Elliot Weisenberg, MD Pathology of the Breast UIC College of Medicine Attending Pathologist, Advocate Illinois Masonic Medical Center & M2 Pathology Course UIC Lecture #57 Associate Professor, Chicago Medical School Thursday, January 29, 2004 Visiting Assistant Professor, UIC 8:30-9:20 Phone #:773-296-5730 e-mail: Elliot.Weisenberg-MD@advocatehealth.com Required reading: Robbins, Sixth edition, pages 1093-1119 and this handout. Objectives: 1. Identify and understand clinical and pathologic features of common -inflammatory breast lesions -fibrocystic changes -benign breast tumors -malignant breast tumors. 2. Appraise the risk of the subsequent development of breast cancer in various types of fibrocystic change. 3. Discuss risk factors of the development of breast cancer. Page 1 of 9 1
The breast develops as an ectodermal ridge from the anterior limb bud to the posterior limb bud on the ventral surface of the fetus, this ridge is known as the milk line. By 9 weeks of gestation, the breast normally persists only over the anterior thorax. Ectopic breast tissue, with or without a nipple, may develop anywhere along the milk line, from the axilla to the vulva. Developmental failure of the breast (amastia) may occur with Turner s syndrome, ovarian agenesis, congenital adrenal hyperplasia, or delayed menarche. Nipple inversion may interfere with nursing. Nipple inversion may also be a sign of malignancy. Congenital hypomastia may occur in association with an underdeveloped pectoralis muscle. Breast asymmetry may necessitate corrective surgery. The physiologic necessity of breast augmentation is non-existent, but for social and/or psychological reasons, hundreds of thousands of women seek surgical breast augmentation. The size of the female breast is largely determined by body habitus and age, it stores fat. In some women, however, macromastia may lead to musculoskeletal pathology in the lower back that may require surgical correction. The raison d être of the breast is to make milk on demand and deliver it to a nursing infant. The hormonally responsive secretory apparatus of the breast is the terminal duct lobular unit (TDLU). The TDLU consists of terminal ductules that differentiate into secretory acini, known as lobules, and specialized stroma. The large duct system is essentially a conduit for getting milk to the nipple. Myoepithelial cells in ductules have contractile properties. The breast undergoes regular increase in TDLU size during the luteal phase of the menstrual cycle and regresses during the follicular phase. During pregnancy, there is an increase in the number of terminal ducts with a concomitant loss of connective tissue. The epithelial cells of the TDLU become vacuolated and the lumens become distended with secretions. Under the influence of oxytocin, prolactin, and neural influences, lactation occurs. The TDLU is the source of most breast pathology. After lactation the lobule regress and atrophy and the breast size shrinks, but some increase in the size and number of lobules is retained and the breast remains somewhat larger than the nulliparous breast. The breast normally undergoes some involution after menopause. The male breast resembles immature female breast; there are large and intermediate sized ducts within a fibrous stroma. The morphology of the male breast appears to be hormonally, not genetically mediated. In a study in Amsterdam of 14 male to female transsexuals who underwent chemical castration and estrogen therapy, full acinar and lobular development occurred. Page 2 of 9 2
Neonatal mammary hyperplasia occurs under the influence of maternal hormones and regresses. Juvenile hypertrophy may occur in either sex, in males essentially it is gynecomastia. It may be unilateral or bilateral and usually will regress spontaneously. The breast bud has been mistaken for hypertrophy and breast tumors, if it is removed surgically, the breast will not develop. Secondary mammary hypertrophy may occur secondary to tumors (ovary, adrenal, pituitary) or drugs. Gynecomastia resembles juvenile hypertrophy; it is due to a relative increase in estrogens, a relative decrease in androgens, or both; that causes an alteration in the ration of estrogens to androgens. The most common type occurs during puberty and usually regresses, but may be resected for social/ psychological reasons. Gynecomastia is also common is elderly men. Drugs (estrogen therapy for prostate cancer, digitalis, chemotherapeutic drugs, thiazides, phenothiazides, marijuana, many