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Management of Disorders of the Ductal System and Infections
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ROLE OF SURGERY
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Santen RJ, Mansel R. Benign breast disorders. N Engl J Med 2005;353: 275–285.
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Management of Disorders of the Ductal System and Infections
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ROLE OF SURGERY
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Breast disease during pregnancy and lactation can represent a clinical and diagnostic dilemma for the clinician due to the significant change to the breast parenchyma from hor- mone-related hypertrophy and increased vascularity. These changes affect the clinical breast examination as well as alter the efficacy of the currently available imaging modali- ties. Added to this is the need to balance concern for the mother with concern for the fetus. Breast cancer remains one of the most common types of cancer to be diagnosed during pregnancy or in the lactational period (1) (see Chapter 67); benign breast disease, however, is even more prevalent during this period. It is critical for the physician to remain as diligent in the evaluation of any breast abnor- mality in the pregnant or lactating patient as one would in any other woman. This chapter reviews the current state of the diagnosis and treatment of benign breast disease during pregnancy and lactation.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Clinical Breast Examination
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During the course of pregnancy, pregnancy-related hormones (estrogen, progesterone, and prolactin) cause breast tissue to undergo significant changes that lead to increased vol- ume and density (see Chapter 1). During the first trimester, the ratio of fatty tissue to glandular tissue decreases; as the volume of glandular tissue increases, so does the overall volume of the breast. As the pregnancy progresses, these changes intensify and make the evaluation of any breast abnormality more difficult. It is preferred, therefore, for the pregnant patient to have a baseline clinical breast exami- nation during the first trimester before these changes have occurred. As the number of women who become pregnant during their fourth decade increases, it is likely that more women will present already having had a baseline mammo- gram before becoming pregnant. A prior mammogram and any other imaging study obtained before pregnancy may help facilitate the evaluation of a new mass.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Clinical Breast Examination
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The pregnant patient who presents with a new mass or physical finding should be evaluated and followed very
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Clinical Breast Examination
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58
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Clinical Breast Examination
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closely. If observation is chosen after completion of the appropriate workup (described later in this chapter), a short interval follow-up examination is indicated because delay in examination may allow pregnancy-related changes (such as an increase in volume or nodularity) to obscure the physical finding. Because the pregnant patient does not undergo the cyclic hormonal changes that the non- pregnant patient experiences, persistence of a mass after a short interval warrants further attention (Fig. 7-1). Ultimately, it is the responsibility of the clinician who identifies a breast mass to rule out a pregnancy-associated breast cancer.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Diagnostic Imaging Issues in Pregnancy and Lactation
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When evaluating a pregnant patient, consideration must be given to minimizing exposure of ionizing radiation to the fetus. For this reason, ultrasonography is an ideal first option in the evaluation of a breast mass in this patient pop- ulation. Ultrasound is a reliable means of differentiating a fluid-filled structure (cyst) versus a solid mass. It can assess the margins and shape of a solid mass or identify shadow- ing, which may help differentiate a benign mass (e.g., lymph node or adenoma) from a malignancy. Ultrasound can eas- ily guide aspiration of a cyst or percutaneous biopsy of a suspicious mass. An important benefit of ultrasound is that it is less affected by pregnancy-related changes than is mammography. Ultrasound can have 100% sensitivity for identifying malignancy as seen in multiple studies, and high specificity rates are seen as well (Table 7-1). For these rea- sons, ultrasound is the optimal first imaging study employed for a pregnancy-related breast mass.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Diagnostic Imaging Issues in Pregnancy and Lactation
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The use of mammography in this patient population, on the other hand, remains controversial. There is concern over the potential for exposure of the fetus to ionizing radia- tion but, with proper abdominal shielding, exposure to the fetus is considered negligible (5). A second issue affecting the use of mammography, however, is the potential for low- ered sensitivity owing to the increased density of the preg- nant breast and the decrease in adipose tissue-to-breast parenchyma ratio (6), although this is not universally seen
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Diagnostic Imaging Issues in Pregnancy and Lactation
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FIGURE 7-1 Flow diagram for manage- ment of clinically suspicious breast masses during pregnancy.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Diagnostic Imaging Issues in Pregnancy and Lactation
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(3,7). Yang et al. (2) documented that a malignancy was visualized in 18 of 20 patients (90%) with breast cancer despite the breast density issue. The lactating patient can improve the quality of the mammographic study by emp- tying her breast either by nursing or pumping immediately prior to the study. In general, mammography should not be the primary imaging tool if there is a suspicious physical examination finding in a pregnant patient. If a patient has a suspicious discrete mass on examination that is not visible on ultrasound, tissue diagnosis with percutaneous biopsy can be performed. Mammography is more useful in the lac- tating patient or in the newly diagnosed pregnant patient to assess for calcifications or extent of disease.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Diagnostic Imaging Issues in Pregnancy and Lactation
