ABERATIONS IN THE NORMAL DEVELOPMENT AND INVOLUTION OF THE BREAST (ANDI)

Dr. Louis Jordaan Moderator: Dr. H. Jekel

INTRODUCTION
ANDI is a term used to describe most benign breast diseases. It is based on the fact that most benign breast disorders are relatively minor aberrations of the normal processes of development, cyclical hormonal response and involution. Benign breast conditions are practically a universal phenomenon among women. Until recently, however, information about the evaluation and diagnosis of benign breast disease was limited. Benign pathological states account for approximately 90% of the clinical presentations related to the breast. These diseases are more common in females 30-50 years old, thus it is hormonal in nature. Previously there was a tendency to include all benign breast disorders and pathology under the designation of fibrocystic disease. This term, when applied to a biopsy or a palpable breast mass, is nonspecific and often includes normal physiologic and morphologic changes in the breast along with specific benign disease process. Another term used in this regard is mammary dysplasia. The purpose of the term ANDI is to refrain from calling normal changes a disease and to eliminate confusion

ANATOMY / HISTOLOGY
Breast tissue components include subcutaneous fat, stromal and parenchymal tissue supported by fibrous bands known as Cooper suspensory ligaments, blood vessels, nerves, and lymphatics. The pigmented areolar tissue contains hair follicles, apocrine sweat glands, and small raised nodular structures called Morgagni tubercles, which define the openings of the Montgomery (sebaceous) glands that are capable of secreting milk.

The nipple contains sensory nerve endings and smooth muscle bundles, with 8 to 20 major ducts opening to the surface. These ducts extend proximally to the lactiferous sinuses leading to terminal ducts that enter a lobe composed of 20 to 40 lobules. Subcutaneous fat surrounds the lobes and is found predominantly in the superficial and peripheral regions of the breast. The glandular nodularity of breast tissue is most pronounced in the upper out quadrant of the breast. During the estrogen-stimulated proliferative phase of the menstrual cycle, the nodularity and texture of the breasts can wax and wane as the stromal tissue becomes edematous with venous congestion.

DEVELOPMENT AND INVOLUTION

In adolescence the breast tissue comprises of fibrous stroma and scattered ducts. At around 12 years of age maturation of these hormone dependant tissues occurs. Increases in fat deposition, formation of new ducts by branching and elongation and development of lobular units are responsible for the growing breast. The mature or resting breast contains fat, stroma, lactiferous ducts and lobular units. Cyclic stimulation with hypertrophy is responsible for the clinically observed changes in the breast morphology during menses and administration of exogenous hormones. Adenosis of pregnancy stimulated by estrogen, progesterone and prolactin lead to milk production and increase in lobular size. Involution during the climacterium is characterized by the disappearance of these lobular units. With administration of exogenous hormones, hyperplasia of ductal epithelium occurs.

ETIOLOGY OF ANDI
The etiology of ANDI is divided into endocrine and non endocrine causes. The endocrine causes are due to a disturbance of the hypothalamic- pituitary gonadal steroid axis with an increase in circulating hormone levels. The altered prolactine profile is responsible for the production of galactorrhoea in some cases. Non endocrine causes include uses of methylxanthines, stress, diet rich in saturated fat (altered essential fatty acid profile causes super sensitivity to normal levels of Estrogen and Prolactin) and Iodine deficiency

CLINICAL FEATURES OF BENIGN BREAST DISORDERS

There is sound clinical evidence that many benign breast conditions, especially pain, nodularity and cysts are likely to have their pathogenesis in hormonal events during reproductive life. An attempt made to devise an accurate and comprehensive terminology that aids understanding and teaching led the Europeans to develop the ANDI terminology

