CHAPTER 5 Locally Advanced Breast Cancer (LABC) and Neoadjuvant Chemotherapy
DEFINITION OF LOCALLY ADVANCED BREAST CANCER
The definition of locally advanced breast cancer (LABC) has continued to evolve since Haagensen and Stout outlined their criteria for operability more than 60 years ago.1 Their conclusions remain a part of the current American Joint Committee on Cancer Classification System for LABC, as depicted in Table 1. LABC includes large tumors (>5 cm), those (of any size) with involvement of the skin or chest wall, and those with clinically apparent axillary nodal involvement (matted or fixed) or ipsilateral internal mammary, infraclavicular, or supraclavicular nodal disease.
Table 1 Primary Tumor (T) and Clinical Regional Lymph Node (N) Categories Comprising LABC in the Current American Joint Committee on Cancer Classification System
| T3 | Tumor >5 cm in greatest diameter |
| T4 | Tumor of any size, with direct extension to chest wall or skin, as described below |
| T4a | Extension to chest wall, not including pectoralis muscle |
| T4b | Edema (including peau d’orange) or ulceration of the skin of the breast or satellite nodules confined to same breast |
| T4c | Both Ta and Tb |
| T4d | Inflammatory carcinoma |
| N2 | Metastases in ipsilateral axillary nodes fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary node metastases. |
| N3 | Metastases in ipsilateral infraclavicular or supraclavicular lymph nodes or in clinically apparent internal mammary nodes in the presence of clinically evident axillary node metastases. |
Data from Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual, 6th ed. New York, Springer Verlag, 2002.
ASSESSMENT OF PATIENTS SUSPECTED TO HAVE LABC
Locoregional staging of breast cancer is covered in depth in Chapter 3, including assessment with mammography, ultrasound, and MRI. The principles outlined in that chapter are identical for the patient who meets the definition of LABC. MRI has proved extremely valuable in accurately estimating tumor size and extent, as well as determining multifocality, multicentricity, and bilaterality (Figure 1). MRI more accurately correlates with tumor size and number of tumors at pathology than mammography or ultrasound. It is the modality of choice for assessment of chest wall invasion (Figure 2).
FIGURE 1 Axial maximal intensity projection (MIP) view from contrast-enhanced, subtracted breast MRI of a 52-year-old woman with newly diagnosed left LABC, a multifocal infiltrating ductal carcinoma (IDC), with involvement of 10 of 11 nodes on axillary dissection. Multiple adjacent left lateral breast masses form a large confluent mass. A satellite nodule projects medially. Several enlarged involved left axillary lymph nodes are demonstrated as well.
FIGURE 2 A, Enhanced, subtracted axial breast MRI demonstrates a neglected left LABC. This tumor would be classified as LABC based on size alone, but it demonstrates other criteria as well, including infiltration of the skin and chest wall (note enhancing, thickened skin and chest wall). B, Enhanced chest CT of the same patient, for comparison. The bulky left breast tumor masses are well seen, and extension into the thickened skin is shown as well. The bulky chest wall involvement in this case is well seen on CT, but lesser degrees of infiltration are less reliably demonstrated on CT than MRI, owing to the lower inherent soft tissue contrast of CT.
ASSESSMENT OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY
Assessment of response to neoadjuvant chemotherapy with anatomic imaging modalities can be problematic. On mammography, breast cancers that initially manifest as masses generally decrease in size in response to chemotherapy, but may not completely resolve. Breast cancer manifesting on mammography as microcalcifications is even more difficult to accurately assess in terms of responsiveness to neoadjuvant therapy because microcalcifications may not resolve, even in responders. On ultrasound, responding tumors show a decrease in size and, occasionally, resolution. MRI appears to be the most reliable anatomic imaging modality in common use today for monitoring patients being treated preoperatively.3–8 In addition to showing decreased tumor size, the enhancement pattern changes in responders. Responding tumors showing intense enhancement and washout initially often show decreased intensity of peak enhancement, as well as more benign patterns of progressive or persistent enhancement (flattening of the enhancement curve). Responding tumors may shrink, retaining a smaller, but still mass-like, morphology, or they can “break apart,” manifesting as less intense, smaller foci of enhancement within the distribution of the initial abnormality. Complete response by MRI (complete resolution of all tumor-associated enhancement) does not confirm a complete pathologic response because some patients with complete imaging responses have microscopic disease at pathology. Conversely, some patients with good, but incomplete, responses by MRI (some residual enhancement in the distribution of the original tumor) prove at pathology to have had complete pathologic responses.