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Magnetic resonance imaging (MRI) of the breast has been used increasingly in the evaluation and treatment of breast cancer. At this time, however, it has not been well studied in the pregnant patient. Pregnancy-associated changes alter the ratio of parenchyma to adipose tissue, causing increased flow and permeability (8). In addition, gadolinium (the contrast agent used in breast MRI) crosses the placenta and, therefore, is a pregnancy category C drug.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Diagnostic Imaging Issues in Pregnancy and Lactation
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It is advised to wait until after first trimester if breast MRI is judged to be absolutely necessary (9). Gadolinium uptake in lactating breast tissue can mimic malignancy, however, and result in a false-positive study result (8). MRI is cur- rently not indicated in the pregnant or lactating patient for these reasons.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Tissue Biopsy in the Pregnant and Lactating Patient
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Percutaneous biopsy has become the standard of care for tissue diagnosis of any breast mass or imaging abnormality in any patient. Surgical incisional or excisional biopsy for diagnosis necessitates an incision and there is a potential need to return for additional surgery if the biopsy reveals malignancy. Each operation contains risks to both the patient and the fetus that should be minimized if possible. Thus, the clinician must protect the fetus while ensuring appropriate treatment for the patient. A secondary benefit to percutaneous biopsy over surgery for diagnosis should be minimal disruption of the ductal structures of the breast
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Tissue Biopsy in the Pregnant and Lactating Patient
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to facilitate successful lactation. An in-depth discussion of the risks and benefits of biopsy needs to be held with the patient to allow for informed consent.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Tissue Biopsy in the Pregnant and Lactating Patient
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For many years, fine-needle aspiration biopsy (FNAB) was thought to be the best method of percutaneous tis- sue diagnosis. In the pregnant or lactating patient, the hormone-mediated hyperproliferation of ductal cells can, however, result in a false-positive diagnosis in the hands of an inexperienced cytopathologist (10). In addition, FNAB can miss the intended target, causing a false-negative result. Percutaneous core biopsy can be more accurate and will provide the cellular architecture needed for a more defini- tive diagnosis. Excisional biopsy should be undertaken only when there is a lack of concordance between clinical suspicion, imaging result, and percutaneous biopsy result (Fig. 7-1). If an excisional biopsy is intended in the pregnant patient, surgery should be carefully planned to minimize the risk to the fetus from anesthesia, including fetal monitoring if indicated. Local anesthesia alone is the preferred method in these cases.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Tissue Biopsy in the Pregnant and Lactating Patient
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Care must be taken in this patient population to mini- mize complications. Gestational or lactational breast tissue is hypervascular, and meticulous hemostasis is mandatory with any intervention to prevent hematoma formation. Breast milk provides a good culture medium for bacteria and, therefore, efforts must be made to minimize the risk of infection. To prevent milk stasis after a biopsy, the lactat- ing patient should either nurse or express milk regularly. If infection should develop, appropriate antibiotics should be administered.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Tissue Biopsy in the Pregnant and Lactating Patient
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The development of a milk fistula, a tract between a lactiferous duct and the skin, is a potential complication of any percutaneous or surgical intervention. The risk of milk fistula, whether from FNA, core biopsy, or excision, is not well documented, although case reports exist in the litera- ture. Some clinicians suggest breast binding as a means of facilitating cessation of milk leakage, but this is not likely to succeed. Bromocriptine, a dopamine agonist that decreases prolactin levels, can be used to treat a milk fistula, but it is not routinely recommended. Cessation of lactation will allow the fistula tract to heal, and remains the only reliable method to control a milk fistula (11). If possible, the patient should stop lactation 1 week before the biopsy to minimize this risk.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Inflammatory and Infectious Problems in Pregnancy
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Breast milk represents a lactose-rich culture medium and, thus, inflammatory or infectious problems remain the most common issues for the pregnant patient (12). Milk stasis, or poor emptying of milk from the breast, results from ineffec- tive suckling, restriction of frequency of feeds, or blockage of milk ducts (13). Poor infant attachment to the breast can lead to cracking of the nipple epithelium, which is thought to allow bacteria to enter the breast in a retrograde direc- tion via the terminal ducts, and it has been shown to be a risk factor for mastitis. Milk stasis provides a medium for bacterial growth and injury to the nipple, with subsequent bacterial translocation. This can then lead to a generalized infection (mastitis) with fever, redness, and tenderness, and it may also result in a breast abscess. Staphylococcus aureus is the most common organism (Table 7-2) and usually it can be treated with oral antibiotics (14). Other known risk factors for mastitis include advanced maternal
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Inflammatory and Infectious Problems in Pregnancy
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age, low parity, difficulty breast-feeding, or employment outside the home (15). It is most important to continue the expression of breast milk to allow for complete empty- ing of the breast and symptom relief. Education concern- ing proper emptying, positioning of the infant, and nipple hygiene should be a key component to prevent future epi- sodes of mastitis (13).
