Each breast develops from the epidermal milk line, an embryonic ridge of tissue between the upper and lower limb buds. The two symmetrical ridges normally atrophy except in the thoracic region, where two thickenings develop into the nipples. Cords of cells grow downward from the nipple, developing lumens to form the ducts of the breast. This degree of development occurs in both sexes during fetal life.
At puberty, under the influence of female sex hormones, the female breast develops further. Outpouchings arise from the terminal ducts that branch extensively into the lobules of the breast. The adult female breast is composed of five to ten segments, each draining at the nipple by a separate lactiferous duct (Figure 56-1).
Structure of the breast and sites in which common pathologic lesions originate.
In the nonpregnant breast, the parenchyma represents only about 10% of the volume. Much of the breast enlargement that occurs at puberty is due to an increase in the amount of fibroadipose stroma, which is also directed by the female sex hormones. Histologically, the normal nonpregnant breast is composed of breast lobule units, comprising approximately 10–20 acini around a terminal ductule. Lobular units are separated from one another by abundant fibroadipose stroma.
The breast responds cyclically to menstruation. During the preovulatory phase, estrogen causes the glands and ducts to undergo mild dilation and hypertrophy. During the postovulatory phase, progesterone causes stromal proliferation and edema. These changes may result in mild enlargement of the breast toward the end of the cycle.
During pregnancy, there is marked hyperplasia of the glands that displace the fibroadipose stroma of the breast (Figure 56-2). Enlargement of the breast occurs in the third trimester and becomes prominent during lactation. Secretion of colostrum, the first milk, begins in the third trimester of pregnancy. The lactating breast is composed of closely packed dilated glands with little intervening stroma. After lactation, the glands atrophy to a level that approaches the prepregnant state.
Lactating breast, showing extreme hyperplasia of the acini (A), which have replaced the normal interlobular adipose tissue. Many acini show secretion into the lumen. D = ductule.
After menopause, glands, ducts, and adipose tissues atrophy further (see Chapter 16: Disorders of Cellular Growth, Differentiation, & Maturation), causing progressive shrinkage in breast size.
Inflammatory Breast Lesions
Acute Mastitis & Breast Abscess
Acute inflammation of the breast, often with abscess formation, occurs commonly in the postpartum period at the onset of lactation (puerperal mastitis). Cracks in the nipple provide the portal of entry of bacteria (Figure 56-3A). Stasis of milk in cystically dilated ducts predisposes to infection.
Etiology and pathologic features of acute and chronic mastitis.
Staphylococcus aureus is the most common infecting agent. Acute mastitis causes redness, swelling, pain, and tenderness in the affected area of the breast. Abscess formation occurs rapidly, requiring drainage of pus.
Chronic inflammation of the breast usually occurs in perimenopausal women as a result of obstruction of the lactiferous ducts by inspissated luminal secretions. Obstruction leads to dilation of the ducts (mammary duct ectasia) and periductal chronic inflammation (Figure 56-3B). In most cases, the inflammatory cells are predominantly plasma cells, and the term plasma cell mastitis is used.
In other instances, rupture of small ductules releases secretions into the periductal stroma and evokes a cellular reaction characterized by accumulation of numerous foamy histiocytes (lipid phagocytosis). Foreign body-type giant cells appear along with fibrosis. This entity is called granulomatous mastitis.
Grossly, both plasma cell mastitis and granulomatous mastitis produce irregular fibrosis with induration of the involved area of the breast. This may cause nipple retraction and produce a clinical appearance that closely mimics breast carcinoma.
Fat necrosis is an uncommon yet important disease in the breast. The cause is unknown. Physical trauma was believed to be the main factor—leading to the term traumatic fat necrosis—but is now thought to play a minor role. Ischemia resulting from stretching and narrowing of arteries in pendulous breasts may be a factor.
In the early stage, fat necrosis is characterized by collection of neutrophils and histiocytes around the necrotic fat cells. Later, the necrotic tissue is replaced by granulation tissue and collagen, with numerous foamy histiocytes. Calcification may occur. Grossly, fat necrosis appears as an ill-defined grayish-white nodular lesion. Localized scarring results in a palpable mass that is firm and irregular, clinically resembling cancer. This resemblance may be heightened by the presence of skin retraction over the mass. Histologic examination is essential to differentiate it from carcinoma.
