16 The Breast

Kirby I. Bland, Samuel W. Beenken and Edward E. Copeland, III HISTORY OF MODERN BREAST CANCER SURGERY In 1894, Halsted and Meyer established the radical mastectomy as state-oftheart breast cancer treatment. They advocated complete dissection of axillary lymph node levels IIII and routinely resected the long thoracic nerve and the thoracodorsal neurovascular bundle with the axillary contents. In 1948, to reduce the morbidity of breast cancer surgery, Patey and Dyson of the Middlesex Hospital, London, advocated a modified radical mastectomy for the management of advanced operable breast cancer. Their technique included preservation of the pectoralis major muscle, the long thoracic nerve, and the thoracodorsal neurovascular bundle. They showed that removal of only the pectoralis minor muscle allowed adequate access to and clearance of axillary lymph node levels IIII. Subsequently, Madden advocated a modified radical mastectomy that preserved both the pectoralis major and minor muscles even though this approach prevented dissection of the apical (level III) axillary lymph nodes. The National Surgical Adjuvant Breast and Bowel Project B-04 (NSABP B-04) conducted by Fisher and colleagues compared local and regional treatments of breast cancer. Life table estimates were obtained for 1665 women enrolled and followed for a mean of 120 months. This study randomized clinically node-negative women into three groups: (1) Halsted radical mastectomy (RM); (2) total mastectomy plus radiation therapy(TM+RT); and (3) total mastectomy (TM) alone. Clinically node-positive women were treated with RM or TM+RT. There were no differences in survival between the three groups of node-negative women or between the 2 groups of node-positive women. Correspondingly, there were no differences in survival during the first and second 5-year follow-up periods. FUNCTIONAL ANATOMY OF THE BREAST The breast is composed of 1520 lobes, which are each composed of several lobules. Each lobe of the breast terminates in a major (lactiferous) duct (24mm in diameter), which opens through a constricted orifice (0.4 0.7 mm in diameter) into the ampulla of the nipple. Fibrous bands of connective tissue travel through the breast (suspensory ligaments of Cooper), which insert perpendicularly into the dermis and provide structural support. The axillary tail of Spence extends laterally across the anterior axillary fold. The upper outer quadrant of the breast contains a greater volume of tissue than do the other quadrants. Blood supply, innervation, and lymphatics. The breast receives its blood supply from (1) perforating branches of the internal mammary artery; (2) lateral branches of the posterior intercostal arteries; and (3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery. The veins and lymph vessels of the breast follow the course of the arteries with venous drainage being toward the axilla. The vertebral venous plexus of Batson, which invests the vertebrae and 344
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345 extends from the base of the skull to the sacrum, can provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system. Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm. The boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the position of the axillary lymph nodes. The 6 axillary lymph node groups recognized by surgeons are (1) the axillary vein group (lateral); (2) the external mammary group (anterior or pectoral); (3) the scapular group (posterior or subscapular); (4) the central group; (5) the subclavicular group (apical); and (6) the interpectoral group (Rotters). The lymph node groups are assigned levels according to their relationship to the pectoralis minor muscle. Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral
CHAPTER 16 THE BREAST

groups. Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which make up the subclavicular group. The axillary lymph nodes usually receive more than 75 percent of the lymph drainage from the breast. PHYSIOLOGY OF THE BREAST Breast development and function. Breast development and function are initiated by a variety of hormonal stimuli, including estrogen, progesterone, prolactin, oxytocin, thyroid hormone, cortisol, and growth hormone. Estrogen, progesterone, and prolactin especially have profound trophic effects that are essential to normal breast development and function. Estrogen initiates ductal development, although progesterone is responsible for differentiation of epithelium and for lobular development. Prolactin is the primary hormonal stimulus for lactogenesis in late pregnancy and the postpartum period. It upregulates hormone receptors and stimulates epithelial development. Secretion of neurotrophic hormones from the hypothalamus is responsible for regulation of the secretion of the hormones that affect the breast tissues. The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate the release of estrogen and progesterone from the ovaries. In turn, the release ofLH and FSH from the basophilic cells of the anterior pituitary is regulated by the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Positive and negative feedback effects of circulating estrogen and progesterone regulate the secretion of LH, FSH, and GnRH. INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREAST COMMON BENIGN DISORDERS AND DISEASES OF THE BREAST Aberrations of normal development and involution. The basic principles underlying the aberrations of normal development and involution (ANDI) classification of benign breast conditions are (1) benign breast disorders and diseases are related to the normal processes of reproductive life and to involution; (2) there is a spectrum of breast conditions that ranges from normal to disorder to disease; and (3) the ANDI classification encompasses all aspects of the breast condition, including pathogenesis and the degree of abnormality. The horizontal component of Table 16-1 defines ANDI along a spectrum from normal, to mild abnormality (disorder), to severe abnormality (disease). The vertical component defines the period during which the condition develops. Reproductive Years: Fibroadenomas are seen predominantly in younger women age 1525 years. Fibroadenomas usually grow to 1 or 2 cm in diameter
TABLE 16-1 ANDI Classification of Benign Breast Disorders

348 PART II SPECIFIC CONSIDERATIONS and then are stable, but may grow to a larger size. Small fibroadenomas (1 cm in size or less) are considered normal, although larger fibroadenomas (up to 3 cm) are disorders and giant fibroadenomas (larger than 3 cm) are disease. Similarly, multiple fibroadenomas (more than 5 lesions in one breast) are very uncommon and are considered disease. The precise etiology of adolescent breast hypertrophy is unknown.Aspectrum of changes from limited to massive stromal hyperplasia (gigantomastia) is seen. Nipple inversion is a disorder of development of the major ducts, which prevents normal protrusion of the nipple. Mammary duct fistulas arise when nipple inversion predisposes to major duct obstruction, leading to recurrent subareolar abscess and mammary duct fistula. Later Reproductive Years: Cyclical mastalgia and nodularity are usually associated with premenstrual enlargement of the breast and are regarded as normal. Cyclical pronounced mastalgia and severe painful nodularity that persists for more than 1 week of the menstrual cycle is considered a disorder. In epithelial hyperplasia of pregnancy, papillary projections sometimes give rise to bilateral bloody nipple discharge. The term fibrocystic disease is nonspecific. Too frequently, it is used as a diagnostic term to describe symptoms, to rationalize the need for breast biopsy, and to explain biopsy results. Synonyms include fibrocystic changes, cystic mastopathy, chronic cystic disease, chronic cystic mastitis, Schimmelbusch disease, mazoplasia, Cooper disease, Reclus disease, and fibroadenomatosis. Fibrocystic disease refers to a spectrum of histopathologic changes that are best diagnosed and treated specifically. Treatment of Selected Benign Breast Disorders and Diseases Cysts: In practice, the first investigation of palpable breast masses is frequently needle biopsy, which allows for the early diagnosis of cysts.A21-gauge needle attached to a 10-mL syringe is placed directly into the mass, which is fixed by fingers of the nondominant hand. The volume of a typical cyst is 510 mL, but it may be 75 mL or more. If the fluid that is aspirated is not bloodstained, then the cyst is aspirated to dryness, the needle is removed, and the fluid is discarded as cytologic examination of such fluid is not cost-effective. After

aspiration, the breast is carefully palpated to exclude a residual mass. If one exists, ultrasound examination is performed to exclude a persistent cyst, which is reaspirated if present. If the mass is solid, a tissue specimen is obtained.When cystic fluid is bloodstained, 2 mL of fluid are taken for cytology. The mass is then imaged with ultrasound and any solid area on the cyst wall is biopsied by needle. The presence of blood usually is obvious, but in cysts with dark fluid, an occult blood test or microscopy examination will eliminate any doubt. The two cardinal rules of safe cyst aspiration are (1) the mass must disappear completely after aspiration, and (2) the fluid must not be bloodstained. If either of these conditions is not met, then ultrasound, needle biopsy, and perhaps excisional biopsy are recommended. Fibroadenomas: Removal of all fibroadenomas has been advocated irrespective of patient age or other considerations, and solitary fibroadenomas in young women are frequently removed to alleviate patient concern. Yet most fibroadenomas are self-limiting and many go undiagnosed, so a more conservative approach is reasonable. Careful ultrasound examination with core-needle biopsy will provide for an accurate diagnosis. Subsequently, the patient is counseled concerning the biopsy results, and excision of the fibroadenoma may be avoided. CHAPTER 16 THE BREAST 349 Sclerosing Disorders: The clinical significance of sclerosing adenosis lies in its mimicry of cancer. It may be confused with cancer on physical examination, by mammography, and at gross pathologic examination. Excisional biopsy and histologic examination are frequently necessary to exclude the diagnosis of cancer. The diagnostic work-up for radial scars and complex sclerosing lesions frequently involves stereoscopic biopsy. It is usually not possible to differentiate these lesions with certainty from cancer by mammography features, hence biopsy is recommended. Periductal Mastitis: Painful and tender masses behind the nipple-areola complex are aspirated with a 21-gauge needle attached to a 10-mL syringe. Any fluid obtained is submitted for cytology and for culture using a transport medium appropriate for the detection of anaerobic organisms. Women are started on a combination of metronidazole and dicloxacillin while awaiting the results of culture. Antibiotics are then continued based on sensitivity tests. Many cases respond satisfactorily, but when there is considerable pus present, surgical treatment is recommended. A subareolar abscess usually is unilocular and often is associated with a single duct system. Preoperative ultrasound will accurately delineate its extent. The surgeon may either undertake simple drainage with a view toward formal surgery, should the problem recur, or proceed with definitive surgery. In a woman of childbearing age, simple drainage is preferred, but if there is an anaerobic infection, recurrent infection frequently develops. Recurrent abscess with fistula is a difficult problem and may be treated by fistulectomy or by major duct excision, depending on the circumstances. When a localized periareolar abscess recurs at the previous site and a fistula is present, the preferred operation is fistulectomy, which has minimal complications and a high degree of success. However, when subareolar sepsis is diffuse rather than localized to one segment or when more than one fistula is present, total duct excision is the preferred procedure. The first circumstance is seen in young women with squamous metaplasia of a single duct, although the latter circumstance is seen in older women with multiple ectatic ducts. However, age is not always a reliable guide, and fistula excision is the preferred initial procedure for localized sepsis irrespective of age. Antibiotic therapy is useful for recurrent infection after fistula excision, and a 24-week course is recommended prior to total duct excision. Nipple Inversion: More women request correction of congenital nipple inversion than request correction for the nipple inversion that occurs secondary to duct ectasia. Although the results are usually satisfactory, women seeking correction for cosmetic reasons should always be made aware of the surgical complications of altered nipple sensation, nipple necrosis, and postoperative fibrosis with nipple retraction. Because nipple inversion is a result of shortening of the subareolar ducts, a complete division of these ducts is necessary for permanent correction of the disorder. RISK FACTORS FOR BREAST CANCER Increased exposure to estrogen is associated with an increased risk for developing breast cancer, whereas reducing exposure is thought to be protective. Correspondingly, factors that increase the number of menstrual cycles, such as early menarche, nulliparity, and late menopause, are associated with increased risk. Moderate levels of exercise and a longer lactation period, factors that decrease the total number of menstrual cycles, are protective. The terminal differentiation of breast epithelium associated with a full-term pregnancy is 350 PART II SPECIFIC CONSIDERATIONS

