Breast Cancer

BREAST CARCINOMA

Case  49 F,  Firm, non-tender lump  Irregular, firm fixed mass, right breast  Rough, reddened overlying skin  Mammography: irregular

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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.

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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 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?

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

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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   

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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

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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  Comedocarcinoma  Solid  Cribriform

 Micropapillary  Clinging  Cystic

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:  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

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.