Standards for diagnosis and management of invasive breast carcinoma. American College of Radiology. American College of Surgeons. College of American Pathologists. Society of Surgical Oncology
Authors: D. P. Winchester, J. D. Cox
Journal: CA A Cancer Journal for Clinicians (1998)

The establishment of standards of care for medical treatment is a process of building consensus by using the best available scientific evidence. For many years, representatives of the American College of Surgeons, the American College of Radiology, and the College of American Pathologists have surveyed practices throughout the United States to document patterns of medical care, to track changes in patterns over time, and to relate patterns to patient outcomes. As the treatment of patients with cancer progressively has become multi-disciplinary, studies of patterns of care have become more complex. The three Colleges, the American Cancer Society, and the Society of Surgical Oncology have attempted to promote better and more consistent care of cancer patients. Representatives of these groups first met in 1992 to begin the long process of describing standard practice in one specific area, breast-conservation treatment. The meetings and the resulting guidelines were considered only a point of departure from which to involve other disciplines within medicine, to educate patients, and to establish a framework for developing guidelines for the multidisciplinary management of other types of cancer. Because knowledge has advanced in a variety of fields related to the treatment of early breast cancer, revising these documents is appropriate. The document published in 1992 focused on the treatment of invasive carcinoma of the breast.1 The increased use of and improvements in mammographic technology have resulted in a marked increase in the diagnosis of ductal carcinoma in situ (DCIS). The body of knowledge about DCIS that has developed required a separate treatment of this subject in a companion document, "Standards for Diagnosis and Management of Ductal Carcinoma in Situ (DCIS) of the Breast" published in this issue of CA on pages 108–128.1a Mastectomy (either radical or modified radical) was the historical mainstay of the treatment of stage I and stage II breast cancer for decades. Although mastectomy continues to be appropriate for some patients, breast conservation has become the preferred method of treatment for many patients. The results of prospective randomized trials and the results of large retrospective nonrandomized studies from single institutions have shown that mastectomy and breast-conservation treatment are equally effective for appropriately selected patients with early-stage breast cancer. Six modern prospective randomized trials have compared mastectomy with conservative surgery and radiation for stage I and II breast cancer (Table 1). Whole breast irradiation with doses of 45 to 50 Gy was used in all of the trials, and a boost to the primary site was employed in five of the six trials. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial, a dose of 50 Gy was delivered to the entire breast without a boost. This trial required histologically negative margins of resection for patients undergoing conservative surgery and radiation. For the remaining five trials, the total dose to the primary site was 60 Gy or more. The published results of these trials are presented in Tables 2 and 3. At a follow-up of up to 18 years, none of the trials show significant differences in overall or disease-free survival with either treatment. In particular, survival has not been found to improve in patients with histologically positive nodes treated with mastectomy and chemotherapy in either the Milan I trial or the NSABP B-06 trial.2, 3 The Milan I trial showed a survival benefit that was not statistically significant in axillary node-positive patients treated with quadrantectomy and radiotherapy compared with radical mastectomy.3 In five of the six randomized trials, no significant difference was seen in the risk of a recurrence in the treated breast or chest wall after mastectomy. In the National Cancer Institute (NCI) trial, a significantly higher local failure rate was observed in the breast-conservation group. However, in this trial, only gross tumor removal was required for study entry. Local recurrence after breast preservation may be the result of inappropriate patient selection, inadequate surgery or radiation therapy, or biologically aggressive disease. Inadequate surgery may have contributed to the increased risk of breast recurrence in the NCI trial. Overall, the incidence of recurrence in the treated breast ranges from 3% to 19% (Table 3). Most failures in the treated breast can be salvaged with mastectomy, and survival after such treatment is approximately 70% at 5 years.4-5 As shown in Table 3, primary mastectomy does not guarantee freedom from local recurrence in stage I and II breast cancer. The incidence of chest wall recurrence after mastectomy ranges from 4% to 