BREAST CARCINOMA

Case
 49 F,
 Firm, non-tender lump
 Irregular, firm fixed mass, right breast
 Rough, reddened overlying skin
 Mammography: irregular
 The irregular mass lesion seen here is an infiltrating ductal carcinoma of breast. The center
is very firm (scirrhous) and white because of the desmoplasia. There are areas of yellowish
necrosis in the portions of neoplasm infiltrating into the surrounding breast. Such tumors
appear very firm and non-mobile on physical exam.
 This breast biopsy demonstrates a carcinoma. Note the irregular margins and varied
cut surface. This small cancer was found by mammography. The margins of the
specimen have been inked with green dye following removal to assist in determining
whether cancer extends to the margins once histologic sections are made.
OVERVIEW OF BREAST
CARCINOMA
Incidence
 most common malignancy & leading
cause of CA death in females
 more common in Europeans &
Americans
 localized
 less than 2 cm in diameter or in situ
What about cancer of the male breast?
 Male breast cancer is 100x less common than
breast cancer in women
 Histologically, it has the same features as the
more common cancer of the female breast
 50% of tumors have already metastasize at
the time of diagnosis
Risk Factors
 Country of birth
 Family Hx – 1st degree relative, affected
at an early age, bilateral
chrom 17q --- BRCA1 ~ ovarian CA
chrom 13q12-13 --- BRCA2
3. Menstrual & Reproductive Hx – late
parity
low risk for post-oophorectomy
risk factors…

1. Fibrocystic Dse & Epithelial Hyperplasia

2. Exogenous Estrogens
3. Contraceptive Agents
4. Ionizing Radiation
5. Breast Augmentation
6. Meningioma; Ataxia-Telangiectasia
Location
Multicentricity
 (+) of CA in a breast quadrant other the 1
containing the dominant mass
 more in lobular than duct CA
Bilaterality
 5X for invasive CA, more so for (+)
Family Hx
 more in lobular
 can be synchronous or metachronous
 intramammary or independent spread
Mammography
 extremely small
tumors (1-2 mm)
 calcification
 CA --- 50-60%
 benign --- 20%
Fine Needle Aspiration Biopsy
Microscopic Grading of Breast Carcinoma:
Nottingham Modification of the Bloom Richardson
System
Tubule Formation
1 point Tubular formation in >75% of the tumor
2 points Tubular formation in 10% to 75% of the tumor
3 points Tubular formation in < 10% of the tumor
Nuclear pleomorphism
1 point Nuclei with minimal variation in size and shape
2 points Nuclei with moderate variation in size and
shape
3 ponts Nuclei with marked variation in size and shape

 Grade I : 3-5 points

 Grade II : 6-7 points
 Grade III : 8-9 points Rosai, J. Ackerman’s Surgical Pathology
What are the prognostic factors in breast
cancer?
CATEGORY I

 Proven Prognostic or Predictive

 Tumor stage using AJCC\UICC TNM system
 Tumor size
 Nodal status
 Histologic grade and type
 Hormone receptor status
CATEGORY II

 Promising Prognostic or Predictive

 HER-2/neu
 p53
 Vascular invasion
 Cell proliferation
 Tumor angiogenesis
 Epidermal growth factor receptor (EGFR)
CATEGORY III

 Factors needing further evaluation

 bcl-2
 TGF-a
 Thrombomodulin
 BRCA1 and 2
 Cathepsin D
Hormone Receptor Status
 Correlates well with response to hormone
therapy and chemotherapy
 Can be done by:
 Biochemical method
 Immunohistochemical stains
 In situ hybridization
 Associated with:
 High nuclear & low histologic grades
 Absence of tumor necrosis
 Absence of p53 mutations
 Bcl2 immunoreactivity
 Progesterone receptor (PR) positivity in a breast carcinoma. The usefulness of this
determination is not as well established as for estrogen receptors. Carcinomas that
are PR positive, but not ER positive, may have a worse prognosis.
 Estrogen receptor (ER) positivity in a breast carcinoma. The use of the
immunoperoxidase technique allows determination of ER positivity within just
the nuclei of the neoplastic cells, without interference from other cells.
HER-2/neu Gene
 HER-2/neu is a gene which belongs to a “family” of
genes that produce human epidermal growth factor
receptors.
 It is called HER-2 because it was the second gene of
that gene family identified.
 It is called neu because it was first identified in
tumors of the neurological system.
 The gene was studied by 2 different groups of
researchers. The second group called it c erbB-2.
The HER-2/neu Gene
 HER-2/neu gene is an oncogene
 An oncogene is a gene activated by
mutation/amplification and which promotes
cancer development
 It is localized to chromosome 17q
 Encodes for a transmembrane growth factor
receptor
 Has tyrosine kinase activity
HER-2/neu Protein
 HER-2/neu gene produces a transmembrane 185-kDa protein
which is expressed in normal secretory epithelial cells (including
breast, pancreas, intestine and salivary gland).

 It is also known as neu, c-neu, p185, c-erbB-2

 The HER-2/neu protein is a receptor on the cell surface that

receives signals which regulate cell growth.

