Molecular imaging in breast cancer

Radiol Clin N Am 42 (2004) 885 – 908

Molecular imaging in breast cancer David M. Schuster, MD*, Raghuveer K. Halkar, MD Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Emory University Hospital, 1364 Clifton Road, NE, Atlanta, GA 30322, USA

Molecular imaging is defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level. By definition, molecular imaging is not restricted to any one tool; it may involve optical, gamma ray, positron, or magnetic imaging [1]. The type of probes or imaging tool depends on the size of the imaged objects (eg, optical imaging for cell and tissue cultures and very small animals). The advantage of radionuclide techniques over other imaging approaches is the ability to label any chemical species with an isotope of choice. The gamma emissions of single-photon emission CT (SPECT) or positron emission tomography (PET) radiotracers are energetic enough to travel through sizeable amount of tissues and enable imaging of the whole body. Carbon, nitrogen, hydrogen, and oxygen have positron-emitting isotopes and are ideally suited for designing probes to image natural biochemical and molecular process in vivo. Conventionally used SPECT radioisotopes are usually not elements found in living system and may change the behavior of small-sized probes. Probes can either home in on targets on cell surfaces, such as antigens and receptors, or intracellular structures, such as internalized receptors. Fluorodeoxyglucose (FDG), amino acids, and reporter genes can also be used as probes that monitor a physiologic process. In the last decade, the role of radionuclide imaging has expanded significantly in the clinical management of breast cancer because of scintimammography,

* Corresponding author. E-mail address: [email protected] (D.M. Schuster).

sentinel node detection, and FDG PET. Molecular imaging also plays a major role in drug development, gene therapy, and basic science research of breast cancer. Table 1 provides an overview of various radionuclide imaging procedures available clinically and for research. This article focuses on two of the most commonly used molecular imaging modalities, FDG PET and single-photon imaging.

Positron emission tomography Introduction In 1984 Beaney et al [2] reported on the use of O-15 PET to study blood flow, oxygen extraction ratio, and oxygen use in nine breast cancer patients. They found higher blood flow and slightly higher oxygen use in tumor tissue. The earliest studies on the use of F-18 FDG in the diagnosis of breast cancer were in 1989 [3,4]. Minn and Soini [3] reported on 17 patients with advanced breast cancer imaged with a specially modified gamma camera. There was an 82% rate of visualization of metastatic tumors and 75% for lymph nodes. PET imaging with F-18 FDG has since become the dominant molecular imaging modality for breast cancer, demonstrating its worth with advanced-stage disease, deciding locoregional extent, determining response to therapy, and in suspicion of recurrent and metastatic involvement [5,6]. Effective October 1, 2002, the Centers for Medicare and Medicaid Services approved FDG PET for the staging of patients with distant metastasis; the restaging of patients with locoregional recurrence or metastasis; and for monitoring response to therapy

0033-8389/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.rcl.2004.06.001

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Table 1 Radionuclide imaging procedures available clinically and for research

SPECT

PET

Detection of primary

Staging

Restaging

Perfusion imaging agents Tc 99m MIBI Tc 99m tetrofosmin Tl 201 Nonspecific agents Tc 99m MDP Tc 99m DTPA Receptor imaging In 111 pentetreotide I 131 iodovinyl estradiol-17a I 123 estradiol-16a Monoclonal antibodies Anti-CEA, HMFG1, HMFG2, SM3 Glucose metabolism F-18 FDG Amino acid metabolism C-11 l-methionine Receptor agents 21-F-18 fluoro 16 alpha ethyl 19 nor progesterone 16-alpha F-18 estradiol-17b

Sentinel node localization Tc MDP bone scan Tc 99m MIBI and tetrofosmin

Tc MDP bone scan

Monitoring of treatment and toxicity Tc 99m MIBI Apoptosis agents Tc annexin MUGA and first pass In 111 antimyosin I 123 MIBG

Glucose metabolism F-18 FDG Amino acid metabolism C-11 l-methionine Receptor agents 21-F-18 flouro 16 alpha ethyl 19 nor progesterone 16-alpha F-18 estradiol-17b

Glucose metabolism F-18 FDG Amino acid metabolism C-11 l-methionine Receptor agents 21- F-18 fluoro 16 alpha ethyl 19 nor progesterone 16-alpha F-18 estradiol-17b

Glucose metabolism F-18 FDG Amino acid metabolism C-11 l-methionine Receptor agents 21- F-18 fluoro 16 alpha ethyl 19 nor progesterone 16-alpha F-18 estradiol-17b

Abbreviations: CEA, carcinoembryonic antigen; DTPA, diethylenetriamine pentaacetic acid; FDG, fluorodeoxyglucose; I, iodine; In, indium; MDP, methylene diphosphonate; MIBG, meta-iodobenzylguanidine; MIBI, sestamibi; MUGA, multiple gated acquisition; PET, positron emission tomography; SPECT, single-photon emission computed tomography; Tc, technetium; Tl, thallium.

(when a change in therapy is contemplated) [7]. FDG PET is currently not approved by Centers for Medicare and Medicaid Services for the initial diagnosis of breast cancer or for axillary lymph node staging and surgical planning. Only Food and Drug Administration approved full or partial ring PET scanners (and not coincidence systems) are eligible for reimbursement. Most insurance carriers follow the lead of Centers for Medicare and Medicaid Services in establishing reimbursement policies. In a study by Yap et al [8] based on a clinician questionnaire, FDG PET changed the clinical stage in 36% of breast cancer patients and the overall clinical management in 58%. PET has also been added as an optional imaging procedure to the latest National Comprehensive Cancer Network guidelines in the evaluation for breast cancer recurrence or in the initial work-up for suspected stage IV disease [9]. Fig. 1 is an example of FDG uptake in primary breast mass and axillary lymph nodes.

General principles of fluorodeoxyglucose positron emission tomography Fluorodeoxyglucose is actively transported into the cell where it is irreversibly phosphorylated by hexokinase, trapping it within the cell where it does not proceed further down the glycolytic pathway. The Glut-1 glucose transporter is overexpressed in breast cancer compared with normal breast tissue; this overexpression results in increased visualization with F-18 FDG [10]. When F-18 decays, its nucleus ejects a positron (positive electron), which travels about 2 to 3 mm in soft tissue before combining with a negatively charged electron. The resultant annihilation gives off two 511-keV photons in opposite directions. It is these photons that are detected by the PET scanner or the coincidence-imaging device. Autoradiography of breast cancer tissue grown in Lewis rats [11] strongly correlates FDG uptake to tumor cell density and less so within necrotic,

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Fig. 1. Axial CT (A), attenuation corrected PET (B), fused image (C), and non-attenuation corrected PET (D) in a 50-year-old female with a 4 cm primary right breast cancer (arrow) and malignant axillary lymph nodes (arrowhead).

inflammatory, or granulation tissue. Avril et al [12] reported on the relationship of FDG uptake and tumor histology (ductal greater than lobular); microscopic tumor growth pattern (nodular greater than diffuse); and tumor cell proliferation indices. Surprisingly, the authors did not find a correlation to Glut-1 expression. A comprehensive study was recently completed, however, which demonstrated that there is a positive correlation between FDG uptake and Glut-1 expression; mitotic activity index; percent necrosis (likely reflecting proliferation rate); tumor cells per volume; hexokinase-1 expression; number of lymphocytes (but not macrophages); and microvessel density [13]. Oshida et al [14] reported an association between FDG uptake and tumor size, microvessel density, number of positive lymph nodes, histologic grade, and absence of estrogen receptors (ERs). FDG uptake has also been shown to be higher with infiltrating ductal carcinoma as compared with lobular, with increasing histopathologic grade, and with higher levels of the p53 gene [15]. Others have also reported

lack of correlation between FDG uptake and estrogen receptor status [16]. Positron emission tomography technique Before F-18 FDG is injected, the patient should fast for 4 to 6 hours. Increased plasma glucose has been demonstrated to decrease FDG uptake within breast cancer [17]. Most centers determine blood glucose in all patients, or at least those with known diabetes. When glucose levels are elevated above normal, the possibility of decreased sensitivity should be kept in mind during scan interpretation. At the authors’ facility, if the plasma glucose is greater than 180 mg/100 mL the study may be canceled. The oncologic patient should not be given insulin to decrease blood glucose because this results in poor quality scan and poor tumor conspicuity, because glucose is driven into muscle. It is preferable to inject in an arm or hand vein contralateral to the involved breast or in a foot vein in

