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Surgery_Schwartz. 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 17-21. Mammogram revealing a small, spiculated mass in the right breast A. A small, spiculated mass is seen in the right breast with skin tethering (CC view). B. Mass seen on oblique view of the right breast. C. Spot compression mammography view of the cancer seen in A and B. The spiculated margins of the cancer are accentuated by compression. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Specific mammographic features that suggest a diagnosis of breast cancer include a solid mass with or without stellate features, asymmetric thickening of breast tissues, and clustered microcalcifications. The presence of fine, stippled calcium in and around a suspicious lesion is suggestive of breast cancer and occurs in


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Surgery_Schwartz. asymmetric thickening of breast tissues, and clustered microcalcifications. The presence of fine, stippled calcium in and around a suspicious lesion is suggestive of breast cancer and occurs in as many as 50% of nonpalpable cancers. These microcalcifications are an especially important sign of cancer in younger women, in whom it may be the only mammographic abnormality. The clinical impetus for screening mammogra-phy came from the Health Insurance Plan study and the Breast Cancer Detection Demonstration Project, which demonstrated a 33% reduction in mortality for women after72 screening mam-mography. Mammography was more accurate than clinical examination for the detection of early breast cancers, providing a true-positive rate of 90%. Only 20% of women with nonpal-pable cancers had axillary lymph node metastases, compared with 50% of women with palpable cancers.141 Current guide-lines of the National Comprehensive Cancer Network suggest that normal-risk women ≥20 years of age should


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Surgery_Schwartz. lymph node metastases, compared with 50% of women with palpable cancers.141 Current guide-lines of the National Comprehensive Cancer Network suggest that normal-risk women ≥20 years of age should have a breast examination at least every 3 years. Starting at age 40 years, breast examinations should be performed yearly, and a yearly mammogram should be taken.142 Screening mammography in women ≥50 years of age has been noted to reduce breast cancer mortality by 20% to 25%.72,79 With the increased discussion about the potential harms associated with breast screening, the United Kingdom recently established an independent expert panel to review the published literature and estimate the ben-efits and harms associated with its national screening program for women age >50 years. The panel estimated that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis. Despite this overdiagno-sis, the panel concluded that breast screening programs


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Surgery_Schwartz. that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis. Despite this overdiagno-sis, the panel concluded that breast screening programs confer significant benefit and should continue. The use of screening mammography in women <50 years of age is more controversial for previously noted reasons: (a) reduced sensitivity, (b) reduced specificity, and (c) lower incidence of breast cancer. Because of the combination of these three reasons, targeting mammography screening to women <50 years of age, who are at higher risk of breast cancer, improves the balance of risks and benefits and is the approach some health care systems have taken. There are now a number of risk assessment models—as described earlier in this chapter—that can be used to estimate a younger woman’s risk of developing breast cancer and that help assess the risks and benefits of regular screening.Screen film mammography has replaced xeromam-mography because it


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Surgery_Schwartz. used to estimate a younger woman’s risk of developing breast cancer and that help assess the risks and benefits of regular screening.Screen film mammography has replaced xeromam-mography because it requires a lower dose of radiation and provides similar image quality. Digital mammography was developed to allow the observer to manipulate the degree of contrast in the image. This is especially useful in women with dense breasts and women <50 years of age. Recently, investigators directly compared digital vs. screen film mam-mography in a prospective (DMIST) trial that enrolled over 42,000 women.143 The investigators found that digital and screen film mammography had similar accuracy; however, digital mammography was more accurate in women <50 years of age, women with mammographically dense breasts, and premenopausal or perimenopausal women. The use of digital breast tomosynthesis with 3D images has been introduced as an alternative to standard 2D mammography imaging that is limited by


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Surgery_Schwartz. breasts, and premenopausal or perimenopausal women. The use of digital breast tomosynthesis with 3D images has been introduced as an alternative to standard 2D mammography imaging that is limited by superimposition of breast parenchyma and breast density.144,145 The STORM trial reported that in 7,292 women screened, 3D mammography had a higher cancer detection rate and fewer false-positive recalls than the standard 2D imaging.146,147 Randomized controlled trials are planned to fur-ther study tomosynthesis and its role in breast cancer screen-ing. Standard two-dimensional mammography has limitations, Brunicardi_Ch17_p0541-p0612.indd 57001/03/19 5:04 PM 571THE BREASTCHAPTER 17such as the parenchymal density or superimposition of breast tissue, which obscures cancers or causes normal structures to appear suspicious reducing the sensitivity of mammography and increasing the false-positive rates. Digital breast tomo-synthesis is a technology developed to assist with overcom-ing these


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Surgery_Schwartz. to appear suspicious reducing the sensitivity of mammography and increasing the false-positive rates. Digital breast tomo-synthesis is a technology developed to assist with overcom-ing these limitations. In digital breast tomosynthesis, multiple projection images are reconstructed to allow visual review of thin breast sections, each reconstructed slice as thin as 0.5 mm, which provides better characterization of noncalcified lesions. These multiple projection exposures are obtained by a digi-tal detector from a mammography X-ray source that moves through a limited arc angle while the breast is compressed. Then these projection image data sets are reconstructed using specific algorithms, which provide the clinical reader a series of images through the entire breast.148In 2011, tomosynthesis was approved by the U.S. Food and Drug Administration (FDA) to be used in combination with standard digital mammography for breast cancer screening. The total radiation dose when tomosynthesis is


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Surgery_Schwartz. was approved by the U.S. Food and Drug Administration (FDA) to be used in combination with standard digital mammography for breast cancer screening. The total radiation dose when tomosynthesis is added is about twice the current dose of digital mammography alone but remains below the limits set by the FDA.149The STORM-2 trial reported that synthetic 2D-3D mammography yields similar breast cancer detection as dual-acquisition 2D-3D mammography with the advantage of reduc-ing radiation exposure.150Contrast-enhanced digital mammography (CEDM) was also approved by the FDA in 2001, which utilizes an iodinated contrast material and modified digital mammography units for imaging.148 CEDM has been shown to be feasible and detects breast cancers at a rate similar to MRI, which has potential to offer an alternative to MRI.151 The advantages of CEDM over MRI are that the use of compression limits motion, there is decrease in cost, decrease in exam time, and there is an option for patients who


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Surgery_Schwartz. an alternative to MRI.151 The advantages of CEDM over MRI are that the use of compression limits motion, there is decrease in cost, decrease in exam time, and there is an option for patients who are unable to tolerate MRI or who due to vari-ous reasons cannot have MRI due to incompatibility, such as the presence of a pacemaker or tissue expanders.148,152Ductography. The primary indication for ductography is nipple discharge, particularly when the fluid contains blood. Radiopaque contrast media is injected into one or more of the major ducts, and mammography is performed. A duct is gen-tly enlarged with a dilator, and then a small, blunt cannula is inserted under sterile conditions into the nipple ampulla. With the patient in a supine position, 0.1 to 0.2 mL of dilute con-trast media is injected, and CC and MLO mammographic views are obtained without compression. Intraductal papillomas are seen as small filling defects surrounded by contrast media (Fig. 17-22). Cancers may appear as


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Surgery_Schwartz. injected, and CC and MLO mammographic views are obtained without compression. Intraductal papillomas are seen as small filling defects surrounded by contrast media (Fig. 17-22). Cancers may appear as irregular masses or as mul-tiple intraluminal filling defects.Ultrasonography. Second only to mammography in fre-quency of use for breast imaging, ultrasonography is an impor-tant method of resolving equivocal mammographic findings, defining cystic masses, and demonstrating the echogenic qual-ities of specific solid abnormalities. On ultrasound examina-tion, breast cysts are well circumscribed, with smooth margins and an echo-free center (Fig. 17-23). Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior mar-gins (Fig. 17-24). Breast cancer characteristically has irregular walls (Fig. 17-25) but may have smooth margins with acous-tic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy,


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Surgery_Schwartz. (Fig. 17-24). Breast cancer characteristically has irregular walls (Fig. 17-25) but may have smooth margins with acous-tic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization ABFigure 17-22. Ductogram. Craniocaudal (A) and mediolateral oblique (B) mammographic views demonstrate a mass (arrows) posterior to the nipple and outlined by contrast, which also fills the proximal ductal structures. (Used with permission from B. Steinbach.)of breast lesions. Its findings are highly reproducible, and it has a high patient acceptance rate, but it does not reliably detect lesions that are ≤1 cm in diameter. Ultrasonography can also be utilized to image the regional lymph nodes in patients with breast cancer (Fig. 17-26). The sensitivity of examination for the status of axillary nodes ranges from 35% to 82% and specificity ranges from 73% to 97%. The features of a lymph node involved with cancer include cortical thickening,


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Surgery_Schwartz. of examination for the status of axillary nodes ranges from 35% to 82% and specificity ranges from 73% to 97%. The features of a lymph node involved with cancer include cortical thickening, change in shape of the node to more circular appearance, size larger Brunicardi_Ch17_p0541-p0612.indd 57101/03/19 5:05 PM 572SPECIFIC CONSIDERATIONSPART IIABFigure 17-24. Ultrasonography images of benign breast tumors. A. Fibroadenoma. B. Intraductal papilloma (see arrow). (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)ABCFigure 17-23. Breast cyst. A. Simple cyst. Ultrasound image of the mass shows it to be anechoic with a well-defined back wall, characteristic of a cyst. B. Complex solid and cystic mass. C. Complex solid and cystic mass characteristic of intracystic papillary tumor. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby,


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Surgery_Schwartz. solid and cystic mass characteristic of intracystic papillary tumor. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)than 10 mm, absence of a fatty hilum and hypoechoic internal echoes.153Magnetic Resonance Imaging. In the process of evaluating magnetic resonance imaging (MRI) as a means of character-izing mammographic abnormalities, additional breast lesions have been detected. However, in the circumstance of negative findings on both mammography and physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in the use of MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women who have a strong family history of breast cancer or who carry known genetic mutations require screening at an early age because mammographic evaluation is limited due to the increased breast density


