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Clinical utility of scintimammography: From the Anger-camera to new dedicated devices
ARTICLE IN PRESS
Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285 www.elsevier.com/locate/nima
Clinical utility of scintimammography: From the Anger-camera to new dedicated devices Orazio Schillaci, Roberta Danieli, Pasquale Romano, Elsa Cossu, Giovanni Simonetti Department of Biopathology and Diagnostic Imaging, University ‘‘Tor Vergata’’,Viale G. Mazzini 121, 00195 Rome, Italy Available online 7 September 2006
Abstract Scintimammography is a functional imaging technique which uses a radiation detection camera to detect radionuclide tracers in the patient’s breasts. Tracers are designed to accumulate in tumours more than in healthy tissue: the most used are Tc-99 m sestamibi and Tc99 m tetrofosmin. Scintimammography is useful in some clinical indications as an adjunct to mammography: it is recommended for those lesions where additional information is required to reach a definitive diagnosis. Patients with dubious mammograms may benefit from this test, as well as women with dense breasts or with implants. Scintimammography is a valuable diagnostic tool also in patients with locally advanced breast cancer for monitoring and predicting response to neoadjuvant chemotherapy. Nevertheless, using an Angercamera this technique shows a high sensitivity only for cancers 41 cm. Since other modalities are increasingly employed for the early identification of small abnormalities, the issue of detecting small cancers is critical for the future development and clinical utility of breast imaging with radiopharmaceuticals. The use of high-resolution cameras dedicated for breast imaging is the best option to improve the detection of small cancers: they allow higher flexibility in patient positioning, and the availability of mammography-like projections. Moreover, the detector can be placed directly in contact with the breast allowing a mild compression with reduction of the breast’s thickness, thus increasing the target-to-background ratio and the sensitivity. These new devices have the potential of increasing the total number of breast scintigraphies performed thereby enhancing the role of nuclear medicine in breast cancer imaging. r 2006 Elsevier B.V. All rights reserved. Keywords: Breast cancer; Scintimammography; Dedicated high-resolution gamma-cameras
1. Introduction Breast carcinoma is the most common malignancy in women. In USA, it represents 32% of all invasive tumours in the female population, and it is the second leading cause of death for women following lung cancer, accounting for 15% of all cancer deaths. In 2004, the American Cancer Society estimated in the USA 215,990 new cases of breast cancer among women and 40,110 female deaths from this disease [1]. Trends in incidence and mortality show that there has been a small but steady annual increase in breast cancer incidence over the last 30 years, whereas the mortality rate declined steadily since the beginning of the nineties [1]. This benefit is attributed to earlier detection of breast cancer by mammographic screening.
Corresponding author. Tel.: +39 0620902419; fax: +39 0637359664.
E-mail address: [email protected] (O. Schillaci). 0168-9002/$ - see front matter r 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nima.2006.08.029
Mammography is currently the best imaging modality for early identification of breast cancer: its findings are based on anatomic changes in the breast and it is the method of choice in screening asymptomatic women [2]. This technique has some limitations that reduce its sensitivity and specificity. In fact, not all breast carcinomas are evident on mammograms, especially in dense or dysplastic breasts [3]. Moreover, its specificity and positive predictive value are low: the main limitation is that it cannot always differentiate benign lesions from malignant ones [4]. This is especially the case in women with dense breasts, or those who have architectural distortion of their breasts following radiation therapy or surgery, or those with breast implants [5]. Therefore, abnormalities detected during mammography frequently result in biopsy, and the outcome is that many women without cancer are biopsied [4]. The drawbacks of mammography has led to the development of complementary modalities for breast cancer imaging, including scintimammography [6].
ARTICLE IN PRESS 282
O. Schillaci et al. / Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285
2. Scintimammographic technique Scintimammography is a nuclear medicine imaging technique that uses radionuclides to image malignant breast tumours; it requires the administration of a singlephoton emitting radiotracer to the patient and a gammacamera for imaging. The ideal radiopharmaceuticals for scintimammography would show high and specific tumour uptake and minimal activity within the normal breast [7]: currently, the most widely used ones are Tc-99 m sestamibi and Tc-99 m tetrofosmin, two small cationic complexes of technetium introduced for myocardial perfusion imaging, and then proposed as tumour-seeking agents [8]. Tc-99 m sestamibi uptake and retention in cancer cells depends on several factors such as regional blood flow, plasma and mitochondrial membrane potential, angiogenesis and tissue metabolism, with approximately 90% of tracer activity concentrated in the mitochondria [9–10]. Also for Tc-99 m tetrofosmin, similar mechanisms have been suggested; however, Arbab et al. [11] showed in tumour cell lines that tetrofosmin uptake depends on both cell membrane and mitochondria potentials with only a small fraction accumulating inside the mitochondria. Moreover, both of these radiopharmaceuticals are transport substrates for the P-glycoprotein (Pgp), a Mr 170,000 plasma membrane protein encoded by the multidrug resistance gene (MDR1), and MDR related protein (MRP1) that function as energydependent efflux pumps for many drugs [12]. The radiopharmaceutical is injected (dose: 740 MBq) in the antecubital vein of the opposite arm to the known breast abnormality, or in a dorsalis pedis vein when breast lesions are bilateral, to avoid artifactual axillary lymphnode uptake from extravasated radiotracer via lymphatic drainage. After the injection, patients are imaged in the prone position, which provides improved separation of the breast tissue from the myocardium and the liver, that always show a high uptake which may mask overlying breast activity. The prone position also allows the differentiation of deep breast tissue from the myocardium, the liver, and the thoracic wall, and provides natural landmarks of breast contours, which are very important for lesions localisation. Two lateral views (left and right) in the prone position are usually performed with a special cushion that enables the examined breast to hang freely through an opening, very close to the collimator of the gamma-camera. Next, an anterior chest image with the patient in the supine position is acquired for a better localisation of primary tumours in the inner quadrants and to visualise an eventual involvement of the axillary and internal mammary lymph-nodes [7]. 3. Planar images Khalkhali et al. [13] reported the first series with a relatively large number of patients on the clinical application of planar scintimammography. In their group of 59 patients, in whom abnormal mammogram and physical