Reaction to silicone, either injected directly into the breast or entering breast tissue from a leaking silicone implant, is characterized by a foreign body granulomatous response with numerous foamy macrophages and multinucleated giant cells around the silicone material. Severe fibrosis occurs, leading to pain, contraction, and hard mass lesions that may mimic cancer.
Fibrocystic Changes (Fibrocystic Disease; Cystic Mastopathy)
Fibrocystic “disease” of the breast was once considered to be a very common lesion of the female breast, affecting about 10% of women. In autopsy studies, many of the same changes have been found in up to 50% of women who had no symptoms of breast disease during life, suggesting that they may be physiologic variations rather than disease. The changes occur after puberty, reach a maximum during the late reproductive period, and persist into the postmenopausal period.
Some of the histologic changes of fibrocystic “disease” are associated with an increased risk of breast carcinoma. It is important, therefore, not to use the diagnosis of fibrocystic “disease” indiscriminately. It has been recommended that the diagnosis be discarded altogether in favor of the term “fibrocystic changes” followed by a description of the histologic features observed in the individual case (Table 56-1).
Table 56–1. Relative Risk for Invasive Breast Carcinoma Based on Pathologic Examination of Breast Tissue with Fibrocystic Changes.1 ||Download (.pdf)
Table 56–1. Relative Risk for Invasive Breast Carcinoma Based on Pathologic Examination of Breast Tissue with Fibrocystic Changes.1
|No increased risk|
Slightly increased (1.5–2 times2)Moderately increased risk (4–5 times2)
Adenosis, sclerosing or florid
Cysts, macro- or micro- (or both)
Fibrocystic changes in the breast are believed to result from response of the breast to cyclic changes in levels of female sex hormones, mainly estrogens. No constant endocrine abnormality has been identified. Oral contraceptives do not increase the incidence of fibrocystic changes.
Fibrocystic change, showing fibrosis, formation of microcysts, apocrine metaplasia, and focal ductal epithelial hyperplasia.
Changes Not Associated with Increased Risk of Breast Carcinoma
An increase in stromal fibrous tissue is common; when fibrosis predominates, the term fibrous mastopathy is used. Ill-defined masses may result; these are rubbery in consistency. Fibrosis is sometimes associated with ductal hyperplasia to form a localized lesion called a radial scar. This is usually <2.0 cm in size but has irregular borders, mimicking a small carcinoma when visualized by mammography. The lesion is benign.
Cysts occur commonly, probably as the result of duct obstruction. They vary in size from small (microcysts) to several centimeters in diameter, the latter forming palpable masses. The cysts are lined by flattened or apocrine epithelium and contain a glairy, turbid fluid. On gross examination, many have a bluish color and for that reason are sometimes called blue-domed cysts. Needle aspiration of cysts causes them to collapse.
Chronic inflammation, with lymphocyte and plasma cell infiltration, is commonly present. (“Chronic cystic mastitis” was once an alternative term for fibrocystic changes.) Rupture of cysts may evoke a histiocytic response resembling granulomatous mastitis.
Mild Ductal or Lobular Hyperplasia
Mild hyperplasia of lobules (adenosis) or epithelium within ducts is very common. Hyperplasia may be accompanied by sclerosis (fibrosis), leading to marked distortion of the normal lobular pattern and making histologic distinction from carcinoma difficult. The terms sclerosing adenosis and microglandular adenosis are used for this histologic appearance.
Metaplasia of the ductal epithelium to an apocrine type (large cells with abundant pink cytoplasm and decapitation type secretion) is very common.
Changes Associated with Increased Risk of Carcinoma
Atypical Lobular Hyperplasia
Marked proliferation of lobular epithelium is considered to carry a fourfold to fivefold increased risk of carcinoma. The proliferating cells distend the lobule and show cytologic atypia but do not satisfy the histologic criteria of lobular carcinoma in situ (see below). The histologic differentiation from lobular carcinoma in situ may sometimes be difficult.