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case of extravasation that may result in uptake in benign lymph nodes in the axilla on the same side as the injection. A dose of 10 to 20 mCi (370 – 740 mBq) is used most frequently. It is most common to wait 45 to 60 minutes between injection and scanning. Some centers scan after 90 to 120 minutes because there has been some evidence that increased length of the uptake phase results in better separation between inflammatory and neoplastic lesions [18]; tumor uptake increases relative to inflammatory lesions over time. Boerner et al [19] studied 29 patients with breast cancer over 2 cm in size and reported improved tumor visualization at 3 hours compared with 1.5 hours at both primary and lymph node sites. Delayed imaging or dual time point scanning increases the difficulty of scanning logistics and decreases count statistics because of radiotracer decay. Scanning in the supine position is most common, but some authors advocate scanning the patient prone to improve breast definition and reproducibility [5,20,21]. Prone scanning requires some type of insert similar to one used for scintimammography. Although there is good evidence that prone scanning is preferable for imaging primary breast tumors, most breast cancer patients undergo PET scanning for evaluation of locoregional spread and distant metastases, in which case supine imaging provides diagnostic quality images and is more comfortable for the patient. If possible, the patient should be scanned in the arms-up position to decrease scatter artifact. Most normal breast tissue exhibits diffuse mild FDG uptake with slightly more focal uptake in the nipple and periareolar regions. Even normal breast uptake is inconsistent [22]. Uptake increases with the ratio of glandular versus fatty breast tissue [23]. Uptake in lactating breasts may be variable and asymmetric [24,25]. Little radiotracer activity is present in milk; the main source of radiation exposure is physical proximity to the mother during breast feeding [25]. Because F-18 has a half-life of 110 minutes, there is essentially no radioactive risk to the infant by 24 hours. Normal uptake also increases with hormone replacement in postmenopausal women and around breast implants. It is most common to interpret PET examinations using qualitative parameters (increased uptake over expected background) supplemented by semiquantitative standardized uptake values (SUV) [26]. SUV is defined as activity within the target region divided by injected radiotracer activity corrected for body weight, lean body mass, or body surface area. Avril et al [27] studied two types of interpreting schemes: that of conventional image reading (intense focal up-

take above that of normal breast tissue) and sensitive image reading (moderate focal or diffuse uptake compared with normal breast). Conventional criteria demonstrated 64.4% sensitivity and 94.3% specificity; sensitive criteria resulted in 80.3% sensitivity and 75.5% specificity. With increasingly sensitive positivity criteria, specificity decreases. Standardized uptake values can be especially useful for following response to therapy. SUV normalized to body weight is commonly used, but can be problematic because FDG is taken up less in fat than in muscle. Patients often lose percent body fat during chemotherapy. The apparent SUV of the lesion may change because of weight loss alone. SUV normalized to lean body mass or body surface area is considered more accurate [28]. Vranjesevic et al [23] described the highest maximum SUV (normalized for body weight) in 45 women without breast cancer to be less than 1.5, suggesting that a cutoff of 2 to 2.5 for determining abnormality does not overlap with that of normal breast tissue. Similarly, Avril et al [29] reported that average SUV (normalized for body weight) corrected for partial volume effects and for plasma glucose was the most accurate semiquantitative method with 90% specificity and 85% sensitivity for determining malignancy at a 1.5 SUV. Maximum SUV without such corrections was the least accurate with 90% specificity and 66% sensitivity at a 2.8 SUV threshold. In an earlier paper, Avril et al [30] reported that benign breast lesions had an average SUV of 1.4 ± 0.5 versus malignant tumors with an average SUVof 3.3 ± 1.8. Using a cutoff of 2.5 SUV, benign versus malignant could be predicted with a sensitivity of 75% and a specificity of 100%. If partial volume correction were performed based on anatomic imaging, sensitivity increased to 92% and specificity remained high at 97%. In a more recent paper, Krak et al [31] measured various methods of assessing FDG uptake in breast cancer in response to chemotherapy compared with a gold-standard quantitative technique and reported excellent correlation (r >.95) of average SUV for a three-dimensional region defined by a 50% threshold relative to maximum tumor value, normalized for lean body mass and plasma glucose. Too great of a reliance on SUV is risky. SUV can be variable because of length of the uptake phase, equipment, tumor geometry, partial volume effects, plasma glucose levels, body habitus, and methods of reconstruction and attenuation correction [32,33]. Even with the most accurate techniques there is overlap of the range of SUV for benign and malignant lesions. Furthermore, using average SUV is highly dependent on choosing an appropriate and

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consistent region of interest. Maximum SUV measurements are considered more reliable in a clinical setting and have been correlated to average SUVs for following therapy [34]. In the authors’ experience it is best to use a qualitative approach supplemented by semiquantitative SUV data. The use of SUV alone is not recommended to separate benign from malignant uptake because of its inherent variability and lack of consistent applicability from research to a clinical situation. It is most practical and reliable to use maximum SUV in clinical practice. Whether one corrects for body weight, lean body mass, or body surface area, and for plasma glucose, it should be done consistently. Diagnostic imagers should also be familiar with other sources of artifactual uptake including that of bbrown fatQ described in an excellent recent review by Yeung et al [35]. Granulocyte colony – stimulating factor therapy is known to increase marrow and splenic uptake of FDG and this effect may persist for at least 1 month [36,37]. Granulocyte colony – stimulating factor is often given as part of chemotherapy protocols and may not be clearly identified in the patient record. There are conflicting studies as to whether chemotherapy alone [36,38] increases marrow uptake. In the authors’ experience, granulocyte colony – stimulating factor causes intense homogenous marrow (and splenic) uptake, although chemotherapy alone can also mildly increase FDG marrow uptake. Finally, although the positive predictive value of FDG imaging for breast cancer is high, false-positives have been reported in a wide variety of situations including dysplasia, fibroadenomas, inflammation, infectious, and postsurgical etiologies [27,39,40], and even a bee sting [41]. As always, correlation of the PET findings with other imaging and history and physical examination is important. Uptake at the site of excisional biopsies has been described for weeks after the primary procedure [42]. False-negative results may be present with lesions less than 1 cm, tubular carcinoma, lobular carcinoma, and carcinoma in situ [43]. Diagnosis In 1991, Wahl et al [44] reported that 10 of 10 primary breast cancers measuring 3.2 to 12 cm were imaged with FDG PET with relatively high tumor to background ratios. Adler et al [45] studied 28 patients with 35 breast lesions over 1 cm and determined that FDG PET could discriminate between 8 benign and 27 malignant masses with a sensitivity of 96% and specificity of 100%. In a tabulated summary of the PET literature published in

