EXTENT OF DISEASE

Most breast cancers are evaluated by mammography, ultrasound, or both modalities. It is important to document the size, location, and distribution of the primary lesion, but also to evaluate for satellite lesions. Preoperative identification of additional lesions improves the likelihood of obtaining clear margins if breast-conserving therapy (BCT) is performed. For masses, it is important to look for associated microcalcifications, which may represent an associated noninvasive (in situ) component. The term extensive intraductal component (EIC) is used to refer to invasive tumors in which ductal carcinoma in situ (DCIS) makes up at least 25% of the neoplasm. Of all invasive ductal carcinomas, 15% to 30% have an EIC.¹ Tumors that are predominantly DCIS with focal invasion are also classified as EIC. The presence of EIC may have prognostic implications on the likelihood of obtaining clear margins, as well as the risk for subsequent local recurrence.^2,3

As many as 30% to 60% of breast cancers are pathologically multifocal (more than one tumor focus, separated by normal tissue) at the time of diagnosis.^4,5 The term multicentric has been variably defined. It generally has been used to describe cancers separated by more than 4 cm or tumors located in different quadrants of the breast. BCT generally is not suitable for multicentric carcinomas because of poor cosmetic results, limitations of radiation therapy, and inability to obtain clear margins.

Synchronous contralateral breast cancer may occur in about 3% to 5% of women with breast cancer.^6,7 Identification of these lesions at the time of the contralateral index cancer diagnosis can facilitate treatment in a single surgery, thereby avoiding both delays in diagnosis, as well as the emotional stress of a later diagnosis and second surgery.

MRI is useful to identify residual disease and direct re-excision in patients with positive margins at initial lumpectomy (Figure 1).

FIGURE 1 MRI evaluation can be useful in patients with close or positive surgical margins. A, Post-contrast, subtracted MRI of a right breast shows a focus of residual DCIS (arrow) along the medial aspect of a large lumpectomy cavity. B, Post-contrast, subtracted MRI shows residual invasive tumor (arrow) along the anterior lateral aspect of a small lumpectomy cavity.

EVALUATING ADENOPATHY

Identification of abnormal adenopathy, including axillary, supraclavicular, and internal mammary nodes, is important in staging. Metastatic adenopathy is suspected on imaging when there is cortical thickening (generally >3 mm), loss of the fatty hilum, and enlargement, particularly with increasingly round shapes⁸ (Figure 2 and Figure 3). However, because many benign processes may cause reactive nodes with similar imaging findings, fine-needle aspiration (FNA) or core needle biopsy is necessary to confirm suspected metastatic nodal disease. Conversely, the absence of suspicious imaging findings, whether on mammography, ultrasound, MRI, or molecular imaging studies, does not exclude metastatic nodal involvement, particularly for micrometastasis. Therefore, in addition to imaging, sampling, either with axillary dissection or sentinel lymph node biopsy, is essential in the staging of breast cancer patients.

FIGURE 2 Sonographic appearance of normal axillary lymph nodes. A, Longitudinal image shows uniform thickness of the hypoechoic cortex, surrounding the echogenic fatty hilus. B, Transverse image of the same lymph node. The cortical thickness of 2 mm is within normal limits (<3 mm). C, Color Doppler image shows vascularity in the hilus.

