Breast diseases: Detection, Management, and Surveillance of Breast Disease





Key points





  • The breast consists of approximately 20% glandular tissue and 80% fat and connective tissue; increasing proportions of fibroglandular to fatty tissues are the mark of denser breasts. Breast density is associated with increased risks of malignancy.



  • Lymph drainage of the breast usually flows toward the most adjacent group of nodes. This concept represents the basis for sentinel node mapping in breast cancer. In most instances, breast cancer spreads in an orderly fashion within the axillary lymph node basin based on the anatomic relationship between the primary tumor and its associated regional (sentinel) nodes.



  • The breast undergoes normal maturational changes throughout a woman’s lifetime. The normal maturation involves a gradual increase in fibrous tissue around the lobules; with time the glandular elements are completely replaced by fibrous tissue.



  • The incidence of benign breast disorders begins to rise during the second decade of life and peaks in the fourth and fifth decades. In malignant diseases the incidence continues to increase after menopause.



  • Fibroadenomas are the most common benign breast neoplasm and are most often present in adolescents and women in their 20s.



  • Approximately 35% of fibroadenomas will disappear, and 10% will become smaller after many years.



  • More than two-thirds of women will experience breast pain at some time during their reproductive years, most commonly in the perimenopausal years. Approximately 90% of conditions that cause breast pain are benign.



  • Cyclic bilateral breast pain is the classic symptom of fibrocystic breast change. The signs of fibrocystic changes include increased engorgement and density of the breasts, excessive nodularity, rapid change and fluctuation in the size of cystic areas, increased tenderness, and, occasionally, spontaneous nipple discharge.



  • The majority of nipple discharge complaints have a benign cause; however, 55% present with a coexisting mass, of which 19% are malignant. An underlying malignancy is more likely when the discharge is spontaneous (vs. induced with nipple pressure), arises from a single duct, is blood stained, and is unilateral and persistent (occurring more than twice weekly).



  • Intraductal papilloma and fibrocystic changes are the two most common causes of spontaneous nonmilky nipple discharge.



  • Lactational mastitis commonly occurs in the first pregnancy during the first 6 weeks of breastfeeding. Continued breastfeeding or manual pumping of the affected breast is recommended to decrease engorgement.



  • One out of eight women (12.5%) in the United States will develop carcinoma of the breast over the course of her lifetime.



  • Approximately 50% of newly diagnosed breast cancers are attributable to known risk, whereas 10% are associated with a positive family history.



  • Approximately 5% to 10% of breast cancers have a familial or genetic link. A genetic predisposition to develop breast carcinoma has been recognized in some families. In these families, breast cancer tends to occur at a younger age, and there is a higher prevalence of bilateral disease.



  • Mutations in the BRCA family of genes have been identified that confer a lifetime risk of breast cancer that approaches 85%. BRCA1 and BRCA2 genes are involved in the majority of inheritable cases of breast cancer. These genes function as tumor suppressor genes, and several mutations have been described on each of these genes.



  • Once a woman has developed carcinoma of one breast, her risk is approximately 1% per year of developing cancer in the other breast.



  • Both tamoxifen and raloxifene significantly decrease the relative risk of developing breast carcinoma. Aromatase inhibitors are a reasonable alternative to SERMs for postmenopausal women.



  • Screening mammography is the primary imaging technique for breast cancer detection. The sensitivity of mammography ranges from 80% to 90% and decreases in women with dense breasts.



  • The incidence of carcinoma in biopsy specimens corresponds directly with the patient’s age. Approximately 20% of breast biopsy results in women age 50 are positive, and this figure increases to 33% in women age 70 or older.



  • Breast cancer is usually asymptomatic before the development of advanced disease. Breast pain is experienced by only 10% of women with early breast carcinoma. The classic sign of a breast carcinoma is a solitary, solid, three-dimensional, dominant breast mass. The borders of the mass are usually indistinct.



  • Microscopic metastatic disease occurs early via both hematogenous and lymphatic routes. For example, 30% to 40% of women without gross adenopathy in the axilla will have positive nodes discovered during histologic examination. With the additional assessment tools of immunohistochemical staining for the presence of cytokeratin and serial sectioning of axillary nodes, 10% to 30% of patients considered to have negative nodes by standard histologic analysis are found to be node positive.



  • The initial size of the breast carcinoma is the single best predictor of the likelihood of positive axillary nodes. The presence and number of axillary node metastases are the best predictors of survival.



  • Carcinomas make up the majority of breast malignancies and originate in the epithelium of the collecting ducts (ductal) or the terminal lobular ducts (lobular). Invasive ductal carcinoma is the most common, constituting approximately 70% to 80% of malignancies.



  • A multidisciplinary team approach is necessary in the treatment of breast cancer. Determination of local or systemic treatment is based on several prognostic and predictive factors, including tumor histologic characteristics, tumor hormone receptor status (estrogen/progesterone), tumor HER2 status, multigene testing, axillary lymph node status, evaluation of metastatic disease, patient age, comorbidities, and menopausal status.



  • The primary therapy for the majority of women with stages I and II breast cancer is conservative surgery, which preserves the breast, followed by radiation therapy.



  • Gynecologists should actively address the psychosexual problems that breast cancer causes in women early in the evaluation of the disease and for several years.



The gynecologist’s role in managing breast problems is broad because they often serve as a woman’s primary health care advocate. Historically, gynecologists have played a leadership role in the modern development of women’s breast cancer care. In 1913 they were instrumental in the organization of the American Cancer Society (initially known as the American Society for the Control of Cancer), and in 1976 they assumed a major role in the organization of the American Society of Breast Disease. Strategically, gynecologists, commonly acting as primary health care advocates, continue to maintain a vital and advantageous role in the diagnosis and management of benign, premalignant, and malignant breast disease. In fact, the prevalence and significant psychological and psychosocial effect of breast disease necessitate that a comprehensive plan for the diagnosis and management of breast disease becomes a critical component of high-quality women’s health care. This chapter intends to present a clinically oriented approach to improve the understanding of breast anatomy, the important diagnostic and therapeutic aspects of benign breast disease, and the epidemiology, detection, and management of breast cancer.


In the United States 7.8% of office visits by women (>51 million/year) related to breast disease. Breast pain is a common and chronic symptom in women, with a prevalence of 52% in the general population, and adversely affects the quality of life in more than 40% of women ( ). Additionally, breast cancer accounts for 30% of all new cancer diagnoses in women, is the second most common cause of cancer- related death in women, and is the leading cause of premature mortality from cancer in U.S. women (as measured by total years of life lost).


The role of the gynecologist in the management of breast disease has been addressed in a number of published clinical opinions and practice bulletins from the American College of Obstetrics and Gynecology. The role of the gynecologist, with shared decision making, includes the following:




  • Compiling a comprehensive personal and family history in an effort to identify risk factors and institute care accordingly



  • Performing clinical breast examinations when deemed appropriate in average risk individuals and in those at high risk or with breast symptoms.



  • Promoting breast self-awareness and offering instructions for breast self-evaluation as indicated or desired



  • Distinguishing between benign and malignant disease and offering successful therapy for benign disease.



  • Discussing the risks and benefits of screening mammography and encouraging compliance with guidelines



  • Performing diagnostic procedures or referral to those who specialize in breast disease when clinically indicated (i.e., when a palpable mass has been detected)



Despite the fact that 50% of cases of breast cancer in women 50 years and older and 71% of cases of breast cancer in women younger than 50 years are detected by women themselves (ACOG Practice Bulletin Number 179, 2015), most guidelines have questioned the benefit of breast self-examination. Thus the term breast self-awareness has been coined to imply the potential benefit of women being aware of their breasts and looking for abnormalities or changes, without mention of frequency or proper technique. Additionally, these guidelines indicate that there is insufficient evidence to assess the additional benefit of clinical breast examination (CBE) beyond screening mammography in women aged 40 years or older ( ). However, the American College of Obstetrics and Gynecology and the National Comprehensive Cancer Network suggest that CBE be offered or performed at 1- to 3-year intervals in patients aged 25 to 39 years and annually after 40 (ACOG Practice Bulletin 179, 2015).


