- Email: [email protected]
Scintigraphic imaging of breast tumors
EUROPEAN JOURNAL OF
RADIOLOGY ELSEVIER
European Journal of Radiology 24 (1997) 2- IO
Scintigraphic imaging of breast tumors Jean Maublant’
Received 5 September 1996: revised 5 September 1996: accepted 5 September 1996
Abstract Technetium-99m-sestamibi
scintigraphy has recently emerged as a new procedure for the imaging of malignant breast tumors. has now been collected and this article reviews the main published results. The major drawback of the procedure appears to be its low sensitivity in detecting lesions smaller than 1 cm. The biological background underlying the tracer accumulation is also described. The stimulating potent applications of this functional imaging technique to non-invasively explore the development, and possibly the reversal, of a multidrug resistance under chemotherapy are discussed. The data related to the use of the positron emitter fluor-l&labeled fluorodeoxyglucose (FDG), a very promising agent for imaging breast as well as other solid tumors, are also reviewed. The situation of specific agents, still under development and such as labeled receptor ligands, is examined. Copyright 8 1997 Elsevier Science Ireland Ltd.
A large clinical experience
Keywords: Breast; Breast neoplasms; Deoxyglucose: P-Glycoprotein; Somatostatin receptors: Technetium
Multiple drug resistance; Fluorine radioisotopes; Tc 99m sestamibi; Thallium radioisotopes
1. Introduction Tracking ganism nuclear
molecules
is an old medicine.
once
dream
administered
that
has
come
into
the
to reality
orwith
But the way has been, and is still, paved with numerous difficulties. As per today, suitand commercially available radiopharable y-emitters maceuticals remain very few. Moreover the imaging technique is still penalized by a poor resolution that makes any scintigram look as a low quality, secondrate medical image. But it contains such a unique information, mostly related to function, that strong specific fields of applications have been developed, and many more are under way. Surprisingly, the recent successful applications are not always the fact of specific radiopharmaceuticals. This is particularly true in oncology with the technetium-99m (Tc-99m) la-
’Tel.: + 33 0473278155: [email protected] 0720-048X/97/$17.00 PII 80720-048X(96)01
fax:
+ 33
0473278078;
e-mail:
I .fr
Copyright
I1 l-4
:C: 1997 Elsevier
Science
Ireland
Mammary
neoplasms;
beled sestamibi and the fluor(F-18) labeled glucose derivative fluorodeoxyglucose (FDG). These two normally intp and others, concentrate agents, metabolically active organs such as the brain for FDG and the heart for sestamibi, but they also concentrate into the metabolically very active malignant tumors, and in particular in breast tumors. The first report of scintigraphic breast imaging dates back from 1946 when the radioactive pure fiemitter phosphorus-32 was demonstrated to concentrate into ulcerating carcinoma of the breast [l]. During the following years, various agents were investigated: potassium-42 and analogs such as rubidium86 and cesium-131, but also strontium-87m, bismuth-206 citrate, iodine- 123, gallium-67, Tc-99mpertechnetate and Tc-99m-labeled phosphate derivatives. The sensitivity for the detection of breast carcinoma was generally high but the specificity was low and these procedures did not leave the research field.
Ltd. All rights
reserved
J. Mauhlant
2. Scintimammography
i
European Joumal
with thallium-201
Thallium-201 (Tl-201) has been available since 1975 for the scintigraphic imaging of myocardial blood flow. This cyclotron-produced metallic cation is generally considered, in a first approximation, as a potassium analogue. Its rapid blood clearance makes it favorable for early imaging after injection, but its physical properties are suboptimal for scintigraphy with a too long half-life (73 h) and a too low photonic emission energy (98% in the 69-83 keV range). Uptake of Tl-201 by tumors, first described in a 47-year-old patient with a bronchial carcinoma of the left lung and who was being referred for a myocardial scintigraphy, was initially resented as a pitfall in cardiac scintigraphy [2]. It then emerged as a new potential field of application, especially in lung and thyroid carcinoma [3]. The first series of patients with breast cancer studied prospectively with Tl-201 was reported in 1988 by Sehweil et al. [4]. In 1993, Waxman et al. evaluated the sensitivity and specificity of the method in palpable breast tumors [5]. In a series of 81 patients with a lesion size ranging from 1.3 x 1.1 x 0.9 cm to 3.2 x 3.0 x 2.4 cm, 47 had a proven malignancy and scintigraphy was positive in 96%. Three patients with adenoma (23%) showed an area of increased uptake which could not be differentiated from a malignant lesion. All the scans were normal in a group of 19 patients with fibrocystic changes on biopsy and in 30 patients with no palpable breast abnormalities. Similar results were reported by others [6]. The authors believe that Tl-201 breast imaging could complement the existing diagnosis procedures of palpation, mammography and ultrasonography, especially because of the low rate of false positive results. In the more recent work of Cimitan et al. [7], overall specificity was markedly better for scintigraphy than for mammography and echography (95% versus 40 and 26% respectively). The mechanism of tumor accumulation of Tl-201 is not completely understood. As a myocardial blood flow imaging agent, Tl-201 is always described as a potassium analogue, although around 40% of its cellular accumulation is nonspecific. The uptake of Tl-201 by tumors could be related to the long ago discovered increase of potassium content in carcinoma. The organs and tumor distributions of Tl-201 and K-42 have been found to be highly correlated in VX-2 cancer-bearing rabbits [8]. Ando et al. have suggested that only these monocationic alkali metals with a radius larger than the 133 picometers of potassium can be avidly taken up by tumor cells [9]. In a unique observation [lo], from the measured tumor tissue uptake of Tl-201 and of Tc-99mlabeled microspheres injected into the liver circulation of a patient with hepatic metastases of a colon carcinoma and who was to undergo laparotomy, it could be shown that the distribution of Tl-201 within the
of Radiology
24 (1997) 2-10
3
tumor tissue is not proportional to the regional blood flow or, in other words, that Tl-201 distribution in tumors is not a simple flow dependent process.
