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