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Surgery_Schwartz. pregnancy is also protective, so older age at first live birth is associated with an increased risk of breast cancer. Finally, there is an association between obesity and increased breast cancer risk. Because the major source of estrogen in postmenopausal women is the conversion of andro-stenedione to estrone by adipose tissue, obesity is associated with a long-term increase in estrogen exposure.Nonhormonal risk factors include radiation exposure. Young women who receive mantle radiation therapy for Hodg-kin’s lymphoma have a breast cancer risk that is 75 times greater than that of age-matched control subjects. Survivors of the atomic bomb blasts in Japan during World War II have a very high incidence of breast cancer, likely because of somatic muta-tions induced by the radiation exposure. In both circumstances, radiation exposure during adolescence, a period of active breast development, magnifies the deleterious effect. Studies also sug-gest that the risk of breast cancer increases


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Surgery_Schwartz. In both circumstances, radiation exposure during adolescence, a period of active breast development, magnifies the deleterious effect. Studies also sug-gest that the risk of breast cancer increases as the amount of alcohol a woman consumes increases.49 Alcohol consumption is known to increase serum levels of estradiol. Finally, evidence suggests that long-term consumption of foods with a high fat content contributes to an increased risk of breast cancer by increasing serum estrogen levels.Risk Assessment ModelsThe average lifetime risk of breast cancer for newborn U.S. women is 12%.50,51 The longer a woman lives without cancer, the lower her risk of developing breast cancer. Thus, a woman age 50 years has an 11% lifetime risk of developing breast cancer, and a woman age 70 years has a 7% lifetime risk of developing breast cancer. Because risk factors for breast cancer interact, evaluating the risk conferred by combinations of risk factors is difficult. There are several risk


Surgery_Schwartz

Surgery_Schwartz. has a 7% lifetime risk of developing breast cancer. Because risk factors for breast cancer interact, evaluating the risk conferred by combinations of risk factors is difficult. There are several risk assessment models available to predict the risk of breast cancer. From the Breast Cancer Detec-tion Demonstration Project, a mammography screening program conducted in the 1970s, Gail et al developed the model most frequently used in the United States, which incorporates age, age at menarche, age at first live birth, the number of breast biopsy specimens, any history of atypical hyperplasia, and number of first-degree relatives with breast cancer.52 It predicts the cumula-tive risk of breast cancer according to decade of life. To calculate breast cancer risk using the Gail model, a woman’s risk factors are translated into an overall risk score by multiplying her rela-tive risks from several categories (Table 17-6). This risk score is then compared to an adjusted population risk of breast


Surgery_Schwartz

Surgery_Schwartz. factors are translated into an overall risk score by multiplying her rela-tive risks from several categories (Table 17-6). This risk score is then compared to an adjusted population risk of breast cancer to determine a woman’s individual or absolute risk. The output is a 5-year risk and a lifetime risk of developing breast cancer. A software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc. This model was recently modified to more accu-rately assess risk in African American women.52,53 There have also been modifications that project individualized absolute 5Brunicardi_Ch17_p0541-p0612.indd 55501/03/19 5:04 PM 556SPECIFIC CONSIDERATIONSPART IITable 17-6Relative risk estimates for the Gail modelVARIABLERELATIVE RISKAge at menarche (years) ≥14 12–13 <12Number of biopsy specimens/history of benign breast disease, age <50 y 0 1 ≥2Number of biopsy specimens/history of benign breast disease, age ≥50 y 0 1 ≥2Age at first


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Surgery_Schwartz. at menarche (years) ≥14 12–13 <12Number of biopsy specimens/history of benign breast disease, age <50 y 0 1 ≥2Number of biopsy specimens/history of benign breast disease, age ≥50 y 0 1 ≥2Age at first live birth (years) <20 y Number of first-degree relatives with history of breast cancer 0 1 ≥2 20–24 y Number of first-degree relatives with history of breast cancer 0 1 ≥2 25–29 y Number of first-degree relatives with history of breast cancer 0 1 ≥2 ≥30 y Number of first-degree relatives with history of breast cancer 0 1 ≥21.001.101.211.001.702.881.021.271.621.002.616.801.242.685.781.552.764.911.932.834.17Reproduced with permission from Armstrong K, Eisen A, Weber B: Assessing the risk of breast cancer, N Engl J Med. 2000 Feb 24;342(8):564-571.invasive breast cancer risk for Asian and Pacific Island American women. The Gail model is the most widely used model in the United States. Gail and colleagues have also described a revised model that includes body weight and


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Surgery_Schwartz. for Asian and Pacific Island American women. The Gail model is the most widely used model in the United States. Gail and colleagues have also described a revised model that includes body weight and mammographic density but excludes age at menarche.54Claus et al, using data from the Cancer and Steroid Hor-mone Study, a case-control study of breast cancer, developed the other frequently used risk assessment model, which is based on assumptions about the prevalence of high-penetrance breast cancer susceptibility genes.55 Compared with the Gail model, the Claus model incorporates more information about family his-tory but excludes other risk factors. The Claus model provides individual estimates of breast cancer risk according to decade of life based on presence of firstand second-degree relatives with breast cancer and their age at diagnosis. Risk factors that are less consistently associated with breast cancer (diet, use of oral contraceptives, lactation) or are rare in the general


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Surgery_Schwartz. relatives with breast cancer and their age at diagnosis. Risk factors that are less consistently associated with breast cancer (diet, use of oral contraceptives, lactation) or are rare in the general population (radiation exposure) are not included in either the Gail or Claus risk assessment model. Other models have been proposed that account for mammographic breast density in assessing breast cancer risk.54,56Neither the Gail model nor the Claus model accounts for the risk associated with mutations in the breast cancer suscepti-bility genes BRCA1 and BRCA2 (described in detail in the fol-lowing section). The BRCAPRO model is a Mendelian model that calculates the probability that an individual is a carrier of a mutation in one of the breast cancer susceptibility genes based on their family history of breast and ovarian cancer.57 The prob-ability that an individual will develop breast or ovarian cancer is derived from this mutation probability based on age-specific incidence curves for


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Surgery_Schwartz. history of breast and ovarian cancer.57 The prob-ability that an individual will develop breast or ovarian cancer is derived from this mutation probability based on age-specific incidence curves for both mutation carriers and noncarriers.58 Use of the BRCAPRO model in the clinic is challenging since it requires input of all family history information regarding breast and ovarian cancer. The Tyrer-Cuzick model attempts to utilize both family history information and individual risk information. It uses the family history to calculate the probability that an individual carries a mutation in one of the breast cancer suscep-tibility genes, and then the risk is adjusted based on personal risk factors, including age at menarche, parity, age at first live birth, age at menopause, history of atypical hyperplasia or LCIS, height, and body mass index.59 Once a risk model has been uti-lized to assess breast cancer risk, this must be communicated to the individual and put into context with


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Surgery_Schwartz. atypical hyperplasia or LCIS, height, and body mass index.59 Once a risk model has been uti-lized to assess breast cancer risk, this must be communicated to the individual and put into context with competing risk and medical comorbidities. This information can then be used to discuss options that are available to the individual for manag-ing risk.Risk ManagementSeveral important medical decisions may be affected by a wom-an’s underlying risk of developing breast cancer.60-68 These deci-sions include when to use postmenopausal hormone replacement therapy, at what age to begin mammography screening or incor-porate magnetic resonance imaging (MRI) screening, when to use tamoxifen to prevent breast cancer, and when to perform prophylactic mastectomy to prevent breast cancer. Postmeno-pausal hormone replacement therapy was widely prescribed in the 1980s and 1990s because of its effectiveness in controlling the symptoms of estrogen deficiency, namely vasomotor symp-toms such as hot flashes,


Surgery_Schwartz

Surgery_Schwartz. replacement therapy was widely prescribed in the 1980s and 1990s because of its effectiveness in controlling the symptoms of estrogen deficiency, namely vasomotor symp-toms such as hot flashes, night sweats and their associated sleep deprivation, osteoporosis, and cognitive changes. Furthermore, these hormone supplements were thought to reduce coronary artery disease as well. Use of combined estrogen and progester-one became standard for women who had not undergone hyster-ectomy because unopposed estrogen increases the risk of uterine cancer. Concerns of prolonging a woman’s lifetime exposure to estrogen, coupled with conflicting data regarding the impact of these hormones on cardiovascular health, motivated the imple-mentation of large-scale phase 3 clinical trials to definitively evaluate the risks vs. benefits of postmenopausal hormone replacement therapy. The Women’s Health Initiative (WHI) was therefore designed by the National Institutes of Health as a series of clinical trials


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Surgery_Schwartz. the risks vs. benefits of postmenopausal hormone replacement therapy. The Women’s Health Initiative (WHI) was therefore designed by the National Institutes of Health as a series of clinical trials to study the effects of diet, nutritional supplements, and hormones on the risk of cancer, cardiovascular disease, and bone health in postmenopausal women. Findings from primary studies of postmenopausal hormone replacement therapy were released in 2002, demonstrating conclusively that Brunicardi_Ch17_p0541-p0612.indd 55601/03/19 5:04 PM 557THE BREASTCHAPTER 17breast cancer risk is threefold to fourfold higher after >4 years of use and there is no significant reduction in coronary artery or cerebrovascular risks. The Collaborative Group on Hormonal Factors in Breast Cancer combined and reanalyzed data from a number of studies totaling 52,705 women with breast cancer and 108,411 women without breast cancer. They found an increased risk of breast cancer with every use of estrogen


