Camelia A. Lawrence
Baiba J. Grube
Armando E. Giuliano
• Early detection of breast cancer is improved by risk assessment, clinical breast examination, screening mammography, and magnetic resonance imaging in selected patients.
• Triple-test concordance requires agreement between results of clinical breast examination, breast imaging, and tissue diagnosis. In the absence of concordance, further diagnostic intervention is required.
• The most common benign breast problems include fibrocystic changes and mastalgia. These problems are usually best treated by reassurance. Pharmaceutic agents are available but have side effects that usually are not well tolerated.
• Histologic differences exist between fibroadenomas and phyllodes tumors; phyllodes tumors require excision, whereas small asymptomatic fibroadenomas can be observed if the diagnosis is confirmed by histologic or cytologic assessment and there is no evidence of growth.
• Spontaneous, unilateral, bloody discharge requires histologic evaluation to exclude malignancy, but symptoms usually are caused by a benign process such as intraductal papilloma or duct ectasia.
• Breast abscesses are managed with fine needle aspiration and antibiotics; the use of incision and drainage is reserved for recurrence.
Benign breast diseases are among the most common diagnoses that the busy obstetrician-gynecologist will see in practice. An ability to accurately and promptly diagnose both benign and malignant breast diseases is within the purview of the practicing gynecologist (1). Benign breast disease is a complex entity with a range of physiologic changes and clinical manifestations that have an impact on a woman’s health independent of breast cancer risk (2).
Detection
History
Evaluation of a new breast symptom begins with assessment of symptoms based on a thorough clinical history (3). The history should include questions regarding current symptoms, duration of the condition, fluctuation of the signs and symptoms, and factors that aggravate or relieve the symptom. Assessment of breast problems should focus on the following points:
• Nipple discharge
• Characteristics of discharge (spontaneous or nonspontaneous, appearance, unilateral or bilateral, single or multiple duct involvement)
• Breast mass (size and change in size, density, or texture)
• Breast pain (cyclic versus continuous)
• Association of symptoms with menstrual cycle
• Change in breast shape, size, or texture
• Previous breast biopsies
• History of breast trauma
The patient should be questioned about the following risk factors for breast cancer (see Chapter 40 for more details):
• Sex
• Increasing age (approximately 50% of breast cancers occur after age 65)
• Age of menarche less than 12 years
• Nulliparity or first pregnancy at greater than 30 years of age
• Late menopause (older than 55 years of age)
• Family history of breast cancer (especially premenopausal or bilateral disease)
• Number of first-degree relatives with breast cancer and their ages when diagnosed
• Family history of male breast cancer
• Inherited conditions associated with a high risk for breast cancer, including BRCA1 and BRCA2 genes, Li-Fraumeni syndrome, Cowden’s disease, ataxia telangiectasia syndrome, and Peutz-Jeghers syndrome
• Other malignancies (ovary, colon, and prostate)
• Pathology of previous breast biopsy showing atypia or lobular or ductal carcinoma in situ
• Hormone therapy
• Alcohol consumption
• Postmenopausal weight gain
• Personal history of breast cancer
Breast cancer risk can be determined by the Gail Risk assessment model, which is available electronically (4). The Gail Risk assessment model calculates risk based on patient race, age, age of menarche, age of first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsies, and presence of atypia on the biopsy.
It is important to obtain a current list of medications used, including hormone therapy and herbal medications such as phytoestrogens. The gestational history should take into consideration the possibility that the patient may be pregnant or has a prior history of miscarriage or abortion. A personal history of exposure to radiation, especially in the treatment of childhood malignancies, is associated with a higher incidence of developing breast cancer (5). The goal of breast evaluation is to determine clearly whether the symptom represents a benign breast condition or may be indicative of a neoplastic process.
Physical Examination
Breast tumors, particularly cancerous ones, usually are asymptomatic and are discovered by the patient or through physical examination or screening mammography. Typically, the breast changes slightly during the menstrual cycle. During the premenstrual phase, most women have increased innocuous nodularity and mild engorgement of the breast. Rarely these characteristics can obscure an underlying lesion and make examination difficult. Findings should be carefully documented in the medical record to serve as a baseline for future reference.
Inspection
Inspection is performed initially while the patient is seated comfortably with her arms relaxed at her sides. The breasts are compared for symmetry, contour, and skin appearance. Edema or erythema is identified easily, and skin dimpling or nipple retraction is shown by having the patient raise her arms above her head and then press her hands on her hips, thereby contracting the pectoralis muscles (Fig. 21.1). Palpable and even nonpalpable tumors that distort Cooper’s ligaments may lead to skin dimpling with these maneuvers.
Figure 21.1 Raising the arm reveals retraction of the skin of the lower outer quadrant caused by a small palpable carcinoma. (From Giuliano AE. Breast disease. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2005:628, with permission.)
Palpation
While the patient is seated, each breast should be palpated methodically. Some physicians recommend palpating the breast in long strips, but the exact palpation technique used is probably not as important as the thoroughness of its application over the entire breast. One very effective method is to palpate the breast in enlarging concentric circles until the entire breast is covered. A pendulous breast can be palpated by placing one hand between the breast and the chest wall and gently palpating the breast between both examining hands. The axillary and supraclavicular areas should be palpated for enlarged lymph nodes. The entire axilla, the upper outer quadrant of the breast, and the axillary tail of Spence are palpated for possible masses. While the patient is supine with one arm over her head, the ipsilateral breast is again methodically palpated from the clavicle to the costal margin and from the sternum to the latissimus dorsi laterally. If the breast is large, a pillow or towel may be placed beneath the scapula to elevate the side being examined; otherwise, the breast tends to fall to the side, making palpation of the lateral hemisphere more difficult. The major features to be identified on palpation of the breast are temperature, texture and thickness of skin, generalized or focal tenderness, nodularity, density, asymmetry, dominant masses, and nipple discharge. Most premenopausal patients have normally nodular breast parenchyma. The nodularity is diffuse but predominantly in the upper outer quadrants, where there is more breast tissue. These benign parenchymal nodules are small, similar in size, and indistinct. By comparison, breast cancer usually occurs in the form of a nontender, firm mass with irregular margins. A cancerous mass feels distinctly different from the surrounding nodularity. A malignant mass may be fixed to the skin or to the underlying fascia. A suspicious mass is usually unilateral. Similar findings in both breasts are unlikely to represent malignant disease (6).
Breast Self-Examination
There is controversy about recommending breast self-examination (BSE). There is no evidence that doing BSE improves survival rates from breast cancer (7). Staunch opponents of BSE argue that it doubles a woman’s risk of undergoing a breast biopsy for benign pathology (8). BSE increases breast health awareness and helps promote early detection of cancer (9–11). Most breast cancers are detected by women themselves (48%), followed by breast imaging (41%), and by physician clinical examination in only 11% (12). Although young women have a low incidence of breast cancer, it is important to teach BSE early so it becomes habitual. Organizations such as the American Cancer Society sponsor courses in BSE. Reassurance, support, and patient education may encourage women to overcome psychological barriers to routine BSE (13). Such instruction is available through electronic resources (14).
The following seven “P”s represent the essential components of breast examination:
• Positions
• Palpation
• Pads of fingers for palpation
• Pressure
• Perimeter
• Pattern of search
• Patient education
The woman should inspect her breasts while standing or sitting before a mirror, looking for any asymmetry, skin dimpling, or nipple retraction. Elevating her arms over her head or pressing her hands against her hips to contract the pectoralis muscles will highlight any skin dimpling. Finally, the woman should examine her breasts while bending over and leaning forward. While standing or sitting, she should carefully palpate her breasts with the fingers of the opposite hand. She should lie down and again palpate each quadrant of the breast as well as the axilla using the pads of the three middle fingers with three pressures—light, medium, and deep—covering the entire breast from the clavicle to the inframammary fold, from sternum to latissimus dorsi laterally. The area within the perimeter of the breast should be palpated, preferably using an up-and-down method called vertical stripe, rather than the concentric circular or radial methods, in which the edges of the breast tissue often are omitted. Many women feel anxious about performing breast examination. The examination may be performed while showering; soap and water may increase the sensitivity of palpation, and the privacy of the shower may provide a less anxiety-provoking environment.
It is helpful for all women to examine their breasts at the same time each month to develop a routine. Premenopausal women should examine their breasts monthly 7 to 10 days after the onset of the menstrual cycle. For postmenopausal women, selection of a specific calendar date is a helpful way to remember to perform a monthly BSE. Women should be instructed to report any abnormalities or changes to their physicians. If the physician cannot confirm the patient’s findings, the examination should be repeated in 1 month or after her next menstrual period.