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2001 [46], the authors analyzed 12 papers published between 1993 and 2000 in which a total of 430 patients were studied; they reported overall 91% sensitivity, 93% specificity, and 95% accuracy. Other studies have demonstrated the limitations of FDG PET as a primary diagnostic modality. Lesion detection is clearly related to lesion size. In the study by Avril et al [27], only 68% of T1 (
2 cm) lesions were detected with even sensitive interpretive criteria. For lesions less than 1 cm, sensitivity decreased to 25%. Whereas 98 of 108 lesions over 1 cm were detected with sensitive criteria (moderate focal or diffuse uptake compared with normal breast), only 81 of 108 were detected with conventional image reading (intense focal uptake above that of normal breast tissue). Although sensitivity increases using sensitive image reading, specificity decreases. In addition, invasive lobular cancers demonstrated a 65.2% false-negative rate (using conventional criteria). Of 18 patients with multicentric disease, only 27.8% were correctly identified with conventional and 50% by sensitive criteria. PET is more sensitive in detecting multifocal disease, however, compared with other imaging modalities [47]. Avril et al [27] conclude that sensitivity and specificity vary with tumor size and histology, and accuracy of FDG PET is not high enough for routine clinical use; because of the high positive predictive value of PET (96.6%), it may be useful in a select group of patients and for staging and response to therapy. Avril et al [27] comments that smaller tumors had been excluded in earlier studies. In a study by the Blue Cross and Blue Shield Association Evidence-Based Practice Center, Samson et al [26] performed a meta-analysis of 13 articles culled from the literature and concluded that FDG PET should not be used routinely in deciding to perform a biopsy. The pooled sensitivity was 88% and specificity 79%. The mean tumor size in most studies was 2 to 4 cm. In a patient population with a 50% prevalence of cancer, false-negative risk is 12.1%, unacceptably high. Samson et al [26] suggested that future studies concentrate on PET as an adjunct in patients with indeterminate mammograms referred for short-term mammographic follow-up and for those with dense breasts. There have also been a number of studies comparing the use of MR imaging versus FDG PET. Walter et al [48] studied 42 lesions in 40 patients preoperatively. The sensitivity of FDG PET was 63% and the specificity was 91%; the sensitivity of MR imaging was 89% and the specificity was 74%. MR imaging is more sensitive, whereas PET is more specific. Most of the false-negative masses on

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FDG PET were smaller than 1.5 cm. The authors suggest a diagnostic algorithm whereby MR imaging is used in place of follow-up for an indeterminate lesion on mammography, ultrasound, or clinical examination. If the MR image is indeterminate, FDG PET is performed for further characterization. Brix et al [49] also found similar accuracy for PET and MR imaging for local disease, but PET detected additional lymph node or distant metastases compared with MR imaging. Fluorodeoxyglucose PET had demonstrated initial promise in the primary diagnosis of breast cancer, but later studies pointed out limitations, mostly because of a lack of sensitivity with small lesions. Although PET may be of limited value in the routine diagnosis of breast cancer, it has a role to play in a select group of patients, such as those with dense breasts or with implants and other surgery (Fig. 2), in determining multiplicity, in localizing the primary tumor in

patients with metastases of breast origin when mammography is indeterminate, and in those patients in which biopsy is not a desirable option [6,40,50,51]. It remains to be seen if sensitivity for initial diagnosis improves as device resolution advances and as special PET-mammography imaging systems are developed and marketed. Staging Determining lymph node status is important for accurate staging of the breast cancer patient. Patients with four or more involved axillary lymph nodes have a significantly increased risk for recurrence [9]; the larger the size of the primary tumor, the greater the chance of lymph node involvement. In 1990 Wahl et al [52] reported on FDG uptake in breast cancer – involved lymph nodes in an animal model. In 1993, Adler et al [45] reported 90%

Fig. 2. Axial CT (A), attenuation corrected PET (B), fused image (C), and non-attenuation corrected PET (D) in a 49-year-old female with a peri-implant recurrence in the left breast (arrow).

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sensitivity and 100% specificity in axillary lymph node staging, although in a later study they reported lower specificity of 66% [53]. A review of the literature on staging by FDG PET analyzed 20 papers (total of 1678 patients) published between 1993 and 2000 [46]. PET had a pooled sensitivity of 91% and a specificity of 88% with 90% accuracy. PET also changed management in an average of 24% of cases noted in four studies. In a study of 167 patients with T1 or T2 breast cancers scheduled to undergo axillary lymph node dissection [54], an overall 94.4% sensitivity, 86.3% specificity, and 95.3% negative predictive value were reported for determining lymph node status by FDG PET. Lymph nodes were sectioned in two or three parts and examined with hematoxylin-eosin staining. Schirrmeister et al [47] also reported on the use of FDG PET in the preoperative staging of breast cancer in 177 patients compared with standard imaging (mammography, chest films, ultrasound of the breast and liver, and bone scanning) and found that FDG PET was 79% sensitive and 92% specific in detecting axillary lymph node metastases. The study authors also noted that FDG PET was twice as sensitive (63% versus 32%) in detecting multifocal disease compared with ultrasonography and mammography. All of the missed axillary lesions were 1 cm or less. The authors recommended against FDG PET as the sole primary staging method for the axillae because of a 21% falsenegative rate, but observed that the use of PET surpasses that of other noninvasive techniques including physical examination and is valuable in assessing preoperatively for intramammary (IM) nodes, distant metastases, and multifocal lesions. In the Blue Cross analysis, Samson et al [55] analyzed four studies involving a total of 203 patients; the pooled sensitivity was 80% and the specificity 89%. The study authors noted that the confidence interval was too broad and the literature too sparse for PET-based staging to recommend PET in the place of sentinel lymph node staging, which has a high sensitivity and a narrow confidence interval. Other studies have further demonstrated the limitations of FDG PET as a primary staging modality by comparing it with fine pathologic sectioning and immunohistochemical staining used in the sentinel lymph node technique. Barranger et al [56] evaluated 32 patients with breast cancer and clinically negative lymph nodes. FDG PET was performed followed by a sentinel lymph node procedure and a complete axillary dissection. Tumor size ranged from 7 mm to 4 cm. PET identified metastases in only 3 of 14 patients with no false-positives. PET had 20% sensitivity but

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100% specificity. All the false-negative nodes on PET were smaller than 1 cm and no micrometastases were detected with PET. There were no false-positives. The authors noted that earlier studies used standard pathologic node analysis with macrosectioning, whereas their study used more sensitive microsectioning as a gold standard. Van der Hoeven et al [42] also documented low sensitivity by FDG PET for lymph node staging, and correlated FDG uptake with axillary tumor load and the avidity of the primary tumor for FDG. The authors commented that earlier studies used hematoxylin-eosin staining of formal axillary nodal dissection specimens as the gold standard and that PET cannot compare with the sensitivity and resolution of immunohistochemical analysis of finely sectioned samples in their study. Others also have reported similarly poor sensitivity for PET in axillary lymph node staging [57 – 59]. PET may prove useful in certain clinical scenarios for initial staging, but these need to be better defined. For example, Danforth et al [21] suggest that for higher stage disease, PET can provide a comprehensive overview of involvement including that of IM nodes, skin involvement, and extent of tumor, including contralateral breast involvement not detected by standard means. Eubank et al [60] reported 88% accuracy for IM nodal disease compared with 70% for CT. Although most IM nodes occur with axillary nodal metastases, 4% to 6% of IM nodal metastases are localized to IM nodes alone; these patients may benefit from regional IM nodal radiation therapy [61]. The importance of IM nodal metastases and its therapeutic implications have not been clarified [6,9]. Fluorodeoxyglucose PET has been shown to locate unsuspected metastases better than any other imaging examination. Avril et al [62] found unsuspected extension to remote sites in 12 of 41 patients. In a study by Dose et al [63] of 50 breast cancer patients, FDG PET was compared with conventional imaging modalities, such as chest films, bone scanning, and abdominal ultrasound. FDG PET detected remote metastases (lung, bone, liver, and mediastinal lymph nodes) with a sensitivity of 86% and a specificity of 90% compared with 36% sensitivity and 95% specificity for the other modalities. Others also have demonstrated FDG PET to be more accurate than technetium 99m methylene diphosphonate bone scanning in the detection of bone metastases from breast cancer [64 – 66]. If the PET scan is negative, bone scanning should still be performed because of the lower sensitivity of PET scanning for osteoblastic metastases compared with