examination warranted biopsy or fine needle citology of the breast, sensitivity of scintimammography was 95.8%, specificity 86.85, positive predictive value 82.15 and negative predictive value 97.1%, respectively. On the basis of these results, the authors concluded that scintimammography is very sensitive and is able to improve the specificity of mammography, thereby being potentially useful in reducing the high rates of negative biopsies performed. After this report, numerous studies have been published on the clinical usefulness of scintimammography. A review [14] including 2009 patients from 20 studies has yielded these results in evaluating the diagnostic accuracy of breast scintigraphy in patients with mammary lesions (total number ¼ 2304 lesions): sensitivity 85%, specificity 89%, negative predictive value 84%, positive predictive value 89%, global accuracy 86%. The aggregated overall summary estimates of a recent meta-analysis selecting 64 unique studies [15], with data on 5340 patients including 5354 breast lesions, were: sensitivity 85.2%, specificity 86.6%, negative predictive value 81.8%, positive predictive value 88.2%, accuracy 85.9%. It is worth noting that 80% of the studies yielded sensitivity and specificity values over 80%, and nearly half of them values over 90%. Furthermore, in the more than 5660 cases reported to date, the sensitivity and specificity of Tc-99 m sestamibi scintimammography in detecting primary breast cancer was 83.8% and 86.4%, respectively [16]. Nevertheless, it is of the utmost importance to highlight that the sensitivity of scintimammography is strictly dependent on the size of lesions. A multi-centre study on 420 patients with 449 breast lesions (21% were benign) reported a sensitivity of 26%, 56%, 95% and 97% for T1a, T1b, T1c and T2 breast cancers, respectively [17]; in particular, sensitivity was significantly different between malignant lesions p1 cm (46.5%) and those 41 cm (96%). Waxman et al. [18] showed that lesions greater than 12 mm are visualised by scintigraphy in more than 92% of cases, whereas smaller tumours are detected only in 50% of cases. Similar results regarding sensitivity are obtained when breast lesions are divided in palpable and non-palpable, which always show a lower sensitivity [17,19–20], as confirmed by the review of Liberman et al. [15], that reported a sensitivity of 87.8% for patients with a palpable breast mass and of 66.8% for patients without a palpable lesion. Moreover, the results of a North American multicentre trial involving 673 patients in 42 institutions [21] indicate a sensitivity for breast cancer detection of 87% and 61% for palpable and non-palpable abnormalities, respectively. However, also biological factors, such as tumour type, determining the net radiotracer uptake in the cancer [22] have to be taken into account for their in vivo visualisation by scintigraphy. 4. SPECT and SPECT/CT Since other breast imaging modalities are increasingly used for the early identification of small suspicious lesions,
ARTICLE IN PRESS O. Schillaci et al. / Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285
the detection of small cancers is critical for the clinical development and acceptance of scintimammography. The acquisition of tomographic images, by means of single photon emission computed tomography (SPECT), can play a role in increasing the sensitivity of planar scintimammography. Until now, some discordant results have been reported in the studies comparing tomographic and planar imaging in primary breast cancer diagnosis. It is important to highlighting that a good SPECT imaging quality can be obtained only with the patient in the supine position with elevated arms, because SPECT imaging with patients in prone position is limited by the geometric constraints of the patient, imaging table and gantry [7]. In a group of 63 patients with 67 mammographically suspicious breast abnormalities [23] we observed a sensitivity of 93 for supine SPECT and of 86 for planar imaging, whereas accuracy resulted 91% and 88%, respectively. Moreover, in breast lesions p1 cm, supine SPECT yielded a significantly higher sensitivity than planar images both in T1b and non-palpable breast cancers, without any decrease in specificity [24], thus indicating that a SPECT acquisition is mandatory if scintimammography is performed for the imaging of small lesions. These clinical data are confirmed by a breast phantom study demonstrating that a better detection of small-sized lesions is achieved with tomoscintigraphic than with planar images [25]. Moreover, from a technical point of view, the same authors suggest that SPECT should be reconstructed using iterative algorithms instead of back-projection methods, and a 128 128 matrix is preferable to a 64 64 one. Although SPECT imaging has better contrast resolution, a clear and accurate definition of the sites of radiopharmaceutical uptake can be difficult to obtain. On the other hand, prone images with planar lateral views provide natural landmarks of breast contours, which are very useful for lesions localisation. The co-registration of SPECT with structural information obtained through radiological examinations allows the precise correlation of functional and anatomic data on the same image. The commercial availability of a hybrid gamma-camera/CT scanner, which is able to provide, in addition to scintigraphic data, cross-sectional X-ray transmission images, has facilitated the fusion of anatomical maps and SPECT images [26]. The first clinical applications of this new technology are very encouraging; in particular, when used for breast imaging, SPECT/CT correlative data are particularly useful in the most difficult cases, facilitating the interpretation of SPECT findings with a more accurate anatomical assessment of sites of abnormal activity [27]. 5. Dedicated high-resolution devices The best option for improving the sensitivity of scintimammography in the detection of small tumours is the use of dedicated gamma-cameras specifically built for breast imaging. To date, scintimammography has been usually performed with conventional gamma-cameras that