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Inflammatory and Infectious Problems in Pregnancy
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A breast abscess will not resolve with antibiotics alone, however, and further intervention is necessary. Ultrasound will help differentiate mastitis from a breast abscess. Repeated aspiration can be successful and it can avoid a disfiguring incision and drainage (16). Aspirate cultures should be taken to ensure appropriate antibiotic coverage. Skin and parenchymal biopsies should be considered to rule out inflammatory breast cancer if no improvement is seen. Despite concerns of the risk to the infant from bacterial con- tamination in the breast milk, the World Health Organization currently does not recommend cessation of breast-feeding in the presence of a breast abscess (13).
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Management of Breast Masses in Pregnancy and Lactation
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Most solid masses in the pregnant or lactating patient are benign lesions, such as fibroadenomas and hamartomas, and often predate the pregnancy. Any cause for a breast mass in the nonpregnant woman can also exist in pregnancy or the postpartum period.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Management of Breast Masses in Pregnancy and Lactation
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Lactating adenomas are the most common cause of breast masses in this patient population and may arise sec- ondary to hormones associated with pregnancy and lacta- tion and are thought to be related to tubular adenomas, fibroadenomas, or hyperplasia (17). Biopsy can determine if a mass is a true lactating adenoma or is caused by lacta- tional change in a preexisting fibroadenoma. Most of these lesions will involute once lactation has stopped, although excision may be required for those that do not. Hemorrhage or infarction will occur in 5% of lactating adenomas owing to vascular insufficiency seen occasionally in pregnancy- induced proliferative breast tissue (18).
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Management of Breast Masses in Pregnancy and Lactation
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Galactoceles are milk-filled cysts, which are thought to occur because of ductal obstruction during lactation. These usually present as tender masses; ultrasound can differenti- ate a galactocele from a solid mass. Asymptomatic patients can safely be observed. Local breast care, including ice packs and breast support, may help alleviate the discom- fort, although aspiration provides the greatest likelihood of symptom relief (12). Rarely, galactoceles can become infected, but they can be effectively treated with repeated aspiration or drain placement in addition to appropriate antibiotics (16).
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Management of Breast Masses in Pregnancy and Lactation
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MANAGEMENT SUMMARY
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Management of Breast Masses in Pregnancy and Lactation
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Localized breast infarction can occur in the pregnant or lactating breast and often results in a palpable mass that must be differentiated from breast cancer (19). Other benign breast lesions, such as fibroadenomas, lipomas, and papil- lomas, can occur in these patients and, overall, are just as likely to be the cause of a breast mass as pregnancy-related lesions (6,17,20) (Table 7-3).
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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The presence of bloody nipple discharge creates sig- nificant patient anxiety because of its association with breast cancer. In the nonpregnant patient, the evaluation of bloody nipple discharge has been well described (see Chapter 6). The workup in the pregnant or lactating patient remains controversial because of the issues with imaging as previously discussed. As in the nonpregnant population, most cases of bloody nipple discharge are of benign etiology.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Bloody nipple discharge can occur as a result of the epi- thelial proliferation and new capillary formation that occurs during the second and third trimesters (12). A careful clini- cal breast examination should be performed to identify if the discharge is from a single duct or multiple ducts as multiple-duct discharge is likely to be of physiologic etiol- ogy. The location of the draining duct should be carefully documented. The use of cytology is controversial due to low sensitivity rates that can be seen even in the nonpregnant, nonlactating patient (21). Cytology that shows benign ductal cells or is a “nondiagnostic evaluation” should not preclude further evaluation. If the examination does not reveal a pal- pable mass, retroareolar ultrasound can be undertaken. If retroareolar ultrasound is negative, imaging with mammog- raphy and ductography can be performed to identify the lesion location, which then should be biopsied. Terminal duct excision remains an option if all other diagnostic stud- ies are negative, but potential difficulty with postoperative lactation should be discussed with the patient as part of the informed consent.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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REFERENCES