Anatomy/embryology


Breast (mammary gland) development begins from the integument along the epithelial mammary ridges during the sixth gestational week in utero. Ducts and acini are derived from ectoderm, whereas supporting tissue arises from mesenchyme. Embryologic development requires a series of orderly events regulated by systemic and local hormones and growth factors. Before puberty, male and female mammary glands are identical. Ductal tissue and secretory lobule development occurs under the influence of the hormonal changes that occur during puberty (see Chapter 38 ). Actual milk production is initiated by hormonal changes that occur during and after pregnancy.


The breasts are large, structurally dynamic, modified apocrine/sweat glands located on the superficial fascia anterior to the deep pectoralis major fascia of the chest wall. Posteriorly the retromammary space, a loose connective tissue plane, allows free movement over the chest wall (i.e., the breast is not firmly attached to the deep fascia). Breast tissue is suspended from the clavicle and deep clavipectoral fascia by the suspensory ligaments of Cooper that weave through the breast tissue and attach to the dermis of the skin ( Fig. 15.1 ). These fibrous septa maintain the natural shape of the breast. Clinically, malignant involvement (particularly locally advanced disease) of these ligaments often produces skin retraction.




Fig. 15.1


Lactating breast.

(From Shah P, ed. Breast. In: Standring S, ed. Gray’s Anatomy. London: Churchill Livingstone; 2005:969.)


Breast size and shape depend on genetic, racial, and dietary factors as well as age, parity, and menopausal status. The “average” adult breast during reproductive years weighs approximately 250 g. Typically a superolateral projection of glandular tissue (the axillary tail of Spence) pierces the deep fascia and extends toward the axilla. Glandular tissue comprises approximately 20% of the mature breast, with the remainder composed of adipose and connective tissue. The major determinant of breast size is adipose tissue volume. The periphery of the breast is predominantly adipose, and glandular tissue comprises a higher proportion of the central breast ( Fig. 15.2 ). Typically, glandular tissue regresses and is replaced by adipose tissue after menopause.




Fig. 15.2


The structures of the breast.

(From Shah P, ed. Breast. In: Standring S, ed. Gray’s Anatomy. London: Churchill Livingstone; 2005:969.)


Breast density refers to the proportion of fibrous or glandular tissue to adipose tissue. Breast density is only determined mammographically, because dense breasts are not clinically characterized by a certain size or shape, and they may or may not be palpably firm. The percentage of breast density on a mammogram correlates with breast cancer risk. Importantly, when comparing the lowest density category with highest, the relative risk is increased more than fivefold.


A breast is composed of 10 to 20 variably sized, triangular-shaped lobes distributed radially from the nipple. Each lobe contains its own duct system draining the 10 to 100 lobules with alveoli (acini). These functional lobules include epithelial (ductal) and stromal components and are affected by hormonal changes (estrogen, progesterone, and prolactin) resulting in development, maturation, and differentiation ( Fig. 15.3 ). The organization of the ductal system is stimulated at puberty. Secretory cells drain into alveoli, which drain into “terminal” ducts that coalesce into larger collecting ducts and join with ducts from other lobules to end in lactiferous ducts, terminating at the excretory ducts of the nipple.




Fig. 15.3


Histologic photograph of a mammary lobule. Note the ductal tissue surrounded by fibrous tissue. Terminal ductules (TD) surround the central ductule (ID). EF, Extralobular fibrocollagenous tissue.

(From Stevens A, Lowe J. Human Histology. 3rd ed. Philadelphia: Mosby; 2005:390.)


Approximately 5 to 20 areolar (Montgomery) glands produce an oily secretion functioning to keep the nipple supple and protected, which is particularly important during breastfeeding. They also produce a volatile compound that has been implicated in stimulating infants’ appetite through olfactory pathways ( ). These generally sensitive glands are located in the areola and nipple. Infection, blockage, or irritation can result in significant clinical symptoms or problems.


The principal blood supply of the breast is derived from the perforating branches of the internal mammary arteries that originate from the internal thoracic artery. Additional sources include the lateral thoracic and thoracoacromial arteries, which originate from the axillary artery, and the posterior third, fourth, and fifth intercostal arteries, which are branches of the thoracic aorta. The inferior and central portions of the breast are less vascular.


Breast lymphatics converge in the subareolar plexus of Sappy . Approximately 75% of the lymphatics, particularly from the outer quadrants, drain to the 30 to 60 ipsilateral axillary regional nodes. The axillary nodes are classified by three anatomic levels defined by their relationship to the pectoralis minor muscle. Level I nodes are located lateral to the lateral border of the pectoralis minor muscle. Level II nodes are located posterior to the pectoralis minor muscle. Level III nodes include the infraclavicular nodes medial to the pectoralis minor muscle. The remaining lymphatics drain to the internal mammary or parasternal nodes, which have direct drainage to the mediastinum, the medial quadrants of the opposite breast, or the inferior phrenic nodes. The latter is important because it provides a route for metastatic disease to the liver, ovaries, and peritoneum ( Fig. 15.4 ). Lymphatic fluid usually flows toward the most adjacent group of nodes, forming the foundation for using sentinel node mapping to evaluate for nodal spread in breast cancer. In most instances, breast cancer spreads in an orderly fashion within the axillary lymph node basin based on the anatomic relationship between the primary tumor and its associated regional (sentinel) nodes. However, lymphatic metastases from one specific area of the breast may be found in any or all of the groups of regional nodes.




Fig. 15.4


Lymph vessels of the breast and axillary lymph nodes.

(From Shah P, ed. Breast. In: Standring S, ed. Gray’s Anatomy. London: Churchill Livingstone; 2005:971.)


Breast ductal epithelium is extremely sensitive to cyclic hormonal changes. Parenchymal proliferation of the ducts is seen during the follicular phase, and there is dilation of the ductal system and differentiation of the alveolar cells into secretory cells during the luteal phase. Alveolar elements respond to both estrogen and progesterone. The stroma and myoepithelial cells also respond to estrogen and progesterone. Women often experience cyclic breast fullness and tenderness likely related to the 25 to 30 mL average volume fluctuation of the premenstrual breasts. Additionally, premenstrual breast symptoms are produced by an increase in blood flow, leading to vascular engorgement, and water retention. A parallel enlargement of the ductal lumen and an increase in ductal and acinar cellular secretory activity also occur. Menstruation brings a regression of cellular activity in the alveoli, and the ducts become smaller. These changes are clinically reflected by the cyclic changes noted on breast examination.


The breast undergoes normal maturational changes. In addition to the pubertal and pregnancy-induced changes in the lactiferous duct lobule, the fibrous and adipose components also evolve. Normal maturation involves a gradual increase in fibrous tissue around the lobules, and with time the glandular elements are completely replaced by fibrous tissue. Women in their 20s and 30s have a gradual increase in nodularity as the lobular tissue increases with repetitive cyclic hormonal stimulation. Compared with the prepregnancy or postpregnancy state and lactation, breasts may decrease in size and shape. Thus breast examination often yields different findings in the 20-year-old and the 40-year-old, as well as in women experiencing perimenopause and postmenopause. These changes underscore the value of breast self-awareness because each woman should personally know those changes in her breast at different times in her cycle and life ( Fig. 15.5 ).




Fig. 15.5


A, Micrograph showing normal breast tissue from a 23-year-old woman. At the center is a breast lobule in which the system of terminal ducts and ductules is embedded in loose intralobular fibrocollagenous stroma (F). There is a narrow surrounding zone of dense extralobular fibrocollagenous support tissue (DF), outside of which is the soft adipose tissue (A) that forms the bulk of the breast. B, Micrograph showing normal breast tissue from a 43-year-old woman. As women age, the amount of fibrocollagenous tissue (F) in the breast increases, replacing some of the adipose tissue. The mammary lobules become enclosed in dense collagen.

(From Stevens A, Lowe J. Human Histology. 3rd ed. Philadelphia: Mosby; 2005:393.)


Congenital developmental breast abnormalities


Nipple


Accessory nipples may occur along the breast or milk lines running from the axilla to the groin. Polythelia (supernumerary or accessory nipples) occurs in less than 1% (white European descent) to 2.5% (Jewish population) of women. They most commonly present in the inframammary region (90%), may be unilateral or bilateral, and occur in equal frequency in men and women. Development may be partial or complete, and the condition is both sporadic and familial. Obstructive or duplicative urologic anomalies may be present as well, and an increased risk of renal cancer has been reported. When present, accessory nipples have the same risk for disease as normal nipples. Treatment is generally restricted to managing irritation or improving cosmesis when necessary.


