breast pathology

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L♥ 1 Breast Pathology P.B. Casuela, Jr., MD, FPSP November 2012 THE FEMALE BREAST The mammary glands are highly evolved, modified skin with the following major functions: For the offspring Complete source of nourishment Immunonological protection (infection, allergies, and autoimmune diseases) Maternal antibodies (secretory IgA, vitamins, enzymes and Other immune mediators (cytokines, antioxidants, fibronectin, and lysozyme) augment the infant’s developing immune defenses FUNCTIONAL HISTOLOGY From the skin the stratified squamous epithelium dips into the orifices at the nipple and changes into double-layered cuboidal epithelium lining large ducts eventually leading to the terminal duct lobular unit In adult women, this terminal duct branches into a grapelike cluster of small acini to form a lobule Two cell types line the ducts and lobules Contractile myoepi-thelial cells containing myofilaments lie in a meshlike pattern on the basement membrane. These cells assist in milk ejection during lactation and provide structural to the lobules Only the lobular luminal cells produce milk Changes occur during the reproductive years in relation to the menstrual cycle After ovulation, under the influence of estrogen and increasing progesterone levels, cells, acini, and lobule proliferate After the third decade, lobules and fibrous stroma begin to involute The lobules atrophy in elderly women BREAST DISORDERS I. Inflammatory disorders A. Acute mastitis 1. Most commonly seen during the first month of breastfeeding 2. Acute suppurative inflammation / abscess formation 3. S. Aureus most commonly implicated bacteria B. Mammary duct ectasia 1. Predilects women in the fifth or sixth decade of life 2. Presenting with poorly defined palpable periareolar mass associated With nipple secretions or skin retraction 3. Pathology Dilated ducts with inspissated secretions Marked periductal and interstitial lymphohistiocytic or plasmacytic cell infiltrates C. Granulomatous inflammation 1. Prediclects immunocompromised females 2. Causes: Tuberculosis Fungal infection D. Fat necrosis 1. Reaction of adipose tissue to injury 2. Common, particularly after surgery 3. Clinical Features Most commonly presents as a firm mass May be skin retraction, thickening or tethering May clinically mimic carcinoma History of trauma May occur after surgery or radiotherapy 4. Radiologic Features Mammographic appearance is variable Ultrasound shows hyperechogenicity in the acute phase & later usually shows a mass 5. Prognosis and Treatment Benign Important to establish diagnosis as clinically can mimic CA Mammary Ductectasia Granulomatous Mastitis Fat Necrosis

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Breast Pathology

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Page 1: Breast Pathology

L♥ 1

Breast Pathology P.B. Casuela, Jr., MD, FPSP November 2012 THE FEMALE BREAST The mammary glands are highly evolved, modified skin with the following major functions: For the offspring Complete source of nourishment Immunonological protection (infection, allergies, and

autoimmune diseases) Maternal antibodies (secretory IgA, vitamins, enzymes and Other immune mediators (cytokines, antioxidants, fibronectin,

and lysozyme) augment the infant’s developing immune defenses

FUNCTIONAL HISTOLOGY From the skin the stratified squamous epithelium dips into the

orifices at the nipple and changes into double-layered cuboidal epithelium lining large ducts eventually leading to the terminal duct lobular unit In adult women, this terminal duct branches into a grapelike

cluster of small acini to form a lobule Two cell types line the ducts and lobules Contractile myoepi-thelial cells containing myofilaments lie in

a meshlike pattern on the basement membrane. These cells assist in milk ejection during lactation and

provide structural to the lobules Only the lobular luminal cells produce milk

Changes occur during the reproductive years in relation to the menstrual cycle After ovulation, under the influence of estrogen and increasing

progesterone levels, cells, acini, and lobule proliferate After the third decade, lobules and fibrous stroma begin to involute The lobules atrophy in elderly women BREAST DISORDERS I. Inflammatory disorders

A. Acute mastitis 1. Most commonly seen during the first month of

breastfeeding 2. Acute suppurative inflammation / abscess formation 3. S. Aureus – most commonly implicated bacteria

B. Mammary duct ectasia 1. Predilects women in the fifth or sixth decade of life 2. Presenting with poorly defined palpable periareolar mass

associated With nipple secretions or skin retraction 3. Pathology

Dilated ducts with inspissated secretions Marked periductal and interstitial lymphohistiocytic or

plasmacytic cell infiltrates C. Granulomatous inflammation

1. Prediclects immunocompromised females 2. Causes:

Tuberculosis Fungal infection

D. Fat necrosis 1. Reaction of adipose tissue to injury 2. Common, particularly after surgery 3. Clinical Features

Most commonly presents as a firm mass May be skin retraction, thickening or tethering May clinically mimic carcinoma History of trauma May occur after surgery or radiotherapy

4. Radiologic Features Mammographic appearance is variable Ultrasound shows hyperechogenicity in the acute

phase & later usually shows a mass 5. Prognosis and Treatment

Benign Important to establish diagnosis as clinically can mimic

CA

Mammary Ductectasia

Granulomatous Mastitis

Fat Necrosis

Page 2: Breast Pathology

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II. Benign epithelial lesions A. Fibrocystic change