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are large, bulky, and not specifically designed for imaging the breast, making them less than optimal for this application. The use of small field of view high-resolution cameras allows both greater flexibility in patient positioning (improving breast imaging by limiting the field of view and reducing image contamination from other organs, i.e. liver and heart) and breast compression, with an important increase in the target-to-background ratio [28]. In fact, the detector can be placed directly in contact with the breast allowing a mild compression with reduction of the breast’s thickness, thus improve the camera’s sensitivity. Moreover, owing to their design, dedicated cameras can also provide a better intrinsic and extrinsic spatial resolution when compared to standard cameras, with an enhancement of the contrast resolution of small lesions [29]. These cameras, using appropriate adapters, can be easily fit on most upright mammography apparatuses, replacing the radiographic Bucky. An important advantage is also the possibility of acquiring scintigraphic scans using standard mammographic views (craniocaudal and lateral oblique), making the comparison between the two imaging modalities simpler. The results obtained in a limited number of studies indicate a better sensitivity of high-resolution cameras when compared to conventional large field of view camera, especially in detecting small breast cancers. Scopinaro et al. [30] performed a comparison between a 10 cm FOV detector and a standard Anger-camera in a group of 53 patients. Breast cancer was found in 31 patients, 16 were p1 cm and 15 41 cm. Both the high-resolution and the conventional camera detected 14 out of 15 cancers 41 cm. In the group of small tumours, the difference between the sensitivity of the two detectors was significant: 81% for the dedicated camera and only 50% for the Anger-camera. Brem et al. [29] evaluated 50 patients with 58 lesions (range: 0.3–6.0 cm): 41 (71%) were non-palpable and 30 were (52%) benign. The sensitivity of Tc-99 m sestamibi scintimammography was 64% for the standard and 79% for the dedicated gamma-camera. The sensitivity for tumours p1 cm was 47% for the general-purpose and 67% for the dedicated camera; the sensitivity for nonpalpable cancer was 56% and 72%, respectively. The results of a study specifically designed to evaluate the utility of a dedicated breast-specific camera as a screening modality has been recently reported: Coover et al. [31] demonstrated cancer that was otherwise undetectable by conventional methods in three out of five scintimammography positive cases; only one of the three carcinomas identified with the dedicated gamma camera was detectable also with a standard camera. Rhodes et al. [32] have recently used a CZT camera in a group of 40 women. The detector head was composed of an array of 80 80 CZT elements (each of 2.5 2.5 mm), with a FOV of 20 20 cm. Scintimammography with Tc-99 m sestamibi detected 33 out of 36 malignant lesions (sensitivity 92%) in 26 patients. In particular, the sensitivity was 86% in tumours o1 cm and 100% in larger ones and 75% in T1a and 89% in T1b
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tumours. Their data indicate that high-resolution imaging is able to visualise smaller and deeper breast cancers, overcoming the main limitations of conventional scintimammography. 6. Clinical applications of scintimammography In any patient in which there is doubt about the results of mammography or other diagnostic test, scintimammography might provide added value [33]. Because radiopharmaceuticals’ uptake is independent of the breast density, scintimammography can be very useful in the subgroup of population with mammographically dense breasts [34]. Moreover, scintimammography is particularly useful in patients with doubtful microcalcifications or parenchymal distortions, in the presence of scar tissue in the breast following surgery or biopsy, and in breasts with implants [7]. It is well known that mammography is less accurate in evaluating breasts that have been previously submitted to surgery, biopsy, radiation therapy or chemotherapy. Patients who have a scar within the breast due to these iatrogenic interventions are often difficult for mammographic interpretation, whereas scintimammography is not affected by these morphologic changes. Some considerations regarding the possible role of scintimammography in the identification of multifocal–multicentric breast cancer and in the detection of the possible primary breast tumour in patients with metastatic axillary lymphnode involvement. The detection of multicentric lesions is of the utmost importance, because it can determine the surgical management of the patient (i.e. total mastectomy instead of quadrantectomy). It has been reported that scintimammography is able to assess the presence of a multifocal–multicentric disease, detecting bilateral breast cancers, with higher sensitivity when compared to mammography/ultrasound [35]. However, due to the limited data available in this specific application along with the low sensitivity of scintimammography in visualising small additional malignant lesions [36], this potential indication deserves further studies in larger series; moreover, the good performance of MRI in this field should be taken into account. In patients with axillary lymph-node metastases due to adenocarcinoma with negative mammography and ultrasound, scintimammography may be useful for detecting the possible primary tumour in the breast. Nevertheless, also for this application, until now there is not sufficient evidence for recommend a routinE clinical use of breast scintigraphy. Scintimammography in patients with locally advanced breast cancer can be useful both for monitoring and predict response to neoadjuvant chemotherapy. In a study protocol including two scintigraphies before and after neoadjuvant chemotherapy, scintimammography proved accurate in predicting tumour presence or absence after treatment, and useful for the in vivo detection of intrinsic and acquired resistant cancers, a very important factor for planning the best therapeutic strategy [37].