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma during preg- nancy. International recommendations from an expert meeting. Cancer 2006;106:237–246.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Yang WT, Dryden MJ, Gwyn K, et al. Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology 2006;239: 52–60.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Robbins J, Jeffries D, Roubidoux M, et al. Accuracy of diagnostic mam- mography and breast ultrasound during pregnancy and lactation. AJR Am J Roentgenol 2011;196:716–722.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Ahn B, Kim HH, Moon WK, et al. Pregnancy- and lactation-associated breast cancer: mammographic and sonographic findings. J Ultrasound Med 2003;22:491–497.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Streffer C, Shore R, Kinermann G, et al. Biologic effects after prenatal irra- diation (embryo and fetus). A report of the International Commission on Radiological Protection. Ann ICRP 2003;33:205–206.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Son EJ, Oh KK, Kim EK. Pregnancy-associated breast disease: radiologic features and diagnostic dilemmas. Yonsei Med J 2006;47:34–42.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Swinford AE, Adler DD, Garver KA. Mammographic appearance of the breasts during pregnancy and lactation: false assumptions. Acad Radiol 1998;5:467–472.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Talele AC, Slantez PJ, Edminster WB, et al. The lactating breast: MRI find- ings and literature review. Breast J 2003;9:237–240.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Kanal E. Pregnancy and the safety of magnetic resonance imaging. Magn Reson Imaging Clin N Am 1994;2:309–317.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Finley JL, Silverman JF, Lannin DR. Fine-needle aspiration cytology of breast masses in pregnant and lactating women. Diagn Cytopathol 1989;5:255–260.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Schackmuth EM, Harlow CL, Norton LW. Milk fistula: a complication after core biopsy. AJR Am J Roentgenol 1993;161:961–962.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Scott-Conner CEH, Schorr SJ. The diagnosis and management of breast problems during pregnancy and lactation. Am J Surg 1995;170:401–405.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
World Health Organization. Mastitis: causes and management. Geneva, Switzerland: WHO/FCH/CAH/00.13; 2000.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
| null |
Niebyl J, Spence M, Parmely T. Sporadic (nonepidemic) puerperal masti- tis. J Reprod Med 1978;20:97–100.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Branch-Elliman W, Golen T, Gold H, et al. Risk factors for Staphylococcus aureus postpartum breast abscess. Clin Inf Dis 2012;54(1):71–77.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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O’Hara RJ, Dexter SPL, Fox JN. Conservative management of infective mas- titis and breast abscesses after ultrasonographic assessment. Br J Surg 1996;83:1413–1414.
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Slavin JC, Billson VR, Ostor AG. Nodular breast lesions during pregnancy and lactation. Histopathology 1993;22:481–485.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Baker TP, Lenert JT, Parker J, et al. Lactating adenoma: a diagnosis of exclusion. Breast J 2001;7:354–357.
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Lucy JJ. Spontaneous infarction of the breast. J Clin Pathol 1975;28:937–943.
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Management of Disorders of the Ductal System and Infections
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Collins JC, Liao S, Wile AG. Surgical management of breast masses in preg- nant women. J Reprod Med 1995;40:785–788.
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Simmons R, Adamovich T, Brennan M, et al. Nonsurgical evaluation of pathologic nipple discharge. Ann Surg Oncol 2003;10(2):113–116.
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CLINICAL PROBLEMS
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Bloody Nipple Discharge
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Benign proliferation of the glandular tissue of the male breast constitutes the histologic hallmark of gynecomastia, which, if sufficiently great, appears clinically as palpable or visual enlargement of the breast. This condition, which is exceedingly common, may (a) be a sign of a serious under- lying pathologic condition, (b) cause physical or emotional discomfort, or (c) be confused with other breast problems, most significantly carcinoma.
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PREVALENCE
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Breast glandular proliferation commonly occurs in infancy, during puberty, and in older age. It has been estimated that between 60% and 90% of infants exhibit the transient devel- opment of palpable breast tissue owing to estrogenic stimu- lation from the maternal–placental–fetal unit. This stimulus for breast growth ceases as the estrogens are cleared from the neonatal circulation, and the breast tissue gradually regresses over a 2- to 3-week period, but may persist longer. Although population studies have shown that the preva- lence of pubertal gynecomastia varies widely, most have indicated that 30% to 60% of pubertal boys exhibit gyne- comastia, which usually begins between 10 and 12 years of age, with the highest prevalence between 13 and 14 years of age (corresponding to Tanner stage III or IV of pubertal development), followed by involution that is usually com- plete by age 16 to 17 years (1). The percentage of men who exhibit gynecomastia increases with advancing age, with the highest prevalence found in the 50- to 80-year age range (Fig. 8-1). The prevalence of the condition in men ranges between 24% and 65%, with the differences between series being accounted for by the defining criteria and by the popu- lation studied (2).
