Benign disease of the breast

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CHAPTER 46 Benign disease of the breast

Paul TR. Thiruchelvam, William E. Svensson, John Lynn

More than 90% of women presenting to a breast clinic will have benign breast disease (BBD), a heterogeneous condition consisting of a large number of pathophysiological lesions of the different components of the breast (stromal, epithelial, vascular or adipocytes). BBD can be divided into congenital abnormalities, aberrations of normal breast development and involution (ANDI), and conditions secondary to another extrinsic factor. The ANDI classification (1987) of BBD enables a framework and states that breasts are under endocrine control and have a wide range of appearances during reproductive life. The incidence of BBD is difficult to estimate, as women with BBD are often not symptomatic and many do not present for a consultation. However, the incidence of BBD can be estimated by the prevalence in post-mortem examinations and cohort studies.

Stages of Human Breast Development

The lifecycle of the breast involves three main stages: development (and early reproductive life), mature reproductive life and involution. The mammary buds develop during the sixth week as outgrowths of epidermis into the underlying mesenchyme. These mammary buds develop as downgrowths from mammary crests, which are thickened strips of ectoderm extending from the axilla to the inguinal region. During the fourth week, the mammary crests appear and persist in humans in the pectoral region where the breasts develop (Sandler 2006). Several mammary buds developing from each primary bud eventually form lactiferous ducts, and by gestation 15–20 lactiferous ducts are formed. The adipose tissue and fibrous connective tissue of the breast develop from the surrounding mesenchyme. In the late fetal period, the epidermis at the origin of the mammary gland forms a shallow mammary pit, from which the nipples arise soon after birth due to epithelial proliferation of the surrounding connective tissue of the areola. At birth, the mammary glands of males and females are identical, enlarged and, on occasion, may produce a secretion called ‘witch’s milk’. The mammary gland remains undeveloped until puberty, with only the main lactiferous duct formed.

Breast development proceeds identically in boys and girls until puberty. During puberty, the female breast enlarges rapidly. The elevated level of circulating oestrogens causes growth of the ductal system; however, progesterones, growth hormone, prolactin and corticoids also play a role. During pregnancy, an increase in the number of lobules and a loss of fat occurs due to raised oestrogen levels and a sustained increase in the level of progesterone. The intralobular ducts form buds that become acini; the lactating breast is composed of dilated acini that contain milk. During weaning, following the suckling stimulus, the breast involutes and the secretory cells are removed by apoptosis and phagocytosis (Howard and Gusterson 2000). The two-layer epithelium of the breast is reformed following weaning. Following successive pregnancies and periods of involution, the terminal duct lobular units (the functional unit of the breast) increase and decrease in size, with an increase and decrease in the number of acini. During involution, the breast stroma is replaced by fat and, as a result, the breast becomes less radiodense, softer and more ptotic (Dixon 1994).

Congenital Abnormalities

These disorders are not uncommon referrals at breast clinics and can cause considerable concern.

Accessory breast tissue and supernumerary nipples

Accessory breast tissue consists of ectopic breast tissue resulting from the failure of the embryonic mammary ridge to regress, commonly found in the anterior axillary line (Qian et al 2008). This occurs in 0.4–0.6% of the population, although is more common in Asian women, and is bilateral in one-third of cases. Accessory breast tissue can cause discomfort, cosmetic problems and restriction in arm movement. This breast tissue may become prominent during pregnancy, and both benign and malignant conditions may occur within this tissue. An explanation of the ‘abnormality’ and reassurance is often all that is required, and surgical excision should be reserved for symptomatic patients as a good cosmetic outcome is difficult and associated with significant morbidity.

The nipple is normally positioned slightly inferomedial to the centre of the breast. The nipple areola complex is composed of pigmented squamous epithelium, but also contains a layer of circumferential smooth muscle and sebaceous glands which open through small prominences (Montgomery tubercles) surrounding the periphery of the areola. Common congenital malformations, including supernumerary nipple or nipples, may be found along the milk-line extending bilaterally from the axilla to the groin. Most commonly, these supernumerary or accessory nipples are found below the breast and above the umbilicus, with the most inferior location being the proximal medial thigh. Should an accessory nipple become irritating, excision can be offered.