 In a normal cell there are 2 copies of the HER-2/neu gene in

the nucleus and approximately 50,000 copies of the HER-2/neu
protein on the cell surface.
HER-2/neu and Breast Cancer
 HER-2/neu gene amplification was linked to adverse outcome in
1986
 >100 studies of gene amplification and protein overexpression
published by late 1997
 >85% of studies have associated increased HER-2/neu activity
with poor prognosis in lymph node negative disease
 Expression of c-erbB-2 is significantly related to positive lymph
nodes, poor nuclear grade, and lack of steroid receptors and
high proliferative activity.
 Patients expressing this antigen have a poor prognosis.
Anthracyclin adjuvant therapy is more beneficial to patients
expressing this antigen.
HER-2/neu Staining Intensity
CB11, Breast Carcinoma
What is the significance of HER-2/neu
positivity in breast carcinoma?
HER-2/neu as Target of Therapy
 Anti-HER-2/neu therapeutic antibodies (Herceptin®)
 HER-2/neu antibody directed therapy
 chemotherapy delivery (adriamycin)
 radioisotope delivery
 HER-2/neu mediated immunocytotoxicity
 HER-2/neu vaccination
 HER-2/neu gene therapy (antisense oligonucleotides;
promoter gene inactivation
 This is positive immunoperoxidase staining for C-erb B-2 (C-neu) in a breast
carcinoma. Note the membranous staining of the neoplastic cells. There is a
correlation between C-erb B-2 positivity and high nuclear grade and aneuploidy.
IN SITU CARCINOMA
DUCTAL CARCINOMA IN-SITU
Morphologic
variants:

 Papillary  Micropapillary
 Comedocarcinoma  Clinging
 Solid  Cystic
 Cribriform
hypersecretory
EVOLUTION
 The transformation into an invasive
phenotype does not occur in all cases.
 When such transformation occurs, the
process usually evolves over years or
decades.
 There is a substantial difference in the
frequency w/ which this phenomenon occurs
depending on the type of DCIS. . . The risk for
dev’t of invasive CA is directly proportional to
the cytologic grade of the tumor.
 Evolution
Cont.
 There is a definite relation ship between
microscopic type of DCIS and the invasive
component.
 Not all invasive breast CA go through the
sequence just described
LOBULAR CA IN SITU
 a.k.a. lobular neoplasia
 Found incidentally in breast removed for other
reason
 Multicentric in 70% of cases, bilateral 30-40%
 Most cases are within 5 cm of the nipple from
the skin surface in the outer and inner upper
quadrants.
 Residual tumor foci in 60% of breast removed
ff diagnosis of LCIS
 LCIS
Microscopic
 The lobules are distended and completely
filled by relatively uniform, round, small to
medium size cells with round normochromatic
(or mildly hyperchromatic) nuclei.
 Atypia, polymorphism, mitotic activity and
necrosis are minimal or absent.
 Fig 8 : Lobular carcinoma in situ
 LCIS
Minor Morphologic Variations
 Moderate nuclear pleomorphism
 Large nuclear size
 Loss of cohesiveness
 Appreciable mitotic activity
 Scattered signet ring cells
 Apocrine changes
 Focal necrosis
 Variation in shape of the involved lobule
DUCTAL CHANGES IN LCIS
 The neighboring terminal ducts may exhibit
proliferation of cells similar to those involving
the lobules.
 May form a mural/ pagetoid pattern
 Can also grow in solid cribrifrom or
micropapillary
 Fig 9 : Involvement of duct by lobular CA In situ.
LCIS
 May also be found in found in fibroadenomas
and in foci of sclerosing adenosis
 To establish diagnosis from these, cellular
proliferation must has resulted in the
formation of solid nests that have expanded
the lobules.
Lobular CA In Situ
Special stains: Immunohistochemically:
 Mucin – positive in  (+) keratin,
scattered tumor cells in  (+) EMA
¾ of cases.  (+) Milk fat globule
antigen
 Laminin & collagen type  (+) S-100 in 60% of
IV can be demonstrated cases
in underlying basement
membrane
EVOLUTION
 20%-30% of px will develop Invasive CA,
(a risk about 8-10x higher)
 The risk seems greater in well developed
LCIS than in atypical lobular hyperplasia.
 The increase risk applies to both breast,
although it is greater on the side of the
biopsy.
 The invasive CA may be of either lobular or
ductal type.
Cont..
 The amount of LCIS or its morphologic
variations bears little or no relation to the
magnitude of the risk.
 If a patient with a biopsy diagnosis of LCIS is
examined periodically, the chances of her
dying as a result of breast CA are minimal.
 “ Careful life long follow up”
 Simple mastectomy can be considered in the
presence of strong family history of CA,
extensive FCC or excessive apprehension in
part of the patient, ….. Or if prolong follow-up
evaluation cannot be assured.
 This high power microscopic view demonstrates intraductal
carcinoma. Neoplastic cells are still within the ductules and have
not broken through into the stroma. Note that the two large
lobules in the center contain microcalcifications. Such
microcalcifications can appear on mammography.
 Lobular carcinoma in situ is seen here. Lobular CIS consists of
a neoplastic proliferation of cells in the terminal breast ducts and
acini. The cells are small and round. Though these lesions are
low grade, there is a 30% risk for development of invasive
carcinoma in the same or the opposite breast.
 Invasive lobular carcinoma of the breast is shown here. This neoplasm
arises in the terminal ductules of the breast. About 5 to 10% of breast
cancers are of this type. There is about a 20% chance that the opposite
breast will also be involved, and many of them arise multicentrically in
the same breast.
 "Indian file" strands of infiltrating lobular
carcinoma cells are seen in the fibrous
stroma. Pleomorphism is not great.