also protective, so older age at first live birth is associated with an increased risk of breast cancer. Risk assessment. The average lifetime risk of breast cancer for newborn U.S. females is 12 percent. The longer a woman lives without cancer, the lower her risk of developing breast cancer. Thus, a woman age 50 years has an 11 percent lifetime risk of developing beast cancer, and a woman age 70 years has a 7 percent lifetime risk of developing breast cancer. As risk factors for breast cancer interact, evaluating the risk conferred by combinations of risk factors is difficult. From the Breast Cancer Detection Demonstration Project, a mammography screening program conducted in the 1970s, Gail and colleagues developed the most frequently used model, which incorporates age at menarche, the number of breast biopsies, age at first live birth, and the number of first-degree relatives with breast cancer. It predicts the cumulative risk of breast cancer according to decade of life. To calculate breast cancer risk with the Gail model, a womans risk factors are translated into an overall risk score by multiplying her relative risks from several categories. This risk score is then compared to an adjusted population risk of breast cancer to determine a womans individual risk. A software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc. Risk management. Several important medical decisions may be affected by a womans underlying risk of breast cancer. These decisions include when to use postmenopausal hormone replacement therapy; at what age to begin mammography screening; when to use tamoxifen to prevent breast cancer; and when to perform prophylactic mastectomy to prevent breast cancer. Postmenopausal hormone replacement therapy reduces the risk of coronary artery disease and osteoporosis by 50 percent, but increases the risk of breast cancer by approximately 30 percent. Routine use of screening mammography in women age 50 years and older reduces mortality from breast cancer by 33 percent. This reduction comes without substantial risks and at an acceptable economic cost. However, the use of screening mammography is more controversial in women younger than age 50 years for several reasons: (1) breast density is greater and screening mammography is less likely to detect early breast cancer; (2) screening mammography results in more false-positive tests, resulting in unnecessary biopsies; and (3) youngerwomen are less likely to have breast cancer so fewer youngwomen will benefit from screening. However, on a population basis, the benefits of screening mammography in women between the ages of 40 and 49 years still appear to outweigh the risks. Tamoxifen, a selective estrogen receptor modulator,was the first drug shown to reduce the incidence of breast cancer in healthy women. The Breast Cancer Prevention Trial (NSABP P-01) randomly assigned more than 13,000 women, with a 5-year Gail relative risk of breast cancer of 1.70 or greater, to tamoxifen or placebo. After a mean follow-up period of 4 years, tamoxifen had reduced the incidence of breast cancer by 49 percent. Tamoxifen currently is only recommended for women who have a Gail relative risk of 1.70 or greater and it is unclear whether the benefits of tamoxifen apply to women at lower risk. Additionally, deep venous thrombosis occurs 1.6 times, pulmonary emboli 3.0 times, and endometrial cancer 2.5 times as often in women taking tamoxifen. The increased risk for endometrial cancer is restricted to early stage cancers in postmenopausal women. Cataract surgery is required almost twice as often among women taking tamoxifen. Although no formal risk-benefit CHAPTER 16 THE BREAST 351 analysis is currently available, the higher a womans risk o f breast cancer, the more likely it is that the reduction in the incidence of breast cancer conveyed by tamoxifen will outweigh the risk of serious side effects. EPIDEMIOLOGY AND NATURAL HISTORY OF BREAST CANCER Epidemiology. Breast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for women age 40 44 years. It accounts for 33 percent of all female cancers and is responsible for 20 percent of the cancer-related deaths in women. It is predicted that approximately 211,240 invasive breast cancers will be diagnosed in women in the United States in 2005 and 40,410 of those diagnosed will die from that cancer. Breast cancer was the leading cause of cancer-related mortality in women until 1985, when it was surpassed by lung cancer. In the 1970s, the probability of a woman in the United States developing breast cancer was estimated at one in 13, in 1980 it was 1:11, and in 2002 it was 1:8. Cancer registries in Connecticut and upper New York state document that the age-adjusted incidence of new breast cancer cases has steadily increased since the mid-1940s. This increase was about 1 percent per year from 19731980, and there was an additional increase in incidence to 4 percent between 1980 and 1987, which was characterized by frequent detection of small primary cancers. The increase in

breast cancer incidence occurred primarily in women age 55 years or older and paralleled a marked increase in the percentage of older women who had mammograms. At the same time, incidence rates for regional metastatic disease dropped and breast cancer mortality declined. From 1960 1963, 5-year overall survival rates for breast cancer were 63 and 46 percent in white and African Americanwomen, respectively, although the rates for 19811987 were 78 and 63 percent, respectively. Natural history. Bloom and colleagues described the natural history of breast cancer based on the records of 250 women with untreated breast cancers who were cared for on charity wards in Middlesex Hospital, London, between 1805 and 1933. The median survival of this population was 2.7 years after initial diagnosis. The 5- and 10-year survival rates for these women were 18.0 and 3.6 percent, respectively. Only 0.8 percent survived for 15 years or longer. Autopsy data confirmed that 95 percent of these women died of breast cancer, although the remaining 5 percent died of other causes. Almost 75 percent of the women developed ulceration of the breast during the course of the disease. The longest surviving patient died in the nineteenth year after diagnosis. HISTOPATHOLOGY OF BREAST CANCER

DEFINISI Fibroadenoma adalah benjolan padat yang kecil dan jinak pada payudara yang teridiri dari jaringan kelenjar dan fibrosa. Benjolan ini biasanya ditemukan pada wanita muda, seringkali ditemukan pada remaja putri. PENYEBAB Penyebabnya tidak diketahui. GEJALA Benjolan mudah digerakkan, batasnya jelas dan bisa dirasakan pada SADARI (Pemeriksaan Payudara Sendiri). Teraba kenyal karena mengandung kolagen (serat protein yan gkuat yang ditemukan di dalam tulang rawan, urat daging dan kulit).

SADARI (Pemeriksaan Payudara Sendiri) 1. Berdiri di depan cermin, perhatikan payudara. Dalam keadaan normal, ukuran payudara kiri dan kanan sedikit berbeda. Perhatikan perubahan perbedaan ukuran

2.

3. 4.

5.

6.

antara payudara kiri dan kanan dan perubahan pada puting susu (misalnya tertarik ke dalam) atau keluarnya cairan dari puting susu. Perhatikan apakah kulit pada puting susu berkerut. Masih berdiri di depan cermin, kedua telapak tangan diletakkan di belakang kepala dan kedua tangan ditarik ke belakang. Dengan posisi seperti ini maka akan lebih mudah untuk menemukan perubahan kecil akibat kanker. Perhatikan perubahan bentuk dan kontur payudara, terutama pada payudara bagian bawah. Kedua tangan di letakkan di pinggang dan badan agak condong ke arah cermin, tekan bahu dan sikut ke arah depan. Perhatikan perubahan ukuran dan kontur payudara. Angkat lengan kiri. Dengan menggunakan 3 atau 4 jari tangan kanan, telusuri payudara kiri. Gerakkan jari-jari tangan secara memutar (membentuk lingkaran kecil) di sekeliling payudara, mulai dari tepi luar payudara lalu bergerak ke arah dalam sampai ke puting susu. Tekan secara perlahan, rasakan setiap benjolan atau massa di bawah kulit. Lakukan hal yang sama terhadap payudara kanan dengan cara mengangkat lengan kanan dan memeriksanya dengan tangan kiri. Perhatikan juga daerah antara kedua payudara dan ketiak. Tekan puting susu secara perlahan dan perhatikan apakah keluar cairan dari puting susu. Lakukan hal ini secara bergantian pada payudara kiri dan kanan. Berbaring terlentang dengan bantal yang diletakkan di bawah bahu kiri dan lengan kiri ditarik ke atas. Telusuri payudara kiri dengan menggunakan jari-jari tangan kanan. Dengan posisi seperti ini, payudara akan mendatar dan memudahkan pemeriksaan. Lakukan hal yang sama terhadap payudara kanan dengan meletakkan bantal di bawah bahu kanan dan mengangkat lengan kanan, dan penelusuran payudara dilakukan oleh jari-jari tangan kiri.

Pemeriksaan no. 4 dan 5 akan lebih mudah dilakukan ketika mandi karena dalam keadaan basah tangan lebih mudah digerakkan dan kulit lebih licin.

DIAGNOSA Diagnosis ditegakkan berdasarkan gejala dan hasil pemeriksaa fisik. Benjolan cenderung berbentuk bundar dan memiliki pinggiran yang dapat dibedakan dengan jaringan payudara di sekitarnya, sehingga seringkali teraba seperti ada kelereng di dalam jaringan payudara. Untuk membantu menegakkan diagnosa biasanya dilakukan aspirasi jarum atau biopsi. PENGOBATAN Fibroadenoma seringkali berhenti tumbuh atau bahkan mengecil dengan sendirinya. Pada kasus seperti ini, tumor biasanya tidak diangkat. Jika fibroadenoma terus membesar, maka harus dibuang melalui pembedahan.

21.1 Benign conditions of the breast

The demand for specialist treatment of patients with breast disease is increasing for several reasons. Firstly, the subject has become more complex, and an integrated approach involving not only surgeons but also radiologists, radiotherapists, pathologists, and medical oncologists is necessary. Secondly, the scope of the subject has increased dramatically. Not long ago the majority of surgeons who dealt with breast disease perceived their role as little more than differentiating benign conditions from malignancy and treating the latter. Patients now demand specific management of benign disorders that were previously ignored. Increased understanding of the relation between benign and malignant disease has increased awareness of conditions previously dismissed as benign changes', mastitis, or fibroadenosis. Finally, the development of new therapeutic and diagnostic methods, such as screening, breast conservation, and adjuvant chemotherapy, has increased the complexity of the management of breast cancer itself. Many institutions have now developed specialized breast disease units with surgeons having a special interest and training.

Anatomy and physiology of the breast

Development The breasts are modified sweat glands in that they are embryologically derived from a downward growth of ectoderm into the underlying mesenchyme. The first stage of development occurs at 6 or 8 weeks of gestation, when two strips of thickened ectoderm, the mammary ridges, grow in a line extending from the embryonal axilla to the inguinal region. In many animals breasts develop along the whole length of this ridge, but in humans true breast tissue occurs only in the pectoral region. Branching epithelial cords appear as 15 to 20 buds, which eventually become lactiferous ducts and associated alveoli. Each cord becomes surrounded by a stroma of mesenchymally derived fat, connective tissue, and vascular tissue. These cords form the basis of the segmental pattern of the adult breast. Towards the end of gestation the lactiferous ducts become canalized and open on to a pit in the epidermis. At the same time, mesenchymal proliferation beneath the epidermis allows nipple development; failure to do so results in inversion. Lobular development within the breast occurs particularly at puberty, with the ultimate development of 15 to 20 lobes, each of which drains into a single lactiferous duct; true secretory alveoli develop only during pregnancy and lactation. Few breast changes occur in the early years of childhood. However, at the age of 10 years there is growth of mammary tissue beneath the areola, producing a characteristic protuberance on the chest wall called the breast bud or mound. True nipple development occurs at about the age of 12 years, followed 2 or 3 years later by further subareolar growth and the formation of the bulk of the breast tissue. Finally, there is areolar recession, resulting in the classical shape of the adult breast. These changes at puberty are a result of the action of follicle-stimulating and luteinizing hormones, produced by hypothalamic stimulation of the pituitary gland on oestrogen production from the ovary. The anatomy of the adult breast Gross anatomy