Ductal Hyperplasia Without Atypia
(Also called ductal hyperplasia of the usual type, “papillomatosis,” and “epitheliosis.”) Moderate to severe hyperplasia of the ductal epithelium without features of intraductal carcinoma carries a one and one-half- to twofold increased risk of carcinoma. This type of ductal hyperplasia is characterized by proliferation of small oval cells with overlapping nuclei, poorly demarcated cell outlines, and absence of necrosis and cribriform spaces.
Atypical Ductal Hyperplasia
Marked atypical proliferation of ductal epithelium, causing stratification and often filling the lumen of the distended duct, is associated with a fourfold to fivefold increased risk of cancer. The risk of cancer associated with atypical ductal hyperplasia doubles if the patient also has a family history of breast cancer. The term “borderline lesion” is sometimes used for this process.
The histologic differentiation of atypical ductal hyperplasia from intraductal carcinoma may sometimes be difficult (see below).
Patients with fibrocystic changes may present with pain, nipple discharge, and an irregular lumpy consistency of the breast. Bilateral involvement is common. On occasion, there may be breast masses that mimic carcinoma. Needle aspiration may yield fluid from a cyst, resulting in disappearance of the mass. In many cases, however, biopsy is necessary to rule out carcinoma.
Fibroadenoma of the Breast
Fibroadenoma is a common benign breast neoplasm that occurs at all ages. The highest incidence is in young women. It presents as a discrete, firm, freely movable nodule in the breast. Multiple fibroadenomas occur in 10% of cases. Grossly, fibroadenomas are encapsulated, firm, and uniformly grayish-white. Fibroadenomas are usually 1–5 cm in diameter but may be larger (giant fibroadenoma). Rarely, fibroadenomas occur in adolescents as rapidly growing mass lesions with evidence of proliferative activity in both glandular and stromal elements. These tumors, called juvenile fibroadenomas, are benign.
Histologic examination reveals proliferation of both glandular and stromal elements. The relative amount of each component varies from case to case. When the glandular component dominates, the term “tubular adenoma” or “pericanalicular fibroadenoma” is used; when the stroma dominates, the term “intracanalicular fibroadenoma” is used Figure 56-5). These histologic variants have no significance.
Fibroadenoma, showing the typical relationship of glands and stroma.
A lactating adenoma is probably a fibroadenoma in which lactational changes have supervened. Lactating adenomas may be associated with a rapid increase in size, raising a suspicion of carcinoma. Fine-needle aspiration (FNA) is a simple method of confirming the diagnosis of lactating adenoma. When FNA shows cytologic features that are suspicious for malignancy, biopsy is indicated.
Ductal papillomas are benign neoplasms, commonly originating in a major lactiferous duct near the nipple (Figure 56-6). They present with a bloody nipple discharge. Most ductal papillomas are small—about 1 cm in diameter; the larger tumors are palpable as a subareolar mass.
Intraductal papilloma. The lactiferous duct has been opened longitudinally (outline of duct marked by dotted lines) to show the small tumor within the duct (arrow). The patient presented with a bloody discharge from the nipple.
Grossly, the tumor is seen as a papillary mass projecting into the lumen of a large duct (Figure 56-6). Histologically, there are numerous delicate papillae composed of a fibrovascular core covered by a layer of epithelial and myoepithelial cells. Rarely, papillomas are histologically very complex, and distinction from papillary carcinoma may be difficult.
Granular cell tumor (previously called granular cell myoblastoma) is a rare benign neoplasm of the breast. It is probably derived from neural Schwann cells. It presents clinically and on gross pathologic examination as a hard infiltrative mass that resembles breast cancer. Microscopic examination, which shows large cells with small nuclei and abundant granular cytoplasm, is essential to make the diagnosis.
Currently, there are more than 180,000 new cases of breast cancer every year in the United States and 46,000 deaths, and it has been estimated that one of every eight American women living to age 95 years will develop breast carcinoma. Until 1983, breast cancer was the leading cause of cancer deaths among females; despite an increase in the incidence of breast carcinoma, it is now second to lung cancer because of the larger increase in the number of women developing lung cancer.
There is a marked geographic variation in the incidence of breast cancer. It is especially common in North America and Western Europe but rare in Japan, where the incidence is about 20% of that in the United States.