Surgery_Schwartz

Surgery_Schwartz. and reanalyzed data from a number of studies totaling 52,705 women with breast cancer and 108,411 women without breast cancer. They found an increased risk of breast cancer with every use of estrogen replacement therapy. They also reported increased risk among current users but not past users and risk increased with increasing duration of use of hormone replacement therapy.69 Cheblowski et al also reported from the WHI study that estrogen + progesterone increased the incidence of breast cancer.70 This was con-firmed by the Million Women study, which also showed that the increased risk was substantially greater for the combined estrogen + progesterone replacement therapy than other types of hormone replacement therapy.71Breast Cancer Screening. Routine use of screening mam-mography in women ≥50 years of age has been reported to reduce mortality from breast cancer by 25%.72 This reduc-tion comes at an acceptable economic cost. More recently, there has been debate over the potential


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Surgery_Schwartz. women ≥50 years of age has been reported to reduce mortality from breast cancer by 25%.72 This reduc-tion comes at an acceptable economic cost. More recently, there has been debate over the potential harms associated with breast screening.73 Controversy over the age to initiate screening mammography is evident in the current recommendations. The U.S. Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), and the National Comprehensive Cancer Network (NCCN) are three organizations with differing recom-mendations for screening mammography in average risk women. The guidelines, however, similarly define high-risk women as those with personal history of breast cancer, history of chest radiation at young age, and confirmed or suspected genetic mutation known to increase risk for developing breast cancer. The USPSTF recommends biennial screening mammog-raphy for women age 50 to 74 years. The USPSTF applies these guidelines to asymptomatic women age >40 years who do not


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Surgery_Schwartz. for developing breast cancer. The USPSTF recommends biennial screening mammog-raphy for women age 50 to 74 years. The USPSTF applies these guidelines to asymptomatic women age >40 years who do not have a preexisting breast cancer or who were not previously diagnosed with a high-risk breast lesion, and who are not at high risk for breast cancer because of a known underlying genetic mutation or history of chest radiation at a young age.74-76 In October 2015, the ACS released updated guidelines stating average-risk women should start annual screening mammogra-phy at 45 years of age. Women age 45 to 54 years should be screened annually, and those 55 years and older should transi-tion to biennial screening or have the opportunity to continue annual screening. Women should have the opportunity to begin annual screening between the ages of 40 and 44 years and should continue screening as long as their overall health is good and have a life expectancy of 10 years or longer. The ACS does not


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Surgery_Schwartz. to begin annual screening between the ages of 40 and 44 years and should continue screening as long as their overall health is good and have a life expectancy of 10 years or longer. The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age.77 The NCCN recommends that average-risk women begin annual screening mammograms at ≥40 years of age, along with annual clinical breast exams and breast awareness.78The United Kingdom recently established an independent expert panel to review the published literature and estimate the benefits and harms associated with screening women >50 years of age in its national screening program.79 The expert panel estimated that an invitation to breast screening delivers about a 20% reduction in breast cancer mortality. At the same time, however, the panel estimated that in women invited to the screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis. Despite the


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Surgery_Schwartz. cancer mortality. At the same time, however, the panel estimated that in women invited to the screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis. Despite the overdiagnosis, the panel concluded that breast screening confers significant benefit and should continue. The use of screening mammography in women <50 years of age is more controversial for several reasons: (a) breast density is greater, and screening mammography is less likely to detect early breast cancer (i.e., reduced sensitivity); (b) screening mammography results in more false-positive test findings (i.e., reduced specificity), which results in unneces-sary biopsy specimens; and (c) younger women are less likely to have breast cancer (i.e., lower incidence), so fewer young women will benefit from screening.80,81 In the United States, on a population basis, however, the benefits of screening mam-mography in women between the ages of 40 and 49 years is still felt to outweigh the risks;


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Surgery_Schwartz. from screening.80,81 In the United States, on a population basis, however, the benefits of screening mam-mography in women between the ages of 40 and 49 years is still felt to outweigh the risks; although targeting mammography to women at higher risk of breast cancer improves the balance of risks and benefits and is the approach some health care sys-tems have taken. In one study of women age 40 to 49 years, an abnormal mammography finding was three times more likely to be cancer in a woman with a family history of breast cancer than in a woman without such a history. Furthermore, as noted previously in the section Risk Assessment Models, mounting data regarding mammographic breast density demonstrate an independent correlation with breast cancer risk. Incorporation of breast density measurements into breast cancer risk assess-ment models appears to be a promising strategy for increasing the accuracy of these tools. Unfortunately, widespread applica-tion of these modified models is


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Surgery_Schwartz. into breast cancer risk assess-ment models appears to be a promising strategy for increasing the accuracy of these tools. Unfortunately, widespread applica-tion of these modified models is hampered by inconsistencies in the reporting of mammographic density. Ultrasonography can also be used for breast cancer screening in women with dense breasts, but there is no data available that the additional cancers detected with this modality reduce mortality from breast cancer.Current recommendations by the United States Preventive Services Task Force are that women undergo biennial mammo-graphic screening between the ages of 50 and 74 years.77 The use of MRI for breast cancer screening is recommended by the ACS for women with a 20% to 25% or greater lifetime risk using risk assessment tools based mainly on family history, BRCA mutation carriers, those individuals who have a family member with a BRCA mutation who have not been tested themselves, individuals who received radiation to the chest


Surgery_Schwartz

Surgery_Schwartz. mainly on family history, BRCA mutation carriers, those individuals who have a family member with a BRCA mutation who have not been tested themselves, individuals who received radiation to the chest between the ages of 10 and 30 years, and those individuals with a history of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome or those who have a first-degree relative with one of these syndromes. MRI is an extremely sensitive screening tool that is not limited by the density of the breast tissue as mammography is; however, its specificity is moderate, leading to more false-positive events and the increased need for biopsy.Chemoprevention. Tamoxifen, a selective estrogen receptor modulator, was the first drug shown to reduce the incidence of breast cancer in healthy women. There have been four pro-spective studies published evaluating tamoxifen vs. placebo for reducing the incidence of invasive breast cancer for women at increased risk. The largest trial was the


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Surgery_Schwartz. women. There have been four pro-spective studies published evaluating tamoxifen vs. placebo for reducing the incidence of invasive breast cancer for women at increased risk. The largest trial was the Breast Cancer Preven-tion Trial (NSABP P-01), which randomly assigned >13,000 women with a 5-year Gail relative risk of breast cancer of 1.66% or higher or LCIS to receive tamoxifen or placebo. After a mean follow-up period of 4 years, the incidence of breast cancer was reduced by 49% in the group receiving tamoxifen.60 The decrease was evident only in ER-positive breast cancers with no significant change in ER-negative tumors. The Royal Marsden Hospital Tamoxifen Chemoprevention Trial,78 the Italian Tamox-ifen Prevention Trial,82 and the International Breast Cancer Intervention Study I (IBIS-I) trial all83 showed a reduction in 6Brunicardi_Ch17_p0541-p0612.indd 55701/03/19 5:04 PM 558SPECIFIC CONSIDERATIONSPART IIER-positive breast cancers with the use of tamoxifen compared with


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Surgery_Schwartz. trial all83 showed a reduction in 6Brunicardi_Ch17_p0541-p0612.indd 55701/03/19 5:04 PM 558SPECIFIC CONSIDERATIONSPART IIER-positive breast cancers with the use of tamoxifen compared with placebo. There was no effect on mortality; however, the trials were not powered to assess either breast cancer mortality or all-cause mortality events. The adverse events were similar in all four randomized trials, including an increased risk of endo-metrial cancer, thromboembolic events, cataract formation, and vasomotor disturbances in individuals receiving tamoxifen.Tamoxifen therapy currently is recommended only for women who have a Gail relative risk of 1.66% or higher, who are age 35 to 59, women over the age of 60, or women with a diagnosis of LCIS or atypical ductal or lobular hyperplasia. In addition, deep vein thrombosis occurs 1.6 times as often, pulmonary emboli 3.0 times as often, and endometrial cancer 2.5 times as often in women taking tamoxifen. The increased risk for endometrial


Surgery_Schwartz

Surgery_Schwartz. addition, deep vein thrombosis occurs 1.6 times as often, pulmonary emboli 3.0 times as often, and endometrial cancer 2.5 times as often in women taking tamoxifen. The increased risk for endometrial cancer is restricted to early stage cancers in postmenopausal women. Cataract surgery is required almost twice as often among women taking tamoxifen. Gail et al sub-sequently developed a model that accounts for underlying risk of breast cancer as well as comorbidities to determine the net risk-benefit ratio of tamoxifen use for chemoprevention.84The NSABP completed a second chemoprevention trial, designed to compare tamoxifen and raloxifene for breast cancer risk reduction in high-risk postmenopausal women. Raloxifene, another selective estrogen receptor modulator, was selected for the experimental arm in this follow-up prevention trial because its use in managing postmenopausal osteoporosis suggested that it might be even more effective at breast cancer risk reduc-tion, but without the


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Surgery_Schwartz. arm in this follow-up prevention trial because its use in managing postmenopausal osteoporosis suggested that it might be even more effective at breast cancer risk reduc-tion, but without the adverse effects of tamoxifen on the uterus. The P-2 trial, the Study of Tamoxifen and Raloxifene (known as the STAR trial), randomly assigned 19,747 postmenopausal women at high-risk for breast cancer to receive either tamoxi-fen or raloxifene. The initial report of the P-2 trial showed the two agents were nearly identical in their ability to reduce breast cancer risk, but raloxifene was associated with a more favor-able adverse event profile.85 An updated analysis revealed that raloxifene maintained 76% of the efficacy of tamoxifen in pre-vention of invasive breast cancer with a more favorable side effect profile. The risk of developing endometrial cancer was significantly higher with tamoxifen use at longer follow-up.86 Although tamoxifen has been shown to reduce the incidence of LCIS and DCIS,