Although the adult breast varies greatly in size, its base is fairly consistent anatomically, extending from the second to the sixth rib in the midclavicular line and overlying the pectoralis major, serratus anterior, and external oblique muscles. Medially, the breasts reach the sternal edge and laterally the midaxillary line. The pyramidal axillary tail extends into the axilla. The fascial covering of the breast is of importance to surgical technique. As it develops from the skin the breast is invested with superficial fascia, which divides into two layers. The anterior layer provides a plane of dissection subcutaneously between the relatively small, subcutaneous fat lobules and the larger lobules of mammary fat. The posterior layer of superficial fascia abuts the deep fascia derived from the pectoralis major and serratus anterior, thus producing a potential space; this retromammary space is easily located surgically (Fig. 1). Fig. 1. The fascial coverings of the breast. Between the two layers of superficial fascia there are condensations of fibrous tissue. These form the suspensory ligaments of Cooper, which both divide the breast into lobes and act as a supportive framework. Blood supply The breast has a rich vascular supply from the internal mammary artery and from the thoracoacromial, subscapular, and lateral thoracic branches of the axillary artery. The main supply is via the second perforating branch of the internal mammary and lateral thoracic arteries; the former should be preserved during subcutaneous mastectomy. The regional venous drainage forms a rich subareolar plexus that drains via the intercostal, internal mammary, and axillary veins. Lymphatic drainage The lymphatic drainage of the breast has obvious implications in the management of breast cancer and has been well documented in an elegant series of studies by Turner-Warwick. Approximately 75 per cent of the lymphatic vessels drain to the 30 or so regional lymph nodes in front of and below the axillary vein. These nodes can conveniently be subdivided into three main groups according to their relation to the pectoralis minor muscle: nodes at level 1 lie below the muscle, level 2 lymph glands lie behind it, and those of level 3 are in the apex of the axilla above the muscle. Most lymph drains from nodes at level 1 sequentially to those at levels 2 and 3; a small amount drains to the subscapular and interpectoral (Rotter's) groups of nodes. Extension of tumour to these latter nodes may imply retrograde spread and heavy involvement of axillary nodes by metastases (Fig. 2). A small amount of lymph drains from the superior aspect of the breast directly to the apical nodes. These pathways account in part for the well-documented, but relatively unusual, findings of nodal disease at level 3 but negative nodes in the lower axillary chain. Fig. 2. The anatomy of the axilla showing lymph-node groups, major vessels, and nerves: (1) most lateral border of level 1 at medial border of latissimus dorsi; (2) central portion of level 2; (3) most medial border of level 3 at Halstead's ligament. About 25 per cent of lymph drains to the internal mammary nodes in the second, third, and fourth intercostal spaces. This drainage is from the whole breast, although the majority of these pathways arise in its medial half. Some lymph drains to the opposite breast and down the rectus sheath. Drainage to the contralateral axilla and to

intercostal nodes via the pectoral fascia is, however, minor. Similarly, there are few direct lymphatic communications between the breast and the nodes above the axillary vein. The distribution of major lymphatics accompanies the blood supply. The original description by Sappey in 1885 of a subareolar plexus that receives lymph centripetally and then redirects it to the axilla has been discounted. Innervation The nervous supply to the breast is primarily by sensory and sympathetic nerves; little parasympathetic innervation has been demonstrated. The nipple has a rich sensory supply, whereas most of the sympathetic innervation is to the breast parenchyma. Microscopic anatomy The microscopic anatomy of the breast is a complex subject that has been the source of much controversy and confusion. Basically, there is a system of major ducts arranged in a segmental and radial pattern; these lead to the secretory component of the breast, the terminal ductallobular unit. The breast is thus subdivided into lobes, although these are not precisely defined anatomically. The interlobar fascia (the most prominent of which are Cooper's ligaments) is dense and fibrous, whereas the periductal and intralobular connective tissue is much more loose and vascular. The connective tissue round the lobule is particularly loose, allowing expansion during pregnancy and lactation (Fig. 3). Fig. 3. A normal lobule composed of multiple acini with surrounding loose connective tissue (by courtesy of Dr D. Tarin). The terminal ductule' of the terminal ductallobular unit has two components (Fig. 4): one lies outside the lobule and is known as the extralobular terminal ductule; the other lies within the lobule (intralobular terminal ductule). The terminal ramifications of the intralobular terminal ductule form the secretory units of the breast (terminal ductules or acini), with morphological similarity to the terminal units of respiratory alveoli in the lung. Fig. 4. The structure of the terminal ductal lobular unit (TDLU). The whole subject is complex because of difficulties with nomenclature. The term terminal duct' has been used for both the smallest epithelial unit in the lobule and the largest duct that opens on to the nipple surface. The same term has been used interchangeably with tertiary duct', ductule', and terminal ductule'. The problem is compounded by some authorities wishing to retain the term acinous' only for those terminal units during breast-feeding. Histologically, that part of the duct system adjacent to the skin of the nipple is lined with stratified squamous epithelium. However, a sudden change to a double layer of columnar or cuboidal epithelium characterizes the remainder of the duct system. The terminal ductules (acini) can undergo secretory changes and therefore have a role of both transport and secretion. Between the epithelial cell layers and the basement membrane is a network of myoepithelial cells; these respond to oxytocin and are responsible for milk ejection during lactation. Physiological changes in the breast Changes during the menstrual cycle

Despite widespread anecdotal belief to the contrary, there is little evidence of substantial histological change in the breast throughout the different phases of the menstrual cycle. Retention of fluid may occur during the luteal phase, but this does not appear to be associated with morphological change. Changes during pregnancy and lactation The main histological change that occurs in the breast during pregnancy is lobular alveolar growth and the development of new secretory units; this gives rise to the characteristic microscopic description of adenosis of pregnancy' (Fig. 5). It is characterized histologically by alveolar dilatation and conversion of the resting twolayer epithelium to a monolayer that demonstrates secretory changes. Colostrum formation, capillary growth, vascular engorgement, and myoepithelial cell hypertrophy are also apparent as pregnancy progresses. There is a doubling of breast weight from about 200 to 400 g, much of which is due to fluid retention. These changes occur under the influence of increased concentrations of luteal and placental sex hormones, placental lactogens, and chorionic gonadotrophins. Fig. 5. Adenosis of pregnancy: there is alveolar dilation and additional secretory units (by courtesy of Dr D. Tarin). Although some colostrum is formed within the breast during pregnancy, true milk is not produced until about 2 days after parturition; this occurs due to the high post-partum concentrations of prolactin, which are maintained despite falling concentrations of other sex hormones that normally inhibit lactogenesis. During lactation the alveoli are distended with milk, the cells become cuboidal, and there is a resultant diminution of the intralobular space. On cessation of breast-feeding there is gradual return to the non-pregnant state; this may take as little as 3 months, but in some individuals may take much longer. This process, known as postlactational involution, is characterized histologically by lymphocytic infiltration and hyalinization of the lobules (Fig. 6). There is, however, little or no reduction in the number of ducts and lobules present. Fig. 6. Postlactational change: in one area of the lobule is adenosis of pregnancy; elsewhere there is a decrease in the number of acini, an increased amount of fibrous tissue, and lymphocytic infiltration (by courtesy of Dr D. Tarin). Changes at the menopause Involutional changes occur from about the age of 35 years, with regression of glandular tissue and its replacement by fat and fibrosis. Before the age of 50 years this process is characterized by loss of some lobular tissue; in older women, its progression results in the almost complete replacement of lobular tissue by collagen and fat. The end result is that, although major duct systems are visible, few lobules are seen. This is in contrast to postlactational involution, which is characterized by minimal loss of lobular units. Changes at the menopause have two important clinical implications. Firstly, fat infiltration of the breast produces the low-density appearance of the parenchyma seen on mammography, and thus makes this technique more successful in older woman. Secondly, aberrations of this involutional change may explain some of the benign

disorders that occur in this age group.

Breast milk
It is not the purpose of the present discussion to elaborate on the advantages and disadvantages of breast-feeding. However, breast milk from a healthy mother allows normal development of an infant for 6 months or longer without need for any supplementation. In many underdeveloped countries, breast-feeding provides a major source of nutrition for the infant for up to 2 years. Breast-feeding will continue despite a poor nutritional state of the mother. Breast milk has a relatively low protein content; that present is in the form of casein and lactoglobulin. Carbohydrate is present as lactose, and fat as triglyceride. Human breast milk is rich in vitamins C and D, and is a source of IgA. It is therefore important in helping provide an immune mechanism for the newborn. A number of drugs are transmitted in breast milk; this should always be taken into account when prescribing for breast-feeding women. Of particular importance are alcohol, barbiturates, anticoagulants, tetracycline, and metronidazole.

Benign breast disease

Until recently, benign disorders of the breast were regarded as relatively unimportant; far more attention was focused on breast cancer. As a result, many patients with benign breast disease received rather scant attention from clinicians. There has been relatively little academic investigation into this complex subject. Benign breast disease has also suffered from the major disadvantage of a hopelessly confusing terminology, inadequate classification, and poor correlation between clinical, radiological, and pathological features. During the past decade there has been increasing interest in benign breast disease for a number of reasons. Firstly, patients demand investigation and treatment for symptoms of benign disease, which, in turn, has increased the number of women referred to specialist breast disease units; these have participated in scientific studies on the classification and treatment of their condition. Secondly, there is the question of premalignant disorders and histological features that may imply an increased risk of breast cancer. Increasing understanding of these conditions may prove important in understanding the pathogenesis of breast cancer and in defining highrisk groups in whom regular surveillance may be beneficial. Finally, the recently introduced breast screening programmes are likely to present pathologists and clinicians with as yet ill-defined histological entities that may be of importance in understanding the development of invasive cancer and its eventual treatment. Classification There is no completely satisfactory classification of benign breast disease. Previous attempts have been based on a number of different factors such as clinical symptoms, patient age, histological features, or that part of the secretory system in which the abnormality has arisen. They all have inherent disadvantages. Firstly, there is poor correlation between clinical, pathological, and radiological features in any particular case. Secondly, benign breast disorders encompass a wide spectrum of clinicopathological features, ranging from near normality to severe disease. Finally, the breast must be regarded as a physiologically dynamic structure in which

cyclical variations are superimposed on changes of development and involution throughout the woman's life. These physiological changes may themselves be so extensive that they fall outside what is regarded as the normal spectrum. The histological features of an individual abnormality must therefore be evaluated within the context of a wide range of normality. It has therefore been suggested that the broad concept of benign breast disease should be reconsidered. Many so-called diseases of the breast might now be regarded more accurately as disorders that are based on aberrations of the processes of development, cyclical change, and involution (aberrations of normal development and involution; ANDI). This does not mean that benign breast disease does not occur, but that the term should be reserved for disorders of such severity that they are frankly abnormal. This concept is, of course, rather ill defined and will depend on interpretation and perception by both patient and clinician. Aberrations of normal development and involution can account for many, if not all, benign breast disorders. A simplified system based on the various stages of physiological change (development, cyclical change, pregnancy, lactation, and involution) is shown in Table 1. It follows that most conditions listed under benign breast disorders' can be regarded as minor aberrations of normal development or involution. Many patients with these conditions require reassurance rather than specific treatment, and explanation that they do not have a disease process. Table 1 Classification of the pathogenesis of non-malignant breast disease based on the concept of aberration of normal development and involution This approach is well demonstrated in patients with cyclical mastalgia and nodularity. The vast majority of premenopausal women experience a degree of breast discomfort and increasing nodularity before menstruation. For most, this amounts to little more than an inconvenience and is regarded as a normal physiological process. About 2 or 3 per cent of women are referred to a clinic with cyclical mastalgia, the symptoms of which are more severe, with distressing discomfort lasting a week or more. Despite exhaustive investigation there is little evidence of any specific histological or endocrinological abnormality in these women with more severe cyclical breast pain, and if abnormal microscopic features are observed they correlate poorly with clinical features. Thus, these women with severe cyclical mastalgia are regarded not as having a disease process but as representing an extreme, or aberration, of the normal developmental and involutional processes that occur with each menstrual cycle. Only in exceptional cases may the term disease' be cautiously adopted for patients with breast pain. It follows that cyclical mastalgia and nodularity, like other benign breast conditions, must be regarded in its broadest terms. Symptoms Despite the complexity of its classification there are relatively few presenting symptoms of benign breast disease. Symptoms fall into three main groups: breast pain, lumps, and disorders of the nipple and periareolar region. Infection of the breast causes further symptoms. As has been previously stated, attempts to correlate

pathological and radiological findings with clinical features are a cause of much confusion and should be discouraged. A working clinical classification of benign breast disease is shown in Table 2, although it must be stressed that this does not imply whether the process is physiological or pathological, and in no way does it attempt to correlate symptoms with pathological features. Table 2 Symptoms of benign breast disease Finally, it must be remembered that the reason for many referrals is anxiety on the part of either the patient or her doctor, which accounts for the increasing number of patients seen with non-breast conditions, including skin rashes and chest-wall pain. An important function of any breast clinic is not only to treat symptoms but also to allay the patient's fears of breast cancer. Breast pain (mastalgia) Pain is the most common reason for referral to a breast clinic and accounts for up to 50 per cent of patients seen. It is, however, the least understood of all breast symptoms, and the one whose management causes the most controversy. Reports on breast pain are often anecdotal, uncontrolled, and of poor quality. Nomenclature poses a major problem: a number of different terms, such as mastitis, mastodynia, and mazoplasia, have been used to describe breast pain. Mastalgia has also been correlated with specific histological criteria, resulting in its description as fibrocystic disease', although this has lost favour for reasons described above. It must be stressed that mastalgia is a symptom and does not imply any specific pathological process, any more than does pain in other sites of the body. Classifications Attempts to classify breast pain are surprisingly recent. There are two distinct group of patients with these symptoms (Table 2): one group has symptoms that bear a definite relation to the menstrual cycle (cyclical mastalgia); in the remainder there is no such correlation (non-cyclical mastalgia). Non-cyclical mastalgia has recently been reclassified to distinguish pain in the breast from that originating in surrounding tissues such as the chest wall. Cyclical mastalgia This is the most common type of breast pain, accounting for 40 per cent of all cases referred to a breast clinic. There is an important correlation with the menstrual cycle, with discomfort lasting for a varying period of time before menstruation. Because of this cyclical relation, mastalgia is generally a condition of premenopausal women, with a median presenting age of about 35 years. Characteristically, the features of cyclical mastalgia wax and wane. Episodes of discomfort may last for some months; there may then be years of freedom until symptoms begin again. The pain of cyclical mastalgia is frequently, but not always, bilateral and is usually located in the upper, outer quadrants. It is poorly localized and may radiate across the chest wall into the axilla or down the inside of the arm. The breasts are frequently described as being heavy' as if pregnant, and many patients describe marked nodularity at the time of the discomfort. There is a wide spectrum of symptoms in cyclical mastalgia. The majority of patients have only mild discomfort lasting 2 or 3 days before menstruation and are not unduly concerned. Such individuals are therefore best classified as having a breast disorder' (ANDI) rather than a disease. The small minority who have severe symptoms lasting throughout the cycle with relief only during menstruation are those to whom the term disease' may be applied.