14%. The desire to avoid local recurrence is not a reason to encourage a patient who otherwise is a good candidate for breast conservation to choose mastectomy, because the procedures are associated with an equal risk of local failure. Nine prospective randomized trials comparing conservative surgery and radiation with mastectomy recently underwent meta-analysis.6 No survival differences were found in seven of these trials. Local recurrence was reported in 6.2% of the mastectomized patients and 5.9% of the patients treated with breast conservation.6 The randomized trials also have addressed the issue of a second malignancy related to radiation. No difference was seen in the incidence of contralateral breast cancer or that of a second malignancy that was not breast cancer. In addition to the randomized trials comparing breast conservation consisting of excision and radiation with mastectomy, six randomized trials have compared conservative surgery alone with conservative surgery and radiation. These trials are summarized in Tables 4 and 5. They vary regarding patient selection, the extent of surgery and radiotherapy, and the use of adjuvant systemic therapy. Quadrantectomy was used in the Milan and Swedish studies, and combination chemotherapy or tamoxifen was used in the NSABP, Milan, British, and Scottish trials. Despite these differences, all trials showed a reduction in the rate of recurrence in the breast in the irradiated group (an average crude rate of reduction of 84%, with a range of 73% to 97%). Most women who developed a recurrence in the breast after conservative surgery alone either required or desired mastectomy. Subset analyses within these trials have failed to identify consistently a group of patients who do not benefit from radiation. The results of multiple nonrandomized retrospective studies further support the equal effectiveness of breast-conservation treatment and mastectomy in appropriately selected patients (Tables 6 and 7). At 10 years, overall survival has ranged from 67% to 86%, depending upon the stage of the disease (Table 6). Disease-free survival at 10 years is approximately 70%.5, 7 These series have also shown excellent long-term control within the treated breast with primary tumors 5 cm in diameter or smaller (Table 7). At 10 years, local recurrence rates range from 8% to 19%. For patients with negative margins of resection, the 10-year actuarial risk of breast recurrence is 10% or less.8-11 The overall survival and local control rates in the breast reported by these retrospective series are comparable to the results of the six prospective randomized trials. Because of the potential options for treatment of early-stage breast cancer, careful patient selection and a multidisciplinary approach are necessary. Four critical elements in patient selection for breast-conservation treatment are history and physical examination, mammographic evaluation, histologic assessment of the resected breast specimen, and assessment of the patient's needs and expectations. Much of the information needed to determine a patient's suitability for breast-conservation therapy can be obtained from a detailed history and physical examination. Age per se, whether young or old, is not a contraindication to breast conservation. In the elderly, physiologic age and the presence of comorbid conditions should be the primary determinants of local therapy. The elements of the breast history and physical examination are listed in Tables 8 and 9. Retractions of skin, nipple, and breast parenchyma are not signs of locally advanced breast cancer and are not contraindications to breast conservation. Recent preoperative mammographic evaluation is necessary to determine a patient's eligibility for breast conservation treatment. It should be done with high-quality, dedicated mammographic equipment in a facility certified by the US Food and Drug Administration under the Mammography Quality Standards Act. Recent (usually within 3 months) mammographic evaluation, before biopsy or definitive surgery, plays an important role in establishing the appropriateness of breast-conservation treatment. Mammographic evaluation defines the extent of a patient's disease, the presence or absence of multicentricity, and other factors that might influence the treatment decision and evaluates the contralateral breast. Bilateral mammography is needed for palpable lesions and nonpalpable lesions that can be identified only radiographically. An increasing percentage of carcinomas treated with breast conservation are nonpalpable masses and microcalcifications. The breast tumor should be measured in at least two dimensions on the mammographic views or from the sonogram during ultrasonography, if it is performed. The size of the tumor should be included in the mammographic report. If the tumor is a poorly marginated mass, approximate dimensions can be given from either the mammogram or the sonogram. The skin of the breast in the area of a mass should be evaluated for thickening that