Breast Imaging
Mammography
Screen-film mammography was considered the best method for imaging the breast (15). Full-field digital mammography, which records mammographic images on a computer, is a modification of screen-film mammography (16). Some advantages of digital mammography include lower radiation exposure, ability to manipulate a computerized image for optimal viewing, and access to distance consultations through telemammography (17). Studies comparing the sensitivity of full-field digital mammography with screen-film mammography in detecting cancer had mixed results. The Digital Mammographic Imaging Screening Trial (DMIST) consisted of 49,528 asymptomatic women presenting for screening mammography, who underwent both digital and film mammography. Results suggested that while the overall accuracy of digital and film mammography for screening breast cancer is similar, digital mammography may be more accurate in women under the age of 50 years, women with radiographically dense breast, and premenopausal or perimenopausal women (18).
Slow-growing breast cancers can be identified by mammography at least 2 years before the mass reaches a size detectable by palpation. These tumors have a less aggressive biologic behavior than interval breast cancers (19–21). Mammography is the only reproducible method of detecting nonpalpable breast cancer, but its use depends on the availability of state-of-the-art equipment and a dedicated breast radiologist.
Compression of the breast is necessary to obtain good images, and patients should be forewarned that breast compression is uncomfortable. With good technique and well-maintained modern equipment, exposure to radiation can be limited. Full-field digital mammography (FFDM) has a 22% lower mean glandular radiation dose than film-screen mammography per acquired view. FFDM delivers 1.86 mGy average breast radiation dose per view compared to 2.37 mGy for film screen (22).
Indications for Mammography
The indications for mammography are as follows:
1. To screen, at regular intervals, women who are at high risk for developing breast cancer. About one-third of the abnormalities detected on screening mammography prove malignant when biopsy is performed (23).
2. To evaluate a questionable or ill-defined breast mass or other suspicious change in the breast that is detected by clinical breast examination.
3. To establish a baseline breast mammogram and reevaluate patients at yearly intervals to diagnose a potentially curable breast cancer before it has been diagnosed clinically.
4. To search for occult breast cancer in a patient with metastatic disease in axillary nodes or elsewhere from an unknown primary origin.
5. To screen for unsuspected cancer before cosmetic operations or biopsy of a mass.
6. To monitor breast cancer patients who were treated with a breast-conserving surgery and radiation.
Screening
Screening programs to evaluate asymptomatic, healthy women combine physical examination with mammographic screening to identify breast abnormalities. During the past 30 years, there was an increase in the use of mammography, mammographic screening, and public awareness of breast health care. The cancer detection rate for screening mammography is 5 per 1,000 screening examinations (24). The cancer detection rate is 11-fold higher, at 55 per 1,000 examinations, when breast imaging is performed for a specific finding (i.e., diagnostic imaging) (24). Of seven randomized mammographic screening trials performed, five demonstrated a reduction in overall mortality from breast cancer screening programs (25–32). A study from the Rhode Island Cancer Registry indicates that the institution of population-based breast cancer screening programs can result in the reduction in the median tumor size at initial detection from 2.0 to 1.5 cm, which is associated with a 25% reduction in mortality (33). A study from the Norwegian breast-cancer screening program was associated with a reduction in the rate of death from breast cancer, but the screening itself accounted for only about a third of total reduction (30). Detecting breast cancer before it spreads to the axillary nodes greatly increases the chance of survival; about 85% of women with such cancer will survive at least 5 years (31,34). Because breast cancer presents first as local disease, screening mammography for breast cancer in asymptomatic women can detect small tumors and offer a better prognosis. These tumors had less opportunity to metastasize regionally or systemically; thus women have more options for treatment with reduced toxicity.
The American Cancer Society published an extensive review of the benefits, limitations, and potential harms of screening mammography (35). It addresses the role of physical examination, discusses screening in older and high-risk women, and reviews the role of newer technologies. A summary of the guidelines recommends that women of average risk for breast cancer begin mammographic screening at age 40. The rationale for beginning mammographic screening at age 40 is a 24% reduction in mortality in screened populations (28). For women in their 20s and 30s, a clinical breast examination is suggested at least every 3 years, and preferably annually, as part of a well-woman examination. For women older than age 40 years, annual clinical breast examination and mammography are recommended. For older women, recommendations for mammographic screening may be individualized based on the presence of any comorbidities. Chronologic age alone should not be considered a contraindication to mammographic screening as long as a woman is in reasonable health and would be a candidate for breast cancer surgery (35). The American Geriatrics Society recommends annual or at least biennial mammography for women up to age 75 years, and after that age, every 2 to 3 years if the woman has a life expectancy of more than 4 years (36). The reasons for liberalization of the screening interval recommendations for older women include improved biology profile, slower growth rate, and lower risk for recurrence (37–41). The natural history of the disease in older women must be balanced against life expectancy as a function of overall health (42). For high-risk women, consideration can be given to earlier initiation of screening (5 to 10 years earlier than the age of the index case) and shorter intervals between screening, and the use of additional imaging modalities such as breast ultrasonography and magnetic resonance imaging (MRI) with dedicated breast coils. No screening test is perfect, and false-negative imaging studies or benign clinical examinations may lead the patient to an erroneous sense of well-being only to be confronted later with a subsequent cancer. Likewise, a false-positive result can lead to significant anxiety and unnecessary biopsy.
Mammographic Abnormalities
A mammographic abnormality includes a mass (solid versus cystic), microcalcifications (benign, indeterminate, suspicious), asymmetric density, architectural distortion, and appearance of a new density. There are eight morphologic categories of mammographic abnormalities (43,44):
1. Calcification distribution
2. Number of calcifications
3. Description of calcifications
4. Mass margin
5. Shape of mass
6. Density of mass
7. Associated findings
8. Special cases
Mammographic abnormalities should be visible on two views, usually craniocaudal (CC) and mediolateral oblique (MLO). The lesion should triangulate to the same location on those two views. Calcifications can be macrocalcifications, which are coarse and usually represent benign degenerative breast conditions. Calcifications associated with breast cancer are clustered pleomorphic microcalcifications; typically five to eight or more calcifications are aggregated in one part of the breast (45). These calcifications may be associated with a mammographic mass density. A mass density may appear without evidence of calcifications. It can represent a cyst, benign tumor, or a malignancy. A malignant density usually has irregular or ill-defined borders and may lead to architectural distortion, which may be subtle and difficult to detect in a dense breast. Other mammographic findings suggesting breast cancer are architectural distortion, asymmetric density, skin thickening or retraction, or nipple retraction. Examples of mammographic abnormalities can be found in several electronic sources (46).
Mammographic Reports
The American College of Radiology recommended the Breast Imaging Reporting and Data System (BI-RADS) as a standardized scheme for describing mammographic lesions (47). In the BI-RADS system, there are six categories for mammographic findings (other than incomplete) (43,44).
0. Incomplete, needs further imaging
1. Negative
2. Benign finding
3. Probably benign, short-interval follow-up recommended
4. Suspicious finding and biopsy should be considered
5. Highly suggestive of malignancy and appropriate action should be undertaken
6. Known malignancy (a category that is often used for follow-up of a lesion that is undergoing neoadjuvant treatment)
The patient should be referred for tissue diagnosis if the report identifies a lesion as a category 4 or 5 (47). A category 0 indicates incomplete evaluation, and further diagnostic studies are required. Category 3 connotes a finding that is most likely benign; a short-interval follow-up is recommended, and breast examination by an expert should be considered.
Correlation of Findings
Biopsy must be performed on patients with a dominant or suspicious mass despite absence of mammographic findings (48). Mammography should be performed before biopsy so other suspicious areas can be noted and the contralateral breast can be checked (Fig. 21.2). Mammography is never a substitute for biopsy because it may not reveal clinical cancer, especially when it occurs in the dense breast tissue of young women with fibrocystic changes. The sensitivity of mammography is 75%, with a specificity of 92.3% depending on the patient’s age; breast density; use of hormone therapy; and the size, location, and mammographic appearance of the tumor (49). Mammography is less sensitive in young women with dense breast tissue than in older women, who tend to have fatty breasts, in which mammography can detect at least 90% of malignancies (50). Small tumors, particularly those without calcifications, are more difficult to detect, especially in women with dense breasts.
Figure 21.2 Bilateral mammography shows the extent of breast carcinoma, illustrating the importance of bilateral mammography in the workup of a clinically apparent mass. (From Giuliano AE. Breast disease. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2005:630, with permission.)