FIGURE 3 The spectrum of abnormal axillary node sonographic findings (all FNA-proven to have breast cancer metastases). A, Cursors delineate borderline thickening of the hypoechoic cortex. The fatty hilus is preserved. A second, similar-appearing axillary lymph node is seen to the left. These findings are not clearly pathologic by sonographic criteria. Subtle findings on staging MRI, CT, and positron emission tomography (PET) studies (for inflammatory breast cancer) suggested axillary involvement. FNA confirmed metastatic carcinoma. B, Cortical thickening in this case is more eccentric and measures 5 mm. Ultrasound-guided FNA of the axillary lymph node confirmed metastatic carcinoma. C, Axillary node sonography of a 55-year-old woman with locally advanced breast cancer (LABC) shows highly suspicious morphology. The cortex is very hypoechoic, as well as abnormally thickened and nodular. There is a rat-bite, scalloped appearance and mass effect on the echogenic hilus. D, Same case as C, with color Doppler. Increased and abnormal vascularity is seen. Normal lymph node vascularity is seen only at the hilus. E, A 45-year-old woman with a new infiltrating ductal carcinoma (IDC) diagnosis. The cortical mantle of this axillary lymph node is markedly thickened, and the echogenic hilus is nearly completely effaced. F, Although small, this axillary node morphology is quite abnormal. The cortex is very hypoechoic. The node is “thick-waisted,” with nearly complete effacement of the fatty hilus, which is hinted at in profile. G, A 56-year-old woman with a neglected LABC (IDC with secondary inflammation) and multiple abnormal axillary nodes, which were FDG-avid on PET. This lymph node shows diffuse cortical thickening, without hilar effacement. H, Another lymph node of the same patient shows complete hilar loss and an abnormally rounded shape. I, A 41-year-old woman with a large postpartum pregnancy-associated breast cancer. This lymph node is massively enlarged and would be considered abnormal on any modality. Size, the primary criterion for judging normalcy on CT and MRI, is a weaker criterion by which to judge axillary nodes. Other morphologic criteria, including shape, cortical thickening and nodularity, and mass effect on or effacement of the fatty hilus, are more reliable in the assessment of the axillary lymph nodes of breast cancer patients. These more subtle findings are most easily assessed with ultrasound. This lymph node shows many of these features: marked cortical hypoechogenicity, nodularity, and thickening, with partial loss of the fatty hilus. The intracortical and peripheral vascularity is highly abnormal and also suggests malignancy. J, The same lymph node seen transversely shows that the hilus is incompletely effaced. Echogenic remnants are seen surrounded by the grossly thickened hypoechoic cortex. The abnormally increased vascularity, seen on the periphery of the cortex, is highly suggestive of malignancy. K, Even more normal-appearing adjacent lymph nodes, with visible echogenic fatty hila, have borderline thickened cortices and are notable for their ease of visualization and increased number. L, A 49-year-old woman with newly diagnosed, node-positive (five of eight nodes, largest 1.9 cm, with extracapsular extension), 1.8-cm left breast IDC. Her preoperative ultrasound predicted the extracapsular extension. This very hypoechoic axillary lymph node shows no echogenic hilus. The left side is rounded by a cortical nodule, and the right side has frankly angular margins. M, Oblique, noncontrast, T1-weighted MRI of the left axilla shows an abnormal lymph node (arrow), notable for the loss of the fatty hilum and the rounded and expanded shape.

The axillary nodes form a chain from the underarm to the collarbone (Figure 4). The axillary lymph nodes are named in relation to the pectoralis minor muscle, with level I the lowest, lateral to the pectoralis minor muscle. Level I receives the most lymphatic drainage from the breast. Level II axillary nodes are beneath the pectoralis minor muscle. Level III is above and medial to the pectoralis minor muscle. A traditional axillary lymph node dissection usually removes nodes in levels I and II. Sentinel lymph node sampling involves the mapping and removal of the first lymph node or nodes (usually 1 to 3) that drain the involved area of the breast (Figure 5 and Figure 6). Instead of removing 10 or more lymph nodes as performed in a standard dissection, the status of the axilla can be predicted by excision and close pathologic examination of the sentinel node. Sentinel lymph node biopsy has significantly reduced the number of women undergoing standard axillary dissection, avoiding dissection-associated side effects such as arm lymphedema. The identification of abnormal lymph nodes on physical exam or imaging studies favors proceeding directly to axillary dissection over sentinel node biopsy.

FIGURE 4 Schematic of axillary lymph node nomenclature. The axillary lymph nodes ascend from the axilla medially to the clavicle and are named in relation to the pectoralis minor muscle. Level I, the lowest, is lateral to the pectoralis minor; level II, deep to it; and level III, medial to it.