Breast hypoplasia and Poland syndrome

Breast hypoplasia is failure of a breast to fully develop, which is usually unilateral but may be bilateral. Breast asymmetry usually only requires reassurance, but if asymmetry is significant, augmentation of the affected side with or without the contralateral breast may be required. Breast hypoplasia may be associated with tubular breasts; a deformity that can affect one or both breasts as a result of constriction at the base of the breasts, limiting growth. Surgical intervention in this group is often difficult and unsatisfactory.

Poland syndrome is a group of conditions in which amastia develops with varying degrees of absence of the pectoralis muscles and syndactyly, affecting one in 30,000 live births (Figure 46.1). It was first described by Alfred Poland in 1841, whilst he was a medical student at Guys Hospital, London (Ram and Chung 2009). Subsequent reports have added numerous additional components to the syndrome including mammary hypoplasia, costal cartilage defects and rib defects. One study evaluating 75 patients showed 100% with an absence or hypoplasia of the pectoralis major, 67% with a hand abnormality, and 49% with athelia (congenital absence of one or both nipples) and/or amastia (breast tissue, nipple and areola is absent; differs from amazia which only involves the absence of breast tissue, and the nipple and areola remain present) (Katz et al 2001). The syndrome is almost always unilateral, with the right side more often affected than the left side, and is more common in men than women (3:1). Patients with Poland syndrome often request reconstruction of the muscular defect, producing symmetry and improving psychological well-being. This can be performed with an ipsilateral latissimus dorsi pedicled flap with or without an implant.

Figure 46.1 Poland syndrome (right side).

Image courtesy of Jacqueline Lewis, Imperial College NHS Trust, London, UK.

Aberrations of Normal Development and Involution

Most BBD arises from normal physiological processes, ranging from mild abnormality (aberration) to severe abnormality (disease). The breast passes through three phases relating to circulating hormone levels: development, cyclical change and involution.

Juvenile hypertrophy

Generalized hypertrophy of the adolescent breast is known as ‘juvenile hypertrophy’ and, in some cases, ‘juvenile gigantomastia’. It can be bilateral or unilateral and is characterized by diffuse enlargement of the breast without nodularity or discrete masses. Growth of the breast is usually rapid and can be significant. Breasts can grow to be as large as 13–23 kg. The pathophysiology is thought to involve an abnormal response of the breast to hormonal stimulation, but the exact mechanism is not known. Hypertrophy is not associated with elevation in serum oestrogen, progesterone, prolactin or gonadotropins, and evidence is lacking for an increased number of oestrogen receptors in the breast. The weight of the breasts can cause back and neck pain, shoulder grooving, poor posture and an inability to perform daily tasks.

Psychological stress and social embarrassment are also common in these young women in whom body image is developing. Histologically, the breast shows stromal and ductal hyperplasia with dilated ducts. The treatment in most cases is reduction mammaplasty, for which there are a number of techniques. Depending on the timing of the operation in relation to puberty, there is a risk of recurrent hypertrophy of the remaining breast tissue, which may require further surgery. The closer surgery is to the end of puberty, the greater the chance of a permanent reduction in size. Hypertrophy of remaining breast tissue can occur with pregnancy. Several reports have shown that giving danazol during rapid breast enlargement has some benefit.

Premature breast development between the age of 6 months and 9 years requires investigation for signs of precocious puberty. Pubic hair, accelerated bone growth and genital development may be signs of an ovarian or adrenal tumour. Isolated thelarche [first stage of secondary (postnatal) breast development] can be observed, but patients should undergo careful physical examination every 6–12 months to look for other signs of puberty. Isolated breast development in the prepubertal child should regress within 1–2 years. Persistent or progressive development in the prepubertal child that does not regress requires endocrine assessment.

