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Pathobiology of Breast Cancer
Associate ProfessorDepartment of Pathology and Laboratory Medicine
Ruth A. Lininger, MD MPH
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1. Anatomy and Histology of the Normal Breast
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Terminal duct/lobular unitsNipple
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Histology of the Normal Breast
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Terminal duct
Lobular unit
Intralobular stroma
Interlobular stroma
Ductal CarcinomasArise Here
Lobular CarcinomasArise Here
Terminal Duct Lobular Unit
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Epithelium
Myoepithelium
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Immunostain for Smooth Muscle Actin
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Epithelium
Myoepithelium
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2. Normal Physiologic States of the Breast
•Pregnancy and Lactation
•Post-Menopausal State
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Pregnancy and Lactation Changes• Breast changes in response to hormonal stimulation
secondary to B-HCG and progesterone (pregnancy) and prolactin (lactation)
• Rapid growth of the terminal ducts and lobules• Secretory epithelial changes
– Vacuolated cytoplasm, enlarged “activated” nuclei with prominent nuceoli (biosynthetic center for the cell)
– Occurs in a patchy fashion throughout the breast with progressive recruitment of lobules with successive pregnancies
• Depletion of fibrofatty stroma• Increased stromal vascularity• Increased areolar pigmentation• Involution post cessation of lactation
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Foamy cytoplasm
Secretory material
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Prominent nucleoli
Lactational Change
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Post-menopausal Changes
• Breast undergoes atrophic changes in response to LOSS of hormonal support (decrease in estrogen and progesterone)
• Loss of glandular epithelium
• Fatty replacement of breast tissue
• Atrophy occurs in a patchy fashion with interspersed unaffected lobules
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Intralobular stromal collagenization
Post-Menopausal Breast
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3. Genetics and Epidemiology of Breast Cancer
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Breast Carcinoma Statistics
• THE most common cancer in women in the United States (excluding skin cancer)
• The second most common cause of cancer mortality in women (lung cancer is first)
• One in eight women will get breast cancer, and one third of women with breast cancer will die of the disease.
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Age-adjusted Cancer Incidence Rates Among Females: 1973 to 1998
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Risk Factors for Development of Breast Cancer
• Genetic
• Environmental
• Hormonal
• Radiation
• History of previous breast pathology
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Genetic Factors
• Approximately 10% breast cancers are familial (90% sporadic)
• Positive Family History, especially in 1st degree relatives (mother, daughter, sister) confers increased risk for breast cancer
• Risk is greatest with:• Relative with BILATERAL disease• Relative affected at a YOUNG AGE
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BRCA1 Gene (17q21)
• Responsible for up to 1/2 of “inherited” breast cancers (5% of cancers)
• Increased risk of ovarian and colon cancers (“Breast-Ovarian” cancer gene)
• 85% lifetime risk of breast cancer• Breast cancer develops in >50% of these women
by age 50 (“Early onset” breast cancer gene)• Carried by 1 in 200-400 people
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BRCA2 Gene (13q)
• Responsible for up to 70% of inherited breast cancer NOT due to BRCA1 (3.5% of cancers)
• Characterized by increased risk of breast cancer in women and MALE breast cancer (“Male Breast Cancer” gene)
• 30-40% lifetime risk of breast cancer
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Li-Fraumeni Syndrome (p53)
• Due to Inherited p53 Tumor Suppressor Gene Mutation (cell cycle checkpoint)
• Family cancer syndrome characterized by increased risk of breast cancer, osteosarcoma, soft tissue sarcomas, brain tumors, leukemia, other
• Accounts for approximately 1% of breast cancers detected before age 40
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OTHERRecognized Susceptibility Loci
• ESR 6q24-27 (Estrogen receptor)
• AR X11.2-q12 (Androgen receptor)
• PTEN 10q22-23 (Cowden’s syndrome)
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PUTATIVE Susceptibility Loci
• ATM11q22 (Ataxia Telangiectasia)
• HRAS1 11p15.5
• GSTM1 (Glutathione-S-transferase)
• CYP1A1 (Cytochrome P-450)
• NAT (N-acetyl-transferase)
• CYP17 (C2:C16-alpha-estrone)
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Hormonal Factors
• “Incessant ovulation”: Early menarche, late menopause, nulliparity, late age at first term pregnancy all INCREASE the risk of breast cancer.