There are no mammographic or pathological characteristics of cyclical mastalgia: indeed this lack of correlation between clinical, radiological, and histological findings is one of the major characteristics of the condition. The mammograms shown in Fig. 7 are from patients with severe breast pain. In one there is almost complete replacement with fat, giving a translucent appearance, whereas the other is dense and nodular (Wolfe DY pattern). Fig. 7. Mammograms in patients with breast pain: in one the breast is radiologically translucent whereas the other is dense and nodular, the Wolfe DY pattern (by courtesy of Dr B. Shepstone). Aetiology The fact that symptoms of cyclical mastalgia correlate with the menstrual cycle implies a hormonal background. Early investigations suggested that hormonal imbalance was the cause, the fundamental abnormality being relative hyperoestrogenism due to either increased oestrogen secretion or deficient progestogen production. However, the vast majority of studies have failed to demonstrate either abnormality in women with mastalgia. More recently, abnormal prolactin secretion has been incriminated as an aetiological factor in cyclical mastalgia. Although both random and basal concentrations of prolactin are normal in women with cyclical mastalgia, there is some evidence of impaired hypothalamic control of the release of this hormone in patients with severe symptoms. It should be appreciated, however, that the control of prolactin release is extremely complicated and that our current knowledge of its physiology is rather rudimentary. The belief that cyclical mastalgia has a hormonal basis resulted in the suggestion that there would be an associated effect on fluid retention. However, despite a widespread belief that breast pain is due to water retention, this has never been scientifically confirmed. Other aetiological factors, including excessive caffeine ingestion or inadequate essential fatty acid intake, have been suggested. The latter is of particular interest as there is good evidence that unsaturated fatty acid supplements can reduce the symptoms of cyclical mastalgia. The actual mechanism is unclear, but it may relate to correcting the amounts of prostaglandin E1 in epithelial cell membranes and the subsequent effect of prolactin on breast sensitivity. Psychoneurosis has been widely incriminated as an important factor. However, there is no evidence of excessive anxiety, depression, or phobia in these patients when they are evaluated against appropriate control groups. Treatment More than 80 per cent of women attending a breast clinic with cyclical mastalgia require no treatment other than simple reassurance, particularly that such symptoms do not imply any form of neoplastic process. Fear of cancer drives many women to seek specific advice about breast pain, and the importance of such reassurance cannot be overemphasized. About 5 to 10 per cent of patients with cyclical mastalgia experience pain despite all reassurance. For them, specific drug therapy may be considered. There is a sound theoretical basis for the use of most, but not all, agents that have been tried, despite the fact that no constant physiological or pathological changes have been identified in this condition. Furthermore, no drug satisfies the criteria of being universally effective, free from side-effects, and freely available for use in patients

suffering from benign breast disease. A large number of studies evaluating the efficacy of these drugs have been performed. However, because of the placebo effect of such treatment the results of many studies are inherently flawed, and reliance can only be placed on prospective, randomized, placebo-controlled trials. A further problem of many studies is that they do not take into account the natural history of mastalgia. As a result a false impression of benefit may occur merely from natural remission, such as occurs in pregnancy or at the menopause. Table 3 shows some of the agents widely used for the treatment of cyclical mastalgia, their possible modes of action, and common side-effects. Their overall efficacy is shown in Table 4. Table 3 Drugs used for treatment of cyclical mastalgia Table 4 Efficacy of drugs used for cyclical mastalgia Unproved therapies Diuretics have been widely prescribed, although there is little rational basis for their use, and it is widely believed that much of their efficacy is due to a placebo effect. Similarly, there is no rationale for using antibiotics. The concept of relative hyperoestrogenism as a result of luteal deficiency has stimulated the evaluation of progestogens in cyclical mastalgia; the results have been generally disappointing in placebo-controlled trials. Other widely adopted treatments of cyclical mastalgia, such as vitamins A or B6, have failed to show any effect on cyclical mastalgia. Oral contraceptives may reduce the symptoms of cyclical breast pain, but total success can by no means be guaranteed. A possible metabolic effect produced by xanthine administration in the form of caffeine has resulted in a vogue for recommending decaffeinated drinks for patients with breast pain, this approach has not been validated in clinical studies. Tamoxifen Relative hyperoestrogenism can also be treated with the antioestrogen drug tamoxifen, which was shown to be of benefit in randomized trials but as yet only has a licence for use in malignant disease. Pain relief is provided by 10 mg tamoxifen daily; there seems little benefit in increasing the dose. Side-effects such as weight gain and hot flushes are troublesome, and, as tamoxifen is contraindicated in pregnancy, appropriate contraception is necessary. Despite these potential problems, tamoxifen is increasingly used for patients with mastalgia. Danazol Danazol probably acts as an antigonadotrophin by its effect on the pituitaryovarian axis. At a dose of 200 to 400 mg daily it depresses production of follicle-stimulating and luteinizing hormones, and ovarian function. It significantly reduces breast pain, but is associated with side-effects in 20 per cent of patients: these include weight gain, acne, amenorrhoea, masculinization with hirsutism, voice changes, and reduction of breast size. Adequate non-hormonal contraception is necessary. Bromocriptine The suggestion of abnormal prolactin concentrations in patients with cyclical mastalgia, and the possibility that prolactin stimulates glandular breast tissue, led to hopes that the specific prolactin-lowering agent bromocriptine would be useful in the treatment of cyclical mastalgia. This, a dopamine agonist, significantly reduced symptoms of cyclical mastalgia in benign breast disease. However, as with danazol, its use has been curtailed by side-effects, such as nausea,

postural hypotension, vomiting, and dizziness, which occur in up to 20 per cent of patients. Evening primrose oil Although it is regarded as homeopathic by many patients and their doctors, there is, in fact, a pharmacological basis for the use of evening primrose oil. As discussed above, prostaglandin E1 appears to influence the sensitivity of breast epithelium to hormones such as prolactin; it is synthesized via the following pathway: Interest in the relation between fat intake and breast cancer risk resulted in studies evaluating the effect of dietary fat in benign disease. Women with breast pain have significantly higher concentrations of circulating saturated fatty acids than controls. Furthermore, the saturated to unsaturated fatty acid ratio is inverted in favour of saturated fat in patients with breast pain. According to the above pathway, this results in inhibition of prostaglandin E1 synthesis. The addition of unsaturated fatty acid to the diet in the form of gamolenic acid from evening primrose oil reverses the imbalance of saturated to unsaturated fat and is associated, in randomized controlled trials, with a significant reduction in breast pain. Side-effects are uncommon. A daily therapeutic dose of 320 mg of gamolenic acid is required; many non-prescription preparations of evening primrose oil fail to provide this dose. Summmary of treatment Patients with cyclical mastalgia should be treated initially with evening primrose oil, followed by danazol for those refractory to treatment. Bromocriptine is a third choice, with activity similar to that of evening primrose oil but a significant incidence of side-effects. The response rates tend to be lower for second and third lines of treatment. Tamoxifen has the drawback that it is not strictly registered for use in benign disease, but is increasingly used as second-line therapy after evening primrose oil. Responses to treatment are relatively short lived, usually of the order of 6 months. When using danazol, bromocriptine or tamoxifen it is our policy to treat for 3 months and then to see whether relapse occurs on cessation of therapy. Any relapse is an indication for restarting treatment, perhaps at a lower dose than originally used, or for a change in therapy if the initial response has been poor. Satisfactory treatment is particularly difficult in young women, in whom mastalgia is often resistant to treatment, whose potential for breast pain may span several decades, and whose fertility must be considered. Bromocriptine and danazol are potentially teratogenic; they also require the use of a barrier contraceptive because they interfere with oral contraceptives. Many younger women also dislike the amenorrhoea induced by tamoxifen and danazol. Occasionally, women with a long history of mastalgia unresponsive to all medical treatment demand consideration of mastectomy to release them from their discomfort. Although occasional patients may benefit from subcutaneous mastectomy, the general impression is that it should be avoided if at all possible. Case selection is all important if considering surgery. Non-cyclical mastalgia Non-cyclical mastalgia (Table 2) is even less well defined than its cyclical counterpart. It occurs in both pre- and postmenopausal women, with a median age of presentation of 45 years. As well as having no close relation to the menstrual cycle, non-cyclical mastalgia tends to be more chronic, unilateral, and located in the

medial quadrants of the breast or the periareolar regions. It is not associated with lumpiness to the same degree as cyclical mastalgia, and the pain is frequently described as burning' or dragging' rather than a heavy feeling'. The mastalgia is sometimes well localized; the term trigger spot zone' has been used in these individuals. Attempts to classify non-cyclical mastalgia have been compromised by the dubious inclusion of other conditions that may cause breast pain, the best example of which is duct ectasia/periductal mastitis. The inclusion of this condition was based on the mammographic appearances of many patients with non-cyclical mastalgia, which showed widespread, coarse calcification throughout he substance of the breast, also a feature of duct ectasia/periductal mastitis. However, the use of this term for patients with non-cyclical mastalgia has fallen into disfavour because of the principle of not mixing symptomatology with pathology, and because of lack of evidence that the pathological changes of duct ectasia correlate with breast pain. Up to 50 per cent of patients with non-cyclical mastalgia have pain that arises not from the breast but from surrounding musculoskeletal structures (Table 2). A careful history and examination will identify these patients, who, unlike those with true noncyclical mastalgia, can be provided with relatively simple and effective therapy. Aetiology The aetiology is unclear, but some of the factors associated with cyclical mastalgia may also be associated with non-cyclical breast pain. Treatment The management of true non-cyclical mastalgia is unsatisfactory. Many principles in the treatment of cyclical mastalgia may be applied to non-cyclical breast pain, but overall response rates to various drug therapies are only about 50 per cent of those observed in patients receiving treatment for cyclical mastalgia. Both bromocriptine and evening primrose oil have shown particularly disappointing results. Response rates to the various drugs improve if patients with true non-cyclical mastalgia are differentiated from those with musculoskeletal pain. Some success has been ascribed to surgical excision of trigger spot zones', but this approach has not been widely adopted. Other causes Musculoskeletal pain This had previously been included as a cause of non-cyclical mastalgia, but was recently shown to be a separate entity. It is the most common cause of apparent pain in the breast originating from other sites. Musculoskeletal pain is often unilateral and localized along the lateral chest wall or the costochondral junction (Tietz syndrome). Injection of local anaesthetic or steroids into the affected area produces good relief of symptoms. Sclerosing adenosis This may be found microscopically either as a single entity or in association with other abnormalities. It may be a minimal histological change or a macroscopically obvious condition. It is classified as an ANDI; microscopically it is characterized by proliferation of terminal duct lobules, myoepithelial cell proliferation, increased number of acini, and fibrous stromal change (Fig. 8). Multifocal and nodular types are described; either may be painful and have been documented as a cause of mastalgia. Fig. 8. Sclerosing adenosis: note proliferation of duct lobules, increased number of acini, and fibrosis (by courtesy of Dr D. Tarin). The pain associated with sclerosing adenosis may be due to perineural invasion, and this may account for some patients with trigger spot zones'. The main