Fibroadenoma

Fibroadenomas are classified as an aberration of normal development, arising from the hormone-sensitive terminal ductal lobular unit, typically composed of stromal and epithelial cells. The stromal element defines its behaviour and classification.

Simple fibroadenoma

These are discrete, firm, highly mobile, benign breast masses which may present symptomatically or as an incidental screening finding. Fibroadenomas usually present unilaterally; however, in 20% of cases, multiple lesions may present in the same breast or bilaterally. They are found most commonly at the time of greatest lobular development in women aged 15–35 years. The encapsulation explains the motility of the masses, making them appear more superficial than they truly are (Figure 46.2). Fibroadenomas develop from the special stroma of the lobule. They are hormone dependent, lactate during pregnancy and involute with the rest of the breast in the perimenopause (Hughes et al 1987). A direct association has been reported between use of the oral contraceptive pill before the age of 20 years and risk of fibroadenoma. The Epstein–Barr virus is thought to play a causative role in the development of this tumour in immunosuppressed patients (Kleer et al 2002). Observation of fibroadenomas in younger women showed that 55% do not change size, 37% get smaller and 8% increase in size. Fifty percent of fibroadenomas contain other proliferative changes such as adenosis, sclerosing adenosis and duct epithelial hyperplasia; these are known as ‘complex fibroadenomas’. Complex fibroadenomas, but not simple fibroadenomas, are associated with an increased risk of breast cancer (Carter et al 2001). Fibroadenomas in older women or in women with a family history of breast cancer have a higher risk of associated breast cancer (Dupont et al 1994, Shabtai et al 2001).

Figure 46.2 Fibroadenoma. Oval area of reduced echogenicity (arrows) with bright up due to good through transmission of sound and brighter echos deep to the fibroadenoma (arrow heads).

Image courtesy of Dr William E. Svensson, Consultant Radiologist, Imperial College NHS Trust, London, UK.

Fibroadenomas over 5 cm in size are known as ‘giant fibroadenomas’, and are seen more commonly in women of African origin. Cancers rarely appear within a fibroadenoma. Patients with a histologically confirmed fibroadenoma can be managed conservatively, with follow-up imaging at 6 months to confirm that the lesion is not increasing in size. Excision is recommended if the mass increases in size, if it is larger than 3–4 cm or at the patient’s request. Recurrence is rarely due to incomplete excision, and is often due to an undiagnosed adjacent mass. A minimally invasive technique, such as ultrasound-guided cryoablation, is a treatment option for fibroadenomas in women who do not wish to have surgery (Caleffi et al 2004). Rapid growth of a fibroadenoma can occur in adolescence (juvenile fibroadenoma) or in women of perimenopausal age. Juvenile fibroadenomas usually present as painless, solitary unilateral masses over 5 cm in size (reaching up to 15–20 cm). Although benign, surgical excision of these masses is advised (Wechselberger et al 2002).

Phyllodes tumour

Johannes Muller (1838) first described a large mammary tumour with a cystic appearance and leaf-like growth pattern; he named this ‘cystosarcoma phyllodes’. Treves and Sunderland (1951) proposed that benign, premalignant and malignant forms of this disease existed. The term ‘phyllodes tumour’ (PT) was adopted by the World Health Organization in 1981 to describe this rare fibroepithelial lesion, which accounts for less than 1% of all breast neoplasms. They are less common than fibroadenomas (ratio 1:40), from which they need to be distinguished. PTs can present in women of any age, including adolescents and the elderly, but the majority occur in women aged 35–55 years; the median age of presentation is 45 years. PTs present clinically as a well-circumscribed, mobile mass which may be growing rapidly. The size of presentation of PTs is larger than that for fibroadenomas, although with increased breast awareness and the advent of breast screening, there has been a trend towards smaller tumours. Other signs and symptoms include dilated skin veins, blue skin discolouration, nipple retraction, fixation to the skin or pectoralis muscle, and pressure necrosis of the skin. Palpable axillary lymphadenopathy has been identified in up to 20% of patients, but axillary metastatic involvement is rare. PTs are more commonly found in the upper outer quadrant of the breast. Prevalence is higher in Latin American White and Asian populations. Certain clinical features may raise the index of suspicion, including a sudden increase in a longstanding breast mass, a fibroadenoma over 3 cm in size in a patient aged over 35 years, lobulated appearance on mammography, cystic areas within a solid mass on ultrasonography, and indeterminate features on fine needle aspiration cytology (FNAC) (Jacklin et al 2006). PTs are often not clinically distinguishable from fibroadenomas.