• Oophorectomy before age 35 DECREASES the risk of breast cancer.
• Oral contraceptive use and hormone replacement therapy may be associated with a SMALL increased risk
• Etiology: ? hormonal stimulation of proliferation and differentiation of cycling breast epithelium.
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Environmental Factors• 4-5 fold greater incidence of breast cancer in
industrialized countries than in less developed countries.
• Increased risk may be related to:– Higher fat diet
– Earlier menarche
– Less physical activity
– Decreased parity
– Later age at parity
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Radiation Exposure• Increased risk of breast cancer after:
– Radiation therapy for Hodgkin’s Disease in young women, postpartum mastitis in mothers
– Survivors of atomic bomb blasts
• Increased risk when exposure is at a young age, little increase in risk after age 40– Indicates that the risk is GREATEST to the
developing and hormonally cycling breast
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4. Histopathologic Risk FactorsFor Breast Cancer
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Histopathology
• Presence of a history of breast pathology increases risk of breast cancer
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Relative Risk for Invasive Carcinoma Based on Histologic Evaluation of Breast Tissue Without Invasive Carcinoma
• NON-Proliferative Fibrocystic Changes (1X, No increased risk) – Small simple cysts, apocrine metaplasia, mild epithelial hyperplasia
• Proliferative Fibrocystic Changes (1.5-2X, Slight increased risk) – Moderate to florid hyperplasia– Sclerosing adenosis– Intraductal papilloma– Fibroadenoma
• Proliferative Fibrocystic Changes WITH ATYPIA (3-5X, Moderate increased risk)– Atypical ductal hyperplasia– Atypical lobular hyperplasia
• Carcinoma IN SITU (8-10X, HIGH RISK)– Ductal carcinoma in situ (DCIS)– Lobular carcinoma in situ (LCIS)
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Proliferative Fibrocystic Change WITHOUT Atypia
Intraductal Hyperplasia, Moderate to FloridSclerosing AdenosisIntraductal Papilloma (A benign breast “tumor”)Fibroadenoma (A benign breast “tumor”)
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Intraductal Hyperplasia
• Definition: An increase above the normal
2-cell layer thickness– Mild hyperplasia: 3-4 cell layers thick– Moderate hyperplasia: with epithelial tufting
and bridging– Severe (florid) hyperplasia: filling and
distending ducts
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Moderate hyperplasia
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Florid hyperplasia
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Intraductal Papilloma
• Discrete benign neoplasm arising from the ductal epithelium of mammary duct
• May be solitary or multiple• Most frequent in the 6th decade• Presents as nipple discharge (>75%) which may
be bloody, and/or subareolar mass• Infarction of the lesion may occur• Gross appearance: Papillary growth of ductal
epithelium within a duct lumen
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Most papillomas arise in larger mammary ducts
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Intraductal papilloma
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Duct lining
Stalk
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Fibrovascular core
Myoepithelium
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Homogeneous lesion with well circumscribed border
FibroadenomaFibroadenoma (Benign Biphasic Tumor)
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Fibroadenomas will “shell out” at surgery
Fibroadenoma
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Cleft
Fibroadenoma
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Branching compressed ducts
Homogeneous stroma
Fibroadenoma
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Proliferative Fibrocystic Change WITH Atypia
• Atypical Intraductal Hyperplasia• Atypical Lobular Hyperplasia
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Atypical hyperplasia with family history or in a premenopausal woman has a risk of invasive carcinoma similar to DCIS
Relative Risk of Invasive Breast Carcinoma
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5. Breast Pathology Specimens
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Surgical Procedures to Sample Breast Lesions
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Fine Needle Aspirate Biopsy of the Breast
• Analogy- predicting the picture of a completed puzzle by examining the unassembled pieces
• May be the initial evaluation of a palpable mass• Advantages over open biopsy:
– Fast– Cost effective– May eliminate an unnecessary procedure
• Disadvantages:– False negatives and false positives
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Fine Needle Aspirate Biopsy of the Breast
• Benign Breast Cytology- – Cohesive groups of uniform ductal epithelial cells
without atypia
• Malignant Breast Cytology-– Poorly cohesive cells with atypia (pleomorphism,
enlarged nuclei, large nucleoli, mitotic activity)– May see necrosis
• The “Triple Test”:– Clinical picture– Mammographic findings– Cytologic findings
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Fine Needle Aspiration (FNA)
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FNA Cytology Smear Specimen
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Fine Needle Aspiration: Benign Ductal Epithelium Versus Breast Cancer
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Needle Core Biopsy
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Lumpectomy
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Mastectomy: Modified Radical
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6. Breast Cancer Pathology
In Situ CarcinomasInvasive CarcinomasSpecial Subtypes
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Ductal Carcinoma In Situ (DCIS)
• Arises in the terminal duct lobular unit (TDLU) and DOES NOT demonstrate invasion through the myoepithelial layer and basement membrane
• DCIS is a surgically treatable entity• The likelihood of developing an invasive
carcinoma, or recurrent DCIS varies witha) Histologic subtype of the in situ carcinoma
b) Size/ extent of DCIS
c) Distance to the margins of excision.