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Surgery_Schwartz. who have a strong family history of breast cancer or who carry known genetic mutations require screening at an early age because mammographic evaluation is limited due to the increased breast density in younger women. In the second case, an MRI study of the contralateral breast in women with a known breast cancer has shown a contralateral breast cancer in 5.7% of these women (Fig. 17-27). MRI can also detect additional tumors in the index breast (multifocal or multicen-tric disease) that may be missed on routine breast imaging and this may alter surgical decision making (Fig. 17-28). In fact, MRI has been advocated by some for routine use in surgical treatment planning based on the fact that additional disease can be identified with this advanced imaging modality and the Brunicardi_Ch17_p0541-p0612.indd 57201/03/19 5:05 PM 573THE BREASTCHAPTER 17Figure 17-25. Ultrasonography images of malignant breast lesions. A. 25 mm irregular mass. B. Ultrasound 30 mm mass anterior to an


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Surgery_Schwartz. 57201/03/19 5:05 PM 573THE BREASTCHAPTER 17Figure 17-25. Ultrasonography images of malignant breast lesions. A. 25 mm irregular mass. B. Ultrasound 30 mm mass anterior to an implant. C. Ultrasound breast cancer with calcification. D. Ultrasound shows a 9 mm spiculated mass (see arrow) with attenuation. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)extent of disease may be more accurately assessed. A random-ized trial performed in the United Kingdom (COMICE trial) that enrolled 1623 women did not show a decrease in rates of reoperation in those women randomized to undergo MRI in addition to mammography and ultrasonography (19%) com-pared to those undergoing standard breast imaging without MRI (19%).154 Houssami and colleagues performed a meta-analysis including two randomized trials and seven compara-tive cohort studies to examine the effect of preoperative MRI compared to standard preoperative


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Surgery_Schwartz. Houssami and colleagues performed a meta-analysis including two randomized trials and seven compara-tive cohort studies to examine the effect of preoperative MRI compared to standard preoperative evaluation on surgical out-comes.155 They reported that the use of MRI was associated with increased mastectomy rates. This is problematic because there is no evidence that the additional disease detected by MRI is of clinical or biologic significance, particularly in light of the low local-regional failure rates currently reported in patients undergoing breast conserving surgery who receive whole breast irradiation and systemic therapies. There is an ongoing trial in the Alliance for Clinical Trials in Oncology that is randomizing patients to preoperative MRI vs. standard imaging to assess the impact of MRI on local regional recur-rence rates in patients with triple receptor negative and HER2 positive breast cancers.The use of dedicated breast coils is mandatory in the MRI imaging of the


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Surgery_Schwartz. impact of MRI on local regional recur-rence rates in patients with triple receptor negative and HER2 positive breast cancers.The use of dedicated breast coils is mandatory in the MRI imaging of the breast. A BIRADS lexicon is assigned to each examination and an abnormality noted on MRI that is not seen on mammography requires a focused ultrasound examination for further assessment. If the abnormality is not seen on corre-sponding mammogram or ultrasound, then MRI-guided biopsy is necessary. Some clinical scenarios where MRI may be use-ful include the evaluation of a patient who presents with nodal metastasis from breast cancer without an identifiable primary tumor; to assess response to therapy in the setting of neoadjuvant ABCDBrunicardi_Ch17_p0541-p0612.indd 57301/03/19 5:05 PM 574SPECIFIC CONSIDERATIONSPART IIFigure 17-26. Ultrasonography images of lymph nodes. A. Nor-mal axillary lymph node (see arrows). B. Indeterminate axillary lymph node. C. Malignant appearing axillary


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Surgery_Schwartz. CONSIDERATIONSPART IIFigure 17-26. Ultrasonography images of lymph nodes. A. Nor-mal axillary lymph node (see arrows). B. Indeterminate axillary lymph node. C. Malignant appearing axillary lymph node. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)ABCsystemic treatment; to select patients for partial breast irradia-tion techniques; and evaluation of the treated breast for tumor recurrence.Breast BiopsyNonpalpable Lesions. Image-guided breast biopsy specimens are frequently required to diagnose nonpalpable lesions.156 Ultrasound localization techniques are used when a mass is present, whereas stereotactic techniques are used when no mass is present (microcalcifications or architectural distortion only). The combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-needle aspiration (FNA) biopsy achieves almost 100% accuracy in the preoperative diag-nosis of breast cancer.


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Surgery_Schwartz. combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-needle aspiration (FNA) biopsy achieves almost 100% accuracy in the preoperative diag-nosis of breast cancer. However, although FNA biopsy permits cytologic evaluation, core-needle permits the analysis of breast tissue architecture and allows the pathologist to determine whether invasive cancer is present. This permits the surgeon and patient to discuss the specific management of a breast cancer before therapy begins. Core-needle biopsy is preferred over open biopsy for nonpalpable breast lesions because a single sur-gical procedure can be planned based on the results of the core biopsy. The advantages of core-needle biopsy include a low complication rate, minimal scarring, and a lower cost compared with excisional breast biopsy.Palpable Lesions. FNA or core biopsy of a palpable breast mass can usually be performed in an outpatient setting.157 A 1.5-in, 22-gauge needle attached to a 10-mL syringe


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Surgery_Schwartz. excisional breast biopsy.Palpable Lesions. FNA or core biopsy of a palpable breast mass can usually be performed in an outpatient setting.157 A 1.5-in, 22-gauge needle attached to a 10-mL syringe or a 14-gauge core biopsy needle is used. For FNA, use of a syringe holder 7Figure 17-27. MRI examination revealing contralateral breast cancer (see arrows) in a patient diag-nosed with unilateral breast cancer on mammography (two arrows). (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 57401/03/19 5:05 PM 575THE BREASTCHAPTER 17enables the surgeon performing the FNA biopsy to control the syringe and needle with one hand while positioning the breast mass with the opposite hand. After the needle is placed in the mass, suction is applied while the needle is moved back and forth within the mass. Once cellular material is seen at the hub of the needle, the suction is released


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Surgery_Schwartz. After the needle is placed in the mass, suction is applied while the needle is moved back and forth within the mass. Once cellular material is seen at the hub of the needle, the suction is released and the needle is with-drawn. The cellular material is then expressed onto microscope slides. Both air-dried and 95% ethanol–fixed microscopic sec-tions are prepared for analysis. When a breast mass is clinically and mammographically suspicious, the sensitivity and specific-ity of FNA biopsy approaches 100%. Core-needle biopsy of palpable breast masses is performed using a 14-gauge needle, such as the Tru-Cut needle. Automated devices also are avail-able. Vacuum-assisted core biopsy devices (with 8–10 gauge needles) are commonly utilized with image guidance where between 4 and 12 samples can be acquired at different posi-tions within a mass, area of architectural distortion or micro-calcifications. If the target lesion was microcalcifications, the specimen should be radiographed to confirm


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Surgery_Schwartz. acquired at different posi-tions within a mass, area of architectural distortion or micro-calcifications. If the target lesion was microcalcifications, the specimen should be radiographed to confirm appropriate sam-pling. A radiopaque marker should be placed at the site of the biopsy to mark the area for future intervention. In some cases the entire lesion is removed with the biopsy technique and clip placement allows for accurate targeting of the site for surgi-cal resection. Tissue specimens are placed in formalin and then processed to paraffin blocks. Although the false-negative rate for core-needle biopsy specimens is very low, a tissue speci-men that does not show breast cancer cannot conclusively rule out that diagnosis because a sampling error may have occurred. The clinical, radiographic, and pathologic findings should be in concordance. If the biopsy findings do not concur with the clinical and radiographic findings, the multidisciplinary team (including clinician,


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Surgery_Schwartz. radiographic, and pathologic findings should be in concordance. If the biopsy findings do not concur with the clinical and radiographic findings, the multidisciplinary team (including clinician, radiologist, and pathologist) should review the findings and decide whether or not to recommend an image-guided or open biopsy to be certain that the target lesion has been adequately sampled for diagnosis.BREAST CANCER STAGING AND BIOMARKERSBreast Cancer StagingThe clinical stage of breast cancer is determined primarily through physical examination of the skin, breast tissue, and regional lymph nodes (axillary, supraclavicular, and internal mammary).158 However, clinical determination of axillary lymph node metastases has an accuracy of only 33%. Ultrasound (US) is more sensitive than physical examination alone in determining axillary lymph node involvement during preliminary staging of breast carcinoma. FNA or core biopsy of sonographically inde-terminate or suspicious lymph nodes can


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Surgery_Schwartz. examination alone in determining axillary lymph node involvement during preliminary staging of breast carcinoma. FNA or core biopsy of sonographically inde-terminate or suspicious lymph nodes can provide a more defini-tive diagnosis than US alone.153,159 Pathologic stage combines the findings from pathologic examination of the resected pri-mary breast cancer and axillary or other regional lymph nodes. Fisher and colleagues found that accurate predictions regarding the occurrence of distant metastases were possible after resec-tion and pathologic analysis of 10 or more levels I and II axillary lymph nodes.160 A frequently used staging system is the TNM (tumor, nodes, and metastasis) system. The American Joint Committee on Cancer (AJCC) has recently modified the TNM system for breast cancer to include both anatomic and biologic factors161 (Tables 17-10 and 17-11). Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary lymph node metastases (see