PET and PET/CT are assuming an increasing role in this assessment, and a larger role for breast-specific gamma imaging and positron emission mammography can be anticipated in the future. Quantitative PET assessment, using the standardized uptake value (SUV), has shown early success in separating responders from nonresponders.10–12 Careful attention must be paid to all the factors influencing SUV measurement, especially region-of-interest assignment and patient glucose level. Flare responses (increased uptake as a manifestation of response), which can be seen on PET with initiation of tamoxifen therapy, are not seen with chemotherapy.
ASSESSMENT OF SENTINEL NODE STATUS IN LABC TREATED NEOADJUVANTLY
A controversial issue in the use of neoadjuvant chemotherapy is whether to assess preoperatively the status of the axilla with sentinel lymph node (SLN) sampling. It has been demonstrated that information from SLN biopsy or axillary dissection performed after completion of chemotherapy correlates well with overall prognosis. The role of SLN sampling and axillary dissection in the postchemotherapy setting was reviewed in a meta-analysis, with an overall accuracy of 95%.13
ASSESSMENT FOR SYSTEMIC METASTASES (EXCLUSION OF STAGE IV DISEASE)
The most common sites of breast cancer metastasis are bone, lung, and liver, in that order.14 Evaluation of bone should begin with a careful history to elicit any symptoms or history of recent trauma. Serum alkaline phosphatase and calcium measurements may be helpful if positive and heighten suspicion of bony involvement. Imaging options, discussed in greater depth in Chapter 8, include bone scanning, CT, MRI, and PET. Bone scintigraphy, using a technetium-based agent (e.g., methylene diphosphonate), is exquisitely sensitive to changes in bone metabolism. Localization of these agents into bone is dependent on many factors, with the most important two being blood flow and osteoblastic activity. This results in a very predictable concentration in osteoblastic metastases (Figure 3). Positive findings on scintigraphy antedate findings on plain radiography by weeks to months. Drawbacks of bone scanning include suboptimal specificity, reduced sensitivity in osteolytic metastases, and persistent positivity at sites where active tumor is no longer present. Additionally, the well-recognized flare phenomenon, resulting in apparent worsening on scintigraphy due to treatment response, may mislead the unaware clinician or imager. Specificity is arguably the most problematic feature of whole-body skeletal scintigraphy. Any process that results in an increase in bone remodeling will demonstrate increased uptake of radiopharmaceutical. For this reason and because of the implications of labeling a patient as having bony metastases, correlative imaging (or even tissue sampling) is required. Correlation can be accomplished with plain radiography, CT, or MRI.
FIGURE 3 Anterior and posterior images from whole-body bone scan in a patient with known breast cancer. Typical bone scan findings of extensive breast cancer bone metastases are demonstrated: multiple lesions in a random distribution, with several rib lesions displaying a particularly suggestive pattern of elongated uptake.
Plain radiography is of minimal value as a screening modality, requiring 30% to 50% loss of bone mineral for a metastasis to become visible.15 Plain radiographic correlation with a scintigraphic abnormality may be of benefit; however, the increased sensitivity and improved anatomic detail (including surrounding soft tissues) are factors favoring CT (Figure 4) or MRI. Although MRI has a higher rate of detection of skeletal metastases than scintigraphy in the spine, pelvis, limbs, sternum, scapulae, and clavicles,16 the logistics and cost of whole-body MRI give scintigraphy the edge as an initial screening examination.
FIGURE 4 Chest CT image, displayed with bone windowing, from the same patient in Figure 3, shows abnormal, mottled, partially blastic bone mineral texture involving a long segment of a right posterior rib, corresponding to the bone scan.