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bone scanning [3,64]. PET is more sensitive for the metabolic process in lytic lesions, whereas bone scanning is more sensitive to the increased turnover in sclerotic lesions. F-18 sodium fluoride scanning has also been studied for the evaluation of bone metastases and performed better than bone scanning with SPECT but at greater cost [67]. It should also be noted that PET is not useful for brain metastases because of native intense uptake of FDG by the brain; MR imaging is the standard to screen for suspected brain involvement. Sentinel lymph node dissection has high sensitivity and specificity to detect lymph node involvement and avoid unnecessary full axillary dissections. FDG PET is not of sufficient sensitivity to take the place of fine sectioning and immunohistochemical lymph node evaluation. In suspected high-risk disease, PET can provide important information by detecting IM and supraclavicular nodes and distant metastases. Because of its high positive predictive value, FDG PET may obviate a sentinel lymph node procedure and axillary dissection. PET may also improve the small false-negative rate of the sentinel lymph node method by detecting remote metastases or in nonsentinel lymph nodes. Prognosis and response to therapy The use of neoadjuvant chemotherapy has increased the rate of breast conservation surgery [5]. Patients with minimal residual disease or complete pathologic response have higher survival than those with gross residual disease. Clinical response does not necessarily correlate with pathologic response. Anatomic imaging, such as mammography or ultrasound, can be useful to assess response but may not easily distinguish scar from viable tumor [34,43,68]. Varied accuracy has been reported with MR imaging including an overlap in the appearance of benign and malignant lesions [68,69]. FDG PET has been shown to aid in monitoring response to chemotherapy and has prognostic benefit [43]. In 1989, Minn and Soini [3] reported that an increase in FDG uptake in treated breast cancer correlated with progressive disease. Subsequently, Wahl et al [70] studied 11 women receiving chemohormonotherapy with PET during the first three cycles of therapy and reported a decrease in FDG uptake in responding patients, whereas no significant decrease was present in nonresponders. Changes on PET preceded changes in tumor diameter. In a tabulated summary of the PET literature [46], 11 papers published between 1993 and 2000 involving 178 patients were analyzed. The authors report an

overall 81% sensitivity, 96% specificity, and 92% accuracy for monitoring response to therapy. Oshida et al [14] studied Kaplan-Meier survival curves in 70 patients with primary breast cancer after classifying the patients into low tumor SUV (<3) and high SUV (>3) and found a statistically significant worse prognosis for overall and relapse-free survival in the high-SUV group. SUV was found to be an independent predictor of relapse-free survival in breast cancer. Smith et al [71] studied 31 breast cancer lesions over 3 cm in patients undergoing chemotherapy before surgery. Dynamic scans were obtained before, after the first, and second, fifth, and eighth courses of chemotherapy. The authors noted that mean pretreatment SUV (corrected for body surface area) of the eight lesions that achieved a complete microscopic pathologic response was significantly higher than the 23 lesions that did not undergo such a response. They speculated that these tumors are more susceptible to antineoplastic therapy because they have higher metabolic rates as reflected in FDG uptake. In addition, the authors reported that the reduction in SUV even after the first course of chemotherapy is greater in patients achieving a pathologic response. When a 20% reduction in SUV was used as a cutoff, one could predict a complete macroscopic or microscopic pathologic response with 90% sensitivity and 74% specificity. Mankoff et al [72] reported similar results to Oshida et al [14] in that high pretherapy glucose metabolism predicted a poor response to chemotherapy. Patients with relatively low glucose metabolism compared with blood flow (measured with O-15 water) demonstrated increased macroscopic pathologic complete response. It was postulated that a high glucose metabolic ratio to blood flow is indicative of tumor hypoxia in which a larger amount of glucose is extracted by cancer cells. Hypoxia has been implicated in chemotherapy resistance. In a later study by the same group [73] in 35 patients with locally advanced breast cancer in which PET scans were obtained at baseline and after 2 months of chemotherapy, it was noted that the decrease in tumor blood flow more than the decrease in glucose metabolism predicted disease-free and overall survival. The authors caution that apparent decrease in FDG uptake may be partially caused by tumor shrinkage and resultant partial volume effect; correction for lesion size is important in following tumor response with FDG uptake. Schelling et al [34] studied 22 patients with 24 lesions undergoing therapy for breast cancer with baseline FDG PET, which was repeated after the first and second courses of chemotherapy. All the lesions

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were larger than 3.5 cm, and pathologic and clinical follow-up were obtained. Patients were divided into those with gross residual disease, who had macroscopic tumor or extensive microscopic tumor, and minimal residual disease, which included those patients with scattered foci of microscopic disease or complete pathologic response. The study authors found that minimal residual disease could be identified after the first course of chemotherapy (sensitivity 100%, specificity 85%) by a 55% drop in SUV below baseline. (SUV was normalized to body weight and blood glucose and determined by using the mean of the maximum and average activity values in three contiguous 1.5-cm regions of interest.) In those patients with no clinical or pathologic response, mean SUV increased to 104.5% of baseline after the second course of chemotherapy. The authors concluded that PET can help tailor chemotherapy, but with current technology cannot differentiate between microscopic residual tumor and complete response. In a recent editorial Biersack and Palmedo [74] conclude that FDG PET is a useful tool for predicting response to chemotherapy in patients with locally advanced breast cancer. They note that careful attention to technique should be used including allowance for partial volume effects caused by tumor shrinkage, and that SUV should be normalized to blood glucose levels. Tamoxifen therapy initially increases FDG uptake in certain patients, and scans should be interpreted in that light. Mortimer et al [75] studied 40 patients with

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ER-positive breast cancer before and 7 to 10 days after tamoxifen initiation. In patients who responded to hormonal therapy, FDG uptake increased by a mean of 28.4% ± 23.3%; nonresponders had no significant change (10.1% ± 16.2%). Similar increased uptake in breast cancer lesions has not been reported after chemotherapy alone [74]. Fluorodeoxyglucose PET is valuable in providing prognostic information and following response to therapy, although minimal residual tumor cannot be detected with sufficient sensitivity. Nonresponders and those developing progressive disease or distant metastases can be identified earlier and this information may prove useful in changing therapies and avoiding side effects of chemotherapy that is not effective. A baseline PET combined with a PET after the first course of chemotherapy is more accurate in this regard than are conventional imaging techniques [6]. Fig. 3 illustrates a dramatic response of metastatic breast cancer to fulvestrant (Faslodex) therapy. Recurrence Detection of early recurrence may have important survival benefit prompting the use of new therapies and curative or palliative surgery. Locoregional recurrence most commonly affects the breast, skin, axillary and supraclavicular nodes, and the chest wall. It is difficult to differentiate true recurrence from postsurgical and radiation sequelae using conventional imaging.

Fig. 3. Anterior view from a maximal intensity projection of an FDG-PET scan showing extensive breast cancer pleural implants in the left chest (A), and after one dose of fulvestrant (Faslodex), after which the implants resolved (B). Note normal cardiac (arrow) and renal (arrowhead) uptake better seen in B than in A. Patient was status post unrelated remote right nephrectomy.