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PATHOGENESIS
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No inherent differences appear to exist in the hormonal responsiveness of the male or female breast glandular tissue
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PATHOGENESIS
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(3). The hormonal milieu, the duration and intensity of stim- ulation, and the individual’s breast tissue sensitivity deter- mine the type and degree of glandular proliferation. Under
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PATHOGENESIS
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the influence of estrogens, the ducts elongate and branch, the ductal epithelium becomes hyperplastic, the periductal fibroblasts proliferate, and the vascularity increases. This histologic picture is found early in the course of gyneco- mastia and is often referred to as the florid stage. Acinar development is not seen in the male because it requires the presence of progesterone in concentrations found during the luteal phase of the menstrual cycle (3). Androgens exert an antiestrogen effect on rodent breast cancer models and the human MCF-7 breast cancer cell line; they are thought to antagonize at least some of the effects of estrogens in nor- mal breast tissue (4). Accordingly, gynecomastia is usually considered to represent an imbalance between the breast- stimulatory effects of estrogen and the inhibitory effects of androgens. In fact, alterations in the estrogen-to-androgen ratio have been found in many of the conditions associated with gynecomastia. Such alterations can occur through a variety of mechanisms (Table 8-1; Fig. 8-2).
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PATHOGENESIS
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In men, the testes secrete 95% of the testosterone, 15% of the estradiol, and less than 5% of the estrone produced daily. Most of the circulating estrogens are derived from the extraglandular conversion of estrogen precursors by extragonadal tissues, including the liver, skin, fat, muscle, bone, and kidney (Fig. 8-2). These tissues contain the aro- matase enzyme that converts testosterone to estradiol and androstenedione, an androgen primarily secreted by the adrenal glands, to estrone. Estradiol and estrone are inter- converted in extragonadal tissues through the activity of the 17-ketosteroid reductase enzyme. This enzyme is also responsible for the interconversion of testosterone and androstenedione. When androgens and estrogens enter the circulation, either through direct secretion from gonadal tis- sues or from the sites of extragonadal metabolism, most are bound to sex hormone-binding globulin (SHBG), a protein derived primarily from the liver and one that has a greater affinity for androgens than for estrogens. The non-SHBG sex hormones circulate either in the free or unbound state or are weakly bound to albumin. These fractions are able to cross the plasma membrane of target cells and are bound to ste- roid receptors. Testosterone and dihydrotestosterone bind to the same hormone-responsive element. Each also binds to the hormone-responsive element of the appropriate genes, resulting in the initiation of transcription and hormone
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63
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FIGURE 8-1 Prevalence of gynecomastia 90
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at various chronologic ages. Data were
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derived from multiple population studies. 80
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(Adapted from Braunstein GD. Pubertal 70
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gynecomastia. In: Lifshitz F, ed. Pediatric
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endocrinology. New York: Marcel Dekker, 60
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1996:197–205, with permission.)
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FIGURE 8-2 Pathways of estrogen and androgen production, action, and metabo- lism, and pathologic and physiologic changes that alter the pathways. (Adapted from Braunstein GD. Gynecomastia. N Engl J Med 2007;357:1229–1237, with permission.)
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Management of Disorders of the Ductal System and Infections
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PATHOGENESIS
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action. A similar sequence of events occurs after the binding of estradiol or estrone to the estrogen receptor (5).
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Management of Disorders of the Ductal System and Infections
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PATHOGENESIS
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From a pathophysiologic standpoint, an imbalance between estrogen and androgen concentrations or effects can occur as a result of abnormalities at several levels (Table 8-1; Fig. 8-2). Overproduction of estrogens from tes- ticular or adrenal neoplasms or enhanced extraglandular conversion of estrogen precursors to estrogens can ele- vate the total estrogen concentration. Such extraglandular conversion can occur directly in the breast tissue. Indeed, increased aromatization of androgens to estrogens has been noted in pubic skin fibroblasts from some patients with idio- pathic gynecomastia (6). Elevations of the absolute quantity of circulating free estrogens can occur if estrogen metabo- lism is slowed or if SHBG-bound estrogens are displaced from the protein. Conversely, decreased secretion of andro- gens from the testes—caused primarily by defects in the testes or secondary to loss of tonic stimulation by pituitary gonadotropins, enhanced metabolic degradation of andro- gens, or increased binding of androgens to SHBG—results in decreases in free androgens that could antagonize the effect of estrogens on the breast glandular tissue. As noted previ- ously, androgen and estrogen balance depends not only on the amount and availability of free androgens and estrogens but on their ability to act at the target tissue level. Thus, defects in the androgen receptor or displacement of andro- gens from their receptors by drugs with antiandrogenic effects (e.g., spironolactone) result in decreased androgen action and, hence, decreased estrogen antagonism at the breast glandular cell level. Finally, the inherent sensitivity of
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Management of Disorders of the Ductal System and Infections
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PATHOGENESIS
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an individual’s breast tissue to estrogen or androgen action may predispose some persons to development of gyneco- mastia even in the presence of apparently normal concentra- tions of estrogens and androgens.