7. Conclusions Mammography remains the first imaging modality for the early detection of breast cancer. Scintimammography can be a useful complement to non-diagnostic mammography in some specific indications and is able to potentially reduce the number of unnecessary biopsies. Scintimammography is recommended for those patients where additional information is required in order to reach a definitive diagnosis. Nevertheless, probably only the development and large availability of dedicated highresolution cameras will allow scintimammography to become of routinary use. References [1] A. Jemal, R.C. Tiwari, T. Murray, et al., CA Cancer J. Clin. 5 (2004) 8. [2] L.K. Tabar, B. Vitak, H.H.T. Chen, M.F. Yen, S.W. Duffy, R.A. Smith, Cancer 91 (2001) 1724. [3] R.L. Birdwell, D.M. Ikeda, K.F. O’Shaughnessy, E.A. Sickles, Radiology 219 (2001) 192. [4] D. Kopans, AJR 158 (1992) 521. [5] R.L. Birdwell, D.M. Ikeda, K.F. O’Shaughnessy, E.A. Sickles, Radiology 219 (2001) 192. [6] D.D. Adler, R.L. Wahl, AJR 164 (1995) 19. [7] O. Schillaci, J.R. Buscombe, Eur. J. Nucl. Med. Mol. Imaging 31 (Suppl. 1) (2004) S35. [8] K. Schomacker, H. Schicha, Eur. J. Nucl. Med. 27 (2000) 1845. [9] J. Maublant, Z. Zhang, M. Rapp, et al., J. Nucl. Med. 34 (1993) 1949. [10] F. Scopinaro, O. Schillaci, M. Scarpini, et al., Eur. J. Nucl. Med. 21 (1994) 984. [11] A.S. Arbab, K. Koizumi, K. Toyama, T. Araki, J. Nucl. Med. 37 (1996) 1551. [12] N.H. Hendrikse, E.J. Franssen, W.T. van der Graaf, W. Vaalburg, E.G. de Vries, Eur. J. Nucl. Med. 26 (1999) 283. [13] I. Khalkhali, I. Mena, E. Jouanne, et al., J. Am. Coll. Surg. 178 (1994) 491. [14] R. Taillefer, Semin. Nucl. Med. 24 (1999) 16. [15] M. Liberman, F. Sampalis, D.S. Mulder, J.S. Sampalis, Breast Cancer Res. Treat. 80 (2003) 115. [16] R. Taillefer, Semin. Nucl. Med. 35 (2005) 100. [17] F. Scopinaro, O. Schillaci, W. Ussof, et al., Anticancer Res. 17 (1997) 1631. [18] A. Waxman, N. Nagaraj, M. Kovalevsky, et al., J. Nucl. Med. 36 (1995) 194P. [19] S. Mekhmandarov, J. Sandbank, M. Coehn, S. Lelcuk, E. Lubin, J. Nucl. Med. 39 (1998) 86. [20] J. Tolmos, J.A. Cutrone, B. Wang, et al., J. Natl. Cancer Inst. 90 (1998) 846. [21] I. Khalkhali, J. Villanueva-Meyer, S.L. Edell, et al., J. Nucl. Med. 41 (2000) 1973. [22] J.R. Buscombe, J.B. Cwikla, D.S. Thakrar, A.J. Hilson, Anticancer Res. 17 (1997) 1693. [23] O. Schillaci, Eur. J. Nucl. Med. Mol. Imaging 32 (2005) 521. [24] O. Schillaci, F. Scopinaro, R. Danieli, et al., Nucl. Med. Commun. 18 (1997) 839. [25] A. Spanu, O. Schillaci, G.B. Meloni, et al., Int. J. Oncol. 21 (2002) 831. [26] E. Garin, A. Devillers, S. Girault, et al., Nucl. Med. Commun. 22 (2001) 1045. [27] O. Schillaci, R. Danieli, C. Manni, G Simonetti, Nucl. Med. Commun. 25 (2004) 705. [28] O. Schillaci, E. Cossu, O. Buonuomo, et al., J. Nucl. Med. 46 (2005) 550.
ARTICLE IN PRESS O. Schillaci et al. / Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285 [29] R.F. Brem, J.M. Schoonjans, D.A. Kieper, S. Majewski, S. Goodman, C. Civelek, J. Nucl. Med. 43 (2002) 909. [30] F. Scopinaro, R. Pani, G. De Vincentis, A. Soluri, R. Pellegrini, L.M. Porfiri, Eur. J. Nucl. Med. 26 (1999) 1279. [31] L.R. Coover, G. Caravaglia, P. Kuhn, J. Nucl. Med. 45 (2004) 553. [32] D.J. Rhodes, M.K. O’Connor, S.W. Phillips, R.L. Smith, D.A. Collins, Mayo Clin. Proc. 80 (2005) 24. [33] O. Schillaci, J. Nucl. Med. 46 (2005) 1571.
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[34] I. Khalkhali, J.K. Baum, J. Villanueva-Meyer, et al., Radiology 222 (2002) 149. [35] J.B. Cwikla, J.R. Buscombe, B. Holloway, et al., Nucl. Med. Commun. 22 (2001) 1287. [36] H.I. Vargas, R.V. Agbunag, A. Kalinowski, et al., Am. Surg. 67 (2001) 1204. [37] S. Mezi, F. Primi, F. Capoccetti, F. Scopinaro, M. Modesti, O. Schillaci, Int. J. Oncol. 22 (2003) 1233.
Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285 www.elsevier.com/locate/nima
Clinical utility of scintimammography: From the Anger-camera to new dedicated devices Orazio Schillaci, Roberta Danieli, Pasquale Romano, Elsa Cossu, Giovanni Simonetti Department of Biopathology and Diagnostic Imaging, University ‘‘Tor Vergata’’,Viale G. Mazzini 121, 00195 Rome, Italy Available online 7 September 2006
Abstract Scintimammography is a functional imaging technique which uses a radiation detection camera to detect radionuclide tracers in the patient’s breasts. Tracers are designed to accumulate in tumours more than in healthy tissue: the most used are Tc-99 m sestamibi and Tc99 m tetrofosmin. Scintimammography is useful in some clinical indications as an adjunct to mammography: it is recommended for those lesions where additional information is required to reach a definitive diagnosis. Patients with dubious mammograms may benefit from this test, as well as women with dense breasts or with implants. Scintimammography is a valuable diagnostic tool also in patients with locally advanced breast cancer for monitoring and predicting response to neoadjuvant chemotherapy. Nevertheless, using an Angercamera this technique shows a high sensitivity only for cancers 41 cm. Since other modalities are increasingly employed for the early identification of small abnormalities, the issue of detecting small cancers is critical for the future development and clinical utility of breast imaging with radiopharmaceuticals. The use of high-resolution cameras dedicated for breast imaging is the best option to improve the detection of small cancers: they allow higher flexibility in patient positioning, and the availability of mammography-like projections. Moreover, the detector can be placed directly in contact with the breast allowing a mild compression with reduction of the breast’s thickness, thus increasing the target-to-background ratio and the sensitivity. These new devices have the potential of increasing the total number of breast scintigraphies performed thereby enhancing the role of nuclear medicine in breast cancer imaging. r 2006 Elsevier B.V. All rights reserved. Keywords: Breast cancer; Scintimammography; Dedicated high-resolution gamma-cameras
1. Introduction Breast carcinoma is the most common malignancy in women. In USA, it represents 32% of all invasive tumours in the female population, and it is the second leading cause of death for women following lung cancer, accounting for 15% of all cancer deaths. In 2004, the American Cancer Society estimated in the USA 215,990 new cases of breast cancer among women and 40,110 female deaths from this disease [1]. Trends in incidence and mortality show that there has been a small but steady annual increase in breast cancer incidence over the last 30 years, whereas the mortality rate declined steadily since the beginning of the nineties [1]. This benefit is attributed to earlier detection of breast cancer by mammographic screening.
Corresponding author. Tel.: +39 0620902419; fax: +39 0637359664.
E-mail address: [email protected] (O. Schillaci). 0168-9002/$ - see front matter r 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nima.2006.08.029
Mammography is currently the best imaging modality for early identification of breast cancer: its findings are based on anatomic changes in the breast and it is the method of choice in screening asymptomatic women [2]. This technique has some limitations that reduce its sensitivity and specificity. In fact, not all breast carcinomas are evident on mammograms, especially in dense or dysplastic breasts [3]. Moreover, its specificity and positive predictive value are low: the main limitation is that it cannot always differentiate benign lesions from malignant ones [4]. This is especially the case in women with dense breasts, or those who have architectural distortion of their breasts following radiation therapy or surgery, or those with breast implants [5]. Therefore, abnormalities detected during mammography frequently result in biopsy, and the outcome is that many women without cancer are biopsied [4]. The drawbacks of mammography has led to the development of complementary modalities for breast cancer imaging, including scintimammography [6].
ARTICLE IN PRESS 282
O. Schillaci et al. / Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285
2. Scintimammographic technique Scintimammography is a nuclear medicine imaging technique that uses radionuclides to image malignant breast tumours; it requires the administration of a singlephoton emitting radiotracer to the patient and a gammacamera for imaging. The ideal radiopharmaceuticals for scintimammography would show high and specific tumour uptake and minimal activity within the normal breast [7]: currently, the most widely used ones are Tc-99 m sestamibi and Tc-99 m tetrofosmin, two small cationic complexes of technetium introduced for myocardial perfusion imaging, and then proposed as tumour-seeking agents [8]. Tc-99 m sestamibi uptake and retention in cancer cells depends on several factors such as regional blood flow, plasma and mitochondrial membrane potential, angiogenesis and tissue metabolism, with approximately 90% of tracer activity concentrated in the mitochondria [9–10]. Also for Tc-99 m tetrofosmin, similar mechanisms have been suggested; however, Arbab et al. [11] showed in tumour cell lines that tetrofosmin uptake depends on both cell membrane and mitochondria potentials with only a small fraction accumulating inside the mitochondria. Moreover, both of these radiopharmaceuticals are transport substrates for the P-glycoprotein (Pgp), a Mr 170,000 plasma membrane protein encoded by the multidrug resistance gene (MDR1), and MDR related protein (MRP1) that function as energydependent efflux pumps for many drugs [12]. The radiopharmaceutical is injected (dose: 740 MBq) in the antecubital vein of the opposite arm to the known breast abnormality, or in a dorsalis pedis vein when breast lesions are bilateral, to avoid artifactual axillary lymphnode uptake from extravasated radiotracer via lymphatic drainage. After the injection, patients are imaged in the prone position, which provides improved separation of the breast tissue from the myocardium and the liver, that always show a high uptake which may mask overlying breast activity. The prone position also allows the differentiation of deep breast tissue from the myocardium, the liver, and the thoracic wall, and provides natural landmarks of breast contours, which are very important for lesions localisation. Two lateral views (left and right) in the prone position are usually performed with a special cushion that enables the examined breast to hang freely through an opening, very close to the collimator of the gamma-camera. Next, an anterior chest image with the patient in the supine position is acquired for a better localisation of primary tumours in the inner quadrants and to visualise an eventual involvement of the axillary and internal mammary lymph-nodes [7]. 3. Planar images Khalkhali et al. [13] reported the first series with a relatively large number of patients on the clinical application of planar scintimammography. In their group of 59 patients, in whom abnormal mammogram and physical