PET and, more recently, PET/CT have been used to evaluate the entire body for metastases, including bone. An emerging consensus is that PET and scintigraphy have a similar sensitivity for detection of metastases, whereas PET shows a definite in-crease in specificity.17–20 There also appears to be a significantly higher sensitivity with fluorodeoxyglucose (FDG) PET for osteolytic metastases. Conversely, bone scintigraphy has shown superiority for demonstration of osteoblastic lesions. Currently, PET and bone scintigraphy are viewed as complementary imaging modalities for the detection of skeletal metastases.
Lung metastases are relatively common in patients with metastatic disease and in those who die from breast cancer. However, lung metastases are very uncommon at initial diagnosis of breast cancer.21 Many centers still recommend a chest x-ray at initial screening (in part, because of the age of their breast cancer population); however, positive findings on chest x-ray generally necessitate CT correlation. CT is the modality of choice for chest evaluation. PET/CT offers advantages over CT alone in evaluating the mediastinum and as a whole-body survey.22
Evaluation of the liver is covered in depth in Chapter 9. In addition to CT, MRI, and PET, ultrasound may be appropriate in selected patients. The number of patients with hepatic metastases at initial presentation is extremely low. Screening, whether using liver enzymes or imaging, is nonspecific and of low diagnostic yield. For symptomatic patients and those with clinical evidence of liver involvement, CT and MRI are considered the imaging modalities of choice.23 Ultrasound may be useful to help characterize small lesions identified on CT.24 Finally, FDG PET is best viewed as complementary in the liver; it carries an excellent specificity and will occasionally find lesions not appreciated prospectively on CT or MRI, but it has limited sensitivity for small lesions (<1 cm) and can be difficult to interpret when there is heterogeneous FDG uptake, which can be exacerbated by attenuation correction (Table 2).
1 Haagensen C, Stout A. Carcinoma of the breast: Criteria of operability. Ann Surg. 1943;118:859-868.
2 Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual, 6th ed. New York: Springer Verlag, 2002.
3 Rieber A, Brambs HJ, Gabelmann A, et al. Breast MRI for monitoring response of primary breast cancer to neo-adjuvant chemotherapy. Eur Radiol. 2002;12(7):1711-1719.
4 Partridge SC, Gibbs JE, Lu Y, et al. Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. AJR Am J Roentgenol. 2002;179:1193-1199.
5 Rosen EL, Blackwell KL, Baker JA, et al. Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy. AJR Am J Roentgenol. 2003;181:1275-1282.
6 Londero V, Bazzocchi M, Del Frate C, et al. Locally advanced breast cancer: comparison of mammography, sonography and MR imaging in evaluation of residual disease in women receiving neoadjuvant chemotherapy. Eur Radiol. 2004;14(8):1371-1379.
7 Martincich L, Montemurro F, De Rosa G, et al. Monitoring response to primary chemotherapy in breast cancer using dynamic contrast-enhanced magnetic resonance imaging. Breast Cancer Res Treat. 2004;83(1):67-76.
8 Yeh E, Slanetz P, Kopans DB, et al. Prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant chemotherapy for palpable breast cancer. AJR Am J Roentgenol. 2005;184(3):868-877.
9 Bassa P, Kim EE, Inoue T, et al. Evaluation of preoperative chemotherapy using PET with fluorine-18-fluorodeoxyglucose in breast cancer. J Nucl Med. 1996;37(6):931-938.
10 Schelling M, Avril N, Nahrig J, et al. Positron emission tomography using [(18)F]-fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J Clin Oncol. 2000;18:1689-1695.
11 Biersack HJ, Palmedo H. Locally advanced breast cancer: is PET useful for monitoring primary chemotherapy? J Nucl Med. 2003;44(11):1815-1817.
12 Rosen EL, Eubank WB, Mankoff DA. FDG PET, PET/CT, and breast cancer imaging. RadioGraphics. 2007;27:S215-S229.
13 Xing Y, Ding M, Ross M, et al. Meta-analysis of sentinel lymph node biopsy following preoperative chemotherapy in patients with operable breast cancer. ASCO Annual Meeting, 2004, New Orleans, LA abstract 561.