importance, however, is that macroscopically sclerosing adenosis may have a stellate appearance and may calcify: it may thus mimic carcinoma, both clinically and radiologically. The increased cellularity associated with sclerosing adenosis has been confused with carcinoma histologically, especially when examining frozen sections. Previous surgery A small number of patients continue to complain of pain after biopsy for benign breast disease. There is no clear reason for this, although if the biopsy was performed in an area already subject to mastalgia it is likely that the original process will continue and be painful. Cancer Cancer is an uncommon cause of breast pain, although women do occasionally complain of discomfort, which may be more pronounced before menstruation, at the site of a tumour. The author has seen one young, intelligent woman complaining solely of breast pain, while failing to notice that the breast had been largely replaced by tumour. Referred cervical root pain This cause of pain in the breast should be considered in elderly patients in whom no other cause for mastalgia can be found. Benign breast lumps Approximately 40 per cent of all patients attending a breast clinic have a benign breast lump (Table 2). In the past there was a tendency to excise all lumps, and an excessive amount of unnecessary surgery was performed for benign disease. The main problem from the woman's point of view is fear that such a lump may be cancer. The clinician must therefore provide a high degree of diagnostic accuracy while at the same time ensuring that an excessive biopsy rate is prevented. It is now easier to exclude cancer with the development of diagnostic aids such as mammography, ultrasonography, and aspiration cytology. The surgeon in the breast clinic has two important tasks when confronted with a patient with a breast lump: firstly, to decide whether the lump is truly an abnormality, that is, different in consistency from the surrounding breast, or whether it can be regarded as being within the spectrum of normality; secondly, if the lump is a true abnormality, to determine whether it is malignant. The history is of particular importance. The lump's duration, pain, change in size, and relation to the menstrual cycle should be the subject of detailed enquiry. The presence of menstrual irregularity and a previous history of similar problems should be sought. It is also important to enquire into the patient's risk factors for breast cancer, such as her age, number of children, age at first pregnancy, family history, and other potential predisposing factors such as hormone replacement therapy or oral contraceptive use. Having established the risk or otherwise for breast cancer, the clinical impression must be confirmed by careful examination. Tethering of the skin, distortion of the breast, and nipple retraction are common features of malignancy, but they can also occur as a result of benign change. Mobility of the lump should be assessed: this is characteristic of a fibroadenoma and also quite obvious in cysts. Cancers tend to be more fixed, but are occasionally quite mobile. Finally, the surface of the lump should be assessed. Fibroadenomas have a lumpy, bosselated surface whereas cysts are usually smooth and tense. Cancerous lumps are usually, but not always, hard. While a cancerous lump is likely to be hard, irregular, and fixed, it is not uncommon to see malignant tumours that are firm, quite regular, and have a degree of mobility.

If there is any doubt, a pathological diagnosis or biopsy is necessary; this should always be undertaken in any woman over the age of 25 years with a solid, discrete lump. In the majority of patients, aspiration cytology is sufficient, but if this is in any way unsatisfactory, or if any doubt remains, then biopsy is mandatory. It is a daring clinician who does not remove a discrete breast lump from a 40-year-old nulliparous woman with a family history of breast cancer even if fine-needle aspiration cytology is benign and mammography is reassuring. Fibroadenomas and associated conditions Fibroadenoma and related tumours are derived from the breast lobule and are characterized by proliferation of both connective tissue and epithelium. They encompass a wide spectrum of conditions, ranging from the totally benign simple fibroadenoma to locally invasive and, rarely, frankly malignant tumours. There has been great confusion over their pathogenesis, particularly at the more malignant end of the spectrum. Such are now commonly known as phyllodes tumours, but were previously described as cystosarcoma or phyllodes sarcoma. Those descriptions are inappropriate because they imply a totally mesenchymal stromal origin whereas all of these tumours, whether benign, locally invasive, or malignant, also have an epithelial component. The major features of fibroadenomas and associated conditions are summarized in Table 5. Table 5 Features of fibroadenoma and associated conditions Benign simple fibroadenoma Fibroadenomas are benign tumours showing evidence of both connective tissue and epithelial proliferation. They originate from the breast lobule and can be regarded as an aberration of normal lobular development rather than a true benign tumour. Their origin explains why fibroadenomas are common in young women at the time of lobular development, and why they are occasionally seen in combination with lobular carcinoma. The aetiology of a fibroadenoma is unknown; hypersensitivity to oestrogen within a lobule has been suggested. The most important pathological aspect of a fibroadenoma is its connective tissue stroma. In the past, great importance was attached to whether this stroma compressed adjacent ducts to form curved, slit-like structures (intracanalicular pattern) or whether it simply surrounded a duct circumferentially (pericanalicular pattern). The fibrous stroma of fibroadenoma has low cellularity and a regular cytology (Fig. 9). Occasionally there is histological evidence of fat, smooth muscle, squamous metaplasia, and infarction. The epithelial proliferation may be quite hyperplastic, but this is of no prognostic importance. Fig. 9. (a) Fibroadenoma: note the low cellularity and regular cytology of the benign fibroadenoma; (b) phyllodes tumour: note the hypercellularity, atypia, and abundant mitoses (by courtesy of Dr D. Tarin). If the fibrous stroma shows a marked increase in both cellularity and atypia, then the locally invasive and occasionally metastatic phyllodes tumour should be considered (see below). This entity can be regarded as an extreme end of the disease spectrum, the simple fibroadenoma representing the other end. Clinical features Most fibroadenomas present in young women 16 to 24 years old. However, with the use of pathological examination in the diagnosis of breast lumps in older women,

the overall median age of presentation is nearer 30 years. Fibroadenomas decrease in incidence after the menopause, when they undergo involution. During this time they may calcify and thus become apparent on mammography. As a result, they are commonly identified on mammographic screening programmes. Fibroadenomas are smooth or slightly lobulated structures, usually measuring about 2 or 3 cm in diameter. With the exception of those adjacent to the nipple, they are characteristically mobile. In young women the term breast mouse' is thus aptly applied. With increasing age the degree of mobility lessens because of the restraining effects of surrounding, involuting fibrotic tissue. In the elderly woman they can still present as a small, hardened mass that is still quite mobile. About 10 per cent of all patients have multiple fibroadenomas on presentation, and occasionally one sees young women in whom the whole breast seems to be replaced by fibroadenotic tissue. Others present with multiple recurrent fibroadenomas; this occurs particularly among black and oriental individuals. Diagnosis Up to the age of 25 years a clinical diagnosis will suffice, although diagnosis by aspiration cytology is preferable. Thereafter, pathological confirmation is required because of the need to exclude carcinoma, tubular cancers in particular being a source of clinical confusion. Fine-needle aspiration cytology provides an accurate method of diagnosis (Fig. 10), although hyperplastic epithelial cells can occasionally be mistaken for neoplasia. Fig. 10. (a) Fine-needle aspiration cytology of fibroadenoma: note the regular groups of benign epithelial cells with associated bare nuclei; (b) fine-needle aspiration cytology of phyllodes tumour: the aspirate shows gross cellularity, a hypercellular stroma, and atypia (by courtesy of Dr I. Buley). As fibroadenomas usually present clinically in younger women, mammography has little place in routine diagnosis. In older patients, fibroadenomas appear mammographically as a solitary, smooth lesion with a density similar to or slightly greater than that of the surrounding tissue. With increasing age, stippled calcification becomes apparent (Fig. 11). Fig. 11. Calcified fibroadenoma on mammography: note the smooth opacity with coarse calcification within its structure (by courtesy of Dr B. Shepstone). Management The practice of surgically removing all fibroadenomas has now been condemned because of greater understanding of the natural history of this condition. If left untreated, most fibroadenomas will slowly increase in size from 1 to 3 cm in diameter over a period up to 5 years. The active growth phase is about 6 to 12 months, during which time there is a doubling of size. Thereafter they remain static or may (in up to one-third of cases) gradually become smaller. In women under the age of 25 years, routine removal is unnecessary. This conservative approach may be recommended for women under 35 years old, provided that cytological examination, repeated after 3 months, rules out malignancy. Such a policy may, however, result in a small number of cancers being missed and removal of fibroadenomas is recommended by some authorities after the age of 25 years. Excision can be done under either local or general anaesthetic. Recurrence of a fibroadenoma after removal is uncommon. If there is recurrence, it may be due to a number of factors. Firstly, a truly metachronous fibroadenoma may

develop. Secondly, the original tumour may have been incompletely removed or missed at operation; and, finally, it may be the mode of presentation of a previously undiagnosed phyllodes tumour. Giant fibroadenoma Giant fibroadenoma has a bimodal age of presentation at the extremes of reproductive life; those occurring in the younger age group have been described as juvenile fibroadenomas. Giant fibroadenomas thus occur particularly in the 14- to 18- and the 45- to 50-year age groups, and are characterized by rapid growth to a large size. They are, by definition, bigger than the common type of fibroadenomas, being at least 4 or 5 cm in diameter, and sometimes achieving a diameter of 10 cm or more (Fig. 12). Fig. 12. A giant fibroadenoma 12 cm in size (by courtesy of Dr D. Tarin). Histologically, giant fibroadenomas contain the typical hypocellular stromal and epithelial components showing variable, though usually mild, degrees of hyperplasia and atypia; mitoses are uncommon. These features are different from those of phyllodes tumours, which generally exhibit much more cellularity, pleomorphism, and mitotic activity, but there is some overlap of microscopic appearances between these two conditions (Table 5). Clinical features Giant fibroadenomas are more common in black and oriental individuals. Clinically, patients present with pain in the breast associated with a rapid increase in size. On examination the breast is enlarged and the nipple may be displaced. The overlying skin frequently has a characteristic shiny appearance, and dilated veins may be apparent. In extensive, neglected cases, skin necrosis can occur. Occasionally, young women may present with unilateral breast enlargement and the fact that a mass is the cause is not appreciated. Giant fibroadenomas may be confused with virginal hypertrophy, although this bilateral and not associated with cutaneous or venous changes. Treatment Management is by enucleation through an appropriately cosmetic incision. While this treatment initially results in some discrepancy in breast size, the remaining breast tissue expands to virtual normality within a few months. Wide excision or mastectomy are contraindicated. Although some giant fibroadenomas can appear somewhat aggressive histologically and may even be confused with phyllodes tumour, their clinical behaviour is completely benign. There is no evidence that they recur locally with any frequency or metastasize. Phyllodes tumour Phyllodes tumours have been the cause of much misunderstanding and argument, partly related to their varied nomenclature. They have been described as phyllodes sarcoma, cystosarcoma, cystosarcoma phyllodes, and benign cystosarcoma. They have also been equated with giant fibroadenoma, but this is also misleading as it understates the malignant potential of the phyllodes tumour and implies a similar histological appearance. Conversely, terms such as cystosarcoma overstate the malignant potential and imply a false correlation with true mesodermally derived sarcomas. Phyllodes tumours show a wide spectrum of activity, varying from an almost benign condition to a locally aggressive, and sometimes metastatic, tumour.