Congenital nipple inversion occurs in 2% of women, typically in those with a family history of the same condition. The cause is related to shortening and tethering of breast ducts or the development of fibrous bands during intrauterine life. Although nipple inversion may increase mechanical problems with breastfeeding, surgical correction often leads to loss of sensation and inability to breastfeed.


Athelia, complete unilateral or bilateral absence of nipple and areola, can be familial (autosomal dominant) and is associated with amastia (absent nipple, areola, and breast tissue) or other rare syndromes (e.g., Poland syndrome). Associated ectodermal abnormalities (such as absence of the pectoral muscles) should be excluded. Treatment includes nipple and areola reconstruction commonly using tissue flaps and tattooing.


Breast tissue


Aplasia is diagnosed when the nipple and areola are present but glandular tissue is absent. Amastia, complete absence of both breast tissue and the nipple-areola complex, occurs with regression or failure to develop the mammary ridge. It is often associated with other ectodermal defects, including cleft palate.


Polymastia , accessory breast tissue or supernumerary breasts, occurs in approximately 1% to 2% of the general population, with a female preponderance. Accessory breast tissue most commonly presents in the axilla, and multiple site occurrence is not uncommon (~33%). The initial diagnosis is often at puberty or during pregnancy, when the accessory breast tissue development and stimulation parallel that of normal breast tissue. Supernumerary breast tissue, be it rudimentary or fully developed, is customarily asymptomatic; however, it can cause discomfort and may be considered cosmetically unacceptable. Importantly, supernumerary breast tissue is subject to normal changes and is susceptible to the entire disease spectrum that occurs in the normal breast. Conservative management is encouraged because surgery can be associated with unattractive scars, restriction of movement, pain, and other complications. Liposuction may useful to decrease the fatty element of accessory breasts.


Asymmetric breast development, common in adolescence and in maturity, represents a benign, normal variation unless an associated palpable abnormality is present. In the extreme a breast can be hypoplastic or absent (aplasia), which can occur in isolation or in association with a defect in (one or both) pectoral muscles. Significant asymmetry can be deeply disturbing and may affect a teenager’s self-image. Full breast development usually occurs by age 18 to 21 years, and if deemed necessary, corrective augmentative or reduction surgery should be timed accordingly.


Breast hypertrophy may be related to excessive development of glandular tissue during puberty, weight gain, or naturally occurring fat deposition of breast tissue associated with aging. It may be asymmetric and is separated into pubertal (virginal hypertrophy), gestational (gravid macromastia), and adult types. Medical treatment is typically not successful, and reduction mammoplasty is not indicated until a significant volume of breast tissue requires removal to relieve associated symptoms such as headache, neck or back pain, upper extremity paresthesia, brassiere strap grooving, or intertrigo. The best surgical outcome can be expected when the planned procedure occurs after 6 to 12 months of breast size stabilization.


Tubular breasts or tuberous breast deformity is associated with a constriction in the lower pole of the breast. This unilateral or bilateral congenital breast abnormality occurs in both sexes. During puberty, breast development is stymied and the breasts fail to develop normally and fully. The transverse breast diameter is narrowed and the base constricted related to glandular hypoplasia with a deficiency in the circumferential skin envelope of the breast base. The breast appears to herniate into an oversized and protuberant areola. The exact cause of this condition is as yet unclear; however, a genetic link to a disorder of collagen deposition is suspected. Corrective procedures can be divided into operations that involve augmentation, mastopexy, combined augmentation/mastopexy, lipomodeling, and tissue expansion followed by augmentation ( ).


Benign breast disorders


Benign breast disorders (BBDs) and their wide range of symptoms represent the majority (~90%) of breast-related complaints and abnormalities evaluated in an obstetrician/gynecologist’s office. This heterogeneous group of lesions or abnormalities may be incidental or may be detected clinically or radiographically.


BBDs are often misdiagnosed and misunderstood secondary to their varied spectrum at presentation and associated anxiety concerning the possibility and fear of malignancy. Understanding the causes and management of BBD is essential to provide proper clinical management and to psychologically allay patients’ and families’ fears. Various terminology has been used to describe BBD. Most emphasize clinical signs, symptoms, or histologic findings. BBDs can be classified as follows:



  • 1.

    Aberrations of normal development and involution (ANDI)


  • 2.

    Pathologic classification


  • 3.

    Clinical classification


  • 4.

    Classification based on the risk for malignancy



The ANDI classification incorporates symptoms, signs, histology, physiology, pathogenesis, and degree of breast abnormality, classified in relation to the normal processes of reproductive life and involution through a spectrum of breast conditions that range from “normal” to “disorder” to “disease” ( ). Thus ANDI classification suggests that BBDs are a result of minor aberrations in the normal development process, hormonal response, and involution of the breast (see Table 15.1 ).



TABLE 15.1

ANDI Classification of Benign Breast Disorders
























Normal Disorder Disease
Early reproductive years (age 15-25)


  • Lobular development



  • Stromal development



  • Nipple eversion




  • Fibroadenoma



  • Adolescent hypertrophy



  • Nipple inversion




  • Giant fibroadenoma



  • Gigantomastia



  • Subareolar abscess

Later reproductive years (age 25-40)


  • Cyclical changes of menstruation



  • Epithelial hyperplasia of pregnancy




  • Cyclical mastalgia



  • Nodularity



  • Bloody nipple discharge

Incapacitating mastalgia
Involution (age 35-55)


  • Lobular involution



  • Duct involution



  • Dilation



  • Sclerosis



  • Epithelial turnover




  • Macrocysts



  • Sclerosing lesions



  • Duct ectasia



  • Nipple retraction



  • Epithelial hyperplasia

Periductal mastitisEpithelial hyperplasia with atypia

ANDI, Aberrations of normal development and involution.


Commonly, BBDs are subdivided histologically by their potential future cancer risk (ACOG Practice Bulletin 164, 2016):




  • Nonproliferative disorders: no increased risk



  • Proliferative disorders without atypia: mild to moderate increase in risk



  • Atypical hyperplasia: substantial increase in risk (relative risk 3 to 5×) ( Table 15.2 )



    TABLE 15.2

    Breast Lesions and Breast Cancer Risk

    Data from Morrow M, Schnitt SJ, Norton L Current management of lesions associated with an increased risk of breast cancer. Nat Rev Clin Oncol 2015;12:227–38.
























    Lesion Type Lesion Subtype * Aggregate Relative Risk of Future Breast Cancer (95% CI)
    Nonproliferative


    • Simple cysts



    • Mild hyperplasia (usual type)



    • Papillary apocrine change

    1.17 (0.94-1.47)
    Proliferative without atypia


    • Fibroadenoma



    • Giant fibroadenoma



    • Intraductal papilloma



    • Moderate/florid hyperplasia (usual type)



    • Sclerosing adenosis



    • Radial scar

    1.76 (1.58-1.95)
    Atypical hyperplasia


    • Atypical ductal hyperplasia



    • Atypical lobular hyperplasia

    3.93 (3.24-4.76)
    Lobular carcinoma in situ 6.9-11

    * Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146–51.


    Dyrstad SW, Yan Y, Fowler AM, Colditz GA. Breast cancer risk associated with benign breast disease: systematic review and meta-analysis. Breast Cancer Res Treat 2015;149:569–75.


    Confidence interval not reported.




Finally, a clinical classification is often used in which abnormalities can be subgrouped as follows:




  • Physiologic swelling and tenderness



  • Nodularity



  • Breast pain (not usually associated with malignancy)



  • Palpable breast lumps



  • Nipple discharge including galactorrhea



  • Breast infection and inflammation—typically associated with lactation



Most commonly BBD involves pain, discharge, or a mass. Infection or mastitis is less common. These symptoms and subsequent physical findings may result in denial, anxiety, and fear as patients worry that the symptoms represent cancer. The increase in size, density, and nodularity during the second half of the menstrual cycle is often associated with increased sensitivity or breast pain. Importantly, cancer-related breast pain is generally a late symptom and is a lone presenting symptom in less than 6% of women with malignant disease. Nipple discharge is also a less common sign of cancer. The correlation of a mass with malignancy is dependent on the patient’s age. The incidence of BBD begins to rise during the second decade of life and peaks in the fourth and fifth decades, as opposed to malignant diseases, whose incidence continues to increase after menopause.


