Breast Cancer and Related Diseases

Catherine M. Dang and M. William Audeh

Breast cancer is the most common malignancy in women throughout the world, and particularly in Westernized, developed countries. The relative roles of genetic, environmental, and lifestyle factors in explaining the high incidence of breast cancer in the modern world is a subject of much debate. However, it is clear that the complex biology of the human breast and its involvement in the reproductive cycle is also the basis for the increased susceptibility of this organ to malignant transformation.¹

EPIDEMIOLOGY

Key Points

1. The most significant risk factors for breast cancer include increasing age and deleterious mutations in the BRCA1 and BRCA2 genes.

2. Reproductive factors that contribute to breast cancer risk are related to the length of estrogen and progesterone exposure.

3. The total number of ovulatory cycles promotes an increased estrogenic exposure that can modulate breast cancer risk.

Breast cancer remains the most common cancer diagnosed in women worldwide. In the United States, more than 209,060 new cases of breast cancer are expected in 2011.² Despite the preponderance of epidemiologic studies examining risk factors and causes of breast cancer, only very few highly significant risk factors, such as increasing age and deleterious mutations in the BRCA genes, have been identified.³ Epidemiologic factors reproducibly associated with increased risk of breast cancer are shown in Table 15-1.^4–6 Although increasing age is recognized as a universal risk factor for many cancers, including that of the breast, reproductive factors play a significant role in modulating breast cancer risk. The common thread appears to be the timing and length of exposure to estrogen and progesterone, and the age at which a pregnancy is first carried to term, leading to differentiation of the breast epithelium, lactation, and eventual involution. Furthermore, breast density, as measured on mammography, appears to be an anatomical surrogate for the glandular and potentially proliferative cellular content of the breast and is increasingly recognized as an additional marker of risk.⁷ In addition, a growing body of evidence supports the cancer-promoting effect of increasing length of exposure of the breast tissue to estrogen and progestin as a result of the use of postmenopausal hormone replacement therapy (HRT).⁸ The use of as little as 2 years of postmenopausal HRT yields an increased risk.⁹

Table 15-1 Risk Factors for Breast Cancer

Beyond purposeful exposure to postmenopausal HRT, however, there are the underlying changes in the lifestyle of women in Westernized, developed countries and societies that also affect hormonal factors.^8,10 Women in such societies have on average earlier onset of menses, later and fewer full-term pregnancies, and a lesser likelihood of breast feeding than women in less developed societies, where the rates of breast cancer are much lower. The overall result of these factors is to dramatically increase the total number of ovulatory cycles a woman may undergo in her lifetime. Although this increased estrogen effect has been primarily attributed to lifestyle and reproductive history, worldwide environmental exposure to estrogenic compounds is of increasing concern, with potential sources being dietary phytoestrogens, xenobiotic pesticides, and plastic-related exposures to estrogenic substances such as dioxin and bisphenol-A.^11,12

Efforts to identify genetic factors associated with breast cancer risk have succeeded in identifying very likely all highly penetrant, but relatively rare genes, which are associated with positive family history of cancer¹³ (Table 15-2). These genes are all involved in DNA damage detection and repair and, when mutated, confer extremely high lifetime risks of breast (and other) cancers. Of all the identified high-penetrance genes associated with breast cancer, the BRCA1 and BRCA2 genes account for as much as 5% or 10% of all breast cancers, with the lifetime risk of breast cancer in mutation carriers ranging from 55% to 87%.^14,15

Table 15-2 Germ-line Genes Associated With Increased Risk of Breast Cancer

The search for genetic factors which may affect the risk of breast cancer in women without a family history has involved genome-wide association studies, seeking genetic markers and polymorphisms.¹⁶ These studies have yielded a growing list of common genetic variants and polymorphisms that exert their effect by modest functional changes, rather than loss of function through mutation. The strongest candidate for a “universal” breast cancer risk factor is fibroblast growth factor receptor 2 (FGFR2),^16,17 in which single nucleotide polymorphisms (SNPs) have been associated with risk of breast cancer. However, as this and the 6 other major risk-associated SNPs were identified from unselected populations in genome-wide searches, no gene–environment or gene–gene interactions have been defined, and no functional biologic associations have been proposed. Therefore, attempts to combine these 7 SNPs with traditional epidemiologic risk factors, as developed in the Gail model, have failed to show any additional predictive power with the addition of this level of genetic information.¹⁸