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In 1997, Bender et al [76] reported on the superiority of FDG PET in detecting recurrent disease as compared with CT and MR imaging. In an analysis of eight papers involving 341 patients [46] in the use of PET for detecting recurrent disease, PET was found to be 30% to 100% sensitive and 50% to 100% specific with an overall accuracy of 82%, similar to the reported accuracy of CT of 89%. Samson et al [55] in their report for Blue Cross concluded that there was insufficient data to recommend PET as a primary modality for the detection of recurrence. They noted only two studies met their selection criteria. Many other studies have demonstrated the value of PET for detecting recurrent disease and distant metastases. Vranjesevic et al [77] performed a retrospective study of 61 patients in a mixed population by stage, histologic type, and therapy. Conventional imaging, such as bone scan, chest CT, abdominal CT, chest films, MR imaging, mammography, and ultrasound, was compared with FDG PET in the detection of residual or recurrent neoplasia. Thirty-eight of 61 patients had evidence of residual or recurrent disease by the end of the follow-up period. PET had 92.9% sensitivity and 84.2% specificity in the detection of recurrence compared with 78.6% sensitivity and 68.4% specificity for conventional imaging. A negative PET scan also had important prognostic significance with enhanced Kaplan-Meier estimates of disease-free survival compared with a positive PET study. Two out of the three cases with false-negative PET scans had lobular cancer. Kamel et al [78] in a recent study evaluated FDG PET in 60 consecutive patients with suspected recurrent breast cancer based on clinical or radiologic findings. FDG PET demonstrated 89% sensitivity, 84% specificity, and 87% accuracy for locoregional recurrence, and 100% sensitivity, 97% specificity, and 98% accuracy in detecting distant metastases. FDG PET was also compared with the tumor marker CA 15-3 in detecting recurrent disease in a subset of patients and was found to be more sensitive. CA 15-3 levels were normal in 8 of 19 patients with truepositive PET findings. Grahek et al [79] studied 134 patients with suspected recurrence based on clinical, imaging, or serum tumor markers. Seventy-five patients were followed-up using pathology results (26 of 75) or 1-year follow-up (49 of 75). The sensitivity of PET for detecting recurrence was 84% and the specificity was 78%. This compared with conventional imaging (mammography, CT, bone scan, and ultrasound) sensitivity of 63% and specificity of 61%. The nine false-negatives on PET included lesions less than

1 cm or mucinous neoplasia, which are known to have less FDG uptake. False-positive cases included tuberculosis, inflammation, and fibrous lymph nodes. There was also a 44% change in management based on physician questionnaires. Others also have reported similar use of FDG PET in detecting recurrent or residual breast cancer [61,80 – 83]. In a recent paper by Siggelkow et al [82], PET documented metastatic or recurrent disease in 25 of 27 cases of clinical suspicion, and correctly identified absence of disease in 35 of 38 scans. Goerres et al [84] studied 32 patients with suspected local or regional breast cancer recurrence or secondary tumor of the contralateral breast, and found PET had 100% sensitivity and 72% specificity, whereas MR imaging had 79% sensitivity and 94% specificity. PET also detected five metastases outside the MR imaging field of view. The authors believe that both examinations can be complementary in selected clinical circumstances. Others investigators [60] also have determined the accuracy of PET in detecting mediastinal or internal mammary lymph node involvement in recurrent disease compared with CT (88% accuracy for PET versus 73% for CT). PET has also been shown to be superior in detecting brachial plexus involvement in comparison with CT [85]. The use of PET in detecting recurrent disease in patients with elevated tumor markers has also been well documented [86 – 89]. Finally, in the evaluation of locoregional metastases, Hathaway et al [90] compared MR imaging with FDG PET in 10 patients with a clinical suspicion of local involvement of the axilla or brachial plexus. MR imaging correctly made the diagnosis in five of nine positive patients, whereas PET was correct in nine of nine patients and also found distant metastases. The study authors suggest a complementary role for both modalities. Fluorodeoxyglucose PET is considered of great efficacy in the evaluation of patients with suspected recurrent breast cancer, surpassing the use of other conventional imaging modalities for whole-body evaluation (Figs. 4 and 5).

Single-photon imaging In contrast to PET, single-photon imaging has been used since the1960s in clinical practice and has worldwide availability. The radionuclides used in single-photon imaging have half-lives varying from 6 hours to a few days and allow imaging of physiologic processes for a longer duration than PET. Static, dynamic, and planar imaging and SPECT are rou-

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Fig. 4. Axial CT (A), attenuation corrected PET (B), fused image (C), and non-attenuation corrected PET (D) in a patient with cancer recurrence in the right breast (arrow) and skin implants (arrowhead).

tinely used in clinical practice. The disadvantage of single-photon imaging is lack of attenuation correction and the use of radionuclides that are foreign to living systems.

Diagnosis Use of scintimammography in the primary detection of breast cancer Women are becoming increasingly aware of breast cancer. The number of women who undergo screening for breast cancer is increasing. Of the different techniques used in detecting breast cancer, such as self-examination, examination by a physician, mammography, ultrasound, and fine-needle aspiration cytology, mammography has become the standard of care. Mammography has high false-positive rates and

reported positive predictive values of 10% to 30% [91]. Combining ultrasound with mammography increases positive predictive value to 46%. Indeterminate mammograms lead to repeat mammograms and delayed detection. High rates of false-positive screening mammograms have economic and psychologic repercussions. Scintimammography is a noninvasive test and has a good interobserver and intraobserver correlation. Scintimammography started serendipitously when thallium 201 uptake in breast cancer was noted during myocardial perfusion imaging in the 1970s. Scintimammography can be performed using perfusion agents, immunoscintigraphy, and receptor imaging. Perfusion agents Thallium 201 has an ionic radius similar to the hydrated potassium ion and is a monovalent cation. It

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Fig. 5. Axial CT (A), attenuation corrected PET (B), fused image (C), and non-attenuation corrected PET (D) in the same patient as Fig. 4 demonstrating an unexpected vertebral body metastasis (arrow).

enters the cell through the Na and K ATPase pump [92]. Thallium 201 uptake in breast cancer reflects increased blood flow and increased metabolic activity in cancer tissue. Even though physiologically thallium 201 is an ideal agent for cancer detection, it has poor physical characteristics (60 – 80 keV energy and 72-hour half-life) for imaging and is not being used routinely. Technetium 99m sestamibi is a cationic, lipophilic compound and is an agent for myocardial perfusion imaging. Sestamibi crosses the plasma membrane and adheres in the cytoplasm with the negatively charged mitochondria [93]. Increased vascularity and increased mitochondrial concentration in malignancy facilitate increased sestamibi concentration compared with surrounding tissue. Technetium 99m tetrofosmin has similar biologic behavior as technetium 99m sestamibi and has been successfully used in the detection of breast cancer [94].

Scintimammography involves injection of radiopharmaceuticals intravenously and subsequent planar imaging of both breasts in different projections (Fig. 6). Routine imaging of the axilla is performed for the assessment of axillary lymph node involvement. The addition of SPECT imaging has not shown added value. A meta-analysis and review of the literature from 1967 to 1999 of 64 studies including 5354 lesions by Liberman et al [95] showed sensitivity of 85% and specificity of 87% for scintimammography. A total of nine different radiopharmaceuticals were used in these studies and technetium 99m sestamibi was the most popular agent. The authors conclude that scintimammography is an adjuvant test to mammography and adds to sensitivity and specificity. In younger women with dense breasts and women with implants, where mammography often gives equivocal results, scintimammography decreases unnecessary biopsies.

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Fig. 6. Scintimammography showing Tc-99m MIBI concentration in a breast cancer (arrows).