Breast carcinoma is rare before 25 years of age and uncommon before 30 years; the incidence increases sharply after 40 years, with a mean and median age of 60 years.
Table 56–2. Clinical Risk Factors for Breast Cancer. ||Download (.pdf)
Table 56–2. Clinical Risk Factors for Breast Cancer.
|Sex:Race:Age:Family historyMedical historyMenstrual historyPregnancy historyOthers|
Statistically, the risk of breast cancer is increased in nulliparous women (nuns have a high incidence), in women who have early menarche and late menopause, and in those who have their first pregnancy after age 30. Breast feeding appears to have a protective effect for the mother. Evidence linking oral contraceptives to breast carcinoma is scant; a few studies suggest a very slightly increased incidence in women who use oral contraceptives.
The presence of atypical lobular and ductal hyperplasia in a breast biopsy increases the risk fourfold to fivefold. A family history (limited to first-degree relatives—ie, mother, sister, daughter) of breast carcinoma increases the risk fivefold. The first-degree relatives of a woman who develops bilateral breast cancer before menopause are at greatly increased risk. The increased risks resulting from atypical hyperplasia and family history are additive (ie, the presence of both increases the risk eightfold to tenfold).
The occurrence of carcinoma in one breast increases the risk of carcinoma in the other breast about sixfold. Women without any of the above risk factors still have a high incidence of breast cancer.
The cause of breast carcinoma is unknown but is probably multifactorial. The following factors have been proposed.
Genetic factors are suggested by the strong familial tendency. There is no inheritance pattern, suggesting that the familial incidence is due either to the action of multiple genes or to similar environmental factors acting on members of the same family. Mutation of the BRCA-1 gene, located on chromosome 17q, is believed to account for 45% of families with a high incidence of breast cancer. BRCA-1 is thought to encode a tumor suppressor protein. A second gene, BRCA-2, located on chromosome 13q, has also been reported as important in familial breast cancer. Furthermore, mutations in the gene that encodes the tumor suppressor protein p53 and activation of oncogenes such as erb B2/neu and c-ras have been reported, but are believed to be less important than BRCA-1 and BRCA-2.
Hormones are widely believed to play a role in the etiology of breast cancer. Estrogen has been the most extensively studied hormone because of the epidemiologic evidence that prolonged estrogen exposure (early menarche, late menopause, nulliparity, and delayed pregnancy) increases the risk of breast cancer. A weaker case can be made for prolactin as a possible cause.
While the role of hormones in the induction of breast carcinoma is uncertain, there is no doubt that some breast cancers are hormone dependent. Hormone dependency is related to the presence of estrogen, progesterone, and other steroid hormone receptors in the nuclei of breast carcinoma cells. Estrogen is believed to exert its effect by causing the cancer cells to secrete growth factors (eg, epidermal growth factor (EGF)) that promote tumor progression. In neoplasms that possess such receptors, hormone (antiestrogen) therapy may slow the growth or cause regression of the tumor.
Viruses are also suspected of causing breast carcinoma. The Bittner milk factor is a virus (mouse mammary tumor virus; see Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia) that causes breast carcinoma in mice; it is transmitted via breast milk. The virus has also been found in the genome of these mice, being transmitted vertically and leading to genetic strains of mice with a high incidence of breast carcinoma. Antigens similar to those present in mouse mammary tumor virus are present in some cases of human breast carcinoma, but their significance is not clear.
Based upon histologic criteria, several different types of breast carcinoma are recognized, subclassified according to origin (lobular versus ductal) or invasiveness (in situ versus infiltrating) (Table 56-3).
Table 56–3. Pathologic Types of Breast Carcinoma. ||Download (.pdf)
Table 56–3. Pathologic Types of Breast Carcinoma.
