BREAST CARCINOMA

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BREAST CARCINOMA
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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.

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OVERVIEW OF BREAST CARCINOMA
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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

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• What about cancer of the male breast?

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• 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

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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
• Menstrual Reproductive Hx late parity
• low risk for post-oophorectomy

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risk factors

1. Fibrocystic Dse Epithelial Hyperplasia
2. Exogenous Estrogens
3. Contraceptive Agents
4. Ionizing Radiation
5. Breast Augmentation
6. Meningioma Ataxia-Telangiectasia

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Location
UOQ
50
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10
5
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Multicentricity

• () of CA in a breast quadrant other the 1
  containing the dominant mass
• more in lobular than duct CA

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Bilaterality

• 5X for invasive CA, more so for () Family Hx
• more in lobular
• can be synchronous or metachronous
• intramammary or independent spread

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Mammography

• extremely small tumors (1-2 mm)
• calcification
• CA --- 50-60
• benign --- 20

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Fine Needle Aspiration Biopsy
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Microscopic Grading of Breast Carcinoma
Nottingham Modification of the Bloom Richardson
System
Tubule Formation Tubule Formation
1 point Tubular formation in gt75 of the tumor
2 points Tubular formation in 10 to 75 of the tumor
3 points Tubular formation in lt 10 of the tumor
Nuclear pleomorphism 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. Ackermans Surgical Pathology

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• What are the prognostic factors in breast cancer?

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CATEGORY I

• Proven Prognostic or Predictive
• Tumor stage using AJCC\UICC TNM system
• Tumor size
• Nodal status
• Histologic grade and type
• Hormone receptor status

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CATEGORY II

• Promising Prognostic or Predictive
• HER-2/neu
• p53
• Vascular invasion
• Cell proliferation
• Tumor angiogenesis
• Epidermal growth factor receptor (EGFR)

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CATEGORY III

• Factors needing further evaluation
• bcl-2
• TGF-a
• Thrombomodulin
• BRCA1 and 2
• Cathepsin D

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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.

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• 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.

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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.

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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

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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.

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HER-2/neu and Breast Cancer

• HER-2/neu gene amplification was linked to
  adverse outcome in 1986
• gt100 studies of gene amplification and protein
  overexpression published by late 1997
• gt85 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.

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HER-2/neu Staining IntensityCB11, Breast
Carcinoma
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• What is the significance of HER-2/neu
  positivity in breast carcinoma?

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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.

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• IN SITU CARCINOMA

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DUCTAL CARCINOMA IN-SITU

• Morphologic variants
• Papillary
• Comedocarcinoma
• Solid
• Cribriform

• Micropapillary
• Clinging
• Cystic hypersecretory

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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
  devt of invasive CA is directly proportional to
  the cytologic grade of the tumor.

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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

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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

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LCISMicroscopic

• 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.

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• Fig 8 Lobular carcinoma in situ

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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

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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

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• Fig 9 Involvement of duct by lobular CA In situ.

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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.

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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

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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.

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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.

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• 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.

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• 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.

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• 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.

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• 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.

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• "Indian file" strands of infiltrating lobular
  carcinoma cells are seen in the fibrous stroma.
  Pleomorphism is not great.