basics of breast pathology

1. BREAST
PATHOLOGY
DR.ANILA.R.SHARMA

2. ANATOMY AND HISTOLOGY OF THE NORMAL BREAST

3. ANATOMY AND HISTOLOGY OF THE NORMAL BREAST

4. Terminal duct
Lobular
unit
Intralobular
stroma
Interlobular
stroma
Ductal
CarcinomasArise
Here
Lobular Carcinomas
Arise Here
Terminal Duct Lobular Unit

6. GENETICS AND EPIDEMIOLOGY
OF BREAST CANCER

7. 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.
• A woman’s risk of breast cancer nearly doubles if she has a 1*relative who has been diagnosed with breast
cancer.
• Less than 15% of women who get breast cancer have a family member diagnosed with it.
• About 5-10% of breast cancers can be linked to gene mutations inherited from one’s mother or father.
• Mutations of the BRCA1 and BRCA2 genes are the most common.
• On average, women with a BRCA1 mutation have a 55-65% lifetime risk of developing breast cancer. For women
with a BRCA2 mutation, the risk is 45%.
• Breast cancer that is positive for the BRCA1 or BRCA2 mutations tends to develop more often in younger
women.
• In men, BRCA2 mutations are associated with a lifetime breast cancer risk of about 6.8%; BRCA1 mutations are
a less frequent cause of breast cancer in men.

10. BREAST CANCER IN INDIA

14. Risk Factors for Development of Breast Cancer
• Genetic
• Environmental
• Hormonal
• Radiation
• History of previous breast pathology

15. 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

16. 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

17. 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

18. 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

19. Recognized Susceptibility Loci
• ESR 6q24-27 (Estrogen receptor)
• AR X11.2-q12 (Androgen receptor)
• PTEN10q22-23 (Cowden’s syndrome)
Putative susceptibility loci
ATM 11q22 (Ataxia Telangiectasia)
HRAS1 11p15.5
GSTM (Glutathione-S-transferase)
CYP1A1 (Cytochrome P-450)
NAT (N-acetyl-transferase)
CYP17 (C2:C16-alpha-estrone)

20. 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.

21. 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

22. 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

23. Histopathologic Risk Factors
For Breast Cancer

24. Histopathology
• Presence of a history of breast pathology increases
risk of breast cancer

25. 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)

26. MODELS OF BREAST CARCINOGENESIS

27. Models of Breast Carcinogenesis
• Multistage Model of Carcinogenesis
• Skip-stage Model of Carcinogenesis
• Divergence vs. Convergence Hypothesis

28. MULTISTAGE MODEL OF CARCINOGENESIS
Normal
Atypical
Hyperplasia
Carcinoma
In Situ
Invasive
Carcinoma
Metastasis

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

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

31. Convergence Hypothesis

32. Divergence Hypothesis

34. HISTOPATHOLOGY
PRECURSOR LESIONS

35. 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
with
a) Histologic subtype of the in situ carcinoma
b) Size/ extent of DCIS
c) Distance to the margins of excision.
DCIS is confined to
within the ductal system

36. 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

37. Grossly
visible
comedo
necrosis

38. 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

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

40. Solid DCIS, uniform
monotonous cell
population

41. Cribriforming
DCIS
Secondary
lumina

42. Micropapillary DCIS
Papillae

43. Nuclear grade 1
Nuclear grade 3

44. Florid
hyperplasia
D/D

45. UDH
ADH
CK5
CK5
DCIS CK5

46. 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

47. INVASIVE CARCINOMA

50. Well differentiated
infiltrating ductal
carcinoma
Poorly
differentiated
infiltrating ductal
carcinoma
High grade
nuclei
High mitotic rate
INVASIVE CARCINOMA ,NST

53. INVASIVE LOBULAR CARCINOMA

54. TUBULAR CARCINOMA

55. INVASIVE CRIBRIFORM CARCINOMA
D/D RADIAL SCAR

56. MEDULLARY CARCINOMA

57. MUCINOUS CARCINOMA CYSTADENOCA

58. PAPILLARY CARCINOMA

59. INVASIVE MICROPAPILLARY CARCINOMA
• These tumour cell cluster lie within
artefactual stromal spaces caused by
shrinkage of the surrounding tissue.
• The stromal spaces lack an endothelial
lining
• Peritumoural angioinvasion may be
present in up to 60% of cases.
• Intravascular tumour emboli, lymph
node metastases and malignant cells in
pleural fluids