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Surgery_Schwartz. profile. The risk of developing endometrial cancer was significantly higher with tamoxifen use at longer follow-up.86 Although tamoxifen has been shown to reduce the incidence of LCIS and DCIS, raloxifene did not have an effect on the frequency of these diagnoses.Aromatase inhibitors (AIs) have been shown to be more effective than tamoxifen in reducing the incidence of contra-lateral breast cancers in postmenopausal women receiving AIs for adjuvant treatment of invasive breast cancer. The MAP.3 trial was the first study to evaluate an AI as a chemopreventive agent in postmenopausal women at high risk for breast cancer. The trial randomized 4560 women to exemestane 25 mg daily vs. placebo for 5 years. After a median follow-up of 35 months, exemestane was shown to reduce invasive breast cancer inci-dence by 65%. Side effect profiles demonstrated more grade II or higher arthritis and hot flashes in patients taking exemestane.87 The IBIS II trial on the other hand, randomized 3864


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Surgery_Schwartz. cancer inci-dence by 65%. Side effect profiles demonstrated more grade II or higher arthritis and hot flashes in patients taking exemestane.87 The IBIS II trial on the other hand, randomized 3864 postmeno-pausal women to either anastrozole, a nonsteroidal aromatase inhibitor, vs. placebo with a further randomization to bisphospho-nate or not based on bone density.88,89 After a median follow-up of 5 years, anastrozole reduced the incidence of invasive breast cancer by about 50%. The trial also had an initial sub-study that looked at the effect of the aromatase inhibitor on cogni-tive function and reported no adverse effects.90 The American Society of Clinical Oncology recommends tamoxifen for chemoprevention in premenopausal or postmenopausal women and consideration for raloxifene or exemestane in postmeno-pausal women who are noted to be at increased risk of breast cancer.91,92 The discussion with an individual patient should include risk assessment and potential risks and benefits


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Surgery_Schwartz. in postmeno-pausal women who are noted to be at increased risk of breast cancer.91,92 The discussion with an individual patient should include risk assessment and potential risks and benefits with each agent.Risk-Reducing Surgery. A retrospective study of women at high risk for breast cancer found that prophylactic mastectomy reduced their risk by >90%.62 However, the effects of prophylac-tic mastectomy on the long-term quality of life are poorly quan-tified. A study involving women who were carriers of a breast cancer susceptibility gene (BRCA) mutation found that the ben-efit of prophylactic mastectomy differed substantially according to the breast cancer risk conferred by the mutations. For women with an estimated lifetime risk of 40%, prophylactic mastec-tomy added almost 3 years of life, whereas for women with an estimated lifetime risk of 85%, prophylactic mastectomy added >5 years of life.66 Domchek et al evaluated a cohort of BRCA1 and 2 mutation carriers who were followed


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Surgery_Schwartz. life, whereas for women with an estimated lifetime risk of 85%, prophylactic mastectomy added >5 years of life.66 Domchek et al evaluated a cohort of BRCA1 and 2 mutation carriers who were followed prospectively and reported on outcomes with risk-reducing surgery.93 They found that risk-reducing mastectomy was highly effective at preventing breast cancer in both BRCA1 and 2 mutation carriers. Risk-reducing salpingo-oophorectomy was highly effective at reducing the incidence of ovarian cancer and breast cancer in BRCA mutation carriers and was associated with a reduction in breast cancer-specific mortality, ovarian cancer-specific mor-tality, and all-cause mortality. While studies of bilateral pro-phylactic or risk-reducing mastectomy have reported dramatic reductions in breast cancer incidence among those without known BRCA mutations, there is little data to support a survival benefit. Another consideration is that while most patients are satisfied with their decision to pursue


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Surgery_Schwartz. incidence among those without known BRCA mutations, there is little data to support a survival benefit. Another consideration is that while most patients are satisfied with their decision to pursue risk-reducing surgery, some are dissatisfied with the cosmetic outcomes mostly due to reconstructive issues.BRCA MutationsBRCA1. Up to 5% of breast cancers are caused by inheritance of germline mutations such as BRCA1 and BRCA2, which are inherited in an autosomal dominant fashion with varying degrees of penetrance (Table 17-7).94-100 BRCA1 is located on chromosome arm 17q, spans a genomic region of approximately 100 kilobases (kb) of DNA, and contains 22 coding exons for 1863 amino acids. Both BRCA1 and BRCA2 function as tumor-suppressor genes, and for each gene, loss of both alleles is required for the initiation of cancer. Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, cell-cycle control, and DNA damage repair pathways. More than 500 sequence


Surgery_Schwartz

Surgery_Schwartz. for the initiation of cancer. Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, cell-cycle control, and DNA damage repair pathways. More than 500 sequence variations in BRCA1 have been identified. It now is known that germline mutations in BRCA1 represent a predisposing genetic factor in as many as 45% of hereditary breast cancers and in at least 80% of hereditary ovarian cancers. Female mutation carriers have been reported to have up to an 85% lifetime risk (for some families) for developing breast cancer and up to a 40% lifetime risk for developing ovarian cancer. The initial families reported had high penetrance and subsequently the average lifetime risk has been reported to lie between 60% and 70%. Breast cancer susceptibility in these families appears as an autosomal dominant trait with high pen-etrance. Approximately 50% of children of carriers inherit the trait. In general, BRCA1-associated breast cancers are invasive ductal carcinomas, are


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Surgery_Schwartz. as an autosomal dominant trait with high pen-etrance. Approximately 50% of children of carriers inherit the trait. In general, BRCA1-associated breast cancers are invasive ductal carcinomas, are poorly differentiated, are in the majority Brunicardi_Ch17_p0541-p0612.indd 55801/03/19 5:04 PM 559THE BREASTCHAPTER 17Table 17-7Incidence of sporadic, familial, and hereditary breast cancerSporadic breast cancer65%–75%Familial breast cancer20%–30%Hereditary breast cancer5%–10% BRCA1a45% BRCA235% p53a (Li-Fraumeni syndrome)1% STK11/LKB1a (Peutz-Jeghers syndrome)<1% PTENa (Cowden disease)<1% MSH2/MLH1a (Muir-Torre syndrome)<1% ATMa (Ataxia-telangiectasia)<1% Unknown20%aAffected gene.Data from Martin AM, Weber BL: Genetic and hormonal risk factors in breast cancer, J Natl Cancer Inst. 2000 Jul 19;92(14):1126-1135.hormone receptor negative, and have a triple receptor negative (immunohistochemical profile: ER-negative, PR-negative, and HER2-negative) or basal phenotype (based on gene


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Surgery_Schwartz. Jul 19;92(14):1126-1135.hormone receptor negative, and have a triple receptor negative (immunohistochemical profile: ER-negative, PR-negative, and HER2-negative) or basal phenotype (based on gene expression profiling). BRCA1-associated breast cancers have a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases; a higher prevalence of bilateral breast cancer; and the presence of associated cancers in some affected individuals, specifically ovarian cancer and possibly colon and prostate cancers.Several founder mutations have been identified in BRCA1. The two most common mutations are 185delAG and 5382insC, which account for 10% of all the mutations seen in BRCA1. These two mutations occur at a 10-fold higher frequency in the Ashkenazi Jewish population than in non-Jewish Caucasians. The carrier frequency of the 185delAG mutation in the Ashkenazi Jewish population is 1% and, along with the 5382insC mutation, accounts for almost all BRCA1


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Surgery_Schwartz. population than in non-Jewish Caucasians. The carrier frequency of the 185delAG mutation in the Ashkenazi Jewish population is 1% and, along with the 5382insC mutation, accounts for almost all BRCA1 mutations in this population. Analysis of germline mutations in Jewish and non-Jewish women with early-onset breast cancer indicates that 20% of Jewish women who develop breast cancer before age 40 years carry the 185delAG mutation. There are founder BRCA1 mutations in other populations including, among others, Dutch, Polish, Finnish, and Russian populations.101-105BRCA2. BRCA2 is located on chromosome arm 13q and spans a genomic region of approximately 70 kb of DNA. The 11.2-kb coding region contains 26 coding exons.94-100 It encodes a pro-tein of 3418 amino acids. The BRCA2 gene bears no homology to any previously described gene, and the protein contains no previously defined functional domains. The biologic function of BRCA2 is not well defined, but like BRCA1, it is postulated to play


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Surgery_Schwartz. to any previously described gene, and the protein contains no previously defined functional domains. The biologic function of BRCA2 is not well defined, but like BRCA1, it is postulated to play a role in DNA damage response pathways. BRCA2 mes-senger RNA also is expressed at high levels in the late G1 and S phases of the cell cycle. The kinetics of BRCA2 protein regu-lation in the cell cycle is similar to that of BRCA1 protein, which suggests that these genes are coregulated. The mutational spec-trum of BRCA2 is not as well established as that of BRCA1. To date, >250 mutations have been found. The breast cancer risk for BRCA2 mutation carriers is close to 85%, and the life-time ovarian cancer risk, while lower than for BRCA1, is still estimated to be close to 20%. Breast cancer susceptibility in BRCA2 families is an autosomal dominant trait and has a high penetrance. Approximately 50% of children of carriers inherit the trait. Unlike male carriers of BRCA1 mutations, men with


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Surgery_Schwartz. in BRCA2 families is an autosomal dominant trait and has a high penetrance. Approximately 50% of children of carriers inherit the trait. Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have an estimated breast cancer risk of 6%, which represents a 100-fold increase over the risk in the general male population. BRCA2-associated breast cancers are invasive ductal carcinomas, which are more likely to be well differentiated and to express hormone receptors than are BRCA1-associated breast cancers. BRCA2-associated breast cancer has a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases, a higher prevalence of bilateral breast cancer, and the presence of associ-ated cancers in some affected individuals, specifically ovarian, colon, prostate, pancreatic, gallbladder, bile duct, and stomach cancers, as well as melanoma. A number of founder mutations have been identified in BRCA2. The 6174delT mutation is found


