This document discusses breast cancer, including: 1. Breast cancer is the most common cancer in women in the United States, and the second most common cause of cancer death in women. One in eight women will get breast cancer. 2. Risk factors for breast cancer include age, family history, benign breast disease, reproductive history, and environmental/lifestyle factors. 3. Genetic changes like mutations in BRCA1, BRCA2, and p53 genes can increase the risk of breast cancer. 4. The main types of breast cancer are ductal carcinoma in situ, invasive ductal carcinoma, and invasive lobular carcinoma. Prognosis depends on cancer stage and characteristics.

1. BREASTBREAST
TUMORSTUMORS

4. LYMPHATIC
DRAINAGE
AXILLARY (MOSTLY)
INTERNAL MAMMARY
SUPRACLAVICULAR

5. 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.

7. 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

10. 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?

11. Causes of Breast Cancer
• Genetic
• Environmental
• Hormonal

12. Genetic changes
Proto-oncogen
• HER2/NEU
• 30%
• Poor prognosis
• RAS & MYC
Tumor suppressor gene
• Rb,
• p53,
• ER gene inactivation

13.  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.

14. Genetic Factors
Inhereted 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

15. 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

16. 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)

17. 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

18. OTHER
Recognized Susceptibility Loci
• ESR 6q24-27 (Estrogen receptor)
• AR X11.2-q12 (Androgen receptor)
• PTEN 10q22-23 (Cowden’s syndrome)

19. 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.

20. 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

21. 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

22. Histopathologic Risk Factors
For Breast Cancer
• Presence of a history of breast
pathology increases risk of breast
cancer

23. 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)

24. 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

25. Lumpectomy

26. Mastectomy: Modified Radical

27. 6. Breast Cancer Pathology
In Situ Carcinomas
Invasive Carcinomas
Special Subtypes

28. 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.

29. 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

30. DCIS is
confined to
within the
ductal
system

31. Mammography showing a normal breast (left) and a cancerous breast
(right).

33. Linear and
branching
calcifications

34. Grossly
visible
comedo
necrosis

35. 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

36. Normal Breast Histology

37. Comedo
necrosis
Calcification
Tumor cells
confined to
duct, i.e. DCIS

39. Cribriforming
DCIS
Secondary
lumina

40. Micropapillary DCIS
Papillae

41. Nuclear grade 1

42. Nuclear grade 3

45. 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

46. 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

47. Lobular
carcinoma in
situ

49. 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

50. Stellate lesion
Calcifications

51. 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

52. Stellate lesion
invading adjacent
breast tissue

53. Well differentiated
infiltrating ductal
carcinoma

54. Poorly differentiated
infiltrating ductal
carcinoma
High grade
nuclei
High mitotic rate

55. INFILTRATING DUCTAL

56. Infiltrating ductal carcinoma,
invading and replacing breast
stroma

57. Invasion of adipose tissue of
breast

58. 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)

59. 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

60. Linear arrangement of
malignant cells

61. INFILTRATING LOBULAR CA.,INFILTRATING LOBULAR CA.,
““INDIAN” FILE PATTERNINDIAN” FILE PATTERN

63. Positive cytokeratin stain
confirming the epithelial
nature of lobular carcinoma

64. Infiltrating ductal
carcinoma, in
contrast, with
architectural
distortion

65. 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

66. INFILTRATING DUCTAL CA.,INFILTRATING DUCTAL CA.,
““TUBULAR” PATTERN or TYPETUBULAR” PATTERN or TYPE

67. INFILTRATING DUCTAL CA.,INFILTRATING DUCTAL CA.,
MUCINOUS (COLLOID) PATTERN or TYPEMUCINOUS (COLLOID) PATTERN or TYPE

68. Mucinous (Colloid)
Carcinoma

69. INFILTRATING DUCTAL CA.,INFILTRATING DUCTAL CA.,

71. 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

72. INFLAMMATION?
Peau d’orange

73. Inflammatory carcinoma

76. 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

77. Paget’s
disease:
nipple
ulceration

78. Paget’s Disease of the Nipple
Intra-epidermal
adenocarcinoma cells

79. Breast cancer showing an inverted
nipple, lump and skin dimpling.

80. BREAST CANCER
TNM stage groupingTNM stage grouping
Stage 0Stage 0 Tis N0 M0
Stage IStage I T1* N0 M0
Stage IIAStage IIA T0 N1 M0
T1* N1** M0
T2 N0 M0
Stage IIBStage IIB T2 N1 M0
T3 N0 M0
Stage IIIAStage IIIA T0, T1,* T2 N2 M0
T3 N1, N2 M0
Stage IIIBStage IIIB T4 Any N M0
Any 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.

81. BREAST CANCER
Tumor 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 carcinoma
AJCC®
Cancer Staging Manual, 5th
edition (1997)
published by Lippincott-Raven Publishers, Philadelphia,
Pennsylvania.

82. BREAST CANCER
Commonly assessed prognosticCommonly 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/progesterone
receptors
HER2/neu overexpression
Number of positive axillary nodes
Tumor size
Lymphatic and vascular invasion
Histologic tumor type
Histologic grade

83. BREAST CANCER
5-year survival as function of the number5-year survival as function of the number
of positive axillary lymph nodesof positive axillary lymph nodes
0%
20%
40%
60%
80%
5-YearSurvival5-YearSurvival
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.

84. Other Prognostic Markers
• DNA content (DNA ploidy)
• Tumor suppressor genes (p53,
others)
• Angiogenesis (Microvessel density)
• Proteases
• Gene profiling by microarrays***

85. c-erbB-2 (HER-2/neu)
• Oncogene which shares extensive sequence
homology with epidermal growth factor receptor
(EGFR)

86. Strong overexpression of
HER-2/neu (c-erbB-2) at
cell surfaces

87. HER-2 Gene Amplification by FISH

88. BREAST CANCER
HER-2/neuHER-2/neu overexpressionoverexpression
• 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.

89. Histopathologic Grade

91. Total Cancers Per Cent
In Situ Carcinoma 15–30
Ductal carcinoma in situ, DCIS 80
Lobular carcinoma in situ, LCIS 20
Invasive Carcinoma 70–85
No 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)

92. MALE BREAST
• GYNECOMASTIA (related to
hyperestrogenism)
• CARCINOMA (1% of ♀ )

93. 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

94. Gynecomastia

95. GYNECOMASTIA (NO lobules)

96. Periductal
edema
Epithelial hyperplasia

97. 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

98. Breast Anatomy and Location of
Disease Processes

100. Multistage Model of
Carcinogenesis
Normal
Atypical
Hyperplasia
Carcinoma
In Situ
Invasive
Carcinoma
Metastasis

101. “Skip Stage” Model of
Carcinogenesis
Normal
Atypical
Hyperplasia
Carcinoma
In Situ
Invasive
Carcinoma
Metastasis

102. “Skip Stage” Model of
Carcinogenesis
Normal
Atypical
Hyperplasia
Carcinoma
In Situ
Invasive
Carcinoma
Metastasis

103. Tissue Microarrays

104. Microdissection
of a single duct
of DCIS
Microdissection
of single cells
Microdissection Methodologies