A useful classification system emphasizing the variety of benign breast disorders seen by clinicians has been described by Love et al and is based on symptoms and physical findings represented in the following table:
I. II. III. IV. Physiological swelling and tenderness Nodularity Mastalgia (breast pain) Dominant lumps A. Gross cysts (macro cysts) B. Galactocoeles C. Fibroadenoma V. Nipple discharge A. Galactorea B. Abnormal nipple discharge VI. Breast infections A. Intrinsic mastitis 1. Postpartum engorgement 2. Lactational mastitis 3. Lactational breast abscess B. Chronic recurrent subareolar abscess C. Acute mastitis associated with macrocystic breasts D. Extrinsic infections

Classification of benign breast disease based on clinical features

From: Love SM., Gelman RS., Silen W. Fibrocystic disease of the breast A nondisease. New England Journal of Medicine. 1982; 307: 1010 - 14

ANDI CLASSIFICATION OF BENIGN BREAST DISORDERS:

DISORDERS OF DEVELOPMENT Polymastia and polythelia (exposed to the same scope of disease as normal breast tissue) Accessory axillary breast tissue Congenital inversion of nipples Macromastia Fibroadenoma Phylloides tumor Adolescent hypertrophy - gross stromal hyperplasia at time of development, of unknown origin

DISORDERS OF CYCLICAL CHANGE Mastalgia and nodularity

DISORDERS OF INVOLUTION Fibrocystic breast disease /fibrocystic change /chronic cystic mastitis /mammary dysphasia. This includes a variety of changes in the glandular and stromal tissue

in response to the levels of Estrogen and Progesterone and often presents with cyclical breast pain (mastalgia). Fibrocystic changes: Cysts Fibrosis Sclerosing adenosis Duct ectasia with periductal mastitis

FIBROADENOMAS
Fibroadenomas are the most common benign tumors of the female breast and represent the most common benign breast tumor in women with a peak incidence at 20-30 years of age. They are composed of stromal and glandular tissue. They often contain estrogen receptors and are therefore hormonally influenced, with regression after menopause and increases in size in the late phase of menstrual cycle. Clinically fibroadenomas are painless, well circumscribed, freely movable tumors with a rounded, lobulated, or discoid configuration. They are usually rubbery and firm, but when calcified, they may be stoney hard. According to a prospective study by West General in Edinburgh, a short term (2 year) follow up of 219 fibroadenomas confirmed with Ultra sound and FNA, 55% of fibroadenomas showed no change, 8% increased in size (all of these excisedfibroadenomas), 12% decreased significantly in size and 25% resolved. Roughly 50% will disappear in 5 years Giant fibroadenomas occur and are bigger than 10 cm according to some authors, other authors suggests bigger than 5cm. These tumors are multiple in 10-15% of cases.

MANAGEMENT OF FIBROADENOMA
Can be managed either conservatively or surgically. Conservative management requires histology (FNA or core needle biopsy), clinical examination and imaging (US/ mammography). There must be no family history of breast cancer. The patient must understand the pathology and do regular self examination in the correct way. These cases need annual follow up. Surgical management entails Lumpectomy (always with histology) or cryoablation or ultrasound guided percutaneous suctioning. The following criteria are used to establish a patient as a potential candidate for cryoablation or percutaneous suctioning: Lesion must be visible on ultrasound

The diagnosis must be histologically confirmed The mass must be less than 3cm in its largest diameter

Exclusion criteria: Histology of Cystosarcoma Phylloides or any other malignancy Poor visualization of the tumor on ultrasound. A core biopsy of fibroadenoma that is non-concordant with the physical examination or imaging finings. Cryoablation is where a small needle is placed in the tumor centre under US guidance and local anesthesia. The tip of the needle is freezed twice, separated by a thaw cycle inbetween. The mass of ice can be seen on ultrasound. A one year follow-up of 50 patients showed a 92% reduction on average of the tumor size. This procedure can be done on an out patient basis. Percutaneous suctioning is the ultrasound guided placement of a 12 gauge ATEC vacuum needle and suction of the tumor under local anesthesia. There has been no recurrence to date if the whole tumor is removed. It is a 20-40 minute procedure followed by 10 minutes of compression.