others), tumors, liver disease, obesity, Klinefelter s syndrome, testicular feminization syndrome, hyperthyroidism, recovery from prolonged illness or malnutrition, and other things may predispose to gynecomastia, but many cases are idiopathic in origin. Idiopathic disease may more likely be unilateral. Most authorities believe there is no increased risk of the development of breast cancer in longstanding gynecomastia; however, others feel that longstanding gynecomastia does carry a slightly increased risk of cancer development. There is general agreement that transient gynecomastia occurring during youth is not associated with increased risk. Acute mastitis is caused by a bacterial infection that often occurs postpartum or in lactating women. The duct system is obstructed and inspissated secretions lead to infection. Staph and Strept are the usual culprits. Antibiotics and suction may lead to relief, but if abscess formation occurs, surgical intervention may be necessary. Infection may mimic breast cancer. Periductal mastitis (recurrent subareolar abscess, squamous metaplasia of lactiferous ducts) is characterized by squamous epithelium extending into the nipple ducts. Keratin is trapped and causes dilation and rupture of ducts leading to a chronic and granulomatous response to extravasated keratin, often associated with abscesses and fistulous tracts. Women present with a painful erythematous subareolar mass. Page 3 of 9 3
Interestingly, the vast majority of women with this lesion are smokers. It is not associated with lactation, age or reproductive history. Mammary duct ectasia tends to occur in the fifth or sixth decade of life and is characterized by dilated ducts containing inspissated secretions. The lining cells of the ducts are largely atrophic and necrotic and the stroma near the ducts contains a lymphohistiocytic infiltrate, often with numerous plasma cells. Patients usually present with a poorly defined periareolar mass, often with skin retraction and thick cheesy nipple discharge. This lesion is not correlated with smoking. Fat necrosis is related to trauma that may be unrecognized. It is usually superficial and consists of dead fat cells, hemorrhage, and histiocytes. It may lead to scarring and calcification that can mimic carcinoma. Granulomatous mastitis is usually due to the presence of foreign material, especially silicone from implants. It is not uncommon for silicone to leak. Implants may develop a dense fibrous capsule around them that may calcify. This may contract and cause pain and/or disfigurement. Sometimes the capsule can be manipulated and cracked relieving symptoms, other times it may require surgical intervention. Infectious causes of granulomatous mastitis include mycobacteria and fungi. Fungal infections are uncommon. Sarcoidosis may involve the breast. The majority of breast lumps (~90%) are benign. In a study of women referred for evaluation of breast lumps cited in your text 30% had no disease, 40% had fibrocystic changes, 7% had fibroadenomas, 13% had other benign conditions, and 10% had cancer. Fibrocystic changes of the breast are very common, at autopsy; the majority of women will have some fibrocystic change. Symptomatic fibrocystic change occurs in about 10% of women, usually between the ages of 35 and 55. It originates from the terminal duct lobular unit. The most important distinction is between nonproliferative fibrocystic change that has no increased risk of malignancy and proliferative fibrocystic change that may convey increased risk. Hormonal influences, either a relative or absolute increase in estrogen, or possibly abnormal end organ metabolism are likely related to fibrocystic change. Oral contraceptives that provide a balanced source of estrogen and progesterone decrease the risk of fibrocystic changes. Some functional tumors may cause fibrocystic changes. Page 4 of 9 4
