Knowledge is a burden,If it robs you of innocence,If it makes you feel you are special, If it gives you an idea you are wise, If it is not integrated into life,If it does not bring you joy,If it does not set you free.Sri Sri Ravi Shankar, Humanitarian and founder of the Art of Living Foundation, India.

CPC 4.5 – 42y Woman, sore R. breast.

“odd change in my left breast when I was showering last week” Duration. Noticed it 8 days ago What? “My left breast feels a bit thicker – points to upper outer quad* Pain No, Nipple discharge: No, Trauma to breast: No Menstrual cycle: regular, Mastalgia: not usually LMP: about 4/52 ago; K due now. Age of menarche: 13 years*, Parity: none* (failed IVF / infertility*) Appetite, Weight : stable* was on COCP* ages 17yrs – 30 yrs. Cervical smear: Never* Menarche aged 13yrs* Has never had mammogram/breast USS* ‘I check regularly’ *

Mrs JM is a 45y old woman, primary school teacher, living in Weipa.

CPC 4.5- Examinationo R breast NAD, L breast firm thickening ? upper

outer axillary tail ?; no discrete mass ? no skin tethering ? / changes; no nipple inversion ?; no areola changes ?, no axillary or supracla. LN. No nipple discharge(blood/pus) ?

What Differentials: Benign proliferations, Breast malignancy What further investigations? Mammogram, FNAB, CT Scan, PET Scan,

Biopsy + immunochemistry (HER2) ?

Key .. ?FibrocysticTumorCancerCancerPaget’sCancerPapillomaDuct ectasia

Labs:ERPRHER2BRC

CPC 4.5- Examination Mammogram – solid* non mobile* irregular* mass lying at

the 10 o’clock position of the L breast. Mass has prominent radiating spicules*; 2 x small calcifications* within the mass. Overall mass 1x 1.5x 1cm.

US guided FNAB: High grade infiltrating ductal carcinoma ? CT scan: no sign metastatic disease in liver or lung Bone scan: no sign of metastases. Immunochemistry : ER: ++ PR: neg HER2: +++.. ? ? ?

(? Sub types, Luminal B)

CPC 4.5 – 42y Woman, sore R. breast.

2013 Term 4 CPC 5 Title: Breast Cancer System: Breast

Aim: Clinical, Pathology & population study of patients breast disease

Learning outcomesThe student will be

able to

1. Demonstrate competency in history taking & the clinical examination of patients with breast disease.

2. Describe the first line investigation and management of patients with breast disease or symptoms.

3. Describe the Pathophysiology of breast disease (benign and malignant)

4. Outline the basic sciences relating to function of the breasts.

5. Describe the Epidemiology and aetiology of breast disease in Australia and world wide.

6. Illustrate the advantages and disadvantages of the breast screening program in Australia

CPC 4.5- Core Learning Issues

Pathology Major CLI:• Pathology of Breast – overview, classification & common dis..• Breast Lumps - Differential diagnosis.• Trauma, infections & Inflam. – Mastitis, fat necrosis, abscess.• Hyperplasia – Fibrocystic disease• Tumours – Benign – Fibroadenoma, giant fibroadenoma. • Breast cancer – etiology, pathogenesis, morphology &

complications, Laboratory diagnosis, including markers.

Pathology Minor CLI:• Duct ectasia,• Breast Cysts.• Paget’s disease.• Gynecomastia & male breast disorders.

Case studies: 22year female, noticed small mobile round

lump in her right breast, lower inner quadrant. 39year female, multiple small lumps, irregular,

firm, tender more during mid cycle. 41year female, two left axillary LN, no pain, no

breast mass. mild loss of weight. 34year female, diffuse firm left breast. FNAC

reports abnormal cells. No LN. 39year female, painful lump, chronic pus

discharge from nipple. 71year old female. Rough, red scaling pruritic

patch on left nipple and areola. 26y nurse, right breast lump 5m, firm irregular,

6cm firm, fixed lump.

• Fibroadenoma

• Fibrocystic dis

• Ca breast.

• DCIS

• Duct ectasia

• Paget’s dis

• BRCA Ca.