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Management of Disorders of the Ductal System and Infections
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ASSOCIATED CONDITIONS
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Tables 8-1 and 8-2 list the various conditions and drugs that have been associated with gynecomastia. Although the list is relatively long, almost two-thirds of the patients have either pubertal gynecomastia (approximately 25%), drug-induced gynecomastia (10% to 20%), or no underlying abnormality detected (idiopathic gynecomastia, approxi- mately 25%). Most of the remainder have cirrhosis or malnutrition (8%), primary hypogonadism (8%), testicular
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Management of Disorders of the Ductal System and Infections
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ASSOCIATED CONDITIONS
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tumors (3%), secondary hypogonadism (2%), hyperthyroid- ism (1.5%), or renal disease (1%) (2). For most pathologic conditions, alterations in the balance between estrogen and androgen levels or action occur through several of the pathophysiologic mechanisms outlined in Table 8-1 and Figure 8-2. One of the best examples is the gynecomastia associated with spironolactone. This aldosterone antago- nist inhibits the testicular biosynthesis of testosterone, enhances the conversion of testosterone to the less potent androgen androstenedione, increases the aromatization of testosterone to estradiol, displaces testosterone from SHBG (leading to an increase in its metabolic clearance rate), and binds to the androgen receptors in target tissues, thereby acting as an antiandrogen (7). For an in-depth discussion of
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Management of Disorders of the Ductal System and Infections
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ASSOCIATED CONDITIONS
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the pathophysiology of gynecomastia associated with each of the conditions listed in Tables 8-1 and 8-2, the reader is referred to several reviews (2,3,5,7–15).
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Most patients with gynecomastia are asymptomatic, with the condition detected during a physical examination. Patients with recent onset of gynecomastia owing to drugs or one of the pathologic conditions noted in Tables 8-1 and 8-2, however, may present with breast or nipple pain and tenderness. Approximately 10% to 15% of patients recall a history of breast trauma just before or at the time of dis- covery of the breast enlargement (15). It is unclear whether breast trauma itself causes gynecomastia. It is likely that, in many patients with an antecedent history of trauma, the breast irritation from the trauma actually led to the discov- ery of preexisting gynecomastia. Although half of patients have clinically apparent bilateral gynecomastia, histologic studies have shown that virtually all patients have bilateral involvement (16). This discrepancy may be explained by asynchronous growth of the two breasts and differences in the amount of breast glandular and stromal proliferation.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Gynecomastia must be differentiated from other con- ditions that cause breast enlargement. Although neu- rofibromas, dermoid cysts, lipomas, hematomas, and lymphangiomas may enlarge portions of the breast, these abnormalities are usually easily distinguished from gyneco- mastia on historical or clinical grounds. The two conditions that are most important to differentiate are pseudogyneco- mastia and breast carcinoma. Pseudogynecomastia refers to enlargement of the breasts owing to fat deposition rather than to glandular proliferation. Patients with this condition often have generalized obesity and do not com- plain of breast pain or tenderness. In addition, the breast examination should allow the correct diagnosis (Fig. 8-3).
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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The breasts are examined while the patient is lying on the back with hands behind the head. The examiner places a thumb on one side of the breast and the second finger on the other side. The fingers are then gradually brought together without more than superficial pressure being applied to the skin. Patients with gynecomastia have a rub- bery or firm disc of tissue that extends concentrically out from the nipple and that either is easily palpated or offers some resistance to the apposition of the fingers, whereas those with pseudogynecomastia exhibit no such mound of tissue, and no resistance is felt as the fingers are brought together (10). Alternatively, flat palpation with the finger can be used to detect the glandular tissue.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Differentiation of gynecomastia from breast carcinoma usually can be accomplished through careful physical exam- ination. Carcinoma of the breast in men is usually eccentric in location and unilateral (rather than subareolar and bilat- eral) and is hard or firm, whereas gynecomastia tends to be rubbery to firm in texture. Patients with carcinoma may also exhibit skin dimpling and nipple retraction; they are more likely to have a nipple discharge (10%) than are patients with gynecomastia and may present with axillary lymphadenopa- thy (15,17). If the two conditions cannot be differentiated on clinical grounds, then mammography, fine-needle aspira- tion (FNA) for cytologic examination, or core or open biopsy should be done. There is no increased risk of breast cancer in men with gynecomastia followed for 20 or more years (18). Although some epidemiological studies have failed to find an association between Klinefelter’s syndrome and breast can- cer, the largest study found a 19.2-fold increased incidence compared to the general male population (19).