Surgery_Schwartz

Surgery_Schwartz. ovarian, colon, prostate, pancreatic, gallbladder, bile duct, and stomach cancers, as well as melanoma. A number of founder mutations have been identified in BRCA2. The 6174delT mutation is found in Ashkenazi Jews with a prevalence of 1.2% and accounts for 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.106 Another BRCA2 founder mutation, 999del5, is observed in Icelandic and Finnish popula-tions, while more recently 3036delACAA has been observed in a number of Spanish families.107-109Identification of BRCA Mutation Carriers. Identifying hereditary risk for breast cancer is a four-step process that includes: (a) obtaining a complete, multigenerational family history, (b) assessing the appropriateness of genetic testing for a particular patient, (c) counseling the patient, and (d) interpret-ing the results of testing.110 Genetic testing should not be offered in isolation, but only in conjunction with patient education and counseling, including


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Surgery_Schwartz. counseling the patient, and (d) interpret-ing the results of testing.110 Genetic testing should not be offered in isolation, but only in conjunction with patient education and counseling, including referral to a genetic counselor. Initial determinations include whether the individual is an appropriate candidate for genetic testing and whether genetic testing will be informative for personal and clinical decision-making. A thor-ough and accurate family history is essential to this process, and the maternal and paternal sides of the family are both assessed because 50% of the women with a BRCA mutation have inher-ited the mutation from their fathers. To help clinicians advise women about genetic testing, statistically based models that determine the probability that an individual carries a BRCA mutation have been developed. A method for calculating carrier probability that has been demonstrated to have acceptable per-formance (i.e., both in terms of calibration and discrimination) such


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Surgery_Schwartz. BRCA mutation have been developed. A method for calculating carrier probability that has been demonstrated to have acceptable per-formance (i.e., both in terms of calibration and discrimination) such as the Manchester scoring system and BODICEA should be used to offer referral to a specialist genetic clinic. A heredi-tary risk of breast cancer is considered if a family includes Ash-kenazi Jewish heritage; a first-degree relative with breast cancer before age 50; a history of ovarian cancer at any age in the patient or firstor second-degree relative with ovarian cancer; breast and ovarian cancer in the same individual; two or more firstor second-degree relatives with breast cancer at any age; patient or relative with bilateral breast cancer; and male breast cancer in a relative at any age.111 The threshold for genetic test-ing is lower in individuals who are members of ethnic groups in whom the mutation prevalence is increased.BRCA Mutation Testing. Appropriate counseling for the


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Surgery_Schwartz. age.111 The threshold for genetic test-ing is lower in individuals who are members of ethnic groups in whom the mutation prevalence is increased.BRCA Mutation Testing. Appropriate counseling for the individual being tested for a BRCA mutation is strongly rec-ommended, and documentation of informed consent is required.110,112 The test that is clinically available for analyzing BRCA mutations is gene sequence analysis. In a family with a history suggestive of hereditary breast cancer and no previously Brunicardi_Ch17_p0541-p0612.indd 55901/03/19 5:04 PM 560SPECIFIC CONSIDERATIONSPART IItested member, the most informative strategy is first to test an affected family member. This person undergoes complete sequence analysis of both the BRCA1 and BRCA2 genes. If a mutation is identified, relatives are usually tested only for that specific mutation. An individual of Ashkenazi Jewish ancestry is tested initially for the three specific mutations that account for hereditary breast and


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Surgery_Schwartz. relatives are usually tested only for that specific mutation. An individual of Ashkenazi Jewish ancestry is tested initially for the three specific mutations that account for hereditary breast and ovarian cancer in that population. If results of that test are negative, it may then be appropriate to fully analyze the BRCA1 and BRCA2 genes.A positive test result is one that discloses the presence of a BRCA mutation that interferes with translation or function of the BRCA protein. A woman who carries a deleterious mutation has a breast cancer risk of up to 85% (in some families) as well as a greatly increased risk of ovarian cancer. A negative test result is interpreted according to the individual’s personal and family history, especially whether a mutation has been previously iden-tified in the family, in which case the woman is generally tested only for that specific mutation. If the mutation is not present, the woman’s risk of breast or ovarian cancer may be no greater than that of


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Surgery_Schwartz. in the family, in which case the woman is generally tested only for that specific mutation. If the mutation is not present, the woman’s risk of breast or ovarian cancer may be no greater than that of the general population. In addition, no BRCA muta-tion can be passed on to the woman’s children. In the absence of a previously identified mutation, a negative test result in an affected individual generally indicates that a BRCA mutation is not responsible for the familial cancer. However, the possibil-ity remains of an unusual abnormality in one of these genes that cannot yet be identified through clinical testing. It also is possible that the familial cancer is indeed caused by an identifi-able BRCA mutation but that the individual tested had sporadic cancer, a situation known as phenocopy. This is especially pos-sible if the individual tested developed breast cancer close to the age of onset of the general population (age 60 years or older) rather than before age 50 years, as is


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Surgery_Schwartz. This is especially pos-sible if the individual tested developed breast cancer close to the age of onset of the general population (age 60 years or older) rather than before age 50 years, as is characteristic of BRCA mutation carriers. Overall, the false-negative rate for BRCA mutation testing is <5%. Some test results, especially when a single base-pair change (missense mutation) is identified, may be difficult to interpret. This is because single base-pair changes do not always result in a nonfunctional protein. Thus, missense mutations not located within critical functional domains, or those that cause only minimal changes in protein structure, may not be disease associated and are usually reported as indetermi-nate results. In communicating indeterminate results to women, care must be taken to relay the uncertain cancer risk associ-ated with this type of mutation and to emphasize that ongoing research might clarify its meaning. In addition, testing other family members with breast


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Surgery_Schwartz. taken to relay the uncertain cancer risk associ-ated with this type of mutation and to emphasize that ongoing research might clarify its meaning. In addition, testing other family members with breast cancer to determine if a genetic variant tracks with their breast cancer may provide clarification as to its significance. Indeterminate genetic variance currently accounts for 12% of the test results.Concern has been expressed that the identification of hereditary risk for breast cancer may interfere with access to affordable health insurance. This concern refers to discrimina-tion directed against an individual or family based solely on an apparent or perceived genetic variation from the normal human genotype. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) made it illegal in the United States for group health plans to consider genetic information as a preexist-ing condition or to use it to deny or limit coverage. Most states also have passed laws that prevent


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Surgery_Schwartz. illegal in the United States for group health plans to consider genetic information as a preexist-ing condition or to use it to deny or limit coverage. Most states also have passed laws that prevent genetic discrimination in the provision of health insurance. In addition, individuals applying for health insurance are not required to report whether relatives have undergone genetic testing for cancer risk, only whether those relatives have actually been diagnosed with cancer. Currently, there is little documented evidence of genetic dis-crimination resulting from findings of available genetic tests.Cancer Prevention for BRCA Mutation Carriers. Risk man-agement strategies for BRCA1 and BRCA2 mutation carriers include the following:1. Risk-reducing mastectomy and reconstruction2. Risk-reducing salpingo-oophorectomy3. Intensive surveillance for breast and ovarian cancer4. ChemopreventionAlthough removal of breast tissue reduces the likeli-hood that BRCA1 and BRCA2 mutation carriers will


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Surgery_Schwartz. salpingo-oophorectomy3. Intensive surveillance for breast and ovarian cancer4. ChemopreventionAlthough removal of breast tissue reduces the likeli-hood that BRCA1 and BRCA2 mutation carriers will develop breast cancer, mastectomy does not remove all breast tissue, and women continue to be at risk because a germline muta-tion is present in any remaining breast tissue. For postmeno-pausal BRCA1 and BRCA2 mutation carriers who have not had a mastectomy, it may be advisable to avoid hormone replace-ment therapy because no data exist regarding the effect of the therapy on the penetrance of breast cancer susceptibility genes. Because breast cancers in BRCA mutation carriers have the same mammographic appearance as breast cancers in noncarri-ers, a screening mammogram is likely to be effective in BRCA mutation carriers, provided it is performed and interpreted by an experienced radiologist with a high level of suspicion. Pres-ent screening recommendations for BRCA mutation carriers who do


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Surgery_Schwartz. in BRCA mutation carriers, provided it is performed and interpreted by an experienced radiologist with a high level of suspicion. Pres-ent screening recommendations for BRCA mutation carriers who do not undergo risk-reducing mastectomy include clinical breast examination every 6 months and mammography every 12 months beginning at age 25 years because the risk of breast cancer in BRCA mutation carriers increases after age 30 years. Recent attention has been focused on the use of MRI for breast cancer screening in high-risk individuals and known BRCA mutation carriers. MRI appears to be more sensitive at detect-ing breast cancer in younger women with dense breasts.113 How-ever, as noted previously, MRI does lead to the detection of benign breast lesions that cannot easily be distinguished from malignancy, and these false-positive events can result in more interventions, including biopsy specimens. The current recom-mendations from the American Cancer Society are for annual MRI in women


