A. Overview of Diseases

1. Nipple Discharge
2. Breast Pain
3. Benign Breast Mass
   1. Fibrocystic Changes (normal variant; no malignant risk)
   2. Fibroadenomas
4. Breast Neoplasms
   1. Carcinoma in Situ (CIS)
   2. Invasive Carcinoma (CA)
5. Breast Implants
   1. No increased risk of breast cancer
   2. Increased risk of local reactions
   3. No increase in risk of connective tissue diseases

B. Breast Development [2]

1. Subspecialization of skin
2. Ectodermal origin
3. Stimulation peripartum by maternal hormones can lead to milk production
4. Breasts are then quiescent until puberty
   1. Duct system enlarges
   2. Alveolar components become more prominent with progesterone increases
   3. Some breasts have fainly fibrous change and cystic formation, which is a normal variant
   4. Thus, "fibrocystic changes" is a normal development and has no increased cancer risk
   5. In women between adolescence and mid 20s, lobules and stroma respond to hormones
   6. Hormonal responses may be exaggerated at this time with fibroadenoma formation
   7. Fibroadenomas occur in 2-13% of women age 15-25
5. Hormones involved in Breast Development
   1. Estrogen and progesterone
   2. Insulin
   3. Cortisol
   4. Thyroxine
   5. Growth Hormone
   6. Prolactin
   7. Parathyroid hormone related peptide (PTH-RP) - epithelial-mesenchymal interactions [3]
6. Monthly breast exams are essential to early detection of breast mass
7. Mammography should be initiated on an individualized basis after assessing risk factors for breast cancer
8. Relative Risk of Breast Cancer [1]
   1. No Increase: fibroystic changes, benign tumors, traumatic lesions, infections, sarcoidosis, metaplasia, diabetic mastopathy
   2. Risk Increase (1.5-2.0X): proliferation without atypia, usual ductal hyperplasia, complex fibroadenoma, (cysts >3mm diameter, sclerosing adenosis), papilloma, blunt duct adenosis
   3. Risk Increase (>2.0X): proliferation with atypia, atypical ductal hyperplasia and atypical lobular hyperplasia

C. Nipple Discharge (Lactation)

1. Spontaneous or provoked
2. LHRH (GnRH) increase
3. Hyperprolactinemia
   1. Increased prolactin (pituitary hypertrophy)
   2. Pituitary tumor, prolactinoma
   3. Drug induced hyperprolactinemia: dopamine antagonists
4. Hypothyroidism
5. Ovulation
6. Dopamine Antagonists - phenothiazines, butyrphenones
7. Oral contraceptives
8. Physical stimulation
9. Physiologic discharges are typically whitish or greenish in color
   1. Clear or yellow discharges are also found in normal conditions
   2. Frankly bloody or serosanguinous discharges are pathology and require investigation
10. Pathologic Discharges
    1. Usually due to benign intraductal papilloma
    2. Discharge, particularly unilateral, during menopause is suspcious for cancer
    3. Fine needle or excisional biopsy required to confirm diagnosis
    4. Papanicolaou smear of discharge is rarely helpful
    5. Mammography and exploration of duct system are required
11. Evaluation of Nipple Discharge (Figure 3, Ref [1])
    1. Rule out mass (or evaluate mass if present)
    2. Galactorrhea present: evaluate prolactin, thyrotropin (TSH), consider dopamine agonist
    3. Galactorrhea absent: multiple duct involvement is normal variant
    4. Galactorrhea absent: single duct involvement: galactography to identify lesion
    5. Galactography identifies lesion --> surgery
    6. All bloody discharges should be evaluated further