60. INVASIVE MICROPAPILLARY CARCINOMA

61. APOCRINE CARCINOMA
GCDF15 +, ER - ,PR - , AR +

62. METAPLASTIC CARCINOMA

63. METAPLASTIC CARCINOMA

64. METAPLASTIC CARCINOMA

65. METAPLASTIC CARCINOMA

66. SECRETORY CARCINOMA

67. ONCOCYTIC CARCINOMA SEBACEOUS CA

68. ADENOID CYSTIC CARCINOMA
PATTERNS
CRIBRIFORM
SOLID
TUBULAR
APERTURES
PSUEDOLUMINA
TRUE LUMINA
LOW GRADE TREATED BY
MASTECTOMY

69. ACINIC CELL CARCINOMA

70. GLYCOGEN RICH CARCINOMA

71. Branching
compressed
ducts
Homogeneous
stroma
BIPHASIC TUMORS - FIBROADENOMA

72. Phyllodes tumor (PT) of the breast is a rare fibroepithelial neoplasm,
• accounting for 0.3% to 1% of all breast tumors.
• morphologic continuum- from benign to malignant.
• The classification of PT is based on a combination of several histologic features,
Stromal cellularity
nuclear atypia
mitotic activity
stromal overgrowth
tumor margin
• The majority of PTs behave in a benign fashion risk of local recurrence ranging from 17%
in benign PT to 27% in malignant PT.
• Distant metastasis occurs in up to 22% of malignant PTs
PHYLLODES TUMOR

73. PHYLLODES TUMOR

74. Stromal expansion

75. PHYLLODES TUMOR

76. Increased mitotic
activity
Stromal component of
Phyllodes invading adipose
tissue

77. Paget’s
disease:
nipple
ulceration
PAGETS DISEASE OF BREAST

78. INTRA DUCTAL PAPILLOMA

79. PROGNOSTIC MARKERS AND STAGING

80. Prognostic Markers Routinely
Clinically in Use
•Histopathologic grade, subtype
• Good prognosis- mucinous,medullary,secretory,ACC
• Intermediate prognosis -apocrine
• Poor prognosis-PLC,metaplastic ,IMC,NEC
•Stage: Tumor size, lymph Node, Metastases
(TNM)
•Steroid hormone receptors (ER and PR)
•Oncogene expression (HER-2/neu/c-erbB-2)

81. STAGE

83. 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

84. 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!

85. 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-

86. ESTROGEN RECEPTOR POSITIVE SUBTYPES

87. 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

88. ESTROGEN RECEPTOR POSITIVE SUBTYPES

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

93. MOLECULAR CLASSIFICATION

94. Increased understanding of the molecular heterogeneity that is
intrinsic to the various subtypes of breast cancer will likely shape the
future of breast cancer diagnosis, prognosis and treatment
Advances have been remarkable and have clearly translated into
better patient care ---earlier detection, better prognosis and new
targeted therapies
Two recent advances in the breast cancer -paradigm shifts:
identification of intrinsic breast tumor subtypes{which has changed
the way we think about breast cancer }
recent characterization of cancer stem cells (CSCs){ tumor initiation,
recurrence and resistance to therapy}

99. ER
PR
HER2
BASAL LIKE
HER2 +
LUMINAL B
LUMINAL A

100. The main studies that led to the identification of intrinsic
molecular subtypes were almost completely limited to IDC, NST
did not take uncommon histologies into
account
Thus, molecular classification is more a description of the
heterogeneity of IDC rather than an exhaustive representation
of the entire BC landscape.

101. Concept of CSCs -not recent-gained significant -isolation and
characterization -tumor initiating cells
Theory
small subset of cells {tumor initiation and progression}
bulk of the tumor cells {low tumorigenic potential}
The cell of origin for CSCs is still undetermined[hypotheses]
either originate from normal cells within the stem cell hierarchy
arise from a common normal stem cell
Functional classification of breast cancer -use one or more of the CSC
markers to quantify the % of CSCs in a patient’s tumor.
FUNCTIONAL CLASSIFICATION

103. The flow, analysis and integration
of multi-dimensional molecular,
biological and clinical data from
different biomedical
sources leading to a new
classification system, diagnostic
tools and predictive models in
breast cancer

104. THANK YOU