Radioimmunoscintigraphy Immunosurveillance and specificity of antigen antibody reaction are the basis for radioimmunoscintigraphy. In the last two decades, however, the use of this technique has remained marginal, because of a lack of tumor-specific antigens. Carcinoembryonic antigen was thought to be specific for adenocarcinoma of the colon; however, studies have shown expression of carcinoembryonic antigen in other tumors including breast cancer. Whole antibody labeled with radioisotopes has longer biologic half-life and gives enough time to localize to the antigen, but demonstrates high background because of blood pool activity. Radiolabeled Fab fragments are smaller than whole antibody and are rapidly cleared by the blood pool; such fragments are ideally suited for labeling with a short-lived radioisotope, such as technetium 99m [96]. Breast, pancreas, and ovarian cancer express a high molecular glycoprotein called mucin that provides a protective layer on epithelial surfaces. Mucin antibodies have been used to detect primary and metastatic breast cancer [97]. Indium 111 – labeled satumomab pendetide was used to detect breast cancer and found to be sensitive for detecting the primary tumor, but had low sensitivity to detect axillary lymph node involvement. Receptor imaging Primary breast cancers express somatostatin receptors in approximately 70% of tumors. There are five different somatostatin receptors and different tumors express different types of receptors. Indium 111 pentetreotide imaging has been used to detect primary breast cancer [98]. Peptides that localize to receptors are small-sized molecules and clear rapidly

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by the kidney, making these peptides attractive imaging probes. Peptides, such as bombesin labeled with technetium 99m and indium 111, have shown promise in imaging breast cancer [99]. Estrogen and progestin receptors offer another avenue to image breast cancer. Iodine 131 iodovinyl estradiol-17a and iodine 123 estradiol-16a have been used and the results are encouraging; however, these agents are not suitable for the detection of primary breast cancer because only 50% to 70% of breast tumors express estrogen and progestin receptors. Estrogen receptor imaging using iodine 123 – labeled cis-11b-methoxy iodovinyl estradiol-17a seems to be a useful tool for predicting response to antiestrogen treatment. Lack of uptake or faint uptake before tamoxifen or after tamoxifen correctly predicts poor response [100].

Initial staging The current initial staging procedure for breast cancer is axillary lymph node dissection [101]. The presence and number of tumor-positive lymph nodes removed in an axillary lymph node dissection are used to assess prognosis and select adjuvant therapy. Increased public awareness of breast cancer, selfexamination, and use of mammography have led to the detection of tumors smaller in size at the time of diagnosis. Up to 30% may be smaller than 1 cm. Smaller tumors have less of an incidence of axillary metastases (10% – 18% for tumors <1 cm), which has led to patient selection for axillary lymph node dissection based on tumor size [102]. Axillary lymph node dissection is an invasive procedure with significant morbidity; even 20 years after axillary lymph node dissection, about 40% to 45% of women suffer from lymphedema. Among women who have undergone radical mastectomy, up to 60% have lymphedema; about 30% of those treated with modified radical mastectomy or breast-conserving surgery with axillary dissection have lymphedema [16]. For women who are treated with radiation to the axilla, the incidence of lymphedema increases. Lymphedema is unsightly and a distressing reminder of the cancer. It causes limited range of shoulder motion and limited use of the arm, painful seromas, and paresthesias. The sentinel node approach to staging early breast cancer in lieu of the axillary lymph node dissection offers enormous appeal for patients and caregivers [103]. Scintimammography might reveal a focus of axillary lymph node activity that may represent a metastasis. Unfortunately, the accuracy

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of scintimammography to detect metastases to lymph nodes is limited. The sentinel lymph node approach to staging early breast cancer is undoubtedly the most accurate of the less invasive methods. Micrometastases are perhaps even better identified with the sentinel node procedure than with axillary lymph node dissection because multiple sections of the node and immunohistochemical stains (not done in an axillary lymph node dissection when as many as 10 – 25 nodes are submitted at once to the pathologist) are easily done for only one, two, or three sentinel nodes. The ability to microsection with immunohistochemical staining significantly increases the detection of micrometastases. Studies indicate that 16% of primary tumors smaller than 1 cm are associated with micrometastases in sentinel lymph nodes; 33% of tumors 1 to 2 cm are associated with sentinel node micrometastases; 41% of tumors 2 to 5 cm are associated with sentinel node micrometastases; and 75% of tumors greater than 5 cm are associated with lymph node metastases. If the sentinel node is tumor positive, the surgeon may opt to do an axillary dissection for therapeutic and prognostic purposes. Do small tumors (less than 1 or 2 cm) require staging? Because of wide use of mammographic screening and self-examinations, more women present with small tumors (<2 cm) than ever before. Some physicians have suggested that because axillary lymph nodes usually are free of metastases in patients with small tumors, axillary dissection should be abandoned when the tumor is less than 1 to 2 cm. Recent data from sentinel lymph node excisional biopsies and immunohistochemical pathology examinations showed the incidence of micrometastases or macrometastases to be significant (16%) for small tumors (0.1 – 1 cm). There seems to be a need for staging women with breast cancers of less than 1 to 2 cm in size [104]. The sentinel lymph node concept The sentinel lymph node concept was proposed by Cabanas in 1977 [105]. The concept is as follows: the first lymph node to receive lymphatic drainage from a tumor site is the sentinel node, and if there has been lymphatic spread, the sentinel node is the first lymph node to have metastatic involvement. Further, the concept implies that sampling the sentinel node is sufficient for the assessment of a lymphatic bed. The

sentinel node concept applies to both the spread of breast cancer and melanoma. Cabanas used the sentinel node concept in the management of penile cancer. Morton et al [106] applied the concept to the management of melanoma in 1992. The sentinel lymph node can be detected by blue-dye or radiotracer techniques. Blue-dye technique for sentinel lymph node detection Injection of isosulfan blue dye to allow visualization of the lymphatic channels and the sentinel lymph node is called the blue-dye technique. In this technique, the objective is determination of the sentinel lymph node by visualization of blue dye in the sentinel lymph nodes. Visualization is possible if the channels and sentinel lymph nodes are near the skin or if an incision is made that reveals the location of injected dye. The technique has been used successfully in many patients since its introduction in 1977, and its success has expanded the acceptance and application of the sentinel lymph node concept. If the lymphatic channels and sentinel lymph node of the lymphatic bed under consideration are deep, however, localization of the sentinel node requires a large incision, which can lead to accidental disruption of the lymphatic channel and to contamination of the whole surgical area. If contamination occurs, detection of sentinel lymph nodes is often difficult. The use of blue dye alone and in conjunction with radiotracer technique is discussed in more depth by Cody [107]. Radiotracer techniques for sentinel lymph node detection Radiotracer techniques for sentinel lymph node detection can involve counting probes, imaging systems, or both. Imaging of the lymphatic system is known as blymphoscintigraphy.Q Some investigators apply the term lymphoscintigraphy to any procedure involving a radiotracer and the lymphatic system. Here the term is used only for imaging of the lymphatic system. In radiotracer techniques for sentinel lymph node detection, a radioactive pharmaceutical is injected near the site of the primary malignancy. Detection and localization of the sentinel lymph node is then accomplished by identification of locations in the lymphatic bed with higher gamma count rates than background locations. Once there is radioactive tracer in the sentinel lymph node, the sentinel lymph node can be localized by counting with a gamma probe or by imaging with a gamma camera. This can help the surgeon remove the sentinel lymph node with a smaller incision and with less surgical morbidity

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at a display. Sterility requirements, longevity of the battery pack, and cost of consumables, such as sterile sheaths, are also considerations in selection of a probe. Radiopharmaceuticals and injection techniques

Fig. 7. Intraoperative use of a gamma probe (arrow) to locate a radioactive sentinel lymph node in the axilla.