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Surgery_Schwartz. to include both anatomic and biologic factors161 (Tables 17-10 and 17-11). Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary lymph node metastases (see Fig. 17-14B). Others have shown an association between tumor size, axillary lymph node metastases, and disease-free survival. One of the most important predictors of 10and 20-year survival rates in breast cancer is the number of axillary lymph nodes involved with metastatic disease. Routine biopsy of internal mammary lymph nodes is not generally performed; however, it has been reported that in the context of a “triple node” biopsy approach either the internal mammary node or a low axillary node when positive alone carried the same prognostic weight. When both nodes were positive, the prognosis declined to the level associated with apical node positivity. A double node biopsy of the low axil-lary node and either the apical or the internal mammary node gave the same maximum prognostic


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Surgery_Schwartz. declined to the level associated with apical node positivity. A double node biopsy of the low axil-lary node and either the apical or the internal mammary node gave the same maximum prognostic information as a triple node biopsy.162 With the advent of sentinel lymph node dissection and the use of preoperative lymphoscintigraphy for localization of the sentinel nodes, surgeons have again begun to biopsy the internal mammary nodes but in a more targeted manner. The 8th edition of the AJCC staging system does allow for staging based on findings from the internal mammary sentinel nodes.163 Drainage to the internal mammary nodes is more frequent with central and medial quadrant cancers. Clinical or pathologic evi-dence of metastatic spread to supraclavicular lymph nodes is no longer considered stage IV disease, but routine scalene or supraclavicular lymph node biopsy is not indicated.BiomarkersBreast cancer biomarkers are of several types. Risk factor biomarkers are those associated with


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Surgery_Schwartz. stage IV disease, but routine scalene or supraclavicular lymph node biopsy is not indicated.BiomarkersBreast cancer biomarkers are of several types. Risk factor biomarkers are those associated with increased cancer risk.164-168 These include familial clustering and inherited germline abnormalities, proliferative breast disease with atypia, and mammographic density. Exposure biomarkers are a subset of risk factors that include measures of carcinogen exposure such as DNA adducts. Surrogate endpoint biomarkers are biologic alterations in tissue that occur between cancer initiation and development. These biomarkers are used as endpoints in short-term chemoprevention trials and include histologic changes, indices of proliferation, and genetic alterations leading to cancer. Prognostic biomarkers provide information regarding Figure 17-28. MRI imaging of the breast reveal-ing multifocal tumors not detected with standard breast imaging. (Used with permission from Dr. Anne Turnbull, Consultant


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Surgery_Schwartz. provide information regarding Figure 17-28. MRI imaging of the breast reveal-ing multifocal tumors not detected with standard breast imaging. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 57501/03/19 5:05 PM 576SPECIFIC CONSIDERATIONSPART IITable 17-10TNM staging system for breast cancerPrimary tumor (T)The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p” modifier to indicate whether


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Surgery_Schwartz. cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p” modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size.TXT0Tis (DCIS)*Tis (Paget)T1 T1mi T1a T1b T1cT2T3T4 T4a T4b T4c T4dPrimary tumor cannot be assessedNo evidence of primary tumorDuctal carcinoma in situPaget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.Tumor ≤20 mm in greatest dimensionTumor ≤1 mm in greatest dimensionTumor >1 mm


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Surgery_Schwartz. on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.Tumor ≤20 mm in greatest dimensionTumor ≤1 mm in greatest dimensionTumor >1 mm but ≤5 mm in greatest dimension (round any measurement >l.0–1.9 mm to 2 mm).Tumor >5 mim but ≤10 mm in greatest dimensionTumor >10 mm but ≤20 mm in greatest dimensionTumor >20 mm but ≤50 mm in greatest dimensionTumor >50 mm in greatest dimensionTumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinomaBoth T4a and T4b are presentInflammatory carcinoma (see section “Rules for


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Surgery_Schwartz. nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinomaBoth T4a and T4b are presentInflammatory carcinoma (see section “Rules for Classification”)*Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th edition.Regional lymph nodes—Clinical (N)cNX*cN0cN1 cN1mi**cN2 cN2a cN2bcN3 cN3a cN3b cN3cRegional lymph nodes cannot be assessed (e.g., previously removed)No regional lymph node metastases (by imaging or clinical examination)Metastases to movable ipsilateral Level I, II axillary lymph node(s)Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastasesMetastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or


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Surgery_Schwartz. fixed or matted;or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastasesMetastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structuresMetastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastasesMetastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement;or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases;or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvementMetastases in ipsilateral infraclavicular lymph node(s)Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)Metastases in ipsilateral supraclavicular lymph node(s)Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or


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Surgery_Schwartz. lymph node(s)Metastases in ipsilateral supraclavicular lymph node(s)Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy respectively.*the cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.**cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.(Continued)Brunicardi_Ch17_p0541-p0612.indd 57601/03/19 5:05 PM 577THE BREASTCHAPTER 17Table 17-10TNM staging system for breast cancerRegional lymph nodes—Pathologic (pN)pNXpN0 pN0(i+) pN0(mol+)pN1 pN1mi pN1a pN1b pN1cRegional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)No regional lymph node metastasis identified or ITCs


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Surgery_Schwartz. lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)No regional lymph node metastasis identified or ITCs onlyITCs only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s)Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detectedMicrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsyMicrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)Metastases in 1–3 axillary lymph nodes, at least one metastasis larger than 2.0 mmMetastases in ipsilateral internal mammary sentinel nodes, excluding ITCspN1a and pNlb combinedpN2 pN2a pN2bpN3 pN3a pN3b pN3cMetastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastasesMetastases in 4–9 axillary


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Surgery_Schwartz. in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastasesMetastases in 4–9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodesMetastases in 10 or more axillary lymph nodes;or in infraclavicular (Level III axillary) lymph nodes;or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level I, II axillary lymph nodes; or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodesMetastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (Level III axillary lymph)


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Surgery_Schwartz. ipsilateral supraclavicular lymph nodesMetastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (Level III axillary lymph) nodespNla or pN2a in the presence of cN2b (positive internal mammary nodes by imaging); or pN2a in the presence of pNlbMetastases in ipsilateral supraclavicular lymph nodesNote: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy respectively, with NO further resection of nodes.Distant metastasis (M)M0 cM0(i+)cM1pM1No clinical or radiographic evidence of distant metastases*No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastasesDistant metastases detected by


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Surgery_Schwartz. microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastasesDistant metastases detected by clinical and radiographic meansAny histologically proven metastases in distant organs; or if in non-regional nodes, metastases greater than 0.2 mmUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.(Continued)cancer outcome irrespective of therapy, whereas predictive bio-markers provide information regarding response to therapy.169 Candidate prognostic and predictive biomarkers and biologic targets for breast cancer include (a) the steroid hormone recep-tor pathway; (b) growth factors and growth factor receptors such as human epidermal growth factor receptor 2 (HER2)/neu, epidermal growth factor receptor (EGFR), transforming growth factor, platelet-derived growth factor, and the


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Surgery_Schwartz. and growth factor receptors such as human epidermal growth factor receptor 2 (HER2)/neu, epidermal growth factor receptor (EGFR), transforming growth factor, platelet-derived growth factor, and the insulin-like growth factor family; (c) indices of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67; (d) indi-ces of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index; (e) the mammalian target of rapamycin (mTOR) signaling pathway; (f) tumor-suppressor genes such as p53; (g) the cell cycle, cyclins, and cyclin-depen-dent kinases; (h) the proteasome; (i) the COX-2 enzyme; (j) the peroxisome proliferator-activated receptors (PPARs); and (k) indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio.Steroid Hormone Receptor Pathway. Hormones play an important role in the development and progression of breast cancer. Estrogens, estrogen metabolites, and other steroid hor-mones such as progesterone all have


Surgery_Schwartz

Surgery_Schwartz. Receptor Pathway. Hormones play an important role in the development and progression of breast cancer. Estrogens, estrogen metabolites, and other steroid hor-mones such as progesterone all have been shown to have an effect. Breast cancer risk is related to estrogen exposure over time. In postmenopausal women, hormone replacement therapy consisting of estrogen plus progesterone increases the risk of breast cancer by 26% compared to placebo.70 Patients with hor-mone receptor-positive tumors survive two to three times longer after a diagnosis of metastatic disease than do patients with hor-mone receptor-negative tumors. Patients with tumors negative for both estrogen receptors and progesterone receptors are not considered candidates for hormonal therapy. Tumors positive Brunicardi_Ch17_p0541-p0612.indd 57701/03/19 5:05 PM 578SPECIFIC CONSIDERATIONSPART IITable 17-11TNM stage groupingsWhen T is...And N is...And M is...Then the stage group


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Surgery_Schwartz. therapy. Tumors positive Brunicardi_Ch17_p0541-p0612.indd 57701/03/19 5:05 PM 578SPECIFIC CONSIDERATIONSPART IITable 17-11TNM stage groupingsWhen T is...And N is...And M is...Then the stage group is...TisN0M00T1N0M0IAT0N1miM0IBT1N1miM0IBT0N1M0IIAT1N1M0IIAT2N0M0IIAT2N1M0IIBT3N0M0IIBT0N2M0IIIAT1N2M0IIIAT2N2M0IIIAT3N1M0IIIAT3N2M0IIIAT4N0M0IIIBT4N1M0IIIBT4N2M0IIIBAny TN3M0IIICAny TAny NM1IVNotes:1. T1 includes Tl mi.2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.4. M0 includes M0(i+).5. The designation pM0 is not valid; any M0 is clinical.6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are per-formed within 4 months


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Surgery_Schwartz. of response to neoadjuvant therapy.7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are per-formed within 4 months of diagnosis in the absence of disease progres-sion, and provided the patient has not received neoadjuvant therapy.8. Staging following neoadjuvant therapy is denoted with a “yc” or “yp” prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoad-juvant therapy, for example, ypT0ypN0cM0.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.for estrogen or progesterone receptors have a higher response rate to endocrine therapy than tumors that do not express estro-gen or progesterone receptors. The determination of estrogen and progesterone receptor status used to require biochemical evaluation of fresh