14 Huston TL, Osborne MP. Evaluating and staging the patient with breast cancer. In: Ross D, editor. Breast Cancer. 2nd ed. Philadelphia: Elsevier Churchill Livingstone; 2005:309-318.
15 Schirrmeister H. Detection of bone metastases in breast cancer by positron emission tomography. PET Clin. 2006;1(1):25-32.
16 Chom Y, Chan K, Lam W, et al. Comparison of whole body MRI and radioisotope bone scintigram for skeletal metastases detection. Chin Med J (Eng1). 1997;110(6):485-489.
17 Cook GJ, Houston S, Rubens R, et al. Detection of bone metastases in breast cancer by 18 FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol. 1998;16(10):375-379.
18 Ohta M, Tokuda Y, Suzuki Y, et al. Whole body PET for the evaluation of bony metastases in patients with breast cancer: comparison with 99 m Tc-MDP bone scintigraphy. Nucl Med Commun. 2001;22(8):875-879.
19 Yang SN, Liang JA, Lin FJ, et al. Comparing whole body 18F-2 deoxyglucose positron emission tomography and technetium-99 m methylene diphosphonate bone scan to detect bone metastases in patients with breast cancer. J Cancer Res Clin Oncol. 2002;128(6):325-328.
20 Uematsu T, Yuen S, Yukisawa S, et al. Comparison of FDG PET and SPECT for detection of bone metastases in breast cancer. AJR Am J Roentgenol. 2005;184(4):1266-1273.
21 Ciatto S, Pacini P, Azzini V, et al. Preoperative staging of primary breast cancer: a multicentric study. Cancer. 1988;61(5):1038-1040.
22 Dose J, Bleckmann C, Bachmann S, et al. Comparison of fluorodeoxyglucose positron emission tomography and “conventional diagnostic procedures” for the detection of distant metastases in breast cancer patients. Nucl Med Commun. 2002;23(9):857-864.
23 Reinig JW, Dwyer AJ, Miller DL, et al. Liver metastasis detection: comparative sensitivities of MR imaging and CT scanning. Radiology. 1987;162:43-47.
24 Eberhardt SC, Choi PH, Bach AM, et al. Utility of sonography for small hepatic lesions found on computed tomography in patients with cancer. J Ultrasound Med. 2003;22(4):335-343.
CASE 1 LABC (large tumor size)
A 45-year-old woman was noted on routine physical examination by her physician to have an abnormal left breast examination. Although the patient had not noted any discrete masses, an area of induration and irregularity was palpated in the left upper breast, extending from upper inner to upper outer quadrant.
Breast imaging evaluation showed extremely dense breast parenchyma. New clustered microcalcifications were identified in the upper inner quadrant (UIQ). Sonography showed irregular, hypoechoic parenchymal echotexture in the left upper breast at 11 to 12 o’clock with cysts and shadowing (Figure 1), and the region of the microcalcifications was visualized as well. Ultrasound-guided biopsy confirmed infiltrating ductal carcinoma (IDC) with ductal carcinoma in situ (DCIS).
FIGURE 1 A and B, Representative ultrasound images of the 11 to 12 o’clock region show dense shadowing, with irregular anterior margination. The extent of the process is difficult to define and to differentiate from extreme fibrocystic changes.
Breast MRI showed striking asymmetry between the two sides, with findings of a very large, diffusely infiltrating cancer on the left (Figures 2 and 3). The intensely enhancing process, centered at 12 o’clock but spanning 11 to 2 o’clock, showed architectural distortion, with additional extensive clumped enhancement diffusely involving the medial breast. By MRI, the abnormality measured at least 6 cm and involved at least two quadrants extensively, indicating that the patient was not a conservation candidate.
FIGURE 2 Axial enhanced, maximal intensity projection MRI shows extreme asymmetry between sides. The right side shows diffuse low-level, extensive, scattered, tiny fibrocystic foci of enhancement. The left side is dominated by a central mass with architectural distortion, and there is geographic enhancement in the medial breast.