3. Scintimammography
with Tc-99m-sestamibi
Scintimammography reached a new dimension when Tc-99m-sestamibi was described as a potent agent for cancer imaging. Multicenter clinical trials have been launched and this technique has been suddenly exposed I to an unexpected wide-scale publicity, especially in the United States of America. The major reasons of this success were probably that sestamibi was already available on the market as a myocardial blood flow imaging agent (Cardiolite, Du Pont-Merck Pharmaceutical, USA) and that it is labeled by Tc-99m, a low-cost single-photon emitter radionuclide available in every nuclear medicine division, providing instant access to scintimammography for everyone (Fig. 1). Tc-99m-sestamibi is a small lipophilic and cationic molecule of the isonitrile family and utilized routinely since the beginning of the 90s in nuclear cardiology. Tumor accumulation of Tc-99m-sestamibi has been first reported in 1987 [ll]. In 1992, its uptake in breast carcinoma was described in a case report [12] and in a series of patients with various types of malignant tumors [ 131. The same year, the prone position imaging technique was introduced by Khalkhali et al. [14]. The first two prospective studies describing Tc-99m-sestamibi concentration into breast tumors were reported in abstract form in 1993 [15,16]. The first journal article presenting a prospective study with sestamibi was authored by Khalkhali et al. in 1994 [17]. Prone position imaging for the lateral projections is described. Fifty-nine patients were presenting with 62 lesions, among which 41 were palpable. A total of 45 tumors were studied with biopsy and 17 with fine needle aspiration cytology. The mean size was 2.3 ? 1.8 by 1.9 f 1.6 cm. There were 23/24 (95.8%) true positive scintigrams and 33/38 (86.8%) true negative. The only false negative was in a patient with a non palpable mass and microcalcifications at mammography. The five false positive cases involved two fibroadenomas and three fibrocystic disease. The subgroup of 21 non palpable lesions consisted of lesions that were suspicious on screening mammography and warranted excisional biopsy. Among these, 14 were fibrocystic disease (12 true negative and two false positive at scintigraphy), three were fibroadenomas and two were normal breast tissue (all true negative), one was a ductal carcinoma in situ comedo type (true positive) and one was a noninfiltrating ductal carcinoma (false negative). The positive and negative predictive values of scintigraphy come to 82.1% and 97.1%, respectively. In its two further publications, which included 106 [18]
4
Fig. I. Examples of scintimammography obtained after injection of 740 MBq of Tc-99m-sestamibi. Top left: normal distribution of Tc-99m-sestamibi in the thorax in the anterior projection; high uptake is observed in salivary glands, thyroid, myocardium, liver and spleen; breast uptake is very faint. Top right: 63-year-old patient with a I cm infiltrating ductal carcinoma of the left breast, clearly seen on the anterior projection. Middle left: 67.year-old patient with a I cm infiltrating ductal carcinoma of the left breast and a small area of moderately increased uptake seen on the left lateral projection. Middle right: 64-year old patient with a 1.5 cm intiltrating ductal carcinoma of the left breast and an area of increased uptake seen on the left lateral projection. Bottom left: 63-year-old patient with an infiltrating ductal carcinoma and calcifications of the right breast. and a large area of intense uptake on the right lateral projection. Bottom right: 56.year-old patient with skin retraction, a lobulated mass at mammography, liponecrosis and non specific granuloma at histology, and multifocal intense uptake on the right lateral projection.