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Surgery_Schwartz. malignancy, and these false-positive events can result in more interventions, including biopsy specimens. The current recom-mendations from the American Cancer Society are for annual MRI in women with a 20% to 25% or greater lifetime risk of developing breast cancer (mainly based on family history), women with a known BRCA1 or BRCA2 mutation, those who have a first-degree relative with a BRCA1 or BRCA2 mutation and have not had genetic testing themselves, women who were treated with radiation therapy to the chest between the ages of 10 and 30 years, and those who have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or a first-degree relative with one of these syndromes.75,114 Despite a 49% reduction in the overall incidence of breast cancer and a 69% reduction in the incidence of estrogen receptor positive tumors in high-risk women taking tamoxifen reported in the NSABP P1 trial, there is insufficient evidence to recommend the use of tamoxifen uniformly


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Surgery_Schwartz. in the incidence of estrogen receptor positive tumors in high-risk women taking tamoxifen reported in the NSABP P1 trial, there is insufficient evidence to recommend the use of tamoxifen uniformly for BRCA1 mutation carriers.60 Cancers arising in BRCA1 mutation carriers are usually high grade and are most often hormone receptor negative. Approxi-mately 66% of BRCA1-associated DCIS lesions are estrogen receptor negative, which suggests early acquisition of the hor-mone-independent phenotype. In the NSABP P1 trial there was a 62% reduction in the incidence of breast cancer in BRCA2 carriers, similar to the overall reduction seen in the P1 trial. In contrast, there was no reduction seen in breast cancer incidence in BRCA1 carriers who started tamoxifen in P1 age 35 years or Brunicardi_Ch17_p0541-p0612.indd 56001/03/19 5:04 PM 561THE BREASTCHAPTER 17older.115 Tamoxifen appears to be more effective at preventing estrogen receptor-positive breast cancers.The risk of ovarian cancer in


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Surgery_Schwartz. 56001/03/19 5:04 PM 561THE BREASTCHAPTER 17older.115 Tamoxifen appears to be more effective at preventing estrogen receptor-positive breast cancers.The risk of ovarian cancer in BRCA1 and BRCA2 muta-tion carriers ranges from 20% to 40%, which is 10 times higher than that in the general population. Risk-reducing salpingo-oophorectomy is a reasonable prevention option in mutation carriers. In women with a documented BRCA1 or BRCA2 mutation, consideration for bilateral risk-reducing salpingo-oophorectomy should be between the ages of 35 and 40 years at the completion of childbearing. Removing the ovaries reduces the risk of ovarian cancer and breast cancer when per-formed in premenopausal BRCA mutation carriers. Hormone replacement therapy is discussed with the patient at the time of oophorectomy. The Cancer Genetics Studies Consortium recommends yearly transvaginal ultrasound timed to avoid ovulation and annual measurement of serum cancer antigen 125 levels beginning at age 25 years


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Surgery_Schwartz. The Cancer Genetics Studies Consortium recommends yearly transvaginal ultrasound timed to avoid ovulation and annual measurement of serum cancer antigen 125 levels beginning at age 25 years as the best screening modalities for ovarian carcinoma in BRCA mutation carriers who have opted to defer risk-reducing surgery.PALB2 (partner and localizer of BRCA2) has recently been characterized as a potential high-risk gene for breast cancer. PALB2 allows nuclear localization of BRCA2 and provides a scaffold for the BRCA1–PALB2–BRCA2 complex. Analysis by Antoniou et al has suggested that the risk of breast cancer for PALB2 mutation carriers is as high as that of BRCA2 mutation carriers.116 The absolute risk of breast cancer for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25–44) for those with no family history of breast cancer to 58% (95% CI, 50–66) for those with two or more first-degree relatives with breast cancer at 50 years of age. The risk of breast cancer


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Surgery_Schwartz. CI, 25–44) for those with no family history of breast cancer to 58% (95% CI, 50–66) for those with two or more first-degree relatives with breast cancer at 50 years of age. The risk of breast cancer for female PALB2 mutation carriers, depending on the age, was about five to nine times as high compared with the gen-eral population. While screening with mammogram along with MRI has been suggested for PALB2 mutation carriers starting at age 30 with consideration of risk-reducing mastectomy, there is currently insufficient evidence regarding the risk of ovarian cancer and its management.Other hereditary syndromes associated with an increased risk of breast cancer include Cowden disease (PTEN mutations, in which cancers of the thyroid, GI tract, and benign skin and subcutaneous nodules are also seen), Li-Fraumeni syndrome (TP53 mutations, also associated with sarcomas, lymphomas, and adrenocortical tumors), hereditary diffuse gastric cancer syndrome (CDH1 mutations, associated with diffuse


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Surgery_Schwartz. seen), Li-Fraumeni syndrome (TP53 mutations, also associated with sarcomas, lymphomas, and adrenocortical tumors), hereditary diffuse gastric cancer syndrome (CDH1 mutations, associated with diffuse gastric cancer and lobular breast cancers), and syndromes of breast and melanoma. With the discovery of additional genes related to breast cancer susceptibility, panel testing is available for a number of genes in addition to BRCA1 and BRCA2. The inter-pretation of results is complex and is best done with a genetic counselor.EPIDEMIOLOGY AND NATURAL HISTORY OF BREAST CANCEREpidemiologyBreast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for women age 20 to 59 years. Based on Surveillance, Epidemiology, and End Results registries (SEER) data, 266,120 new cases were esti-mated in 2018 with 40,920 estimated deaths attributed to breast cancers.117 It accounts for 30% of all newly diagnosed cancers in women and is responsible for 14% of


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Surgery_Schwartz. data, 266,120 new cases were esti-mated in 2018 with 40,920 estimated deaths attributed to breast cancers.117 It accounts for 30% of all newly diagnosed cancers in women and is responsible for 14% of the cancer-related deaths in women.Breast cancer was the leading cause of cancer-related mortality in women until 1987, when it was surpassed by lung cancer. In the 1970s, the probability that a woman in the United States would develop breast cancer at some point in her lifetime was estimated at 1 in 13; in 1980 it was 1 in 11; and in 2004 it was 1 in 8. Cancer registries in Connecticut and upper New York State document that the age-adjusted incidence of new breast cancer cases had steadily increased since the mid-1940s. The incidence in the United States, based on data from nine SEER registries, has been decreasing by 23% per year since 2000. The increase had been approximately 1% per year from 1973 to 1980, and there was an additional increase in inci-dence of 4% between 1980 and 1987,


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Surgery_Schwartz. has been decreasing by 23% per year since 2000. The increase had been approximately 1% per year from 1973 to 1980, and there was an additional increase in inci-dence of 4% between 1980 and 1987, which was characterized by frequent detection of small primary cancers. The increase in breast cancer incidence occurred primarily in women age ≥55 years and paralleled a marked increase in the percentage of older women who had mammograms taken. At the same time, incidence rates for regional metastatic disease dropped and breast cancer mortality declined. From 1960 to 1963, 5-year overall survival rates for breast cancer were 63% and 46% in white and African American women, respectively, whereas the rates for 1981 to 1983 were 78% and 64%, respectively. For 2002 to 2008 rates were 92% and 78%, respectively.There is a 10-fold variation in breast cancer incidence among different countries worldwide. Cyprus and Malta have the highest age-adjusted mortality for breast cancer (29.6 per 100,000


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Surgery_Schwartz. respectively.There is a 10-fold variation in breast cancer incidence among different countries worldwide. Cyprus and Malta have the highest age-adjusted mortality for breast cancer (29.6 per 100,000 population), whereas Haiti has the lowest (2.0 deaths per 100,000 population). The United States has an age-adjusted mortality for breast cancer of 19.0 cases per 100,000 population. Women living in less industrialized nations tend to have a lower incidence of breast cancer than women living in industrialized countries, although Japan is an exception. In the United States, Mormons, Seventh Day Adventists, American Indians, Alaska natives, Hispanic/Latina Americans, and Japanese and Filipino women living in Hawaii have a below-average incidence of breast cancer, whereas nuns (due to nulliparity) and Ashkenazi Jewish women have an above-average incidence.The incidence rates of breast cancer increased in most countries through the 1990s. Since the estimates for 1990, there was an overall


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Surgery_Schwartz. and Ashkenazi Jewish women have an above-average incidence.The incidence rates of breast cancer increased in most countries through the 1990s. Since the estimates for 1990, there was an overall increase in incidence rates of approximately 0.5% annually. It was predicted that there would be approxi-mately 1.4 million new cases in 2010. The cancer registries in China have noted annual increases in incidence of up to 3% to 4%, and in eastern Asia, increases are similar.Data from the SEER program reveal declines in breast cancer incidence over the past decade, and this is widely attrib-uted to decreased use of hormone replacement therapy as a con-sequence of the Women’s Health Initiative reports.118Breast cancer burden has well-defined variations by geog-raphy, regional lifestyle, and racial or ethnic background.119 In general, both breast cancer incidence and mortality are rela-tively lower among the female populations of Asia and Africa, relatively underdeveloped nations, and nations


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Surgery_Schwartz. or ethnic background.119 In general, both breast cancer incidence and mortality are rela-tively lower among the female populations of Asia and Africa, relatively underdeveloped nations, and nations that have not adopted Westernized reproductive and dietary patterns. In contrast, European and North American women and women from heavily industrialized or Westernized countries have a substantially higher breast cancer burden. These international patterns are mirrored in breast cancer incidence and mortality rates observed for the racially, ethnically, and culturally diverse population of the United States.120Brunicardi_Ch17_p0541-p0612.indd 56101/03/19 5:04 PM 562SPECIFIC CONSIDERATIONSPART II10090807060504030201083%68%54%41%Middlesex Hospital 1805-1933 (250 cases)86%66%44%28%18%9%3.6%2%0.8%1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Median survival 2.7 years Natural survivalSurvival untreated casesDuration of life from onset of symptoms