FIGURE 3 Representative axial, subtracted, enhanced images, from above to below. A, Clumped enhancement medially with larger central tumor nodules involves both the upper inner and upper outer quadrants at this level. B, There is intense central enhancement with distortion and segmental clumped medial enhancement at this level. C, The spiculation and distortion of the central enhancing component are well demonstrated on this section. The oval defect within the enhancing spiculated mass represents a cyst, which was surrounded by the enhancing tumor. Clumped segmental medial enhancement, suggesting DCIS, is again seen. D, At the level of the nipple, extensive clumped segmental enhancement is seen medially and centrally, suggesting an extensive intraductal component, which was subsequently confirmed. E, Sagittal, subtracted, enhanced breast MRI shows how extensively the entire upper half of the breast is infiltrated.
The mastectomy specimen showed an 8-cm IDC of the central breast extending into the upper inner and lower inner quadrants, with a high-grade DCIS component involving 50% of the lesion (extensive intraductal component). Multifocal satellite tumor nodules were noted within the large tumor. Extensive angiolymphatic involvement was seen, and four sentinel lymph nodes showed metastatic carcinoma (Figure 4). Completion axillary dissection showed no additional axillary disease, for a total of 4 of 20 lymph nodes positive for metastatic disease. The deep mastectomy margin was negative.
FIGURE 4 Coronal short tau inversion recovery (STIR) image of the thorax (obtained with the body coil at the time of breast MRI) shows three adjacent mildly prominent left axillary lymph nodes. Although not prospectively interpreted as suspicious because no one lymph node is particularly large, in retrospect the asymmetry in number from the opposite side is a clue to the axillary involvement.
The patient underwent imaging staging postoperatively, with bone scan, CT, and positron emission tomography (PET) (Figures 5 and 6), which showed only postsurgical changes of the axilla and chest wall and no evidence of distant metastatic disease. Final stage was stage IIIA, with T3N1M0 disease, and the tumor was estrogen receptor and progesterone receptor positive.
TEACHING POINTS
Accurate and timely communication between specialties is a critical part of the care of the newly diagnosed breast cancer patient, as this case illustrates. Evaluations up to the point of the breast MRI had not shown clear evidence that the patient was not a lumpectomy candidate, and so the treatment planning was proceeding with this expectation. One examiner’s concern that there might be a discrepancy between the imaging findings and the clinical examination led to performance of breast MRI, which confirmed a very large, locally advanced tumor. Unfortunately, this was ordered at the last minute and without the knowledge of the surgeon. Fortunately, the radiologist charged with performing the needle localization on the day of surgery was able to rectify the situation, which was precipitously, but satisfactorily, resolved in favor of the patient undergoing mastectomy.
CASE 2 LABC with axillary and internal mammary involvement; staging with whole-body PET and PEM
A 77-year-old woman was noted on routine physical examination by her primary care physician to have a palpable 3-cm mass on the right at 6 o’clock. Breast imaging evaluations confirmed this mass, which was best seen on ultrasound as a 3.2-cm mass with lobular and irregular margins (Figure 1). On ultrasound, a second suspicious mass, which was not seen mammographically, was noted medial to the dominant mass, at 4 o’clock (Figures 2 and 3). This was a bilobed, hypoechoic mass. A highly suspicious axillary lymph node was also found, measuring 2.3 cm, with complete effacement of the fatty hilus (Figure 4).
FIGURE 1 Ultrasound of the palpable lump on the right at 6 o’clock shows a very hypoechoic, heterogeneous, vascular mass with lobular and irregular margins, with a highly suspicious sonographic appearance. Biopsy confirmed IDC.
FIGURE 2 Ultrasound of the right 4-o’clock level shows a hypoechoic, bilobed, more smoothly marginated mass, resembling an abnormal lymph node in morphology. Biopsy with ultrasound guidance confirmed IDC.