Ultrasonography
Breast ultrasonography is used for focused scanning of a questionable finding or for evaluation of a mammographic finding (51). Reliable, portable, computer-enhanced ultrasonography with high-frequency transducers and improved imaging is available to evaluate and treat problems of the breast (52). It is a sensitive, minimally invasive technique that is used frequently to evaluate some breast symptoms, especially in younger women with dense breast tissue, but is dependent on the availability of a skilled ultrasonographer (53). Some lesions can be detected only with ultrasonography (54). It is the preferred modality to distinguish a solid from a cystic mass (51). Breast ultrasonography is not recommended for routine screening, but is being studied as a means to screen women with dense breast tissue (54). Ultrasonography has a higher false-positive rate than mammography (51,53–55).
Following are indications for breast ultrasonography:
• Characterization:
Palpable abnormality
Ambiguous mammographic findings
Silicone leak
Mass in woman younger than 30 years, lactating, or pregnant
• Guidance for interventional procedures
• Possible role for additional imaging in high-risk individuals
Ultrasonography is useful in distinguishing benign from malignant lesions identified by mammography (56). Ultrasonography may be especially useful if the patient feels a mass, but the physician cannot detect an abnormality and the mammogram does not disclose one. It may identify cancers in the dense breast tissue of premenopausal women, but it is usually used to distinguish a benign cyst from a solid tumor. Ultrasonography cannot reliably detect microcalcifications, and it is not as useful as mammography in assessing women with fatty breasts.
Handheld or real-time ultrasonography is 95% to 100% accurate in differentiating solid masses from cysts (57). This finding is of limited clinical value because a dominant mass should be evaluated by biopsy, and a cystic mass can be studied by needle aspiration, which is far less expensive than ultrasonography. If a lesion proves to be a simple cyst, no further evaluation is necessary. Rarely ultrasonography may identify a small cancer within a cyst, an intracystic carcinoma. These complex cysts warrant surgical biopsy.
Magnetic Resonance Imaging
Magnetic resonance imaging may be of value in assessing breast lesions of an indeterminate nature detected by clinical and mammographic examination or occurring in patients who have implants (58). Both MRI and positron emission tomography (PET) are used to identify occult lesions, and MRI is increasing in popularity as a means of imaging the breast (58–60). It tends to be highly sensitive but not specific, leading to biopsies of benign lesions. Image enhancement with gadolinium discriminates between benign and malignant lesions with varying degrees of accuracy.
Several roles are proposed for breast MRI. The lack of radiation exposure makes MRI theoretically an ideal method for screening of healthy women, but widespread use is not cost-effective. Focal asymmetry is usually benign but can represent a malignancy. MRI may help identify those patients with focal asymmetric areas who should undergo biopsy. A scar can easily be distinguished from recurrent tumor based on the evaluation and diminution of the scar over time. Some scars do not resolve rapidly and are confused with cancer or, more commonly, with recurrent cancer after breast-conserving surgery and whole breast irradiation. Ideally, such cases are evaluated with MRI, sometimes obviating the need for biopsy. MRI is extremely useful in identifying silicone released by ruptured breast implants in patients with augmented breasts (Fig. 21.3). In patients with implants, MRI with gadolinium may be performed to detect breast cancer even if silicone release is not suspected. There may be a role for MRI in evaluation of specific conditions. It is used for the following indications:
Figure 21.3 Mammography shows implant and extracapsular free silicone (arrow).
• Stage tumor to rule out multicentric disease
• Differentiate postoperative scar from recurrence after breast-conserving surgery
• Find a lesion seen in only one view of mammogram
• Evaluate positive axillary nodes in the presence of negative mammogram and clinical breast examination results
• Rule out silicone implant rupture
• Assess focal asymmetry
• Detect additional ipsilateral and contralateral cancers
• Evaluate the effect of neoadjuvant chemotherapy
The American Cancer Society recommends annual MRI screening for women who are high risk (greater than 20% lifetime risk) and consideration given to women with moderate risk (15% to 20% lifetime risk) (61). A study from the Netherlands in high-risk women reported 71% sensitivity for MRI compared with 17.9% for clinical breast examination and 40% for mammography (62). The International Cooperative Magnetic Resonance Mammography Study will help identify the advantages and limitations of MRI. At present, MRI should be considered only after conventional imaging is performed; it should not be used as a screening tool or a substitute for mammography or biopsy. Centers that perform MRI should have the ability to perform MRI-guided biopsies of lesions detected with MRI only and that are not visible with mammogram or ultrasound.
Positron Emission Tomography Scan
PET scanning is a diagnostic modality that assesses the metabolic activity of tumors. Radioactive fluorodeoxyglucose (FDG) is an analogue of glucose that is metabolized by tissues of high metabolic activity. Although not specifically approved for the initial diagnosis of breast cancer or for staging the axilla, it can be useful in patients with advanced disease (59,63). This technique is used to identify occult breast lesions with positive axillary lymph nodes (59).
Breast Tissue Evaluation: Histology and Cytology
The safest course is tissue or cytologic biopsy evaluation of all dominant masses found on physical examination and, in the absence of a mass, evaluation of suspicious lesions shown by breast imaging. Over 1 million women have breast biopsies each year in the United States. Between 70% and 80% of these biopsies yield a benign lesion (64). The diagnosis of a benign breast lesion versus breast cancer is often difficult to determine based on clinical examination and requires evaluation of tissue by fine needle aspiration cytology (FNAC), core needle biopsy (CNB), or excisional biopsy (EB). Both FNAC and CNB are reasonable techniques for the evaluation of a palpable or image-identified lesion. CNB evolved as the diagnostic procedure of choice. More than half of all breast biopsies use a core-needle technique. The sensitivity of CNBs performed using either stereotactic or ultrasound guidance is 97% to 99% (65). CNB is used increasingly to diagnose breast cancer and to determine tumor histology, grade, and marker expression; select neoadjuvant therapy; and predict sentinel lymph node status (66). CNB and fine needle aspiration (FNA) are less invasive and achieve better cosmesis than excisional or even incisional biopsy. The main limitations of FNA are high rate of insufficient sampling and inability to distinguish invasive from noninvasive cancers. CNB is a well-accepted alternative to surgical biopsy and can avoid surgical biopsies in most patients (67). Investigators of the Fifth Radiologic Diagnostic Oncology Group demonstrated that image-guided biopsy of breast lesions provides high diagnostic accuracy. The sensitivity, specificity, and accuracy of CNB were 0.91, 1.00, and 0.98, respectively (68).
About 30% of lesions suspected to be cancer prove on biopsy to be benign, and about 15% of lesions believed to be benign prove to be malignant (23). Dominant masses or suspicious nonpalpable breast lesions require histopathological examination. Histologic or cytologic diagnosis should be obtained before the decision is made to monitor a breast mass (69). An exception may be a premenopausal woman with a nonsuspicious mass presumed to be fibrocystic disease. An apparently fibrocystic lesion that does not completely resolve within several menstrual cycles should be sampled for biopsy. Any mass in a postmenopausal woman who is not taking estrogen therapy should be presumed to be malignant. Some clinicians will monitor a mass when results of the clinical diagnosis, breast imaging studies, and cytologic studies are all in agreement, such as with fibroadenoma. Many clinicians will not leave a dominant mass in the breast even when FNAC or CNB results are negative, unless the FNA or CNB shows fibroadenoma. Such cases require periodic follow-up. Some surgeons excise lesions when the sampling technique shows only fibrocystic disease. Figures 21.4 and 21.5 present algorithms for management of breast masses in premenopausal and postmenopausal patients. Simultaneous evaluation of a breast mass using clinical breast examination, radiography, and needle biopsy can lower the risk of missing cancer to only 1%, effectively reducing the rate of diagnostic failure and increasing the quality of patient care (70).
Figure 21.4 Algorithm for management of breast masses in premenopausal women. (Revised and updated from Giuliano AE. Breast disease. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2005:640, with permission.)
Figure 21.5 Algorithm for management of breast masses in postmenopausal women. (Revised and updated from Giuliano AE. Breast disease. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2005:641, with permission.)