and 153 lesions [19], respectively, the same group reported values of, respectively, 93.7% and 92.2% for sensitivity, 87.8% and 89.2% for specificity, 76.9% and 81 .O% for the positive predictive value, 97.0% and
95.8%) for the negative predictive value. In the latter study, the false-positive results were associated with epithelial hyperplasia for the eight fibrocystic-disease lesions as well as for the three fibroadenomas. The four
J. Muuhlant / European Journal CI/ Radiology 24 (1997) 2- 10
false negative results were in lesions with their largest diameter equal to or smaller than 8 mm. Ductal carcinoma in situ was correctly identified in eight lesions. The role of scintigraphy was underlined in two interesting subgroups. When the lesions on mammograms were interpreted as indeterminate masses, scintigraphy correctly identified 14 of the benign and three of the malignant lesions. When dense breasts did not allow identification of palpable masses by mammography, scintigraphy correctly identified eight carcinomas and 22 benign lesions, but it was falsely positive in two patients. Other groups have also performed scintimammography, but not always with the prone position for imaging. Kao et al. have studied 38 female patients with palpable breast masses detected by mammography and/ or physical examination [20]. Among the 32 malignant lesions, 27 (84%) were detected, the smallest one being a 1 x 1 x 2 cm adenocarcinoma. Among the five adenocarcinomas that were not visualized, the largest one measured 7 x 4 x 3 cm. The six benign lesions, corresponding to fibrocystic disease, were all negative at scintimammography. From these data, the authors concluded that the likelihood of Tc-99m-sestamibi uptake was not related to tumor size, although they did not have in their series any lesion smaller than 2 cm. Burak et al. [21] have studied 27 patients with malignant breast carcinoma and 14 patients with benign lesions, all with a minimal size of 1.5 x 2 cm. Sensitivity was 93% and carcinomas with a grade of 3 were always lesions greater than 3 x 3 cm. No correlation was found between the pathological diagnosis of the mass and the grade of its tracer accumulation on the scans. Of the two negative studies, one was a 2.5 x 2 cm invasive lobular carcinoma, the other one an occult tubular carcinoma. In the 14 benign lesions, scintigraphy was positive in two showing a high degree of cellularity. The overall sensitivity and specificity of scintigraphy were 93 and 86%, respectively. In comparison, mammography alone or in combination with ultrasound provided values of 100 and 78%, respectively. These authors conclude that mammography and ultrasound remain the basic imaging modalities for screening of the palpable breast masses, but that Tc-99m-sestamibi scintigraphy might provide additional evidence of the differentiation between malignant and benign lesions. It may also improve the specificity in women with a suspect mammogram and who are at high risk of developing breast cancer. A different approach for interpreting the tumor uptake of Tc-99m-sestamibi, based on angiogenesis, has been proposed by Scopinaro et al. [22]. In 19 patients with primary breast cancer, sestamibi images were positive in all N + tumors and negative in all N - . The corresponding microvessel density was 147 _+ 21 and 72 k 12 (p < O.Ol), respectively. This raises the possibil-
5
ity that the development of angiogenesis in breast tumors could trigger some cellular modifications leading to an increase of Tc-99m-sestamibi uptake. Based on the technical approach defined by Khalkahli, the group of Taillefer et al. [23] evaluated the sensitivity and specificity of the procedure in a series of 65 consecutive patients referred for a suspicious breast lesion either at palpation (44 patients) or only at mammography (21 patients) and that required fine needle aspiration cytology or biopsy. The overall sensitivity for detecting primary breast cancer was 91.5% and specificity 94.4%. The four false negative studies were found in a microscopic ductal carcinoma in situ without associated mass and in three lesions of 7 mm or less, two of which were not palpable. The only false positive scan was obtained in a patient with a fibrocystic disease. The authors underline the importance of prone imaging, along with a good chest positioning device and a relatively lengthy acquisition time, in order to be able to detect small and deeply located lesions. The results of a large multicenter study involving 673 patients in North America have recently become available [24]. Overall sensitivity and specificity were 85 and 81%, respectively, while they reached 95 and 74% in the palpable lesions, and 72 and 86% in the non palpable lesions. Since one of the basic limitations of scintimammography is the poor resolution of the scintillation camera which does not allow for detection of lesions smaller than around 7 mm, Maurer et al. [25] have investigated whether an optimized camera could improve detection of small lesions. But the breast imaged under the craniocaudal projection was blurred by an important and variable contribution of scattered counts from the liver, gallbladder and heart. Sensitivity of Tc-99m-sestamibi was 90% (S/10) for the lesions larger than 1.5 cm but unfortunately only one patient with a smaller lesion was evaluated. In the same study, a subgroup of patients received Tl-201. The sensitivity was then 67% (8/12) for the lesions greater than 1.5 cm and only 20% (l/S) for the smaller ones. The specificity was 83% (15jlS) for sestamibi and 93% (28/30) for Tl-201. Most of these studies have included patients with palpable and non palpable lesions, irrespective of the presence of dense breasts at mammography. But recently Khalkhali et al. have studied a group of 48 patients with dense breasts [26]. The sensitivity and specificity of scintimammography was 93.7 and 90.6%, respectively, whereas it was only 82.3 and 45.1%, respectively, for mammography, proving the superiority of scintigraphy over a density-based method of imaging. In conclusion, these clinical studies have demonstrated the good sensitivity and specificity of scintimammography for the detection of malignant breast
6
I
J. Muuhlunt