1. Benign hormonally mediated breast changes: Cyst formation usually with apocrine metaplasia Fibrosis Epithelial hyperplasia (adenosis)

2. Incidence & Location More than 1/3 of females 20-45 y/o 60% of grossly normal breasts (autopsy series) show

microscopic evidence of FCC Usually bilateral and multifocal

3. Morbidity and Mortality Cyclic (premenstrual) breast pain & tenderness Breast lumpiness

FCC the commonest cause of a breast mass in females <50 y/o

No increased risk for subsequent CA development 4. Clinical Features:

Lumpy Premenstrually painful breasts

5. Prognosis & Treatment FCC symptomatology generally ceases 1-2 yrs.

following menopause Hormonal manipulation

B. Papilloma and related lesions 1. Lesions of true ducts with epithelium covered

fibrovascular cores 2. Includes

Papillomas Ductal adenoma Nipple adenoma

3. Incidence & Location Solitary papillomas & nipple adenomas located near

the nipple-areola complex Multiple papillomas often located peripherally Ductal adenoma are located in larger ducts

4. Age Distribution Perimenopausal age group

5. Clinical features Nipple discharge May have a palpable mass Nipple adenoma may present as erosion or ulceration

the nipple 6. Radiologic Features

Can be normal Smooth walled mass on mammogram Galactography identifies a filling degect Ultrasound shows solid & cystic lesions with a smooth

wall or a hypoechoic mass 7. Prognosis & Treatment

2x risk of breast cancer Surgery is adequate treatment

C. Nipple adenoma 1. Irregular, firm area simulating a carcinoma 2. Overlying epithelium may be scaly or ulcerated 3. Microscopic Findings

Adenomatous proliferation of glandular structures set within the nipple stroma

Glandular structures may be expanded by papillary epithelial proliferations

Epithelial hyperplasia of usual type, squamous metaplasia & apocrine metaplasia may be present

Focal necrosis, overlying epithelial ulceration & an inflammatory cell infiltrate are variable features

Fibrocystic Change

Fibrocystic Change

Nipple Adenoma

Page 3: Breast Pathology

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III. BREAST CANCER 1. Carcinoma of the breast is the most common non-skin

malignancy in women 2. Epidemiology

Risk factors Heredity

(1) Breast cancer (mutations in BCRA1/BCRA2), Atypical hyperplasia Estrogen exposure Etc.

3. Carcinogenesis and Tumor Progression: Manifestation of complex genetic and epidgenetic

changes that drive carcinogenesis Initial event - Proliferative changes ER-expressing luminal cells – most likely cytogenesis Final step – transition of carcinoma in situ to invasive

carcinoma: Luminal cells, myoepithelial cells, and stromal

cells. Similar molecular events

(1) Disruption of basement membrane (2) Increased proliferation (3) Loss of contact inhibition (4) Angiogenesis (5) Invasion

A. Ductal carcinoma-in-situ

1. Definition a. Consists of malignant clonal population of cells limited

to the duct and lobules by the basement membrane 2. Clinical Features:

a. Nipple discharge or breast mass 3. Subtypes:

a. Comedocarcinoma b. Solid c. Cribriform d. Papillary e. Micropapillary

DCIS Comedocarcinoma

DCIS Solid

DCIS Cribriform

B. Invasive ductal carcinoma 1. Most common histologic type 2. Malignant invasive epithelial lesion of the breast derived

from the terminal duct lobular unit 3. Incidence & Location

a. Common b. 1 in 9 women will develop breast CA in their lifetime c. Arises anywhere in the breast parenchyma or

accessory breast tissue d. Most common in the UOQ

4. Morbidity & Mortality a. A wide range of clinical behavior is seen with differing

morphologies b. Increasing frequency with increasing patient age

5. Clinical Features a. Presents most commonly with an ill-defined mass

6. Radiologic Features a. Most commonly identified as a mass lesion

i. Mammography (1) Ill-defined if high grade invasive CA (2) Spiculated mass if low grade (grade 1)

invasive CA b. Associated microcalcification may be present c. Ultrasound shows an irregular mass with ill-defined

margins & an inhomogeneous echo texture 7. Gross Findings

a. Firm, well to poorly defined b. Wide range of sizes at presentation from a few mm. to

many cms. 8. Microscopic Findings

a. Malignant cells, often forming trabeculae or growing in sheets

b. >50% of tumor shows no special type patterns 9. Immunohistochemical Findings

a. 70-80 % show estrogen receptor positivity b. 15-30% Her2 positive

10. Prognosis & Treatment a. Varies widely b. Depends on pathologic features of the tumor, in

particular nodal stage, histologic grade and tumor size c. Based on these prognostic factors & hormone receptor

status, extent of surgery performed, adjuvant as hormone manipulation &/or chemotherapy& focal radiotherapy

Page 4: Breast Pathology

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Invasive Ductal Carcinoma

C. Invasive lobular carcinoma 1. Most commonly bilateral 2. Firm, gray, well to poorly defined 3. Average size 2.4 cm 4. Microscopic Findings

a. Small round discohesive neoplastic cells with oval nuclei

b. Small amount of cytoplasm forming “Indian filing” 5. Immunochemical Studies

a. Usually positive for estrogen & progesterone receptors b. Usually negative for Her2

Invasive Lobular Carcinoma

D. Other types: 1. Medullary carcinoma 2. Mucinous or mucoid carcinoma 3. Tubular carcinoma 4. Papillary carcinoma 5. Etc.