Simple breast cysts, occurring in 35% of reproductive aged women, represent the most common nonproliferative breast lesion (ACOG Practice Bulletin 164, 2016). Radiologically simple breast cysts (without septa or mural thickening) are almost always benign and can be managed expectantly. Aspiration is typically reserved to alleviate symptoms. Mild hyperplasia and simple papillary apocrine change are relatively rare benign nonproliferative lesions.


Fibroadenomas , composed of fibrous and epithelial elements, are the most common benign solid breast neoplasms (15% to 20%) and are often noticed accidentally while bathing. They most often occur in adolescents and young women (peak incidence at age 20 to 24) and are related to an aberration in normal lobular development. They demonstrate hormonal dependence, lactate during pregnancy, and involute to be replaced by hyaline connective tissue during perimenopause. Fibroadenomas represent 12% of breast masses after menopause. Clinically they usually present as solitary, slow-growing, painless, freely mobile, firm, solid breast masses. The average size is 2.5 cm, and they usually remain fairly constant in size. Giant fibroadenoma, larger than 5 cm, are rare. Hyperplastic lobules histologically resembling fibroadenomas are present in virtually all breasts. All the cellular elements of fibroadenomas are normal on conventional and electron microscopy, and the epithelium and myoepithelium maintain a normal relationship.


On clinical examination it may be difficult to distinguish a fibroadenoma from a cyst. In fact, diagnosis based solely on CBE is correct 66% of the time. Importantly, imaged complex cysts and any cysts with solid areas should be biopsied or excised. Ultrasound is the initial noninvasive study to differentiate a solid versus a cystic mass because mammography is rarely indicated in a woman younger than 35 with fibroadenomas. Core needle biopsy is indicated when the cause of a palpable mass cannot be established. Surgical evaluation is appropriate for any mass (at any age) that exhibits a rapid increase in size. Fibroadenomas can be followed clinically. Surgical excision of fibroadenomas should be considered if they are symptomatic or to relieve anxiety related to the palpable mass. They have a “rubbery” consistency, are usually well circumscribed, and are easily delineated from surrounding breast tissue in approximately 95% of cases ( Fig. 15.6 ). Nonoperative management can be considered for small, asymptomatic fibroadenomas in women younger than 35 if clinical examination, imaging evaluation (either mammogram or ultrasound), and biopsy (usually core needle) results are 100% concordant. Approximately 35% of fibroadenomas will disappear, and approximately 10% shrink when followed. Conservative management requires continued surveillance at 6-month intervals for at least 2 years. Despite the option of conservative management, many women prefer to have the fibroadenoma excised. Excision should be performed through a cosmetically placed inframammary, axillary, or circumareolar incision. Fibroadenomas are a proliferative disorder, and particularly when accompanied by complex cysts larger than 3 mm in diameter, sclerosing adenosis, epithelial calcification, or papillary changes, are associated with an increased risk of breast cancer; the later development of invasive breast cancer risk also is increased (approximately twofold). Women with fibroadenomas should be made aware of this risk and encouraged to maintain continued close surveillance. The postoperative risk of recurrent fibroadenoma is approximately 20%. Studies support the successful use of ultrasound-guided high-intensity focused ultrasound or cryoablation as an alternative treatment to surgery ( ).




Fig. 15.6


A, Fibroadenoma with a characteristic tan, well-circumscribed nodule. B, Histologic section of fibroadenoma with epithelial cells surrounded by loose mesenchymal fibrous tissue.

(From Voet RL. Color Atlas of Obstetric and Gynecologic Pathology. St. Louis: Mosby-Wolfe; 1997:204.)


Phyllodes tumors , previously termed Cystosarcoma phyllodes, represent the opposite end of the spectrum of fibroepithelial tumors. Phyllodes tumors are rare, representing only 2.5% of fibroepithelial tumors and less than 1% of breast malignancies. The typical age of onset is 15 to 20 years later than fibroadenomas (fourth and fifth decades of life). They are almost exclusively seen in women and may be benign, borderline, or malignant. Differentiating benign from malignant phyllodes can be difficult and involves assessment of the size, histologic stroma/epithelium ratio, border of the lesion, stromal cellularity, number of stromal mitoses, and presence or absence of necrosis. All three generally present as a breast mass, often grow rapidly, and are typically larger at diagnosis than a fibroadenoma or ductal carcinoma. Histologically, stromal elements dominate and will invade the ducts in a leafy projection; hence the name phyllodes, or “leaf” ( Fig. 15.7 ). Even the most experienced pathologists may have difficulty distinguishing among fibroadenoma, benign phyllodes tumors, and malignant cystosarcoma phyllodes. Phyllodes tumors’ mammographic appearance as a rounded density with smooth borders is similar to that of fibroadenomas. Mammography and ultrasonography are therefore unreliable in differentiating among fibroadenomas, benign phyllodes tumors, and malignant phyllodes tumors.




Fig. 15.7


Phyllodes tumor with leaflike projections within the fleshy mass.

(From Voet RL. Color Atlas of Obstetric and Gynecologic Pathology. St. Louis: Mosby-Wolfe; 1997:205.)


These tumors can be locally aggressive and require wide local excision with 1-cm margins. Unlike fibroadenomas, phyllodes tumors should not be shelled out because this surgical technique will result in an unacceptably high recurrence rate. Unfortunately, the pathologic appearance of a phyllodes tumor does not always predict the neoplasm’s clinical behavior; however, risk of local recurrence of the tumor is associated with microscopic margin involvement. Malignant tumors metastasize hematogenously, and the risk of metastases is 25%; local recurrence is common (>20%), even with benign and borderline tumors.


Fibrocystic change


Many breast symptoms stem from fibrocystic changes , previously designated fibrocystic disease, which is a common and natural maturation of breast tissue over time. The functional unit of the breast (the lobule), the alterations associated with the interaction among hormones, and the epithelial and stromal components of the lobule are responsible for many cases of BBDs. Initial or immature lobules, primarily developing in the early reproductive years (ages 15 to 25 years), are typically replaced during pregnancy and subsequently by mature lobules. Lobular changes manifest most commonly during the menstrual cycle. Late cycle peak mitosis, followed by apoptosis, provides a milieu for stromal or ductal tissues to transform from a normal to an abnormal state. Over time these deviations produce marked differences in the structure and appearance of the breast tissue, which is histologically described as fibrosis or adenosis and is often observed in women with no clinical complaint or finding.


Involutional breast changes, clinically apparent before age 35 years, affect stromal and epithelial components of the lobules. Early stromal involution can result in the formation of microcysts from the remaining epithelial acini. Microcyst formation is common and is often present in healthy breasts. Ductule obstruction facilitates progression of microcysts to macrocysts. Loose, hormonally receptive connective tissue in the stroma is replaced by denser connective tissue, and epithelial involution results in gradual disappearance of the ductal elements. Epithelial involution is dependent on the continuing presence of surrounding specialized stroma. Thus cyclical and involutional changes are concurrently present for more than 30 years, and the involutional changes will be extensive, with few ductal and lobular structures spared by the time menopause occurs.


Fibrocystic change, is the most common of all benign breast conditions. Clinicians use the nonspecific term fibrocystic change to describe the clinical, mammographic, and histologic findings associated with multiple irregularities in contour and texture typically associated with cyclical breast pain. Fibrocystic change presents as a spectrum of changes throughout a woman’s reproductive age, with significant patient variation. Fibrocystic change has an extensive list of synonyms and terminology that includes more than 35 different names and terms. The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) calls this diffuse cystic mastopathy.


The true frequency of fibrocystic change is unknown; however, autopsy evidence of histologic fibrocystic change is noted in 53% of normal breasts. Clinical evidence of fibrocystic change is evident in nearly one in two premenopausal women during breast examination; however, depending on the definition, some authors have noted that as many as 90% of women demonstrate some aspect of fibrocystic change. Although no consistent abnormality of circulating hormone levels has been proved, fibrocystic changes represent an exaggeration of the normal physiologic response of breast tissue to the cyclic levels or ovarian hormones. These changes, unusual in adolescence, are most common in women of reproductive age (20 to 50 years) and unusual after menopause unless associated with exogenous hormone replacement.