|Lobular carcinoma |
(10%)Lobular carcinoma in situ
Invasive lobular carcinoma
Does not produce a mass; often discovered incidentally in breast biopsies
Multifocal, bilateral in 70%
Lengthy in situ phase
High risk (10- to 12-fold) of breast carcinoma (either infiltrating ductal or lobular) in both ipsilateral and contralateral breast
Differentiated from infiltrating ductal carcinoma by histologic features only
More frequently bilateral than infiltrating ductal carcinoma
More frequently estrogen receptor-positive than ductal carcinoma
Prognosis similar to that of infiltrating ductal carcinoma
(85%)Ductal carcinoma in situ
Infiltrating ductal carcinomaHistologic variants of infiltrating ductal carcinoma1. With a better prognosis than regular infiltrating ductal carcinoma2. With a worse prognosis than regular infiltrating ductal carcinomaOthers
Produces a breast mass or is detected by mammography
Short in situ phase
Multifocal, bilateral in about 20%
Type of carcinoma most often associated with Paget's disease of the nipple
Paget's disease of the nipple
Unclassifiable and anaplastic types
Mixed lobular and ductal carcinoma
In Situ (Noninvasive) Carcinoma
Lobular Carcinoma in Situ (Lcis)
(Figure 56-7.) LCIS is a neoplastic proliferation of lobular epithelial cells that fill and distend all the acini of at least one complete lobular unit, obliterating their lumens. The basement membrane is intact; there is no risk of disseminated disease as long as the tumor remains in situ. LCIS tends to be multifocal and bilateral.
Lobular carcinoma in situ. The involved lobule (arrow) shows complete filling and distention of all constituent acini by small round cells. Compare with normal breast lobule at top left (labeled N).
LCIS does not produce a palpable lesion and is not apparent on mammography. It is usually an incidental pathologic finding in a patient who has had breast tissue removed for some other reason.
The presence of LCIS increases the risk of future development of breast carcinoma tenfold to twelvefold. Both breasts are at risk, with the ipsilateral slightly more so than the contralateral breast. Infiltrating carcinomas associated with LCIS may be either ductal or lobular.
The management of a patient with LCIS is highly controversial, and recommended treatment ranges from careful follow-up to bilateral simple mastectomy because of the increased risk of infiltrating breast carcinoma.
Ductal Carcinoma in Situ (Dcis)
(Figure 56-8.) Intraductal carcinoma is a neoplastic proliferation of ductal epithelial cells confined within the basement membrane. Pure DCIS does not metastasize. However, DCIS is commonly associated with infiltrating ductal carcinoma. DCIS is frequently multifocal, and it is bilateral in 15–20% of cases.
Ductal carcinoma in situ, cribriform type. The duct is distended by a uniform population of cells. The basement membrane is intact.
Grossly, DCIS may produce a hard mass composed of thickened cord-like structures from which necrotic material can sometimes be expressed. Calcification is a common feature; consequently, DCIS is detectable by mammography. In some cases, however, DCIS is neither palpable nor visualized by mammography (microscopic DCIS).
Histologically, the involved ducts are distended by malignant cells that may be arranged in cribriform, papillary, or solid patterns. The cells are large and uniform, with well-defined cell membranes and nonoverlapping, round nuclei. Central necrosis is a common feature (comedo carcinoma).
The treatment of DCIS varies with the size of the lesion. For microscopic and small (< 2.5 cm) lesions, local complete excision (lumpectomy) is the usual treatment. For larger lesions, mastectomy is usually done. Axillary lymph node dissection is not indicated if there is no invasion, particularly in lesions smaller than 2.5 cm.
Infiltrating (Invasive) Ductal Carcinoma
Invasive Ductal Carcinoma
Invasive ductal carcinoma is the most common type of breast cancer, comprising 75% of all cases. Grossly, it forms a gritty, rock-hard, grayish-white infiltrative mass (Figure 56-9). Yellowish-white chalk streaks are characteristic and correspond to a peculiar deposition of elastic tissue (elastosis) around ducts in the area of involvement. Fibrosis may be extensive, producing a hard (scirrhous) type of cancer.
Invasive carcinoma of the breast. A: Surface view, showing the carcinoma ulcerating through the skin. B: Cut surface of the same breast, showing a large infiltrative mass extending from the skin almost to the deep surface (arrows).
Microscopically, highly pleomorphic ductal epithelial cells infiltrate the fibrous stroma. Lymphatic invasion is common.
Infiltrating Lobular Carcinomas
Infiltrating lobular carcinomas constitute 5–10% of all breast carcinomas. They are similar to infiltrating ductal carcinomas except for (1) a different histologic pattern of infiltration, with a tendency to form single rows of cells (Indian filing; Figure 56-10) and concentric arrangement of cells around ducts (targetoid appearance); (2) a slightly higher incidence of bilaterality; and (3) a greater frequency of estrogen receptor positivity.