If the presence of breast cancer is strongly suggested by physical examination, the diagnosis can be confirmed by FNAC or CNB, and the patient may be counseled regarding treatment. Treatment should not be determined based on results of physical examination and mammography alone, in the absence of biopsy results. The most reasonable approach to the diagnosis and treatment of breast cancer is outpatient biopsy (either FNAC, CNB, or EB), followed by definitive surgery at a later date if needed. This two-step approach allows patients to adjust to the diagnosis of cancer, carefully consider alternative forms of therapy, and seek a second opinion. Studies show no adverse effect from the 1- to 2-week delay associated with the two-step procedure (71). Because cancer is found in the minority of patients who require biopsy for diagnosis of a breast mass, definitive treatment should not be undertaken without an unequivocal histologic diagnosis of cancer.
Fine-Needle Aspiration
With FNAC, cells from a breast tumor are aspirated with a small (usually 22-gauge) needle and examined by a pathologist. Precise guidelines for this technique are available (72). It can be performed easily, with no morbidity, and is much less expensive than excisional or open biopsy. It requires the availability of a pathologist skilled in the cytologic diagnosis of breast cancer to interpret the results, and it is subject to sampling problems, particularly when lesions are deep. Cytologic diagnoses must be correlated with clinical and imaging findings to achieve triple-test concordance and to decrease the false-negative rate (73). The triple-test concordance (i.e., concordance between fine-needle aspiration, physical examination, and mammography) is the foundation of breast evaluation. The triple-test results are more powerful than each modality alone (74). The incidence of false-positive diagnoses was 0% to 0.3%, and the rate of false-negative diagnoses was 1.4% to 2.3% in several recent studies (74,75).
Core Needle Biopsy
A core of tissue can be obtained from palpable lesions using a large cutting needle (76). Image-guided large-core needle biopsy is a reliable diagnostic alternative to surgical excision of suspicious nonpalpable breast lesions (77). As in the case of any needle biopsy, the main drawback is false-negative findings caused by improper positioning of the needle. False-negative findings may be reduced if core biopsy is performed with ultrasonographic guidance. The interpretation of results from CNB is classified by categories B1 to B5 (78):
B1: Normal tissue
B2: Benign lesions: fibroadenomas, fibrocystic change, sclerosing adenosis, duct ectasia, fat necrosis, abscess
B3: Uncertain malignant potential: atypical epithelial hyperplasia, lobular neoplasia, phyllodes tumor, papillary lesions, radial scar, complex sclerosing lesions
B4: Suspicious
B5: Malignant
Open Excisional Biopsy
Open biopsy with local anesthesia as a separate procedure before deciding on definitive treatment is the most reliable means of diagnosis. Its utility is reserved for when the results of needle biopsy are nondiagnostic or equivocal.
Histologic Analysis
Histologic evaluation with hematoxylin and eosin (H&E) staining confirms benign or malignant disease. Images of benign and malignant breast lesions can be viewed through the Internet Pathology Laboratory for Medical Education (79). Assessment of prognostic factors, tumor grade; estrogen, progesterone, her-2/neu receptor status; and proliferative indices is performed on paraffin-fixed tissue by immunohistochemistry (78). Her-2/neu assessment in breast cancer by immunohistochemistry (IHC) is appropriate for patients with tumors that score 3+. Fluorescence in situhybridization (FISH) is recommended for 2+ IHC to more accurately assess her-2/neuamplification and provide better prognostic information (80).
Ductal Lavage Cytology
Ductal lavage using a microcatheter is a modality that was investigated in high-risk women (81). Patients undergo gentle nipple suction to elicit nipple fluid. A duct that yields fluid is cannulated with a microcatheter, and 10 to 20 mL of saline are introduced in 2- to 4-mL increments. The cytologic assessment of a sample obtained by ductal lavage is more sensitive than that of nipple aspiration. Ductal lavage performed to identify abnormal cells is not an effective tool in detecting breast cancer and is rarely performed (81).
Benign Breast Conditions
Benign breast disorders account for most breast problems. These conditions are frequently considered in the context of excluding breast cancer and often are unrecognized for their own associated morbidity (82). To provide appropriate management, it is important to consider benign breast disorders from four aspects: (i) clinical picture, (ii) medical significance, (iii) treatment intervention, and (iv) pathologic etiology (83). A framework for understanding benign breast problems is called Aberrations of Normal Development and Involution (ANDI) (2,82,83). It includes symptoms, histology, endocrine state, and pathogenesis in a progression from a normal to a disease state. Most benign breast conditions arise from normal changes in breast development, hormone cycling, and reproductive evolution (82).
Three life cycles reflect different reproductive phases in a woman’s life and are associated with unique breast manifestations.
1. During the early reproductive period (15–25 years), lobule and stromal formation occurs. The ANDI conditions associated with this period are fibroadenoma (mass) and juvenile hypertrophy (excessive breast development). In this first stage, the progression from ANDI to a disease state results in the formation of giant fibroadenomas and multiple fibroadenomas.
2. During the mature reproductive period (25 to 40 years), cyclic hormonal changes affect glandular tissue and stroma. In this second period, the ANDI is an exaggeration of these cyclic effects, such as cyclic mastalgia and generalized nodularity.
3. The third phase is involution of lobules and ducts or turnover of epithelia, which occurs during ages 35 to 55 years. The ANDI associated with lobular involution are macrocysts (lumps) and sclerosing lesions (mammographic abnormalities). Those associated with ductal involution are duct dilation (nipple discharge) and periductal fibrosis (nipple retraction), and those with epithelial turnover are mild hyperplasia (pathologic description).
Disease conditions with increased epithelial turnover are epithelial hyperplasias with atypia. Breasts are under endocrine control and show a wide range of appearances during reproductive life. ANDI classification allows the clinician to understand the pathogenesis of these conditions and to understand that these disorders are aberrations of a normal process that does not usually require any specific treatment (82).
Fibrocystic Change
Fibrocystic change, the most common lesion of the breast, is an imprecise term that covers a spectrum of clinical signs, symptoms, and histologic changes (76). The term refers to a histologic picture of fibrosis, cyst formation, and epithelial hyperplasia (83). Cysts arise from the breast lobules and are an aberration of normal breast involution (82). Macroscopic cysts occur in approximately 7% of women, and microscopic, nonpalpable cysts occur in about 40% of women (84). It is common in women 35 to 55 years of age, but rare in postmenopausal women not taking hormone therapy. The presence of estrogen seems necessary for the clinical symptoms to occur. This finding is supported by the observation that it is present bilaterally, increased in the perimenopausal age group, and responsive to endocrine therapy (85). In essence, a diagnosis of fibrocystic change can lead to significant patient anxiety but is of little clinical significance as long as malignancy is excluded (86). These lesions are associated with benign changes in the breast epithelium.
Cyst Fluid Analysis
Investigators examined the electrolyte and protein content of cyst fluid, but this is of little significance in the clinical management of fibrocystic disease. The potassium-to-sodium ratio is a marker that may be used to distinguish cyst subtypes (87). Cysts are either lined by apocrine epithelium with a high potassium-to-sodium ratio and a higher hormone or steroid concentration (type I); or by flattened lobule epithelium with a low potassium-to-sodium ratio and a higher concentration of albumin, carcinoembryonic antigen, CA125, and steroid hormone–binding globulin (type II) (87). Apocrine cysts produce and secrete large amounts of prostate-specific antigen (PSA) (88). The role of this serine protease in proliferative breast disease is not fully understood.
Clinical Findings in Fibrocystic Disease
Fibrocystic changes may produce an asymptomatic mass that is smooth, mobile, and potentially compressible. Fibrocystic change is more often accompanied by pain or tenderness and sometimes nipple discharge. In many cases, discomfort coincides with the premenstrual phase of the cycle, when the cysts tend to enlarge. Fluctuations in size and rapid appearance or disappearance of a breast mass are common. Multiple or bilateral masses appear frequently, and many patients have a history of a transient mass in the breast or cyclic breast pain. Cyclic breast pain is the most commonly associated symptom of fibrocystic changes.
Differential Diagnosis
Pain, fluctuation in size, multiplicity of lesions, and bilaterality are the features most helpful to differentiate fibrocystic disease from carcinoma. If a dominant mass is present, the diagnosis of cancer should be suspected until it is disproved by complete aspiration of a cyst, or histopathologic analysis if a mass is present after aspiration, or by breast imaging. Microscopic findings associated with fibrocystic disease include cysts (gross and microscopic), papillomatosis, adenosis, fibrosis, and ductal epithelial hyperplasia (89).