Nonproliferative fibrocystic change consists of stromal fibrosis and cystically dilated terminal ducts, apocrine metaplasia may also occur. Larger cysts may be filled with thick, bluish fluid, these are known as blue domed cysts of Boodgood. Breast cysts may be aspirated, but if they recur, there is a risk of malignancy, and biopsy is recommend. Adenosis is an increase in the number of acini per lobule (it is physiologic during pregnancy). The proliferating acini may have enlarged lumens, this is known as blunt duct adenosis. Adenosis may be associated with calcifications leading to biopsy to excluded malignancy. Adenosis may be associated with sclerosis (vide infra). Proliferative fibrocystic change is usually associated with nonproliferative change. There is an increase in the number of cells lining terminal ducts, known as intraductal hyperplasia or ductal epithelial hyperplasia. Proliferative fibrocystic changes of the lobules also occur. Intraductal hyperplasia is often divided into mild, moderate or florid, or atypical. Intraductal carcinoma may be thought of as an extreme form of proliferative fibrocystic change. More benign proliferation show a mixture of proliferating cell types, a streaming orientation, the presence of irregular spaces, and cells tend to overlap each other. More worrisome proliferations show monotonous cellular proliferations, cells with more defined cell borders, well-defined spaces, and greater cytologic atypia. Risk of the development of malignancy is believed to be as follows: Mild intraductal hyperplasia, no increased risk; moderate or florid intraductal hyperplasia, a risk 1.5 to twice the general population, and atypical hyperplasia, 4 to 5 fold risk. The risk of the development of breast cancer after carcinoma in situ is from 8 to 10 times that of the general population, with a higher risk for women with a positive family history. Sclerosing adenosis is a type of proliferative fibrocystic change where small distorted epithelial cells and myoepithelial cells are embedded in a fibrous stroma. In florid cases it may mimic breast carcinoma. Is conveys a slightly increased risk (1.5-2.0 X) of the development of breast cancer. Fibroadenoma is the most common benign breast neoplasm. It originates from the terminal duct lobular unit. Women are usually 20 to 35 years old, but they occur over a wide age range. Typically they are firm, rubbery freely mobile, and gray white. The size varies, but typically is 2 to 4 cm in diameter. The majority are solitary, but up to 20% are multiple, in either the same or the contralateral breast. The proliferating element of the tumor is stroma; there is secondary epithelial proliferation. Atypical or malignant epithelial proliferation within fibroadenomas is very rare, but described. Typically there is a paucicellular to mildly cellular stroma and entrapped, two layered terminal ducts that may have open or compressed lumens. Over time the lesion may undergo fibrosis and calcification. A juvenile variant may be larger and more cellular. During pregnancy, they may undergo rapid growth. The subject of possible increased risk of breast cancer in women with a history of fibroadenoma is controversial. There has been one large, and Page 5 of 9 5
several smaller studies that have reported an increased risk of the subsequent development of breast cancer in women with fibroadenomas, other studies have shown no increased risk. Most, but not all, authorities believe that women with a history of fibroadenoma are at a slightly increased risk of the development of breast cancer. Phyllodes tumor, formerly cystosarcoma phyllodes, is a more aggressive, uncommon tumor of breast stroma than fibroadenoma. The stroma is more cellular and more atypical than in fibroadenomas. Tumors are usually around 5 cm, but may be smaller or larger on presentation, they tend to occur in an older age group than fibroadenoma, but age cannot distinguish the two. The prognosis depends on the extent of the stroma, with more aggressive lesions showing stromal overgrowth where low power microscopic fields do not contain epithelial elements. They may recur, and malignant tumors may metastasize. They are divided into benign, uncertain malignant potential, and malignant. Intraductal papilloma is a lesion of lactiferous ducts, one of the few lesions of the large duct system. It affects middle aged to elderly women and may be associated with serous or bloody nipple discharge. It consists of a complex proliferation of epithelial and myoepithelial cells. It is a benign lesion, but must be distinguished from papillary carcinoma, which is malignant. It is a different lesion from papillomatosis, which is widespread and affects terminal ductules. Small duct papillomas also occur. Other breast tumors/masses include nipple adenoma, lactational adenoma (probably a localized hyperplasia), lipoma, fibroma, hemangioma, leiomyoma, skin/adnexal tumors, intramammary lymph nodes, lymphomas, angiosarcoma, and other sarcomas. Page 6 of 9 6