might signify tumor involvement. If the mass is associated with microcalcifications, an assessment of the extent of the calcifications within and outside the mass should be made. Dimensions of the area in which calcifications are located should be given. If one or more clusters of microcalcifications are the only markers of the tumor, their location and distribution should be described. For evaluation of masses and microcalcifications, specialized views with positioning adapted to the location of the abnormality may be helpful. Magnification mammography and spot compression are important for characterizing microcalcifications and defining the margins of masses. Ipsilateral multifocality or multicentricity may be present and influence the treatment selection. In every instance, when one abnormality is seen, all areas of each breast should be fully evaluated for the presence of additional disease. Numerous pathologic factors have been assessed for their ability to predict an increased risk of recurrence in the treated breast in patients undergoing conservative surgery and radiation. These factors include histologic type and grade, the presence or absence of tumor necrosis, vascular or lymphatic invasion or an inflammatory infiltrate, the presence of DCIS in association with an invasive ductal carcinoma, margins of resection, and the status of the axillary nodes. The presence of vascular or lymphatic invasion, tumor necrosis, and an inflammatory infiltrate have been associated with a somewhat increased risk of breast cancer recurrence. This risk is approximately 10% to 15% at 5 years.5, 12-16, 17-19, 20-22, 23-44 Some series have also found an increased risk of breast cancer recurrence in patients with high histologic grade tumors compared with those who have low-grade tumors,7, 13, 14 although this has not been a consistent finding.5 Histologic subtype other than invasive ductal carcinoma does not appear to be associated with an increased risk of breast cancer recurrence.15, 16 Patients with invasive lobular cancers are candidates for conservative surgery and radiation if the tumor is not diffuse in the breast and can be completely excised with negative margins. Under these circumstances, no increased risk of breast recurrence has been seen in patients with invasive lobular carcinomas treated with conservative surgery and radiation.15-16a Patients with positive axillary nodes do not have an increased risk of breast recurrence when treated with conservative surgery and radiation.2, 5, 8, 15, 17-19 In contrast, in patients undergoing mastectomy, the number of positive axillary nodes correlates with the incidence of chest wall recurrence. The diminished risk of breast recurrence in node-positive patients may be related to the combined effects of chemotherapy or tamoxifen (or both) with radiation in these patients. One histopathologic feature that formerly appeared to be associated with a high risk of breast cancer recurrence after conservative surgery and radiation is the presence of an extensive intraductal component. This entity was first described by the Joint Center for Radiation Therapy, which defined it as the simultaneous presence of DCIS comprising 25% or more of the primary invasive tumor and DCIS in the surrounding normal breast tissue.19a The definition also includes DCIS with focal areas of invasion. Approximately 20% of women with early-stage breast cancer undergoing conservative surgery and radiation for invasive ductal carcinoma have an extensive intraductal component (EIC). Several series have reported an increased risk of breast recurrence in women with EIC-positive tumors. The risk at 10 years has ranged from 22% to 32%.5, 19b, 19c The increased risk for breast recurrence in EIC-positive tumors appears to be related to the presence of a significant residual tumor burden after gross excision. Holland et al,20 in a serial subgross and correlated mammographic examination of 217 mastectomy specimens, noted that EIC-positive tumors were significantly more likely to have residual tumor and tumor at a greater distance from the primary than were EIC-negative tumors. The residual tumor was predominantly DCIS. Therefore, the clinical and mammographic extent of an EIC-positive tumor may significantly underestimate the pathologic extent. The risk of breast recurrence in EIC-positive patients can be diminished by the use of wide surgical resections and the achievement of negative margins of resection. A recent report from the Joint Center for Radiation Therapy has confirmed that negative margins of resection diminish the risk of breast recurrence in EIC-positive tumors.21 Therefore, the presence of an extensive intraductal component is a pathologic indicator that the disease in the breast may be more extensive than is clinically appreciated. Assessment of resection margins in these patients is important in determining treatment options. Patients with EIC-positive tumors in whom the initial margins of resection are positive should undergo reexcision. If