FIGURE 5 Schematic of the technique of sentinel lymph node injection. The breast lymphatics drain to the skin, and there is a rich periareolar network of lymphatics, with one or two major lymphatic channels draining to the axilla. Anatomic studies indicate 75% of the lymphatic drainage of the breast is to the axilla, with 25% to the internal mammary nodes. In this drawing, a peritumoral injection is depicted, but success has been reported for a variety of techniques (including subdermal or intradermal overlying the tumor, and periareolar), presumably owing to the rich network of the breast lymphatic plexus.

FIGURE 6 Lymphoscintigraphy (from left to right: anterior, left anterior oblique, and left lateral) can be performed in conjunction with injections for sentinel lymph node identification. In this example, intense activity is seen at the injection site of the tumor in the left breast. A lymphatic drainage channel extending to the axilla is clearly delineated, as are a faint, more superior secondary channel and the axillary sentinel lymph node. If a sentinel node is identified at imaging, skin marking can save surgical dissection time. Breast cancer sentinel node mapping with lymphoscintigraphy is not universally performed, unlike in melanoma.

The use of molecular imaging studies, CT, or MRI may identify adenopathy in areas other than the axilla (Figure 7). The presence of internal mammary node adenopathy (Figure 8) affects staging and radiation therapy planning. Identification of abnormal Rotter’s nodes (Figure 9), nodes between the pectoralis minor and major muscles, also has staging and therapeutic implications.

FIGURE 7 Schematic of the lymphatic drainage pathways of the breast. By anatomic studies, 75% of the lymphatic drainage is to the axilla, with 25% to the ipsilateral internal mammary nodes. Note lymphatic communications extending across the midline of the chest to contralateral internal mammary nodes and inferiorly extending channels, which communicate with the abdomen.

FIGURE 8 Internal mammary node metastasis. A, Axial postcontrast MRI in a patient with an implant with an abnormally enlarged left internal mammary node (arrow) adjacent to the internal mammary artery and vein, suspicious for involvement. B, Axial postcontrast MRI shows a small (2–3 mm) right internal mammary node (left). The same area, 5 years later, has a chest wall recurrence (arrow), presumably from metastasis to the internal mammary node (right).

FIGURE 9 Rotter’s nodes. A, Oblique T1-weighted (left) and axial fat-saturated, enhanced T1-weighted (right) MRIs of the left axilla show a small Rotter’s node (arrows) between the pectoralis major and pectoralis minor muscles. B, Enhanced CT scan demonstrates a metastasis to a large Rotter’s node (arrow), as well as within the right axilla.

SKIN, PECTORALIS, AND CHEST WALL INVOLVEMENT

Identification of breast edema and skin thickening in patients with invasive breast cancer may represent an inflammatory component (tumor involving the dermal lymphatics). This materially affects staging and therapeutic approach. Skin punch biopsy may be necessary to confirm the diagnosis if the clinical picture is not characteristic. Identification of pectoralis muscle or chest wall involvement also affects treatment planning. Pectoralis muscle involvement should be looked for in women with posterior lesions. The diagnosis on MRI requires not just effacement or obliteration of the pectoralis fascia but also enhancement of the muscle (Figure 10). Identification of either skin or chest wall involvement classifies a tumor as a locally advanced breast carcinoma (LABC). Large (>5 cm) tumors and those with clinically matted or fixed axillary node involvement or involved supraclavicular or internal mammary nodes by imaging are also considered locally advanced. LABC is generally treated with preoperative (neoadjuvant or primary systemic) chemotherapy, which converts some patients into operative candidates. Multiple examples are presented in Chapter 5.

FIGURE 10 Chest wall invasion. Postcontrast axial MRI in a patient with a breast sarcoma, demonstrating enhancement of the pectoralis major muscle and intercostal muscles (arrows). Chest wall involvement is confirmed by identification of intercostal muscle enhancement, whereas the pectoralis muscle is considered part of the breast.