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Surgery_Schwartz. endocrine therapy than tumors that do not express estro-gen or progesterone receptors. The determination of estrogen and progesterone receptor status used to require biochemical evaluation of fresh tumor tissue. Today, however, estrogen and progesterone receptor status can be measured in archived tis-sue using immunohistochemical techniques. Hormone receptor status also can be measured in specimens obtained with fine-needle aspiration biopsy or core-needle biopsy, and this can help guide treatment planning. Testing for estrogen and progesterone receptors should be performed on all primary invasive breast cancer specimens. The tumor hormone receptor status should be ascertained for both premenopausal and postmenopausal patients to identify patients who are most likely to benefit from endocrine therapy.Growth Factor Receptors and Growth Factors. Overexpres-sion of EGFR in breast cancer correlates with estrogen recep-tor–negative status and with p53 overexpression.170-172 Similarly,


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Surgery_Schwartz. therapy.Growth Factor Receptors and Growth Factors. Overexpres-sion of EGFR in breast cancer correlates with estrogen recep-tor–negative status and with p53 overexpression.170-172 Similarly, increased immunohistochemical membrane staining for the HER2 growth factor receptor in breast cancer is associated with mutated TP53, Ki67 overexpression, and estrogen receptor–negative status. HER2 is a member of the ErbB family of growth factor receptors in which ligand binding results in recep-tor homodimerization and tyrosine phosphorylation by tyrosine kinase domains within the receptor. Tyrosine phosphorylation is followed by signal transduction, which results in changes in cell behavior. An important property of this family of receptors is that ligand binding to one receptor type also may result in heterodimerization between two different receptor types that are coexpressed; this leads to transphosphorylation and transactiva-tion of both receptors in the complex (transmodulation). In this


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Surgery_Schwartz. in heterodimerization between two different receptor types that are coexpressed; this leads to transphosphorylation and transactiva-tion of both receptors in the complex (transmodulation). In this context, the lack of a specific ligand for the HER2/neu receptor suggests that HER2/neu may function solely as a co-receptor, modulating signaling by other EGFR family members. HER2/neu is both an important prognostic factor and a predictive fac-tor in breast cancer.173 When overexpressed in breast cancer, HER2/neu promotes enhanced growth and proliferation, and increases invasive and metastatic capabilities. Clinical studies have shown that patients with HER2/neu–overexpressing breast cancer have poorly differentiated tumors with high prolifera-tion rates, positive lymph nodes, decreased hormone receptor expression, and an increased risk of recurrence and death due to breast cancer.173-177 Routine testing of the primary tumor specimen for HER2/neu expression should be performed on all


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Surgery_Schwartz. receptor expression, and an increased risk of recurrence and death due to breast cancer.173-177 Routine testing of the primary tumor specimen for HER2/neu expression should be performed on all invasive breast cancers. This can be done with immunohis-tochemical analysis to evaluate for overexpression of the cell-surface receptor at the protein level or by using fluorescence in situ hybridization to evaluate for gene amplification. While HER2/ERBB2 activation can also be assessed based on mRNA expression and reverse transcription polymerase chain reaction (RT-PCR) (Oncotype Dx, Genomic Health), this approach is not recommended for clinical decision-making because of the high false negative rate.178 Patients whose tumors show HER2 ampli-fication or HER2/neu protein overexpression are candidates for anti-HER2/neu therapy. Trastuzumab (Herceptin) is a recombi-nant humanized monoclonal antibody directed against HER2. Randomized clinical trials have demonstrated that single-agent trastuzumab


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Surgery_Schwartz. for anti-HER2/neu therapy. Trastuzumab (Herceptin) is a recombi-nant humanized monoclonal antibody directed against HER2. Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is well tolerated and active in the treatment of women with HER2/neu–overexpressing metastatic breast cancer.179 Subsequent adjuvant trials demonstrated that trastu-zumab also was highly effective in the treatment of women with early-stage breast cancer when used in combination with che-motherapy.180-182 Patients who received trastuzumab in combina-tion with chemotherapy had between a 40% and 50% reduction in the risk of breast cancer recurrence and approximately a one-third reduction in breast cancer mortality compared with those who received chemotherapy alone.181,183-185Indices of Proliferation. PCNA is a nuclear protein asso-ciated with a DNA polymerase whose expression increases in phase G1 of the cell cycle, reaches its maximum at the G1/S inter-face, and then decreases through


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Surgery_Schwartz. is a nuclear protein asso-ciated with a DNA polymerase whose expression increases in phase G1 of the cell cycle, reaches its maximum at the G1/S inter-face, and then decreases through G2.186-189 Immunohistochemical staining for PCNA outlines the proliferating compartments in Brunicardi_Ch17_p0541-p0612.indd 57801/03/19 5:05 PM 579THE BREASTCHAPTER 17breast tissue. Good correlation is noted between PCNA expres-sion and (a) cell-cycle distributions seen on flow cytometry based on DNA content, and (b) uptake of bromodeoxyuridine and the proliferation-associated Ki67 antigen. Individual prolif-eration markers are associated with slightly different phases of the cell cycle and are not equivalent. PCNA and Ki67 expression are positively correlated with p53 overexpression, high S-phase fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer specimens, and are negatively cor-related with estrogen receptor content. Ki67 was included with three other


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Surgery_Schwartz. fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer specimens, and are negatively cor-related with estrogen receptor content. Ki67 was included with three other widely measured breast cancer markers (ER, PR, and HER2) into a panel of four immunohistochemical makers (IHC4), which together provided similar prognostic informa-tion to that in the 21 Gene Recurrence Score (Oncotype DX, Genomic Health).190 While there has been significant interest in using Ki67 as a biomarker, and while the IHC4 panel would be much less expensive than the 21 Gene Recurrence Score, there remain issues regarding reproducibility across laboratories.Indices of Angiogenesis. Angiogenesis is necessary for the growth and invasiveness of breast cancer and promotes cancer progression through several different mechanisms, including delivery of oxygen and nutrients and the secretion of growth-promoting cytokines by endothelial cells.191,192 VEGF induces its effect by binding to


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Surgery_Schwartz. through several different mechanisms, including delivery of oxygen and nutrients and the secretion of growth-promoting cytokines by endothelial cells.191,192 VEGF induces its effect by binding to transmembrane tyrosine kinase recep-tors. Overexpression of VEGF in invasive breast cancer is cor-related with increased microvessel density and recurrence in node-negative breast cancer. An angiogenesis index has been developed in which microvessel density (CD31 expression) is combined with expression of thrombospondin (a negative modulator of angiogenesis) and p53 expression. Both VEGF expression and the angiogenesis index may have prognostic and predictive significance in breast cancer.193 Bevacizumab (a monoclonal antibody to VEGF) was approved by the FDA for use in metastatic breast cancer in combination with pacli-taxel chemotherapy. This approval was based on results from a phase 3 trial by the Eastern Cooperative Oncology Group. The group’s E2100 trial showed that when bevacizumab was


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Surgery_Schwartz. combination with pacli-taxel chemotherapy. This approval was based on results from a phase 3 trial by the Eastern Cooperative Oncology Group. The group’s E2100 trial showed that when bevacizumab was added to paclitaxel chemotherapy, median progression-free survival increased to 11.3 months from the 5.8 months seen in patients who received paclitaxel alone.194 The results were not repro-duced in other trials, and the indication for the drug was revoked by the FDA in 2011.Indices of Apoptosis. Alterations in programmed cell death (apoptosis), which may be triggered by p53-dependent or p53-independent factors, may be important prognostic and pre-dictive biomarkers in breast cancer.195-197 Bcl-2 family proteins appear to regulate a step in the evolutionarily conserved pathway for apoptosis, with some members functioning as inhibitors of apoptosis and others as promoters of apoptosis. Bcl-2 is the only oncogene that acts by inhibiting apoptosis rather than by directly increasing cellular


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Surgery_Schwartz. with some members functioning as inhibitors of apoptosis and others as promoters of apoptosis. Bcl-2 is the only oncogene that acts by inhibiting apoptosis rather than by directly increasing cellular proliferation. The death-signal protein bax is induced by genotoxic stress and growth factor deprivation in the presence of wild-type (normal) p53 and/or AP-1/fos. The bax to bcl-2 ratio and the resulting formation of either bax-baxhomodimers, which stimulate apoptosis, or bax–bcl-2 het-erodimers, which inhibit apoptosis, represent an intracellular regulatory mechanism with prognostic and predictive implica-tions. In breast cancer, overexpression of bcl-2 and a decrease in the bax to bcl-2 ratio correlate with high histologic grade, the presence of axillary lymph node metastases, and reduced disease-free and overall survival rates. Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor response to chemotherapy, and decreased overall survival.The


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Surgery_Schwartz. disease-free and overall survival rates. Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor response to chemotherapy, and decreased overall survival.The remaining biomarkers and biologic targets listed ear-lier are still in preclinical testing, and clinical trials are evaluat-ing their importance in breast cancer for both prognostic and predictive purposes.Coexpression of Biomarkers. Selection of optimal therapy for breast cancer requires both an accurate assessment of prog-nosis and an accurate prediction of response to therapy. The breast cancer markers that are most important in determining therapy are estrogen receptor, progesterone receptor, and HER2/neu. Clinicians evaluate clinical and pathologic staging and the expression of estrogen receptor, progesterone receptor, and HER2/neu in the primary tumor to assess prognosis and assign therapy. Adjuvant! Online (http://www.adjuvantonline.com) is one of a number of programs available to