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Ductal Carcinoma in Situ
• Clinical:– DCIS usually does not present as a palpable mass,
if it does it is usually high grade and a large lesion
• Mammogram:– The most common method of detection is by
identifying mammographic calcifications
– The calcifications may be linear and branching...following the lumens of the involved ducts
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DCIS is confined to within the ductal system
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Mammography: DCIS
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Linear and branching calcifications
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Grossly visible comedo necrosis
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Architectural Patterns of DCIS
• Comedo– Grade 3 nuclei and necrosis– Often has associated microcalcifications
• Solid– Carcinoma fills and distends the ducts
• Micropapillary– Papillary structures that extend into the lumen of
the duct
• Cribriform– Forms a rigid “cartwheel” pattern
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Comedo necrosis
Calcification
Tumor cells confined to duct, i.e. DCIS
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Solid DCIS, uniform monotonous cell population
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Cribriforming DCIS
Secondary lumina
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Micropapillary DCIS
Papillae
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Nuclear grade 1
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Nuclear grade 3
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Surgical excision utilizes anatomic distribution in the lobe of involvement
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Ductal Carcinoma in Situ,Axillary Metastases?
• In theory the risk of metastasis is 0%• In reality, the risk is <3%
– Invasive carcinoma outside the biopsy specimen or not in the plane of sections examined
– Invasive carcinoma in a mastectomy specimen not sampled (mastectomy specimens are too large to entirely sample)
– Invasive carcinoma not distinguishable at the light microscopic level (present at EM level)
– Focus of invasive carcinoma overlooked
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Lobular Carcinoma in Situ (LCIS)
• LCIS considered a “marker of risk for invasive cancer in EITHER breast”, rather than an obligate precursor
• Proliferation of neoplastic population of cells within the TDLU which usually fill and distend lobules, and may extend into adjacent ducts.
• Low nuclear grade monotonous cells
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Lobular carcinoma in situ
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Invasive Carcinoma of the Breast
• Infiltrating ductal carcinoma is the most common form of breast cancer.– It is characterized by invasion of the breast stroma by a
malignant epithelial cell population derived from the terminal ducts.