the reexcision margins are negative, current information suggests that these patients are appropriate candidates for conservative surgery and radiation. If the reexcision margins remain positive, mastectomy is the preferred treatment. The influence of the final resection margin on breast cancer recurrence rates varies. In most reported series, positive margins of resection have been associated with an increased risk of breast cancer recurrence, although the magnitude has varied considerably.5, 7, 9, 11, 21, 22, 23 The variation in these results may be related to the extent of the surgical resection for the primary tumor, the presence or absence of an extensive intraductal component, the definition of a positive margin, the number of margins that are positive, and the extent of the margin positivity. In the Milan Cancer Institute Trial II,3 the breast cancer recurrence rate for patients with positive margins was 12% for those undergoing a quadrantectomy compared with 17% for those whose primary surgical procedure was tumorectomy. Gage et al21 have defined focal microscopic involvement as involvement evident in three or fewer low-power fields and diffuse involvement as involvement evident in three or more low-power fields. The 5-year actuarial breast recurrence rate was 9% for patients with focally positive margins, 28% for those with more diffuse involvement, and 3% for those with negative margins. In this series, positive margins of resection were associated with a small increased risk of breast recurrence in EIC-negative tumors (10% compared with 2% for negative margins); however, 42% of EIC-positive tumors with diffuse margin involvement recurred compared with 0% of those with negative margins. Recent information suggests that the use of adjuvant systemic chemotherapy or tamoxifen (or both) may diminish the 5-year rate of breast cancer recurrence in patients with positive margins.22 However, adjuvant therapy appears to delay the interval to recurrence and may not diminish the long-term risk of a recurrence in these patients. The 10-year actuarial breast cancer recurrence rate for patients with positive margins has ranged from 14% to 16%7, 9, 10 compared with 6% to 9% in patients with negative margins of resection. Ideally, negative margins of resection should be achieved before radiation therapy to diminish the risk of a breast cancer recurrence, especially in patients who will not be receiving adjuvant systemic therapy. The ultimate outcome of EIC-negative tumors with focal margin involvement remains to be determined. Presently, reexcision is recommended in patients whose initial margin of resection is unknown or positive. The excised tissue should be submitted for pathologic examination with appropriate clinical history and specification of anatomic site, including laterality (right or left breast) and quadrant. For wide excisions or segmental breast resections, the surgeon should orient the specimen (e.g., superior, medial, lateral) for the pathologist with sutures or other markers. Gross examination should document the type of surgical specimen (e.g., excisional biopsy, quadrantectomy), the size of the specimen, the measured size of the tumor, and the proximity of the tumor or biopsy site to the margins of excision. The margins of excision are marked with India ink or another suitable technique so that the pathologist can determine whether tumor is present or absent at the margins. The pathologist includes certain basic data in each surgical pathology consultation report because the data are important prognostically or are needed for staging or therapy. The following features should be included in the surgical pathology consultation report for invasive carcinoma: How the specimen was received (e.g., number of pieces, fixative, orientation) Laterality and quadrant of the excised tissue and the type of procedure, as specified by the surgeon Measured size of the tumor (in three dimensions if possible) Histologic type and grade Presence or absence of coexistent DCIS or an extensive intraductal component Presence or absence of peritumoral angiolymphatic invasion Presence or absence of gross or microscopic carcinoma (either invasive carcinoma or DCIS) at the margins of excision; if possible, the distance of the tumor or biopsy site from the margin should be stated Lymph node status, including the number of lymph nodes found in the specimen, the number of involved nodes, the size of the largest involved node, and the presence or absence of extension beyond the lymph node capsule It is important to specify the presence of any special histologic type of invasive breast cancer (e.g., tubular, mucinous, papillary), most of which are considered low grade. All ordinary invasive carcinomas (ductal, not otherwise specified) should be assigned a histologic grade; some authors recommend grading invasive lobular carcinoma as well. If a specific grading system is used, this should be stated in the pathology report. The most commonly used histologic grading