D. Painful Breasts

1. Frequent complaint among women of childbearing age
   1. Usually occurs during premenstrual phase (cyclic pain) and is benign
   2. Thorough breast exam for lumps is required
   3. Analgesics
   4. Salt Restriction
   5. Diuretics
   6. Proper fitting of bra
   7. Danazol 200-400mg/d may be considered in severe cases
   8. Progesterones are usually not effective
2. Cystic Changes (see below)
   1. Cystic changes in breast often cause pain
   2. Peak occurrence of cysts age 30-50
   3. Unclear etiology
   4. Generally change with menstrual cycle
   5. Also called fibrocystic changes
3. Fibroadenoma (see below)
   1. Usually in young women
   2. Firm, painless, mobile mass
   3. Bilateral in 10-15% of cases
   4. Do not change with menstrual phase
   5. These generally end up being removed
4. Duct Ectasia
   1. Usually bilateral nipple discharge
   2. Typically multicolored and sticky
   3. Burning or itching and pain around nipple
   4. Swelling under areola
   5. Duct exploration reveals slightly dilated ducts, greenish secretion
   6. Diagnosis confirmed by histology
5. Mastitis
   1. Breast engorgement common postpartum
   2. Low grade fever may occur early after delivery (without infection)
   3. True mastitis occus 2-3 weeks postpartum
   4. Multicolored discharge
   5. Palpable swelling and warmth common
   6. Associated with cellulitis over breast area and fever to >39°C (102.2°F)
   7. Staphylococcus is most common infection; antibiotic therapy is indicated
   8. Thickening of ducts and wall may occur, with nipple retraction (fibrosis)
   9. May be confused with inflammatory breast cancer
   10. Patients should be encouraged to continue breast feeding with contralateral breast
   11. Incision and drainage under local anesthesia do not cure condition
   12. Requires complete excision of involved duct system under anesthesia

E. Benign Breast Mass [1,4]

1. Fibrocystic Condition
   1. Considered to a be normal variation in breast physiology
   2. Increased swelling with menstrual cycle
   3. Diagnosis with ultrasound
   4. Occurs in ~50% of pre-menopausal women
   5. Therefore, this condition is unlikely to be a disease
   6. Rather, this is a normal variation in breast physiology
2. Fibroadenomas
   1. 90% of masses detected on palpation are fibroadenomas
   2. If size changes, should biopsy, with main concern for carcinoma in situ (CIS)
   3. Encapsulated, firm rubbery masses
   4. Usually treated by excision
3. Fibroadenoma - complex types
   1. Cysts
   2. Sclerosing adenosis
   3. Epithelial calcifications
   4. Papillary apocrine changes
   5. These are a risk factor for breast cancer (see below)
4. Palpable Cysts [5]
   1. Believed to be abberations of normal involution
   2. Generally not considered pathological
   3. Two types of cysts are found: Type I and Type II
   4. Palpable breast cysts appear to be a 2-3X risk for breast cancer
   5. Risk of breast cancer is increased in younger women (<40 years) with palpable cysts
5. Type I Breast Cysts
   1. Lined by apocrine epithelium
   2. Cyst fluid has ratio of [Na+] to [K+] <3
   3. Cyst fluid also has high concentrations of steroid hormones
   4. Patients generally have many of these cysts
6. Type II Breast Cysts
   1. Lined by flattened epithelium
   2. Cyst fluid has ratio of [Na+] to [K+] >3
   3. Cyst fluid has lower concentrations of steroid hormones
7. Breast Mass and Cancer Risk [1,4]
   1. Nonproliferative changes on biopsy: 1.27X risk
   2. Proliferative changes without atypia: 1.88X risk
   3. Proliferative changes with atypia: 4.24X risk
   4. Family history of breast cancer was a risk independent of biopsy findings
   5. In women with nonproliferative changes but no family history, there was no increased risk
   6. Relative risks are determined based on a cohort without benign breast disease findings