Cyclic bilateral breast pain is the classic symptom of fibrocystic breast change. Clinical signs include increased breast engorgement and density, excessive breast nodularity, fluctuation in the size of cystic areas, increased tenderness, and, rarely, spontaneous nipple discharge. Signs and symptoms are typically more prevalent during the premenstrual state.


Associated mastalgia is bilateral, often difficult to localize, and most common in the upper, outer breast quadrants. Pain may radiate to the shoulders and upper arms. Severe localized pain occurs when a simple cyst rapidly expands. The pathophysiology that produces these symptoms and signs includes cyst formation, epithelial and fibrous proliferation, and varying degrees of fluid retention. The differential diagnosis of breast pain includes referred pain from a dorsal radiculitis or inflammation of the costochondral junction (Tietze syndrome). The latter two conditions have symptoms that are not cyclic and are unrelated to the menstrual cycle.


The physical findings of excessive nodularity as a result of fibrocystic changes have been described as similar to palpating the surface of multiple peas. There may be multiple areas of seemingly ill-defined thickening or areas of palpable lumpiness that seem more two dimensional than the three-dimensional mass usually associated with a carcinoma ( Fig. 15.8 ). Larger cysts may be ballotable, analogous to a water-filled balloon.




Fig. 15.8


Breast biopsy specimen from a 38-year-old woman demonstrating the characteristic gross appearance of fibrocystic changes. Note the multiple cysts interspersed between the dense fibrous connective tissue.

(Courtesy Fidel A. Valea, MD.)


There are three general clinical stages of fibrocystic change, with each stage having characteristic histologic findings. Clinically these stages are variable and overlap, but they are described to assist in the understanding of the natural history. The first stage, mazoplasia (mastoplasia), is associated with intense stromal proliferation and occurs in the early reproductive years (20s). Breast pain is noted primarily in the upper, outer breast quadrants, with most tenderness in the axillary tail.


The second clinical stage, adenosis, is characterized by marked proliferation and hyperplasia of ducts, ductules, and alveolar cells and typically occurs in women in their 30s. Premenstrual breast pain and tenderness is less severe. Multiple small breast nodules varying from 2 to 10 mm in diameter are present.


The cystic phase is the last stage and typically occurs another decade later, in women in their 40s. Typically there is no breast pain unless a cyst increases rapidly in size, with associated sudden pain, point tenderness, and a lump. Cysts are tender to palpation and vary from microscopic to 5 cm in diameter. Although breast cysts may occur at any age, they are generally simple and may be managed with aspiration alone. Complex cysts have internal septations, debris, or solid components and may require core needle biopsy if stability cannot be documented. The fluid aspirated from a large cyst is typically straw colored, dark brown, or green, depending on the chronicity of the cyst.


Women with a clinical diagnosis of fibrocystic change have a wide variety of histopathologic findings. The histologic aspect of fibrocystic change is characterized by proliferation and hyperplasia of the lobular, ductal, and acinar epithelium ( Fig. 15.9 ). Usually the proliferation of fibrous tissue occurs and accompanies epithelial hyperplasia. Many histologic variants of fibrocystic change have been described, including cysts (from microscopic to large, blue, domed cysts), adenosis (florid and sclerosing), fibrosis (periductal and stromal), duct ectasia, apocrine metaplasia, intraductal epithelial hyperplasia, and papillomatosis. Ductal epithelial hyperplasia with atypia and apocrine metaplasia with atypia are the most prominent histologic findings directly associated with the subsequent development of breast carcinoma. If either of these two conditions is discovered on breast biopsy, the chance of future breast carcinoma is increased fivefold.




Fig. 15.9


Fibrocystic changes from histologic section. Note fibrosis (F), adenomatous changes with increased ductal tissue (A), and cysts (C).

(From Stevens A, Lowe J. Human Histology. 3rd ed. Philadelphia: Mosby; 2005:392.)


Clinical management of fibrocystic change is age dependent and includes appropriate use of breast imaging. Initial evaluation should exclude malignancy, particularly in the presence of a mass or with a concerning or uncertain examination. Thereafter, successful symptom control may involve a number of medical options. Initial therapy for fibrocystic change involves mechanical support using a firm support or sports bra. Dietary changes to reduce methylxanthines or caffeine exposure have been helpful in relieving symptoms for some women. Although confirmatory medical studies evaluating the benefit of these dietary changes are lacking, there seems to be little harm to trying this inexpensive option for 3 to 6 months. The only dietary substance that seems to correlate with fibrocystic symptoms is dietary fat, particularly saturated fat. Studies have demonstrated a dose-related effect between increased saturated fat and fibrocystic breast symptoms. Incorporating a low-fat, nutrient-dense diet makes sense, and limiting intake of saturated fat intake should be considered as a simple therapeutic tool for the management of women with symptomatic, refractory fibrocystic changes. Additionally, some advocate limiting or eliminating alcohol consumption to lessen estrogen levels. Diuretics are sometimes prescribed during the premenstrual phase and may lessen symptoms of breast discomfort and engorgement.


Oral contraceptives or supplemental progestins administered during the secretory phase of the cycle have also been used to treat fibrocystic changes. Oral contraceptives are reported to decrease the incidence of fibrocystic changes by 30% ( ). Unfortunately, 40% of women will have recurrent symptoms after discontinuation.


Danazol, dosed at 100, 200, and 400 mg daily for 4 to 6 months, suppresses gonadotropins and effectively relieves symptoms and decreases breast nodularity in ~90% of patients. Unfortunately, virilizing side effects such as hirsutism, acne, and voice changes often limit its use. Danazol therapy for 6 months or more should be tapered to eliminate side effects. The beneficial effects of danazol persist for several months after discontinuation.


Oral tamoxifen, 20 mg daily, is superior to placebo in randomized, double-blind trials, and pain relief is reported to be sustained in 72% of women for more than 1 year after discontinuation. Tamoxifen administration restricted to the luteal phase of the menstrual cycle abolishes pain in 85% of women; however, adverse side effects are common (21%). After treatment, 25% of women suffer recurrent pain within 1 year. Tamoxifen 10 mg daily can be prescribed during the luteal phase of the menstrual cycle and results in similar improvements in symptoms but with a marked reduction in adverse effects.


The selective estrogen receptor modulator (SERM) centchroman (Ormeloxifene; 30 mg twice weekly), a weak estrogen receptor (ER) agonist and a strong ER antagonist, demonstrated significant efficacy in the management of breast pain and fibrocystic nodularity. On rare occasions, gonadotropin-releasing hormone (GnRH) agonists may benefit women with severe fibrocystic change.


Mastalgia (breast pain)


More than two-thirds of women will experience breast pain at some time during their reproductive years, most commonly in the perimenopausal years. Eleven percent experience moderate to severe cyclic breast pain and 58% experience mild discomfort. Breast pain commonly interferes with usual sexual activity in 48% and with physical (37%), social (12%), and school (8%) activity in others. Approximately 90% of conditions that cause breast pain are benign. Breast pain is typically divided into cyclic pain, related to the menstrual cycle, and noncyclic pain. Cyclic pain is diffuse and bilateral and most commonly associated with fibrocystic changes. Noncyclic breast pain is commonly localized and related to a cyst. Noncyclic breast pain should be evaluated, particularly in older women, because there is a small association with malignancy. Mammography and additional imaging can be valuable. The differential diagnosis includes a cyst, chest wall pain, radicular pain, costochondritis, mastitis, pregnancy-related pain, prolactinomas, and medication exposure ( Box 15.1 ). Laboratory evaluation should include human chorionic gonadotropin (HCG) and prolactin levels in premenopausal women. Breast cysts occur in as many as 7% of women during their lifetime and may be therapeutically aspirated if they are simple. A negative postaspiration breast examination is reassuring. Recurring simple cysts can be followed with ultrasound, typically withholding repeat aspiration for symptomatic cysts. For a more complex cyst, a more detailed workup is usually necessary. Patients with complex cysts should have a tissue diagnosis performed with a core needle biopsy if the cysts are symptomatic or show progressive changes on serial sonography. Pain as a presenting symptom of malignancy is uncommon in general and is extremely rare in the absence of mass or skin changes. Breast pain treatment is directed at the cause; however, nonsteroidal antiinflammatories are often useful when pain is idiopathic.