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Surgery_Schwartz. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Median survival 2.7 years Natural survivalSurvival untreated casesDuration of life from onset of symptoms (years)% SurvivalFigure 17-13. Survival of women with untreated breast cancer compared with natural survival. (Reproduced with permission from Bloom HJG, Richardson WW, Harries EJ: Natural history of untreated breast cancer (1805-1933). Comparison of untreated and treated cases according to histological grade of malignancy, Br Med J. 1962 Jul 28;2(5299):213-221.)Although often related, the factors that influence breast cancer incidence may differ from those that affect mortality. Incidence rates are lower among populations that are heavily weighted with women who begin childbearing at young ages and who have multiple full-term pregnancies followed by pro-longed lactation. These are features that characterize many underdeveloped nations and also many eastern nations. Breast cancer mortality rates


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Surgery_Schwartz. who have multiple full-term pregnancies followed by pro-longed lactation. These are features that characterize many underdeveloped nations and also many eastern nations. Breast cancer mortality rates should be lower in populations that have a lower incidence, but the mortality burden will simultaneously be adversely affected by the absence of effective mammographic screening programs for early detection and diminished access to multidisciplinary cancer treatment programs. These features are likely to account for much of the disproportionate mortal-ity risks that are seen in underdeveloped nations. Similar fac-tors probably account for differences in breast cancer burden observed among the various racial and ethnic groups within the United States. Interestingly, breast cancer incidence and mortality rates rise among secondand third-generation Asian Americans as they adopt Western lifestyles.Disparities in breast cancer survival among subsets of the American population are generating


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Surgery_Schwartz. mortality rates rise among secondand third-generation Asian Americans as they adopt Western lifestyles.Disparities in breast cancer survival among subsets of the American population are generating increased publicity because they are closely linked to disparities in socioeconomic status. Poverty rates and proportions of the population that lack health care insurance are two to three times higher among minority racial and ethnic groups such as African Americans and His-panic/Latino Americans. These socioeconomic disadvantages create barriers to effective breast cancer screening and result in delayed breast cancer diagnosis, advanced stage distribu-tion, inadequacies in comprehensive treatment, and, ultimately, increased mortality rates. Furthermore, the rapid growth in the Hispanic population is accompanied by increasing problems in health education because of linguistic barriers between physi-cians and recently immigrated, non–English-speaking patients. Recent studies also are


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Surgery_Schwartz. population is accompanied by increasing problems in health education because of linguistic barriers between physi-cians and recently immigrated, non–English-speaking patients. Recent studies also are documenting inequities in the treatments delivered to minority breast cancer patients, such as increased rates of failure to provide systemic therapy, use of sentinel lymph node dissection, and breast reconstruction. Some of the treatment delivery disparities are related to inadequately con-trolled comorbidities (such as hypertension and diabetes), which are more prevalent in minority populations. However, some studies that adjust for these factors report persistent and unex-plained unevenness in treatment recommendations. It is clear that breast cancer disparities associated with racial or ethnic background have a multifactorial cause, and improvements in outcome will require correction of many public health problems at both the patient and provider levels.Advances in the ability to


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Surgery_Schwartz. or ethnic background have a multifactorial cause, and improvements in outcome will require correction of many public health problems at both the patient and provider levels.Advances in the ability to characterize breast cancer sub-types and the genetics of the disease are now provoking specula-tion regarding possible hereditary influences on breast cancer risk that are related to racial or ethnic ancestry.121 These questions become particularly compelling when one looks at disparities in breast cancer burden between African Americans and Cau-casians. Lifetime risk of breast cancer is lower for African Americans, yet a paradoxically increased breast cancer mortal-ity risk also is seen. African Americans also have a younger age distribution for breast cancer; among women <45 years of age, breast cancer incidence is highest among African Americans compared to other subsets of the American population. Lastly and most provocatively, African American women of all ages have notably higher


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Surgery_Schwartz. breast cancer incidence is highest among African Americans compared to other subsets of the American population. Lastly and most provocatively, African American women of all ages have notably higher incidence rates for estrogen receptor-negative tumors. These same patterns of disease are seen in con-temporary female populations of western, sub-Saharan Africa, who are likely to share ancestry with African American women as a consequence of the Colonial-era slave trade. Interestingly, male breast cancer also is seen with increased frequency among both African Americans and Africans.Natural HistoryBloom and colleagues described the natural history of breast cancer based on the records of 250 women with untreated breast cancers who were cared for on charity wards in the Middlesex Hospital, London, between 1805 and 1933. The median survival of this population was 2.7 years after initial diagnosis (Fig. 17-13).122 The 5and 10-year survival rates for these women were 18.0% and 3.6%,


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Surgery_Schwartz. London, between 1805 and 1933. The median survival of this population was 2.7 years after initial diagnosis (Fig. 17-13).122 The 5and 10-year survival rates for these women were 18.0% and 3.6%, respectively. Only 0.8% survived for 15 years or longer. Autopsy data confirmed that 95% of these women died of breast cancer, whereas the remaining 5% died of other causes. Almost 75% of the women developed ulcer-ation of the breast during the course of the disease. The longest surviving patient died in the 19th year after diagnosis.Primary Breast Cancer. More than 80% of breast cancers show productive fibrosis that involves the epithelial and stro-mal tissues. With growth of the cancer and invasion of the surrounding breast tissues, the accompanying desmoplastic response entraps and shortens Cooper’s suspensory ligaments to produce a characteristic skin retraction. Localized edema (peau d’orange) develops when drainage of lymph fluid from the skin is disrupted. With continued growth, cancer


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Surgery_Schwartz. suspensory ligaments to produce a characteristic skin retraction. Localized edema (peau d’orange) develops when drainage of lymph fluid from the skin is disrupted. With continued growth, cancer cells invade the skin, and eventually ulceration occurs. As new areas of skin are invaded, small satellite nodules appear near the primary ulceration. The size of the primary breast cancer correlates with disease-free and overall survival, but there is a close associa-tion between cancer size and axillary lymph node involvement (Fig. 17-14). In general, up to 20% of breast cancer recurrences are local-regional, >60% are distant, and 20% are both local-regional and distant.Brunicardi_Ch17_p0541-p0612.indd 56201/03/19 5:04 PM 563THE BREASTCHAPTER 17xxxxxxxxxx**********Diameter (cm)0.980.950.900.800.700.600.500.400.300.20Proportion of patients with metastases10100Volume (ml)2345676891011100908070605040302010Percent survivors31529717363653126317714265321234909214425N + >3 (183)N + (381)N + 1


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Surgery_Schwartz. of patients with metastases10100Volume (ml)2345676891011100908070605040302010Percent survivors31529717363653126317714265321234909214425N + >3 (183)N + (381)N + 1 (198)N (335)Whole series (716)241068Years after mastectomyABFigure 17-14. A. Overall survival for women with breast cancer according to axillary lymph node status. The time periods are years after radical mastectomy. (Reproduced with permission from Vala-gussa P, Bonadonna G, Veronesi U, et al: Patterns of relapse and survival following radical mastectomy. Analysis of 716 consecutive patients, Cancer. 1978 Mar;41(3):1170-1178.) B. Risk of metasta-ses according to breast cancer volume and diameter. (Reproduced with permission from Koscielny S, Tubiana M, Lê MG, et al: Breast cancer: Relationship between the size of the primary tumour and the probability of metastatic dissemination, Br J Cancer. 1984 Jun;49(6):709-715.)Axillary Lymph Node Metastases. As the size of the pri-mary breast cancer increases, some cancer cells are


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Surgery_Schwartz. tumour and the probability of metastatic dissemination, Br J Cancer. 1984 Jun;49(6):709-715.)Axillary Lymph Node Metastases. As the size of the pri-mary breast cancer increases, some cancer cells are shed into cellular spaces and transported via the lymphatic network of the breast to the regional lymph nodes, especially the axillary lymph nodes. Lymph nodes that contain metastatic cancer are at first ill-defined and soft but become firm or hard with con-tinued growth of the metastatic cancer. Eventually the lymph nodes adhere to each other and form a conglomerate mass. Cancer cells may grow through the lymph node capsule and fix to contiguous structures in the axilla, including the chest wall. Typically, axillary lymph nodes are involved sequentially from the low (level I) to the central (level II) to the apical (level III) lymph node groups. Approximately 95% of the women who die of breast cancer have distant metastases, and traditionally the most important prognostic correlate of


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Surgery_Schwartz. (level II) to the apical (level III) lymph node groups. Approximately 95% of the women who die of breast cancer have distant metastases, and traditionally the most important prognostic correlate of disease-free and over-all survival was axillary lymph node status (see Fig. 17-14A). Women with node-negative disease had less than a 30% risk of recurrence, compared with as much as a 75% risk for women with node-positive disease.Distant Metastases. At approximately the 20th cell dou-bling, breast cancers acquire their own blood supply (neovas-cularization). Thereafter, cancer cells may be shed directly into the systemic venous blood to seed the pulmonary circulation via the axillary and intercostal veins or the vertebral column via Batson’s plexus of veins, which courses the length of the vertebral column. These cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of metastatic foci from breast cancer predictably occurs after the primary cancer


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Surgery_Schwartz. vertebral column. These cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of metastatic foci from breast cancer predictably occurs after the primary cancer exceeds 0.5 cm in diameter, which corresponds to the 27th cell doubling. For 10 years after initial treatment, distant metastases are the most common cause of death in breast cancer patients. For this reason, conclusive results cannot be derived from breast cancer trials until at least 5 to 10 years have elapsed. Although 60% of the women who develop distant metastases will do so within 60 months of treatment, metastases may become evident as late as 20 to 30 years after treatment of the primary cancer.123 Patients with estrogen receptor nega-tive breast cancers are proportionately more likely to develop recurrence in the first 3 to 5 years, whereas those with estrogen receptor positive tumors have a risk of developing recurrence, which drops off more slowly beyond 5 years than is seen with