Self assessment: Clinical features of benign, malignant & reactive… Breast cancer screening guidelines. Hyperplasia / tumour features. Familial vs Non familial breast Ca features. Screening Mammogram – policy, procedure &

interpretation. Fibrocystic disease, fibroadenoma & cancer. Breast cancer common types & features (gross,

microscopy, complications etc.) Duct carcinoma, lobular carcinoma, other types. BRCA testing in familial breast ca.

“Strength does not come from winning, Struggles & Hardship develop strength.

- - Arnold SchwarzeneggerBodybuilder, Actor & Leader.

Pathology of Breast

Dr. Venkatesh M. ShashidharAssociate Prof. & Head of Pathology

CPC- 44 – Core learning Issues Major CLI:

Pathology of breast diseases – over view Congenital, Inflammatory & Neoplastic disorders. Breast Lumps – Hyperplasia – Fibrocystic disease. Benign neoplasms: Fibroadenoma, Duct papilloma &

Breast cancer – Ductal Carcinoma & DCIS. Minor CLI:

Cong: Hypertrophy, atrophy, accessory, supernumerary..

Mastitis (acute/chronic), Breast trauma, fat necrosis. Phyllodes tumor, other carcinoma (Lobular etc) Duct ectasia. Paget’s disease.

Introduction: Anatomy

Modified sweat glands.Lobes and lobules of gland in fat tissue stroma.Ducts emerge from acini of glandsSmaller ducts join to form

lactiferous ductsLactiferous ducts merge just

beneath the nipple to form a lactiferous sinus.

Then individually open on nipple

Anatomy

T4 level

Breast Physiology:

Male

Female

Normal Breast – glands & stroma

Dense stroma

Loose stroma

Acinus

Normal Breast – glands & stroma

Dense stroma

Loose stroma

Acinus

Breast – Acini (SEM)

Age changes in breast:

Puberty Adult (Lactating) MenopauseFibrous Fibro-Fatty Fat

Disorders of Breast: Congenital

Aplasia : turners / Juvenile hypertrophy Accessory/ectopic breasts – along milk line

Inflammatory Acute: lactational* / Chronic Mastitis Trauma – Traumatic Fat necrosis Duct ectasia – chronic, discharge, sinus, Galactocele

Proliferative Conditions Fibrocystic disease – common cause of lumps Cysts, Adenosis, Metaplasia & mixed.

Neoplastic Benign – Fibroadenoma, duct papilloma Malignant – Ductal Carcinoma & DCIS – several types.

Disorders of Breast:

Gynecomastia: Breast enlargement in men. Estrogen excess – Klinefelter’s,

Hyperthyroidism, pituitary & adrenal tumors, testicular failure, hormonal.

Liver failure, cirrhosis Lung, Testicular Cancer diethylstilbestrol therapy for

prostatic carcinoma. Drugs (Spironolactone, H2

antagonists, Neuroactive agents). Microscopy – only duct & stromal

hyperplasia. (no acini)

Acute Mastitis: Acute Mastitis:

Non Lactational (central, periductal, rare)

Lactational (periphery, common) First few weeks after delivery. Crack in the nipple – entry point. Staph. aureus, Strep. pyogenes. Localized inflammation, Swelling erythema

& pus.

Chronic Mastitis: Granulomatous (TB, Fungal, Silicone

etc.) Traumatic fat necrosis: Chronic

granuloma, foam macrophages, radial scar – dd Ca.

Diabetic mastopathy: DM1, rubbery lymphocytic.

WBC in gland/duct

Enlarged Ax. Ln

Duct Ectasia:

>50y, multiparous. Periareolar mass with white, cheesy nipple discharge.

Duct obstruction/destruction, inflammation, dilation, fibrosis with fat globules & foamy macrophages in lumen.

Recurrent abscess / fistula. Scarring with nipple inversion may

mimic Ca.

Inflam

Foamy lipid Macrophages

Dilated duct

Mimics Ca.

Lump in Breast: Diagnosis & FeaturesClinical presentation <25 years 25-35 years 35-55 years >55 years

Mobile lump (single) Fibroadenoma Fibroadenoma FibroadenomaPhyllodes tumour

Phyllodes tumour

ill-defined lump/s or lumpy areas – cyclic pain.