FIGURE 3 Ultrasound shows the relationship between the 4- and 6-o’clock masses, which are 3.5 cm apart by ultrasound. A rounded, sub-centimeter nodule interposed between the two masses (arrow) was not noted prospectively. It corresponds to a smaller satellite lesion, which was FDG avid and seen on both whole-body and dedicated breast PET (PEM).
FIGURE 4 Ultrasound of the right axilla shows a round, completely replaced enlarged axillary lymph node. The fatty hilus is completely effaced.
These three abnormalities were biopsied with ultrasound guidance. Both the 4- and 6-o’clock breast masses were poorly differentiated infiltrating ductal carcinomas (IDC), estrogen receptor and progesterone receptor negative, HER-2/neu negative, grade 8/9. The axillary lymph node fine-needle aspiration showed adenocarcinoma, consistent with metastatic breast carcinoma.
Bone scan suggested an L1 compression fracture as the etiology of back pain (Figure 5). A band of modest increased metabolic activity was seen at the superior end plate of L1 on PET, and CT showed superior end-plate invagination, confirming the bone scan impression of a compression fracture (Figure 6). Three right lower inner quadrant FDG-avid breast masses were seen on whole-body PET/CT, with a small additional FDG-avid nodule seen between the two known IDC masses at 4 and 6 o’clock. The known involved right axillary lymph node was intensely hypermetabolic and was accompanied by several smaller additional metabolically active axillary lymph nodes. Activity was also seen in two internal mammary lymph nodes, which on CT measured 8 mm (Figures 7 and 8).
FIGURE 5 Bone scan images show a band of increased activity at the L1 level. This pattern of activity suggests a compression fracture as the etiology of the patient’s back pain.
FIGURE 6 Coronal CT reconstruction of the lumbar spine shows end-plate invagination of the L1 vertebral body, correlating with the bone scan and consistent with a compression fracture (arrows). Modest PET scan activity was present at this level. Other lumbar levels show discogenic changes and a levoscoliotic curvature.
FIGURE 7 Enhanced chest CT images, from above to below. A, An oval, markedly enlarged axillary lymph node is seen on the right, corresponding to the ultrasound. Scatter artifact from a right chest wall pacemaker is noted. B, A rounded, enlarged right internal mammary lymph node is seen adjacent to the enhanced internal mammary artery (arrow). This was hypermetabolic on PET. The vein is seen over the lateral right sternum. C, A second right internal mammary (IM) lymph node is seen adjacent to the artery and vein (from right to left: IM artery, IM vein, IM lymph node) (arrow). This was also hypermetabolic on PET. D, Through the inferior breasts, two right breast masses are seen. The medial one is the same as the 4-o’clock mass on ultrasound. It has a lobulated contour. No fat plane is seen between it and the muscle. A round smaller mass is seen lateral to it. E, Further inferior, the dominant right 6-o’clock irregularly marginated mass is seen, as well as the inferior aspect of the 4-o’clock mass.
FIGURE 8 PET scan images show three multifocal, FDG-avid right lower inner quadrant breast masses, as well as FDG-avid axillary lymph nodes and internal mammary nodes (not shown). A, Cursors are positioned at the level of the 6-o’clock IDC. A small adjacent FDG-avid nodule is seen on the coronal slice. B, Cursors are positioned at the level of the 4-o’clock IDC. The small satellite mass is partially seen on the axial image.
A PEM study was also obtained in this patient after completion of PET/CT, using the same FDG dose. The proven multifocality of her tumor would ordinarily have been an indication for breast MRI, but the patient could not readily undergo breast MRI because of her pacemaker. The dominant mass on the right at 6 o’clock was seen with exquisite detail on PEM, with intense heterogeneous uptake of FDG (Figure 9). The 4-o’clock mass was not seen on either view. This result was anticipated because of its far posterior position on the chest wall on CT. The small, intermediately positioned satellite tumor mass was visualized on the mediolateral oblique (MLO) projection, which shows more posterior breast tissue. The PEM also permitted more thorough screening of the left breast.