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Surgery_Schwartz. receptor, progesterone receptor, and HER2/neu in the primary tumor to assess prognosis and assign therapy. Adjuvant! Online (http://www.adjuvantonline.com) is one of a number of programs available to clinicians that incor-porates clinical and pathologic factors for an individual patient and calculates risk of recurrence and death due to breast cancer and then provides an assessment of the reduction in risk of recurrence that would be expected with the use of combination chemotherapy, endocrine therapy, or both of these. Adjuvant! Online was developed using information from the SEER data-base, the EBCTCG overview analyses, and results from other individual published trials.198 The website is updated and modi-fied as new information becomes available. Clinicopathologic factors are used to separate breast cancer patients into broad prognostic groups, and treatment decisions are made on this basis (Table 17-12). Other indices and programs that are vali-dated and used include the


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Surgery_Schwartz. used to separate breast cancer patients into broad prognostic groups, and treatment decisions are made on this basis (Table 17-12). Other indices and programs that are vali-dated and used include the Nottingham Prognostic Index, and PREDICT.199-201 When an approach, which combines prognostic factors is used, up to 70% of early breast cancer patients receive adjuvant chemotherapy that is either unnecessary or ineffective. As described earlier, a wide variety of biomarkers have been shown to individually predict prognosis and response to therapy, but they do not improve the accuracy of either the assessment of prognosis or the prediction of response to therapy.As knowledge regarding cellular, biochemical, and molec-ular biomarkers for breast cancer have improved, prognostic indices have been developed that combine the predictive power Table 17-12Traditional prognostic and predictive factors for invasive breast cancerTUMOR FACTORSHOST FACTORSNodal statusAgeTumor sizeMenopausal


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Surgery_Schwartz. have been developed that combine the predictive power Table 17-12Traditional prognostic and predictive factors for invasive breast cancerTUMOR FACTORSHOST FACTORSNodal statusAgeTumor sizeMenopausal statusHistologic/nuclear gradeFamily historyLymphatic/vascular invasionPrevious breast cancerPathologic stageImmunosuppressionHormone receptor statusNutritionDNA content (ploidy, S-phase fraction)Prior chemotherapyExtent of intraductal componentPrior radiation therapyHER2/neu expression Modified with permission from Ellis N: Inherited Cancer Syndromes. New York, NY: Springer-Verlag; 2004.Brunicardi_Ch17_p0541-p0612.indd 57901/03/19 5:05 PM 580SPECIFIC CONSIDERATIONSPART IITable 17-13Diagnostic studies for breast cancer patients CANCER STAGE 0IIIIIIIVHistory & physicalXXXXXComplete blood count, platelet count XXXLiver function tests and alkaline phosphatase level XXXChest radiograph XXXBilateral diagnostic mammograms, ultrasound as indicatedXXXXXHormone receptor statusXXXXXHER2/neu


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Surgery_Schwartz. platelet count XXXLiver function tests and alkaline phosphatase level XXXChest radiograph XXXBilateral diagnostic mammograms, ultrasound as indicatedXXXXXHormone receptor statusXXXXXHER2/neu expression XXXXBone scan XXAbdominal (without or without pelvis) computed tomographic scan or ultrasound or magnetic resonance imaging XXAbdominal imaging and bone scanning are indicated for evaluation of symptoms or abnormal laboratory test results at any presenting stage.Data from NCCN Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network, 2006.of several individual biomarkers with the relevant clinicopatho-logic factors.Recent technological advances have enabled implemen-tation of high throughput gene expression assays in clinical practice.202 These assays enable detailed stratification of breast cancer patients for assessment of prognosis and for predic-tion of response to therapy. The Oncotype DX is a 21-gene RT-PCR–based assay that has been


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Surgery_Schwartz. assays enable detailed stratification of breast cancer patients for assessment of prognosis and for predic-tion of response to therapy. The Oncotype DX is a 21-gene RT-PCR–based assay that has been approved for use in newly diagnosed patients with node-negative, ER-positive breast cancer.203 A recurrence score is generated, and those patients with high recurrence scores are likely to benefit from che-motherapy, whereas those with low recurrence scores benefit most from endocrine therapy and may not require chemother-apy. Results from the Trial Assessing Individualized Options for Treatment for breast cancer (TAILORx), designed to pro-spectively validate the use of 21-gene expression assay, have shown that patients with low recurrence score (0 to 10) have a low rate of local-regional and distant recurrence (98.7%) and very good overall survival at 5 years (98%) with endocrine therapy alone without chemotherapy.204 This study has ran-domly assigned patients with an intermediate


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Surgery_Schwartz. and distant recurrence (98.7%) and very good overall survival at 5 years (98%) with endocrine therapy alone without chemotherapy.204 This study has ran-domly assigned patients with an intermediate recurrence score (11 to 25) to endocrine therapy alone or to chemotherapy fol-lowed by endocrine therapy.Additionally, retrospective analysis has shown that the 21-gene recurrence score can be used in postmenopausal patients with ER-positive tumors and 1 to 3 involved axillary lymph nodes to predict the benefit of chemotherapy in addition to endocrine therapy.205 Knowledge of the recurrence score has been shown to alter treatment recommendations by oncologists, and patients likewise change their decision to undergo treatment based on the risk of recurrence.206 The MammaPrint assay uses a 70-gene expression profile to assess the risk of distant metas-tasis. Mammaprint is FDA approved for use in stage-1 or stage-2, node negative, ER-positive or ER-negative breast cancers to identify patients


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Surgery_Schwartz. expression profile to assess the risk of distant metas-tasis. Mammaprint is FDA approved for use in stage-1 or stage-2, node negative, ER-positive or ER-negative breast cancers to identify patients with high or low risk of recurrence. Although fresh tissue was initially required to perform the assay, it has since been adapted for use in paraffin-embedded tissue sam-ples. The prospective RASTER study reported that patients classified as low risk based on MammaPrint had a 97% distant recurrence-free interval at five years.207 Results of the prospec-tive MINDACT (MicroarrayInNode negative and 1–3 positive lymph node Disease may Avoid ChemoTherapy) trial were recently reported.208 The study was designed to assess whether the 70-gene expression assay would help avoid chemotherapy in patients who are considered clinically high risk but categorized as low genomic risk based on the assay. A 5-year rate of distant metastasis-free survival of more than 92% was identified as the cutoff for the


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Surgery_Schwartz. who are considered clinically high risk but categorized as low genomic risk based on the assay. A 5-year rate of distant metastasis-free survival of more than 92% was identified as the cutoff for the benefit of chemotherapy. At 5 years, the rate of survival without distant metastasis in patients with high clinical risk and low genomic risk was 94.7%, meeting the criteria for noninferiority. However, the rate of disease-free survival and overall survival was higher with chemotherapy in the intention to treat population.OVERVIEW OF BREAST CANCER THERAPYBefore diagnostic biopsy, the surgeon must consider the possi-bility that a suspicious mass or mammographic finding may be a breast cancer. Once a diagnosis of breast cancer is made, the type of therapy offered to a breast cancer patient is determined by the stage of the disease, the biologic subtype, and the general health status of the individual. Laboratory tests and imaging studies are performed based on the initial stage as presented


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Surgery_Schwartz. by the stage of the disease, the biologic subtype, and the general health status of the individual. Laboratory tests and imaging studies are performed based on the initial stage as presented in Table 17-13. Before therapy is initiated, the patient and the sur-geon must share a clear perspective on the planned course of treatment. Before initiating local therapy, the surgeon should determine the clinical stage, histologic characteristics, and appropriate biomarker levels.In Situ Breast Cancer (Stage 0)Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from cancers with early invasion.60,209-214 Expert pathologic review is required in all cases. Bilateral mammography is performed to determine the extent of the in situ cancer and to exclude a second cancer. Because LCIS is considered a marker for increased risk rather than an inevitable precursor of invasive disease, the current treatment options for LCIS include observation, chemoprevention, and bilateral


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Surgery_Schwartz. LCIS is considered a marker for increased risk rather than an inevitable precursor of invasive disease, the current treatment options for LCIS include observation, chemoprevention, and bilateral total mastectomy. The goal of treatment is to prevent or detect at an early stage the invasive cancer that subsequently develops in 25% to 35% of these women. There is no benefit to excis-ing LCIS because the disease diffusely involves both breasts in many cases and the risk of developing invasive cancer is equal for both breasts. The use of tamoxifen as a risk-reduction strat-egy should be considered in women with a diagnosis of LCIS.Women with DCIS and evidence of extensive disease (>4 cm of disease or disease in more than one quadrant) usu-ally require mastectomy (Fig. 17-29). For women with lim-ited disease, lumpectomy and radiation therapy are generally recommended. For nonpalpable DCIS, needle localization or other image-guided techniques are used to guide the surgical resection.