Uncommon Fibrocystic change

Fibrocystic change

Uncommon

    Sclerosing adenosis

   

Firm lump ± tethering (fixed)

Uncommon Carcinoma* Carcinoma Carcinoma

        Fat necrosis

Nipple discharge

Clear/pus Uncommon Uncommon Duct ectasia Duct ectasia

Bloody Uncommon Uncommon Duct papilloma Duct papilloma

      In situ carcinoma

In situ carcinoma

Nipple ulceration, eczema Nipple adenoma

Nipple adenoma Paget's disease

Paget's disease

      Nipple adenoma Nipple adenoma

Fibrocystic Disease/change: Pathology: Harmone induced acinar

hyperplasia. Oestrogens* Clinical: Commonest (40%) cause of

lumps in 20-40y. Irregular induration/ lumps. Cyclic pain/discomfort.

Gross: Grey white scar tissue with cysts.

Micro: Fibrosis, cysts, hyperplastic glands.

Pathogenesis: Hyperplasia of glands and stroma DCIS Carcinoma.

Fibrocystic Disease

FibroCystic Disease: types

A. Simple Fibrocystic change.B. Lobular hyperplaisa without atypica (adenosis)C,D - Ductal hyperplasia without atypia (E. with atypia - cribriform)F. Lobular hyperplasia.

Non prol. / low grade

Prol. / High grade

FCD: Cysts, Fibrosis & Proliferation

Fibrosis

Cyst

Prolif

.

FCD + Ductal Hyperplasia*

Hyperplasia may progress to DCIS (Duct Carcinoma In-Situ).

Progress to duct carcinoma.

FCD: Ep. Hyperpl. - Sclerosing Adenosis*

Small duct proliferation. Clinical & biopsy

mimics carcinoma.

Fibrocystic Disease-Blue dome cyst

When single large cyst - blue

Education must instill the fundamental human values; it must broaden the vision to include the entire world and all mankind. Education must equip man to live happily. -- Satya Sai Baba

Breast Neoplasms: Benign: (round, smooth, soft, mobile)

Fibroadenoma Duct Papilloma Others – rare.

Malignant: (irregular, rough, hard, fixed) Ductal carcinoma – classic. Lobular carcinoma Others - rare

Fibrocystic Disease(Not a neoplasm)

Fibroadenoma

Types Solitary Few (< 5 / breast )Multiple (> 5 / breast )Giant (> 4 / 5 cms) & Juvenile

Natural history

Majority remain small & static 50% involute spontaneously No future risk of malignancy

Low grade Benign High grade

Fibroadenoma

Slit like glands

Pathology: Benign tumor of acini tissue (gland & stroma)Clinical: Well demarcated, mobile, round/nod (mouse)Gross: Capsulated, firm grey, nodular tumour, cysts+/-.Micro: Compressed slit like ducts/glands in cellular stroma.

StromaTumour

N. Breast

Capsule

Breast fat

N. Fat

Mammogram - Benign

Fibroadenoma

Note: well demarcated, capsulated, nodular tumour

Fibroadenoma

P

P

P

In

In

Fibroadenoma

C = capsule; In = intracanicular pattern; P = pericanicular pattern

FibroadenomaSummary: Small discrete mobile. Stromal neoplasm with

reactive glands. No malignant potential. Regress / calcify in

menopause. Increase in pregnancy.

Giant Fibroadenoma

Pathology: Benign(young) to malignant(adult) tumor of acinii. Clinical: young (Low grade) /adult (high grade)*, unilateral macromastia,

recurrent, metastasis 15%. Gross: Large 10-15cm . Giant. With linear “leaf-like” clefts and slits –

Giant/Juvenile in young - Phyllodes tumor in adult. Micro: Both stroma & glands are hypercellular & pleomorphic. glands

show branching..

Leafy folds

Fibroadenoma – Giant Fibroadenoma

Flat slit glands, fibrous stroma, Benign. Branching leaf like glands, Cellular stromaBenign 85% malignant 15%.

Intraductal papilloma

Clinical: Middle age, Bloody discharge, sub areolar lump.

Gross: Solitary, Intra-ductal papillary Proliferation.

Micro/Path: Benign papillary proliferation of lactiferous duct epithelium.