examination warranted biopsy or fine needle citology of the breast, sensitivity of scintimammography was 95.8%, specificity 86.85, positive predictive value 82.15 and negative predictive value 97.1%, respectively. On the basis of these results, the authors concluded that scintimammography is very sensitive and is able to improve the specificity of mammography, thereby being potentially useful in reducing the high rates of negative biopsies performed. After this report, numerous studies have been published on the clinical usefulness of scintimammography. A review [14] including 2009 patients from 20 studies has yielded these results in evaluating the diagnostic accuracy of breast scintigraphy in patients with mammary lesions (total number ¼ 2304 lesions): sensitivity 85%, specificity 89%, negative predictive value 84%, positive predictive value 89%, global accuracy 86%. The aggregated overall summary estimates of a recent meta-analysis selecting 64 unique studies [15], with data on 5340 patients including 5354 breast lesions, were: sensitivity 85.2%, specificity 86.6%, negative predictive value 81.8%, positive predictive value 88.2%, accuracy 85.9%. It is worth noting that 80% of the studies yielded sensitivity and specificity values over 80%, and nearly half of them values over 90%. Furthermore, in the more than 5660 cases reported to date, the sensitivity and specificity of Tc-99 m sestamibi scintimammography in detecting primary breast cancer was 83.8% and 86.4%, respectively [16]. Nevertheless, it is of the utmost importance to highlight that the sensitivity of scintimammography is strictly dependent on the size of lesions. A multi-centre study on 420 patients with 449 breast lesions (21% were benign) reported a sensitivity of 26%, 56%, 95% and 97% for T1a, T1b, T1c and T2 breast cancers, respectively [17]; in particular, sensitivity was significantly different between malignant lesions p1 cm (46.5%) and those 41 cm (96%). Waxman et al. [18] showed that lesions greater than 12 mm are visualised by scintigraphy in more than 92% of cases, whereas smaller tumours are detected only in 50% of cases. Similar results regarding sensitivity are obtained when breast lesions are divided in palpable and non-palpable, which always show a lower sensitivity [17,19–20], as confirmed by the review of Liberman et al. [15], that reported a sensitivity of 87.8% for patients with a palpable breast mass and of 66.8% for patients without a palpable lesion. Moreover, the results of a North American multicentre trial involving 673 patients in 42 institutions [21] indicate a sensitivity for breast cancer detection of 87% and 61% for palpable and non-palpable abnormalities, respectively. However, also biological factors, such as tumour type, determining the net radiotracer uptake in the cancer [22] have to be taken into account for their in vivo visualisation by scintigraphy. 4. SPECT and SPECT/CT Since other breast imaging modalities are increasingly used for the early identification of small suspicious lesions,
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the detection of small cancers is critical for the clinical development and acceptance of scintimammography. The acquisition of tomographic images, by means of single photon emission computed tomography (SPECT), can play a role in increasing the sensitivity of planar scintimammography. Until now, some discordant results have been reported in the studies comparing tomographic and planar imaging in primary breast cancer diagnosis. It is important to highlighting that a good SPECT imaging quality can be obtained only with the patient in the supine position with elevated arms, because SPECT imaging with patients in prone position is limited by the geometric constraints of the patient, imaging table and gantry [7]. In a group of 63 patients with 67 mammographically suspicious breast abnormalities [23] we observed a sensitivity of 93 for supine SPECT and of 86 for planar imaging, whereas accuracy resulted 91% and 88%, respectively. Moreover, in breast lesions p1 cm, supine SPECT yielded a significantly higher sensitivity than planar images both in T1b and non-palpable breast cancers, without any decrease in specificity [24], thus indicating that a SPECT acquisition is mandatory if scintimammography is performed for the imaging of small lesions. These clinical data are confirmed by a breast phantom study demonstrating that a better detection of small-sized lesions is achieved with tomoscintigraphic than with planar images [25]. Moreover, from a technical point of view, the same authors suggest that SPECT should be reconstructed using iterative algorithms instead of back-projection methods, and a 128 128 matrix is preferable to a 64 64 one. Although SPECT imaging has better contrast resolution, a clear and accurate definition of the sites of radiopharmaceutical uptake can be difficult to obtain. On the other hand, prone images with planar lateral views provide natural landmarks of breast contours, which are very useful for lesions localisation. The co-registration of SPECT with structural information obtained through radiological examinations allows the precise correlation of functional and anatomic data on the same image. The commercial availability of a hybrid gamma-camera/CT scanner, which is able to provide, in addition to scintigraphic data, cross-sectional X-ray transmission images, has facilitated the fusion of anatomical maps and SPECT images [26]. The first clinical applications of this new technology are very encouraging; in particular, when used for breast imaging, SPECT/CT correlative data are particularly useful in the most difficult cases, facilitating the interpretation of SPECT findings with a more accurate anatomical assessment of sites of abnormal activity [27]. 5. Dedicated high-resolution devices The best option for improving the sensitivity of scintimammography in the detection of small tumours is the use of dedicated gamma-cameras specifically built for breast imaging. To date, scintimammography has been usually performed with conventional gamma-cameras that
