During the course of puberty the mammary gland enlarges and changes shape, undergoing
the classic changes described by Tanner from simple nipple
protuberance to the mature, nonlactational, dome-shaped mammary gland
with a centrally located areolar mamma. Great variability occurs in
the size, shape, and location of the mature mammary gland due to constitutional
factors, differences in amount and location of fat distribution, connective
tissue development, thoracic cage shape, and overall
body height. For example, the taller the individual, the higher the breasts
will be located on the thoracic cage. The overlying skin of the
mature breast is fairly thin, and the dilated mammary veins are frequently
observed. On the periphery of the areolae are located the small
duct openings of the sebaceous glands of Montgomery. These glands contain
no terminal hairs but do contain lanugo hairs. The areolae also contain
smooth muscle fibers that contract on stimulation, wrinkling the
skin of the areolae and causing nipple erection. The majority of the glandular tissue of the breast is located in the central
upper and outer quadrants of the breast. Not surprisingly, it is
in these same locations that carcinoma of the breast most commonly occurs. In
addition, there is a small tongue of glandular tissue, the axillary
tail of Spence, that penetrates the fascia of the axilla and lies
in close proximity to the axillary lymph nodes. This tissue is most
prominent in the lactational state and is occasionally mistaken for lymphatic
pathology. Growth and development of the mammary glands continues after puberty, but
at a much slower pace, during the cyclic fluctuations of the follicular
and luteal phases of the ovulatory cycle. Rising estrogen concentrations
during the follicular phase give rise to proliferation of the
end-ductular structures, maximal at the time of ovulation. After ovulation, the
combined effects of estrogen and rising progesterone stimulate
further development and differentiation, particularly of the alveolar
structures. As estrogen and progesterone begin to diminish toward the
end of the cycle, prolactin-induced secretory changes become apparent
in the alveolar epithelium, with secretory products appearing in the
alveolar lumen during the first few days of the menses. The breasts
reach maximum volume just before the onset of menses due to increased
intracellular and intercellular water, maximal glandular and ductal development, and
the accumulation of secretory materials within the alveolar
structures. The breasts are smallest in volume and least stimulated
on days 4 through 7 of the cycle. The ideal time for examination of
the breasts is during this period of minimal hormonal stimulation. Many irregularities and small, cystically dilated glands appear during
the latter portions of the cycle, under maximal hormonal stimulation, which
are not palpable during the early portions of the new menstrual
cycle. Similarly, symptoms of breast discomfort that are physiologic in
origin rather than pathologic occur on a cyclic basis, being maximal
during the last week of the cycle and minimal during the first half of
the new cycle. A small quantity of nipple secretions also may be detectable
on a physiologic basis during the last few days of the cycle and
first few days of the new cycle. The breast can no longer be considered a passive endocrine target organ. Recent
information documents the capability of breast tissue to alter
significantly the local hormonal environment. Aromatase and other enzymes
necessary for the production and metabolism of steroids are present
in the adipose tissue and glandular epithelium of the mammary gland. Circulating
androgens can be converted locally to other, more potent
androgens or to estrogens, modifying peripheral endocrine signals.15 A second mechanism through which breast tissue alters the local hormonal
milieu is regulation of hormone concentration in ductal fluid. Analyses
of ductal secretions have found high concentrations of estradiol and
progesterone, much in excess of serum concentrations. In addition, prolactin
and other proteins are present in this fluid. For most of these
compounds there is little correlation between the concentration in
serum and that within the ducts.16 The ability of the breast to modulate endocrine signals by conversion
or concentration of circulating hormones explains the poor correlation
between peripheral levels of hormones and pathologic conditions thought
to be endocrine dependent. Understanding of the pathologic conditions
of the breast and the selection of appropriate therapy will be enhanced
greatly as the biochemistry and physiology of the mammary gland are
clarified. Sex Hormones and Breast Disease: Relationship and Therapy Great controversy has existed concerning the possible relationship to the
ingestion of sex hormones of both benign and malignant diseases of
the breast. Although there are reports to the contrary, the preponderance
of existing data suggest no significant relationship between exogenous
hormone ingestion and benign or malignant neoplasia of the breast. Many
studies, including the Cancer and Hormone Study, have demonstrated
no association between breast cancer and the use of oral contraceptives.17 However, there are limited studies suggesting a small increase in breast
cancer among young women with a positive family history. Most research
has been done with higher-dose oral contraceptives, which are in limited
use in the United States today. There is no association between breast cancer and the use of depot medroxyprogesterone
acetate (DMPA), according to data from the World Health
Organization.18 Concerns about DMPA and breast cancer are related to malignancies in beagle
dogs, but this appears to be a species-specific phenomenon. The most controversial area is the potential effect of hormone replacement