Diagnostic Tests
Patients with cystic disease may have a discrete fibrocystic mass that is frequently indistinguishable from carcinoma, based on clinical findings. Mammography may be helpful, but there are no mammographic signs diagnostic of fibrocystic change. Ultrasonography is useful in differentiating a cystic from a solid mass. Characteristic findings on ultrasonography that confirm a simple cyst include the following:
• Mass with thin walls
• Smooth round shape
• Absence of internal echoes
• Posterior acoustic enhancement
If these imaging criteria are not met, a tissue diagnosis of the mass usually requires a FNA, FNAC, or EB. The finding of a simple cyst by ultrasonography rules out carcinoma. Any lesion that is suspicious by mammography or ultrasonography should be biopsied.
When the diagnosis of fibrocystic change is established by ultrasonography or is practically certain because the history is classic, aspiration of a discrete mass, suggestive of a cyst, is indicated if the patient is symptomatic, the cyst obscures visualization of breast tissue on mammography and prevents adequate imaging, or if the ultrasonographic criteria are not met. In one study of a screened population, 1% of individuals developed a new cyst that resolved in more than 50% of cases (90). Aspiration may be performed with ultrasonographic guidance, but image guidance is usually not necessary if the cyst is palpable (91). FNA of a cyst is a minimally invasive procedure performed with a 21- or 22-gauge needle without local anesthesia and is not associated with significant risks or complications. There is minimal pain and little risk for infection or bleeding. Benign cyst fluid is straw colored to dark green to brownish and does not need to be submitted for cytologic evaluation (6). Injection of air into the cyst cavity is reported to reduce the likelihood of cyst recurrence but generally is not performed. The patient should be reexamined at a short interval thereafter for cyst recurrence. Cysts will reoccur in 30% of patients, cause anxiety, and require repeated evaluations (84). Tissue biopsy should be performed in the presence of the following findings:
• No cyst fluid is obtained
• The fluid is bloody
• The fluid is thick
• The cyst is complex
• There is an intracystic mass
• A mass persists after aspiration
• A persistent mass is noted at any time during follow-up
If a needle biopsy is performed and results are negative for malignancy, a suspicious mass that does not resolve over several months should be excised. Surgery should be conservative, because the primary objective is to exclude cancer. Simple mastectomy or extensive removal of breast tissue is not indicated for fibrocystic disease. Most patients do not require treatment for fibrocystic changes, just reassurance that fibrocystic change is a transient phenomenon of aging that is associated with hormonal effects on the breast glandular tissue that eventually subsides.
Fibrocystic Change and Risk for Breast Cancer
Fibrocystic change is not associated with an increased risk of breast cancer unless there is histologic evidence of epithelial proliferative changes, with or without atypia (92–97). The common coincidence of fibrocystic disease and malignancy in the same breast reflects the fact that both processes are common events. Approximately 80% of biopsies show fibrocystic changes. In an evaluation of the relationship between fibrocystic change and breast cancer in 10,366 women who underwent biopsy between 1950 and 1968 and were followed for a median of 17 years, approximately 70% of the biopsies showed nonproliferative breast disease, whereas 30% showed proliferative breast disease (95). Cytologic atypia were present in 3.6% of cases. Women with nonproliferative disease had no increased risk of breast cancer, whereas women with proliferative breast disease and no atypical hyperplasia had a twofold higher risk of breast cancer. Patients whose biopsy results showed atypical ductal or lobular hyperplasia had an approximately fivefold higher risk than women with nonproliferative disease to develop invasive breast cancer in either breast. Patients with carcinoma in situ have an eight- to tenfold risk of developing breast cancer. This risk is bilateral for lobular lesions and ipsilateral for ductal lesions. A family history of breast cancer added little risk for women with nonproliferative disease, but family history plus atypia increased breast cancer risk 11-fold. The presence of cysts alone did not increase the risk of breast cancer, but cysts combined with a family history of breast cancer increased the risk about threefold (76,92–97). Women with these risk factors (family history of breast cancer and proliferative breast disease) should be followed carefully with physical examination and mammography. For such women, age-specific probability of developing invasive breast carcinoma in the next 10 years is 1 in 2,000 (age 20), 1 in 256 (age 30), 1 in 67 (age 40), 1 in 39 (age 50), and 1 in 29 (age 60) (93). The relative risk for developing breast cancer depends on the type of proliferative lesion diagnosed.
Management of Fibrocystic Change
Fibrocystic change is a normal evolutionary change in breast development and involution and does not require a specific treatment other than a good clinical breast examination and age-appropriate mammographic screening or imaging studies directed to signs and symptoms. A number of nutritional and dietary supplements were investigated to relieve symptoms. The role of caffeine consumption in the aggravation of fibrocystic change is controversial (98–101). Results of some studies suggest that eliminating caffeine from the diet is associated with improvement of symptoms (100,101). Many patients are aware of these studies and report relief of symptoms after discontinuing intake of coffee, tea, and chocolate. Similarly, many women find vitamin E (150 to 600 IU daily) or B6 (200 to 800 mg per day) helpful (102,103). Observations about these effects are difficult to confirm and are anecdotal (104–106). A recent review of nutritional interventions for fibrocystic breast conditions that evaluated evening primrose oil, vitamin E, or pyridoxine suggested that there are insufficient data to draw clear conclusions about their effectiveness (107). Exacerbations of pain, tenderness, and cyst formation may occur at any time until menopause, when symptoms usually subside unless patients are taking estrogen. A patient with fibrocystic changes should be advised to examine her own breasts each month just after menstruation and to inform her physician if a mass appears.
Mastalgia
Mastalgia is a recognized organic condition that is studied less thoroughly than other breast problems (108,109). Inflammatory cytokines were implicated in the etiology of breast pain. A study evaluating expression of interleukin-6 and tumor necrosis factor-α in painful and nonpainful breast tissue showed lower levels of these cytokines in painful breast tissue during the luteal phase; however, these levels did not reach statistical significance (110). Elevated estrogen, low progesterone, or an imbalance in the ratio of estrogen and progesterone were suggested as a possible cause for the symptoms (111).
Natural History of Mastalgia
Approximately 70% to 80% of women experience severe breast pain at some time in their lives (112,113). Mastalgia accounts for 30% to 47% of breast clinical evaluations (111,114). In 15% of the patients, the mastalgia is so severe that it alters lifestyle and requires repeated investigations and treatment (112). Mastalgia interferes with sexual (48%), physical (37%), social (12%), and work or school activities (8%) (115).
Types of Mastalgia
Breast pain is a distressing constellation of symptoms that is classified as cyclic, noncyclic, or extramammary (116). Cyclic mastalgia is related to exaggerated premenstrual symptoms beginning in the luteal phase of the menstrual cycle, associated with breast engorgement, pain, ache, heaviness, and tenderness that is bilateral and can last for more than 7 days in 11% of women (116–118). Cyclical mastalgia is more prevalent in women in their third and fourth decades of life and accounts for two-thirds of all breast pain symptoms (119). Noncyclic mastalgia is independent of menstrual cycles and is described as achy, burning soreness. It may be intermittent or constant, is usually unilateral, occurs in the fourth and fifth decades, and is more difficult to treat than cyclic mastalgia (116). Extramammary pain is perceived to be located in the breast but is related to an extramammary site. Chest wall muscular pain, costal cartilage symptoms, herpes zoster, radiculopathies, and rib fractures are among some of the more common causes of extramammary pain. Costochondritis (Tietze syndrome) is a manifestation of chest wall pain that is frequently interpreted as breast pain.
Management of Mastalgia
Breast pain is an unlikely symptom of malignancy, and when malignancy is excluded by a clinical breast examination and age-appropriate breast imaging for focal breast pain, the most important treatment is reassurance. Treatments include medications, such as anesthetics, diuretics, bromocriptine, and tamoxifen; vitamins and supplements, such as evening primrose oil; mechanical support with a well-fitting bra; local excision; and decreased fat intake and reduction in methylxanthines from caffeine, tea, and chocolate (108,116). Discontinuation of hormone therapy may be effective in some women. Maintenance of a pain score diary is important to understand the relationship of pain to factors such as the menstrual cycle, activities of daily living, and stress. External support may be effective for breast pain associated with generalized fibrocystic changes and is best treated by avoiding trauma and by wearing (night and day) a brassiere that gives good support and protection (120). One study evaluated resolution of symptoms in 200 women randomized either to a regimen of danazol (200 mg per day) or to mechanical support with a sports brassiere worn for regular activities for 12 weeks. The group using mechanical support had 85% relief of symptoms compared with 58% improvement in the danazol group. Symptoms recurred after discontinuance of treatment with danazol (113). The danazol group experienced drug-related side effects in 42%, which led to discontinuance of the medication in 15%. The breast has minimal structural support and is at significant risk for motion-related displacement resulting in mastalgia. The use of external support to minimize breast motion appears to be effective in reducing breast pain. The application of heat packs or cold packs and light breast massage may reduce symptoms in some individuals (116).