Phyllodes tumours appear well circumscribed but are characterized by irregular surface projections that may be cut during surgical excision, predisposing to recurrence. The cut surface is soft, brown in colour, and may exhibit cysts, necrosis, or haemorrhage. Histologically, both epithelial and fibrous stromal elements are present, with the stroma showing hypercellularity, much atypia, and numerous mitoses (Fig. 9). Grading of phyllodes tumours is based on their mitotic index and degree of pleomorphism. Low-grade tumours have five or fewer mitoses per 10 highpower fields; high-grade phyllodes have a mitotic count of 10 or more. Grading may relate to liability to local recurrence. Clinical features Phyllodes tumours occur in premenopausal women. They are usually seen in the 30to 50-year age group, but are not uncommon in women aged about 20 years. They have the features of a common fibroadenoma but can grow rapidly to a large size and may involve much of the breast. The overlying skin may become reddened and, in advanced cases, can become frankly ulcerated. However, a degree of mobility is retained, even by large tumours. Axillary lymphadenopathy is uncommon; if it occurs it indicates an extremely aggressive form of the disease. Despite the tendency to grow rapidly to a large size it is not uncommon for phyllodes tumours to present as a much smaller mass that is clinically indistinguishable from a simple fibroadenoma. Treatment Phyllodes tumours occurring in young women under the age of 20 years are said to represent the benign end of the spectrum of this condition. As such, simple enucleation has been recommended, although the author prefers to excise the area more widely. Older patients require wider excision with a 1-cm margin of normal breast tissue. Vary large tumours or those with aggressive histological features may merit even wider excision, with quadrantectomy or even simple mastectomy and reconstruction for the largest. Even with an aggressive surgical policy of wide excision, approximately 25 per cent of phyllodes tumours recur over a 10-year period. Local recurrences should be widely excised. If recurrent tumours develop persistently, mastectomy with reconstruction should be considered. The tendency for recurrence is greater for large and histologically higher-grade tumours. A major worry with persistently recurrent phyllodes tumours is that they may metastasize, although this is a rare occurrence, being described in less than 5 per cent of patients. The most common site of metastasis is the lung. Adjuvant radiotherapy and chemotherapy have no proven role in the management of phyllodes tumour. Breast cysts Breast cysts are among the more common reasons for referral to a breast clinic. They are frequently confused with more extensive cyclical nodularity. The description of cyclical nodularity as fibrocystic disease compounds the problem, and results in the false hope that many patients with cyclical nodularity can be treated by simple cyst aspiration.

True breast cysts are very common: up to 7 per cent of women develop a clinical cyst at some time during their lives. Autopsy studies show that a further 20 per cent of women have evidence of subclinical cysts in the breast, although many of these are only 2 or 3 mm in diameter. As is the case with fibroadenomas, breast cysts can be regarded as an aberration of normal lobular physiology. The specific cause of this aberration is unknown, although there is some weak evidence that cyst formation may relate to hyperoestrogenism, such as may result from hormone replacement therapy. The pathogenesis of breast cysts is similarly unclear. Early workers suggested that they might simply be distended ducts or that they may result from cystic lobular involution. During this process, lobules develop microcysts, which eventually coalesce to become larger cysts; this change is potentiated by obstruction of lobular outflow and replacement of surrounding stroma by fibrous tissue. More recent investigations have suggested that the aetiology of breast cysts is more complex than previously believed. There appear to be two distinct populations of macrocyst defined by their microscopic appearance, their biochemical profile, and clinical features (Table 6). Table 6 Comparison of two types of breast cyst Aspirated fluid from simple, uncomplicated cysts has a high Na+:K+ ratio (greater than 3), similar to that found in plasma. The pH of this fluid is less than 7.4 and it is likely that the flat, rather featureless epithelium of these cysts acts as a simple membrane through which interstitial fluid passively diffuses. Simple cysts tend to be single, not recurrent, and are unlikely to be associated with an increased risk of cancer. The second type of cyst is lined by apocrine epithelium, characterized by large, columnar cells resembling those found in apocrine sweat glands. The Na +:K+ ratio is less than 3, and similar to that of interstitial fluid. The pH of apocrine cysts is higher than that of simple cysts and their lining membrane secretes substances such as androgen conjugates. These observations suggest that apocrine epithelium actively secretes potassium into the cyst fluid. Apocrine cysts tend to recur, as the balance between secretion of fluid and its reabsorption is in favour of reaccumulation. They may also be associated with an increased risk of breast cancer, although the overall evidence is weak on this issue. Other studies have shown that in the early stages of cyst development, microcysts are of the apocrine secretory type. It is only when macrocysts develop that differentiation into simple cysts occurs. Clinical features Cysts are classically seen in perimenopausal women between the ages of 45 and 52 years, although they frequently occur outside this age range, especially in individuals receiving hormone replacement therapy. They are usually single at presentation, but it is not uncommon to see multiple cysts in a breast. In the most extreme examples the whole breast seems to be composed of a number of cysts. A characteristic of breast cysts is that they suddenly appear, even if they are quite large. The reason for this is that the cyst exists in a flaccid, subclinical state before its presentation as a lump. The accumulation of a relatively small amount of fluid causes a disproportionate effect on intracystic pressure, according to La Place's equation (P = 2T/r).

Cysts may be uncomfortable and are often frankly painful. There may be a vague association between the discomfort and the menstrual cycle, with increasing pain before menstruation, although this is not a pronounced feature. Cysts are frequently visible. However, their most characteristic feature is their smooth, tense nature on palpation. They have a degree of mobility but this is not as pronounced as that of fibroadenomas. The classic clinical appearances may be masked if the cyst is situated deep in the breast. Normal nodular breast tissue overlying the cyst may hide its classic smoothness on palpation. The diagnosis of a simple breast cyst is straightforward, as aspiration confirms the diagnosis. The amount of fluid aspirated is variable: it is usually about 6 or 8 ml, although occasionally cysts containing 60 or 80 ml of fluid are encountered. Cyst fluid varies in colour, ranging from pale yellow to almost black; sometimes the aspirate appears translucent whereas on other occasions it is thick and turgid. Mammography and ultrasonography may aid diagnosis (Fig. 13) but these investigations are not essential in symptomatic patients. Little important information is gained from cytological examination of cyst fluid unless it is blood-stained. Fig. 13. (a) Breast cyst on mammography: note the well-delineated, homogeneous opacity; (b) breast cyst on ultrasonogram: note the well-delineated- homogeneous opacity (by courtesy of Dr B. Shepstone). Treatment Breast cysts were previously treated by surgical excision, but such treatment is no longer recommended as simple aspiration will normally suffice. After aspiration the cyst remains as a lax, impalpable structure that may still be seen on mammography. However, there must be no clinical evidence of a mass remaining after aspiration. If a mass does remain, further investigation with fine-needle aspiration cytology or biopsy is indicated. There are two main indications for surgical excision of the cyst. If the aspirate is bloodstained (as long as this is not due to direct trauma from the needle), the rare intracystic carcinoma may be present. The second indication, which is perhaps more contentious, is cyst recurrence. This may be due simply to inadequate aspiration and further such treatment may be attempted before excision. However, if the cyst recurs rapidly and more than twice, its excision is recommended. Patients who develop persistently recurrent cysts throughout their breasts can present a difficult management problem. Recurrence is often at a different site from the presenting cyst. Up to 15 per cent of patients develop further cysts over 5 to 10 years, although the majority will only have one or two recurrences. However, a small number of women develop recurrences regularly and may attend the breast clinic every 2 or 3 months for cysts to be drained. In the past some of these patients were treated by subcutaneous mastectomy. We now recommend danazol or tamoxifen, although evidence in favour of this treatment is sparse and there are side-effects and limitations associated with the use of these drugs. Although it does not aid diagnosis, mammography should be performed as a routine screening procedure on women over the age of 35 years presenting with cysts, but the yield of occult cancers is low. As there is some evidence of increased cancer risk, patients with recurrent apocrine cysts may benefit from continued mammographic

surveillance. Patients with a solitary simple cyst certainly do not require regular mammographic monitoring. Cyclical nodularity Many patients are referred to breast clinics with a lump that is really a manifestation of cyclical nodularity, but in a more localized and clinically discrete form. It is the mass, rather than the pain, that is the predominant feature. A careful history will frequently reveal that the lump has been present for some time and that its size varies with the menstrual cycle. Many patients will also admit to discomfort or pain in the lump when it is most prominent. A variation of this presentation is seen, particularly in teenagers and occasionally in older women approaching the menopause. A large, diffuse, and frequently uncomfortable swelling develops suddenly, often, but not always, in the upper outer quadrant. Examination discloses a diffuse, nodular swelling that may be somewhat tender. These changes usually resolve with the next menstrual cycle. Aspiration cytology with mammography are indicated in older women, and in the young if there is any diagnostic doubt. As long as malignancy is excluded, patients with cyclical nodularity presenting as a breast lump can simply be reassured. Galactocele Galactocele is well documented in older texts on breast disease, but is perhaps less common than previously thought. Classically the galactocele presents as a cyst in a woman who has recently stopped breast-feeding, although they occasionally occur during lactation. Aspiration shows breast milk and is usually successful in resolving the problem. The pathogenesis of galactocele is unclear: it may simply be a pre-existing simple cyst that fills with milk. Sclerosing adenosis Sclerosing adenosis is an uncommon cause of a breast lump. Clinically, it usually presents as a smooth, relatively mobile mass in the 30- to 50-year age group. It is frequently painful and can occasionally be a cause of mastalgia rather than of a mass. Sclerosing adenosis can be regarded as an ANDI, characterized by lobular enlargement and distortion associated with fibrous stromal change. Fat necrosis Fat necrosis is another condition that has attracted much attention, as it has previously been a cause of diagnostic difficulty in women with breast disease. In particular, delayed diagnosis of cancer in patients with a history of trauma, and the occasional mastectomy performed in patients with fat necrosis thought to be a tumour, have been recorded. A history of trauma is readily provided by the patient but this is a trap for the unwary, as many patients with cancer will try to attribute the lump to a previous injury. By the time the patient presents at the clinic, any external evidence of injury has frequently disappeared. The lump can be small and hard, and clinically may easily be confused with a carcinoma. Sometimes there is associated inflammation, tethering, and oedema.

Fine-needle aspiration cytology is usually diagnostic (Fig. 14). Areas of fat necrosis are occasionally cystic, and aspiration can partially resolve the condition. However, in our unit we review patients diagnosed as having fat necrosis after 6 weeks, when the lump is excised if it has not disappeared. Mammography must be interpreted with care as fat necrosis can have similar radiological features to those of cancer (Fig. 15). Fig. 14. Fat necrosis of the breast: fine-needle aspiration showing characteristic foamy, fat-laden macrophages with few epithelial cells (by courtesy of Dr I. Buley). Fig. 15. Fat necrosis of the breast: mammogram showing a speculated opacity with calcification and features similar to a carcinoma (by courtesy of Dr B. Shepstone). Lipoma, adenolipoma Lipomas occur quite frequently in the breast, but not to the extent that might have been thought in view of the amount of fat that is present. They produce a soft mass, which is best excised if there is any doubt as to its nature. The adenolipoma is a variation of lipoma. It sometimes has a marked fibrotic component and is best regarded as a hamartoma. Chronic abscess The increasing use of antibiotics as a treatment for inflammatory breast conditions occasionally results in a chronic, sterile abscess. Treatment is by aspiration, or by open drainage with excision of the wall if recurrence develops. Normal structures Patients may present with the impression of a breast lump that may be due to either a normal structure, such as a rib, or a prominent area of breast tissue, which may be made more obvious by the defect from a previous biopsy or from weight loss. Fatty replacement at the time of breast involution can also give the impression of a lump: at operation, fibrotic fatty tissue is found. Disorders of the nipple and periareolar tissue Disorders of the nipple are no less controversial than other aspects of benign breast disease. There are the usual reasons for these difficulties, such as lack of consensus over terminology and poor correlation between clinical features, mammography, and pathological findings. The symptoms of disorders of the nipple and periareolar tissues are discharge, retraction, and the effects of periareolar sepsis. There are multiple causes for each of these symptoms but one condition, duct ectasia/periductal mastitis, is of paramount importance. Duct ectasia/periductal mastitis Duct ectasia and periductal mastitis has been described for more than a century but until recently it has been relatively ignored by both clinicians and pathologists. In the past it has been regarded as part of the spectrum of fibrocystic disease, and because of its histological appearance it has been given a variety of names such as plasma cell mastitis, mastitis obliterans, and granulomatous mastitis. The clinical features of duct ectasia/periductal mastitis are extremely varied and, as histological or cytological confirmation is not always possible, diagnosis must sometimes be made on clinical grounds alone. Pathogenesis In 1951, Haagensen suggested that the primary change in patients with duct ectasia/periductal mastitis was simple dilatation of the larger periareolar ducts (duct ectasia; Fig. 16). It is unusual for all ducts to become dilated but the changes are frequently bilateral. The dilated ducts fill with a stagnant, thick, green or creamy