CASE 3 LABC with nipple skin involvement
A 56-year-old woman noted new right nipple inversion 4 months before presenting for breast imaging evaluation for a newly developed right palpable axillary lump. Mammography and ultrasound showed a dominant 12-o’clock mass with nipple retraction and localized skin thickening, as well as axillary lymphadenopathy (Figures 1, 2, and 3). Ultrasound-guided biopsy of the dominant mass confirmed invasive ductal carcinoma (IDC), and ultrasound-guided axillary node fine-needle aspiration confirmed metastatic disease. Periareolar dusky erythema was noted, and skin punch biopsy was performed, which was negative. Local staging was completed with breast MRI (Figures 4, 5, 6, 7, and 8).
FIGURE 1 Ultrasound of the right upper outer quadrant shows a hypoechoic, taller-than-wide, sonographically suspicious mass with irregular and angular margins.
FIGURE 3 Ultrasound of the right axilla shows two adjacent, highly abnormal lymph nodes: both are rounded, with very hypoechoic, thickened cortices. Nodular mass effect is exerted on the echogenic fatty hila, which are partially effaced. No increased vascularity is identified.
FIGURE 4 Maximal intensity projection of enhanced, subtracted, axial gradient echo data set shows an intensely enhancing, dominant mass in the central right breast. Numerous linear spicules extend anteriorly toward the nipple. There are enlarged, draining veins on the right, and enlarged, enhancing right axillary lymph nodes.
FIGURE 5 Axial breast MR images through the dominant right IDC (A, enhanced, subtracted, T1-weighted gradient echo; B, STIR) show rim enhancement and spiculation of the mass. Linear spicules extend anteriorly toward the nipple and posteriorly toward the pectoral muscle. The periareolar skin is thickened and edematous, and enhances. A rounded, low-lying axillary or intramammary lymph node enhances intensely in the posterolateral right breast.
FIGURE 6 Sagittal, subtracted, contrast enhanced MRI of the right breast showing the enhancing linear tendrils extending to the nipple, as well as the periareolar skin enhancement.
FIGURE 7 Kinetic information (A, DynaCAD color map; B, enhancement curve) showing washout from portions of the IDC mass.
FIGURE 8 Axial STIR images of the axilla. A, An enlarged right axillary level I lymph node is seen lateral to the pectoralis major and minor muscles (arrow). B, An enlarged interpectoral (Rotter’s) lymph node is seen on the right, between the pectoralis major muscle in front and pectoralis minor muscle behind (arrow).
Systemic staging with positron emission tomography (PET)/CT showed fluorodeoxyglucose (FDG) avidity of the known right breast cancer and axillary lymphadenopathy, but no additional disease. Neoadjuvant chemotherapy was given, consisting of four cycles each of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) (AC) and paclitaxel (Taxol). The nipple inversion resolved, and there was marked clinical regression of the dominant mass. Modified radical mastectomy and axillary dissection were performed. A 4.5-cm residual lesion of admixed IDC and normal breast tissue remained. Margins were negative, and 5 of 13 lymph nodes showed metastatic tumor. Chest wall, supraclavicular, and posterior axillary boost radiation therapy were given, and the patient was placed on anastrozole (Arimidex).
CASE 4 Natural history of untreated inflammatory breast cancer
A 57-year-old woman noted her right breast to be enlarged and heavier feeling. Mammography showed concerning right upper outer quadrant (UOQ) microcalcifications (Figures 1 and 2). Right breast sonogram showed periareolar skin thickening (Figure 3) and an UOQ 1.5-cm shadowing hypoechoic mass with irregular margins (Figure 4), as well as hypoechoic, rounded, axillary lymph nodes (Figures 5 and 6). Ultrasound-guided core needle biopsy of the UOQ mass confirmed infiltrating ductal carcinoma (IDC), estrogen receptor and progesterone receptor negative, HER-2/neu negative. Ultrasound-guided fine-needle aspiration (FNA) of an axillary lymph node confirmed metastatic carcinoma, consistent with breast primary origin. Two skin punch biopsies were performed because of clinical suspicion of inflammatory carcinoma: both were negative. Skin biopsies were subsequently repeated because of persistent high suspicion of inflammatory cancer, and confirmed intralymphatic carcinoma.
