BREASTBREAST
TUMORSTUMORS
LYMPHATIC DRAINAGE
AXILLARY (MOSTLY)
INTERNAL MAMMARY
SUPRACLAVICULAR
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.
Breast Lung & bronchus Leukemia Bladder Brain &CNS NHL Colorectal Larynx Skin excluding Melanoma Stomach Uterus including Cervix and corpus) Hodgkin disease Thyroid Kidney, pelvis& ureter Ovary Prostate Pancreas Bone & cartilage Liver &bile ducts Esophagus
Type of cancer, in Iraq, by primary tumor site (2004)6
Risk Factors for Breast Cancer
• Geography• Age• Menstrual history• Pregnancy• Benign breast disease (Hx of previous breast pathology)• Other:• Estrogen• Oral contraceptive• Lack of breast feeding is a risk.• Obesity• High fat diet• Alcohol• Smoking• Radiation Exposure • Carcinoma of the contralateral breast or endometrium • Environmental Toxins • ABORTIONS?
Causes of Breast Cancer
• Genetic
• Environmental
• Hormonal
Genetic changes
Proto-oncogen• HER2/NEU • 30%• Poor prognosis
• RAS & MYC
Tumor suppressor gene• Rb, • p53,• ER gene inactivation
Gene profiling of breast cancerGene profiling of breast cancer• 1. ER +ve, HER2 –ne
• 2. ER +ve, HER2 +ve
• 3. ER -ne, HER2 +ve
• 4. ER -ne, HER2 –ne
• Different Outcome & Therapy.
Genetic FactorsInhereted Mutations (10%)
• 10% breast cancers are familial (90% sporadic)• Positive Family History, especially in 1st degree
relatives (mother, daughter, sister) confers increased risk for breast cancer
• Tumor suppressor genes (BRCA1, BRCA2)• 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)
• 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)
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)
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
Histopathologic Risk FactorsFor Breast Cancer
• 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)
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
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 BM
• DCIS is a surgically treatable entity• The likelihood of developing an invasive carcinoma, or
recurrent DCIS varies with
a) 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 showing a normal breast (left) and a cancerous breast (right).
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
Normal Breast Histology
Comedo necrosis
Calcification
Tumor cells confined to duct, i.e. DCIS
Cribriforming DCIS
Secondary lumina
Micropapillary DCIS
Papillae
Nuclear grade 1
Nuclear grade 3
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”.
• 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:– Grading (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
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
INFILTRATING LOBULAR CA.,INFILTRATING LOBULAR CA.,
““INDIAN” FILE PATTERNINDIAN” FILE PATTERN
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
INFILTRATING DUCTAL CA., INFILTRATING DUCTAL CA.,
““TUBULAR” PATTERN or TYPETUBULAR” PATTERN or TYPE
INFILTRATING DUCTAL CA., INFILTRATING DUCTAL CA.,
MUCINOUS (COLLOID) PATTERN or TYPEMUCINOUS (COLLOID) PATTERN or TYPE
Mucinous (Colloid) Carcinoma
INFILTRATING DUCTAL CA., INFILTRATING DUCTAL CA.,
MEDULLARY PATTERN or TYPEMEDULLARY PATTERN or TYPE
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
INFLAMMATION?
Peau d’orange
Inflammatory carcinoma
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
Breast cancer showing an inverted nipple, lump and skin dimpling.
BREAST CANCERTNM stage groupingTNM stage grouping
Stage 0Stage 0 Tis N0 M0
Stage IStage I T1* N0 M0
Stage IIAStage IIA T0 N1 M0 T1* N1** M0T2 N0 M0
Stage IIBStage IIB T2 N1 M0T3 N0 M0
Stage IIIAStage IIIA T0, T1,* T2 N2 M0T3 N1, N2 M0
Stage IIIBStage IIIB T4 Any N M0Any T N3 M0
Stage IVStage IV Any T Any N M1
* Note: T1 includes T1 mic.** Note: The prognosis of patients with N1a is similar to that of patients with pN0.
AJCC® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers,
Philadelphia, Pennsylvania.