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Surgery_Schwartz. with lim-ited disease, lumpectomy and radiation therapy are generally recommended. For nonpalpable DCIS, needle localization or other image-guided techniques are used to guide the surgical resection. Specimen mammography is performed to ensure that all visible evidence of cancer is excised. Adjuvant tamoxi-fen therapy is considered for DCIS patients with ER-positive 8Brunicardi_Ch17_p0541-p0612.indd 58001/03/19 5:05 PM 581THE BREASTCHAPTER 17ABFigure 17-29. Extensive DCIS seen on mammography. A. Exten-sive calcifications are seen throughout the breast on this cranial caudal view. B. Magnification view of calcifications. Due to the extent of the disease the patient is not a good candidate for breast conserving surgery. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)disease. The gold standard against which breast conservation therapy for DCIS is evaluated is mastectomy. Women treated with mastectomy


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Surgery_Schwartz. of Breast Screening, Royal Derby Hospital, Derby, UK.)disease. The gold standard against which breast conservation therapy for DCIS is evaluated is mastectomy. Women treated with mastectomy have local recurrence and mortality rates of <2%. There is no randomized trial comparing mastectomy vs. breast conserving surgery, and none of the randomized trials of breast-conserving surgery with or without radiotherapy for DCIS were powered to show a difference in mortality. Women treated with lumpectomy and adjuvant radiation therapy in the initial clinical trials were noted to have a local recurrence rate that is increased compared to mastectomy. About 45% of these recurrences will be invasive cancer when radiation therapy is not used. The B-17 trial was conducted by the NSABP to assess the need for radiation in patients treated with breast conserv-ing surgery for DCIS.215 Patients were randomly assigned to lumpectomy with radiation or lumpectomy alone, and after a mean follow-up time of 90


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Surgery_Schwartz. for radiation in patients treated with breast conserv-ing surgery for DCIS.215 Patients were randomly assigned to lumpectomy with radiation or lumpectomy alone, and after a mean follow-up time of 90 months rates of both ipsilateral noninvasive and invasive recurrences were significantly lower in patients who received radiation. However, in the B-17 trial the margins were not prospectively assessed, and it is estimated that up to half of the patients may have had tumor at the mar-gin of resection. The benefit of the addition of radiation over breast-conserving surgery alone for DCIS has also been dem-onstrated in several other randomized trials where margins were prospectively assessed including the European Organization for Research and Treatment of Cancer (EORTC) protocol 10853; the United Kingdom, Australia, New Zealand DCIS Trial; and the Swedish Trial.209,216-218 In 2016, the Society of Surgi-cal Oncology (SSO), American Society for Radiation Oncol-ogy (ASTRO), and the American


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Surgery_Schwartz. Kingdom, Australia, New Zealand DCIS Trial; and the Swedish Trial.209,216-218 In 2016, the Society of Surgi-cal Oncology (SSO), American Society for Radiation Oncol-ogy (ASTRO), and the American Society of Clinical Oncology (ASCO) established consensus guidelines on margins for patients with DCIS undergoing breast-conserving surgery.219 Based on a multidisciplinary consensus panel using a meta-analysis of margin width and ipsilateral breast tumor recur-rence, a 2-mm margin was determined as adequate width for DCIS for patients undergoing breast-conserving surgery with whole-breast radiation therapy.219Despite the data from randomized trials showing a benefit in all patient subgroups with the addition of radiation in DCIS, there has been an interest in trying to define a subset where radiation could be avoided in order to minimize the cost and inconvenience associated with radiation. In addition, there have been several studies published where patients were treated with excision alone


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Surgery_Schwartz. could be avoided in order to minimize the cost and inconvenience associated with radiation. In addition, there have been several studies published where patients were treated with excision alone and never developed invasive breast cancer even at 25 years of follow-up. Silverstein and colleagues were pro-ponents of avoiding radiation therapy in selected patients with DCIS who have widely negative margins after surgery.213 They reported that when greater than 10-mm margins were achieved, there was no additional benefit from radiation therapy. When margins were between 1 and 10 mm, there was a relative risk of local recurrence of 1.49, compared to 2.54 for those with margins less than 1 mm. These data suggested that appropri-ately selected patients with DCIS might not require postopera-tive radiation therapy.The Eastern Cooperative Oncology Group (ECOG) initi-ated a prospective registry trial (ECOG 5194) to identify those patients who could safely undergo breast-conserving surgery


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Surgery_Schwartz. radiation therapy.The Eastern Cooperative Oncology Group (ECOG) initi-ated a prospective registry trial (ECOG 5194) to identify those patients who could safely undergo breast-conserving surgery without radiation.222 Eligible patients were those with low or intermediate grade DCIS measuring 2.5 cm or less who had negative margins of at least 3 mm and those with high-grade DCIS who had tumors measuring 1 cm or less with a negative margin of at least 3 mm. At a median follow-up of 6.2 years, patients with low or intermediate grade DCIS had an in-breast Brunicardi_Ch17_p0541-p0612.indd 58101/03/19 5:05 PM 582SPECIFIC CONSIDERATIONSPART IIrecurrence rate of 6.1% while those with high-grade DCIS had a recurrence rate of 15.3%. Approximately 4% of patients developed a contralateral breast cancer during follow-up in both the low/intermediate and high-grade groups. This study identi-fied an acceptable recurrence rate for those patients with low or intermediate grade DCIS treated with


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Surgery_Schwartz. cancer during follow-up in both the low/intermediate and high-grade groups. This study identi-fied an acceptable recurrence rate for those patients with low or intermediate grade DCIS treated with excision alone with a margin of at least 3 mm. In contrast, patients with high-grade DCIS had an unacceptably high local recurrence rate.The Radiation Therapy Oncology Group (RTOG) initi-ated the 9804 trial for patients with “good risk” DCIS and randomized them to lumpectomy vs. lumpectomy with whole breast irradiation. Eligible patients were those with unicentric, low or intermediate grade DCIS measuring 2.5 cm or less with a margin of 3 mm or greater. The trial was closed early due to slow accrual; however, the results for 585 patients were recently reported with a median follow-up of 6.46 years.223,224 The local recurrence rate at 5 years was 0.4% for patients ran-domized to receive radiation and 3.2% for those who did not receive radiation.Solin et al utilized samples from the ECOG 5194


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Surgery_Schwartz. The local recurrence rate at 5 years was 0.4% for patients ran-domized to receive radiation and 3.2% for those who did not receive radiation.Solin et al utilized samples from the ECOG 5194 trial to develop a quantitative multigene RT-PCR assay for predict-ing recurrence risk in patients with DCIS treated with surgery alone.201 They were able to define low, intermediate, and high risk groups using a DCIS Score. The DCIS Score was able to quantify the risk of recurrence in the breast for both DCIS and invasive events. This tool has recently been evaluated in another dataset and appears to be a promising tool for clinical use.225 When selecting therapy for patients with DCIS, one must con-sider clinical and pathologic factors, including tumor size, grade, mammographic appearance, and patient preference. There is no single correct surgical treatment, and many patients will require extensive counseling in order to make a decision regarding sur-gical therapy. The role of axillary staging in


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Surgery_Schwartz. preference. There is no single correct surgical treatment, and many patients will require extensive counseling in order to make a decision regarding sur-gical therapy. The role of axillary staging in patients with DCIS is limited. One consideration is for patients undergoing mastec-tomy. Since most lesions are currently diagnosed with needle core biopsy, there is about a 20% incidence of invasive breast cancer on final pathologic assessment of the primary tumor. Since it is not feasible to perform sentinel node dissection after mastectomy, most surgeons will recommend the use of sentinel node dissection at the time of mastectomy for DCIS.Results from the NSABP B-24 trial reported a signifi-cant reduction in local recurrence after 5 years of tamoxifen in women with ER-positive DCIS. Based on this finding, some guidelines have advocated that all patients (women with ER-positive DCIS without contraindications to tamoxifen therapy) should be offered tamoxifen following surgery and


Surgery_Schwartz

Surgery_Schwartz. Based on this finding, some guidelines have advocated that all patients (women with ER-positive DCIS without contraindications to tamoxifen therapy) should be offered tamoxifen following surgery and radiation therapy for a duration of 5 years. The B-24 trial revealed a sig-nificant reduction in recurrence with adjuvant tamoxifen therapy for patients with DCIS; however, the results were not initially assessed based on ER status.226 There were 1804 women with DCIS randomized to lumpectomy and radiation with or without tamoxifen. The rate of breast cancer events was significantly lower in those who received tamoxifen at a median follow-up of 74 months (8.2% vs. 13.4%, P = 0.0009). Subsequently, Allred and colleagues evaluated 41% of patients with DCIS in the NSABP B-24 trial to determine the effect of tamoxifen based on ER status measured in the primary tumor.203 They found that 76% of women had DCIS that was ER-positive and these women had a greater reduction in ipsilateral breast tumor


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Surgery_Schwartz. effect of tamoxifen based on ER status measured in the primary tumor.203 They found that 76% of women had DCIS that was ER-positive and these women had a greater reduction in ipsilateral breast tumor recur-rence with tamoxifen than did patients with ER-negative DCIS (11% vs. 5.2%, P <0.001). However, it should be noted that 15% of patients in B-24 had tumor at the resection margins. For these patients, tamoxifen could be viewed as treating what, by the current standard, would be viewed as inadequate local exci-sion of the primary tumor.Early Invasive Breast Cancer (Stage I, IIA, or IIB)There have been six prospective randomized trials comparing breast-conserving surgery to mastectomy in early stage breast cancer, and all have shown equivalent survival rates regardless of the surgical treatment type. One caveat, however, is that the majority of studies had a restriction of tumor size; most were either 2 cm or 2.5 cm, while the NSABP B-06 trial was 4 cm, and the NCI trial was up to 5


Surgery_Schwartz

Surgery_Schwartz. type. One caveat, however, is that the majority of studies had a restriction of tumor size; most were either 2 cm or 2.5 cm, while the NSABP B-06 trial was 4 cm, and the NCI trial was up to 5 cm. NSABP B-06, which is the largest of all the breast conservation trials, compared total mastectomy to lumpectomy with or without radiation therapy in the treatment of women with stages I and II breast cancer.227-233 After 5and 8-year follow-up periods, the disease-free (DFS), distant dis-ease-free, and overall survival (OS) rates for lumpectomy with or without radiation therapy were similar to those observed after total mastectomy. However, the incidence of ipsilateral breast cancer recurrence was higher in the group not receiving radia-tion therapy. These findings supported the use of lumpectomy and radiation therapy in the treatment of stages I and II breast cancer and this has since become the preferred method of treat-ment for women with early stage breast cancer who have uni-focal disease