Page 5: Breast Pathology

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Prognostic parameters breast cancer I. Major :

A. In situ or invasive B. Distant metastasis C. Lymph node metastasis

II. Minor : A. Histologic subtype B. Histologic grade C. Estrogen/progesterone receptors D. Her2/neu E. Lymphovascular invasion F. Proliferative rate (mitotic count)

III. Staging A. TNM

1. American Joint Committee on Cancer 2. College of American Pathologists

ERA/PRA

HER2

IV. Stromal tumors: A. Fibroadenoma

1. Definition: Hyperplastic, benign fibroepithelial lesion composed of

both stromal and epithelial components 2. Women in their late 20’s and 30’s 3. Clinically

Mobile, painless, well-defined mass Asymptomatic Rarely undergoes infarction

4. Radiologically Well-defined mass w/ or w/o microcalcification

5. Ultrasound Homogenous hypoechoic mass

6. Gross Findings Well-defined masses, 1-3 cm in size Round or ovoid, often gray in color No true capsule Rubbery cut surface, often lobulate with slit-like

spaces

Fibroadenoma

Fibroadenoma

Page 6: Breast Pathology

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B. Phylloides tumor 1. True fibroepithelial neoplasm of epithelial & stromal

components 2. Rare, < 1% of breast tumors involving any age but

commonest in women in their 50’s 3. Clinical Feature:

Rapidly growing but well-circumscribed mass 4. Radiologic Features

Well-defined mass on mammography Internal hyperechoic striations within a hypoechoic

lesion on ultrasonography 5. Gross Findings

Variable size from a few cms to 20 cm Well-defined, often lobulated; ill-defined in malignant

lesions Cross-sectioning shows elongated clefts within a gray-

brown whorled stroma 6. Microscopic Findings

Cellular stroma lined by an epithelial & myoepithelial bilayer, giving a leaf-like structure

Benign lesions Composed of cellular stroma, mild cytologic atypia

& few mitoses (5/10 HPF) Margins well –defined Nostromal overgrowth

Malignant lesions Composed of markedly atypical spindle stromal

sarcomatous cells with abundant mitoses (>10/10 HPF)

Borderline lesions Composed of stroma with minimal to moderate

cellular atypia with frequent mitoses (5-10 HPF) Lacks stromal overgrowth & infiltrative margins

7. Prognosis: Malignant variant – hemomatogenous metastasis

8. Treatment: Surgery – Total mastectomy

Phylloides tumor – Cloverleaf Pattern

Phylloides tumor – Cellular Stroma

Phylloides tumor – Atypia of cells, pleomorphism, mitosis

Page 7: Breast Pathology

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THE MALE BREAST Nipple and rudimentary breast without lobule formation

Causes of Gynecomastia Idiopathic 25 % Puberty 25 % Drugs 10 +/- 20 Cirrhosis or malnutrition 8 Primary hypogonadism 8 Testicular tumor 3 Secondary hypogonadism 2 Hyperthyroidism 2 Renal disease 1 Others 6

I. Gynecomastia

A. Enlargement of the male breast; unilateral or bilateral B. No increased risk of malignancy C. Peri-pubertal children; Males over 50 yrs of age D. Clinical Features

1. Soft nodule; occasionally tender E. Radiologic Features

1. Increased fibro-glandular densities; increased fat F. Gross Findings

1. Non-specific; ill-defined grayish mass G. Microscopic Findings

1. Florid and fibrous type 2. Associated with epithelial hyperplasia, peri-ductal stromal

edema and increased cellularity H. Prognosis & Treatment

1. Benign self-limited disorder 2. Surgery is curative

Gynecomastia

II. Male breast cancer A. 0.2 of all cancers B. Morbidity & Mortality

1. depends on histologic grade and stage 2. Greater than 50 years of age

C. Clinical Features: 1. Self-detected painless mass 2. occasionally bleeding, ulceration and pain

D. Radiologic Features 1. Architectural distortion, spiculated calcification 2. Irregular contour on ultrasound with posterior shadowing

E. Gross Findings : 1. Hard irregular stellate mass

F. Microscopic Findings : 1. Similar to female breast cancer

G. Immunohistochemical features: 1. Similar to female breast cancer

H. Prognosis & Treatment 1. Stage tends to be higher than female breast cancer 2. Prognosis similar to female breast cancer (stage by stage)

Male Breast Cancer