Infiltrating lobular carcinoma of the breast, showing tumor cells arranged in single rows (Indian file appearance) and fibrosis.
Morphologic Variants of Breast Carcinoma
Variant forms of breast carcinoma have been recognized (Table 56-3). Some of them—like medullary carcinoma, mucinous (colloid) carcinoma, and tubular carcinoma—are important to recognize because they have a better prognosis than the usual infiltrating ductal carcinoma. Medullary carcinomas tend to be large, soft, and very well circumscribed, consisting of sheets of large polygonal cells associated with a marked lymphocytic infiltrate (which may contribute to the good prognosis). Mucinous carcinomas form gelatinous lakes of mucoid material in which cancer cells are suspended. Tubular carcinoma is composed of small, irregular infiltrative cancerous glands.
Clinical Features of Infiltrating Breast Carcinoma
Clinical Presentation of Breast Cancer.
Clinical Presentation of Breast Cancer.
Percentage of All Cases
Breast mass, painless
Breast mass, painful
Nipple retraction or crusting
Local edema and inflammation
Metastatic disease in lymph nodes, bone, brain, lung, or pleura
Most patients present with a painless mass. Any breast mass should be regarded as a carcinoma until proved otherwise. Initially, the mass may be small and movable, but typically it enlarges, sometimes rapidly, and in the later stages it becomes fixed to the chest wall and skin. Skin and nipple retraction and ulceration are late features with an unfavorable prognosis. A few patients present with a bloody nipple discharge. Carcinoma may present in pregnancy, when diagnosis is often delayed because of overall breast enlargement and nodularity.
Early detection of breast carcinoma is very important because the smaller the lesion, the greater the likelihood of cure. Self-examination of the breast is strongly recommended at monthly intervals for all women. At present, the majority of breast cancers are discovered by self-examination and screening mammography. Mammography is capable of showing breast cancer at a stage before it is palpable. Small masses or speckled areas of calcification are visible, and biopsy is directed by a needle placed under radiologic guidance into the suspicious areas. Mammography is an effective screening technique that is currently recommended for high-risk groups such as patients with a family history, a previous breast biopsy showing atypical hyperplasia, or a previous history of breast carcinoma. It is also recommended for all women over the age of 40 years. There is a trend to increase the age at which routine mammography begins to age 50 years for reasons of cost benefit and risk of radiation associated with mammography.
A small number of breast carcinomas have a distinctive clinical presentation.
Paget's Disease of the Nipple
Paget's disease presents clinically as an eczematous change in the nipple and surrounding skin. It is characterized microscopically by the presence of carcinoma cells in the epidermis (Figure 56-11; see also Chapter 53: The Uterus, Vagina, & Vulva, the section on extramammary Paget's disease). These cells are believed to spread within the epidermis. The cells are large, with abundant cytoplasm that stains positively for mucin and resembles the cells of ductal carcinoma of the breast. In most cases, the underlying breast shows the presence of a ductal carcinoma.
Paget's disease of the nipple.
Patients with Paget's disease have the prognosis of the underlying breast carcinoma. When Paget's disease occurs in a patient without a palpable mass or in one with only intraductal carcinoma, it is an early manifestation of cancer, and the prognosis is good.
Inflammatory Breast Carcinoma
This rare form of breast carcinoma is characterized by the presence of swelling producing the typical peau d'orange appearance of the overlying skin, redness, pain, and tenderness of the breast. The underlying breast shows diffuse induration, frequently without a definite breast mass. This clinical picture resembles that of acute inflammation of the breast. Inflammatory carcinoma is the result of extensive involvement of the dermal lymphatics by carcinoma (dermal lymphatic carcinomatosis) (Figure 56-12). It has a very poor prognosis, with few patients surviving at 5 years.
Inflammatory breast carcinoma, showing a dermal lymphatic containing carcinoma cells (arrows).