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Surgery_Schwartz. develop recurrence in the first 3 to 5 years, whereas those with estrogen receptor positive tumors have a risk of developing recurrence, which drops off more slowly beyond 5 years than is seen with ER-negative tumors.124 Recently, a report showed that tumor size and nodal status remain powerful predictors of late recur-rences compared to more recently developed tools such as the immunohistochemical score (IHC4) and two gene expression profile tests (Recurrence Score and PAM50).125 Common sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues, and liver. Brain metastases are less frequent over-all, although with the advent of adjuvant systemic therapies it has been reported that CNS disease may be seen earlier.126,127 There are also reports of factors that are associated with the risk of developing brain metastases.128 For example, they are more likely to be seen in patients with triple receptor negative breast cancer (ER-negative, PR-negative, and


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Surgery_Schwartz. are associated with the risk of developing brain metastases.128 For example, they are more likely to be seen in patients with triple receptor negative breast cancer (ER-negative, PR-negative, and HER2-negative) or patients with HER2-positive breast cancer who have received chemotherapy and HER2-directed therapies.HISTOPATHOLOGY OF BREAST CANCERCarcinoma In SituCancer cells are in situ or invasive depending on whether or not they invade through the basement membrane.129,130 Broders’s original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confine-ment within natural ductal and alveolar boundaries.129 Because areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates the analysis of multiple microscopic sec-tions to exclude invasion. In 1941, Foote and Stewart published Brunicardi_Ch17_p0541-p0612.indd 56301/03/19 5:04 PM 564SPECIFIC CONSIDERATIONSPART IITable 17-8Salient


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Surgery_Schwartz. of multiple microscopic sec-tions to exclude invasion. In 1941, Foote and Stewart published Brunicardi_Ch17_p0541-p0612.indd 56301/03/19 5:04 PM 564SPECIFIC CONSIDERATIONSPART IITable 17-8Salient characteristics of in situ ductal (DCIS) and lobular (LCIS) carcinoma of the breast LCISDCISAge (years)44–4754–58Incidencea2%–5%5%–10%Clinical signsNoneMass, pain, nipple dischargeMammographic signsNoneMicrocalcificationsPremenopausal2/31/3Incidence of synchronous invasive carcinoma5%2%–46%Multicentricity60%–90%40%–80%Bilaterality50%–70%10%–20%Axillary metastasis1%1%–2%Subsequent carcinomas: Incidence25%–35%25%–70% LateralityBilateralIpsilateral Interval to diagnosis15–20 y5–10 y Histologic typeDuctalDuctalaIn biopsy specimens of mammographically detected breast lesions.Reproduced with permission from Bland KI, Copeland ED: The Breast: Comprehensive Management of Benign and Malignant Diseases, 2nd ed. Philadelphia, PA: Elsesvier/Saunders; 1998.Table 17-9Classification of breast ductal


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Surgery_Schwartz. from Bland KI, Copeland ED: The Breast: Comprehensive Management of Benign and Malignant Diseases, 2nd ed. Philadelphia, PA: Elsesvier/Saunders; 1998.Table 17-9Classification of breast ductal carcinoma in situ (DCIS)HISTOLOGIC SUBTYPE DETERMINING CHARACTERISTICSDCIS GRADE NUCLEAR GRADENECROSISComedoHighExtensiveHighIntermediateaIntermediateFocal or absentIntermediateNoncomedobLowAbsentLowaOften a mixture of noncomedo patterns.bSolid, cribriform, papillary, or focal micropapillary.Adapted with permission from Koo JS, Kim MJ, Kim EK, et al: Comparison of immunohistochemical staining in breast papillary neoplasms of cytokeratin 5/6 and p63 in core needle biopsies and surgical excisions, Appl Immunohistochem Mol Morphol. 2012 Mar;20(2):108-115.a landmark description of LCIS, which distinguished it from DCIS.130 In the late 1960s, Gallagher and Martin published their study of whole-breast sections and described a stepwise progres-sion from benign breast tissue to in situ cancer and


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Surgery_Schwartz. it from DCIS.130 In the late 1960s, Gallagher and Martin published their study of whole-breast sections and described a stepwise progres-sion from benign breast tissue to in situ cancer and subsequently to invasive cancer. Before the widespread use of mammography, diagnosis of breast cancer was by physical examination. At that time, in situ cancers constituted <6% of all breast cancers, and LCIS was more frequently diagnosed than DCIS by a ratio of >2:1. However, when screening mammography became popular, a 14-fold increase in the incidence of in situ cancer (45%) was demonstrated, and DCIS was more frequently diagnosed than LCIS by a ratio of >2:1. Table 17-8 lists the clinical and patho-logic characteristics of DCIS and LCIS. Multicentricity refers to the occurrence of a second breast cancer outside the breast quadrant of the primary cancer (or at least 4 cm away), whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer


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Surgery_Schwartz. outside the breast quadrant of the primary cancer (or at least 4 cm away), whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer (or within 4 cm of it). Multicentricity occurs in 60% to 90% of women with LCIS, whereas the rate of multicentricity for DCIS is reported to be 40% to 80%. LCIS occurs bilaterally in 50% to 70% of cases, whereas DCIS occurs bilaterally in 10% to 20% of cases.Lobular Carcinoma In Situ. LCIS originates from the termi-nal duct lobular units and develops only in the female breast. It is characterized by distention and distortion of the terminal duct lobular units by cells that are large but maintain a normal nuclear to cytoplasmic ratio. Cytoplasmic mucoid globules are a distinctive cellular feature. LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications associated with LCIS typically occur in adjacent tissues. This neighborhood calcification is a feature


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Surgery_Schwartz. LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications associated with LCIS typically occur in adjacent tissues. This neighborhood calcification is a feature that is unique to LCIS and contributes to its diagnosis. The frequency of LCIS in the general population cannot be reliably determined because it usu-ally presents as an incidental finding. The average age at diag-nosis is 45 years, which is approximately 15 to 25 years younger than the age at diagnosis for invasive breast cancer. LCIS has a distinct racial predilection, occurring 12 times more frequently in white women than in African-American women. Invasive breast cancer develops in 25% to 35% of women with LCIS. Invasive cancer may develop in either breast, regardless of which breast harbored the initial focus of LCIS, and is detected synchronously with LCIS in 5% of cases. In women with a his-tory of LCIS, up to 65% of subsequent invasive cancers are duc-tal, not lobular, in origin.


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Surgery_Schwartz. the initial focus of LCIS, and is detected synchronously with LCIS in 5% of cases. In women with a his-tory of LCIS, up to 65% of subsequent invasive cancers are duc-tal, not lobular, in origin. For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer rather than as an anatomic precursor. Individuals should be counseled regarding their risk of developing breast cancer and appropriate risk reduction strategies, including observation with screening, chemoprevention, and risk-reducing bilateral mastectomy.Ductal Carcinoma In Situ. Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers. Published series suggest a detection frequency of 7% in all biopsy tissue specimens. The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for progres-sion to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in


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Surgery_Schwartz. applied to DCIS, which carries a high risk for progres-sion to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which leads to difficulty in distinguishing early DCIS from benign hyperplasia. The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show hyperchroma-sia and loss of polarity (cribriform growth pattern). Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend the ducts (solid growth pattern). With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on


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Surgery_Schwartz. With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 17-9). Based Brunicardi_Ch17_p0541-p0612.indd 56401/03/19 5:04 PM 565THE BREASTCHAPTER 17on multiple consensus meetings, grading of DCIS has been rec-ommended. Although there is no universal agreement on clas-sification, most systems endorse the use of cytologic grade and presence or absence of necrosis.131The risk for invasive breast cancer is increased nearly fivefold in women with DCIS.132 The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of invasive ductal carcinoma (Fig. 17-15A and B).Invasive Breast CarcinomaInvasive breast cancers have been described as


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Surgery_Schwartz. was originally detected, which suggests that DCIS is an anatomic precursor of invasive ductal carcinoma (Fig. 17-15A and B).Invasive Breast CarcinomaInvasive breast cancers have been described as lobular or duc-tal in origin.128-131 Early classifications used the term lobular to describe invasive cancers that were associated with LCIS, whereas all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by spe-cific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. About 80% of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These can-cers generally have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classifica-tion for invasive breast cancer130:1. Paget’s disease of the nipple2. Invasive ductal


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Surgery_Schwartz. have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classifica-tion for invasive breast cancer130:1. Paget’s disease of the nipple2. Invasive ductal carcinoma—Adenocarcinoma with produc-tive fibrosis (scirrhous, simplex, NST), 80%3. Medullary carcinoma, 4%4. Mucinous (colloid) carcinoma, 2%5. Papillary carcinoma, 2%6. Tubular carcinoma, 2%7. Invasive lobular carcinoma, 10%8. Rare cancers (adenoid cystic, squamous cell, apocrine)Paget’s disease of the nipple was described in 1874. It fre-quently presents as a chronic, eczematous eruption of the nipple, which may be subtle but may progress to an ulcerated, weeping lesion. Paget’s disease usually is associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer


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Surgery_Schwartz. or may not be present. A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium. Paget’s disease may be confused with superficial spreading melanoma. Differ-entiation from pagetoid intraepithelial melanoma is based on the presence of S-100 antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget’s disease. Surgical therapy for Paget’s disease may involve lumpectomy or mastectomy, depending on the extent of involvement of the nipple-areolar complex and the presence of DCIS or invasive cancer in the underlying breast parenchyma.Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 25% of