F. Evolution to Breast Malignancy [2]

1. Relationship between premalignant and carcinoma in situ (CIS) lesions not fully understood
2. Current theories suggest linear progression through various pathological stages
   1. Normal terminal duct lobular unit
   2. Usual ductal hyperplasia
   3. Unfolded lobule with microcalcifications
   4. Atypical ductal hyperplasia / Atypical lobular hyperplasia (ALH)
   5. Ductal carcinoma in situ (DCIS) / Lobular CIS (LCIS)
   6. Invasive breast cancer
3. Atypical Ductal Hyperplasia (ADH)
   1. Midpoint of proliferative breast disease between normal and CIS
   2. Difference between ADH and DCIS is quantitative
   3. Molecular studies show good deal of overlap between ADH and DCIS
   4. Both involve abnormalities of chromosomes (chr) 16q and 17p
   5. ~85% of ADH lesions are estrogen receptor (ER)+ and have ~5% proliferative indices
   6. ADH lesions are precancerous according to epidemiological studies
   7. ADH lesions associated with 20-50% rate of cancer in immediately adjacent tissue
   8. Tamoxifen given to women with ADH risk of invasive breast cancer
   9. Progression of ADH to DCIS accompanied by significantly more chr abnormalities
4. Lobular Neoplasia
   1. Solid proliferation of loosely cohesive, uniform small cells
   2. These small cells fill and distend acini of terminal duct lobular unit
   3. ALH and LCIS differ by proportion of acini affected by neoplasitic cells
   4. Most lobular lesions are strongly ER+, proliferation index ~2%, HER2/neu negative
   5. Lobular neoplasia found in ~1.5% of breast biopsies
   6. ~15% of women with lobular neoplasia have coexistant DCIS or invasive cancer
   7. Risk of invasive breast ca with lobular neoplasia is ~0.75% per year

G. Breast Carcinoma in Situ (CIS) [2]

1. Definition of Ductal CIS (DCIS) [6]
   1. Proliferation of presumably malignant epithelial cells
   2. Occurs within mammary ductal-lobular system without evidence of invasion
   3. Thus, the mass is within ducts and has not yet penetrated basement membrane
2. Epidemiology of DCIS
   1. Most common type of CIS ~70%; around 24,000 new cases per year in USA
   2. Incidence is increasing with institution of routine mammography [6]
   3. About 9% of women in autopsy series have DCIS (~1.5% have frank carcinoma)
   4. Carries 1.25% / year risk of invasive carcinoma in ipsilateral breast
3. Symptoms and Diagnosis of DCIS
   1. Usually in Upper-Outer quadrant
   2. Bloody discharge from nipple may occur
   3. Palpation (usually ~5mm)
   4. Stellate calcification on mammogram
4. Treatment of DCIS [7]
   1. Lumpectomy (usually with radiation) may be recommended for treatment
   2. About 10,000 mastectomies are done annually in USA for DCIS
   3. If initial excision has carcinoma cells in margin, consider total mastectomy + radiation
   4. Risk of recurrence after total mastectomy with DCIS is <2%
   5. Axillary lymph node dissection is not required (only ~1% would be positive)
   6. Addition of radiation to lumpectomy further reduces risk of recurrence or frank cancer
   7. Tamoxifen 20mg/d for 5 years reduced risk of frank cancer in women with DCIS >40%
   8. Therefore, lumpectomy with radiation is considered standard care ± tamoxifen
   9. Chemotherapy is not used for treatment of CIS
5. Lobular CIS (LCIS)
   1. Usually diagnosed as an incidental finding on biopsy examination
   2. "Indian file" cells around ducts, have not penetrated into ducts
   3. Carries 2% per year risk of invasive breast cancer in either breast
   4. Therefore, LCIS is considered to be a marker for generalized breast tissue dysplasia
   5. Bilateral mastectomy is often recommended due to high risk of contralateral cancer

H. Clinical Breast Exam [8]

1. Clinical breast exam has detected 3-45% of breast cancers missed on mamography
2. In general, at least 3 minutes should be devoted to each breast
3. Two positions are recommended with proper positioning
4. Palpation in vertical strip patterns recommended
5. Three levels of pressure should be applied to each breast
6. Intraobserver agreement in 25-50% range
7. A negative clinical breast exam is associated a 0.47 risk for breast cancer
8. Many false positives due to benign breast conditions occur

References

1. Santen RJ and Mansel R. 2005. NEJM. 353(3):275
2. Arpino G, Laucirica R, Elledge RM. 2005. Ann Intern Med. 143(6):446
3. Strewler GJ. 2000. NEJM. 342(3):177
4. Hartmann LC, Sellers TA, Frost MH, et al. 2005. NEJM. 353(3):229
5. Dixon JM, McDonald C, Elton RA, Miller WR. 1999. Lancet. 353(9166):1742
6. Welch HG and Black WC. 1997. Ann Intern Med. 127(11):1023
7. Morrow M and Schnitt SJ. 2000. JAMA. 283(4):453
8. Barton MB, Harris R, Fletcher SW. 1999. JAMA. 282(13):1270