PTs often mimic fibroadenomas at mammography, appearing as large, well-circumscribed, oval or lobulated masses with rounded borders, and a radiolucent halo or coarse microcalcifications. Ultrasonography often shows a non-homogeneous, solid mass, with low-level internal echoes and smooth walls. Discovery of a cyst within a solid mass is highly suggestive of a PT. Dynamic enhancement patterns on magnetic resonance imaging may be useful for the diagnosis of tumours over 3 cm in size, although the role has not been fully elucidated.

Diagnosis of PTs by FNAC is associated with a high false-positive rate due to the heterogeneity of the tumours. The risk of sampling error is reduced following a core biopsy. Criteria have been formulated to help physicians to select patients for core biopsy — the Paddington Clinicopathologic Suspicion Score (Jacklin et al 2006). Twenty-five percent of PTs are categorized as malignant and more than 50% are categorized as benign, with a number of prognostic factors implicated in the risk of local and distant recurrence including tumour size, grade and margin status. Benign PTs have the potential to recur locally, and rarely present at distant sites. Despite having an increased risk of distant spread (20%), malignant lesions have a 15-year survival rate of 89%.

Wide local excision with margins over 1 cm is the preferred primary treatment of PTs, as microprojections of tumour frequently extend into the pseudocapsule of normal tissue surrounding the lesion. One study in which 99% of the patients had histologically negative margins still reported an 8% local recurrence rate, suggesting that risk of recurrence can be reduced with negative margins but not eliminated completely. Adjuvant chemotherapy and hormonal therapy has no role in the treatment of PTs, and there is no high-level evidence to support the role of radiotherapy in these lesions. Local recurrence will occur in 15% of patients with PTs, mostly within 2 years of initial surgery (range 1 month–17 years). These tumours generally present with the same histology, and guidelines advise re-excision with wide margins; the role of adjuvant radiotherapy is controversial. Metastatic lesions often develop within 3 years at sites including the lung, bone and abdominal viscera, with a poor prognosis and average survival of less than 2 years.

Nipple Discharge

Nipple discharge accounts for approximately 5% of breast clinic referrals. Important features to determine include whether the discharge is from one duct or several, is spontaneous or induced, and affects one or more breasts. It is important to note the colour, frequency and consistency of the discharge, with the aim of determining whether the cause of the discharge is physiological or pathological. Fluid can be elicited from the nipple by gentle manipulation in the majority of women (85%) regardless of age or health. Should the nipple discharge present with a mass, the management is directed to the diagnosis of the breast mass. Although nipple discharge usually has a benign aetiology, some studies have shown that the incidence of breast cancer is between 9.3% and 21.3% in women with pathological nipple discharge.

Assessment includes a thorough breast examination to ascertain whether a breast lump is present. Firm areola pressure can identify a dilated duct (and pressure over the duct can produce discharge). Firm digital pressure of the nipple can elicit fluid, and the site and character of the discharge can be noted. The presence of blood can be determined by testing the discharge for haemoglobin; however, only 10% of patients with bloodstained discharge will have an underlying malignancy. The sensitivity of Hemoccult (a guaiac reagent strip test for occult blood) has been shown to be only 50%. Mammography should be performed in women over 35 years of age as part of the assessment, with a sensitivity of 57% in this group. Ultrasonography can identify malignant lesions and papillomas. If no abnormality is found, any patient presenting with spontaneous single duct discharge should undergo surgery if it is associated with a mass, bloodstained or persistent (more than twice per week). Postmenopausal women with new serosanguineous discharge should also undergo surgery.