therapy (HRT) on breast cancer risk. The Nurses' Health Study suggested
an increased risk of 1.4 with long-term use, with no protective
effect of progestins.19 In contrast, numerous studies have shown no effect, or even a benefit, with
low-dose hormone use after menopause. Although there are many studies, most
are limited by study design. The question of breast cancer
and HRT will probably be answered by the ongoing Women's Health
Initiative, a long-term, prospective, randomized, placebo-controlled trial
initiated by the National Institutes of Health. A similar controversy exists regarding the relationship between endogenous
levels of sex steroids and the origin and pathology of fibrocystic
breast disease (benign mastopathy). Histologically, this condition is
defined by dense fibrosis in the stroma, epithelial proliferation with
apocrine metaplasia, cyst formation, and alveolar atrophy.19A These changes are best explained by a relative or absolute estrogen dominance
over progesterone. Hyperestrogenism frequently exists during the
perimenopausal years or with chronic oligoanovulation, as seen in clinical
settings where an increased incidence of fibrocystic breast changes
has been observed. Because of the breasts' ability to modulate peripheral
endocrine signals, levels of estrogen within ductal secretions
may dominate even with seemingly normal ovarian sex steroid production.20 Fibrocystic changes are common; at least one third of women have breast
cysts and epithelial hyperplasia found at autopsy. Atypical lesions—atypical epithelial hyperplasia, atypical lobular
hyperplasia, and diffuse papillomatosis with atypia—are associated
with a higher risk for development of breast cancer. There may be
as much as a doubling of breast cancer risk when atypical lesions are
combined with a positive family history.21 The most common symptoms of fibrocystic breast disease include cyclic breast
pain (mastodynia), tenderness, and palpable thickening with discrete
cysts. A characteristic green nipple discharge is occasionally the
presenting complaint. Often reassurance is adequate and no therapy is
required for women with mild to moderate mastodynia. Nonhormonal treatments, including
use of a supportive brassiere, a decrease in methylxanthines, and
vitamin A and E use, have been suggested. Combination oral
contraceptive pills are effective in alleviating symptoms in many
women.22 Bromocriptine has been found to be effective in reducing mastodynia in
double-blind trials,23 although side effects may make this therapy unacceptable. Various synthetic progestins, given during the second half of the menstrual
cycle, have been found to be effective in alleviating the symptoms
of breast pain and engorgement. Recent trials of danazol, administered
in doses of 200 to 400 mg/day, have resulted in both subjective and
objective improvements in fibrocystic breast disease after 2 to 6 months
of therapy. Improvement was noted in approximately 60% of cases, but
significant side effects were encountered in one third of the patients. Tamoxifen, as
a partial estrogen antagonist, may be useful in the
treatment of painful fibrocystic changes. At a dose of 10 mg/day, symptoms
improve slowly over 2 to 3 months in two thirds of cases.24 The decision as to when to initiate therapy for fibrocystic breast disease
and the selection of an appropriate therapeutic agent must be individualized, because
the role of medical therapy in this disorder is not
completely defined. Nipple Discharge Nipple discharge, found by the patient or by the physician during a physical
examination, is one of the more common abnormalities encountered
in the breast. The nature of the discharge is of great help in determining
the appropriate evaluation and treatment. As indicated earlier, a
slight amount of nipple discharge may be physiologic at the end of the
menstrual cycle or during the first few days of the menses. Galactorrhea, which
is the presence of physiologic milk secretion under nonphysiologic
conditions, appears to be increasing in frequency. Whether this
is occurring because of an increase in the exposure of individuals
to substances stimulating mammary glandular epithelium or whether an
increasing awareness on the part of physicians of the importance of galactorrhea
in relation to possible pituitary adenomas has resulted in
more careful breast examination is unknown at the present time. Galactorrhea
is a milky nipple discharge that is present either spontaneously
or on compression of the breast tissue and is confirmed by the finding
of fat globules on staining of the wet preparation of oil red O or
other fat-staining dyes. Galactorrhea does not indicate underlying inherent
organic breast disease. Galactorrhea may be caused by medications
that block the dopamine receptor, such as tricyclic antidepressants
and antipsychotic medications. The antihypertensives reserpine and methyldopa
may also cause galactorrhea. Rarely, galactorrhea has been reported
with the use of higher-dose oral contraceptives. Unexplained galactorrhea can be evaluated by measurement of the fasting
prolactin concentration and the thyroid-stimulating hormone concentration
to rule out an endocrinopathy. Prolactin-secreting pituitary adenomas
and hypothyroidism can lead to galactorrhea. Commonly these conditions
are also associated with amenorrhea. Intraductal papillomas often manifest with a serosanguineous or bloody
breast discharge. Mammography or ultrasound examination may reveal a dilated
duct near the nipple. Surgical excision of the papillomas is recommended, because
cytology cannot definitively diagnose a benign papilloma. The presence of a sticky or multicolored nipple discharge usually occurs
in the perimenopausal age group and reflects the presence of duct ectasia. The