• Clinical:– Often forms a firm palpable mass– May cause skin dimpling (from traction on Cooper’s
ligaments) or nipple retraction
• Mammogram:– Often shows a stellate distortion, may have associated
calcifications
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Stellate lesion
Calcifications
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Infiltrating Ductal Carcinoma • Gross:
– Firm, pale gray/white, gritty, often stellate
• Micro:– Differentiation depends on:
• 1) degree of tubule formation
• 2) nuclear grade
• 3) mitotic rate
– Desmoplastic stromal response: pronounced fibrosis
– May have associated calcifications
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Stellate lesion invading adjacent breast tissue
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Well differentiated infiltrating ductal carcinoma
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Poorly differentiated infiltrating ductal carcinoma
High grade nuclei
High mitotic rate
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Infiltrating ductal carcinoma, invading and replacing breast stroma
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Invasion of adipose tissue of breast
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Infiltrating Lobular Carcinoma • 2nd most common form of invasive breast
cancer.• Gross:
– May or may not form a mass• Micro:
– Single cells and linear profiles of malignant cells with low nuclear grade, may form a targetoid pattern, may show intracytoplasmic vacuoles, characteristically show minimal mitotic activity
– LACKS a desmoplastic stromal response– Show LOSS of E-cadherin membrane staining (a
cytoplasmic membrane adhesion molecule)
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Infiltrating Lobular Carcinoma
• Often clinically and mammographically occult, and therefore microscopically more extensive than expected
• Propensity to be multifocal and bilateral• Propensity to metastasize to unusual sites:
– Gyn tract, GI tract
• Same prognosis as infiltrating ductal carcinoma, when matched for stage
• Usually ER/PR positive, C-erbB-2 negative• Pleomorphic lobular variant: high nuclear grade,
more aggressive course
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Linear arrangement of malignant cells
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Positive cytokeratin stain confirming the epithelial nature of lobular carcinoma
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Infiltrating ductal carcinoma, in contrast, with architectural distortion
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Uncommon types of Invasive Carcinoma of the Breast
• Mucinous (Colloid) Carcinoma– Older women– Malignant cells floating in pools of mucin– Better prognosis than invasive ductal or lobular
• Tubular Carcinoma– Younger women– Well differentiated, characterized by haphazardly
arranged tubules– Excellent prognosis
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Mucin
“Floating” malignant cells
Mucinous (Colloid) Carcinoma
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Tubular Carcinoma
Well formed tubules
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Inflammatory Carcinoma
• Defined as invasive carcinoma involving superficial dermal lymphatic spaces
• Poor prognosis (T3 disease)• Erythema and induration of the skin, so called
“inflammatory changes”– Peau d’orange-dimpling of involved skin due to
retraction caused by lymphatic involvement and obstruction
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Inflammatory carcinoma
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Inflammatory carcinoma: dermal lymphatic spaces containing tumor cells
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Paget’s Disease
• Invasion of the SKIN of the nipple or areola by malignant cells, singly or in small nests
• Associated with an underlying cancer: either IN SITU OR INVASIVE carcinoma
• Clinically-erythema, scaling, ulceration
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Paget’s disease: nipple ulceration
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Paget’s Disease of the Nipple
Intra-epidermal adenocarcinoma cells
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Phyllodes Tumor (Cystosarcoma Phyllodes)
• Biphasic breast tumor consisting of a benign glandular component and malignant stromal component with leaf-like processes (“adenosarcoma”)
• ?Malignant counterpart to fibroadenoma– Coexistant fibroadenomas in 40%, may arise in fibroadenoma
(history of stable mass that undergoes enlargement)
• Clinical Presentation– Discrete, solitary, firm to hard mass– Larger size > 4 cm and/or history of rapid growth favors phyllodes
tumor over fibroadenoma– Median age 45 years (~15 years older than fibroadenoma)
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Phyllodes Tumor-Pathology• Micro:
– Stromal and epithelial tissue in “leaf-like” arrangement
– *Stroma (compared to fibroadenoma)• Increased cellularity and expansion (“stromal
overgrowth”)
• Increased mitotic rate
• Cellular pleomorphism
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Note the size!