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Surgery_Schwartz. of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 25% of screen-detected cases and up to 60% of symptomatic cases. This cancer occurs most frequently in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins, and its cut surfaces show a central stellate con-figuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologic types with variable cellular and nuclear grades (Fig. 17-16A and B). In a large patient series from the SEER database, 75% of ductal cancers showed estrogen receptor expression.133Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a fre-quent phenotype of BRCA1 hereditary breast


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Surgery_Schwartz. showed estrogen receptor expression.133Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a fre-quent phenotype of BRCA1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physi-cal examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by: (a) a dense lym-phoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (b) large pleomorphic nuclei that are poorly ABFigure 17-15. Ductal carcinoma in situ (DCIS). A. Craniocau-dal mammographic view shows a poorly defined mass containing microcalcifications. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) B. Histopathologic preparation of the sur-gical specimen confirms DCIS with


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Surgery_Schwartz. permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) B. Histopathologic preparation of the sur-gical specimen confirms DCIS with necrosis (100x). (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 56501/03/19 5:04 PM 566SPECIFIC CONSIDERATIONSPART IIABFigure 17-16. Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) A. 100x. B. 200x. (Used with permis-sion from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)Figure 17-17. Lobular carcinoma (100×). Uniform, relatively small lobular carcinoma cells are seen arranged in a single-file orientation (“Indian file”). (Used with permission from Dr. Sindhu Menon,


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Surgery_Schwartz. 17-17. Lobular carcinoma (100×). Uniform, relatively small lobular carcinoma cells are seen arranged in a single-file orientation (“Indian file”). (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consul-tant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)differentiated and show active mitosis; and (c) a sheet-like growth pattern with minimal or absent ductal or alveolar dif-ferentiation. Approximately 50% of these cancers are associated with DCIS, which characteristically is present at the periphery of the cancer, and <10% demonstrate hormone receptors. In rare circumstances, mesenchymal metaplasia or anaplasia is noted. Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular


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Surgery_Schwartz. enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma.Mucinous carcinoma (colloid carcinoma), another spe-cial-type breast cancer, accounts for 2% of all invasive breast cancers and typically presents in the older population as a bulky tumor. This cancer is defined by extracellular pools of mucin, which surround aggregates of low-grade cancer cells. The cut surface of this cancer is glistening and gelatinous in quality. Fibrosis is variable, and when abundant it imparts a firm consis-tency to the cancer. Over 90% of mucinous carcinomas display hormone receptors.133 Lymph node metastases occur in 33% of cases, and 5and 10-year survival rates are 73% and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopic sections, and analysis of multiple sections is essential to confirm the diagnosis of a


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Surgery_Schwartz. 73% and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopic sections, and analysis of multiple sections is essential to confirm the diagnosis of a mucinous carcinoma.Papillary carcinoma is a special-type cancer of the breast that accounts for 2% of all invasive breast cancers. It generally presents in the seventh decade of life and occurs in a dispropor-tionate number of nonwhite women. Typically, papillary car-cinomas are small and rarely attain a size of 3 cm in diameter. These cancers are defined by papillae with fibrovascular stalks and multilayered epithelium. In a large series from the SEER database 87% of papillary cancers have been reported to express estrogen receptor.133 McDivitt and colleagues noted that these tumors showed a low frequency of axillary lymph node metas-tases and had 5and 10-year survival rates similar to those for mucinous and tubular carcinoma.134Tubular carcinoma is another special-type breast cancer and


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Surgery_Schwartz. low frequency of axillary lymph node metas-tases and had 5and 10-year survival rates similar to those for mucinous and tubular carcinoma.134Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammographic screening and usually is diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. In a large SEER database 94% of tubular cancers were reported to express estrogen receptor.133 Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will develop axillary lymph node metastases. However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform


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Surgery_Schwartz. metastases. However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%.Invasive lobular carcinoma accounts for 10% of breast cancers. The histopathologic features of this cancer include small cells with rounded nuclei, inconspicuous nucleoli, and scant cytoplasm (Fig. 17-17). Special stains may confirm the Brunicardi_Ch17_p0541-p0612.indd 56601/03/19 5:04 PM 567THE BREASTCHAPTER 17presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). At presentation, invasive lobular carcinoma varies from clinically inapparent carcinomas to those that replace the entire breast with a poorly defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic fea-tures, invasive lobular carcinoma may be difficult to


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Surgery_Schwartz. defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic fea-tures, invasive lobular carcinoma may be difficult to detect. Over 90% of lobular cancers express estrogen receptor.133DIAGNOSIS OF BREAST CANCERIn ∼30% of cases, the woman discovers a lump in her breast. Other less frequent presenting signs and symptoms of breast cancer include: (a) breast enlargement or asymmetry; (b) nipple changes, retraction, or discharge; (c) ulceration or erythema of the skin of the breast; (d) an axillary mass; and (e) musculoskel-etal discomfort. However, up to 50% of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease.Misdiagnosed breast cancer accounts for the greatest num-ber of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and


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Surgery_Schwartz. accounts for the greatest num-ber of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and mammogram may be misleading. If a young woman (≤45 years) presents with a palpable breast mass and equivocal mammographic findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis.ExaminationInspection. The clinician inspects the woman’s breast with her arms by her side (Fig. 17-18A), with her arms straight up in the air (Fig. 17-18B), and with her hands on her hips (with and without pectoral muscle contraction).135,136 Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d’orange), nipple or skin retraction, or erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.Figure 17-18. Examination of the breast. A. Inspection of the breast with arms at sides. B.


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Surgery_Schwartz. arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.Figure 17-18. Examination of the breast. A. Inspection of the breast with arms at sides. B. Inspection of the breast with arms raised. C. Palpation of the breast with the patient supine. D. Palpa-tion of the axilla.Palpation. As part of the physical examination, the breast is carefully palpated. With the patient in the supine position (see Fig. 17-18C) the clinician gently palpates the breasts, making certain to examine all quadrants of the breast from the sternum laterally to the latissimus dorsi muscle and from the clavicle inferiorly to the upper rectus sheath. The examination is per-formed with the palmar aspects of the fingers, avoiding a grasp-ing or pinching motion. The breast may be cupped or molded in the examiner’s hands to check for retraction. A systematic search for lymphadenopathy then is performed. Figure 17-18D shows the position of the patient for examination of


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Surgery_Schwartz. may be cupped or molded in the examiner’s hands to check for retraction. A systematic search for lymphadenopathy then is performed. Figure 17-18D shows the position of the patient for examination of the axilla. By supporting the upper arm and elbow, the examiner stabi-lizes the shoulder girdle. Using gentle palpation, the clinician assesses all three levels of possible axillary lymphadenopathy. Careful palpation of supraclavicular and parasternal sites also is performed. A diagram of the chest and contiguous lymph node sites is useful for recording location, size, consistency, shape, mobility, fixation, and other characteristics of any palpable breast mass or lymphadenopathy (Fig. 17-19).Imaging TechniquesMammography. Mammography has been used in North Amer-ica since the 1960s, and the techniques used continue to be mod-ified and improved to enhance image quality.137-140 Conventional mammography delivers a radiation dose of 0.1 cGy per study. By comparison, chest radiography delivers


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Surgery_Schwartz. used continue to be mod-ified and improved to enhance image quality.137-140 Conventional mammography delivers a radiation dose of 0.1 cGy per study. By comparison, chest radiography delivers 25% of this dose. However, there is no increased breast cancer risk associated with the radiation dose delivered with screening mammography. Screening mammography is used to detect unexpected breast cancer in asymptomatic women. In this regard, it supplements history taking and physical examination. With screening mam-mography, two views of the breast are obtained: the craniocau-dal (CC) view (Fig. 17-20A,B) and the mediolateral oblique (MLO) view (Fig. 17-20C,D). The MLO view images the great-est volume of breast tissue, including the upper outer quadrant and the axillary tail of Spence. Compared with the MLO view, the CC view provides better visualization of the medial aspect of the breast and permits greater breast compression. Diagnos-tic mammography is used to evaluate women with abnormal


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Surgery_Schwartz. with the MLO view, the CC view provides better visualization of the medial aspect of the breast and permits greater breast compression. Diagnos-tic mammography is used to evaluate women with abnormal Figure 17-19. A breast examination record. Brunicardi_Ch17_p0541-p0612.indd 56701/03/19 5:04 PM 568SPECIFIC CONSIDERATIONSPART IIABCDFigure 17-20. A-D. Mammogram of a premenopausal breast with a dense fibroglandular pattern. E-H. Mammogram of a postmenopausal breast with a sparse fibroglandular pattern. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 56801/03/19 5:04 PM 569THE BREASTCHAPTER 17EFGHFigure 17-20. (Continued)findings such as a breast mass or nipple discharge. In addition to the MLO and CC views, a diagnostic examination may use views that better define the nature of any abnormalities, such as the 90° lateral and spot compression views. The 90° lateral


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Surgery_Schwartz. In addition to the MLO and CC views, a diagnostic examination may use views that better define the nature of any abnormalities, such as the 90° lateral and spot compression views. The 90° lateral view is used along with the CC view to triangulate the exact location of an abnormality. Spot compression may be done in any pro-jection by using a small compression device, which is placed directly over a mammographic abnormality that is obscured by overlying tissues (Fig. 17-21C). The compression device mini-mizes motion artifact, improves definition, separates overlying tissues, and decreases the radiation dose needed to penetrate the breast. Magnification techniques (×1.5) often are combined with spot compression to better resolve calcifications and the margins of masses. Mammography also is used to guide inter-ventional procedures, including needle localization and needle biopsy.Brunicardi_Ch17_p0541-p0612.indd 56901/03/19 5:04 PM 570SPECIFIC CONSIDERATIONSPART IIABCFigure