MALIGNANT DISEASES OF BREAST

Dr. Anju Pradhan. Assistant Professor Department of Pathology BPKIHS, Dharan

Objectives
Risk factors of breast carcinoma.

Etiopathogenesis.
Types: In situ / Invasive.

Histomorphology of different types of breast carcinoma.

Prognostic factors.

Breast Cancer Risk Factors

Factors Relative Risk

Well-Established Influences
1. Geographic factors 2. Age 3. Family history Varies in different areas Increases after age 30yr

i. First-degree relative with breast cancer

ii. Premenopausal iii. Premenopausal and bilateral iv. Postmenopausal v. Postmenopausal and bilateral

1.2-3.0
3.1 8.5-9.0 1.5 4.0-5.4

Breast Cancer Risk Factors

Factors Relative Risk

Well-Established Influences
4. Menstrual history i. Age at menarche <12yr 1.3

ii. Age at menopause >55yr

5. Pregnancy

1.5-2.0

i. First live birth from ages 25 to 29yr 1.5

ii. First live birth after age 30yr 1.9

iii. First live birth after age 35yr

iv. Nulliparous

2.0-3.0
3.0

Breast Cancer Risk Factors

Factors Relative Risk

Well-Established Influences
6. Benign breast disease Proliferative disease without atypia Proliferative disease with atypical hyperplasia Lobular carcinoma in situ 1.6 >2.0 6.9-12.0

Breast Cancer Risk Factors

Factors

Less Well-Established Influences

Exogenous estrogens
Oral contraceptives Obesity Alcohol consumption Cigarette smoking

Pathogenesis
(1) Genetic changes,

(2) Hormonal influences, and

(3) Environmental variables.

Pathogenesis 1. Genetic Changes

i. Hereditary Breast Cancers:
Mutation in tumor supressor genes BRCA1 (about 50% of hereditary breast cancers) & BRCA2 (1/3rd). Germ-line mutations in p53 (Li-Fraumeni syndrome);
Germ-line mutations in PTEN (Cowden disease); ATM gene, carriers of the ataxia-telangiectasia gene.

Pathogenesis 1. Genetic Changes

ii. Sporadic Breast Cancers:
Overexpression of the HER2/NEU protooncogene, which has been found to be amplified in up to 30% of invasive breast cancers.
Mutations of the tumor suppressor genes RB and p53.

A large number of genes including the estrogen receptor may be inactivated by promoter hypermethylation.

Multiple acquired genetic alterations are involved in the sequential transformation of a normal epithelial cell into a CANCEROUS CELL.

Genetics
Gene expression profiling can stratify breast cancer into five subtypes: 1. Luminal A (estrogen receptor positive), 2. Luminal B (estrogen receptor positive),

3. HER2/NEU overexpressing (estrogen receptor negative),

4. Basal-like (estrogen receptor and HER2/NEU negative), and

5. Normal breast like.

These subtypes are reproducible and are associated with different outcomes.

Pathogenesis 2. Hormonal Influences

Endogenous estrogen / hormonal imbalance:

Increased exposure to estrogen peaks during the menstrual cycle (long duration of reproductive life, nulliparity, and late age at birth of first child), Functioning ovarian tumors that elaborate estrogens,

Pathogenesis 2. Hormonal Influences

Estrogens stimulate the production of growth factors by normal breast epithelial cells and by cancer cells. The ER & PR normally present in breast epithelium, and often present in breast cancer cells, may interact with growth promoters, such as TGF-, PDGF, and FGF elaborated by human breast cancer cells, to create an autocrine mechanism of tumor development.

Pathogenesis 3. Environmental Variables

The variable incidence of breast cancer in genetically homogeneous groups and the geographic differences in prevalence, Irradiation and

Exogenous estrogens.

Histologic types of breast cancer

In situ carcinoma
Ductal carcinoma in situ (DCIS; intraductal)
Lobular carcinoma in situ (LCIS)

Invasive carcinoma
Ductal carcinoma (No Special Type)
Lobular carcinoma

Tubular carcinoma
Mucinous carcinoma Medullary carcinoma Papillary carcinoma Metaplastic carcinoma

CARCINOMA IN SITU
1. DCIS (INTRADUCTAL CARCINOMA in situ):
Neoplastic population of cells limited to ducts and lobules by the basement membrane. 15%-30% in well-screened population. Mammographic calcification. Vague palpable mass / nipple discharge / incidental.

Involves a single ductal system.

Spread entire sector of the breast. Initially atypical hyperplasia of ductal epithelium.

DCIS - MICROSCOPY
Architectural subtypes

A. Comedocarcinoma

B. Noncomedocarcinoma
1. Solid 2. Cribriform 3. Papillary 4. Micropapillary

A. COMEDOCARCINOMA
Solid sheets of pleomorphic cells with high grade nuclei and central necrosis.
Periductal fibrosis, chronic inflammation. Necrotic cell membranes calcify microcalcifications (mammography).