system is the Elston modification of the Bloom-Richardson scheme. This system evaluates degree of tubule formation, nuclear grade, and mitotic rate to determine an overall histologic score. In contrast to DCIS, lobular carcinoma in situ (LCIS, lobular neoplasia) is an incidental histologic finding that is considered a marker of increased risk for subsequent breast cancer rather than a malignant lesion requiring surgical excision. This increase in risk applies to both breasts and is probably lifelong. The relation between lobular carcinoma in situ and surgical margins is not important. The assessment of surgical margins is arguably the most important aspect in the pathologic evaluation of breast tumor excision in patients being considered for breast conservation. Although the definitions of "positive" and "negative" margins vary among institutions, microscopic margin involvement appears to be associated with an increased risk of local recurrence and, usually, indicates a need for further surgery, such as reexcision of the tumor site. Frozen-section preparations of tissue obtained from image-guided needle biopsies of nonpalpable lesions or from mammographically directed biopsies done for microcalcifications are strongly discouraged. Lesions such as atypical ductal hyperplasia, radial scar, and papillary proliferations may be difficult to interpret in frozen-section preparations, and small foci of DCIS or microinvasive carcinoma may be lost or rendered incapable of interpretation by freezing artifact. Usually, frozen sections should be prepared only when enough tissue is present that the final diagnosis will not be compromised and when the information is necessary for immediate therapeutic decisions. The presence or absence of regional or distant metastasis must be confirmed microscopically when appropriate tissue is submitted for examination. The AJCC/UICC (American Joint Committee on Cancer/International Union Against Cancer) TNM classification is recommended for appropriate stage grouping. Determination of estrogen and progesterone receptors is standard for invasive breast carcinomas. This can be done either by the traditional ligand-binding assays performed on snap frozen tissue or by immunohistochemistry performed on routinely fixed tissue sections. The results of ancillary studies (such as steroid receptor analysis, DNA ploidy, proliferative rate, and so forth) are usually reported in an addendum or supplement to the surgical pathology report. Long-term survival The possibility and consequences of local recurrence Psychological adjustment (including the fear of cancer recurrence), cosmetic outcome, sexual adaptation, and functional competence For most patients, the choice of mastectomy with or without reconstruction or breast-conservation treatment does not influence the likelihood of survival, but it may affect the quality of life. Psychological research comparing patient adaptation after mastectomy with that after breast conservation treatment shows no significant differences in global measures of emotional distress. Research also does not reveal significant changes in sexual behavior and erotic feelings in the treated breast or nipple and areolar complex. However, women whose breasts are preserved have more positive attitudes about their body image and experience fewer changes in their frequency of breast stimulation and feelings of sexual desirability. Some absolute and relative contraindications exist in the selection of patients for breast conservation treatment with radiation. Pregnancy is an absolute contraindication to the use of breast irradiation. However, in many cases, it may be possible to perform breast-conserving surgery in the third trimester and treat the patient with irradiation after delivery. Women with two or more primary tumors in separate quadrants of the breast or with diffuse malignant-appearing microcalcifications are not considered candidates for breast-conservation treatment. A history of previous therapeutic irradiation to the breast region that, combined with the proposed treatment, would result in an excessively high total radiation dose to a significant volume is another absolute contraindication. Finally, persistent positive margins after reasonable surgical attempts absolutely contraindicate breast-conservation treatment with radiation. The importance of a single focally positive microscopic margin needs further study and may not be an absolute contraindication. A history of collagen vascular disease is a relative contraindication to breast conservation treatment because published reports indicate that such patients tolerate irradiation poorly. Most radiation oncologists will not treat patients with scleroderma or active lupus erythematosus, considering either an absolute contraindication. In contrast, rheumatoid arthritis is not a relative or an absolute contraindication. Patients with multiple gross tumors in the same quadrant and indeterminate calcifications must be carefully assessed for suitability because