Ductoscopy allows direct visualization of the discharging duct, and biopsy, by a microendoscope, was investigated by Okazaki in the early 1990s. The procedure is carried out using local anaesthesia (topical local anesthetic cream plus intradermal local anesthetic injection at the areolar margin) and has no significant complications (Escobar et al 2006). An endoscope is inserted through the duct opening on the nipple surface after dilating the duct with a probe (e.g. lacrimal dilator), and saline solution is injected into the duct through the channel to widen it and facilitate the passage of the endoscope, enabling visualization of the intraductal space (Escobar et al 2006). Whilst ductoscopy can be used as a diagnostic and therapeutic addition in patients with nipple discharge, there is no evidence to support its use in the management or early detection of breast cancer.

A major limitation of nipple aspirate fluid is that insufficient material is present for cytology, which prompted the development of ductal lavage. By cannulating and irrigating a discharging duct, ductal lavage fluid can be sent for cytology (increasing cell yield by 100 times compared with ductal discharge). Ductal lavage is not sufficiently accurate for the assessment of patients with known breast cancers. One study has reported sensitivity of 17% for the diagnosis of breast cancer in the setting of a known malignancy. A number of groups are using a genomic approach to investigate nipple aspirate for malignant potential. Methylation of promoter regions of tumour suppressor genes is common in breast cancer, resulting in silencing of tumour suppressor genes. Promoter hypermethylation has been demonstrated in nipple aspirate fluid of patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. Nipple aspirate may become a surrogate for breast tissue, enabling many types of cellular and genomic assessment without a biopsy. Further advances in intraduct technology and techniques may add to our understanding of the biological progression of breast cancer, its prevention and treatment.

The aetiology of non-surgically-treated nipple discharge can be grouped into four categories:

• Physiological — includes lactation in the peripartum period, normal breast secretions which may be elicited by manual stimulation of the breast (note: all spontaneous discharge must be fully assessed by a clinician).

• Pathological endocrine causes (increased prolactin secretion or failure of normal prolactin inhibition) — prolactinomas are the most common secretory tumours of the anterior pituitary causing unilateral/bilateral galactorrhoea. Primary hypothyroidism can cause hyperprolactinaemia; rarely, bronchogenic carcinomas may result in ectopic production of prolactin. Other causes of increased prolactin include head trauma, encephalitis and hypothalamic infiltration (sarcoid/tumour).

• Pharmacological — several drugs can increase prolactin and galactorrhoea including: (1) psychoactive medication (e.g. phenothiazines, tricyclic antidepressants, selective serotonin reuptake inhibitors, haloperidol and anxiolytics), (2) antihypertensives (e.g. calcium channel blockers, methyldopa, reserpine), (3) gastrointestinal medication (e.g. metoclopramide, cimetidine, rantidine), (4) oestrogens (conjugated oestrogen and medroxyprogesterone acetate), (5) anaesthetics and (6) amphetamines and marijuana.

• Idiopathic — galactorrhoea is a bilateral, copious milky-white discharge from multiple ducts. If the prolactin level is raised (>1000 mIU/l), the cause may be secondary to medication or a primary tumour. If the prolactin level is normal, the patient can be reassured. Excision of the subareola ducts may be required in the case of persistent symptoms.

Duct ectasia

Duct ectasia is characterized by dilatation and shortening of the terminal ducts within 3 cm of the nipple. It is a common condition, increasing with age; post-mortem findings have reported duct ectasia in 24% of all women and in 43% of women over 60 years of age. It may present as a white or green viscous discharge, occasionally bloodstained. The colour of discharge varies significantly and can differ between ducts in the same breast. The nipple discharge may be either spontaneous or expressed by the patient. It typically comes from two or three ducts and may be bilateral. It is not known whether the primary event is inflammatory in origin, or whether lactation and stagnation of secretions leads to a secondary inflammation.