(Fig. 7). The major advantages of radiotracer sentinel lymph node techniques are that surgical time is decreased and that morbidity is decreased. Removal of a single or a few (two to three) representative nodes instead of 10 to 20 lymph nodes facilitates more extensive analysis of the removed nodes. Cutting the sentinel lymph node into more slices makes it easier for extensive immunohistochemical staining. Radiation detection probe An intraoperative probe consists of a detector, collimator, digital or analog display, and an audio signal generator. Commercially available probes have either scintillation crystal (NaI or CsI) or a semiconductor detector (CdZnTe or CdTe). Some manufacturers provide both scintillation and semiconductor probes. NaI crystals are sensitive over a wide range of gamma energies but need a photomultiplier tube. NaI based probes are usually larger and bulkier than semiconductor-based probes that do not have photomultipliers. Semiconductor-based probes tend to have lower sensitivity than scintillation probes, particularly at energies above 140 keV [108]. Shielding and collimation of probes are important features because they influence spatial resolution and angular sensitivity. In the localization of the sentinel lymph node, avoidance of injection site activity is essential; proper shielding and collimation play a major role in this requirement. Probe performance depends on its detector sensitivity, collimation, spatial resolution, and scatter rejection capability. The user friendliness of a probe depends on the size of the probe, the weight of the equipment, and the nature of its audio signal generator. An audio signal allows the operator to detect lesions without the need to look

Technetium 99m sulfur colloid is the most commonly used radiotracer in melanoma and breast cancer. The rate of colloid transport and movement through the lymphatic pathway is related to the particle size of the colloid [109]. In Europe, nanocolloid, a human albumin colloid, is used instead of sulfur colloid because nanocolloid preparation does not involve the heating step. Pharmaceutical companies provide filtered colloid as unit doses. In cases of breast cancer, there is no consensus regarding the route of radiopharmaceutical injection, the size of the particles, the volume of the injection, or the role of imaging. European investigators inject nanocolloid subdermally in small volumes in the vicinity of the breast mass, whereas in the United States and Australia sulfur colloid is injected around the breast mass. Increasing number of institutions are using periareolar injections, which tends to show drainage to lymph node in a shorter time [110]. The basis for the periareolar injection technique is that lymphatic drainage from all over the breast drains to the subareolar plexus of Sappey and then drains to an axillary lymph node. Studies have shown that the same lymph node is identified as a sentinel node whether periareolar or peritumoral injection is performed [111]. In the United States different institutions use particles of different sizes (<0.22 – 1 to 2 mm) and injections of different volumes (<1 – 8 mL). The injection technique also depends on whether a breast cancer is palpable or seen only by mammography. A mammographic- or ultrasound-assisted injection of radiotracer is recommended when a cancer is not palpable. Lymphoseek is a mannose-based technetium 99m – labeled compound, which tends to bind to surfaces of reticuloendothelial cells and may have better specificity and faster localization in sentinel lymph nodes [112]. Large-sized studies are yet to be conducted to prove its superiority to the more easily available and relatively inexpensive technetium 99m sulfur colloid. The size of a breast, the location of a tumor, the history of a previous biopsy or surgery, the age of the patient, and the injection technique are all factors that affect the speed and quality of visualization of sentinel lymph node in breast lymphoscintigraphy. It is not unusual to find internal mammary lymph nodes and there is no consensus regarding the removal or management of these nodes.

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Role of imaging There are institutions that do not use imaging in sentinel lymph node detection [113]. In the authors’ opinion, however, imaging helps to visualize the number of lymphatic channels and to point out correctly the sentinel lymph node because the most proximal lymph node to the primary site may not necessarily be the sentinel lymph node [114]. In cases of melanoma of the torso, imaging is invaluable to detect drainage to the contralateral or inguinal nodes. The same may be true in breast cancer to identify the internal mammary chain of lymph nodes. European investigators routinely use imaging to facilitate intraoperative probe localization [115]. A large field-ofview camera with a low-energy all-purpose collimator is advised for sentinel lymph node imaging. Early dynamic images of 10 seconds per frame for 10 minutes using a 128  128 matrix are acquired, and static images are obtained every 5 minutes for 30 to 40 minutes. Additional regions and projections are obtained as needed. Simultaneous acquisition of a transmission image using a Co-57 flood source is useful, because doing so provides localization images of the body contour. Markers, which assist surgeons in the local-

ization process and decrease surgical time, can be placed on the sentinel node. Alazraki et al [116] have developed a detailed outline of a protocol for imaging, which they recommend for use in association with an intraoperative gamma probe (Fig. 8).

Counting time and significance of detected activity A question often asked is: bHow long should one count to obtain a correct and useful measurementQ? This depends on the activity level in the target area. Counting times in common clinical usage range from 2 to 60 seconds. At the authors’ institution, sentinel lymph node localization is usually accomplished with counting times of 10 seconds at each location investigated. The target-to-background ratio necessary to give 99% confidence depends on the counts. For a hot spot generating 100 detected counts per second, three standard deviations is 30 counts per second and the ratio of target-to-background needs to be 100 to 70, a target-to-background ratio of 1.4. To have the same confidence level when only 40 counts per second are being detected, however, the target-tobackground ratio must be at least 2.

Fig. 8. Anterior and Lateral images of the breast at 10, 15, 20 and 25 minutes after injection demonstating the site of injection (arrow), lymphatic channel and a sentinel node (arrowhead).

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Radiation to patients and clinical personnel Because the injected radiocolloid used in radiotracer sentinel lymph node detection techniques stays near the site of injection, the most significant dose of radiation to the patient is at the site of injection. Several investigators have found that the delivered dose at the site of injection can be as much as .45 Gy/ 37 MBq. Glass et al [117] recommend that no more than 18.5 MBq of technetium 99m be used per study for sentinel lymph node detection. If the primary site is removed with a wide excision within a few hours of injection, however, which is usually the case, the radiation burden is significantly less. The estimated dose for surgeons, technologists, and pathologists is less than .02 mSv/hour. This is less than the NRC guidelines, which suggest a maximum of .05 mSv. Delay in the pathologic processing of a specimen can reduce the radiation exposure to a pathologist if necessary, but it is usually not necessary to do so.

Restaging The routine imaging procedures for restaging have been CT and bone scans. Bone scanning is the standard of care for assessing skeletal metastases. Multiple focal areas of increased uptake are classical for skeletal metastases; solitary rib lesions are usually posttraumatic and carry less than 20% risk for metastases. Breast cancer is unique in that an isolated sternal uptake may represent a bone metastasis. Bone scanning in female patients who have received chemotherapy may show diffuse increased tracer uptake in the skull (hot skull), a benign finding [118]. Paucity of renal uptake because of intense uptake in all the bones results in a striking scan but is often caused by extensive diffuse bone metastases (super scan). Chemotherapy, specifically hormonal therapy with tamoxifen, may transiently increase the uptake in bone lesions for 3 to 6 months and mimic worsening of the disease, whereas in reality may be a sign of good response (flare phenomenon) [119]. A comprehensive assessment of skeletal metastases and soft tissue metastases to liver and lymph node has been made possible since the advent of whole-body FDG PET scanning. The FDG PET scan is not sensitive enough to detect brain metastases, however, and often MR imaging is used for assessing symptomatic patients. F-18 – labeled amino acid radiotracers are being studied for assessing brain metastases [120], especially in differentiating recurrent tumor from radiation necrosis. Amino acids do not cross the

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blood-brain barrier and have the advantage of a higher target-to-background ratio.

