Breast Pathology

Question 1

T/F: The breast is an essential organ

Answer 1

FALSE

The breast is non-essential for survival - major function = nutritional support of the infant

Question 2

Describe the major changes the breast undergoes through life

Answer 2

-Expansion after menarche
-Remodeling during adulthood, especially during and after pregnancy
-Involution and regression

Question 3

List the breast disease symptoms

Answer 3

-Pain
-Inflammation
-Nipple discharge
-Lumpiness
-Palpable masses
-Gynecomastia

Question 4

Describe when the symptom of pain would be present in breast disease

Answer 4

Pain (mastalgia or mastodynia) - common to menses
-When localized usually due to a ruptured cyst of trauma to adipose (fat necrosis)
-Almost al painful masses are benign (10% of cancers cause pain)

Question 5

Describe when the symptom of inflammation would be present in breast disease

Answer 5

Edema and Erythema
-Rare, most often caused by infection typically during lactation/breast-feeding
*one exception = inflammatory breast carcinoma

Question 6

Describe when the symptom of nipple discharge would be present in breast disease

Answer 6

-Normal when small amount and bilateral
-Common benign lesion: Papilloma arising in large ducts below the nipple
-Spontaneous, unilateral and bloody discharge is concerning for malignancy

Question 7

Describe when the symptom of lumpiness would be present in breast disease

Answer 7

Lumpiness (diffuse nodularity)
-Usually normal glandular tissue
-Imaging used to detect if there is a discrete mass

Question 8

Describe when the symptom of palpable masses would be present in breast disease

Answer 8

-Arise from stromal or epithelial cell proliferation
-Generally detected when 2-3cm in size
- ~95% are benign
-Round to oval, circumscribed
-While malignancies generally have irregular borders some are circumscribed - all palpable masses require evaluation

Question 9

Describe when the symptom of gynecomastia would be present in breast disease

Answer 9

-Breast enlargement in males (the only common breast symptom in males)
-Imbalance between estrogens and androgens causes an increase in stromal and and epithelial cells

Question 10

Most symptomatic breast lesions (>90%) are _____

Answer 10

benign

Question 11

What percentage of women with cancer have symptoms?

Answer 11

45%

Question 12

With increasing age, symptoms are associated with increased likelihood malignancy. Describe this for both nipple discharge and for palpable mass

Answer 12

Nipple discharge:
- <60yrs = 7% due to cancer
- >60yrs = 30% due to cancer

Palpable mass
- <40yrs = 10% due to cancer
- >50yrs = 60% due to cancer

Question 13

Describe Inflammatory Lesions

Answer 13

-Often benign, but because they are rare, always should rule out inflammatory carcinoma
-Symptoms: pain, erythema, edea

Question 14

Mastitis

Answer 14

-Inflammatory lesion
-Bacterial infection in/through the nipple
-Caused by Staphyloccocus aureus most often

Question 15

Traumatic fat necrosis

Answer 15

-Inflammatory lesions
-History of trauma to breast
-Small, localized tender lesion that over time scars with calcification, creating a palpable, firm lesion

Question 16

Benign epithelial lesions

Answer 16

Most are incidental findings by mammography; some have risk for cancer development

Question 17

Nonproliferative disease: (“fibrocystic change/disease”)

Answer 17

-Most common benign epithelial lesion; no increased risk of breast cancer
-Ducts keep single layer but are dilated (adenosis) forming variably sized brown/blue cysts and increased fibrous stroma
-Apocrine secretions may create microcalcifications (detected by mammography)
-Rupture induces chronic inflammation and fibrous producing palpable nodularity

Question 18

Benign epithelial lesions - proliferative disease without atypia

Answer 18

Slightly increased risk of cancer (1.5-2x) - “ductal hyperplasia”

Question 19

Benign epithelial lesions - proliferative disease with atypia

Answer 19

(4-5x increased risk). Can occur within the duct (atypical ductal hyperplasia) or the lobule (atypical lobular hyperplasia)

Question 20

Describe the extent of breast cancer

Answer 20

-Most common malignancy of women (excluding nonmelanoma skin cancer)
-In US: incidence stable; 2nd leading cancer-related cause of death behind lung cancer in women
-Worldwide: incidence and mortality increasing
- 1/8 lifetime risk to get it; 25% die of disease
- >50yrs (75% of cases); <40yrs (5%)

Question 21

List the risk factors for breast cancer

Answer 21

-Age
-Gender
-Family history
-Geographic variations
-Race/Ethnicity
-Ionizing radiation
-Reproductive history

Question 22

Describe how age contributes to the risk of breast cancer

Answer 22

risk increases after 30, plateaus at menopause

Question 23

Describe how gender contributes to the risk of breast cancer

Answer 23

1% incidence in men

Question 24

Describe how family history contributes to the risk of breast cancer

Answer 24

-Greater risk = multiple affected first-degree relatives with early onset (<45yrs) breast cancer
-5-10% are related to specific inherited mutations which can lead to lifetime risk >90%

Question 25

Describe how geographic variations contributes to the risk of breast cancer

Answer 25

high risk in western world

Question 26

Describe how Race/Ethnicity contributes to the risk of breast cancer

Answer 26

European descent - highest rate (most often ER positive), Hispanic and AA - younger age, more aggressive tumors

Question 27

Describe how Ionizing radiation contributes to the risk of breast cancer

Answer 27

during breast development increases risk
*mammograms do not increase risk

Question 28

Describe how reproductive history contributes to the risk of breast cancer

Answer 28

All of these increase estrogen stimulation:
-early age of first menarche (period)
-older age at first pregnancy
-nulliparity (no pregnancies)
-absence of breastfeeding
-obesity or hormone replacement therapy (postmenopause)