PREOPERATIVE MAGNETIC RESONANCE IMAGING

MRI is becoming increasingly established as a useful modality in patients with known breast cancer. However, patterns of use of preoperative MRI in women with biopsy-proven breast cancer remain highly variable in practice because of the lack of randomized control trials. It has been firmly established that preoperative MRI can detect unsuspected disease and often changes management in women with known breast cancer.⁹ However, the use of preoperative MRI to alter surgical management has been criticized because of the lack of studies evaluating its effect on tumor recurrence and mortality.^10–12 Fischer and colleagues,¹³ in a study involving more than 40 months of follow-up, reported a reduction in ipsilateral breast tumor recurrence, from 6.8% to 1.2%, in patients who underwent preoperative MRI. However, this study was a retrospective, singleinstitution review of only 346 patients. It has been argued that unsuspected disease detected on MRI and treated with BCT is of little clinical consequence and is controlled by radiation therapy. This argument is primarily based on the fact that 10-year local recurrence rates as low as 10% have been reported in patients with negative surgical margins.^14–16 Concerns about the use of preoperative MRI involve the potential for unnecessary biopsies, delays in treatment, and an increase in unnecessary mastectomies. Despite these arguments, there is ongoing evidence and experience accumulating that supports its benefit in preoperative staging, as follows:

These benefits, although individually small, together have the potential to positively affect a significant number of patients. Preoperative MRI can improve surgical clear margin rates, guide surgical and radiation therapy planning, detect occult contralateral cancers, and potentially reduce recurrences. However, the number of false-positive results and delays in treatment needs to be minimized. Other breast imaging studies, such as mammography and ultrasound, must be correlated with the MRI findings to provide the most accurate interpretation and appropriate recommendations.

FUNCTIONAL (MOLECULAR) BREAST IMAGING: BREAST-SPECIFIC GAMMA IMAGING AND POSITRON EMISSION MAMMOGRAPHY

Functional breast imaging is a growing and evolving field that is assuming a larger role in breast cancer diagnosis, providing complementary information to anatomically based breast imaging modalities. Scintimammography has matured from initial versions using standard gamma cameras, which were limited in resolution and positioning flexibility, to breast-specific gamma imaging (BSGI), which obtains higher-resolution planar images in views emulating mammography.^21–25 Similarly, positron emission mammography (PEM) is performed using a small-field-of-view, high-resolution PET scanner that resembles a mammogram unit and acquires tomographic data sets in planes analogous to mammography.^26–29 Scintimammography is performed after the intravenous administration of 25 mCi of either ^99mTc-sestamibi or ^99mTc-tetrofosmin, whereas PEM is performed after an hour’s uptake of 10 mCi of ¹⁸F-fluorodeoxyglucose (FDG) admin-istered intravenously. The radiation dose is about the same, about 0.4 rad. Imaging time is also similar. Scintimammography planar views are acquired for 5 to 10 minutes, or at least 150,000 counts, whereas PEM tomographic data sets are acquired for 4 to 10 minutes per projection. The lower limit of BSGI detector resolution is 3 mm (although smaller lesions may be identifiable), whereas the in plane resolution of PEM is on the order of 2 mm (Table 2).

Table 2 FUNCTIONAL BREAST IMAGING COMPARISON CHART

The uptake of sestamibi is dependent on regional blood flow and cellular mitochondrial density. Enhanced blood flow due to tumorinduced neo-angiogenesis results in increased delivery of radiopharmaceutical. Cancer cells have higher cytoplasmic mitochondrial density than normal breast tissue and bind more of the radiopharmaceutical than the surrounding tissue.

PEM is performed with ¹⁸F-FDG, a radioactive glucose analogue in wide use as a cancer-imaging agent with whole-body PET. PEM and PET with FDG capitalize on the higher glycolytic rate of cancer cells, with FDG actively transported intracellularly through an up-regulated transmembrane GLUT-1 receptor mechanism. Once intracellular, FDG is phosphorylated by hexokinase like glucose, but because it is not metabolized further, it is trapped intracellularly in proportion to glucose utilization.