BOX 15.1

Medications Associated with Mastalgia





  • Antihypertensives



  • Atenolol and other beta-blockers



  • Hydrochlorothiazide



  • Methyldopa



  • Minoxidil



  • Spironolactone



  • Antidepressants and antipsychotic agents



  • Amitriptyline and other tricyclic antidepressants



  • Chlorpromazine/promethazine



  • Fluoxetine



  • Haloperidol



  • Hormonal agents



  • Estrogens



  • Progestins



  • Androgens



  • Ginseng



  • Clomiphene citrate



  • Digoxin



  • Chlorpropamide




Mastitis and inflammatory disease


Breast infection is often subdivided into lactational, nonlactational, and postoperative. Although decreasing in overall incidence, mastitis, an infection of the ductal systems or smaller sebaceous glands, is most commonly related to Staphylococcus aureus. Empiric treatment with an agent that covers gram-positive organisms is appropriate. If there is poor response to the initial course of antibiotics, cultures for methicillin-resistant S. aureus (MRSA) should be performed and an agent such as a doxycycline or sulfamethoxazole/trimethoprim is indicated; however, these two agents are contraindicated if a woman is pregnant or lactating.


Lactational mastitis commonly occurs in the first pregnancy during the first 6 weeks of breastfeeding. Curiously, mastitis in pregnancy usually responds to first-line antibiotics such as a cephalosporin, even in the presence of MRSA; however, infection may progress to a breast abscess in 5% to 11% of patients. Continued breastfeeding or manual pumping of the affected breast is recommended to decrease engorgement.


Nonpuerperal mastitis is often associated with breast cysts and cyst rupture. Ultrasonography assists in excluding an abscess. Obviously, one should always consider and exclude the presence of malignant breast disease, particularly inflammatory cancer. Additional testing for diabetes and human immunodeficiency virus (HIV) may be indicated, particularly if yeast is the offending organism. Syphilis, tuberculosis, atypical bacterial, and fungal infections may rarely cause nonpuerperal mastitis. In patients with recurrent mastitis, consider choosing an antibiotic to cover MRSA, such as clindamycin, sulfamethoxazole/trimethoprim, doxycycline, or vancomycin. Nipple piercing, particularly in smokers, is associated with mastitis and a 20-fold increase in subareolar abscess formation. As with any infection, the clinician should strongly consider removal of the foreign body. The American College of Obstetricians and Gynecologists (ACOG) recommends counseling women who are planning to get piercings to have prepiercing hepatitis B and tetanus vaccinations.


Idiopathic granulomatous mastitis (IGM), also called idiopathic granulomatous lobular mastitis (IGLM) , is a rare cause of breast inflammation and may affect any age group. This disease may present with a mass, abscess, inflammation, or granuloma formation. The granulomas are often found within the lobules and on biopsy are noted to be sterile. Mammography may be equivocal or may be suspicious for malignancy. Steroid treatment has been reported to be effective in small series with equivocal results. The disease is usually self-limited, resolving within months. Skin scarring and residual small abscesses may remain, often necessitating surgical treatment. Chronic inflammatory diseases, such as lupus, sarcoidosis, and Wegner granulomatosis, are rare causes of noninfectious mastitis, and evaluation for these diseases should be performed if antibiotics are not effective. Importantly, any breast inflammation not responsive to adequate antibiotic treatment warrants a tissue diagnosis. Core needle biopsy is often performed when there is a lack of response to antibiotics. The diagnosis is commonly made when the biopsy specimen indicates sterile granulomas after excluding other causes of granulomatous mastitis such as tuberculosis.


Nipple discharge


Nipple discharge is responsible for 7% of physician visits involving breast complaints. The majority have a benign cause; however, 55% present with a coexisting mass, of which 19% are malignant. An underlying malignancy is more likely when the discharge is spontaneous (vs. induced with nipple pressure), arises from a single duct, is blood stained, and is unilateral and persistent (occurring more than twice weekly). Age is important because an underlying malignancy is present in 3% of women younger than 40, 10% of women between 40 and 60, and 32% of women older than 60 when nipple discharge is the only presenting symptom.


Intraductal papilloma and fibrocystic changes are the two most common causes of spontaneous nonmilky discharge. Galactorrhea is likely when breast discharge is bilateral, copious, milky pale in color, and occurs from multiple ducts. Importantly, numerous medications and conditions can affect the hypothalamic-pituitary axis and lead to prolactin secretion and galactorrhea. As many as 65% of premenopausal women may have a normal benign physiologic discharge with gentle squeezing of the nipple. Evaluation includes physical examination, mammography, and sonography. The patient’s history may not differentiate spontaneous discharge from elicited discharge because a woman may continually attempt to express the discharge, which causes more fluid to leak.


Evaluation and diagnosis include clinically separating the discharges into those that are spontaneous and those that only are expressed by pinching or squeezing the nipple ( Fig. 15.10 ). Nipple discharges range in color from milky to green, brown, purple, and bloody. Hemoccult testing for detection of blood in the discharge is neither sensitive nor specific. Malignancy should be excluded in any woman with a bloody discharge or any discharge associated with a mass or if the discharge originates from only one or two adjacent ducts.




Fig. 15.10


Algorithm for Evaluation of Nipple Discharge.

(From Santen RJ. Benign breast disease in women. [Updated May 25, 2018.] In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. South Dartmouth, MA: MDText.com, Inc.; 2000.)


Assessment of pathologic nipple discharge involves a careful breast examination to identify the presence or absence of a breast mass. Firm areola pressure can assist in identifying the site of any dilated duct (pressure over a dilated duct will produce the discharge); this finding helps to define where an incision should be made for any subsequent surgery. The nipple is squeezed with firm, gentle digital pressure, and if fluid is expressed, the site and character of the discharge are recorded. Although bloodstained breast discharge is more likely to be associated with malignancy, fewer than 20% of patients who have a bloodstained discharge or who have a discharge containing moderate or large amounts of blood will have an underlying malignancy. Importantly, the absence of blood in nipple discharge does not exclude an underlying malignancy. Cytologic examination of nipple discharge can be helpful but has a poor sensitivity (<50%).


Management of a suspicious discharge begins with a physical examination and mammography, ultrasound, or magnetic resonance imaging (MRI). Any mass associated with discharge requires appropriate biopsy. A number of techniques have been evaluated to determine the cause and avoid unnecessary extirpative surgery. Ductoscopy (using a microendoscope passed into the offending duct) allows direct visualization. Ductal lavage involves duct canalization, and collection of fluid for cytologic evaluation. This technique increases cell yield by 100 times that of simple discharge cytologic examination but can be uncomfortable for the patient. Ductography (imaging of the ductal system by infecting contrast into the symptomatic duct), also called a galactogram , has 60% sensitivity for detecting malignancy. This study can identify intraductal filling defects or cutoff lesions, which have a high positive predictive value for the presence of either a papilloma or a carcinoma. The procedure can be technically challenging and cause significant patient discomfort. Surgical excision of the duct and its associated lobular unit is both diagnostic and therapeutic. With the patient anesthetized, a 4-0 lacrimal probe is passed through the duct. A periareolar flap is then created, and the retroareolar duct with the probe can be identified and excised individually.


Intraductal papilloma


Intraductal papillomas are broad-based or pedunculated polypoid epithelial lesions that may obstruct and distend the involved duct. They are most commonly diagnosed in perimenopausal women. Classically their clinical presentation includes an intermittent but spontaneous discharge from one nipple involving one or two ducts. The associated discharge can be watery, serous, or bloody, and of variable volume. Approximately 75% of intraductal papillomas are located beneath the areola, are small and soft, and are often difficult to palpate, typically measuring 1 to 3 mm in diameter. During examination of the breast it is important to circumferentially put radial pressure on different areas of the areola. This technique helps to identify whether the discharge emanates from a single duct or multiple openings. When the discharge comes from a single duct, the differential diagnosis includes both intraductal papilloma and carcinoma.


Treatment of intraductal papilloma involves excisional biopsy of the involved duct and a small amount of surrounding tissue. Although these tumors tend to regress in postmenopausal women, excision should be considered to rule out malignancy. Careful surveillance at 3- to 4-month intervals is necessary if the papilloma is not surgically excised. Women with a solitary papilloma have a twofold increase in subsequent development of breast carcinoma.