BREAST CANCERTumor definitionsTumor definitions
• TX Primary tumor cannot be assessed• T0 No evidence of primary tumor• Tis Carcinoma in situ: Intraductal carcinoma, lobular carcinoma in situ,
or Paget’s disease of the nipple with no tumor• T1 Tumor 2 cm or less in its greatest diameter
T1mic Microinvasion more than 0.1 cm or less in its greatest diameter
T1a Tumor more than 0.1 cm but not more than 0.5 cm in its greatest diameter
T1b Tumor more than 0.5 cm but not more than 1 cm in its greatest diameter
T1c Tumor more than 1 cm but not more than 2 cm in its greatest diameter• T2 Tumor more than 2 cm but not more than 5 cm in its greatest diameter• T3 Tumor more than 5 cm in its greatest diameter• T4 Tumor of any size with direct extension to (a) chest wall or (b) skin, only as
described below
T4a Extension to chest wall
T4b Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast
T4c Both (T4a and T4b)
T4d Inflammatory carcinomaAJCC® Cancer Staging Manual, 5th edition (1997)
published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.
BREAST CANCER
Commonly assessed prognostic Commonly assessed prognostic factorsfactors
Slamon DJ. Chemotherapy Foundation. 1999;46.Winer E, et al. Cancer: Principles & Practice of Oncology. 6th
ed. 2001;1651-1717.
Nuclear grade
Estrogen/progesteronereceptors
HER2/neu overexpression
Number of positive axillary nodes
Tumor size
Lymphatic and vascular invasion
Histologic tumor type
Histologic grade
BREAST CANCER5-year survival as function of the number 5-year survival as function of the number
of positive axillary lymph nodesof positive axillary lymph nodes
0%
20%
40%
60%
80%
5-Y
ear
Su
rviv
al
5-Y
ear
Su
rviv
al
0 1 2 3 4 5 6-10 11-15 16-20 >20
Number of Positive NodesNumber of Positive Nodes
Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557-1616.
Other Prognostic Markers
• DNA content (DNA ploidy)
• Tumor suppressor genes (p53, others)
• Angiogenesis (Microvessel density)
• Proteases
• Gene profiling by microarrays***
c-erbB-2 (HER-2/neu)
• Oncogene which shares extensive sequence homology with epidermal growth factor receptor (EGFR)
Strong overexpression of HER-2/neu (c-erbB-2) at cell surfaces
HER-2 Gene Amplification by FISH
BREAST CANCERHER-2/neuHER-2/neu overexpression overexpression
• There is a significant decrease of 5-year survival in patients whose tumors overexpress HER-2/neu
• This decrease in survival for both node-positive and node-negative patients
• In vitro studies show that HER-2/neu overexpression increases the following cell activities in malignant breast epithelial cells:
DNA synthesis
Cell growth
Anchorage-dependent growth
Tumorgencity
Metastatic potential
Slamon DJ. Chemotherapy Foundation Symposium. 1999;46. Abstract 39.
Goldenberg MM. Clinical Therapeutics. 1999;21(2):309-318.
Histopathologic Grade
Total Cancers Per Cent
In Situ Carcinoma 15–30Ductal carcinoma in situ, DCIS 80
Lobular carcinoma in situ, LCIS 20
Invasive Carcinoma 70–85No special type carcinoma ("ductal") 79
Lobular carcinoma 10
Tubular/cribriform carcinoma (Better prognosis than average)
6
Mucinous (colloid) carcinoma (Better prognosis than average)
2
Medullary carcinoma (Better prognosis than average) 2
Papillary carcinoma 1
Metaplastic carcinoma, (Squamous)
MALE BREAST
• GYNECOMASTIA (related to hyperestrogenism)
• CARCINOMA (1% of ♀ )
Gynecomastia
• Reversible enlargement of the male breast• Unilateral or bilateral subareolar mass +/-pain• 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
GYNECOMASTIA (NO lobules)
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
Breast Anatomy and Location of Disease Processes
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
Tissue Microarrays
Microdissection of a single duct of DCIS
Microdissectionof single cells
Microdissection Methodologies