i Europeun Journd of’Radiolog~~ 24 (1997) 2-10
tumors, but some false positive and false negative results are clearly encountered. The discrepancies could originate from the imaging technique or from the tissular uptake of the tracer. In order to clarify this issue, we have measured the actual uptake of Tc-99m-sestamibi in tissue samples collected just after surgery [27]. All the malignant tumors were found to have an increased sestamibi uptake but with a wide range of variations, not related to any of the usual clinically or histologically measured parameters. An interesting point was that four tumors which were presenting a high actual uptake were not seen at scintimammography. Two of these were smaller than 8 mm and the two other, with a size of 10 and 25 mm respectively, were located in the lower internal quadrant of the left breast. So tumor size is certainly a limitation of scintimammography, but an internal location and a possible superimposition with the heart image can also be a cause of false negative results. Of notice is that the two false positive at scintigraphy had benign epithelial hyperplasia. Do we have a biological explanation for the uptake of Tc-99m-sestamibi in malignant cells? This issue has been initially clarified in cardiac cells by the extensive research work of D. Piwnica-Worms and coworkers. By modifying the plasma and mitochondria transmembrane electrical potential of cultured myocytes with metabolic inhibitors and ionophores, they could demonstrate that the total amount of cellular uptake of sestamibi closely follows the value of this potential [28]. Other investigators have shown that nearly 90% of the cellular activity is concentrated into the mitochondria, the reason being that their transmembrane potential is higher than at the plasma membrane level [29]. Eventually, direct localization by electron probe X-ray microanalysis has determined that the intracellular target for sestamibi is the mitochondrial inner matrix [30]. In fact, this property is shared by other molecules of biological interest which have in common to be small lipophilic cations, as for example rhodamine[31]. The original in vitro demonstration of an increased avidity of Tc-99m-sestamibi by carcinoma cells was published by Delmon-Moingeon in 1990 [32]. We have observed with different carcinoma cells lines and several normal cells lines that sestamibi is generally more discriminating than Tl-201 [33]. A potential new field of applications for sestamibi tumor imaging was opened when Piwnica-Worms demonstrated [34] that this molecule is a substrate of the 170-kDa transmembrane P-glycoprotein (Pgp- 170) present in the cells overexpressing the multidrug resistance (MDRI) gene. Pgp-I 70 is an energy-dependent ATP consuming efflux pump which acts as a protective device by extruding a wide range of structurally unrelated amphiphilic hydrophobic molecules such as cytotoxic drugs like adriamycin, vincristine, daunorubicin, as well as sestamibi. It is a rather ubiquitous molecule
but it can reach a particularly high level of expression in many tumor cells that become consequently resistant to chemotherapy. The interesting issue is that sestamibi allows visualization of the A4DRl level of expression in vivo. In vitro, Piwnica-Worms et al. have reported that the content of sestamibi at steady-state is in the ratio of l/40 between the highly resistant LZ cells and the low resistant V79 Chinese hamster lung fibroblasts from which the LZ are derived [34]. Incidentally, it was reported in the same study that the Tl-201 uptake is not modified at various levels of A4DR expression, showing that this agent is not a Pgp transport substrate. Other authors have reported for Tc-99m-sestamibi a ratio of 1/lo-20 between MCF7 cell lines expressing A4DRl and eight other breast cell lines showing no detectable levels of PEP-170 [35]. Evidence that this mechanism also plays a role on the washout rate of Tc-99m-sestamibi has been provided [36]. It remains now to be demonstrated that these results can be extrapolated to in vivo imaging in human. But there are already some difficulties lying ahead since Pgp-170 is not the only protein involved in the multidrug resistance. It can also be related to the overexpression of the multidrug-resistance-associated protein (MRP) gene, encoding for a MRP 190-kDa protein, and of the anionic glutathione-S-transferase (GST) gene, which regulates the intracellular level of glutathione (GSH) through the GST enzyme activity. Preliminary results suggest that Tc-99m-sestamibi is also a substrate for MRP, but not for GST [37]. This would implicate that the presence of sestamibi uptake in a tumor would not necessarily indicate that this tumor is sensitive to chemotherapy. Other investigators have also recently described a non-Pgp and non-MRP rhodamine efflux and anthracycline resistance in a selected cancer cell line [38]. Finally, the MDR phenotype appears as a complex multifactorial phenomenon and it seems likely now that only studies comparing the prognosis with the uptake or rate of release of sestamibi will possibly be able to demonstrate the predictive value of scintimammography. Nevertheless, being able to detect the level of resistance of a tumor by scintigraphy could open an innovative way of testing very quickly the effect of the so-called reversal or modulation agents. These agents can block the activity of Pgp- 170 and could therefore be used as adjuvant to chemotherapy in the chemoresistant patients. They belong to the families of calcium channel blockers as verapamil, calmodulin antagonists, quinine derivatives, synthetic isoprenoids, tamoxifen and cyclosporins. In vitro, the effect of verapamil on sestamibi has been assessed by Piwnica-Worms [34] in cultured V79 and the derived MDR enriched cell lines. The observed increase of the steady-state level of intracellular sestamibi concentration in verapamil treated resistant lines strongly suggests a reversal of the MDR
J. Mauhlanr
1European Journal of Radiology 24 (I 997) 2- IO