discharge is frequently associated with a burning and itching
sensation of the nipple. If a mass is palpable, it should be biopsied. A purulent nipple discharge is almost always associated with an infective
process such as acute puerperal mastitis, chronic lactation mastitis, or
simple abscess. Antibiotic therapy for a diffuse infection and occasionally
surgical drainage for organized infection are the treatment
choices. Watery, serous, serosanguineous, and bloody nipple discharges should be
considered symptoms of underlying carcinoma of the mammary gland until
proved otherwise. In patients older than 50 years of age, carcinoma
of the mammary gland is the leading cause of discharge of these types. Cytologic
analysis of the discharge should be obtained whenever possible. If
the slide is carefully prepared, one should expect a positive
cytologic finding in 80% of the cases in the presence of carcinoma. In
the younger age group, benign cytology findings, a normal breast examination, and
normal mammography are usually sufficient to evaluate these
forms of nipple discharge. Breast Mass The most common presentation for breast cancer is a breast lump. In women
older than 50 years of age, 23% of breast masses are breast cancer. In
younger women, most breast masses are benign, with only 4% representing
cancer.25 Because the majority of women with a breast mass are first seen by their
obstetrician-gynecologist, it is critical for these physicians to be
well trained in the evaluation of breast masses (Table 2). TABLE 2. Factors Associated With an Increased Risk of Developing Breast
Carcinoma
Increase-risk patients Late first pregnancy
Nulliparous
No lactation
Family history of breast and other malignancy
Previous breast surgery
Extreme-risk patients Mother and sister with breast carcinoma
Mother or sister with bilateral breast carcinoma
Mother or sister with early (<35) onset breast carcinoma
Breast self-examination (BSE) for detection of masses is somewhat controversial. Although
studies suggest that BSE can detect cancer at an earlier
stage, before nodal involvement, other research suggests that BSE
does not significantly improve the rate of early detection of breast
cancer. Still, most health organizations and practitioners strongly recommend
monthly examinations. The examination should include an evaluation
of the skin for retraction, dimpling, or inflammatory changes. Palpation
of the axillary area is also important to include with the breast
examination. The American Cancer Society recommends monthly self-examinations after
the age of 20 years and a physical examination by a trained examiner every 3 years
between the ages of 20 and 40 years. After 40 years of age, a
yearly physical examination is recommended.26 In addition to breast self-examination and physical examination by a trained
examiner, mammography plays an integral role in the early detection
of breast cancer. Several large studies have documented the effectiveness
of mammography as a screening tool that increases the detection
of stages I and II cancers. However, despite the acceptance of this
modality, the precise screening interval remains somewhat controversial. The
American Medical Association has recommended that a baseline mammogram
be performed between the ages of 35 and 40 years. An earlier examination
is warranted when there is a personal history of breast cancer
or a history of premenopausal breast cancer in the patient's
sister or mother. Mammograms should be obtained every 1 to 2 years from
age 40 to 49 years, the precise frequency depending on the patient's
family history and the ability to perform a satisfactory physical
examination. After 50 years of age, annual mammograms are recommended.27 Mammography also is important in the evaluation of a palpable breast mass
as an adjuvant to fine-needle aspiration. With a documented malignancy, mammography
helps to define the required extent of the resection
and to determine the presence or absence of a subclinical lesion in the
contralateral breast. This modality is also very helpful in ruling out
significant pathology when breast pain or nipple discharge occurs without
a palpable abnormality. Finally, a mammogram should be obtained
when a women has detected an abnormality on breast self-examination that
cannot be confirmed by a trained examiner. The properly obtained and
evaluated mammogram should yield an accuracy of approximately 90% in
the presence of carcinoma. Only 1 in 40 palpable breast masses harboring
a neoplasm show no abnormality on mammography. Once a breast mass is detected by examination and/or mammography, further
evaluation can include ultrasound, fine-needle biopsy, core biopsy, or
excisional biopsy. Ultrasound is useful in differentiating cystic
masses and fibroadenomas from more concerning lesions. A simple cystic
mass identified by ultrasound typically requires no further therapy. Aspiration
can be performed if the cyst causes discomfort or concern. Fibroadenomas
have clear margins by ultrasound and have low-level homogenous
internal echoes. Fine-needle aspiration or excision can be performed
when there is concern about the lesion based on the patient's
history and age. Solitary, discrete lesions can also represent intraductal papillomas or, rarely, lymphomas. The
presence of multiple large masses suggests phyllodes
tumors. Because phyllodes tumors can be malignant, complete excision
is recommended. Suspicious lesions on mammogram and ultrasound are most typically seen
as irregular masses with spiculated or indistinct borders. Calcifications
are often seen within these masses. Benign lesions, such as sclerosing
adenomas, radial scar, and fat necrosis, can mimic these findings. Mammography
can also be used for needle localization of masses before
biopsy or excision.28 | 