The pathogenesis of breast cancer is complex. The evolutionary function of the breast in all mammals is primarily to provide nourishment to newly born offspring. Therefore, breast development and differentiation to provide this function in the female is limited to the reproductive years; it is not required to begin until puberty and is no longer required after menopause. As a result, the breast tissue is minimally formed during embryogenesis, with a single epithelial ectodermal bud, and grows postnatally but without differentiation in keeping with body size. Breast tissue then enters a phase of rapid proliferation and ductal branching with puberty.¹ The development of the breasts under the influence of pituitary and ovarian hormones at the onset of puberty is a so-called invasive process, in which branching morphogenesis by the epithelial ductal tree spreads through the mammary fat pad. The tips of the branching structure are the terminal end buds (TEBs), in which highly proliferative cells drive growth and expansion through the stroma. This process is driven by molecular pathways involved in the so-called epithelial-mesenchymal transition, similar to those seen in embryogenesis, as well as those frequently identified in aggressive invasive malignancies¹⁹ (Figure 15-1). Molecular pathways involving epidermal growth factor, insulin-like growth factor, src kinase, hepatocyte growth factor/scatter factor, Wnt, transforming growth factor β, and matrix metalloproteinases, among others, are integral to the biology of the developing breast and may explain why they are often upregulated in breast cancers and provide active targets for cancer therapy.²⁰ In addition, many of the cells of the breast TEB possess stem-cell properties and may represent the vehicle by which mammary stem cells, thought by many to be the origin of breast cancer, spread and populate the breast tissue.^21,22

FIGURE 15-1. Similarities between breast development and invasive breast cancer.

From puberty until first pregnancy, the breast epithelial ductal structure is made up of 15 to 20 lactiferous ducts ending in a terminal duct containing from 6 to 11 ductules, forming the terminal duct lobular unit (TDLU)²³ (Figure 15-2). This initial lobular unit is the least differentiated in postpubertal, nulliparous women; has the highest proliferative rate as measured by Ki-67; and has been termed Lob 1.²⁴ Nearly all epithelial malignancies of the breast are thought to arise from the Lob 1 TDLU. In order to perform the function for which the breast has evolved, namely to produce milk after a full-term pregnancy, the lobular units must remain poised to rapidly proliferate in response to the hormones of pregnancy, first from the pituitary and ovaries, and later from the placenta and fetus itself. Until this occurs, the cells of the breast epithelium must remain in a state of undifferentiated plasticity, which carries with it the risk of malignant transformation.

FIGURE 15-2. The terminal duct lobular unit. (Reproduced, with permission, from World Cancer Research Fund and American Institute for Cancer Research.¹⁰)

In animal models, these undifferentiated lobules have been found to be most susceptible to carcinogen-esis, with susceptibility diminishing and DNA-repair proficiency increasing, with the differentiated state induced by pregnancy. With pregnancy, the Lob 1 structure is induced to differentiate and branch to a level of approximately 65 to 90 ductules per TDLU, known as Lob 3, and during lactation, Lob 4. The majority of TDLUs in the breasts of women who have undergone full-term pregnancy before age 30 years are Lob 3, whereas those of nulliparous or late pregnancy women remain primarily Lob 1. Although the classification of lobules as Lob 1 or 3 is based on histology and morphology, the genomic signature underlying these phenotypes has recently been studied and may provide insights into the differing susceptibility to malignant transformation and the observed protective effects of early pregnancy.^25,26 The genomic signature induced by the first full-term pregnancy remains detectable in the breast epithelium after menopause and is characterized by more than 200 genes that have either been up- or downregulated and involve functions of DNA repair, carcinogen metabolism, and regulation of apoptosis, among others. The analysis of the genomic pathways that may affect breast cancer development could allow the identification of factors that may be used to identify women at increased risk, interventions to reduce risk, and new targets for therapy of established cancer. Indeed, the management of breast cancer, perhaps more than any other solid tumor, has been dramatically changed by the introduction of genomic and molecular information into the clinic.²⁷

DIAGNOSIS

Key Points

1. The Gail model can predict breast cancer risk in women older than 35 years and includes reproductive history, history of prior breast biopsies, history of hormone use, and family history.

