US features of malignant masses

Answer 75

o Irregular shape o Indistinct, microlobulated, spiculated margins o Height > length o Hypoechogenicity o shadowing

Question 76

Lymphoedema

Answer 76

Definitions and epidemiology o Abnormal accumulation of interstitial fluid and fibroadipose tissue due to impaired lymphatic drainage Pathophysiology • Normal flow o Lymphatic capillaries normally uptake interstitial fluid in low flow state ▪ Facilitated by skeletal muscle contraction o Capillaries merge into vessels which have specialized smooth muscle providing peristaltic contraction o Lymphatic vessels have unidirectional valves o Vessels drain into thoracic duct which enters left subclavian vein and left IJ junction ▪ Right upper body drains into right lymphatic duct via similar IJ SC vein junction • Lymphoedema o Occurs when lymphatic load exceeds transport capacity of lymphatic system causing fluid accumulation in interstitium o Imbalance occurs ▪ Congenital malformation of lymphatic system ▪ Damage to lymphatic vessels or lymph nodes o Persistent accumulation of lymphatic fluid promotes proliferation of adipocytes and deposition of collagen in the ECM resulting in fibroadipose tissue accumulation ▪ Inflammatory response with macrophages, fibroblasts → fibrosis, adipose hypertrophy, acanthosis, hyperkeratosis ▪ Predisposes to recurrent cellulitis and lymphangitis ▪ Chronic lymphoedema can degenerate to an aggressive lymphangiosarcoma (Stewart Treves syndrome) o NOTE ▪ Rate of capillary filtration remains normal • In generalised oedema, intact lymphatics are overwhelmed by excessive capillary infiltrate

Question 77

Causes for lymphodema

Answer 77

Primary - congenital -lymphodema precox (<35) - lymphodema tarda (>35) Secondary (TRIMS)

Question 78

Staging of lymphodema

Answer 78

0 - no odema, subclinical 1 - pitting odema, resolves with elevation, no fibrosis 2 - non pitting odema, not resolves with elevation, mild fibrosis. 3- lymphagiostatic elephantiasis, non pitting odema, not resolves with elevation, severe fibrosis

Question 79

Managemet of lymphoedema

Answer 79

• General measures o Self-monitoring o Limb elevation o Diet and exercise (weight loss) o Avoid skin infection/injury ▪ Treat cellulitis aggressively ▪ Avoid blood tests / IVCs ▪ Avoid limb constriction with blood pressure cuffs (LND but not SLNB) • Compression therapy o Compression bandaging o Compression garments o Intermittent pneumatic compression • Physiotherapy o Manual lymphatic drainage o Complete decongestive therapy o Surgery • Lymph node transplantation • Lymphovenous bypass ▪ Debulking procedures to remove fibrofatty tissue deposits -> Liposuction