Hormone-modulating drugs, including danazol, bromocriptine, tamoxifen, and Depo-Provera, are recognized drug treatments for mastalgia, although tamoxifen is not approved for this use in the United States (116,121–124). These drugs are associated with significant side effects that limit their general use (116). Withdrawal of birth control pills or hormone therapy may be all that is required to alleviate symptoms (116).
Danazol is a synthetic androgen that suppresses release of pituitary gonadotropin, prevents luteinizing hormone surge, and inhibits ovarian steroid formation. It is the only medication approved by the U.S. Food and Drug Administration for mastalgia (116). The androgenic effects—acne, edema, change in voice, weight gain, headaches, depression, and hirsutism—often are intolerable, and many patients stop taking danazol even when symptoms are improved (122). It can be initiated at doses of 100 to 200 mg twice daily orally for patients with severe pain and then tapered to a lower dose of 100 mg per day (122). A survey of surgeons in Great Britain revealed that 75% prescribed danazol as first-line therapy (108). A study conducted to evaluate the response to administration of danazol revealed a 79% amelioration of symptoms (125). This approach reduced the premenstrual mastalgia and resulted in virtually no side effects.
The use of oral progesterone agents reduces cyclical breast pain (111). Further studies may be warranted to see whether medroxyprogesterone acetate suppresses cyclic mastalgia in reproductive-age women.
Breast pain is increased in some individuals who have elevated prolactin (PRL) levels induced by thyrotropin-releasing hormone (TRH) (116). Bromocriptine is a dopamine antagonist that inhibits the release of PRL. Bromocriptine(2.5 mg twice daily) given for 3 to 6 months is effective in reducing mastalgia in women who have TRH-induced elevation of PRL (123). Patients who have normal TRH levels, are resistant to bromocriptine, or do not tolerate the side effects of nausea, vomiting, and headache respond favorably to progesterone and systemic nonsteroidal anti-inflammatory drugs (NSAIDs).
Prolactin induces active transport of iodine in breast tissue (126,127). Iodine deficiency in rats causes hyperplasia and atypia (128). Iodine replacement is associated with improvement in subjective pain (129). A randomized, double-blind study with supraphysiologic levels of iodine in women with documented cyclic mastalgia demonstrated dose-dependent reduction in physician-assessed and self-reported pain at 3 and 6 months of treatment (130).
Goserelin is a potent synthetic analogue of luteinizing hormone-releasing hormone (LHRH) that causes reversible reduction in serum estrogen level and decrease in breast pain (131). Side effects of goserelininclude vaginal dryness, hot flushes, decreased libido, oily skin and hair, and decreased breast size. A recent clinical trial randomized 147 women into goserelin versus placebo groups. The study had a 49% drop-out rate. The mean breast pain score decreased by 67% in the goserelin arm and 35% in the placebo arm. The authors concluded that goserelin is an effective treatment for mastalgia with significant side effects and should be kept as second-line therapy. Hormonal blockade of the estrogen receptor is another approach to minimizing the effects of circulating estrogen on breast pain. Treatment with the selective estrogen receptor modulator tamoxifen demonstrated reduction in breast pain at 10 and 20 mg per day, with equivalent effects compared with danazol and bromocriptine in most studies (124,132–134). Topical nonsteroidal therapy is another option for women with mastalgia (135). Gel forms of NSAIDs often are used for relief of pain. Patients were stratified by cyclic versus noncyclic pain and then randomized to treatment with NSAIDs versus placebo. There was a significant reduction in cyclic and noncyclic pain in all groups, but the magnitude of change was greater in the treatment arms and similar for cyclic and noncyclic pain. Use of NSAIDs appears to be a less toxic treatment and may be considered as an option for both cyclic and noncyclic breast pain.
Nonhormonal therapies such as dietary restrictions, vitamins and supplements, and restriction of methylxantines were investigated as possible treatments for mastalgia because they are less likely to be associated with adverse drug-related side effects (116). Because mastalgia is one of the symptoms associated with fibrocystic disease, the treatments described for fibrocystic disease are relevant to mastalgia. A low-fat diet was effective in one randomized trial (136). Ninety percent of patients taking in 15% dietary fat experienced resolution of pain symptoms after 6 months compared with only 22% of those on a diet containing 36% fat (p = .0023). Evening primrose oil containing essential fatty acids (γ-linolenic acid [GLA]) was studied because of its affect on prostaglandin synthesis (137). It was used as first-line therapy, reserving danazol and bromocriptine for treatment of more severe symptoms (112). In a small prospective mastalgia trial, women were given eight capsules of evening primrose oil daily for 4 months (320 mg GLA) (138). Those who responded had a lower level of essential fatty acids at the time of initiation when compared with poor responders, suggesting that evening primrose oil increases essential fatty acids and that this increase may be associated with the improvement in symptoms in the responders. Two other trials failed to demonstrate efficacy of evening primrose oil capsules over placebo (139,140). In a Dutch trial, 124 women with cyclic or noncyclic pain lasting on average 7 or more days (minimum 5 days) were randomized to receive the following regimens: (i) fish oil and control oil, (ii) evening primrose oil and control oil, (iii) fish and evening primrose oil, or (iv) both control oils for 6 months (139). There was a statistically significant reduction in the number of days per month with pain but not in the pain score in the entire study population. There was a greater reduction in cyclic than noncyclic pain symptoms, and this finding was true for both the test oils and for the control oils. The authors concluded that neither fish oil nor evening primrose oil had a better effect than the less expensive wheat germ and corn oils. A second large double-blind randomized prospective trial was conducted in 555 women with cyclic mastalgia of moderate to severe degree present for at least 7 days of a menstrual cycle (140). The four groups were (i) GLA and placebo antioxidants, (ii) placebo fatty acids and antioxidants, (iii) GLA and placebo antioxidants, and (iv) placebo fatty acids and placebo antioxidants. The treatments were given in a blinded fashion for 4 months. All groups had a similar 35% reduction in symptoms. This treatment was followed by open treatment with GLA in all groups and blinded treatment with antioxidants. There was continued improvement of symptoms in all groups with a reduction in mastalgia by 50% over the next 12 months. This is the largest and best-controlled study to date evaluating GLA for relief of mastalgia, and GLA was not found to be superior to placebo. The results of this study were not consistent with those from previous smaller studies. The authors cannot exclude a significant psychologic impact that may confound the effect of GLA. GLA use was found to be safe, without any significant side effects, and was prescribed as therapy for mastalgia because of its lack of side effects. The randomized trials, however, bring into serious question the efficacy of these options.
Fibroepithelial Lesions
Fibroadenoma
Fibroadenomas are the most common benign tumors of the breast. In one series, they accounted for 50% of all breast biopsies (141). They usually occur in young women (age 20 to 35 years) and may occur in teenagers (142). In women younger than 25 years, fibroadenomas are more common than cysts. They rarely occur after menopause, although occasionally they are found, often calcified, in postmenopausal women. For this reason, it is postulated that fibroadenomas are responsive to estrogen stimulation. A study reports the de novo occurrence of fibroadenoma in 51 women older than age 35 years who had no evidence of a palpable or mammographic visualized lesion in well-documented prior visits (143). Fibroadenomas may appear as single masses or as multiple lesions.
Clinically, a young woman usually notices a mass while showering or dressing. Most masses are 2 to 3 cm in diameter when detected, but they can become extremely large (i.e., the giant fibroadenoma). On physical examination, they are firm, smooth, and rubbery. They do not elicit an inflammatory reaction, are freely mobile, and cause no dimpling of the skin or nipple retraction. They are often bilobed, and a groove can be palpated on examination. On mammographic and ultrasonographic imaging, the typical features are of a well-defined, smooth, solid mass with clearly defined margins and dimensions that are longer than wide and craniocaudad dimensions that are less than the length.