2. Abnormal mammogram findings that are often associated with malignancy include masses, clustered calcifications, architectural distortion, asymmetric density, skin thickening, and abnormal axillary lymph nodes.

3. The American Congress of Obstetrics and Gynecology recommends screening mammography every 1 to 2 years in women between the ages of 40 and 49 years and annually for women 50 years of age and older.

4. Breast imaging for screening and diagnosis may include mammography, ultrasound, and/or magnetic resonance imaging (MRI).

Traditionally, the diagnosis of breast cancer and related diseases was based primarily on history and physical examination. A detailed reproductive history (age at menarche, childbearing, breastfeeding, age at menopause); history of previous breast surgeries or biopsies, particularly biopsies showing atypia or lobular carcinoma in situ (LCIS); history of medication and hormone use; and family history of breast and ovarian cancer are particularly important components of the initial history. These factors form the basis of the Gail model, which may be used to predict breast cancer risk in women older than 35 years.²⁸ Additionally, the patient should be asked about breast symptoms, including pain, tenderness, mass, nipple discharge and retraction, changes in size or contour of the breast, and changes in the skin of the breasts. In patients in whom a cancer diagnosis has been confirmed or is suspected, systemic complaints of weight loss, fatigue, abdominal pain, bone pain, and neurologic symptoms should also be elicited.

Physical examination usually begins with visual inspection with the patient sitting upright. Asymmetries; skin changes such as erythema, edema, ulceration, or thickening; nipple retraction or excoriation (a sign of Paget disease); and skin dimpling should be noted. Having the patient raise the arms overhead may exaggerate subtle skin dimpling or nipple retraction. Next, examination of the regional lymph node basins (supraclavicular, infraclavicular, cervical, and axillary) is performed to detect enlarged and/or firm lymph nodes. Finally, the breasts are systematically examined with the patient supine and the ipsilateral arm raised above the head. Aside from distinct masses, more vague asymmetrically dense areas and any nipple discharge should be noted and characterized by color and whether it is emanating from a single or multiple ductal orifices. Nipple fluid that is bloody, spontaneous, and arises from a single ductal orifice is more likely to be related to underlying malignancy than nipple discharge that is bilateral, nonspontaneous, and non-bloody. Although malignancy must be excluded, intraductal papillomas, which are generally benign, are the most common cause of spontaneous, bloody nipple discharge. Milky nipple discharge, or galactorrhea, in a nonpregnant or nonlactating woman may be sign of a pituitary prolactinoma or hypothyroidism. Thyroid function tests and prolactin levels should be evaluated in this instance. Hemoccult testing can be performed on nipple fluid if it seems bloody, although this is not strictly necessary. Of potentially greater value is preparation of smears of nipple fluid for cytologic analysis, which can identify atypical or even malignant epithelial cells in nipple fluid.²⁹

Breast imaging is preferably performed before biopsy of any physical exam finding and for screening purposes in asymptomatic women. Since its introduction in the 1930s, mammography, in which the breast is compressed and x-ray images are obtained, has become the standard modality for breast imaging. Screening mammography, which images each breast in 2 views, is performed in asymptomatic women.³⁰ Diagnostic mammography, in which magnification and/or additional views of the breast are obtained, is usually performed in patients with breast symptoms, physical examination findings, lesions detected by screening mammography, and for short-interval follow-up of probably benign findings detected on prior mammograms.³¹ Mammography is effective as a screening tool because cancers are often denser radiographically than the surrounding normal glandular breast tissue, which in turn is denser than fatty breast tissue. Premenopausal women, especially women younger than 30 years, may have very dense glandular breast tissue, which severely limits the sensitivity of mammography. Generally, the glandular breast tissue atrophies and is replaced by fatty tissue as a woman ages, especially after menopause. Consequently, the breasts become less dense mammographically and the sensitivity of mammography for cancer detection increases with age.