Direct spread occurs along the ductal system at an early stage, often before invasion has occurred. Such intraepithelial spread may result in involvement of multiple ducts and lobules (cancerization of lobules). Extension to the nipple in this manner results in Paget's disease. Local invasion may also occur into the breast stroma and then into overlying skin and underlying pectoralis major. Chest wall muscle involvement has a poor prognosis.
Lymphatic spread follows predictable routes according to the site of the primary lesion. The axillary lymph nodes are the primary node group affected. The nodes along the internal mammary artery may be involved in carcinomas located in the medial half of the breast. Spread beyond the axillary node into supraclavicular and cervical nodes is evidence of advanced disease. Local dermal lymphatic obstruction, most commonly due to extensive axillary node involvement, causes edema of the skin (peau d'orange).
Bloodstream spread, with metastatic deposits in bone, liver, and lungs, occurs in the later stages in almost all cases not cured by initial treatment. Entry of cancer cells into the bloodstream probably occurs early in the course of invasive breast carcinoma, but most of these cells are either killed by the immune system or remain dormant in distant organs. The mechanisms underlying dormancy of metastatic cancer cells and the reasons for their later activation to cause clinically detectable tumor masses are unknown. Dormancy and activation of cancer cells are necessary to explain the occurrence of metastases many years after treatment of the primary tumor.
Spread via the pleural or peritoneal cavity occurs when the pleura or peritoneum is secondarily involved by the breast cancer.
Histologic examination of a biopsy of the mass is the definitive diagnostic method. Excisional, incisional, or needle biopsies may be performed. Immediate diagnosis of a biopsy specimen by frozen section examination has a high degree of accuracy in experienced hands.
A complete pathologic diagnosis of breast carcinoma should provide the following information: (1) the histologic type of carcinoma; (2) the size of the tumor; (3) the stage of disease (Table 56-5); and (4) the estrogen and progesterone receptor status.
Staging of Breast Carcinoma Using the TNM System.
Staging of Breast Carcinoma Using the TNM System.
Primary tumor (T)
Carcinoma in situ. Includes LCIS, DCIS, Paget's disease of the nipple with no underlying tumor
Tumor 2 cm or less in greatest dimension
Tumor >2 cm but not greater than 5 cm in greatest dimension
Tumor >5 cm in greatest dimension
Tumor of any size with extension to chest wall or skin. Includes inflammatory carcinoma.
Lymph node (N)
No regional lymph node metastasis
Metastasis to movable ipsilateral axillary lymph nodes
Metastasis in ipsilateral axillary lymph nodes fixed to one another or other structures
Metastasis to ipsilateral internal mammary lymph nodes
Distant metastasis (M)
No distant metastasis
Distant metastasis present. (
Supraclavicular lymph node metastasis counts as distant metastasis.)
Clinical Staging Based on Above Criteria
Tis N0 M0
T1 N0 M0
T1 N1 M0 or T2 N0 M0
T2 N1 M0 or T3 N0 M0
T1 N2 M0, T2 N2 M0, T3 N1 M0, T3 N2 M0
T4 Any N M0 or Any T N3 M0
Any T Any N M1
Receptor status is currently established by bioassay, for which a specimen from the tumor must be removed for freezing by the pathologist immediately after excision. Delay in preservation greatly interferes with the results of receptor assay. Immunohistochemical techniques are available for receptor determination on fixed tissue.
Cytologic diagnosis utilizing a specimen obtained by fine-needle aspiration is increasing in popularity because it is rapid and cost-effective. Cytologic diagnosis is capable only of identifying carcinoma cells. Definitive diagnosis of the histologic type of carcinoma still requires histologic examination of tissue sections.
Surgery has been the mainstay of treatment of breast cancer for the past several decades. The standard treatment was radical mastectomy, which involves removal of the breast along with the pectoral muscles and axillary contents. The realization that this type of surgery may be too extensive led to new approaches. Presently, two forms of treatment are recognized as being equally effective in treating all but very large (> 4 cm) lesions. These are (1) modified radical mastectomy, which includes axillary node dissection but preserves the pectoralis muscle; and (2) complete excision with clear margins (lumpectomy), with axillary node dissection followed by radiation. There is a trend toward breast-conserving surgery for treatment of breast carcinoma.