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are large, bulky, and not specifically designed for imaging the breast, making them less than optimal for this application. The use of small field of view high-resolution cameras allows both greater flexibility in patient positioning (improving breast imaging by limiting the field of view and reducing image contamination from other organs, i.e. liver and heart) and breast compression, with an important increase in the target-to-background ratio [28]. In fact, the detector can be placed directly in contact with the breast allowing a mild compression with reduction of the breast’s thickness, thus improve the camera’s sensitivity. Moreover, owing to their design, dedicated cameras can also provide a better intrinsic and extrinsic spatial resolution when compared to standard cameras, with an enhancement of the contrast resolution of small lesions [29]. These cameras, using appropriate adapters, can be easily fit on most upright mammography apparatuses, replacing the radiographic Bucky. An important advantage is also the possibility of acquiring scintigraphic scans using standard mammographic views (craniocaudal and lateral oblique), making the comparison between the two imaging modalities simpler. The results obtained in a limited number of studies indicate a better sensitivity of high-resolution cameras when compared to conventional large field of view camera, especially in detecting small breast cancers. Scopinaro et al. [30] performed a comparison between a 10 cm FOV detector and a standard Anger-camera in a group of 53 patients. Breast cancer was found in 31 patients, 16 were p1 cm and 15 41 cm. Both the high-resolution and the conventional camera detected 14 out of 15 cancers 41 cm. In the group of small tumours, the difference between the sensitivity of the two detectors was significant: 81% for the dedicated camera and only 50% for the Anger-camera. Brem et al. [29] evaluated 50 patients with 58 lesions (range: 0.3–6.0 cm): 41 (71%) were non-palpable and 30 were (52%) benign. The sensitivity of Tc-99 m sestamibi scintimammography was 64% for the standard and 79% for the dedicated gamma-camera. The sensitivity for tumours p1 cm was 47% for the general-purpose and 67% for the dedicated camera; the sensitivity for nonpalpable cancer was 56% and 72%, respectively. The results of a study specifically designed to evaluate the utility of a dedicated breast-specific camera as a screening modality has been recently reported: Coover et al. [31] demonstrated cancer that was otherwise undetectable by conventional methods in three out of five scintimammography positive cases; only one of the three carcinomas identified with the dedicated gamma camera was detectable also with a standard camera. Rhodes et al. [32] have recently used a CZT camera in a group of 40 women. The detector head was composed of an array of 80 80 CZT elements (each of 2.5 2.5 mm), with a FOV of 20 20 cm. Scintimammography with Tc-99 m sestamibi detected 33 out of 36 malignant lesions (sensitivity 92%) in 26 patients. In particular, the sensitivity was 86% in tumours o1 cm and 100% in larger ones and 75% in T1a and 89% in T1b
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tumours. Their data indicate that high-resolution imaging is able to visualise smaller and deeper breast cancers, overcoming the main limitations of conventional scintimammography. 6. Clinical applications of scintimammography In any patient in which there is doubt about the results of mammography or other diagnostic test, scintimammography might provide added value [33]. Because radiopharmaceuticals’ uptake is independent of the breast density, scintimammography can be very useful in the subgroup of population with mammographically dense breasts [34]. Moreover, scintimammography is particularly useful in patients with doubtful microcalcifications or parenchymal distortions, in the presence of scar tissue in the breast following surgery or biopsy, and in breasts with implants [7]. It is well known that mammography is less accurate in evaluating breasts that have been previously submitted to surgery, biopsy, radiation therapy or chemotherapy. Patients who have a scar within the breast due to these iatrogenic interventions are often difficult for mammographic interpretation, whereas scintimammography is not affected by these morphologic changes. Some considerations regarding the possible role of scintimammography in the identification of multifocal–multicentric breast cancer and in the detection of the possible primary breast tumour in patients with metastatic axillary lymphnode involvement. The detection of multicentric lesions is of the utmost importance, because it can determine the surgical management of the patient (i.e. total mastectomy instead of quadrantectomy). It has been reported that scintimammography is able to assess the presence of a multifocal–multicentric disease, detecting bilateral breast cancers, with higher sensitivity when compared to mammography/ultrasound [35]. However, due to the limited data available in this specific application along with the low sensitivity of scintimammography in visualising small additional malignant lesions [36], this potential indication deserves further studies in larger series; moreover, the good performance of MRI in this field should be taken into account. In patients with axillary lymph-node metastases due to adenocarcinoma with negative mammography and ultrasound, scintimammography may be useful for detecting the possible primary tumour in the breast. Nevertheless, also for this application, until now there is not sufficient evidence for recommend a routinE clinical use of breast scintigraphy. Scintimammography in patients with locally advanced breast cancer can be useful both for monitoring and predict response to neoadjuvant chemotherapy. In a study protocol including two scintigraphies before and after neoadjuvant chemotherapy, scintimammography proved accurate in predicting tumour presence or absence after treatment, and useful for the in vivo detection of intrinsic and acquired resistant cancers, a very important factor for planning the best therapeutic strategy [37].