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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After a clinical diagnosis of gynecomastia has been made, several causes should be investigated through a thorough history and physical examination. A careful history of medi- cation use is essential, specifically regarding ingestion of the drugs listed in Table 8-2. A history of liver or renal disease, especially if the patient has been receiving hemodialysis for
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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FIGURE 8-3 Differentiation of gynecomastia from pseudogynecomastia and other disorders by physical examination. (From Braunstein GD. Gynecomastia. N Engl J Med 2007;357:1229–1237, with permission.)
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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Measure Serum hCG, LH, T, E2
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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FIGURE 8-4 Algorithm providing interpretation of serum hormone levels and recommen- dations for further evaluation of patients with gynecomastia. CT, computed tomography; E2, estradiol; hCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic reso- nance imaging; NI, normal; T, testosterone; T4, thyroxine; TSH, thyroid-stimulating hormone. (From Braunstein GD. Gynecomastia. N Engl J Med 1993;328:490–495, with permission.)
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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the latter, may point to the underlying cause. A history of weight loss, tachycardia, tremulousness, diaphoresis, heat intolerance, and hyperdefecation, with or without the pres- ence of a goiter, raises the possibility of hyperthyroidism. The patient should be evaluated for the signs and symptoms of hypogonadism, including loss of libido, impotence, decreased strength, and testicular atrophy. A careful examination for abdominal masses, which may be present in nearly one-half the patients with adrenocortical carcinoma, and a meticulous examination for testicular masses are essential parts of the evaluation.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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The next step depends on the results of the clinical evalua- tion. If any of the drugs listed in Table 8-2 have been ingested, they should be discontinued and the patient reexamined in 1 month. If the drug was the inciting agent, then a decrease in breast pain and tenderness should occur during that time. If the patient is of pubertal age and has an otherwise negative general physical and testicular examination, he probably has transient or persistent pubertal gynecomastia. Reexamination at 3-month intervals should determine whether the condition is transient or persistent. At this time, medical or surgical therapy should be considered. If, during routine clinical exam- ination, an adult is found to have asymptomatic gynecomas- tia without the presence of underlying disease, biochemical assessments of liver, kidney, thyroid function, and testoster- one should be performed. In a patient with normal results, no further tests are necessary, but he should be reevaluated in 6 months. Conversely, if the gynecomastia is of recent onset or if the patient complains of pain or tenderness, additional studies—including measurements of serum concentrations of human chorionic gonadotropin (hCG), estradiol, testoster- one, and luteinizing hormone—should be done, although the diagnostic yield is often low (20).
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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The algorithm outlined in Figure 8-4 can be used to discern the underlying abnormality, if any, that is respon- sible for the breast enlargement (6). An elevated level of hCG in the serum indicates the presence of a testicular or nongonadal germ cell tumor or, rarely, a nontrophoblastic neoplasm that secretes the hormone ectopically. Testicular ultrasonography should be done, and, if no testicular mass is found, a chest radiograph and abdominal computed tomo- graphic scan or magnetic resonance imaging (MRI) study should be performed in an effort to localize an extragonadal hCG–producing tumor. Most nontrophoblastic tumors that secrete the hormone are bronchogenic, gastric, renal cell, or hepatic carcinomas. An elevated serum concentration of luteinizing hormone associated with a low testosterone level is indicative of primary hypogonadism, whereas a low testosterone level and a low or normal luteinizing hormone level suggest secondary hypogonadism owing to a hypo- thalamic or pituitary abnormality. Serum prolactin concen- tration should be determined in this situation to rule out a prolactin-secreting pituitary adenoma, which can cause hypogonadotropic hypogonadism. Elevated serum concen- trations of luteinizing hormone and testosterone are found with hyperthyroidism and in patients with various forms of androgen resistance caused by androgen receptor disor- ders. Thyroid function tests can distinguish between these conditions.