Assessment of response to treatment and toxicity Bone scanning plays a major role not only in the early detection of skeletal metastases but also in the response to treatment. ER – positive breast tumors often develop bone metastases and often respond to hormonal treatment. Radiotracer uptake is commonly increased in the first 3 months of treatment with hormonal therapy; this flare phenomenon indicates a good response to treatment. Technetium 99m sestamibi and other lipophilic cations have been used to assess the tumor response to neoadjuvant (preoperative) chemotherapy, and detect response earlier and more accurately than conventional imaging, such as mammography; however, they are unable to differentiate responders from nonresponders after the first course of treatment. P-glycoprotein expression is involved in multidrug resistance and also causes enhanced clearance of technetium 99m sestamibi from tumor cells. Initial poor uptake and enhanced clearance of technetium 99m sestamibi have been shown to be a sign of poor prognosis in breast cancer [121]. Apoptosis or programmed cell death is an elementary process of life that maintains homeostasis. Apoptosis is physiologic and is different from necrosis, which is pathologic, often eliciting an inflammatory reaction. Apoptosis is an active genetically controlled process with signal transduction occurring from nucleus to lysosomes, mitochondria, cytosol, and cell membrane. Phosphatidylserine is only found in the inner leaflet of bilayered cell membranes. It moves to the outer layer early in cell apoptosis [122]. Annexin V is a naturally occurring human protein that binds avidly to phosphatidylserine. In apoptotic cells, phosphatidylserine moves to the outer layer of the cell membrane and becomes available to attach to annexin. Recombinant human annexin has been labeled with technetium 99m. Human studies have shown uptake of this probe in apoptosis [123]. F-18 – labeled annexin has also been used to assess apoptosis [124]. Successful chemotherapy increases apoptosis and enhances the uptake of annexin in tumor that is responding to chemotherapy. As the tumor becomes necrotic, the uptake of annexin reduces. Assessment of irradiation-induced and anthracycline-associated cardiac damage Breast cancer patients are at risk for developing late myocardial damage because radiotherapy fields

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may include the heart, and anthracycline-based chemotherapy often has cardiotoxicity. Measurement of resting left ventricular ejection fraction, which can be evaluated either by echocardiogram or by radionuclide techniques (multiple gated acquisition or first pass) is the standard of care in the assessment of cardiotoxicity. Unlike echocardiography, radionuclide techniques are observer independent and do not require an ideal body habitus. Both radiation and anthracycline drugs have early and late effects. Even though congestive heart failure caused by anthracycline is low in incidence (3% at a dose of 400 mg/m2 and 7% at 500 mg/m2) subclinical cardiac damage in the form of decreased left ventricular ejection fraction can occur in 50% of cases and increases with prior cardiac disease and concomitant radiation. Use of molecular ligands, such as indium 111 antimyosin and iodine 123 iobenguane, may help in detecting subclinical cardiotoxicity. Indium 111 antimyosin is specific for myocardial necrosis. It binds irreversibly to exposed myosin filaments of damaged myocytes. The antibody is targeted against the heavy chain of human cardiac myosin, a large intracellular protein in cardiac muscle cells that is exposed only when the integrity of the cell membrane is disrupted, resulting in irreversible injury. No adverse effects or allergic reactions have been reported. The agent also normally concentrates in the kidneys, liver, and less prominently in the bone marrow. Antimyosin – Fab – diethylenetriamine pentaacetic acid – indium 111 is a Fab monoclonal antibody fragment; there is little or no risk of human antimouse antibody formation. No human antimouse antibody has been documented in any patient who has received one or multiple injections. Iobenguane is a guanethidine derivative that images the adrenergic neurotransmitter system. Reduction of iodine 123 iobenguane uptake has been reported in patients with anthracycline-induced cardiomyopathy, not only at the time of therapy, but also several years later [125].

to detect estrogen receptor – positive metastases and can also help in following response to treatment. Initial work has shown promising results [127]. Whole monoclonal antibodies are large in size, have longer plasma half-life, and require a delayed imaging time, making them prohibitive for use with short-lived positron-emitting radioisotopes. Fab fragments have faster plasma clearance, however, and can be labeled with Cu-64 with a 12-hour half-life. Tumor grade and metastatic potential may correlate with expression of transferrin receptor on the cell surface [128]. Estrogen receptors have been successfully targeted using 16-alpha fluoro estradiol-17b and early clinical studies have shown them to be as sensitive as FDG imaging and probably more specific. Results with progestin receptors have been less successful [16]. Several gene therapy approaches have been considered for the management of breast cancer, such as ablation of oncogenic products; restoration of receptor expression (estrogen receptor); alteration of genes that are involved in apoptosis; or activation of tumor suppressor genes. Reporter genes have been used to study promoter-regulatory elements involved in gene expression. Reporter genes used as probes have been conventionally studied by tissue biopsy and immunohistochemistry. Now noninvasive in vivo methods are available in the form of radionuclide techniques or optical imaging. The ability to image deeper structures in larger animal models and in humans is the main advantage of radionuclide technique over optical imaging. Her-2 /neu overexpression in breast cancer is associated with poor response to chemotherapy and an unfavorable prognosis. Phase I clinical trials of enzyme immunoassay gene therapy targeting Her-2/ neu overexpressed breast cancer has shown increased apoptosis [129]. In vivo molecular imaging techniques will play a major role in drug development by decreasing the number of animal sacrifices needed to study longterm pharmacokinetics and pharmacodynamics.

Newer molecular imaging probes Molecular process that occur within the cell can be imaged by using slightly altered substrate, such as FDG, or amino acids like methionine and choline. FDG as an imaging agent has been reviewed previously. C-11 methionine and choline have been used in assessing breast cancer and metastases [126]. FDG is a suboptimal tracer for detecting brain metastases because normal brain has significant FDG uptake with resultant poor target-to-background ratio of metastatic lesions. Tamoxifen labeled with F-18 can be useful

Summary Although FDG PET does not have sufficient sensitivity to enable it to be a primary screening or initial staging modality, it is useful in a select group of patients, such as those with dense breasts, for diagnosis and for primary lymph node staging because of its high positive predictive value. PET has been demonstrated to have great use in patients with suspected distant metastases, to evaluate loco-

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regional extent in the high-risk patient, and to detect recurrence and monitor response to therapy. Sentinel lymph node procedures, often using radiotracers, are rapidly becoming the standard of care in breast cancer lymph node staging. Bone scanning still plays a major role in the detection of skeletal metastases, but is being supplemented by PET. Other single-photon techniques, such as scintimammography, tumor-specific molecular probing, and myocardial imaging to monitor for therapy toxicity, will have an ongoing and increasing part to play in clinical care and research. However specific imaging gets, histologic proof is almost always needed before starting chemotherapy and radiation therapy or performing major surgery. Combining a functional imaging tool with a stereotactic x-ray mammography unit makes it possible to obtain biopsies of breast lesions that have shown characteristics of malignancy in functional images but appear normal in morphologic images. High-resolution positron emission mammography scanners allowing coregistration of molecular to anatomic imaging and guidance for biopsies are being developed and currently undergoing clinical evaluation [130 – 132]. The impact of PET-CT also is just now being studied [133]. The potential for therapy with high-dose F-18 FDG has also been recently reported [134]. Resolution of PET scanners currently is limited in comparison with anatomic imaging, but continued technologic improvements are expected. The need for early detection of breast cancer has led to many attempts to improve the spatial resolution of imaging devices. Better detector materials in the form of solidstate detectors and design changes that enable the detector to be as close as possible to the lesion have led to solid-state and small field-of- view cameras. Tornai et al [135] have developed an ingenious way of obtaining enhanced contrast and signal-to-noise ratio in small-sized tumors using a pinhole camera with incomplete circular orbits, which creates a SPECT image with three-dimensional information. Small field-of-view cameras not only offer better sentinel lymph node and primary tumor detection because of increased spatial resolution, but also can be mounted on maneuverable arms and used in an intraoperative setting, helping the surgeon realize a tumor-free margin [136]. The progress made in molecular imaging will lead to more specific therapy, accurate staging, and treatment monitoring resulting in improved survival and quality of life for patients with breast cancer. Imaging devices that are specifically designed for breast imaging with enhanced spatial resolution will enable image-guided biopsies, and facilitate early detection

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and better therapy of breast cancer. Areas that need further study include (1) determining the clinical importance of PET-positive IM nodes, (2) improving image resolution, (3) developing technology to enable PET-guided biopsies, (4) synthesizing radiotracers more specific for breast cancer, and (5) demonstrating the cost-effectiveness and added value of molecular imaging in breast cancer.

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