Mammogram reports generally specify whether the breasts are fatty, heterogeneously dense, dense, or extremely dense. Abnormal mammogram findings that are often associated with malignancy include masses, clustered calcifications (≥ 5 calcifications in area), architectural distortion, asymmetric density, skin thickening, and abnormal axillary lymph nodes. Specifically, masses are noted to be suspicious for malignancy if the margins are obscured, ill-defined, or spiculated (irregular) (Figure 15-3), and calcifications are noted to be indeterminate or more likely to be malignant if they are amorphous or pleomorphic (heterogeneous) in shape and linear or branching in orientation (Figure 15-4). To standardize the reporting of mammograms and other breast imaging modalities, radiologic findings in the breast are rated using the Breast Imaging Reporting and Data System (BIRADS) developed by the American College of Radiology (Table 15-3). The positive predictive value of a lesion identified as being suspicious on mammography is estimated to be between 10% and 40%. Thus the vast majority of mammographically detected lesions are benign. Breastfeeding and pregnancy are relative contraindications to the use of mammography.³²

Table 15-3 Breast Imaging Reporting and Data System (BI-RADS) Categories and Recommendations

FIGURE 15-3. Mammogram images (A, B) indicate an irregular mass in the upper outer left breast. Ultrasound of the left breast (C) shows this to be a solid, hypoechoic mass with very irregular borders and confirms its suspicious nature. The mass was subsequently biopsied and demonstrated to be an invasive ductal carcinoma.

FIGURE 15-4. Mammogram images indicate a suspicious cluster of microcalcifications, which were subsequently biopsied and demonstrated to be associated with ductal carcinoma in situ.

Current recommendations for annual screening mammography are controversial. Screening mammography is performed in asymptomatic women because, theoretically, screen-detected cancers will be smaller, associated with better prognosis, and require less radical treatment than cancers detected by physical examination. The Health Insurance Plan (HIP) of Greater New York study was the first randomized controlled trial to demonstrate a survival benefit with the use of screening mammography. The trial followed a cohort of women aged 40 to 64 years who were randomly assigned to either undergo 3 annual screening mammograms versus no mammography. After 18 years of follow-up, women ages 40 to 49 and 50 to 59 years at enrollment who had undergone screening mammography had a 25% reduction in breast cancer-related mortality.³³ Subsequently, 7 other prospective, randomized trials worldwide have demonstrated that screening mammography decreases the risk of death from breast cancer.³² However, the age of mammogram screening, screening interval, and method varied in these trials, and the benefit of mammogram screening in average-risk women between the ages of 40 and 49 years is highly debated. Proponents for mammo-gram screening in women 40 to 49 years argue that breast cancer is the leading cause of death in this population; this population accounts for 20% of all breast cancer–related deaths and 34% of years of life lost to breast cancer; and breast cancers in younger women tend to be more aggressive. Arguments against routine annual screening mammograms in this younger age group include the following: only 16% of breast cancers occur in women under the age of 50 years, there is a decreased sensitivity of screening mammography in this age group, and there are significant psychological and physical harms associated with the relatively high false-positive rate of biopsies and unnecessary imaging tests associated with screen-detected lesions.^32,34 Furthermore, in 2009, the US Preventative Services Task Force (USPSTF) dramatically changed their recommendation for screening mammography to biennially (every 2 years) for women between the ages of 50 and 74 years. They recommended against screening mammography for all women ages 40 to 49 years, with the disclaimer that the decision to begin screening mammography before the age of 50 years should be made on an individualized basis. The USPSTF acknowledged that the relative risk reduction of screening mammography was similar in the 40 to 49 and 50 to 59 year age groups (15% and 14%, respectively). However, they argued that the absolute benefit is less in women 40 to 49 years of age because of the lower incidence of breast cancer in this age group. The USPSTF also noted that there are insufficient data to recommend for or against mammogram screening in women 75 years of age and older. However, The American Cancer Society, with support from the American College of Surgeons, continues to recommend annual screening mammography in addition to clinical breast examination in women aged 40 years and older and note that women ages 20 to 39 years of age should undergo clinical breast examination every 3 years.^35,36 The American Congress of Obstetrics and Gynecology, meanwhile, recommends screening mammography every 1 to 2 years in women between the ages of 40 and 49 years and annually for women 50 years of age and older.³⁷ Women with family history of premenopausal breast cancer in first-degree relatives (ie, mother, sister) may choose to begin annual mammogram screening 10 years before the age at diagnosis of the affected relative, but no later than age 40 years.³⁵