effect. This has been confirmed by others with verapamil and a non-immunosuppressive analogue of cyresistant breast closporin A, PSC833, in adenocarcinoma cell lines [36]. Studying the effect of verapamil on two of their 9 breast cancer cell lines, Cordobes et al. [35] have also observed that Tc-99msestamibi uptake was increased by a factor of 2 in the sensitive line and by a factor of 12 in the resistant line. Verapamil is also efficient on MCF7 resistant cells, increasing sestamibi uptake by nearly 30% [37]. Two other compounds labeled by Tc-99m could have potential application for breast imaging. Tc-99m-tetrofosmin is another lipophilic cation utilized for myocardial blood flow imaging. Its biological behaviour seems to be similar to that of Tc-99m-sestamibi and it is consequently not surprising that it shows some degree of tumor uptake. Preliminary results have confirmed its potential in breast tumor imaging [39]. Tc-99m-methylene diphosphonate (MDP) is one of the most widely used agents for skeletal scintigraphy. Extraskeletal accumulation in malignant tumors has been described, in particular in breast tumors. In a series of 200 patients with elevated suspicion or proven diagnosis of breast cancer, imaging during the lo-20 min time interval following injection revealed a sensitivity of 92% and a specificity of 95”/;1 [40]. Although the mechanisms of tissular uptake of MDP in tumors remain unclear, the low cost of this agent and its wide utilization for bone scanning are important factors that should stimulate its validation in that indication. In conclusion, initially sought at being a pure blood flow imaging agent, Tc-99m-sestamibi was demonstrated to be extracted from the circulating blood through mechanisms that are not directly related to the blood flow level but to cellular metabolism. This turned out to be of interest first in the assessment of myocardial viability, and now in tumor imaging, with great promise.
4. Breast tumor positron emission tomography F-1%FDG
with
Among the radiotracers that could, in the future, be useful for breast cancer imaging, a special place should be reserved for the positron emitter F-18-FDG. The overconsumption of glucose in tumor cells has been known since the 30s. Its analogue 2-deoxyglucose can only undergo the first step of glycolysis. The resulting 2-deoxyglucose-6-phosphate is not recognized as a substrate by the second enzyme of the glycolytic pathway, glucose-6-phosphatase. It slowly accumulates inside the cells as long as some 2-deoxyglucose remains available in the circulating blood. FDG is very similar to 2-deoxyglucose, but the missing oxygen in the 2 position is substituted by a fluoride atom. F-l8-FDG is a FDG in
7
which the stable fluor is substituted by the unstable, positron emitter, fluor-18. The accumulation of the non metabolisable derivative of F- 18-FDG, namely F-l 8FDG-6-phosphate, in the cells results in an increased signal, appearing as an area of hyperactivity at scintigraphy. Even if hyperglycolysis of tumor cells has long been recognized, its origin remains poorly understood. However it is linked with the overexpression of glucose transporters, called Glut-l to Glut-5.. It was recently demonstrated that breast cancers express higher levels of Glut-l, usually called the brainerythrocyte type, I than of Glut-2 and Glut-4, but not the Glut-3 nor Glut-5 glucose transporters [41]. These results differ from what has been reported for other localizations, suggesting diversity of overexpression between different tissues. Besides malignancy, ischaema is also a well-known biological cause of increased glucose uptake, even in tumor cells [42]. Parallely, macrophages, neutrophils and lymphocytes infiltrating from blood and resulting into a granulation tissue containing fibroblasts, collagen fibers and neocapillaries also utilize glucose as a substrate, especially the activated macrophages and the young granulation tissue [43], causing possible false positive results in case of inflammation, sarcoidosis and early post-operative scar. Following case reports [44,45], the first clinical study with F-18-FDG in breast cancer was reported by Wahl et al. in 1991 [46]. One particularity of PET imaging is the high tumor/background ratio. In this series, it averaged 8.1/l, with a range between 1.8 and > 800. In 1992, Tse et al. assessed the value of F-18-FDG imaging in 14 patients [47]. Of the 10 patients with breast cancer, eight had a positive FDG study. The smallest detected lesion measured 1.0 x 0.7 x 0.3 cm. There was no false positive. In another study involving 20 patients, the tumors were detected with a median tumor/background contrast of 4.911 in 10 of the 11 patients with primary breast cancer [48]. In 35 suspect breast masses found in 28 patients, Adler et al. have obtained a sensitivity of 96% and a specificity of 100% [49]. It was reported by Crowe et al. in 28 patients, that FDG uptake in the primary tumor was not associated with age, menopausal status, race, tumor size, laterality, histology grade, ploidy, DNA index, estrogen or progesterone receptor value, pathologic stage nor serum glucose level [50]. Overall, the number of breast tumor patients that have been studied with FDG is now rather large but multicenter clinical trials have not yet been conducted. Only these will allow us to compare this promising approach with mammography and single photon emission scintigraphy for the detection of the primary tumor. Moreover, FDG provides a unique and powerful way of detecting the associated metastasis on a whole-
body basis. This method could modify dramatically the management of breast cancer in the future. A very interesting application of FDG imaging is the rapid monitoring of the response to chemohormonotherapy. An initial evaluation in nine patients with a large primary breast cancer in whom the tumor response was sequentially measured during three cycles of treatment demonstrated that a successful treatment is associated with a rapid and significant decrease (8 1% of the basal value) in tumor uptake of FDG that antedates any decrement in tumor size [51]. Finally, the potential role of FDG imaging in breast carcinoma could be for (a) the differentiation between benign and malignant tumors, (b) the staging of a primary lesion, especially by the detection of axillary lymph nodes involvement, and the detection of distant metastasis, (c) the evaluation of response to therapy.