secretion (grumous). These stagnant secretions lead to loss of duct epithelial lining, and associated ulceration can cause further discharge, with bleeding from the nipple. There may also be a chronic inflammatory response (periductal mastitis) in the periareolar tissues because of leakage of the secretions through the damaged duct walls. Periductal mastitis may produce a painful mass or even a frank periareolar abscess; repeated inflammatory processes cause fibrosis and result in nipple retraction. Fig. 16. Duct ectasia (by courtesy of Dr D. Tarin). The various pathogenetic processes of duct ectasia explain many of its symptoms. A difficult question to answer is what causes the initial duct dilatation. Suggested possibilities include hormonally induced muscular relaxation of the duct wall, inadequate absorption of secretions, or obstruction of the system by squamous debris. Unfortunately, there is little scientific basis for these suggestions. An alternative theory is that the periareolar inflammation rather than the duct ectasia is the primary process. Periareolar inflammation may result in secondary duct dilatation and the consequent discharge, fibrosis, and nipple retraction. This alternative theory explains why younger women tend to suffer the inflammatory complications of duct ectasia, whereas nipple inversion and discharge occur in older women. Duct ectasia/periductal mastitis is, therefore, a complex disorder of uncertain aetiology. Even smoking has been incriminated as an aetiological factor in younger women with periductal mastitis. The wide variety of clinical symptoms can best be explained and understood by appreciating that there is more than one process in its pathogenesis. Indeed, because inflammatory complications tend to occur in younger women whereas the effects of duct dilation are seen in the more elderly, some authorities believe that periductal mastitis and duct ectasia are two separate diseases. The more severe symptoms of duct ectasia/periductal mastitis, such as abscess formation, can be regarded as a true benign breast disease. However, in all but its most severe form, duct ectasia is best classified as a breast benign disorder originating from the normal process of duct involution with fibrosis. Nipple discharge Nipple discharge is a common symptom presenting to breast clinics. The patient may fear cancer and the discharge may in itself be a cause of social embarrassment and annoyance. Treatment is therefore directed not only at diagnosing the cause of the discharge accurately but, if necessary, stopping the discharge itself. Patients presenting with nipple discharge should be questioned about whether it has been bloodstained, whether it is unilateral or bilateral, and whether it is associated with a lump. If a lump is present, then diagnosis of the cause of the discharge becomes secondary to investigation of the lump. Although inspection may reveal the source of discharge as one or more ducts, most patients have little visible abnormality. Excessive crusting may occasionally be seen on the nipple: this may simply be the dried products of secretion. Sometimes a skin disorder such as eczema may be found, the associated serous exudate producing the impression of nipple discharge. Routine palpation of the breast must be followed by firm but gentle pressure around the areola. This will determine whether the discharge is unifocal or multifocal and whether it occurs in one or both breasts. It should also determine the nature of the discharge. Particular attention should be paid to whether the discharge has the

greycreamish, shiny characteristic of human milk (galactorrhoea in the nonpregnant or non-lactating patient), whether it is watery, serous or, as is often the case, of a thick, opalescent nature that may vary in colour from cream to almost black. Of paramount importance is whether the discharge is spontaneous or contains blood; this may be bright red and fresh or much darker in colour due to the presence of degradation products. Investigations Our own experience in investigating nipple discharge radiologically and with cytology has been disappointing, although others have reported success. All women aged 35 years or more require mammography. Particular features of note on the mammogram include the intraductal microcalcifications of carcinoma in situ and the dilated ducts associated with secretory granules that indicate duct ectasia (Fig. 17). Ductography may demonstrate the presence of duct papillomas, but this investigation tends to be painful, insensitive, and technically demanding. Fig. 17. Mammographic appearances of duct ectasia, showing coarse calcifications of secretory granules in dilated ducts (by courtesy of Dr B. Shepstone). A number of centres recommend cytological examination of the discharge; this occasionally produces a positive finding, although false-negative results are common. Causes There are a number of causes of nipple discharge (Table 7). Unfortunately, it is difficult to correlate accurately the nature of the discharge with the cause, although certain features do act as a diagnostic guide. The presence of bright red blood in the discharge, a watery discharge, or spontaneous drainage from a single duct are all factors that indicate a potentially serious cause and require thorough investigation. Table 7 Disorders of the nipple and periareolar region Physiological Discharge of milk is a normal phenomenon during pregnancy and lactation. During pregnancy, blood-staining is occasionally observed: this is of no significance and reassurance is all that is required. A milky nipple discharge may occur transiently in the neonate due to transplacental passage of luteal and placental hormones from the mother's circulation. Galactorrhoea Galactorrhoea is secretion of milk not related to pregnancy or lactation, although in itself it can be a primary physiological process. Physiological causes include mechanical stimulation of the breast and stress. It may occur for some years after cessation of breast-feeding. Under these physiological circumstances, simple reassurance is all that is required. Galactorrhoea may also be a secondary phenomenon, occurring as a side-effect of drugs that enhance dopamine activity, such as chlorpromazine, haloperidol, metoclopramide, and methyldopa. Hyperprolactinaemia due to a primary prolactinsecreting tumour or from a secondary source, such as bronchogenic cancer, is an uncommon cause of galactorrhoea, but should be excluded if symptoms persist in the absence of an obvious cause. Duct ectasia Duct ectasia is a common cause of nipple discharge. Characteristically it causes a multifocal, bilateral discharge that is thick and opalescent, and of

variable colour. However, the discharge of duct ectasia can be unifocal and frankly bloodstained, particularly in the perimenopausal and older age groups. Duct papillomas Papillomas are one of the more important causes of nipple discharge. The discharge is often from a single duct; it is frequently serous or serosanguinous, and is frankly bloodstained in 50 per cent of cases. Papillomas also account for many of the relatively unusual cases of a watery discharge. Most papillomas are solitary and are not considered to be premalignant. Occasionally, two or three papillomas may be found in a single duct, and they too are unlikely to have neoplastic potential (Fig. 18). Multiple papillomas, however, especially those occurring in the periphery of the breast and affecting more than one duct, carry an increased risk of malignant change. In one series, 15 of 39 patients with multiple papillomas developed carcinoma. These peripheral lesions are more likely to cause a breast mass than a nipple discharge. Fig. 18. Multiple intraduct papilloma (by courtesy of Dr D. Tarin). Carcinoma As discussed below, intraductal carcinoma, and even invasive cancer, can present as nipple discharge. This is usually from a single duct, is frequently watery or serous, and is often frankly bloodstained. Cysts Cysts may be more common as a cause of nipple discharge than is generally appreciated. Some regard cysts simply as dilated ducts and patients can occasionally produce a discharge simply by compressing an area of cystic change. Idiopathic Despite all attempts at establishing a diagnosis, even with biopsy, about 10 per cent of patients have no obvious pathological entity ascribed to the discharge. If the discharge has been blood-stained it must be considered that the cause has been missed. However, if it was serous and not bloodstained, simple reassurance with careful follow-up will suffice. Management If the nipple discharge is associated with a mass, then appropriate treatment for the lump is instituted. If no mass is felt, the management depends on the nature of the discharge. Indications for exploration would include a single-duct discharge, especially if watery or frankly blood-stained. The most common causes for a watery or bloody discharge from a single duct are duct ectasia or papilloma, although carcinoma may rarely present in this way. A serous discharge from a single duct is likely to be due to duct ectasia. Discharge from multiple ducts, particularly if bilateral, is also due to duct ectasia and may be managed conservatively unless the symptoms are cosmetically embarrassing. Bloody discharge superimposed on a multifocal discharge is usually due to duct ectasia. If this symptom causes the patient distress, then exploration is indicated; if a conservative approach is chosen, the patient should be reviewed after 3 months. There has been a recent trend to reduce the amount of duct surgery performed because of the relatively low yield of unsuspected malignancy and because of the attendant complications from wound infection, and distortion and numbness of the nipple. Two surgical options are possible. The more conservative approach is microdochetomy, which has the advantage that the woman should be able to breastfeed after the operation. It is therefore probably the treatment of choice in younger

individuals with a single-duct discharge. However, as many patients with a singleduct discharge will have a more widespread disorder, simple microdochetomy may be followed by recurrence of symptoms. A more appropriate operation for older women is major duct excision, which also allows treatment of potentially multifocal disease. Nipple inversion and retraction The terms nipple inversion and retraction have been used interchangeably, and the distinction is somewhat arbitrary. Nipple inversion describes a congenital failure of eversion during development, whereas retraction relates to a secondary process, usually due to duct ectasia or carcinoma (Table 7). Congenital nipple inversion Congenital nipple inversion is a common problem occurring, to a greater or lesser extent, in up to 20 per cent of all women. Frank inversion causing difficulty with breast-feeding is much less common: a degree of flattening of the nipple does not seem to interfere with the breast-feeding process. This is hardly surprising because the nipple itself probably plays a relatively small part in anatomical aspect of suckling; the infant creates a teat' from surrounding breast tissue as well as from the nipple. Congenitally inverted nipples tend to be bilateral and patients can generally be reassured that there are few long-term sequelae. They should certainly be encouraged to breast-feed. Women with congenitally inverted nipples have a higher incidence of duct ectasia/periductal mastitis. Young women with congenitally inverted nipples often request surgical eversion. If possible this should be resisted, as the only satisfactory way of everting the nipple is to divide all the underlying ducts, which will prevent subsequent breast-feeding. Furthermore, after such cosmetic surgery the nipples still have a rather flattened appearance rather than being protuberant. Nipple retraction The three main causes of nipple retraction are duct ectasia, carcinoma, and the effects of injudicious previous surgery (Table 7). Duct ectasia Nipple retraction due to duct ectasia is characterized by bilateral changes and a characteristic, linear transverse defect in its early stages. At this time it is possible to evert the nipple, but as the process progresses digital eversion becomes more difficult. Other features of duct ectasia, such as a creamy, multifocal discharge or stigmata of previous periareolar abscesses, are often present. An earlier belief that these changes often begin during pregnancy has not been confirmed. Carcinoma Retraction due to carcinoma is characterized by a shorter history and is unilateral. It is frequently associated with a mass. The effects of nipple retraction itself and any associated inflammation can make clinical assessment of the retroareolar area difficult. If there is any doubt, mammography and biopsy by major duct excision should be performed. Postsurgical Injudicious surgery with inadequate care in reconstituting the breast can result in nipple inversion. This is often associated with an ugly periareolar defect and is difficult to rectify. It should be avoided by due attention to surgical technique. Other disorders of the nipple and periareolar region