CARCINOMA IN FIBROADENOMA
Invasive carcinoma may secondarily involve fibroadenomas. This occurs at a mean age of 43 years (2 decades after mean age of fibroadenomas). It ranges from a small focus within a fibroadenoma to complete replacement of the epithelial component with lobular carcinoma in situ more common than intraductal cancer. The intraductal cancer arising in a fibroadenoma usually grows with comedo or cribiform growth patterns.

MANAGEMENT OF PHYLLOIDES TUMORS

These are usually large, benign tumors of epithelial and mesechymal origin that occur primarily in the perimenopausal era. However they may be observed in any age group. Phyllodes tumors have a fairly dramatic clinical presentation and an aggressive histological pattern, although they usually exhibit benign clinical behavior. Histological confirmation is necessary with primary excision with a margin of normal tissue the treatment of choice. For local recurrence, re-excision or simple mastectomy can be done. Poor results are obtained with chemo- and radiotherapy for recurrence or metastasis.

MASTALGIA OR MASTODINIA
This is the most common complaint associated with disorders of the breast. It denotes the symptom of pain in the breast parenchyma or stroma in the absence of any specific physical or pathological abnormality. It can be cyclical or non cyclical. The cyclical type

is often associated with nodularity. Occurs in both pre and post menopausal woman with nodularity being less prominent in post menopausal group.

MASTALGIA : ETIOLOGY
Cyclic pain is caused by a relatively high estrogen, low progesterone and by target organ hypersensitivity to these hormones. Non cyclic pain is caused by a cause inside breast (Spesific/Non spesific) or by a cause outside breast. Non spesific causes inside the breast (15%) are estrogen replacement or the continous cyclic type. Spesific causes are devided into beningn (8%) causes (Duct ectasia, mastites abcess, trauma and Mondor disease) or malignant causes (2%). Causes outside breast are neuro musculo skeletal referred pain, tietze syndrome, supra diaphragmatic (pleuritis, angina, pericarditis) or infra diaphragmatic (esofagitis, cholecystitis, diafragmatic irritation).

MANAGEMENT OF MASTALGIA
Underlying pathology needs to be excluded - biopsy lumps or radiology investigations (mammography) for non- palpable disease. Always reassure the patient that she does not have cancer, as this is mostly the fear driving them to seek medical help. The patient must be encouraged to start a pain dairy to determine whether or not the pain is cyclical in nature. She must also grade the daily pain on a pain scale. For mild pain, good supportive underwear is recommended. The pt must stop all methylxantine (caffeine) intake and also stop any oral hormone intake. If the patient however wish to stay on oral contraceptives, switch to higher progesterone pills. For severe pain, start with evening primrose oil (Efamol caps I tds po) as a 1st line treatment. If this fails, use hormonal treatment as a 2nd line: Ladazol or Danazol (Decrease FSH and LH. Hirsutism an occasional side effect) Tamoksifen Parlodel (Bromocriptine)

BREAST CYSTS
Gross cysts, or macro cysts are the most common dominant lump found in the breast, and most are often found in women between 35 50 years of age. This entity consists of a fluid filled sac within the breast tissue. Clinically, gross cysts may be silent or painful and they may cause palpable lumps or be seen only on mammography or ultrasound. The consistency depends on the pressure of the fluid within the cyst and the amount of normal breast tissue surrounding it. They are often solitary, but can be multiple, feeling like a cluster of grapes on palpation. Nipple discharge can be associated with gross cysts

MANAGEMENT OF CYSTS
Most importantly, they must be differentiated from a cancerous mass. Ultrasound is the investigation of choice. Complex cysts can be difficult to diagnose without aspiration of the cyst. For painful cysts aspiration with collapse often relieves pain. The aspirate of drained cysts must be sent for cytological examination, especially if it is bloody in nature.

FIBROSIS
Occurs when there is a rupture of a cyst into the adjacent stroma, causing an inflammatory reaction with scarring fibrosis and palpable firmness.