Surgery_Schwartz

Surgery_Schwartz. radiation therapy in the treatment of stages I and II breast cancer and this has since become the preferred method of treat-ment for women with early stage breast cancer who have uni-focal disease and who are not known BRCA mutation carriers. Reanalysis of the B-06 study results was undertaken after 20 years of follow-up and confirmed that there was no differ-ence in disease-free survival rates after total mastectomy or after lumpectomy with or without adjuvant radiation therapy. The in-breast recurrence rate was substantially higher in the lumpec-tomy alone group (39.2%) compared with the lumpectomy plus adjuvant radiation therapy group (14.3%), confirming the importance of radiation therapy in the management of patients with invasive disease. However, it should be noted that there were several criteria in the B-06 study. There was a specific lymphadenopathy exclusion criteria. Secondly, all patients ran-domized to breast-conserving surgery had a frozen section, and if the margins


Surgery_Schwartz

Surgery_Schwartz. several criteria in the B-06 study. There was a specific lymphadenopathy exclusion criteria. Secondly, all patients ran-domized to breast-conserving surgery had a frozen section, and if the margins were involved, they were converted to mastec-tomy but were included in the analysis as having had a breast-conserving operation (on the basis of intention to treat). Finally, in the breast-conserving group recurrences in the treated breast were considered as a “nonevent.”Data from all of the randomized trials where breast con-servation was performed with or without radiation therapy have been examined by the EBCTCG.12 At 15 years of follow-up, the absolute reduction in mortality with the use of radiation therapy after lumpectomy was 5.1% in node-negative patients and 7.1% in node-positive patients. These data support the concept that the addition of radiation not only improves local control but also has an impact on survival. Similar to DCIS, clinicians have sought to identify subgroups of


Surgery_Schwartz

Surgery_Schwartz. These data support the concept that the addition of radiation not only improves local control but also has an impact on survival. Similar to DCIS, clinicians have sought to identify subgroups of patients who may not benefit from the addition of radiation therapy, particularly older patients who may have a shorter life expectancy due to medical comor-bidities. Randomized trials have shown that in selected patients with small, ER-positive, low-grade tumors, lumpectomy alone without radiation therapy may be appropriate.211,212 The Cancer and Leukemia Group B (CALGB) C9343 trial enrolled women over the age of 70 with T1N0 breast cancer and randomized them to lumpectomy with or without radiation therapy. All patients received adjuvant tamoxifen.233a At 5 years, although Brunicardi_Ch17_p0541-p0612.indd 58201/03/19 5:05 PM 583THE BREASTCHAPTER 17there were fewer local recurrences with radiation (1% vs. 4%, P <0.001), there were no differences in DFS and OS. While long-term follow-up at


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Surgery_Schwartz. 58201/03/19 5:05 PM 583THE BREASTCHAPTER 17there were fewer local recurrences with radiation (1% vs. 4%, P <0.001), there were no differences in DFS and OS. While long-term follow-up at 10 years showed fewer local recurrences with radiation (2% vs. 10%), there were no significant differ-ences in time to distant metastasis, breast cancer–specific sur-vival, or OS between the two groups. A trial similar to CALGB C9343 was conducted in Canada where they enrolled women age 50 years and older and randomized them to lumpectomy with or without radiation. Mean age was 68 years, and 80% of women had ER-positive tumors. Again, local recurrence rates were lower in women who received radiation (0.6% vs. 7.7%, P <0.001); however, at a median follow-up of 5.6 years, there were no differences in DFS or OS. The PRIME-2 study enrolled women age 65 years or older with ER-positive, node-negative, up to 3 cm breast cancers, who had undergone breast-conserving surgery and were candidates for adjuvant


Surgery_Schwartz

Surgery_Schwartz. or OS. The PRIME-2 study enrolled women age 65 years or older with ER-positive, node-negative, up to 3 cm breast cancers, who had undergone breast-conserving surgery and were candidates for adjuvant endocrine treatment. They were assigned to receive whole-breast irradiation or no treatment. After a median follow-up of 5 years, ipsilateral breast tumor recurrence was 1.3% with radiation vs. 41% in those assigned to no radiotherapy. However, no differences in distant metastases, contralateral breast cancers, or overall survival were noted between the groups.234 These studies suggest that radia-tion can be avoided in select older patients with ER-positive, early-stage breast cancer.Accelerated partial breast irradiation (APBI) is also an option for carefully selected patients with DCIS and early-stage breast cancer. Since the majority of recurrences after breast conservation occur in or adjacent to the tumor bed, there has been interest in limiting the radiation to the area of the


Surgery_Schwartz

Surgery_Schwartz. and early-stage breast cancer. Since the majority of recurrences after breast conservation occur in or adjacent to the tumor bed, there has been interest in limiting the radiation to the area of the primary tumor bed with a margin of normal tissue. APBI is delivered in an abbreviated fashion (twice daily for 5 days) and at a lower total dose compared with the standard course of 5 to 6 weeks of radiation (50 Gy with or without a boost) in the case of whole breast irradiation. Proponents have suggested that this shortened course of treatment may increase the feasibility of breast con-servation for some women and may improve radiation therapy compliance. The RTOG 04-13/NSABP B-39 trial is a random-ized comparison of whole breast irradiation to APBI in women with early stage breast cancer. The trial has completed accrual, and it will likely be several years before data are mature to report outcomes between the two radiation treatment strategies. TARGIT is another study that randomized


Surgery_Schwartz

Surgery_Schwartz. The trial has completed accrual, and it will likely be several years before data are mature to report outcomes between the two radiation treatment strategies. TARGIT is another study that randomized 3451 patients in 33 centers in over 10 countries to intraoperative breast irradiation (IORT) or external beam radiotherapy (EBRT). The prelimi-nary results were reported in 2012: with a median follow-up of 2.4 years, use of IORT had a recurrence rate of 3.3% vs. 1.3% with EBRT, a 2% increased recurrence risk.235,236 ASTRO developed guidelines for the use of APBI outside of clinical trials based on data reported from published studies.237,238 The ASTRO guidelines describe patients “suitable” for APBI to include women age 60 years or older with a unifocal, T1, ER-positive tumor with no lymphovascular invasion and margins of at least 2 mm. They describe a group where there is uncer-tainty about the appropriateness of APBI (“cautionary” group) to include patients with invasive lobular


Surgery_Schwartz

Surgery_Schwartz. invasion and margins of at least 2 mm. They describe a group where there is uncer-tainty about the appropriateness of APBI (“cautionary” group) to include patients with invasive lobular histology, a tumor size of 2.1 cm to 3 cm, ER-negative disease, focal lymphovascular invasion, or margins less than 2 mm. Finally, a group felt to be “unsuitable” for APBI includes those with T3 or T4 disease, ER-negative disease, multifocality, multicentricity, extensive LVI, or positive margins.Currently, mastectomy with axillary staging and breast conserving surgery with axillary staging and radiation therapy are considered equivalent treatments for patients with stages I and II breast cancer. Breast conservation is considered for all patients because of the important cosmetic advantages and equivalent survival outcomes; however, this approach is not advised in women who are known BRCA mutation carriers due to the high lifetime risk for development of additional breast cancers. Relative


Surgery_Schwartz

Surgery_Schwartz. equivalent survival outcomes; however, this approach is not advised in women who are known BRCA mutation carriers due to the high lifetime risk for development of additional breast cancers. Relative contraindications to breast conserva-tion therapy include (a) prior radiation therapy to the breast or chest wall, (b) persistently positive surgical margins after reex-cision, (c) multicentric disease, and (d) scleroderma or lupus erythematosus.For most patients with early-stage disease, reconstruc-tion can be performed immediately at the time of mastectomy. Immediate reconstruction allows for skin-sparing, thus optimiz-ing cosmetic outcomes. Skin-sparing mastectomy with immedi-ate reconstruction has been popularized over the past decade as reports of low local-regional failure rates have been reported and reconstructive techniques have advanced. There is a grow-ing interest in the use of nipple-areolar sparing mastectomy with reports suggesting the oncologic safety of this approach in


Surgery_Schwartz

Surgery_Schwartz. reported and reconstructive techniques have advanced. There is a grow-ing interest in the use of nipple-areolar sparing mastectomy with reports suggesting the oncologic safety of this approach in early stage breast cancer. Patients who are planned for postmastec-tomy radiation therapy may not be ideal candidates for nipple-sparing mastectomy because of the effects of radiation on the preserved nipple. In addition to providing optimal cosmesis from preservation of the skin and/or the nipple-areolar complex, immediate reconstruction allows patients to wake up with a breast mound, which provides some psychological benefit for the patient. Immediate reconstruction is also more economical as both the extirpative and reconstructive surgery are combined in one operation.Immediate reconstruction can be performed using implants or autologous tissue; tissue flaps commonly used include the transverse rectus abdominis myocutaneous flap, deep inferior epigastric perforator flap, and latissimus


Surgery_Schwartz

Surgery_Schwartz. can be performed using implants or autologous tissue; tissue flaps commonly used include the transverse rectus abdominis myocutaneous flap, deep inferior epigastric perforator flap, and latissimus dorsi flap (with or without an implant). If postmastectomy radiation therapy is needed, a tissue expander can be placed at the time of mastec-tomy to save the shape of the breast and reduce the amount of skin replacement needed at the time of definitive reconstruc-tion. The expander can be deflated at the initiation of radiation therapy to allow for irradiation of the chest wall and regional nodal basins. Removal of the tissue expander and definitive reconstruction, usually with autologous tissue, can proceed 6 months to 1 year after completion of radiation therapy.Axillary lymph node status has traditionally been an important determinant in staging and prognosis for women with early stage breast cancer. Historically, axillary lymph node dis-section (ALND) was utilized for axillary staging