FIGURE 1 MLO (A) and CC (B) mammograms show heterogeneous breast parenchymal density. No parenchymal changes were detected compared with the prior study, 4 years before. An area containing concerning microcalcifications is circled in the UOQ.
FIGURE 2 Lateral magnification view of the right upper breast shows concerning new microcalcifications.
FIGURE 3 Sonographic image of the right periareolar skin is thickened to nearly 4 mm. An edematous appearance of the subjacent tissues is seen, without a discrete mass.
FIGURE 4 A very hypoechoic, highly suspicious mass with angular margins was found in the right UOQ. Ultrasound-guided biopsy confirmed IDC.
FIGURE 5 Right axillary ultrasound shows two oval, adjacent, very hypoechoic lymph nodes, with no identifiable fatty hila.
FIGURE 6 Another right axillary lymph node shows cortical mantle thickening, effaced hilus, and abnormally increased vascularity. FNA confirmed metastatic disease.
Breast MRI showed multiple intensely enhancing right breast masses, as well as enhancement of the skin (Figures 7, 8, 9, 10, and 11). Systemic staging consisted of positron emission tomography (PET)/CT and enhanced body CT scans. Hypermetabolism was identified in the right breast and axillary lymph nodes, but no evidence of distant metastatic disease was found (Figures 12, 13, 14, 15).
FIGURE 7 Coronal STIR image of the thorax, acquired with the body coil, shows a cluster of small, but asymmetrical, right axillary lymph nodes.
FIGURE 8 Axial STIR MRI shows the right breast to be much larger than the left. The skin is thickened and edematous, and the breast itself shows diffuse increased edema, extending throughout the breast, back to the muscle.
FIGURE 9 Enhanced axial maximal intensity projection view shows multiple intensely enhancing masses in the larger right breast.
FIGURE 10 Enhanced axial, subtracted image of the breasts shows some of the enhancing right masses. The thickened skin can be seen to enhance as well.
FIGURE 11 Kinetic data from the breast MRI, displayed as a color-coded overlay on the breast MRI data (A). A region of interest has been placed, and kinetic data from this is displayed graphically (change in signal intensity versus time) in B. There is a sharp and rapid upstroke, reflecting rapid enhancement, and washout, which correlates with angiogenesis.
FIGURE 12 Axial PET/CT, through the axilla, shows hypermetabolism of a small right axillary lymph node (cursors), suggesting metastatic involvement.
FIGURE 13 Axial PET/CT, through the breasts, shows one of several hypermetabolic masses in the right breast. The entire breast, including the thickened skin, shows mild, generalized increased uptake compared with the left side.
FIGURE 14 Enhanced chest CT image for correlation. The right axilla is filled with asymmetrical, mildly enlarged lymph nodes, and there is diffuse axillary stranding. Although no one of these lymph nodes is markedly enlarged by absolute size criteria, the constellation of findings is highly suspicious, and the stranding is concerning for extranodal extension.
FIGURE 15 Enhanced chest CT images through the breasts (A above B) show multiple small, enhancing right breast masses, corresponding to the MRI and PET, with several small, enhancing right lateral chest wall lymph nodes. Note the skin thickening on the right.
The patient initially declined all conventional therapies and opted against medical advice for a trial of an alternative soy product. After 3 months, she underwent repeat breast MRI and PET/CT to assess her response. The breast MRI showed growth of the multiple breast masses to near confluency (Figures 16 and 17). PET/CT showed progression in the breast and axilla, but no distant metastases. Four cycles of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) (AC) neoadjuvant chemotherapy were given, after which the patient underwent a right modified radical mastectomy and axillary lymph node dissection. The mastectomy specimen showed a 5.5-cm IDC with high-grade comedo DCIS and dermal intralymphatic carcinoma. Angiolymphatic invasion was extensive, both peritumoral and distant. The margins showed intralymphatic carcinoma at skin margins. Fourteen out of 14 lymph nodes showed tumor, with extranodal soft tissue extension and involvement of perinodal lymphatic spaces.