Advances in mammographic technology including digital mammography and computer-aided diagnosis (CAD) systems may improve the efficacy of screening mammography. Full-field digital mammography captures digital images of the breasts that can be manipulated and processed to optimize image quality while minimizing radiation exposure. The average radiation dose to the breast with digital mammography is approximately 22% less than with film screen mammography.³⁸ The Digital Mammographic Imaging Screening Trial, a retrospective, multicenter trial conducted at 33 academic medical centers by the American College of Radiology Imaging Network (ACRIN) demonstrated that the sensitivity of digital mammography for cancer detection (59%) is greater than that of film mammography (27%) in pre- or perimenopausal women younger than 50 years with dense breasts, although this did not apply to other subgroups, particularly older women with fatty breasts.³⁹ With CAD, digital or digitized mammogram images are subjected to computer analysis after initial radiologist interpretation of the films. The computer software may highlight additional lesions for the radiologist to review and make the final determination regarding whether the lesion is real or artifact and the nature of the lesion. No prospective randomized, controlled trials of CAD exist, although multiple retrospective and cohort studies have demonstrated some improvement in sensitivity (range, 1.7%-19.5% increased sensitivity) along with decreased specificity and increased recall rate for additional imaging with the use of CAD.⁴⁰

Ultrasound is an important adjunct to mammography in evaluation of the breasts. It can help distinguish cystic from solid lesions and further characterize solid lesions as being probably benign or suspicious in nature (Figure 15-3). Unlike mammography, ultrasound is usually performed in a targeted fashion for diagnostic purposes rather than for breast cancer screening. Breast ultrasound is commonly used to evaluate palpable masses or lesions, mammographic abnormalities, and nipple discharge and is also used to guide percutaneous needle biopsies and cyst aspirations and localize nonpalpable lesions for surgical excision; it is also used for intra-operative assessment of margins at surgery.⁴¹ Advantages of ultrasound include no exposure to ionizing radiation, patient comfort, and anatomic evaluation of the breast. Ultrasound, however, is operator dependent and can be time-consuming. Because of the limited sensitivity of mammography in women with denser breasts, screening whole-breast ultrasound in conjunction with screening mammography is currently being investigated in the prospective, multicenter ACRIN 6666 trial of a high-risk cohort of 2637 women. Initial results of the first round of screening with both mammography and ultrasound indicate that the addition of ultrasound screening detected an additional 4.2 (95% confidence interval, 1.1-7.2) cancers per 1000 women at high risk for breast cancer, but also increased the false-positive biopsy rate.⁴²