5. Other agents for breast scintigraphy Various approaches are under investigation, based on the use of possibly more specific agents. The most promising results are presented below. Scintigraphic imaging of steroid receptors could help to measure non invasively their in vivo concentration, providing a possible gain over the in vitro analysis of the cancer tissue which suffers from an uncertainty due to the heterogeneity of the receptor distribution. It could also provide a way for in situ radiotherapy if highly selective molecules were available. Interesting results are appearing for estrogen receptors. For instance, there was an excellent correlation (r = 0.96) between the uptake of 16x-[F-l 8]-fluoroestradiol-17p within the primary breast tumor and the estrogen-receptor concentration in a series of 13 patients [52]. But in the most significant effort dealing with progesterone21-[F-18]fluoro-l6r-ethyl-19-norreceptor imaging, progesterone appeared suboptimal for a proper quantification of the receptors [53]. The a-receptors are known to be present in human malignant melanoma, glioma cells and non-small cell lung carcinoma cells. But breast cancer MCF-7 cells also express these receptors through a iodine-125 labeled iodobenzamide derivative [54]. Bakir et al. [55] have labeled with the positron emitter iodine-l 24 a monoclonal antibody recognizing the external domain of the human c-erb B-2 proto-oncogen, a transmembrane glycoprotein showing similarities with the EGF-receptor and which can therefore function as an autocrine growth factor receptor in breast cancer. Tumor imaging was successful in nude mice bearing human breast carcinoma xenografts overexpressing the c-erb B-2 gene product. Indium- 111 -labeled octreotide, a commercially available somatostatin analogue for scintigraphic imaging of
carcinoids, islet cells’ tumors and paragangliomas, has been found to concentrate into 75% of 52 primary breasts tumors, most of them being invasive ductal carcinomas [56]. It could help selecting somatostatin-receptor positive tumors or detecting recurrence in these patients.
6. Conclusion Scintigraphic imaging of the primary breast cancer is feasible with several radiopharmaceuticals either currently available or still under investigation. The discovery that Tc-99m-sestamibi, a common agent for myocardial imaging, concentrates into most of the malignant breast tumors has caused a sudden and wide surge of interest for scintimammography. Now that a significant experience has been gained, the main weakness of the method appears to be its low sensitivity in the detection of lesions smaller than 1 cm. But functional imaging of the tumors is possible, a new approach that is not possible with any of the other imaging procedures. The role of Tc-99m-sestamibi in the management of breast cancer has now to be evaluated, comparing its feasibility, reproducibility, availability and cost effectiveness with the other imaging and diagnostic procedures in view of diagnosis but also of staging, prognosis and evaluation of the therapeutic response. The emerging capabilities of other promising agents, as for example the positron emitter F-18-FDG, give hope that functional imaging of the primary breast tumors and of their secondary localizations will soon become a reality.
