pathobiology of breast cancer associate professor department of pathology and laboratory medicine...
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Pathobiology of Breast Cancer
Associate ProfessorDepartment of Pathology and Laboratory Medicine
Ruth A. Lininger, MD MPH
1. Anatomy and Histology of the Normal Breast
Terminal duct/lobular unitsNipple
Histology of the Normal Breast
Terminal duct
Lobular unit
Intralobular stroma
Interlobular stroma
Ductal CarcinomasArise Here
Lobular CarcinomasArise Here
Terminal Duct Lobular Unit
Epithelium
Myoepithelium
Immunostain for Smooth Muscle Actin
Epithelium
Myoepithelium
2. Normal Physiologic States of the Breast
•Pregnancy and Lactation
•Post-Menopausal State
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
Foamy cytoplasm
Secretory material
Prominent nucleoli
Lactational Change
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
Intralobular stromal collagenization
Post-Menopausal Breast
3. Genetics and Epidemiology of Breast Cancer
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.
Age-adjusted Cancer Incidence Rates Among Females: 1973 to 1998
Risk Factors for Development of Breast Cancer
• Genetic
• Environmental
• Hormonal
• Radiation
• History of previous breast pathology
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
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
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
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
OTHERRecognized Susceptibility Loci
• ESR 6q24-27 (Estrogen receptor)
• AR X11.2-q12 (Androgen receptor)
• PTEN 10q22-23 (Cowden’s syndrome)
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)
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.
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
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
4. Histopathologic Risk FactorsFor Breast Cancer
Histopathology
• Presence of a history of breast pathology increases risk of breast cancer
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)
Proliferative Fibrocystic Change WITHOUT Atypia
Intraductal Hyperplasia, Moderate to FloridSclerosing AdenosisIntraductal Papilloma (A benign breast “tumor”)Fibroadenoma (A benign breast “tumor”)
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
Moderate hyperplasia
Florid hyperplasia
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
Most papillomas arise in larger mammary ducts
Intraductal papilloma
Duct lining
Stalk
Fibrovascular core
Myoepithelium
Homogeneous lesion with well circumscribed border
FibroadenomaFibroadenoma (Benign Biphasic Tumor)
Fibroadenomas will “shell out” at surgery
Fibroadenoma
Cleft
Fibroadenoma
Branching compressed ducts
Homogeneous stroma
Fibroadenoma
Proliferative Fibrocystic Change WITH Atypia
• Atypical Intraductal Hyperplasia• Atypical Lobular Hyperplasia
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
5. Breast Pathology Specimens
Surgical Procedures to Sample Breast Lesions
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
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
Fine Needle Aspiration (FNA)
FNA Cytology Smear Specimen
Fine Needle Aspiration: Benign Ductal Epithelium Versus Breast Cancer
Needle Core Biopsy
Lumpectomy
Mastectomy: Modified Radical
6. Breast Cancer Pathology
In Situ CarcinomasInvasive CarcinomasSpecial Subtypes
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.
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
DCIS is confined to within the ductal system
Mammography: DCIS
Linear and branching calcifications
Grossly visible comedo necrosis
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
Comedo necrosis
Calcification
Tumor cells confined to duct, i.e. DCIS
Solid DCIS, uniform monotonous cell population
Cribriforming DCIS
Secondary lumina
Micropapillary DCIS
Papillae
Nuclear grade 1
Nuclear grade 3
Surgical excision utilizes anatomic distribution in the lobe of involvement
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
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
Lobular carcinoma in situ
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
Stellate lesion
Calcifications
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
Stellate lesion invading adjacent breast tissue
Well differentiated infiltrating ductal carcinoma
Poorly differentiated infiltrating ductal carcinoma
High grade nuclei
High mitotic rate
Infiltrating ductal carcinoma, invading and replacing breast stroma
Invasion of adipose tissue of breast
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)
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
Linear arrangement of malignant cells
Positive cytokeratin stain confirming the epithelial nature of lobular carcinoma
Infiltrating ductal carcinoma, in contrast, with architectural distortion
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
Mucin
“Floating” malignant cells
Mucinous (Colloid) Carcinoma
Tubular Carcinoma
Well formed tubules
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
Inflammatory carcinoma
Inflammatory carcinoma: dermal lymphatic spaces containing tumor cells
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
Paget’s disease: nipple ulceration
Paget’s Disease of the Nipple
Intra-epidermal adenocarcinoma cells
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)
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
Note the size!
“Leaf-like” architecture
Stromal expansion
Increased mitotic activity
Stromal component of Phyllodes invading adipose tissue
7. Male Breast Pathology
Gynecomastia (Benign) Male Breast Cancer (Malignant)
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
Gynecomastia
Periductal edema
Epithelial hyperplasia
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
8. Prognostic Markers and Staging
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)
Histopathologic Grade
T= primary tumor size
N= presence or absence of nodal metastases
M= presence or absence of distant metastases
TNM Clinical Pathologic Staging
The presence of axillary lymph node metastasis is the most important prognostic indicator
Regional NodalStations for Breast CancerStaging
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
Lymphangiosarcoma
Lymphangiosarcoma
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
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!
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-
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
Strong overexpression of HER-2/neu (c-erbB-2) at cell surfaces
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
HER-2 Gene Amplification by FISH
Other Prognostic Markers
• DNA content (DNA ploidy)
• Tumor suppressor genes (p53, others)
• Angiogenesis (Microvessel density)
• Proteases
• Gene profiling by microarrays***
9. Models of Breast Carcinogenesis
Models of Breast Carcinogenesis
• Multistage Model of Carcinogenesis
• Skip-stage Model of Carcinogenesis
• Divergence vs. Convergence Hypothesis
Multistage Model of Carcinogenesis
NormalAtypicalHyperplasia
Carcinoma In Situ
Invasive Carcinoma
Metastasis
“Skip Stage” Model of Carcinogenesis
NormalAtypicalHyperplasia
Carcinoma In Situ
Invasive Carcinoma
Metastasis
“Skip Stage” Model of Carcinogenesis
NormalAtypicalHyperplasia
Carcinoma In Situ
Invasive Carcinoma
Metastasis
Convergence Hypothesis
Divergence Hypothesis
10. Tissue Sampling Techniques
Tissue Microarrays
Tissue Microarrays
Microdissection of a single duct of DCIS
Microdissectionof single cells
Microdissection Methodologies