Prognosis: recurrent, but no risk of malignancy. (rare)

Duct wall

Stalk & papillae

Education has two important characteristics. One is learning of a subject & skill. The other is the personality to apply this knowledge to the benefit of community.

--Baba

One without the other is either useless or dangerous…. !

Knowledge, Skill & Attitude * JCU graduate attributes..

Breast Carcinoma – Aus. stat. The most common cancer among Australian women (also

in aboriginals). (20%) UK 1 in 10 women, 1 in 8 in US, 1 in 9 Aus. One in nine women before the age of 85. 28% of all cancer diagnoses in 2006. Increased from 5,289 in 1982 to 12,614 in 2006 Commonest cause of death in young < 55y Rare before age 30. (30-50 genetic, >50 sporadic) Much less incidence in Asia, Japan. Majority of cancers arise in the ducts. Survival is improving with therapy. (96% 5y – 2006)

Etiology of Breast Carcinoma:

• Overexposure to oestrogens and underexposure to progesterone • No definite relationship to oral contraceptives • Some tumours contain hormone receptors and respond to hormone manipulation • No good evidence for viral involvement

GeneticsHormone

Environment

• Family history – First degree relative.• Premenopausal & bilateral.• Early menarche/Late menopause.

• Estrogen therapy.• Alcohol, Smoking.• High fat diet, Obesity.

• HER2/NEU• RAS & MYC• BRC A1, A2.

Pathogenesis of Breast Cancer.

Hyperplasia Dysplasia DCIS CarcinomaFibrocystic change Cancer

Duct Ca. in-SituDCIS

Pathogenesis:

Ductal Carcinoma in Situ (DCIS)

Dysplastic cells filling ducts with Ca+, no invasion. Pre-cancer state.

Increasing incidence of DCIS due to mammographic screening. (diffuse irregular firm/lumpy areas)

Spreads throughout ductal system to produce extensive lesions.

Many types: solid cribriform, papillary, and micropapilary, comedo type or mixed pattern. (dysplasia: low – high grade)

Progress to invasive carcinoma.

Ductal Carcinoma in Situ, DCIS

DCIS – Comedo type (high grade)

Intact ME cells

DCIS

Central necrosis (comedo)

Myoepithelial Cells in DCIS (imunoperoxidase stain note intact BM & ME cells)

All ducts, ductules and acini are separated from the interlobular and intralobular connective tissue (stroma) by a basement membrane & Myoepithelial cells.

DCIS

Myoepithelial cells

DCIS- High grade

Ca Breast: Histological Types

Histologic Type Freq. (UK)

Infiltrating Duct Ca 63.6 (75)

Lobular Carcinoma 5.9 (10)

Infiltrating Ductal & Lobular Ca 1.6

Medullary Carcinoma 2.8 (3)

Mucinous (colloid) Carcinoma 2.1 (3)

Comedocarcinoma 1.4

Carcinoma-In-Situ 5%

Prognostic / Genetic Classification: (new)

1. Luminal A – 50% of NST. ER+, HER2 –ve. Low grade, slow growing, post menopausal, respond to harmone therapy. – Better prognosis.

2. Luminal B – 20% of NST. ER+, HER2/neu +ve. (triple positive ca.) high grade, respond to chemo.

3. Basal like – (Triple neg) 15% of NST. ER-, HER2/neu –ve, BRCA1+, young. Poor prog.

4. HER2 positive – 10% ER- HER2 +, high grade, poor prognosis, early brain mets. (Trastuzumab)

L

H

HER - Human Epidermal Growth factor Receptor Growth.ER - Estrogen receptor function. ER is good & HER is bad…!

Breast Ca-Clinical

Nipple retraction

Skin Puckering

Lymphnode mets.

Breast Carcinoma Irregular, hard,

gritty Painless nodule.

Tethering/puckeringfixation

Nipple retraction Oedema Lymphnodes

Infiltrating Duct Carcinoma: Breast Ca.

Note: Fibrotic tumor, radiating fibrous scar around resulting in nipple retraction & skin pulling (puckering)

(NOS or Classic or typical “Schirrhous carcinoma”)

Mammogram - Ca

Breast Carcinoma Inflammatory / medullary

Inflamed, bulging without nipple/skin retraction.