studies in this area are not definitive. Tumor size is not an absolute contraindication to breast conservation treatment, although few reports have been published about treating patients with tumors larger than 4 to 5 cm. However, a relative contraindication is the presence of a large tumor in a small breast in which an adequate resection would result in significant cosmetic alteration. Breast size can be a relative contraindication. Women with large or pendulous breasts can be treated by irradiation if reproducibility of patient set-up can be ensured and if 6-MV photon beam irradiation is technically possible to obtain adequate dose homogeneity. Certain clinical and pathologic features should not prevent patients from being candidates for breast-conservation treatment. These features include the presence of clinically suspicious and mobile axillary lymph nodes or microscopic tumor involvement in axillary nodes. In addition, evaluating the breast for local recurrence is feasible. The changes associated with recurrence can be detected at an early stage by physical examination and mammography. The delivery of irradiation in this setting does not result in a meaningful risk of second tumors in the treated area or in the untreated breast. Tumor location is not a factor in the choice of treatment. Tumors in a superficial subareolar location occasionally may require the resection of the nippleareolar complex so that negative margins can be achieved, but this does not affect outcome. The patient and her physician need to assess whether such a resection is preferable to mastectomy. A family history of breast cancer is not a contraindication to breast conservation. Several studies have shown that the rate of breast recurrence in patients with first- or second-degree relatives with breast cancer does not differ from than that seen in patients without a family history of breast cancer. Little is known about the risk of breast recurrence in patients with hereditary breast cancer, but currently this is not a contraindication to breast-conserving therapy. A high risk of systemic relapse is not a contraindication for breast conservation but is a determinant of the need for adjuvant therapy. When breast-conservation treatment is appropriate, the goals of any surgical procedure on the breast are total gross removal of the suspicious or known malignant tissue with minimal cosmetic deformity. These goals apply to either diagnostic biopsy or definitive local excision before radiation therapy. Failure to consider these goals at all stages may jeopardize conservation of the breast. Usually, local anesthesia can be used for the biopsy. Frequently, local anesthesia also can be used for the definitive local excision, particularly when it is combined with intravenous sedation in selected patients. The placement and performance of the skin incision can be critical to the quality of cosmesis. Curvilinear skin incisions following Langer's lines generally achieve the best cosmetic result (Fig. 1). However, in the mid-inner aspect of the breast and the lower breast, a radial incision may provide a better result, particularly if skin removal is necessary. The incision should be over or close to the tumor and of adequate size to allow the tumor to be removed in one piece. In the upper inner aspect of the breast, some retraction of the skin may be necessary to avoid an incision that may be visible with clothing. Periareolar incisions are inappropriate for lesions in the periphery of the breast. Recommended location of incisions for performing breast biopsy. For larger lesions in the lower breast, particularly when skin must be excised, a radial incision often results in better cosmesis. Reproduced with permission from Souba and Bland.45 Excision of a segment of skin is rarely necessary and is undesirable because it may alter the position of the nipple or the inframammary crease. Preservation of the subcutaneous tissue with separate closure improves the cosmetic result. The skin should be closed with a subcuticular technique. The primary lesion should be excised with a rim of grossly normal tissue, avoiding excessive sacrifice of breast tissue. Tumors in the subareolar area may require excision of the nipple-areolar complex to ensure adequate tumor margins and to avoid devascularization. (Partial areolar excision with careful approximation for small lesions in the immediate subareolar area can provide adequate tissue removal and good cosmesis.) Closure of the breast tissue may reduce the occurrence of a saucer-like defect, but the overall cosmetic result with nipple-areolar sacrifice is less than optimal. The surgeon should approach lesions within the substance of the breast by incising the overlying breast tissue. A superior cosmetic effect is usually achieved when the breast is not reapproximated. Reapproximation that appears to be adequate with the patient relaxed and supine often results in distortion of the breast when the patient is upright and mobile. Meticulous hemostasis is cr