References [I] Low-Beer
[2]
[3]
[4]
[5]
[6]
[7]
BVA. Surface measurements of radioactive phosphorus in breast tumors as possible diagnostic method. Science 1946; 104: 399. Cox PH. Belfer AJ, Van der Pompe WB. Thallium-201 chloride uptake in tumors, a possible complication in heart scintigraphy. Br J Radio1 1976; 49: 767-768. Hisada K, Tonami H, Miyamae T, Hiraki Y, Yamazaki T, Maeda T, Nakajo M. Clinical evaluation of tumor imaging with thallium-201 chloride. Radiology 1978; 129: 497-500. Sehweil A, McKillop JH, Ziada G, Al-Sayed M, Abdel-Dayem H, Omar YT. The optimum time for tumor imaging with thallium-201. Eur J Nucl Med 1988; 13: 5277529. Waxman A, Ramanna L, Memsic L, Foster CE, Silberman AW, Gleischman SH, Brenner RJ, Brachman MB, Kuhar CJ, Yadegar J. Thallium scintigraphy in the evaluation of mass abnormalities of the breast. J Nucl Med 1993; 34: 18-23. Lee VW, Sax EJ, McAneny DB, Pollack S, Blanchard RA, Beazley RM, Kavanah MT, Ward RJ. A complementary role for thallium-201 scintigraphy with mammography in the diagnosis of breast cancer. J Nucl Med 1993; 34: 2095-2100. Cimitan M, Volpe R, Candiani E, Gusso G, Ruffo R, Borsatti E, Massarut S. Rossi C, Morassut S, Carbone A. The use of
J. Mmhlunt
I European Journal of Rudiology 24 (1997) 2-10
thallium-201 in the preoperative detection of breast cancer: an adjunct to mammography and ultrasonography. Em J Nucl Med 1995; 22: 1110~1117. [S] Ito Y, Murankka A, Harada T, Matsudo A, Yokobayashi T, Terashima H. Experimental study on tumor affinity of TI-201. Eur J Nucl Med 1978; 3: 81-86. [9] Ando A, Ando I, Katayama M, Sanada S, Hiraki T, Mori H, Tonami N, Hisada K. Biodistributions of radioactive alkaline metals in tumor bearing animals: comparison with TI-201, Eur J Nucl Med 1988: 14: 3522357. [IO] Sehweil AM, McKillop JH, Milroy R. Wilson R. Abdel-Dayem HM, Omar YT. Mechanism of TI-201 uptake in tumours. Eur J Nucl Med 1989: 15: 3766379. [l I] Muller ST, Guth-Tougelids B. Creutizig H. Imaging of malignant tumors with Tc-99m MIBI SPECT. Eur J Nucl Med 1987; 28: 562 (abstract). [I21 Campeau RJ, Kronemer KA, Sutherland CM. Concordant uptake of Tc-99m sestamibi and TI-201 in unsuspected breast tumor. Clin Nucl Med 1992; 17: 9366937. [I31 Atkolun C, Bayhan H, Kir M. Clinical experience with Tc-99m MIBI in patients with malignant tumors: preliminary results and comparison with Tl-201. Clin Nucl Med 1992: 17: 17lll76. [I41 Khalkhali I, Mena I, Jouanne E, Diggles L, Jackson B, Klein S. Breast cancer detection with Tc-99m-sestamibi prone imaging: its correlation with mammography and pathology. Clin Nucl Med 1992; 9: 761 (abstract). [15] Azaloux H. Baudin J, Chanol MA. Boisseron D. Lefebur S, Kerjean J, Escarmant P, Lemab G, Moretti JL, Vilcoq JR. Facteur pronosScintigraphie du cancer du sein au mibi-Tc-99m. tic‘? Med Nucl 1993; 18: 319 (abstract). [16] de Maesschalck P, Demonceau G. InterPt du Tc-MIBI dans la detection du cancer du sein. Med Nucl 1993; 18: 324 (abstract). [I71 Khalkhali I. Mena I. Jouanne E, Diggles L, Venegas R, Block J, Alle K, Klein S. Prone scintimammography in patients with suspicion of carcinoma of the breast. J Am Coll Surg 1994: 178: 491-497. [I81 Khalkhali I, Cutrone. Diggles L, Venegas R, Vargas H. Jackson B, Klein S. Technetium-99m-sestamibi scintimammography of breast lesions: clinical and pathological follow-up. J Nucl Med 1995: 36: 178441789. I, Cutrone JA. Mena 1. Diggles LE. Venegas RI, [I91 Khalkhali Vargas HI, Jackson BL. Khalkhali S. Moss JF, Klein S. Scintimammography: the complementary role of Tc-99m-sestamibi prone breast imaging for the diagnosis of breast carcinoma. Radiology 1995: 196: 42 I -426. WI Kao CH, Wang SJ. Liu TJ. The use of technetium-99m methoxyisobutylisonitrile breast scintigraphy to evaluate palpable breast masses. Eur J Nucl Med 1994: 21: 4322436. PII Burak Z, Argon M, Memis A. Erdem S. Balkan Z, Duman Y, Ustun EE, Erhan Y, Ozkilic H. Evaluation of palpable breast masses with Tc-99m-MIBI: a comparative study with mammography and ultrasonography. Nucl Med Comm 1994: 15: 604612. m Scopinaro F, Schillaci 0, Scarpini M. Mingazzini PL, DiMacio L. Banci M. DanielIi R. Zerilli M, Limiti MR. Colella AC. Technetium-99m sestamibi: an indicator of breast cancer invasiveness. Eur J Nucl Med 1994: 21: 984- 987. ~31 Taillefer R. Robidoux A, Lambert R. Turpin S. Laperriere J. Technetium-99m-sestamibi prone scintimammography to detect primary breast cancer and axillary lymph node involvement. J Nucl Med 1995; 36: 175881765. J. Edell SL. Hanelin LG. Lugo P41 Khalkhali 1. Villanueva-Meyer CE. Taillefer R. Freeman LM, Neal CE, Scheff AM, Connolly JL. Schnitt SJ. Baum JK. Houlihan MJ, Hale CA, Haber SB. Diagnostic accuracy of Tc-99m-sestamibi breast imaging in breast cancer detection, J Nucl Med 1996: 37: 74P (abstract).