While discharge and retraction account for the majority of patients presenting with nipple disorders, a number of other problems are occasionally encountered. Skin disorders, especially eczema, often affect the nipple and periareolar regions. Eczema must be differentiated from Paget's disease and is characterized by a long, intermittent history, bilaterality, and its presence at other cutaneous sites. Features such as itching, serous discharge, and the nature of the periphery of the lesion are of little diagnostic significance. If there is any diagnostic doubt, biopsy is required; a blind trial of topical steroids is to be condemned as Paget's disease can resolve temporarily in response to this treatment. Fibroepithelial polyps present in adolescence and in young women. Excision, if required, can be performed under local anaesthetic. Chronic sebaceous cysts and retention cysts arising from Montgomery's tubercles are occasionally seen. Nipple adenomas produce an uncomfortable mass beneath the nipple. They can cause ulceration and may be confused with Paget's disease. Simple excision will suffice; the condition is completely benign. Pain and hypersensitivity in the nipples is difficult to explain. Sometimes this has a cyclical nature and enquiry will show a traumatic cause. Other patients describe hypersensitivity to cold, as in a Raynaud's type of phenomenon. Infection of the breast The majority of breast infections can be subdivided into those occurring during lactation and those that are a complication of duct ectasia/periductal mastitis. The two have entirely different causes, pathogenesis, and treatment, and may be considered completely separately. Lactational breast abscess Lactational breast abscesses occur during breast-feeding, are generally somewhat peripherally situated, and are the result of infection by Staphylococcus aureus. They tend to occur at the commencement of breast-feeding when an inexperienced mother develops cracked nipples. They also occur at weaning when engorgement results from incomplete drainage of breast milk. Cracked nipples resulting from the trauma of breast-feeding are seen in the first week after delivery and again after about 6 months when the child's teeth first develop. There is acute pain in the nipple and examination reveals a linear fissure, which may become secondarily infected. Clinical features The patient initially complains of discomfort in the breast, followed by painful swelling. The overlying skin may appear red and in extreme cases may undergo necrosis. Constitutional symptoms are common, and by the time the patient presents she may have a high fever and be systemically unwell. If ignored, breast abscesses, like those elsewhere, will point and spontaneously discharge on to the skin surface. Treatment If lactational breast infection is seen before frank abscess formation, antibiotic treatment alone is often successful. Aspiration should be attempted to ensure that no pus is present. As many cases, especially those occurring in hospital, are due to penicillinase-producing staphylococci, treatment must be with a penicillinaseresistant

antibiotic such as a second-line penicillin or a cephalosporin. Such treatment will be successful in about 90 per cent of early cases. If, on aspiration, pus is found, or if other systemic features of an abscess are present, drainage is necessary. However, some recent authorities have recommended repeated daily aspiration under antibiotic cover rather than formal surgical intervention. If formal drainage is performed, however, further antibiotic therapy is no longer required. The incision used to drain the abscess should limit any cosmetic deficit and allow drainage of pus under the influence of gravity. The majority of surgeons leave the wound open and pack it daily with antiseptic-soaked ribbon gauze, although primary closure under antibiotic cover has also been recommended. An area of confusion is whether breast-feeding should continue after treatment of a breast abscess. There is no place for suppression of lactation. The infant should be encouraged to feed from the contralateral breast while the affected side should be emptied either manually or with a breast pump. Cracked nipples should be washed gently and dried by dabbing rather than by rubbing. If there is evidence of nipple infection, a nystatin-containing ointment should be applied topically. Non-lactational breast abscesses Non-lactational breast abscesses are entirely different from those occurring during breast feeding. They arise in the periareolar tissues, frequently recur, and the infecting organisms (if successfully cultured) are a mixture of bacteroides, anaerobic streptococci, and enterococci. Non-lactational abscesses are a manifestation of duct ectasia/periductal mastitis and are usually seen in the 30- to 60-year age groups. Clinical features Patients with non-lactational breast abscesses often have a history of previous infective episodes in the periareolar region. Abscesses often begin as a slightly tender, periareolar mass. Spontaneous resolution is common but they often progress, with associated reddening of the overlying skin and increasing tenderness until the features of a frank abscess are present. Systemic upset is less pronounced than in patients with lactational abscesses. Scarring and distortion arising from treatment of similar episodes may be present, and there may be other manifestations of duct ectasia/periductal mastitis, such as nipple retraction. Treatment If a non-lactational abscess is suspected, the inflammatory mass should be aspirated and sent for both aerobic and anaerobic culture. Initial treatment with metronidazole and flucloxacillin may be successful, although repeated aspiration may be required. Many patients will require drainage, although open drainage should be avoided if possible. If drainage is necessary, it should be performed through the smallest possible incision. Because of the association between smoking and periductal mastitis, patients with chronic relapsing symptoms should be urged to stop smoking. Definitive treatment requires duct excision and possible nipple eversion, which should be performed under appropriate antibiotic prophylaxis and only when the condition is quiescent. The majority of surgeons leave the wound open to heal secondarily, although there is an increasing vogue for primary closure under antibiotic cover if local conditions are suitable.

Surgical or spontaneous discharge of an abscess from periductal mastitis may result in a mammary fistula with intermittent drainage of pus or serous fluid on to the areola; this may be superimposed on further episodes of periductal sepsis. Characteristically, the breast demonstrates multiple incisions for drainage of previous abscesses, distortion, nipple retraction, and a fistula at the edge of the areola (Fig. 19). The basic cause is, again, duct ectasia/periductal mastitis. Fig. 19. Mammary fistula: note the fistula opening on to the border of the areola. Treatment is by fistulectomy, excision of the offending duct, and nipple eversion if required. If there is extensive periareolar disease or the nipple is grossly retracted, a major duct excision should be performed. Most surgeons prefer to leave the wound open, but again there is a growing trend for primary closure. Fistula recurs in about 5 per cent of patients. The cause is variable, but includes continuation of duct ectasia/periductal mastitis in adjacent ducts and persistence of the proximal duct adjacent to the nipple because of an inadequate surgical technique. Other causes of breast infection Postoperative wound infections are relatively common after breast surgery, especially following surgical treatment of duct ectasia/periductal mastitis. Reasons for this include the relatively poor blood supply to fat, ischaemia resulting from deep sutures, and an accumulation of serum in the wound itself. Prophylactic antibiotics and drainage seem to have little impact in reducing the incidence of such problems; they are best minimized by meticulous technique. The incidence of wound infection after surgery for duct ectasia/periductal mastitis has been so high in some centres that antibiotic prophylaxis with drugs such as combination metronidazole and flucloxacillin is now widely used. Breast abscesses occasionally occur in neonates due to infection of milk induced by the transplacental passage of maternal hormones. If antibiotics do not help this condition, great care must be taken during surgical drainage as damage to the breast disc at this age may lead to distortion in later life. Tuberculosis, syphilis, hidradenitis, and pilonidal abscess have all been described as causing inflammation in the breast.

The relation of benign to malignant breast disease

General risk factors for breast cancer are discussed in the following chapter. Some pre-existing benign breast lesions are considered to be a risk factors, although the literature on the subject is conflicting. Studies have generally been based on selected populations who have had incomplete follow-up for an inadequate amount of time. A major problem has been lack of consensus between pathologists in ascribing individual terms to the various microscopic features and an obsession with the cancer risk associated with fibrocystic disease. Descriptive terms The following terms require definition before further discussion. Hyperplasia This is cellular proliferation (Fig. 20). In the breast the normal ducts are lined by two layers of cells above a basement membrane. Hyperplasia is therefore defined as the presence of three or more layers of cells, although individual cells may fill up, or protrude into, epithelial-lined spaces. It is synonymous with the terms papillomatosis and epitheliosis.

Fig. 20. Hyperplasia: note the benign epithelial proliferation; normal ducts are filled with hyperplastic cells (by courtesy of Dr D. Tarin). Atypia This occurs when hyperplastic cells exhibit bizarre or unusual features, either in the pattern of their cellular relations or in the appearance of their nuclei (Fig. 21). The extent of atypia can be graded from 1 to 3, although this classification is empirical and subject to variation between pathologists. Fig. 21. Atypical ductal hyperplasia: cells lining the duct show loss of polarity, nuclear pleomorphism, and atypia (by courtesy of Dr D. Tarin). Adenosis This is an increase in the number of glandular elements. There is a normal relation between the cells and the basement membrane (Fig. 22). Fig. 22. Nodular adenosis (by courtesy of Dr D. Tarin). Epitheliosis This controversial term has found greater acceptance in the United Kingdom than in the United States. It has been used to describe the solid or semisolid, benign epithelial proliferation that is found predominantly in the small ducts, ductules, and lobules. It has been implied that severe forms of epitheliosis amount to carcinoma in situ, although this point of view has been widely criticized. There has been a recent tendency to replace the term epitheliosis with hyperplasia. Papillomatosis This is also a controversial term, which has found favour in North America. It has been criticized as it implies a derivation from the term papilloma yet the vast majority of examples bear no resemblance to a papillary pattern. Hyperplasia is being used instead of papillomatosis. Studies of risk The first study to use accurate data to assess the risk of cancer in patients with benign breast disease was that of Page et al.. Its results formed the basis of an American Cancer Society consensus statement on the risk of breast cancer in patients with benign disease, which was first published in 1986 (Table 8). Cancer risk is defined as a liability to develop breast cancer in the ensuing 10 to 20 years, compared with development in age-matched women who have had no breast biopsy. It should be noted that these are not lifetime risks. Table 8 Relation between benign and malignant breast disease In their original study, Dupont and Page ascribed a slightly increased cancer risk to patients with sclerosing adenosis. Other studies did not confirm this finding and sclerosing adenosis is therefore currently considered as having no increased cancer risk. The American consensus statement maintained that breast cysts were not associated with an increased cancer risk. Other studies have confirmed this opinion, but there is an increasing body of data suggesting that macroscopic cysts, especially those of the apocrine type, may be associated with an increased risk of breast cancer. Further work is required to clarify this question. The inclusion of in situ cancer may be criticized, as this diagnosis implies a neoplastic rather than a benign process. Conversely, multiple papillomatosis, not included in

the above discussion, has been clearly demonstrated to be associated with an increased cancer risk. On the other hand, recent data do indicate a slight long-term risk from fibroadenoma, especially if of a histologically complex type. The relative risk of developing invasive breast cancer following benign disease implies the existence of the classical pathway from normality to invasive cancer: Normal hyperplasia atypia (grades 13) carcinoma in situ microinvasive cancer clinically invasive cancer. Care must be taken in interpreting this rather crude and perhaps naive pathway. There is no evidence that the progression from normality to invasive cancer needs to pass through all the above stages. Furthermore, once a certain point in the pathway has been reached there does not have to be further progression; in theory, regression may occur.

Fibroadenoma - breast
URL of this page: http://www.nlm.nih.gov/medlineplus/ency/article/007216.htm

Fibroadenoma of the breast is a noncancerous (benign) tumor.

Causes
Fibroadenoma is the most common benign tumor of the breast and the most common breast tumor in women under age 30. A fibroadenoma is made up of breast gland tissue and tissue that helps support the breast gland tissue. Black women tend to develop fibroadenomas more often and at an earlier age than white women. The cause of fibroadenomas is not known.

Symptoms
Fibroadenomas are usually single lumps, but about 10 - 15% of women have several lumps that may affect both breasts. Lumps may be:

Easily moveable under the skin Firm Painless Rubbery

They have smooth, well-defined borders. They may grow in size, especially during pregnancy. Fibroadenomas often get smaller after menopause (if a woman is not taking hormone replacement therapy).

Exams and Tests

After a physical examination, one or both of the following tests are usually done:

Breast ultrasound Mammogram

A core needle biopsy must be performed to get a definite diagnosis. Women in their teens or early 20s may not need a biopsy if the lump goes away on its own or if the lump does not change over a long period of time. For more information on the different types of breast biopsies, see:

Breast biopsy - open Breast biopsy - sterotaxic Breast biopsy - ultrasound (core needle)

Treatment
If a biopsy shows that the lump is a fibroadenoma, the lump may be left in place or removed. The decision to remove the lump is made by the patient and the surgeon. Reasons to have it removed include:

Abnormal biopsy results Shape of the breast has changed Worry or concern about cancer

If the lump is left in place, it may be watched over time with:

Mammogram Physical examination Ultrasound

Alternative treatments include removing the lump with a needle and destroying the lump without removing it (such as by freezing, in a process called cryoablation).

Outlook (Prognosis)
Women with fibroadenoma have a slightly higher risk of breast cancer later in life. Lumps that are not removed should be checked regularly by physical exams and imaging tests, following the doctor's recommendations.

Possible Complications
If the lump is left in place and carefully watched, it may need to be removed at a later time if it changes, grows, or doesn't go away.

In very rare cases, the lump may be cancerous and you may need further treatment.

When to Contact a Medical Professional

Call your health care provider if you have a lump that is thought to be a fibroadenoma and it grows or changes in any way.