Fat necrosis


Fat necrosis , a benign nonsuppurative inflammatory process of adipose tissue, is a condition with a wide variety of presentations on mammography, ultrasound, and MRI. The incidence of fat necrosis of the breast is estimated to be 0.6%, representing 2.75% of all breast lesions. Fat necrosis is found in 0.8% of breast tumors and 1% in breast reduction mammoplasty cases, and the average age of patients is 50 years. Fat necrosis is most commonly the result of trauma to the breast, although it can be associated with radiotherapy, anticoagulation (warfarin), infection, or breast procedures, including breast aspiration or biopsy, lumpectomy, reduction mammoplasty, implant removal, and breast reconstruction. Other rare causes for fat necrosis include polyarteritis nodosa, Weber-Christian disease, and granulomatous angiopanniculitis.


Patients commonly present with a firm, tender, indurated, ill-defined mass that may have coexisting ecchymosis, erythema, inflammation, pain, skin retraction or thickening, nipple retraction, and occasionally lymphadenopathy. As many as 70% present as an occult lesion without a history of trauma. The area of fat necrosis may liquefy and become cystic, forming an oil cyst with a characteristic calcified rim. Mammography may demonstrate coarse calcifications, focal asymmetries, or microcalcifications. Treatment of fat necrosis is excisional biopsy. There is no relationship between fat necrosis and the development of subsequent breast carcinoma.


Breast carcinoma


Globally, breast carcinoma is the most common malignancy of women, and in the United States it is the second most common cause of all cancer deaths in women. Approximately 12.35% of women (1 in 8 women) will develop carcinoma of the breast at some point during their lifetime. In 2020, approximately 276,480 women in the United States were diagnosed with invasive breast cancer, with 42,170 women dying from the disease ( ). The importance of early detection and diagnosis of breast carcinoma cannot be overemphasized. An increase in public awareness combined with improvements in mammography and newer imaging techniques have facilitated earlier detection of breast carcinoma. Earlier detection, combined with improvements in therapy, has resulted in improved survival rates. With the advent of chemoprevention in high-risk women, there is an opportunity to alter the natural course of the disease.


Breast carcinoma generally presents in one of two ways: either with clinical symptoms or found on screening evaluation. In the United States most breast cancer is diagnosed as a result of an abnormal screening test. Screening includes examination by a health provider (referred to as clinical breast examination ) and imaging. The ideal time to initiate screening, along with determination of intervals, is individualized for each woman based on her risk factors. A thorough understanding of the epidemiology of breast cancer is warranted when calculating the risk of developing breast cancer. Several models are available that help assess a patient’s risk. If no risk factors are noted, she is said to be at average or normal risk, corresponding to the 12% (or 1 in 8) risk for a woman of developing breast malignancy during her lifetime. Because a woman’s risk may change as her family history evolves or new findings develop on imaging, risk assessment should be ongoing.


Epidemiology and risks for breast cancer


Breast cancer continues to be the most commonly diagnosed cancer in women worldwide. It is caused by a progressive accumulation of mutations in the cell’s DNA. Epidemiologic studies help identify factors that through either exposure or inheritance place a woman at risk for a greater chance of cellular change. Approximately 50% of newly diagnosed breast cancers are attributable to known risk, whereas 10% are associated with simply a positive family history. The degree of risk is important to know in order to advise women and establish plans for screening or interventions.


Most epidemiologic literature when reporting breast cancer risks describes the risk from any given factor as a relative risk. Relative risk is the risk of subjects in an exposed group compared with subjects in a nonexposed group. In contrast, clinical and genetic studies usually report results as a woman’s lifetime risk: the risk of developing or dying from a disease over the course of one’s lifetime. The distinction can be confusing for patients and families. For example, a BRCA mutation may increase the relative risk 10-fold and the lifetime risk up to 85%. Clinicians must be aware of the difference when reviewing the literature and subsequently when counseling patients and their families.


The risk factors for breast cancer may be divided into several categories ( Table 15.3 ): demographic, estrogen exposure, lifestyle, personal breast characteristics, familial and inherited genetic mutations, and radiation exposure ( ; ). Risk is generally grouped as minor and major. Minor risk factors increase a woman’s lifetime risk from 12% to approximately 15%. Importantly, epidemiologic studies have also noted factors that decrease a woman’s risk ( Table 15.4 ).



TABLE 15.3

Risk Factors for Breast Cancer
























































































Risk Factor Qualification Relative Risk
Age


  • ≤49 y



  • 50-59 y



  • Age 60-69 y



  • ≥70 y




  • 2.0



  • 2.3



  • 3.5



  • 6.7

Geographic Common in Western countries
Age at menarche >14 y (low risk) vs. <12 y 1.5
Age at first full-term pregnancy <20 y (low risk) vs. >30 y 1.9-3.5
Late menopause <45 y (low risk) vs. >55 y (high risk) 2.0
Hormone replacement therapy No use vs. current 1.2
Contraceptive pill use None vs. past or current use 1.07-1.2
Alcohol use None vs. 2-5 drinks/day 1.4
Postmenopausal weight gain Women with a higher BMI 1.1 per 5 BMI units
Bone density Lowest vs. highest quartile 2.7-3.5
Nightshift work Exposed to nightshift work 1.48
Smoking History of smoking 1.10 *
Benign breast disease None vs. positive biopsy result 1.7
Breast density (as measured by mammography) 0% vs. ≥75% 1.8-6.0
Hyperplasia with atypia None vs. positive biopsy result 3.7
Multiple relatives, not first degree, with breast cancer
One first-degree relative with breast cancer (mother or sister) None vs. yes 2.6
Two or more first-degree relatives Increased risk if the cancers are premenopausal
Deleterious BRCA1/BRCA2 genes Negative vs. positive 2.0-7.0
Mantle radiation for treatment of malignancy Very high risk, which increases with age

* Summary relative risk.



TABLE 15.4

Factors Associated with a Decreased Risk for Breast Cancer
























































Demographic Qualification Relative Risk
Born and living outside Western countries
Late menarche After age 14
Oophorectomy Yes vs. no 0.3
Lactation >16 mo vs. none 0.73
Parity ≥5 vs. 0 0.73
Postmenopausal body mass (kg/m 2 ) <22.9 vs. >30.7 0.63
Physical activity Yes vs. no 0.70
Vitamin D Low levels associated with risk
Intake of vitamin D Associated with decreased risk
Olive oil and omega-3 fatty acids
Low-fat diet Results suggestive but not yet conclusive
Aspirin >1×/wk for ≥16 mo vs. no use 0.79


Demographic associations


Age continues to remain the strongest risk factor for developing breast cancer. The risk of breast carcinoma increases directly with the patient’s age ( Table 15.5 ). Data from the Surveillance, Epidemiology, and End Results (SEER) database report the probability of a woman developing breast cancer from birth to age 49 as 2% (1 in 49 women) compared with 7% (1 in 14 women) at age 70 or older ( ).



TABLE 15.5

A Woman’s Risk of Having Developed Breast Cancer

Data from National Cancer Institute. Painter K. Factoring in cost of mammograms. USA Today. December 5, 1996, p 11D.

















































Age Risk
25 1 in 19,608
30 1 in 2525
35 1 in 622
40 1 in 217
45 1 in 93
50 1 in 50
55 1 in 33
60 1 in 24
65 1 in 17
70 1 in 14
75 1 in 11
80 1 in 10
85 1 in 9
Ever 1 in 8


The incidence of breast cancer varies based on geographic region. The highest rates are found in North America, Australia/New Zealand, and Western and Northern Europe. Women in Eastern Europe, South Africa, Japan, and the Caribbean form a middle group in terms of incidence. The lowest incidences are found in Asia and sub-Saharan Africa.


In the United States white women have the highest rate of breast cancer; however, black women have higher breast cancer mortality. Data from 2005 to 2009 the rate of newly diagnosed breast cancer was 122 per 100,000 white women and 117 per 100,000 black women. Black women more commonly presented with regional or advanced disease (45% vs. 35%) and had a 41% higher breast cancer–specific mortality rate (32 vs. 22 deaths per 100,000 women) ( ). This difference may be due to several factors, including both socioeconomic aspects and the histologic variety of tumors.


Estrogen-related exposure risks


Breast cancer risk is increased with high endogenous estrogen levels in both premenopausal and postmenopausal women. This effect is especially noted in hormone receptor–positive breast cancer. Various studies have shown that both prolonged exposure to and higher concentrations of estrogen are associated with a higher risk of breast cancer. Breast cancer is rare in prepubertal girls. Women who have breast cancer and undergo oophorectomy have a lower recurrence rate. Interestingly, the rate of recurrence in oophorectomized women is decreased, even in women with hormone receptor–negative cancers.


