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
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
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
low risk for post-oophorectomy
1. Fibrocystic Dse & Epithelial Hyperplasia 2. Exogenous Estrogens 3. Contraceptive Agents 4. Ionizing Radiation 5. Breast Augmentation 6. Meningioma; Ataxia-Telangiectasia
(+) of CA in a breast quadrant other the 1
containing the dominant mass more in lobular than duct CA
5X for invasive CA, more so for (+)
Family Hx more in lobular can be synchronous or metachronous intramammary or independent spread
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 Tubular formation in >75% of the tumor 1 point Tubular formation in 10% to 75% of the tumor 2 points Tubular formation in < 10% of the tumor 3 points Nuclear pleomorphism Nuclei with minimal variation in size and shape 1 point Nuclei with moderate variation in size and 2 points shape Nuclei with marked variation in size and shape 3 ponts
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?
Proven Prognostic or Predictive
Tumor stage using AJCC\UICC TNM system Tumor size Nodal status Histologic grade and type Hormone receptor status
Promising Prognostic or Predictive
HER-2/neu p53 Vascular invasion Cell proliferation Tumor angiogenesis Epidermal growth factor receptor (EGFR)
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 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 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
Papillary Comedocarcinoma Solid Cribriform Micropapillary Clinging Cystic
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.
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
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
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.
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: Mucin – positive in scattered tumor cells in ¾ of cases.
Laminin & collagen type
IV can be demonstrated in underlying basement membrane
Immunohistochemically: (+) keratin, (+) EMA (+) Milk fat globule antigen (+) S-100 in 60% of cases
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.
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.