MRI is now also commonly used to evaluate the breasts. Dynamic contrast-enhanced MRI to evaluate the breast parenchyma employs intravenous gadolinium, which is contraindicated in patients with renal insufficiency and during pregnancy. MRI relies on angiogenesis and the abnormal microvasculature surrounding tumors to detect cancers. Both the degree of contrast enhancement and the perfusion pattern or kinetics of a lesion, along with lesion morphology, are taken into consideration to distinguish between suspicious and benign lesions⁴³ (Figure 15-5). Although it does not replace mammography, MRI has a number of advantages over mammography: no exposure to ionizing radiation, no limitations due to breast density, better spatial localization, and assessment of the extent of lesions.³² Furthermore, the sensitivity of MRI for detection of invasive breast cancer, ranging from 91% to 100% in the literature, is far greater than that of mammography and ultrasound, although the specificity of MRI is certainly no better and perhaps worse (as low as 30%) than that of mammography and ultrasound. The sensitivity of MRI for detection of ductal carcinoma in situ (DCIS) is especially low and is also lower for intermediate-grade DCIS.⁴³ Diagnostic breast MRI is frequently performed for the following reasons: to define the extent of the index lesion, to identify of otherwise occult ipsilateral or contralateral breast lesions, and to evaluate response to neoadjuvant chemotherapy.⁴⁴ In women diagnosed with breast cancer, meta-analysis of observational studies indicates that preoperative MRI identifies otherwise occult (not detected by physical examination, mammography, or ultrasound) cancer foci in the ipsilateral breast in 16% of cases and in the contralateral breast in 4% of cases. Accordingly, preoperative MRI changes surgical management in 11.3% of cases, generally resulting in more extensive surgical resection than originally planned, and has been linked to increased rates of mastectomy in women with early-stage breast cancer.⁴⁵ However, use of MRI preoperatively has not been shown to decrease rates of reoperation after lumpectomy to achieve adequate surgical margins in the randomized, prospective Comparative Effectiveness of MRI in Breast Cancer (COMICE) trial.⁴⁶ Furthermore, to date, there are no randomized prospective trials that demonstrate that preoperative MRI use improves breast cancer survival or reduces recurrence.⁴⁵ In summary, routine use of preoperative MRI in women newly diagnosed with breast cancer remains controversial.

FIGURE 15-5. Dynamic contrast-enhanced MRI of an enhancing, irregular mass that has a “washout” perfusion pattern of enhancement, indicative of malignancy.

Screening breast MRI in high-risk, asymptomatic populations, by contrast, is routinely performed. The American Cancer Society and American College of Surgeons recommends annual screening breast MRI be performed in the following populations at high risk for developing breast cancer: (1) women with deleterious BRCA1 or BRCA2 gene mutations and first-degree relatives of BRCA carriers who themselves have not undergone genetic testing; (2) women estimated to have at least 20% lifetime risk of breast cancer; (3) women who have undergone chest wall radiation therapy (eg, Hodgkin disease treatment) between the ages of 10 and 30 years; and (4) women with p53 gene mutations (Li-Fraumeni syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome) and their first-degree relatives. Currently, there is insufficient evidence to support the use of routine screening MRI in women who are at moderately increased risk for breast cancer (15%-20% lifetime risk), including those with a personal history of breast cancer, history of biopsy showing atypia or lobular carcinoma in situ (LCIS), or extremely dense breasts.³⁵

After breast imaging, tissue diagnosis is obtained either with an open surgical biopsy or preferably via minimally invasive, percutaneous needle biopsy. Surgical biopsy, both excisional and incisional, is generally performed in the outpatient setting. Surgical biopsy of nonpalpable lesions detected by mammography, ultrasound, or MRI requires preoperative placement of a wire (or needle) by radiology under local anesthesia to guide surgical excision. Intraoperative specimen radiograph or ultrasound should be performed to confirm complete excision of these nonpalpable lesions. Because 70% to 80% of all biopsies yield benign results, surgical incisions should be made as cosmetically as possible, generally along the Langer lines of skin tension, which are oriented concentric with the nipple. Incisions in the cleavage area (upper inner quadrants) should be avoided if possible.⁴⁷ Surgical biopsy, however, is more costly and has the potential for greater disfigurement, morbidity, and loss of productivity for the patient. Additionally, patients whose cancer diagnosis is made by surgical biopsy will frequently need at least one other surgery for definitive treatment of their cancer.⁴⁸