Comedo DCIS fills several adjacent ducts and is characterized by large central zones of necrosis with calcified debris.

B.NONCOMEDO DCIS
Monomorphic population of cells.
Nuclear grade low to high.

B.1. SOLID DCIS

Filling & plugging of ductal lumina by tumor cells.

Not usually associated with calcification.

Maybe clinically occult.

B.1. SOLID DCIS

B.2.CRIBRIFORM DCIS
Intraepithelial spaces:
- even distribution.
-

regular in shape, size.

(Cookie cutter-like)

Lumens: often filled with calcifying secretory material.

B.2.CRIBRIFORM DCIS

B.3.PAPILLARY DCIS
Papillary growths into spaces, lined by a monomorphic population of tall columnar cells.

Lined by fibrovascular core.

Lack myoepithelial layer.

B.3.PAPILLARY DCIS

B.4. MICROPAPILLARY
Papillae - narrow base, solid, no fibrovascular core.

Bulbous protrusions.

Calcifications.

PAGET DISEASE OF NIPPLE

Rare manifestation (1%-2% of breast cancers). Unilateral, erythematous eruption with a scale crust. Pruritus common, mistaken for eczema.

Paget cells : extend from DCIS within the ductal system into nipple skin without crossing basement membrane. Disrupt normal epithelial barrier extracellular fluid to seep out into the nipple surface.
50 to 60% of Paget disease have palpable mass with underlying invasive carcinoma.

PAGET DISEASE OF NIPPLE

Paget disease of the nipple. DCIS arising within the ductal system of the breast can extend up the lactiferous ducts into nipple skin without crossing the basement membrane. ET DISEASE OF NIPPLE

DCIS WITH MICROINVASION

Foci of tumor cells < 0.1cm d invading the stroma.

In association with comedocarcinoma.

TREATMENT
Mastectomy DCIS curative in over 95%.

Currently surgical excision usually followed by radiation largely curative.

LOBULAR CARCINOMA IN SITU

Always an incidental finding.
Not associated with calcification and stromal reaction. 1%-6% of all carcinomas with or without mammographic screening. Bilateral: 20%-40% Frequently multicentric. Common in young, 80 to 90% prior to menopause.

LOBULAR CARCINOMA IN SITU

Microscopy:
Cells : round or oval nuclei with small nucleoli that do not adhere to one another.

Solid nests, expands the lobule.

Signet ring cells present commonly.

Lobular carcinoma in situ. A monomorphic population of small, rounded, loosely cohesive cells fills and expands the acini of a lobule.

LOBULAR CARCINOMA IN SITU

LOBULAR CARCINOMA IN SITU

Treatment : bilateral prophylactic mastectomy, tamoxifen.

INVASIVE (INFILTRATING )CARCINOMA

Age: Young / older not undergoing mammographic screening. Palpable mass, often with axillary lymph node metastasis at presentation. Lymphedema and thickening / dimpling of the skin peau d orange. Retraction of nipple. Inflammatory carcinoma - carcinoma involving dermal lymphatics enlarged & erythematous breast.

INVASIVE DUCTAL CARCINOMA NST (No Special Type)

Gross: Firm to hard irregular borders, foci of calcification.

INVASIVE DUCTAL CARCINOMA NST

Microscopy:
Well differentiated tubules with minimally atypical cells or anastomosing sheets of pleomorphic cells.

Desmoplastic stroma.

Well-differentiated invasive carcinoma of no special type. Well-formed tubules and nests of cells with small monomorphic nuclei invade into the stroma with a surrounding desmoplastic response.

Poorly differentiated invasive carcinoma of no special type. Ragged sheets of pleomorphic cells without tubule formation infiltrate into the adjacent stroma.

2.INVASIVE LOBULAR CARCINOMA

Presents as palpable mass or mammographic density. One fourth of cases: Diffuse pattern of involvement, may produce vaguely thickened breast. Increasing among postmenopausal HRT. Gross:

Firm to hard, irregular margin.

Microscopy: Single file pattern.

2.INVASIVE LOBULAR CARCINOMA

Cellular morphology similar to LCIS.

Metastasis:

Peritoneum, retroperitoneum, leptomeninges (carcinomatous meningitis), GIT , ovaries, uterus.

3.MEDULLARY CARCINOMA
Well circumscribed mass.

Mistaken clinically and radiographically for a fibroadenoma.

H/o rapid growth. Better prognosis than NST. Lymph node metastasis are infrequent.

3.MEDULLARY CARCINOMA
Gross:
Wellcircumscribed.

Soft fleshy consistency.

MEDULLA = MARROW (Latin)

3.MEDULLARY CARCINOMA
Microscopy:
Solid sheets, large cells with vesicular nuclei, prominent nucleoli, frequent mitosis. Lymphoplasmacytic infiltrate. Pushing borders. All Med. Ca.: poorly differentiated. No lymphatic / vascular invasion.

Medullary carcinoma. The cells are highly pleomorphic with frequent mitoses and grow as sheets of cohesive cells. A lymphoplasmacytic infiltrate is prominent.