WHAT YOU LEARN ABOUT BREAST CANCER IN 2004 SHOULD BE WRITTEN ON PAPER, NOT CARVED IN GRANITE. The American Cancer Society estimated that breast cancer will affect an estimated 217,440 Americans in 2004, all but 1450 of them women and will kill an estimated 40,580 patients, all but 470 of them women. The lifetime risk of developing breast cancer has been estimated at 1 in 8 to 1 in 10. Approximately one third of breast cancers are lethal. Breast cancer is uncommon before the age of 40, with a risk from birth to 39 of 1 in 229; the incidence increases after that, from 40 to 59 years it is 1 in 24, from 60 to 79 1 in 14. The incidence of breast cancer increased from 1950 to 1987, increasing by 3% a year from 1980 to 1987, from 1987 to 1998 the rate stabilized. The death rate has declined by 1.6% per year from 1989 to 1995 and by 3.4% per year from 1996 to 2001. The most important risk factor for breast cancer is family history, especially a first degree relative (FDR) with breast cancer. This risk is increased with more than one FDR, cancer in a FDR at an early age, or bilateral breast cancer in a FDR. Genetic factors are clearly important in breast cancer risk, and about 10% of breast cancer is inherited. The Li Fraumeni syndrome involves mutated p53 and causes a small proportion of inherited breast cancer. The BRCA1 gene (chromosome 17q21) is a tumor suppressor gene. Mutations in this gene affect from 1 in 200 to 1 in 400 Americans and these mutations are over-represented in Ashkenazi Jews. Affected females are at an 85% risk of developing breast cancer and are high risk of developing ovarian cancer. Individuals of both sexes are at increased risk of colon carcinoma, and men are at increased risk of prostate cancer. The BRCA2 gene (chromosome 13q) is less common. Women with this mutation are at a 30 to 40% lifetime risk of developing breast cancer and at increased risk for ovarian cancer. Affected men are at increased risk of breast cancer and prostate cancer. Both sexes are at increased risk of cancers of the pancreas and urinary bladder Other risk factors are proliferative fibrocystic change, radiation exposure, prior cancer of the breast or endometrium, and hormonal events/status. Early menarche, late menopause, nulliparity, and older age at first pregnancy (>30-35) are associated with higher risk. Recent studies have shown that hormone replacement therapy (HRT) in postmenopausal women, at least as currently formulated for use in women who have not undergone hysterectomy, increases the risk of breast cancer. The risk increases with the duration of HRT. Currently, most authorities recommend that HRT be given only for a short period of time to relieve acute menopausal symptoms. Obesity is a likely risk factor, and a high fat diet with a sedentary lifestyle are considered to be a risk factor by many authorities, primarily based on epidemiologic studies concerning migrants from low incidence to high incidence countries which show that after one or two generations, risk is nearly identical to the new country as a whole. Page 7 of 9 7
Ductal carcinoma in situ is divided into low, intermediate or high grades or (high grade and low-grade types). There is some controversy about the subsequent risk of the development of breast cancer after detection of low-grade ductal carcinoma in situ (DCIS). In one study where low grade DCIS was misdiagnosed as benign disease, 32% of women developed invasive disease over 20 years. Low grade DCIS shows a monotonous intraductal proliferation of cells without significant cytologic atypia and at most only minimal necrosis. Microcalcifications are usually present. Micropapillary, cribriform, and solid types are described. Work is ongoing trying to determine how to stratify risk in patients with a diagnosis of low grade ductal carcinoma in situ. High grade DCIS or comedocarcinoma is composed of large ugly cells with anaplastic nuclei and usually central necrosis with a gross resemblance to comedos. The tumor may elicit an inflammatory reaction and fibroplasia around it, thus women may present with a mass. The present recommendation for surgical management of DCIS is a one-centimeter margin. Lobular carcinoma in situ (LCIS) consists of small, monotonous cells that distend lobules. Only minimal anaplasia is present. Necrosis does not occur, but microcalcifications are likely. LCIS is a marker for the development of breast cancer, in either breast. There is a 20 to 30% risk of breast cancer over 20 years. It may be of either ductal or lobular type. Paget disease of the nipple presents as an eczematous change in the nipple-areolar complex. Malignant cells are present