Question 29

What is the pathogenesis of breast cancer

Answer 29

Genetics, hormonal influences (estrogen excess) and environment

Question 30

Describe how genetics plays role in breast cancer

Answer 30

Driver mutations in epithelial cells of the duct/lobular system cause differential expression of:
1. estrogen receptors (ER)
2. progesterone receptors (PR)
3. overexpression (due to amplification) of HER2

*These define the 3 major breast cancer subtypes with direct treatment implications (a tumor that is “triple negative” does not express these 3 things)

Question 31

________ mutations account for 5-10% of breast cancers

Answer 31

Germline mutations

Question 32

Genetics - Inherited Mutations

Most often in DNA repair genes

Answer 32

(BRCA1, BRCA2)
- 50% of inherited cases show BRCA1 mutations (often triple negative)
- ~1/3 of inherited cases show BRCA2 mutations (often ER positive)

Question 33

Other mutated genes in familial breast cancer

Answer 33

• Li-Fraumeni syndrome (p53)
• Cowden disease (PTEN)
• Ataxia-telangiectasia

Question 34

Histological Classification - Noninvasive

Answer 34

-Ductal carcinoma in situ (DCIS)
-Lobular carcinoma in situ (LCIS)

Question 35

Histological Classification - Invasive (infiltrating)

Answer 35

-Invasive ductal carcinoma (most common, 70-80%)
-Invasive lobular carcinoma (10-15%)

Question 36

Ductal carcinoma in situ (DCIS)

Answer 36

-Wide variety of histologic appearances (e.g. comedo necrosis - central necrosis within ducts)
-Calcifications commonly seen in mammograms
-With tx, 97% survival (surgery or irradiation)
-If ER positive, anti-estrogenic agents (tamoxifen) decreases risk of recurrence
-Untreated, 1/3 progress to cancer in same location
-Paget disease of the breast: extension of DCIS up lactiferous ducts onto skin of nipple

Question 37

Lobular carcinoma in situ (LCIS)

Answer 37

-Monomorphic, bland cells in clusters in lobule
-Rarely forms calcifications - harder to detect on mammogram
-Tx w/ clinical/radiographic follow-up, tamoxifen (competitive inhibitor of the estrogen receptor) or bilateral prophylactic mastectomy
- 1/3 eventually develop invasive carcinoma (of these: 2/3 same breast, 1/3 contralateral breast)

Question 38

Breast Cancer - Invasive Carcinomas.
Greater than 95% are ____________

Answer 38

adenocarcinomas

Question 39

Breast Cancer - Invasive Carcinomas

Clinical classification (3 major groups)

Answer 39

-ER positive (HER2 negative; 50-65% of cancers)
-HER2 positive (ER positive or negative; 10-20% of cancers)
-Triple negative (ER, PR, and HER2 negative (10-20 percent))

Question 40

Describe the clinical exam for breast cancer detection

Answer 40

-At detection, lesions average size = 2-3cm with 50% LN involvement
-In unscreened populations (including young women before mammograms) - most breast cancers detected as a palpable mass by the patient

Question 41

Describe a mammogram

Answer 41

-Detects early, non-palpable (average 1cm), asymptomatic breast cancer before metastasis
-Only 15% LN involvement upon diagnosis with mammogram
-Most cancers in women >50yrs are detected by mammography
-More sensitive with age as fat replaces fibrous tissue
-Abnormal mammographic finding is more likely to be caused by malignancy with increasing age (10% at age 40, 25% at >50yrs)

Question 42

Describe breast cancer screening

Answer 42

-Screening (exam + mammogram) guidelines vary
-Average risk:
*40-49yrs- individual choice whether to screen
*50-74yrs- every other year (biennial)
*>75yrs- optional, may continue if life expectancy is >10yrs
-High risk:
*parent, sibling or child with breast cancer start screening at ~40yrs
*BRCA1, BRCA2 mutation: 1-2x/yr screening and add MRI

Question 43

Breast Cancer - Spread

Answer 43

-Progression of disease leads to:
*adherence to pectoral muscles/deep fascia
*adherence to skin causes retraction or dimpling of the skin or apple
-Lymphatic involvement may cause lymphedema causing skin thickening (peau d’orange)
-Distant metastasis may occur to almost any organ, up to many years later
*lung, skeleton, liver, adrenals, and brain are preferred sites

Question 44

Breast Cancer - Prognosis

Answer 44

-Based on molecular and morphologic features and stage
-Size: <1.0cm excellent prognosis if no LN spread
-Lymph node involvement:
*sentinal node biopsy highly predictive of absence of metastatic CA in other nodes
*no axillary nodes - 5yr survival = 90%
*survival decreases with each positive node
-Distant metastasis - rarely curable
-Carcinoma grade and histologic type (ductal carcinomas have worst prognosis of subtypes)
-Hormone receptors- used to predict response to tamoxifen and aromatase inhibitors (aromatase turns androgen into estrogen)
-Targeted therapy of HER2/NEU (i.e. Herceptin) - getting better responses now

Question 45

Oral Contraceptives

Answer 45

-Don’t increase breast cancer risk
-Increase risk of cervical cancer in women who are HPV+
-Increase risk of venous thrombosis and pulmonary thromboembolism because they increase coagulation factors
-Increase risk of cardiovascular disease in women smokers over 35 years