Intraductal papilloma and papillomatosis

Intraductal papillomas are benign intraductal proliferations, usually found in the major ducts beneath the nipple (lactiferous sinuses); however, they can be found anywhere in the breast. The term ‘papilloma’ describes the fibrovascular cores covered by a double layer of cells comprising an outer myoepithelial layer and an inner luminal cell layer (Mallon et al 2000). The cells are cytologically benign. Squamous and apocrine metaplasia are common findings. There are three types of intraduct papilloma: solitary, multiple or juvenile papillomas. Solitary duct papillomas are the most common; these occur in large ducts (within 5 cm of the nipple) and present with either bloody or a serous single duct discharge (Figure 46.3). Two studies have demonstrated a correlation between the presence of atypical ductal hyperplasia (ADH) in a papillary lesion on needle core biopsy and the presence of invasive or in-situ carcinoma of the breast in the excisional biopsy (Agoff and Lawton 2004, Ivan et al 2004). It has been suggested that the risk of recurrence of papilloma is related to the presence of proliferative breast lesions in the surrounding breast tissue (MacGrogan and Tavassoli 2003). Papillomatosis (multiple intraductal papillomas; 10% of intraductal papilloma) is defined as a minimum of five discrete papillomas within a localized segment of breast tissue. Papillomatosis tends to occur in younger patients and is less often associated with nipple discharge. Multiple papillomas are more frequently peripheral, bilateral, present as a palpable mass and have a higher probability of having an in-situ or invasive carcinoma than central papilloma. Thorough radiological imaging of the contralateral breast is required to exclude malignancy (Ali-Fehmi et al 2003). Multiple papillomas are associated with an increased risk of developing subsequent breast cancer (Krieger and Hiatt 1992, Page et al 1996, Levshin et al 1998). Juvenile papillomatosis is a rare condition defined as severe ductal papillomatosis occurring in women under 30 years of age (median age 20 years). It often presents as a discrete mass up to 8 cm in diameter, and consists of a mixture of cysts, nodules of sclerosing adenosis and complex intraduct proliferations containing myoepithelial cells and luminal cells. Due to the holes seen in the cut surface of the tumour, it has been called ‘Swiss cheese disease’. A number of studies have suggested an association between juvenile papillomatosis and familial breast cancer; therefore, long-term follow-up is advised (Bazzocchi et al 1986).

Figure 46.3 Intraduct papilloma. (A) The intraduct papilloma can be seen within the slightly dilated duct (arrow heads) allowing it to be differentiated from other lesions of reduced heterogeneous echogenicity. Intraduct papillomas are often quite vascular, which can be demonstrated with colour Doppler (B).

Bloody nipple discharge in pregnancy

Bloody nipple discharge during pregnancy or lactation is a common finding. It occurs in 20% of women who present with nipple discharge during pregnancy, and is likely to be due to the increased vascularity of the developing tissue. It is benign and requires no specific treatment.

Ductal carcinoma in situ

Approximately one-third of symptomatic ductal carcinomas present with nipple discharge, and invasive cancers rarely cause nipple discharge in the absence of a mass. DCIS is thought to be responsible for approximately 10% of cases of unilateral nipple discharge.

Surgical treatment of nipple discharge

Historically, all patients with pathological nipple discharge are offered an operation. Patients with surgically significant nipple discharge aged 40 years or more are recommended to undergo Hadfield’s procedure (radical subareolar duct excision). Patients under 40 years of age with persistant discharge are given the option of microdocectomy, particularly if they are intending to breast feed.

Microdocectomy

Microdocectomy involves the removal of a single duct through a circumareolar incision. Expression of nipple discharge is performed when the patient is in theatre, and the duct is then cannulated with a lacrimal probe. The probe aids identification of the discharging duct and enables the surgeon to dissect it from the surrounding tissue. At least 2–3 cm of duct should be removed and the excised duct should be opened and the distal remnant inspected. The procedure should not damage the surrounding ducts and should therefore allow subsequent breast feeding.