Fibroadenoma is not associated with an increased risk for breast cancer (144). The natural history of fibroadenoma can be regression, growth, or no change in size. Most fibroadenomas are static or cease growth at approximately 2 to 3 cm, about 15% of tumors regress spontaneously, and only 5% to 10% progress (145). Because transformation of a fibroadenoma into cancer is rare and regression is frequent, current management recommendations are conservative unless there is evidence of growth (141). A suspected fibroadenoma should be confirmed by FNAC or CNB and observed for increase in size or excised based on patient preference. Rarely will the fibroadenoma increase to more than 2 to 3 cm in size. Large or growing fibroadenomas must be excised. Complete excision of a fibroadenoma with local anesthesia can be performed to treat the lesion and confirm the absence of malignancy. Less invasive local treatment of a fibroadenoma is advocated by some and can be performed with either ultrasonographically guided percutaneous vacuum-assisted biopsy devices or percutaneous cryoablation (146,147). A young woman with a clinical fibroadenoma can undergo needle cytology and observation of the mass (148). Acceptance of observation varies, and many women choose to have the fibroadenoma excised (149).
On gross examination of an excised mass, the fibroadenoma appears encapsulated and sharply delineated from the surrounding breast parenchyma. Microscopically, there is proliferation of both the epithelial and stromal component. In longstanding lesions and in postmenopausal patients, calcifications may be observed within the stroma.
Multiple Fibroadenomas
Multiple fibroadenomas occur in some women and were reported to occur more frequently in premenopausal women undergoing immunosuppression for transplant (150–152). Excision of all lesions through separate incisions could leave significant scarring and deformity. Excision of these mobile lesions through a single periareolar incision was suggested, but this approach can lead to significant ductal disruption (153). Another approach is through an incision in the inframammary crease. Alternatively, these lesions can be treated with observation based on triple-test concordance of results of a classic clinical examination with histologic corroboration with FNAC and ultrasonographic diagnostic criteria consistent with a fibroadenoma (151).
Phyllodes Tumor
Phyllodes tumors are rare fibroepithelial tumors that display a spectrum of clinical and pathologic behaviors that are benign, borderline, and malignant (154,155). The distribution of phyllodes tumors demonstrates that most tumors are benign (70%) compared with malignant (23%) and borderline lesions (7%) (156). This distribution is similar to a larger, older study that reported an incidence of 64% benign, 21% malignant, and 14% borderline phyllodes tumors (157). The incidence in some studies should be viewed with caution because of variation in histologic interpretation (156). Phyllodes tumors may occur at any age but tend to be more common in women who are in their late 30s, 40s, and 50s (156,158–162). These lesions are rarely bilateral and usually appear as isolated masses that are difficult to distinguish clinically from a fibroadenoma. Patients often relate a long history of a previously stable nodule that suddenly increases in size. Reported sizes range from 1.0 to 50 cm (154,163,164). Size is not a dependable diagnostic criterion, although phyllodes tumors tend to be larger than fibroadenomas, probably because of their rapid growth. There are no good clinical criteria by which to distinguish a phyllodes tumor from a fibroadenoma. Whereas observation of a fibroadenoma is acceptable, excision of a phyllodes tumor is necessary for local control and for determination of benign or malignant features. To avoid unnecessary excision of benign fibroadenomas that are indistinguishable from phyllodes tumors on clinical examination, imaging criteria were sought to aid in identifying patients who require EB for complete histopathologic evaluation and local control. Mammography may show a halo around a phyllodes tumor mass but cannot reliably distinguish a fibroadenoma from a phyllodes tumor (165–167). Ultrasonography evaluation has limitations even when color and pulse Doppler ultrasonography are used in conjunction with it (163).
Microscopic evaluation of a lesion is important to determine the diagnosis. The histologic distinction between fibroadenoma, benign, borderline, and malignant phyllodes tumor can be very difficult on minimal tissue sampling with FNAC or CNB (168,169). It may be easier to distinguish benign phyllodes from malignant phyllodes tumors than benign phyllodes tumors from fibroadenomas (170). Histologic features that stratify lesions include number of mitoses per high power field, stromal cellularity, pushing or infiltrating tumor margin, cellular atypia, tumor necrosis, and stromal overgrowth (171).
If a lesion cannot be clearly characterized as a fibroadenoma, excision may be necessary. Factors that are considered in recommending excision include older age, new mass in a well-screened individual, rapid growth, size greater than 2.5 to 3 cm, suspicious FNAC or CB, and mammographic or ultrasonographic features that demonstrate lobulation and intramural cysts. If observation is elected, repeat clinical examination and imaging in a short interval is essential to evaluate change in size.
Treatment of biopsy-proven phyllodes tumor is wide local excision, attempting to obtain a 1- to 2-cm margin (156–161). Massive tumors, or large tumors in relatively small breasts, may require mastectomy; otherwise, mastectomy should be avoided, and axillary lymph node dissection is not indicated. Often, however, a patient will undergo excisional biopsy of a mass believed to be fibroadenoma, and final histologic examination reveals a phyllodes tumor. Reexcision with normal breast margins is recommended for borderline and malignant phyllodes tumors (159). An expectant approach is an option for unanticipated diagnosis of benign phyllodes tumors (157).
The prognosis of benign and malignant phyllodes tumors is variable (154,155,157,162,172). Tumors judged to be benign phyllodes tumors can recur locally in up to 10% of patients (159–161). Recurrence is associated with margin involvement, whereas mortality correlates with size and grade (173). In a series reviewing only high-grade malignant phyllodes tumors, size and excision margins were associated with local recurrence and metastatic spread, and mastectomy may be required to achieve complete surgical excision (174). Malignant phyllodes tumors tend to recur locally and occasionally may metastasize to the lung, although brain, pelvic, and bone metastases also may occur (160–162). The stromal component of the tumor is malignant and metastasizes, behaving like a sarcoma. Axillary involvement is extremely unusual. Often, the appearance of metastasis is the first sign that a phyllodes tumor is malignant. Chemotherapy for metastatic phyllodes tumors should be based on regimens for sarcoma, not adenocarcinoma (159). Radiation therapy generally is not used in the treatment of phyllodes tumors. In the presence of a bulky tumor, positive margins, recurrence, or malignant histology, radiation therapy may be of some benefit (175).
Breast Conditions Requiring Evaluation
Nipple Discharge
Nipple discharge is a presenting breast symptom in 4.5% of patients seeking evaluation of a breast symptom, with 48% spontaneous and 52% provoked (176). Nipple discharge that does not occur spontaneously has no pathologic significance. Provoked or self-induced nipple discharge should be managed by reassurance and instruction to discontinue manipulation. Spontaneous nipple discharge is more likely to be associated with an underlying pathologic problem than provoked discharge. Although it is a distressing finding, spontaneous nipple discharge is infrequently found to be associated with carcinoma, ranging from 4% to 10% (176–178). Nipple discharge can be caused by neoplastic or nonneoplastic processes (179). Nonneoplastic processes include galactorrhea, physiologic changes resulting from mechanical manipulation, parous condition, periductal mastitis, subareolar abscess, fibrocystic change, and mammary duct ectasia. Neoplastic causes of nipple discharge in nonlactating women are solitary intraductal papilloma, carcinoma, papillomatosis, squamous metaplasia, and adenosis (176,179,180). Extramammary causes are related to hormones and drugs (179). Following are the important characteristics of the discharge and other factors to be evaluated by history and physical examination (180):
1. Nature of discharge (serous, bloody, or milky)
2. Association with a mass
3. Unilateral or bilateral
4. Single or multiple ducts
5. Discharge that is spontaneous (persistent or intermittent) or expressed by pressure at a single site or on entire breast
6. Relation to menses
7. Premenopausal or postmenopausal
8. Hormonal medication (contraceptive pills or estrogen)
Unilateral, spontaneous, bloody, or serosanguinous discharge from a single duct is usually caused by an intraductal papilloma or, rarely, by an intraductal cancer. In either case, a mass may not be palpable. The involved duct may be identified by pressure at different sites around the nipple and at the margin of the areola. Bloody discharge is more suggestive of cancer but usually is caused by a benign papilloma in the duct. In premenopausal women, spontaneous multiple-duct discharge, unilateral or bilateral, is most marked just before menstruation. It often is caused by fibrocystic change. Discharge may be green or brownish. Papillomatosis and ductal ectasia are usually seen on biopsy. If a mass is present, it should be removed. Milky discharge from multiple ducts in nonlactating women presumably reflects increased secretion of pituitary prolactin; serum prolactin and thyroid-stimulating hormone levels should be evaluated to detect a pituitary tumor or hypothyroidism. Hypothyroidism may cause galactorrhea. Alternatively, phenothiazines may cause milky discharge that disappears when the medication is discontinued. Oral contraceptive agents may cause clear, serous, or milky discharge from multiple ducts or, less often, from a single duct. The discharge is more evident just before menstruation and disappears when the medication is stopped.