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“Leaf-like” architecture
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Stromal expansion
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Increased mitotic activity
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Stromal component of Phyllodes invading adipose tissue
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7. Male Breast Pathology
Gynecomastia (Benign) Male Breast Cancer (Malignant)
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Gynecomastia
• Potentially reversible enlargement of the male breast
• Clinical- Unilateral or bilateral subareolar mass with or without pain
• Microscopic-Ductal and stromal proliferation• Etiology- Systemic disease-hyperthyroidism, cirrhosis,
chronic renal failure– Drugs-cimetidine, digitalis, tricyclic antidepressants,
marijuana– Neoplasms-pulmonary, testicular germ cell tumors– Hypogonadism: testicular atrophy, exogenous estrogen,
Klinefelter’s syndrome
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Gynecomastia
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Periductal edema
Epithelial hyperplasia
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Carcinoma of the Male Breast• < 1% of breast cancer• Infiltrating ductal carcinoma is by far the most
common type• Tends to present at a more advanced stage
– Less fat and breast tissue, therefore involvement of chest wall occurs earlier
• Similar prognosis when matched, stage for stage, with female breast cancer
• Associated with inherited BRCA2 mutation
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8. Prognostic Markers and Staging
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Prognostic Markers Routinely Clinically in Use
• Histopathologic grade, subtype• Stage: Tumor size, lymph Node, Metastases
(TNM)• Steroid hormone receptors (ER and PR)• Oncogene expression (HER-2/neu/c-erbB-2)
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Histopathologic Grade
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T= primary tumor size
N= presence or absence of nodal metastases
M= presence or absence of distant metastases
TNM Clinical Pathologic Staging
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The presence of axillary lymph node metastasis is the most important prognostic indicator
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Regional NodalStations for Breast CancerStaging
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Morbidity (and Mortality!) from Axillary Lymph Node Dissection
• Arm edema• Increased risk of infection• Nerve injury• Winged scapula• Rare but devastating complication:
development of lymphangiosarcoma in the setting of long-term lymphedema– High grade sarcoma with rapid spread and dismal
prognosis
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Lymphangiosarcoma
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Lymphangiosarcoma
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Sentinel Lymph Nodes
• Sentinel Lymph Node- the first draining lymph node from a specified site
• Identified at UNC using two methods simultaneously– Radioactive technetium labeled sulfur colloid– Isosulfan blue dye
• Currently:– Sentinel LN(s) submitted to histology and examined
at multiple levels (at least 3) by H&E and, if necessary, also with immunohistochemistry
– The remainder of the axilla is also dissected
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Significance of Sentinel Lymph Nodes
• Sentinel lymph node examination is a valid method of determining axillary status
• Efforts have shown improved detection of micrometastases through concentrated examination of the most likely positive node(s)
• Complete removal of the axillary lymph nodes is no longer standard treatment for all patients with invasive disease!
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Estrogen and Progesterone Receptors (ER, PR)
• >50% of carcinomas are ER positive, slightly less are PR positive
• Hormone receptor positivity is associated with longer disease-free survival, better overall survival, and longer survival after recurrence
• Hormone receptor positivity predicts better response to hormonal (anti-estrogen) therapy:– ER+PR+ > ER-PR+ > ER+PR- > ER-PR-
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c-erbB-2 (HER-2/neu)
• Oncogene which shares extensive sequence homology with epidermal growth factor receptor (EGFR)
• Overexpression by invasive carcinoma associated with:– Decreased time to recurrence– Decreased overall survival
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Strong overexpression of HER-2/neu (c-erbB-2) at cell surfaces
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c-erbB-2 ( HER2/neu)
• Herceptin® – Recombinant humanized anti-HER2
– Inhibits growth of breast cancer cells that overexpress c-erbB-2
– Enhances tumoricidal effects of doxorubicin and taxol
– Approved by the FDA September 1998
– Used in patients with metastatic disease and
c-erbB-2 overexpression
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HER-2 Gene Amplification by FISH
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Other Prognostic Markers
• DNA content (DNA ploidy)
• Tumor suppressor genes (p53, others)
• Angiogenesis (Microvessel density)
• Proteases
• Gene profiling by microarrays***
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9. Models of Breast Carcinogenesis
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Models of Breast Carcinogenesis
• Multistage Model of Carcinogenesis
• Skip-stage Model of Carcinogenesis
• Divergence vs. Convergence Hypothesis
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Multistage Model of Carcinogenesis
NormalAtypicalHyperplasia
Carcinoma In Situ
Invasive Carcinoma
Metastasis
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“Skip Stage” Model of Carcinogenesis
NormalAtypicalHyperplasia
Carcinoma In Situ
Invasive Carcinoma
Metastasis
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“Skip Stage” Model of Carcinogenesis
NormalAtypicalHyperplasia
Carcinoma In Situ
Invasive Carcinoma
Metastasis
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Convergence Hypothesis
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Divergence Hypothesis
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10. Tissue Sampling Techniques
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Tissue Microarrays
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Tissue Microarrays
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Microdissection of a single duct of DCIS
Microdissectionof single cells
Microdissection Methodologies