in the epidermis. An underlying ductal carcinoma, either in situ or invasive, is present. The prognosis is related to the underlying malignancy. Invasive ductal carcinoma is graded as well (grade I), moderately (grade II), or poorly differentiated (grade III). The grade is based on the extent of nuclear pleomorphism, the mitotic rate, and the extent of tubule formation. Grossly and microscopically, invasive ductal carcinoma is often associated with a desmoplastic stroma and may be referred to as scirrhous carcinoma. Calcifications are often apparent. Invasive ductal carcinoma is often associated with DCIS. Male breast cancer is of the ductal type. Invasive lobular carcinoma is composed of small cells that may have signet rings. It commonly will be found surrounding existing structures in the breast (targetoid growth) and infiltrate stroma in single file (known as Indian files from the old Hollywood westerns). Some authorities and the author of your text book believe that lobular carcinoma has a better prognosis than ductal carcinoma, but other authorities believe that stage per stage it is carries the same prognosis. A pleomorphic variant exists. It usually lacks expression of the cell adhesion molecule e-cadherin. Page 8 of 9 8
Other types of invasive breast cancer are colloid carcinoma, where clusters of tumor cells are found in pools of mucin (good prognosis); tubular carcinoma, where small well differentiated tumor cells infiltrate entirely in tubules (good prognosis); medullary carcinoma, where synctia of ugly tumor cells are well delineated and associated with a dense lymphoid infiltrate (good prognosis), and metaplastic carcinoma with squamous or sarcomatoid differentiation (worse prognosis). Most breast cancers are invasive ductal carcinomas, not otherwise specified (NOS). The most important determinant of survival is stage, the size of the tumor, the presence or absence of involvement of adjacent structures such as dermal lymphatics (inflammatory carcinoma) or the chest wall; the presence or absence of lymph node metastasis, and the presence or absence of distant metastasis. Tumor grade does affect prognosis, but is of lesser importance. Estrogen and progesterone receptor (ER and PR) positive tumors tend to be better differentiated and have better survival. ER positive tumors are candidates for therapy with tamoxifen or other anti-estrogenic therapies. Tumors with high proliferation indexes and aneuploidy tend to do worse. Tumors with expression of Her2/neu (related to the epidermal growth factor receptor) tend to be more aggressive, but are candidates for anti-her2/neu monoclonal antibody therapy (Herceptin). Lymphatic and vascular invasion are adverse prognostic findings. Mutation of the tumor suppressor gene p53 is associated with a worse prognosis, as is expression of cathepsin D, a proteolytic enzyme. Trials are ongoing using tamoxifen and other antiestrogens in high-risk women and may reduce cancer incidence. While controversy exists concerning the extent of risk reduction, and the details of utilization, especially in women between 40 and 50 years of age; regular physical examination and mammography enables detection of lower stage tumors with a much greater potential for cure. It is important to realize, however, that a small percentage of breast cancers will not be detected by mammography. The most recent recommendations from the American Cancer Society (see CA Cancer J Clin 2003;53, caonline.amcancersoc.org) for asymptomatic average risk women is for monthly self-examination starting at age 20, clinical breast examination (prior to mammography) every 3 years from ages 20 to 39 and annual clinical breast exam starting at age 40. The recommendation is for mammography starting at age 40. The article discusses the risks and benefits of annual mammography vs. longer intervals and while it argues that annual screening is likely the best strategy to detect early cancers, it acknowledges that at this time the data does not allow a definitive judgment. The American Cancer Society recommends that women be informed about the benefits, limitations, and potential harm of regular screening. Surgery, radiation therapy, chemotherapy, hormone therapy, and in some cases immunotherapy are all used in the treatment of breast cancer. Optimal therapy and detection of breast cancer depends on extensive communication between primary care physicians, radiologists, surgeons, medical oncologists, radiation oncologists, and pathologists. Page 9 of 9 9