Reproductive factors must also be considered in determining the risk of developing breast cancer. Nulliparous women are at an increased risk of breast cancer compared with parous women, but the protective effect of pregnancy is not noted until 10 years after delivery. It is unclear whether an association exists between either multiparity or nulliparity and breast cancer. The age at which a woman delivers her first child is an important risk factor. Age at first pregnancy was analyzed in the Nurses’ Health Study. Compared with nulliparous women at or near menopause, women who delivered their first child at age 20, 25, or 35 years had a cumulative incidence of breast cancer (up to age 70) that was 20% lower, 10% lower, and 5% higher, respectively ( ). Early age at menarche is associated with a higher risk of breast cancer. Women with menarche at or after age 15 years of age were less likely to develop ER-positive breast cancer compared with those with menarche before the age of 13 years. Additionally, a 16% decreased risk of ER-negative breast cancer was noted in women with menarche at or after age 15 years.


Breastfeeding decreases the risk of breast cancer. A pooled analysis of data from 47 studies involving 50,302 women with breast cancer and 96,973 women without the disease found a direct correlation between the length of time of lactation and decreasing risk for breast malignancy ( ). Women who breastfed longer were more protected against breast cancer. The relative risk of breast cancer decreased by 4.3% per 12 months of breastfeeding. This decrease did not vary significantly by parity, ethnicity, age of menarche and menopause, and geographic factors. Newcomb and colleagues reported that after adjusting for parity, age at first delivery, and other confounding factors, lactation was associated with a slight reduction in the risk of breast cancer among premenopausal women compared with those who had never lactated (relative risk [RR], 0.78; confidence interval [CI], 0.6 to 0.91) ( ). Overall, breastfeeding decreases the risk of breast cancer in a dose-response relationship.


Hormone replacement—specifically the use of combined estrogen and progesterone—is an established risk factor for breast cancer. Data from the Women’s Health Initiative (WHI) showed that compared with the placebo group, combined hormone replacement increases the risk of breast cancer by 24%. Of note, estrogen-only use in women with a history of a hysterectomy did not increase the risk of breast cancer ( ). The decision to use hormone replacement therapy in patients with and without other risk factors should be individualized and the risks and benefits discussed so that the woman may make an informed decision. Unlike combination hormonal replacement (estrogen and progesterone), oral contraceptives and other forms of estrogen-related contraception do not increase the risk of breast cancer. Multiple studies have noted that the oral contraceptives used since the 1980s do not pose an increased risk compared with the extremely high levels of estrogen used in oral contraceptives in the 1960s and 1970s. There is no association between abortion and breast cancer incidence.


Lifestyle and dietary risk factors


The relationship between dietary habits and the risk of breast cancer is not clear. A direct association between dietary fat and the risk of breast cancer has not been clearly established, and various studies have failed to show a significant association between the highest and the lowest category of consumed dietary fat and an increased risk of breast cancer. In the WHI study of postmenopausal women, the dietary arm of the study evaluated 48,835 healthy postmenopausal women who tried to reduce fat intake ( ). There was a minimal effect on decreasing malignancy in the breast (RR, 0.91; CI, 0.83 to 1.01) after a mean follow-up of 8.1 years. Although no direct association between dietary fat intake and breast cancer risk has been established, there may be a modest effect when comparing extremes of fat intake. In the AARP Diet and Health Study, women in the highest quintile of fat intake had rates of invasive breast cancer 11% to 22% higher than those of women in the lowest quintile ( ). Although obesity is associated with a general increase in morbidity and mortality, the risk of breast cancer related to body mass index (BMI) is linked to the menopausal status of women ( ). Obese women are at a higher risk for developing breast cancer during their postmenopausal years, with increased amounts of peripheral conversion of androstenedione to estrone. In premenopausal women, an increased BMI is associated with a lower risk of breast cancer.


Studies also have found a significant association with decreased levels of vitamin D and decreased calcium and increased risks of breast cancer and increased morbidity once breast cancer is diagnosed. An increase in plasma 25-hydroxyvitamin D (25[OH]D) levels between 27 and 35 ng/mL was associated with a decrease in breast cancer risk in postmenopausal women ( ). No association between 25(OH)D levels and breast cancer risk has been noted in premenopausal women. Antioxidant supplementation (vitamin A, E, or C, or beta-carotene) has not been shown to be protective for breast cancer. Data regarding the effect of nonsteroidal antiinflammatory drugs (NSAIDs) on breast cancer risk are varied. Several small studies and a nested study from the WHI noted aspirin to decrease risk for breast cancer, breast cancer recurrence, and breast cancer mortality; however, data from the Nurses’ Health Study showed no association between use of aspirin, NSAIDs, or acetaminophen and the incidence of breast cancer ( ).


Alcohol consumption has been associated with increased risk for multiple cancers, including breast cancer. Older studies reported a 40% to 50% increase in the relative risk of developing breast cancer related to alcohol consumption. The alcohol effect was primarily in ER-positive tumors. Breast cancer risk is higher in women consuming both low and high levels of alcohol compared with no consumption. Longnecker showed that the risk of breast cancer was strongly related to the amount of alcohol consumed and that even light drinking was associated with a 10% increase in relative risk ( ). A 2013 meta-analysis of 110 epidemiologic studies reported a 5% increase (RR, 1.05%) in female breast cancer with light alcohol intake ( ).


Phytoestrogens are naturally occurring plant substances with a chemical structure similar to 17-beta estradiol. They consist mainly of isoflavones (found in high concentrations in soybeans and other legumes) and lignans (found in a variety of fruits, vegetables, and cereal products). There is low-quality evidence that soy-rich diets in Western women prevent breast cancer. A 2008 meta-analysis of eight studies evaluated the effect of soy food intake and breast cancer risk ( ). A higher intake of isoflavones (≥20 mg per day) was associated with a 29% reduction in breast cancer risk in Asian women, but no association with soy intake was noted among Western women. Of note, the highest level of soy intake in Western women was only about 0.8 mg daily, which may not have been an adequate amount to detect an effect.


Various miscellaneous environmental exposures have been studied for possible associations with the development of breast cancer. In a 2005 meta-analysis of 13 studies, Megdal and associates found that altered day/night exposure, shift work, and increased light exposures were associated with an increased risk of breast cancer (RR, 1.48; CI, 1.36 to 1.61). Suppression of nocturnal melatonin production by the pineal gland secondary to nocturnal light exposure may contribute to the increased risk of developing breast cancer. Magnetic radiation, power lines, computer terminals, and electric blanket exposure do not increase the risk of breast cancer. Breast implants have not been shown to increase the risk for breast cancer.


Breast history and breast characteristics


Women with a personal history of breast cancer or ductal carcinoma in situ are at an increased risk of developing invasive breast cancer in the contralateral breast. Analysis of SEER data showed the incidence of invasive contralateral breast cancer in women with a history of primary breast cancer was 4% during a 7.5-year follow-up period ( ). The risk of a contralateral breast cancer depends on the age at the time of the index breast cancer diagnosis in conjunction with the hormone receptor status of the primary tumor. The presence of ductal carcinoma in situ did not modify the rate of contralateral breast cancer.


Boyd and coworkers reported that women with dense breasts, as defined by more fibrous tissue, have a relative risk of 4.7 (CI, 2 to 6.2) for breast cancer ( Fig. 15.11 ) ( ). This finding has been verified in other studies, and the increased risk is not due to a more difficult or later diagnosis but to the biologic characteristics of the breast itself. Women with dense breasts noted on mammograms (dense tissue involving at least 75% of the breast) have a risk of breast cancer four to five times greater compared with women with less dense tissue. Both usual and atypical hyperplasia increases the risk of breast cancer. There is a mild increase in risk when biopsy results have shown hyperplasia; however, hyperplasia with atypia increases the risk by 4 to 6 orders of magnitude. The cumulative incidence of breast cancer among women with atypical hyperplasia approaches 30% at 25 years of follow-up.


Aug 8, 2021 | Posted by in GYNECOLOGY | Comments Off on Breast diseases: Detection, Management, and Surveillance of Breast Disease
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