At this writing, BSGI is becoming more available, with sites with early experience finding it useful both for problem solving of ambiguous conventional breast imaging findings, and as an adjunct to local staging, looking for multifocality, multicentricity, and contralateral lesions (Figure 11). BSGI does not require a diagnosis of breast cancer for reimbursement, and increasingly is being performed in patients with suspicious conventional breast imaging findings as an aid to biopsy decision making (e.g., deciding how many areas need sampling). Currently, PEM is approved for patients with known or prior breast cancer diagnoses. Several cases incorporating the use of PEM have been included in this chapter. Its performance compared with MRI in preoperative local staging of apparently localized breast cancer is being assessed by a multicenter, prospective clinical trial, which at this writing is accruing patients. Early pilot studies show high sensitivity for depiction of primary breast cancers, on the order of 91%. Similarly high sensitivity for primary tumor depiction is reported for BSGI. Both modes of functional breast imaging appear to have improved specificity compared with MRI, on the order of 87% to 89% for BSGI and 93% for PEM, offering hope that increased use of functional breast imaging in the future may decrease the number of unnecessary benign biopsies now being performed.

FIGURE 11 An 89-year-old woman with a prior right upper outer quadrant benign biopsy (scar marked on mammographic views (arrows)—A, MLO; B, CC). Multiple lobular and circumscribed masses are seen within moderately dense breast tissue, especially in the upper outer quadrant near the scar. Ultrasound of the corresponding area suggested two cysts and one solid mass, for which biopsy was recommended. Breast-specific gamma imaging (BSGI) (C, MLO; D, CC) shows multifocal upper outer quadrant increased activity, with three discrete sites of increased uptake. At surgical pathology, a multilobed mucinous carcinoma, with ductal carcinoma in situ was confirmed.

(Case courtesy of Dilon Technologies)

Currently, no biopsy capability using functional imaging modalities for guidance is readily available, although feasibility studies have been done and this should be available in the near future.

DISTANT METASTASES

Routine imaging with bone scan, CT, and PET is not indicated for early-stage (stage I and II) breast cancers. Patients with limited-stage breast cancer who have symptoms, such as back or bone pain, or right upper quadrant pain; physical examination abnormalities (such as jaundice or hepatomegaly), or laboratory abnormalities can be considered for imaging to exclude distant metastatic disease. Patients with locally advanced breast cancer or evidence of axillary nodal involvement by physical examination or imaging should be considered for systemic imaging after a detailed history, physical exam, and laboratory evaluation.

TEACHING POINTS

Breast imagers need to constantly guard against “satisfaction of search.” By fully defining the extent of disease, the appropriate surgical therapy can be planned. The occurrence of synchronous ipsilateral or bilateral breast cancer is about 3% to 5%. For localized breast cancer, the 20-year follow-up reports of two pivotal prospective randomized trials demonstrated that survival after a lumpectomy with radiotherapy is equal to survival after mastectomy. However, these studies are based on patients in whom clear margins were obtained. By better defining the extent of disease preoperatively, the likelihood of obtaining clear margins at initial surgery can be improved. Pathologic margin status is the most important predictor of local recurrence after breast conservation with radiation. Even when clear margins are obtained, many patients have remaining foci of disease. The role of radiation therapy is to treat these areas of occult residual tumor. The risk for local recurrence may be diminished if the residual tumor burden after surgery is minimized. This is even more important in patients who undergo partial breast irradiation rather than whole breast irradiation.

TEACHING POINTS

This case illustrates well how a multimodality approach can yield critical additional information to most accurately stage a newly identified breast cancer. Mammography was not particularly useful in this patient, owing to breast density, but confirmed that there were no microcalcifications. Prospectively, ultrasound identified the index tumor and provided guidance to confirm the diagnosis of IDC. However, no additional disease sites were recognized prospectively on ultrasound to suggest multicentric disease. However, with the breast MRI as a roadmap for a directed, second-look ultrasound, more subtle correlates could be discerned and targeted for sampling, confirming two separate sites of DCIS remote from the IDC, indicating that the patient’s disease should be treated surgically with mastectomy.

This case also illustrates ductal extension on ultrasound, a sonographic sign suspect for malignancy, as delineated by Stavros and colleagues. This feature is less frequently seen or recognized than other features of malignancy, such as taller-than-wide shape and shadowing.