4.MUCINOUS ( COLLOID) CARCINOMA

Unusual type (1-6%) Circumscribed mass.

Older patients.
Slow growth.

4.MUCINOUS ( COLLOID) CARCINOMA

Gross Extremely soft. Sharply circumscribed Pale grey blue gelatinous appearance.

4.MUCINOUS ( COLLOID) CARCINOMA

Microscopy

Clusters of welldifferentiated tumor cells are seen floating in a sea of mucin.

Mucinous (colloid) carcinoma. The tumor cells are present as small clusters within large pools of mucin. The borders are typically well circumscribed, and these cancers often mimic benign masses.

5. TUBULAR CARCINOMA
2% - before, now 10%.

Irregular mammographic densities.

Excellent prognosis.

5. TUBULAR CARCINOMA
Microscopy:
Well formed tubules, no myoepithelial cells.

Tumor cells in direct contact with the stroma.

6. INVASIVE PAPILLARY CARCINOMA

Rare, 1% or fewer.

Microscopy

Stromal invasion - papillary architecture.

Overall prognosis- better.

7.METAPLASTIC CARCINOMA
Rare (<1%)

Conventional adenocarcinoma
with

Chondroid stroma
Squamous cell carcinoma

Carcinomas with prominent spindle component.

Difficult to distinguish from sarcomas.

MAJOR PROGNOSTIC FACTORS

1. Tumor size

Carcinomas < 1 cm have an excellent prognosis in the absence of lymph node metastases. 90% survival without treatment.

MAJOR PROGNOSTIC FACTORS

2. Distant metastasis
Cure unlikely.
Disease palliation hormone responsive tumors. Sites: lungs, bones, liver, adrenals, brain and meninges.

3. Lymph node metastasis

In the absence of distant metastasis; axillary lymph node status most important prognostic factor.

MAJOR PROGNOSTIC FACTORS

No: of nodes affected
No node involved
1 to 3 positive nodes >10 positive nodes

10yr survival rate

o 70 to80%
o 35 to 40% o 10 to 15%

Sentinel nodes: Predictor of status of remaining nodes. Spare complete axillary node dissection if negative.

MAJOR PROGNOSTIC FACTORS

4. Locally advanced disease

Skin / skeletal metastasis: frequently associated with distant metastasis.

5. Inflammatory carcinoma Poor prognosis: three yr. survival rate is 310%.

MINOR PROGNOSTIC FACTORS

Used to decide chemotherapy / hormonal therapies those who might not need any additional treatment a. Estrogen receptors (50 - 85% tumors, postmenopausal)
Positive better prognosis Valuable to predict response to therapy

b. Progesterone receptors
c. HER2/neu

MINOR PROGNOSTIC FACTORS

1.Histologic subtypes

Tubular, mucinous, medullary, lobular & papillary better as compared to NST.

2. Tumor Grade Bloom Richardson Grading System 10 yr survival Gr1 60%, Gr2 15%, Gr 3 10%

MINOR PROGNOSTIC FACTORS

3. ERPR

80% positive for ERPR respond to hormonal therapy.

40% positive for one type respond to therapy. Negative - <10% response.

MINOR PROGNOSTIC FACTORS

4.HER2/neu ( human epidermal growth factor receptor 2) Evaluation determine response to therapy targeted to this protein ("Herceptin") .

5. Lymphovascular invasion: poor prognosis.

6. Proliferative rate: High proliferative rates are associated with a poorer prognosis. 7. DNA content : Aneuploid tumors worse prognosis

THERAPEUTIC APPRAOACHES
Current:

Combination of surgery & postoperative radiation & systemic control hormonal or chemotherapy or both.

Newer strategies:

Inhibition of HER2 / neu Herceptin.

Summary

Carcinoma of breast: In situ / Invasive. In situ: limited by basement membrane. Invasive: Invasion into the stroma. The normal breast is maintained by a complex set of interactions among luminal cells, myoeithelial cells, the basement membrane, and the stromal cells. Multiple acquired genetic alterations are involved in the sequential transformation of a normal epithelial cell into a cancerous cell.

Risk factors: delayed child bearing, long duration between menarche and menopause, atypical proliferative lesions, and

family history of breast cancer in a first-degree relative, particularly if the disease was multifocal or premenopausal.

Only 5% to 10% of all breast cancers are related to inherited mutations; The majority are in the BRCA1 and BRCA2 genes, less commonly in p53, PTEN or ATM genes.

Prognosis is dependent on:

tumor size, lymph node involvement, distant metastasis at presentation, tumor grade and histologic type,

proliferation rate,
estrogen receptor status, aneuploidy, and overexpression of HER2/NEU.

"When you make a mistake, don't look back at it long. Take the reason into your mind, and then look forward. Mistakes are lessons of wisdom. The past cannot be changed. The future is yet in your power."
Phyllis Bottome 1884-1963, Novelist and Lecturer