A number of options for percutaneous biopsy exist. Fine-needle aspiration (FNA) biopsy is inexpensive and easy to perform in the office setting with a 10-or 20-mL syringe and 22- or 25-gauge needle. Local anesthetic can be used to anesthetize the skin if desired. While pulling back on the syringe to generate suction, the needle is moved back and forth at different angles within the lesion of interest to dislodge cells, which are then aspirated into the syringe. Slides can then be made with the aspirated material, which are sent in fixative for review by a qualified cytopathologist. The accuracy of FNA approaches 80%, but false-negative rates remain as high as 15%-20%, and in some cases, there is insufficient material for analysis. FNA can identify malignant cells but cannot distinguish between in situ and invasive carcinoma. FNA can also be used to completely aspirate cystic lesions. Core (cutting) needle biopsy can be performed on any palpable lesion and on nonpalpable lesions with ultrasound, MRI, and mammogram (stereotactic core needle biopsy) guidance. Because core needle devices are larger (18 to 7 gauge), the skin and surrounding tissue should be well anesthetized with local anesthetic before making the small skin incision required to accommodate introduction of the biopsy needle into the breast.⁴⁷ Using a larger-gauge needle and vacuum assistance decreases the potential for sampling error. A radiopaque tissue marker (clip) is generally placed at the time of biopsy to facilitate subsequent lesion identification and confirm sampling of benign lesions on follow-up imaging. Core needle biopsy provides an accurate tissue diagnosis in approximately 98% of cases. The potential for sampling error, however, exists with any needle biopsy technique, and surgical excision is still recommended after benign core needle biopsy results if the pathology findings are discordant with the imaging impression, atypical ductal or lobular hyperplasia (discussed later), LCIS, papillary lesion, or radial scar. When surgical excision is performed subsequent to core needle biopsy showing atypical ductal hyperplasia, for example, 10% to 20% of cases will be found to have DCIS or invasive cancer. Also as a result of sampling error, surgery performed for DCIS may occasionally yield invasive cancer.^44,48

PATHOLOGY

Key Points

1. The majority of breast cancers are classified as invasive ductal carcinoma and invasive lobular carcinoma.

2. The critical proteins resulting from underlying genomic abnormalities in breast cancer include Ki67, estrogen receptor (ER), progesterone receptor (PR), and HER2; presence or absence of these proteins correlates with clinical outcome and affects adjuvant therapy.

3. Lobular carcinoma in situ (LCIS) is associated with increased risk of both ipsilateral and contralateral breast cancer.

Breast cancer is a clinically heterogeneous and diverse disease, and morphology-based histopathology has attempted to classify breast cancer into categories that would predict clinical and biologic behavior, with limited success.⁴⁹ The true basis of the pathology that produces the clinically recognizable entity of “breast cancer” is to be found at the level of the genome: genetic changes inherited and acquired in the course of carcinogenesis, passed on through cell division to daughter cells, involving multiple molecular networks and pathways that have promoted the survival of the malignant clone and produce the phenotype of breast cancer.⁵⁰

Traditional histopathology identifies the phenotypic effects of the underlying molecular and genetic lesions. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) identify the presence and amount of specific proteins expressed as a result of the underlying genomic abnormalities associated with malignancy of the breast. The critical proteins include Ki67, a general marker of proliferation⁵¹; nuclear and cytoplasmic receptors for estrogen and progesterone, ER and PR⁵²; and the cell surface signaling molecule HER2.⁵³ This gene expression profiling of breast cancers yields the beginnings of a molecular “taxonomy” of breast cancer that has added considerable insight to the previously identified but clinically heterogeneous histopathologically defined subtypes. Standard management guidelines for breast cancer at the present time are based on traditional histopathology and IHC—the tissue, cellular, and protein level of analysis.⁴⁹

The current morphologic classification of invasive epithelial cancers of the breast cancer recognizes at least 18 distinct histologic types (Table 15-4), although the majority of all breast cancers (50%-80%) are classified in this system as invasive ductal carcinoma, not otherwise specified (IDC-NOS).⁴⁹ This places the burden of identifying clinically meaningful subtypes at the molecular level, by IHC and genomic measures. Therefore, within invasive ductal (Figure 15-6) and invasive lobular (Figure 15-7), an additional 5% to 15%, subsets are more usefully defined by ER, PR, and HER2 expression through IHC. HER2-positive cancers represent approximately 20% of all breast cancers, ER negative/PR negative/HER2 negative (triple negative) cancers approximately 15%, with the remaining being ER positive/PR positive and ER positive/PR negative.

Table 15-4 Histopathologic Subtypes of Epithelial Breast Cancer

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