Surgery_Schwartz

Surgery_Schwartz. traditionally been an important determinant in staging and prognosis for women with early stage breast cancer. Historically, axillary lymph node dis-section (ALND) was utilized for axillary staging and regional control by removing involved lymph nodes. Randomized tri-als evaluating immediate ALND over ALND performed in a delayed fashion once clinically palpable axillary disease became evident have not shown any detriment in survival.9,239 With increased mammographic screening and detection of smaller, node-negative breast cancers, it became clear that routine use of ALND for axillary staging was not necessary in up to 75% percent of women with operable breast cancer presenting with a negative axilla at the time of screening. Lymphatic mapping and sentinel lymph node (SLN) dissection were initially devel-oped for assessment of patients with clinically node-negative melanoma. Given the changing landscape of newly diagnosed breast cancer patients with a clinically node-negative axilla,


Surgery_Schwartz

Surgery_Schwartz. initially devel-oped for assessment of patients with clinically node-negative melanoma. Given the changing landscape of newly diagnosed breast cancer patients with a clinically node-negative axilla, sur-geons quickly began to explore the utility of SLN dissection as a replacement for ALND in axillary staging.Brunicardi_Ch17_p0541-p0612.indd 58301/03/19 5:05 PM 584SPECIFIC CONSIDERATIONSPART IIIn the early 1990s, David Krag at the University of Vermont began performing SLN dissection with injection of a radioisotope in the primary tumor site and localizing the SLN node with a handheld gamma probe.240 He was able to identify a SLN in 18 of 22 patients examined, and the SLN was posi-tive in all 7 patients with positive lymph nodes. Giuliano and colleagues initiated a pilot study in 1991 to examine the use of SLN dissection using blue dye in patients with clinically nega-tive nodes. They reported successful identification of a SLN in 114 (65.5%) of 174 patients, and in 109 (95.6%),


Surgery_Schwartz

Surgery_Schwartz. to examine the use of SLN dissection using blue dye in patients with clinically nega-tive nodes. They reported successful identification of a SLN in 114 (65.5%) of 174 patients, and in 109 (95.6%), the SLN accurately predicted the status of the axillary nodes.241,242 These studies along with initial work by Doug Reintgen and Charles Cox at the Moffitt Cancer Center and Umberto Veronesi and his colleagues at the European Institute of Oncology in Milan led the way toward validation of the technique in large single institution and multicenter studies.Following validation of the technique of SLN dissection for staging of the axilla by multiple centers, randomized tri-als were initiated in order to determine if SLN dissection could replace ALND in the contemporary management of breast cancer patients. The ALMANAC trial randomized 1031 patients with primary operable breast cancer to SLN dissection vs. standard axillary surgery. The incidence of lymphedema and sensory loss for the SLN group


Surgery_Schwartz

Surgery_Schwartz. The ALMANAC trial randomized 1031 patients with primary operable breast cancer to SLN dissection vs. standard axillary surgery. The incidence of lymphedema and sensory loss for the SLN group was significantly lower than with the standard axillary treatment. At 12 months, drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were also statistically significantly lower in the SLN group.221The NSABP B-32 trial compared clinically node-negative patients undergoing SLN dissection followed by ALND with patients undergoing SLN dissection with ALND only if a SLN was positive for metastatic disease.243 A total of 5611 patients were randomized with a SLN identification rate of 97% and a false-negative rate of 9.7%. A total of 26% of these clini-cally node-negative patients had a positive SLN. Over 60% of patients with positive SLNs had no additional positive lymph nodes within the ALND specimen. The B-32 trial and other randomized trials


Surgery_Schwartz

Surgery_Schwartz. node-negative patients had a positive SLN. Over 60% of patients with positive SLNs had no additional positive lymph nodes within the ALND specimen. The B-32 trial and other randomized trials demonstrated no difference in DFS, OS, and local-regional recurrence rates between patients with negative SLNs who had SLN dissection alone compared with those who underwent ALND.244,245 Most important, patients who had SLN dissection alone were found to have decreased morbidity (arm swelling and range of motion) and improved quality of life vs. patients who underwent ALND.245,246The American College of Surgeons Oncology Group (ACOSOG) initiated the Z0010 and Z0011 trials in order to evaluate the incidence and prognostic significance of occult metastases identified in the bone marrow and SLNs (Z0010) of early-stage clinically node-negative patients and to evaluate the utility of ALND in patients with clinical T1-2, N0 breast cancer with 1 or 2 positive SLNs for patients treated with


Surgery_Schwartz

Surgery_Schwartz. SLNs (Z0010) of early-stage clinically node-negative patients and to evaluate the utility of ALND in patients with clinical T1-2, N0 breast cancer with 1 or 2 positive SLNs for patients treated with breast-conserving surgery and whole breast irradiation (WBI) (Z0011).247,248The Z0010 study enrolled 5539 patients with clinical T1-2 breast cancer planned for breast conserving surgery and WBI.247 Of these patients, 24% proved to have positive SLNs based on standard pathologic assessment, and of the negative SLNs sub-jected to immunohistochemical staining for cytokeratin, 10.5% proved to have occult metastasis. Of the patients who had bone marrow aspiration, 3.0% had immunohistochemically detected tumor cells in the bone marrow. Although the presence of dis-ease in the bone marrow identified a population at high risk for recurrence, neither immunohistochemical detection of disease in the SLNs or the bone marrow was statistically significant on multivariable analysis with clinicopathologic


Surgery_Schwartz

Surgery_Schwartz. population at high risk for recurrence, neither immunohistochemical detection of disease in the SLNs or the bone marrow was statistically significant on multivariable analysis with clinicopathologic and treatment factors included. The investigators concluded that routine use of immunohistochemistry to detect occult disease in SLNs is not warranted.The Z0011 trial was a companion study to Z0010 and was designed to study the role of completion ALND on survival in women with positive SLNs. Patients were not eligible if they received neoadjuvant chemotherapy or neoadjuvant hormonal therapy or if their treatment plan included mastectomy, lumpec-tomy without radiation, or lumpectomy with APBI. WBI was to be administered using standard tangential fields without specific treatment of the axilla or additional fields targeting other nodal basins. Patients with 1 or 2 positive SLNs were randomized to completion ALND or no further surgery. Adjuvant systemic therapy recommendations were left to


Surgery_Schwartz

Surgery_Schwartz. or additional fields targeting other nodal basins. Patients with 1 or 2 positive SLNs were randomized to completion ALND or no further surgery. Adjuvant systemic therapy recommendations were left to the treating clinicians. After median follow-up of 6.3 years, there was no difference between patients randomized to ALND and those randomized to no further surgery (SLN only) in terms of OS (91.9% and 92.5%, respectively; P = 0.25) or DFS (82.2% and 83.8%, respectively; P = 0.14). The low local regional failure rates and similar survival outcomes were recently reported with 10-year follow-up.249,250The morbidity of SLN dissection alone vs. SLN dissec-tion with completion ALND has been reported by the ACOSOG investigators.251,252 Immediate effects of SLN dissection in the Z0010 trial included wound infection in 1%, axillary seroma in 7.1%, and axillary hematoma in 1.4%.251 At 6 months following surgery, axillary paresthesias were noted in 8.6% of patients, decreased range of motion in the


Surgery_Schwartz

Surgery_Schwartz. wound infection in 1%, axillary seroma in 7.1%, and axillary hematoma in 1.4%.251 At 6 months following surgery, axillary paresthesias were noted in 8.6% of patients, decreased range of motion in the upper extremity was reported in 3.8%, and 6.9% of patients had a change in the arm circum-ference of >2 cm on the ipsilateral side, which was reported as lymphedema. Younger patients were more likely to report paresthesias, whereas increasing age and body mass index were more predictive of lymphedema. When adverse surgical effects were examined in the Z0011 trial, patients undergoing SLN dissection with ALND had more wound infections, seromas, and paresthesias than those women undergoing SLN dissec-tion alone. Lymphedema at 1 year after surgery was reported by 13% in the SLN plus ALND group but only 2% in the SLN dissection alone group. Arm circumference measurements were greater at 1 year in patients undergoing SLN dissection plus ALND, but the difference between study groups was not


Surgery_Schwartz

Surgery_Schwartz. but only 2% in the SLN dissection alone group. Arm circumference measurements were greater at 1 year in patients undergoing SLN dissection plus ALND, but the difference between study groups was not statisti-cally significant.252 This supports the results published from the ALMANAC trial.Prior to the publication of ACOSOG Z0011, completion ALND was standard of care for patients with positive SLNs. Since the reporting of ACOSOG Z0011, the National Com-prehensive Cancer Network (NCCN) guidelines now state that there was no OS difference for patients with 1 or 2 positive SLNs treated with breast-conserving surgery who underwent completion ALND vs. those who had no further axillary sur-gery. In addition, the American Society of Breast Surgeons issued a consensus statement supporting omission of ALND for patients who meet Z0011 criteria.253 The results of ACOSOG Z0011 have revolutionized management of the axilla and changed practice such that selected patients with axillary metas-tasis can


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Surgery_Schwartz. ALND for patients who meet Z0011 criteria.253 The results of ACOSOG Z0011 have revolutionized management of the axilla and changed practice such that selected patients with axillary metas-tasis can now avoid ALND if they have clinical and pathologic features similar to those patients enrolled on Z0011. However, there have been some concerns raised about the Z0011 study that include the fact that the study only recruited about half of Brunicardi_Ch17_p0541-p0612.indd 58401/03/19 5:05 PM 585THE BREASTCHAPTER 17the intended patients and that there was no standardization of whether or not patients received irradiation to the low axilla when the radiation oncologist irradiated the breast. These issues have thus far limited the uptake of the results of Z0011 by some centers.The International Breast Cancer Study Group (IBCSG) 23-01 trial was similar in design to Z0011 but enrolled only patients with micrometastases in the SLNs. Patients with SLN micrometastases were randomized to ALND