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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If an elevated serum estradiol level is found along with
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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a normal or suppressed concentration of luteinizing hor- mone, testicular ultrasonography is indicated to rule out a Leydig cell, Sertoli cell, or sex cord testicular tumor. If the ultrasonogram is negative, a computed tomographic scan or MRI scan of the adrenal glands should be done to detect an estrogen-secreting adrenal neoplasm. If both the testes and
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Management of Disorders of the Ductal System and Infections
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EVALUATION
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adrenal glands appear normal, the increased estradiol level is probably caused by enhanced extraglandular aromatiza- tion of estrogen precursors to estrogens. In this situation, estrone levels are often relatively higher than estradiol con- centrations. Finally, if all of these endocrine measurements are normal, the patient is considered to have idiopathic gynecomastia.
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Management of Disorders of the Ductal System and Infections
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PREVENTION
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Two situations exist in which gynecomastia can be pre- vented. The first is in patients who require a medication. Avoidance of the drugs listed in Table 8-2 decreases the risk for drug-induced breast stimulation. Also, not all the thera- peutic agents in the drug groups listed in the table cause
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Management of Disorders of the Ductal System and Infections
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PREVENTION
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gynecomastia to the same extent. For example, when consid- ering the use of a calcium channel blocker in an older man, the clinician should remember that nifedipine has been associated with the highest frequency of gynecomastia, fol- lowed by verapamil, with diltiazem having the lowest asso- ciation (7,14). Among the mineralocorticoid antagonists, spironolactone, but not eplerenone is strongly associated with gynecomastia (14,21). Similarly, the incidence of gyne- comastia in patients receiving histamine receptor or pari- etal cell proton pump blockers is highest with cimetidine, then ranitidine, and least with omeprazole (7,14). The sec- ond area of prevention occurs among patients with prostate cancer who are about to receive monotherapy with antian- drogens. Numerous studies have shown that prophylactic administration of the antiestrogen tamoxifen is superior to either the aromatase inhibitor anastrozole or low-dose breast irradiation (22,23).
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Management of Disorders of the Ductal System and Infections
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TREATMENT
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Discontinuation of the offending drug or correction of the underlying condition that altered the estrogen–androgen balance results in regression of gynecomastia in recent- onset breast growth. As was noted, histologic studies of the breast tissue from men with gynecomastia have shown a marked duct epithelial cell proliferation, inflammatory cell infiltration, increase in stromal fibroblasts, and enhanced vascularity early in the course of the disorder. It is during this proliferative, or florid, stage that patients may com- plain of breast pain and tenderness. This stage persists for a variable period, but usually lasts less than a year and is followed by spontaneous resolution or enters an inactive stage. There is a reduction in the epithelial proliferation, dilatation of the ducts, and hyalinization and fibrosis of the stroma (16,24). The inactive stage is usually asymptomatic. This histologic picture predominates in men whose gyneco- mastia is detected during a routine physical examination. When considering therapeutic approaches, it is important to appreciate that, after the inactive stage is reached, the gyne- comastia is unlikely spontaneously to regress and is also unlikely to respond to medical therapies. Another impor- tant factor to consider is that most gynecomastia regresses spontaneously. Indeed, pubertal gynecomastia develops in a large proportion of boys, but very few exhibit persis- tent breast glandular enlargement. Similarly, in a group of patients with gynecomastia from various causes, 85% of untreated patients had spontaneous improvement (15). This finding emphasizes the difficulties in assessing the response to any medical intervention.
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Management of Disorders of the Ductal System and Infections
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TREATMENT
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The indications for therapy are severe pain, tenderness,
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Management of Disorders of the Ductal System and Infections
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TREATMENT
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or embarrassment sufficient to interfere with the patient’s normal daily activities. The objectives of surgery are to flat- ten the chest, eliminate the inframammary fold, align the two nipple-areola complexes, and conceal or contain the scars (25). Surgical removal of the breast glandular and stro- mal tissue has been the mainstay of interventional therapy. Subcutaneous mastectomy through a periareolar incision with contouring of the breast by suction-assisted lipectomy and ultrasound-assisted liposuction to remove the subglan- dular adipose tissue are currently the surgical procedure that are usually performed (25). These techniques should be used as primary therapy in patients with long-standing gynecomastia and as definitive therapy in patients who fail to respond to a series of medical therapies.
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Management of Disorders of the Ductal System and Infections
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TREATMENT
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Three types of medical therapy—androgens, anties- trogens, and aromatase inhibitors—have been tested in patients with gynecomastia. Because this condition has a
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Management of Disorders of the Ductal System and Infections
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TREATMENT
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high frequency of spontaneous regression, the decision of when to treat is often difficult. It is also difficult to assess the use of most medications that have been tried, given the small sample sizes and nonblinded, uncontrolled designs of most studies. Nevertheless, with the exception of early pubertal gynecomastia that has been present for less than 3 months, a trial of medical therapy for patients with moder- ate to severe symptoms is recommended (26).
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