7. Conclusions Mammography remains the first imaging modality for the early detection of breast cancer. Scintimammography can be a useful complement to non-diagnostic mammography in some specific indications and is able to potentially reduce the number of unnecessary biopsies. Scintimammography is recommended for those patients where additional information is required in order to reach a definitive diagnosis. Nevertheless, probably only the development and large availability of dedicated highresolution cameras will allow scintimammography to become of routinary use. References [1] A. Jemal, R.C. Tiwari, T. Murray, et al., CA Cancer J. Clin. 5 (2004) 8. [2] L.K. Tabar, B. Vitak, H.H.T. Chen, M.F. Yen, S.W. Duffy, R.A. Smith, Cancer 91 (2001) 1724. [3] R.L. Birdwell, D.M. Ikeda, K.F. O’Shaughnessy, E.A. Sickles, Radiology 219 (2001) 192. [4] D. Kopans, AJR 158 (1992) 521. [5] R.L. Birdwell, D.M. Ikeda, K.F. O’Shaughnessy, E.A. Sickles, Radiology 219 (2001) 192. [6] D.D. Adler, R.L. Wahl, AJR 164 (1995) 19. [7] O. Schillaci, J.R. Buscombe, Eur. J. Nucl. Med. Mol. Imaging 31 (Suppl. 1) (2004) S35. [8] K. Schomacker, H. Schicha, Eur. J. Nucl. Med. 27 (2000) 1845. [9] J. Maublant, Z. Zhang, M. Rapp, et al., J. Nucl. Med. 34 (1993) 1949. [10] F. Scopinaro, O. Schillaci, M. Scarpini, et al., Eur. J. Nucl. Med. 21 (1994) 984. [11] A.S. Arbab, K. Koizumi, K. Toyama, T. Araki, J. Nucl. Med. 37 (1996) 1551. [12] N.H. Hendrikse, E.J. Franssen, W.T. van der Graaf, W. Vaalburg, E.G. de Vries, Eur. J. Nucl. Med. 26 (1999) 283. [13] I. Khalkhali, I. Mena, E. Jouanne, et al., J. Am. Coll. Surg. 178 (1994) 491. [14] R. Taillefer, Semin. Nucl. Med. 24 (1999) 16. [15] M. Liberman, F. Sampalis, D.S. Mulder, J.S. Sampalis, Breast Cancer Res. Treat. 80 (2003) 115. [16] R. Taillefer, Semin. Nucl. Med. 35 (2005) 100. [17] F. Scopinaro, O. Schillaci, W. Ussof, et al., Anticancer Res. 17 (1997) 1631. [18] A. Waxman, N. Nagaraj, M. Kovalevsky, et al., J. Nucl. Med. 36 (1995) 194P. [19] S. Mekhmandarov, J. Sandbank, M. Coehn, S. Lelcuk, E. Lubin, J. Nucl. Med. 39 (1998) 86. [20] J. Tolmos, J.A. Cutrone, B. Wang, et al., J. Natl. Cancer Inst. 90 (1998) 846. [21] I. Khalkhali, J. Villanueva-Meyer, S.L. Edell, et al., J. Nucl. Med. 41 (2000) 1973. [22] J.R. Buscombe, J.B. Cwikla, D.S. Thakrar, A.J. Hilson, Anticancer Res. 17 (1997) 1693. [23] O. Schillaci, Eur. J. Nucl. Med. Mol. Imaging 32 (2005) 521. [24] O. Schillaci, F. Scopinaro, R. Danieli, et al., Nucl. Med. Commun. 18 (1997) 839. [25] A. Spanu, O. Schillaci, G.B. Meloni, et al., Int. J. Oncol. 21 (2002) 831. [26] E. Garin, A. Devillers, S. Girault, et al., Nucl. Med. Commun. 22 (2001) 1045. [27] O. Schillaci, R. Danieli, C. Manni, G Simonetti, Nucl. Med. Commun. 25 (2004) 705. [28] O. Schillaci, E. Cossu, O. Buonuomo, et al., J. Nucl. Med. 46 (2005) 550.
ARTICLE IN PRESS O. Schillaci et al. / Nuclear Instruments and Methods in Physics Research A 569 (2006) 281–285 [29] R.F. Brem, J.M. Schoonjans, D.A. Kieper, S. Majewski, S. Goodman, C. Civelek, J. Nucl. Med. 43 (2002) 909. [30] F. Scopinaro, R. Pani, G. De Vincentis, A. Soluri, R. Pellegrini, L.M. Porfiri, Eur. J. Nucl. Med. 26 (1999) 1279. [31] L.R. Coover, G. Caravaglia, P. Kuhn, J. Nucl. Med. 45 (2004) 553. [32] D.J. Rhodes, M.K. O’Connor, S.W. Phillips, R.L. Smith, D.A. Collins, Mayo Clin. Proc. 80 (2005) 24. [33] O. Schillaci, J. Nucl. Med. 46 (2005) 1571.
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[34] I. Khalkhali, J.K. Baum, J. Villanueva-Meyer, et al., Radiology 222 (2002) 149. [35] J.B. Cwikla, J.R. Buscombe, B. Holloway, et al., Nucl. Med. Commun. 22 (2001) 1287. [36] H.I. Vargas, R.V. Agbunag, A. Kalinowski, et al., Am. Surg. 67 (2001) 1204. [37] S. Mezi, F. Primi, F. Capoccetti, F. Scopinaro, M. Modesti, O. Schillaci, Int. J. Oncol. 22 (2003) 1233.