SCLEROSING ADENOSIS
Caused by reduplication of the acini with increased numbers of distorted and compressed acini. Acini numbers are increased at least twofold per terminal duct in comparison to the uninvolved lobules. The stromal fibrosis may compress the lumens of the acini giving them the appearance of solid cords of double strands of cells which verges on the appearance of carcinoma

DUCT ECTASIA
Periductal mastitis is the primary condition that often precedes duct ectasia. It can clinically present with non cyclic mastalgia, nipple retraction or discharge, periareolar abscess, subareolar mass, thick cheesy nipple secretion or lactiferous duct fistula. The cause of periductal mastitis is most likely bacterial (particularly anaerobic organisms). Organisms most often identified are S. aureus and streptococcal bacteria. If duct ectasia progresses to an abscess, it is usually superficial and associated with cellulitis. The disease is more common 5th to 6th decade of life, usually multiparous women and is not associated with cigarette smoking. On cytology the most common findings are heavy infiltrates of lymphocytes and histiocytes. Fibrosis may follow with nipple retraction, that can be confused with carcinoma

MANAGEMENT OF DUCT ECTASIA

Always exclude cancer : do a biopsy if a mass is present, do cytology of any nipple discharge. If it presents as an abscess, simple drainage is often insufficient, recurrence is common, the causes of which appear to be multifactorial. Studies have suggested that a primary inflammatory process of the periareolar and areolar components (sweat and sebaceous glands) and accessory mammary glands are involved in the process. Oral antibiotics should be used for the mastitis picture. Excision of affected duct(s) is often helpful.

PERIDUCTAL MASTITIS/ RECURRENT SUBAREOLAR ABSCESS/ SQUAMOUS METAPLASIA OF THE LACTIFEROUS DUCTS
This usually occurs outside the postpartum period. It presents with a painful subareolar erythematous mass that commonly recurs if treated with I&D alone. The recurrent type forms fistulas from under the smooth muscle of the areola extending to the skin edge of areola. The underlying pathology is keratinizing squamous epithelium extending deep into the ducts, with keratin trapped in the ductal system. This causes dilation that lead to rupture that cause an intense chronic granulomatous inflammatory response. Treatment involves removal of the causative epithelium.

PROLIFERATIVE BREAST DISEASE

Epithelial hyperplasia is an increase in the layers of cells, due to increased proliferation or failed apoptosis. It involves apocrine metaplasia, ductal metaplasia and lobular displasia. The ductal and lobular displasia can also present as atypical displasia resembling carcinoma in situ.

TUMORS
Stromal tumors consist of intralobular, breast specific tumors, fibroadenomas and phylloides as well as interlobular, general connective tissue tumors, lipomas and angiosarcomas. Epithelial tumors include the large duct papillomas.

CONCLUSION
Benign breast diseases are common Never treat any lump conservatively without histology Histology is relative and not an absolute risk factor for future malignancy Uncertainty still exists on the etiology Special attention to patients with benign disease and family history of malignancy Good education of SBE Be aware of benign disease co-existing with carcinoma

REFERENCES:
Isaacs JH, Benign Neoplasms. W.B Saunders Company, 1997, pages 66-7 Cant PJ, Madden MV. Non-operative management of breast masses diagnosed as fibroadenoma. Br J Surg 1995; 82: 792-4

Dixon JM , Dobie V. Assessment of the acceptability of conservative management of firoadenoma of the breast. Br J Surg, 1996, vol 83, nr 2, pp 264-5 OGrady, Lois et al. A practical approach to breast disease. L Brown and company, 1995, 186-187 Cotran, Kumar, Collins. Pathologic basis of disease. Robbins, 1999, pages 1093-1104 The Breast, Comprehensive management of benign and malignant disorders, pg 223-5 Current Surgical Diagnosis and Treatment, Lawrence W. Way and Gerard M. Doherty, 11th edition