Uncommon. High grade / medullary type

(HER2 & BCRA1)

Breast Carcinoma - Schirrous

Nipple

Infiltrating Duct Carcinoma: small hard

Typical Invasive Ductal Carcinoma / Duct Ca (NOS)

Ca-tubules

collagen stroma

DCIS component within Duct Ca (NOS)

DCIS

Infiltrating Duct Carcinoma

Glands

Fibrosis

Breast Ca. Lymphedema Pathogenesis of Peu-de Orange in High grade Ca.

Tumor in lymph Vessel

Tumour emboli within lymphatic vessels obstruction Lymphedema(also radiation induced lymphangitis can cause peu-de orange)

Medullary type (high grade): * note lymphocytes, no collagen/scar

Lymphocytes

Ca. cells

Expansile tum

Lobular Carcinoma: Multifocal, Bilateral. Small cells, uniform, no tubules.

Target like growth around normal tubules.

‘Indian file (single cell lines) between collagen bundles. No tubule formation.

Lobular Ca-in-situ(LCIS) E-cadherin –ve (unlike IDC) ER/PR neg, HER2/neu pos.

Spread of Breast Carcinoma:

Pagets Disease Spread of Breast cancer

cells to skin (areola) & resulting in Eczematous reaction.

Ca. Cells

Ca. Cell

Diagnosis: History First….! Mammorgraphy Fine Needle Aspiration Biopsy Core/Needle Biopsy Excision Biopsy Ultrasound Special molecular tests on Biopsy:

Immunoperoxidase – HER2, ER & PR. Molecular techniques – Gene detection (BRCA).

Triple Assessment Clinical, Imaging & Biopsy

Breast clinic: incidence

Breast clinic: incidence

Mammorgram• Low radiation (0.1rad)• Light compression by plates to stabilize and spread its interior structures.

• Detect Fibrosis & Calcifications <100 µm• Reveals a lump 1-2y before BSE. • Women >40y should have yearly* mammogram. • More for those at risk or symptoms.

Mammogram:

Malignant

Cancer

Normal – 18y Normal 40y Carcinoma

Dusty Ca+

Breast Ca. screening: new research Cochrane Summaries: Research involving 600,000 women, results showed “for

every 2000 women screened one will avoid dying of breast cancer 10 healthy women will be treated unnecessarily. >200 experience distress due to false positive findings.

Breast Cytology - FNAB

BenignMalignant

Tumor Markers in Breast Ca.

ER: Estrogen Receptors.PR: Progesterone Receptors.HER2/neu: Human Epidermal growth factor Receptor 2E-Cadherin: Cell adhesion protein.BRCA: Breast Carcinoma Antigen.

Immunoperoxidase stain: (ER, PR, HER, BCL, p53, E-Cad),

Neg 1+

2+ 3+

Nuclear ER positivity - 3+

+ve

-ve

Gene expressions portraits of breast carcinomas. (micro array)

Identify new breast cancer subtypes (“luminal A,” “HER2/neu positive,” & “basal-like”).

HER2 (Human Epidermal growth factor Receptor 2)

The HER2 proto-oncogene encodes a cell surface receptor that is over expressed in approximately 25%-30% of breast cancers. (normally 2 copies).

HER2 positive breast cancers grow quickly and spread more than others. (poor prognosis)

HER2 testing (Immunohistochemistry/FISH) results are critical to ensuring that patients who may benefit from the anti-HER2 antibody therapy.

Trastuzumab (Herceptin®) is the first monoclonal antibody that targets the extra cellular domain of the HER2 protein, and inhibits growth of breast cancer cells that over express this protein.

BRCA1 (FISH Technique) BRCA2 52% of genetic type (2% overall) Young age. Risk of Ca – 40-90% High grade, necrosis, inflam (.. Medullary) Triple –ve (ER,PR, HER2)

F/H of ovarian, prostate, pancreas ca. Chromosome 17q

32% of genetic type (1% overall) Not specific. Risk of Ca 30-90% Low grade, NOS type. Scaring (..Schirrous) ER positive. F/H of male breast ca (ovary, prostate also) Chromosome 13q.