Total duct excision (Hadfield’s operation)

In women of non-childbearing age, total/major duct excision is a surgical option for single duct discharge, multiple duct discharge and periductal mastitis. The procedure involves division of ducts underneath the nipple and removing the breast tissue to a depth of 2 cm under the nipple–areolar complex through a circumareolar incision. Complications include nipple necrosis, nipple inversion and reduced nipple sensation. Recurrence of periductal mastitis may occur if all of the ducts are not removed during the operation. The procedure can also be performed in women having a cosmetic nipple eversion procedure.

Mastalgia

The majority of women will suffer from mastalgia (breast pain) at some point in their lives. It is important to differentiate true mastalgia (originating from the breast) from referred pain. Referred pain is often unilateral, reproduced by pressure on the chest wall and associated with activity. Non-steroidal anti-inflammatory drugs, either orally or topically, can improve these symptoms. True breast pain is associated with swelling and nodularity, and can resolve spontaneously. This pain is often worse before menstruation and is relieved after the cessation of menstruation. It is not important to differentiate between non-cyclical and cyclical mastalgia as the treatment is the same. Symptoms may be exacerbated by exogenous hormones (hormone replacement therapy or oral contraceptive pill) and the perimenopausal state. The cause of mastalgia is unknown, but a number of theories have been postulated including excess oestrogen or prolactin, and low progesterone.

Assessment includes history, examination and, in women over 35 years of age, mammography. Five percent of women with breast cancer complain of pain, whilst only 2.7% of women with breast pain as their only complaint will have an underlying breast cancer. A pain chart can allow better interpretation of the pattern of pain and gives an objective evaluation of treatment.

The majority of patients can be managed by exclusion of cancer and reassurance. Evening primrose oil (EPO) was previously used in the treatment of mastalgia, but has recently been withdrawn from prescription by the Medicines Control Agency. A recent randomized, double-blind controlled trial of 121 women comparing EPO and fish oil with control oils in the treatment of mastalgia showed no clear benefit from either EPO or fish oils (Blommers et al 2002). This study showed that 33% of women with cyclical mastalgia and 17% of women with non-cyclical mastalgia showed an improvement in symptoms with EPO compared with the control group (46% and 17% improvement, respectively). Other agents have shown some benefit, including phytoestrogens (soya milk) and Vitex agnus-castus (a fruit extract). A reduction in dietary fat intake has also been shown to improve symptoms. Second-line treatments include tamoxifen 10 mg daily and danazol 200 mg daily. Tamoxifen given in the luteal phase of the menstrual cycle controlled mastalgia in 85% of women, with recurrent pain noted in 25% of patients at 1 year. Tamoxifen has been found to be superior to danazol with a better toxicity profile. Fifty-three percent of patients receiving tamoxifen compared with 37% of patients receiving danazol were pain-free after 1 year. It is important to note that tamoxifen is not licenced for use in mastalgia. Due to the high toxicity rate (80%), bromocriptine is no longer used in the treatment of mastalgia.

Fibrocystic Change

Fibrocystic change (FCC; also called fibrocystic disease, cystic mastopathy, chronic cystic disease, mazoplazia, Reculus’s disease) is the most common benign disorder of the breast, affecting women between 20 and 50 years of age (Cole et al 1978, Hutchinson et al 1980, Cook and Rohan 1985, La Vecchia et al 1985, Bartow et al 1987, Sarnelli and Squartini 1991, Fitzgibbons et al 1998). FCC is observed in approximately 50% of women clinically and in 90% histologically (Love et al 1982). The most common symptoms of FCC are breast pain and tender nodularity. FCC is thought to be due to a hormonal imbalance, particularly the predominance of oestrogen over progesterone; however, the pathogenesis is not completely understood (Dupont and Page 1985). FCC is made up of cystic lesions (macrocystic and microcystic) and solid lesions, and includes adenosis, epithelial hyperplasia with or without atypia, apocrine metaplasia, papilloma and radial scar. FCC can be classified into non-proliferative lesions, and proliferative lesions with or without aytpia (atypical hyperplasia) (Dupont and Page 1985).