Chronic unilateral nipple discharge, especially if it is bloody, is an indication for resection of the involved ducts. Mammography and ultrasonography are performed to rule out an associated mass. On occasion, ductography may be performed to identify a filling defect before excision of the duct system, but usually this technique is of little value (178). Ductography is not a substitute for excision because it misses multiple lesions and cannot visualize the periphery (181).
Fiberoptic ductoscopy is a technology used to evaluate patients with nipple discharge (182). In 259 patients with nipple discharge, fiberoptic ductoscopy successfully detected intraductal papillary lesions in 92 patients (36%). Office-based, minimally invasive breast ductoscopy with intraductal biopsy is available in some centers (183,184). It was performed for diagnosis in 83 patients with nipple discharge (183). A diagnosis of severe or malignant atypia was established in 21% of patients.
Cytologic examination of nipple discharge or cyst fluid rarely is performed. Cytologic examination usually is of no value but may identify malignant cells (178). Negative findings do not rule out cancer, which is more likely in women older than 50 years of age. In any case, the involved duct—and a mass, if present—should be excised (177,178,180,185). Complete histopathologic evaluation of the involved ductal system is the preferred method of diagnosis, and cytologic assessment should not be relied on for diagnosis.
The usual approach for nipple discharge is surgical excision through a periareolar incision adjacent to the trigger point, the pressure point that elicits nipple discharge (179). A microdochetomy of a single duct or a central duct excision of the major subareolar ducts can be performed under local or general anesthesia. The putative duct can be cannulated, methylene blue can be injected, or a lacrimal probe can be inserted into the duct for localization. A resection of breast tissue for 3 to 5 cm, or until no bloody fluid can be identified in the ductal system, is performed. The patient must be warned of possible skin and nipple loss as a result of compromised vascularity, change in nipple sensation, deformity, inability to breastfeed, and recurrence if only a single duct if removed.
When there is a history of unilateral nipple discharge, localization is not possible, and no mass is palpable, the patient should be reexamined every week for 1 month. When unilateral discharge persists, even without definite localization or tumor, surgical exploration should be considered. The alternative is careful follow-up at intervals of 1 to 3 months. Mammography should be performed. Purulent discharge may originate in a subareolar abscess and requires excision of the related lactiferous sinus (186).
Erosive Adenomatosis of the Nipple
Erosive adenomatosis is a rare benign condition of the nipple that mimics Paget’s disease (187). Patients seek treatment for pruritus, burning, and pain. On clinical examination, the nipple can appear ulcerated, crusting, scaling, indurated, and erythematous. The nipple can be enlarged and more prominent during menstrual cycles (188). The differential diagnosis includes squamous cell carcinoma, psoriasis, contact dermatitis, seborrheic keratosis, adenocarcinoma metastatic to the skin, and unusual primary tumors of the nipple (187). Biopsy should be performed to diagnose the lesion. Local excision is curative (187).
Fat Necrosis
Fat necrosis of the breast is rare but clinically important because it produces a mass, often accompanied by skin or nipple retraction, which is indistinguishable from carcinoma. Fat necrosis often presents as a confusing clinical finding. Trauma is presumed to be the cause, although only about one-half of patients have a history of injury to the breast. Ecchymosis is occasionally seen near the tumor. Tenderness may or may not be present. If untreated, the mass associated with fat necrosis gradually disappears. Diagnostic imaging studies are usually insufficient (189). As a rule, the safest course is needle-core or excisional biopsy of the entire mass to rule out carcinoma (189). Fat necrosis is common after segmental resection and radiation therapy or transverse rectus abdominis musculocutaneous (TRAM) flap (190).
Breast Abscess
Lactational Abscesses
Infection in the breast is rare unless the patient is lactating. Lactational mastitis must be distinguished from lactational abscess (191). During lactation, an area of redness, tenderness, and induration frequently develops in the breast. Lactational mastitis is caused by transmission of bacteria during nursing and poor hygiene. The organism most commonly found in lactational mastitis and abscesses is Staphylococcus aureus (192). If mastitis is diagnosed, manual pressure, antibiotics, and continued breastfeeding are recommended. In its early stages, the infection often can be treated while breastfeeding is continued by administering an antibiotic such as dicloxacillin 250 mg four times daily, or oxacillin 500 mg four times daily, for 7 to 10 days. If the lesion progresses to a localized mass with local and systemic signs of infection, an abscess is present. It should be drained, and breastfeeding should be discontinued.
Nonlactational Abscess
Rarely, infections or abscesses may develop in young or middle-aged women who are not lactating (193). The approach to nonlactational abscess is conservative (194,195). A suspected abscess should be evaluated with preliminary ultrasonography to detect the presence of an inflammatory mass, frank pus, solitary cavity, or a multiloculated abscess (196). Aspiration of pus, if present, and antibiotic therapy is instituted with reaspiration, if necessary (196). When the fluid collection is greater than 3 mL, percutaneous drain placement is an option (194). A single aspiration is sufficient in about one-half of patients (194). Recurrent abscess formation is low (10%) (194). Bacteriologic analysis of 190 abscesses in nonlactating and lactating women showed a preponderance of gram-positive cocci. S. aureus was the most common organism isolated (51.3%). Of these, 8.6% were methicillin-resistant S. aureus. Other common organisms included mixed anaerobes (13.7%) and anaerobic cocci (6.3%) (196). If these infections recur after multiple aspirations, incision and drainage followed by excision of the involved lactiferous duct or ducts at the base of the nipple may be necessary during a quiescent interval. In virtually all cases, mammillary sinus (lactiferous duct fistula) can be confirmed as the cause of reinfection or persistent infection (197). Inflammatory carcinoma is a consideration when erythema of the breast is present. Patients should not undergo prolonged treatment for an apparent infection unless biopsy eliminated the possibility of inflammatory carcinoma.
Subareolar Abscess and Lactiferous Duct Fistula
Subareolar abscess and fistula of the lactiferous ducts secondary to squamous metaplasia can occur (198). The distal duct can be occluded with inspissated debris. Two large reviews report a high association of lactiferous duct fistulae in women who smoke (199,200). The definitive treatment for lactiferous duct sinus is excision of the lactiferous duct and drainage of the abscess cavity. In both studies, the recurrence rate was greater when only incision and drainage were performed. The most common organism occurring in primary subareolar abscess was S. aureus, but anaerobic organisms occurred more frequently in chronic recurring abscesses (200).
Disorders of Breast Augmentation
Estimates indicate that nearly 4 million women in the United States have undergone augmentation mammoplasty. Breast implants are usually placed under the pectoralis muscle or, less desirably, in the subcutaneous tissue of the breast. Most implants are made of an outer silicone shell filled with a silicone gel or saline.
The complications of breast implantation are significant. Rates of contracture vary in the literature from less than 10% to over 60%. Capsular contraction or scarring around the implant, leading to firmness and distortion of the breast, can be painful and sometimes requires removal of the implant and capsule. Implant rupture may occur in as many as 5% to 10% of women, and bleeding of gel through the capsule is even more common (201). In 2006, the U.S. Food and Drug Administration approved silicone gel filled implants for use in women 22 years or older for cosmetic purposes and for reconstruction after breast surgery or in women with traumatic or congenital breast defects (202). The agency recommends MRI scanning 3 years after the first implant surgery and then every 2 years for the detection of implant rupture.
The agency advised symptomatic women with ruptured implants to discuss the need for surgical removal with their physicians. When there is no evidence of associated symptoms or rupture, implant removal is generally not indicated because the risks of removal are probably greater than the risk of retention. If screening ultrasonography shows no rupture, the probability of rupture is 2.2% (203). If ultrasonography shows rupture, true rupture is present in 37.8%. In this setting, a large number of women would have normal implants removed. When MRI is used in addition to ultrasonography, the probability of rupture increases to 86%.
The suggested association between silicone gel and autoimmune disease is poorly documented (204,205). Among the multiple meta-analyses conducted thus far, none have identified a significant association between breast implants and connective-tissue disease (206). Subsequent studies demonstrated no clinical data proving an increased incidence of connective tissue disorders in patients with silicone gel breast implants (207–209). The data continue to reaffirm previous observations that there is no evidence of an association between breast implants and connective tissue diseases (210). In a study of Danish women undergoing reduction mammoplasty compared with silicone implant augmentation, there was no increased incidence of antinuclear antibodies or other autoantibodies between the groups (211). The augmentation group experienced capsular contraction and more pain than the group undergoing reduction mammoplasty. Any association between implants and an increased incidence of breast cancer is unlikely (212). Breast cancer may develop in any patient with a silicone gel prosthesis.
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