Breast carcinoma is a moderately radiosensitive tumor. Radiotherapy is indicated when breast-conserving surgery has been performed and in patients who develop locally recurrent disease in the chest wall.
Chemotherapy has increased the disease-free survival periods in breast carcinoma but is not curative. The rationale for chemotherapy after successful surgical treatment (adjuvant chemotherapy) is that it removes microscopic foci of neoplastic cells in distant sites, thus complementing the role of surgery. Adjuvant chemotherapy is indicated in all but small, well-differentiated, node-negative cancers with no adverse prognostic indicators.
Hormonal manipulation—usually antiestrogen therapy—is most effective in patients with estrogen or progesterone receptor-positive carcinomas. (Sixty to 80% of such patients respond; only 10% of receptor-negative patients respond.) Removal of estrogens may be achieved surgically (removal of ovaries and adrenal glands) or by antiestrogenic drugs such as tamoxifen. Antiprogesterone agents (RU 486; mifepristone) have recently become available and are in trial.
Infiltrating carcinoma of the breast has a 5-year survival rate of about 70%. About 20% of patients who survive 5 years will develop late recurrences. Recurrences of breast carcinoma have been recorded as late as 25 years after the primary tumor was successfully treated. The most important factors affecting prognosis are the following:
The Clinicopathologic Stage
Staging of breast carcinoma is based on defined criteria relating to the primary tumor, lymph nodes, and distant metastasis (Table 56-5). Staging is the most important predictor of prognosis. Ninety-six percent of patients with stage I disease survive 5 years.
(Table 56-3.) The prognosis varies according to the histologic type. This is a minor factor, included in the histologic grade.
Infiltrating ductal carcinomas are graded histologically into grades I–III by a system that uses architectural pattern, nuclear features, and frequency of mitotic figures. Grade III tumors have a poor prognosis.
The Presence of Neu Oncogene
The presence of neu oncogene, especially when large numbers (more than 20 copies per cell) are present, indicates a poor prognosis.
Absence of Steroid Hormone Receptors
Absence of steroid hormone receptors indicates a poor prognosis quite apart from the lack of response to hormonal therapy that is associated with absence of receptors. The lack of progesterone receptors has a greater value in predicting poor prognosis than lack of estrogen receptors.
High Proliferative Activity
High proliferative activity of the cancer cells, as indicated by a high (> 12 %) S-phase fraction on flow cytometry or high expression of the proliferative antigen Ki67 indicates a poor prognosis.
Aneuploidy in the Cancer Cells
Aneuploidy in the cancer cells, as shown by flow cytometry, indicates a poor prognosis.
Other indicators, such as angiogenesis, epidermal growth factor, cathepsin D, and heat shock protein, have been reported but are not routinely used.
Phyllodes Tumor (Cystosarcoma Phyllodes)
Phyllodes tumor is (in 80–90% of cases) a low-grade malignant neoplasm that is locally infiltrative with a tendency to recur locally after simple excision. In 10–20% of cases, the tumor behaves like a high-grade neoplasm, metastasizing to distant sites, mainly the lungs.
Phyllodes tumor typically forms a large mass, commonly over 5 cm in diameter. Grossly, it is a fleshy tumor with poorly circumscribed margins and areas of cystic degeneration. Histologically, it is composed—like a fibroadenoma—of epithelial and stromal components. The epithelial component resembles that of fibroadenoma. The stroma is much more cellular than that of fibroadenomas and frequently shows cytologic atypia. The presence of increased mitotic activity in the stroma (more than three mitotic figures per ten high-power fields) and stromal overgrowth at the expense of the epithelial component are useful criteria to predict metastatic potential in phyllodes tumors.
Because of its infiltrative behavior, phyllodes tumors must be removed with a surrounding margin of breast tissue. With large tumors, simple mastectomy may be necessary. Tumors that metastasize usually cause death, since chemotherapy and radiotherapy are not very effective.
Other Malignant Neoplasms of the Breast
Primary malignant neoplasms other than carcinomas and phyllodes tumors occur very rarely in the breast. They include angiosarcoma, acute myeloblastic leukemia (granulocytic sarcoma), malignant lymphomas, and sarcomas derived from stromal cells. Metastases to the breast from primary cancers in other organs are rare.