Progression of Breast Ca: (new)

Common Ca. Breast: NST / NOS / Schirrhous Ca / Infiltrating duct Ca.Mammogram: Stellate Lesion on MammogramGross: Hard irregular - SchirrhousMicro: Pleomorphic cells forming tubules in dense fibrous stroma.

Summary: Anatomy & Physiology. Congenital, Inflammatory & Neoplastic dis. Fat Necrosis, Abscess, Duct ectasia. Proliferative Disorders:

Fibrocystic Disease – hormonal, benign. Neoplastic Disorders

Benign – Fibroadenoma, papilloma Malignant – Invasive Duct Carcinoma, Lobular

Carcinoma, DCIS – Ductal carcinoma in-situ.

Sign or symptom Pathological basisLUMP

DIFFUSE Fibrosis, epithelial hyperplasia and cysts in fibrocystic change

DISCRETE Neoplasm or solitary cyst

MOBILE Benign neoplasm (usually fibroadenoma)

TETHERED Invasive neoplasm (carcinoma)

SKIN FEATURES

OEDEMA (PEAU D'ORANGE)

Impaired lymphatic drainage due to carcinoma

PUCKERING AND TETHERING

Invasion of skin by carcinoma

ERYTHEMA Increased blood flow due to inflammation or tumour

NIPPLE

DISCHARGE Milky-pregnancy or prolactinoma

  White/green-duct ectasia

  Bloody-duct papilloma or carcinoma (rare)

RETRACTION Tethering by invasive carcinoma

ERYTHEMA AND SCALING Paget's disease of nipple (cancer) or eczema

BREAST PAIN

CYCLICAL Benign breast changes – fibrocystic change

ON PALPATION Inflammatory lesion (e.g. mastitis)

MICROCALCIFICATION invasive carcinoma (also in cysts, benign changes, DCIS)

BONE PAIN OR FRACTURE Possibly due to metastatic breast carcinoma or associated with hypercalcemia

Confusion Distinction and explanation

Fibroadenoma & Fibroadenosis

Fibroadenoma is a localized circumscribed benign neoplasm comprising epithelial cells and specialised fibrous tissue. Fibroadenosis is an obsolete name for fibrocystic change, a diffuse hyperplastic lesion.

Fibroadenoma & phyllodes tumour

both comprise neoplastic epithelial and fibrous tissue components. However, in phyllodes tumours the fibrous tissue component is more cellular and abundant, and the lesion has less well defined margins; borderline and malignant variants occur.

Ductal epithelial hyperplasia & ductalcarcinoma in situ

Ductal epithelial hyperplasia is a benign proliferation of duct epithelium, whereas ductal carcinoma in situ has undergone neoplastic transformation, although it is not yet invasive. These lesions can have morphological similarities. A proportion share genetic alterations.

Radial scar & complex sclerosing lesion

Radial scars and complex sclerosing lesions differ only in size: the latter are >10 mm diameter. Both mimic carcinomas radiologically and histologically, but they are benign non-neoplastic lesions.

Medullary carcinoma of the breast & of the thyroid

The term medullary refers only to the soft consistency (resembling the medulla of the brain). There is no other relationship between these lesions.

Paget's disease of the nipple & of bone

Both lesions were described by Sir James Paget (1814-1899). There is no other relationship between these lesions.

Benign vs Malignant Young <35y Multiple Painful No bleeding Soft, cystic,

rubbery Regular,

nodular Mobile No lymphnodes No weight loss.

Old >35y Single Painless Bleeding Hard gritty Irregular Fixed Lymphnodes Weight loss

What is this?

• What is PET Scan?• What contrast is used?• What does it show? • What are its Indications ?

• Positron Emission Tomography.• Radiolabelled glucose by IV.• High metabolic rate cells (cancer cells)• 3D view of cancer spread over body.

Infections

2. NonLactational infections : Central Usually due to Periductal mastitis Affects younger women. Often smokers

in the West May present as : inflammation +/-

mass, abscess, mammary duct fistula Aerobic + anaerobic organisms may

be involvedTreatment : Antibiotics (E.G. Co amoxyclav etc)

before pus formation Abscess : Repeated aspiration / mini

incision with topical anaesthetic cream ( I& D under GA occasionally)

MDF : Excision fistula + Total duct excision