1251 Maurer
9
AH, Caroline DF, Jadali FJ, Manzone TA, Maier WP, Au FC, Schnall SF. Limitations of craniocaudal thallium-201 and technetium-99m-sestamibi mammoscintigraphy. J Nucl Med 1995; 36: 16966 1700. J, Edell SL, Hanelin LG, Lugo WI Khalkhali I, Villanueva-Meyer CE, Taillefer R, Freeman LM, Neal CE, Scheff AM, Connolly JL, Schnitt SJ, Baum JK, Houlihan MJ, Hale CA, Haber SB. Impact of breast density on the diagnostic accuracy of Tc-99msestamibi breast imaging in the detection of breast cancer. J Nucl Med 1996; 37: 74PP75P (abstract). ~271Maublant J, de Latour M, Mestas D, Clemenson A, Charrier S, Feillel V, Le Boudec G, Kaufmann P, Dauplat J, Veyre A. Tc-99m-sestamibi uptake in breast tumors and associated lymph nodes uptake. J Nucl Med 1996; 37: 922-925. D. Effect of mitochonWI Chiu ML, Kronauge JF, Piwnica-Worms drial and plasma membrane potentials on accumulation of hexakis-(2-methoxyisobutylisonitrile) technetium (1) in cultured mouse fibroblasts. J Nucl Med 1990; 31: 164661653. v91 Crane P, Laliberte R, Heminway S, Thoolen M, Orlandi C. Effect of mitochondrial viability and metabolism on technetium99m-sestamibi myocardial retention. Eur J Nucl Med 1993; 20: 20-25. D, Hackett D, Kronauge J, Lieber[301 Backus M, Piwnica-Worms man M, Ingram P, LeFurgey A. Microprobe analysis of TcMIBI in heart cells: Calculation of mitochondrial membrane potential. Am J Physiol 1993; 265: Cl78C187. [311 Davis S, Weiss MJ, Wong JR, Lampidis TJ, Chen LB. Mitochondrial and plasma membrane potentials cause unusual accumulation and retention of rhodamine 123 by human breast adenocarcinoma-derived MCF-7 cells, J Biol Chem 1985; 260: 13844 13850. LI, Piwnica-Worms D, Van den Abbeele ~321Delmon-Moingeon AD, Holman BL. Uptake of the cation hexakis (2.methoxyisobutyl-isonitrile)-technetium-99m by human carcinoma cell lines in vitro. Cancer Res 1990; 50: 219882202. [331 Maublant J, Zhang Z. Rapp M, Oilier M, Michelot J. Veyre A. In vitro uptake of technetium-99m teboroxime in carcinoma cell lines and normal cells: comparison with technetium-99m-sestamibi and thallium-201. J Nucl Med 1993; 34: 194991952. D, Chiu ML, Budding M, Kronauge JF, [341 Piwnica-Worms Kramer RA, Croop JM. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res 1993: 53: 9777984. L, Blanchot C, [351 Cordobes MD, Starzec A, Delmon-Moingeon Kouyoumdjian JC. Prevost G, Caglar M, Moretti JL. Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: correlation with mdr gene expression. J Nucl Med 1996; 37: 2866289. [361 Ballinger JR, Hua HA, Berry BW, Firby P, Boxen I. Tc-99m-sestamibi as an agent for imaging P-glycoprotein-mediated multidrug resistance: in vitro and in vivo studies in a rat breast tumour cell line and its doxorubicin-resistant variant, Nucl Med Commun 1995; I6 (4): 253-257. L, Ozker K, Hayward M, Akansel G, Griffith 0, [371 Kabasakal Isitman AT. Hellman R, Collier D. Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance. Eur J Nucl Med 1996; 23: 5688570. [381 Sandor VA, Robey R, Alverez M et al. Rhodamine efflux and anthracycline resistance by a non-Pgp and non-MRP mechanism in a selected breast cancer cell line. Proc ASCR 1996; 37: 320 (abstract). PF, Mansi L, Procaccini E, Di Gregorio F, Del [391 Rambaldi Vecchio E. Breast cancer detection with Tc-99m tetrofosmin. Clin Nucl Med 1995; 20: 7033705. L, [401 Piccolo S, Lastoria S, Mainolfi C, Muto P, Bazzicalupo Salvatore M. Technetium-99m-methylene diphosphonate scinti-
10
III
J. Mauhlunt ! Europrcrn Journd of’Rcrdiiolog~ 24 (1997) 2-10
mammography to image primary breast cancel. J Nucl Med 1995; 36: 7188724. of Glut-l glucose trans1411 Brown RS, Wahl RL. Overexpression porter in human breast cancer: an immunohistochemica1 study. Cancer 1993; 72: 2979-2985. uptake in ~421 Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose human cancer cell lines is increased by hypoxia. J Nucl Med 1995; 36: 162551632. S, Kubota K, Ishiwata K, Tamahashi N, 1431 Kubota R, Yamada Ido T. Intratumoral distribution of fluorine-IS-fluorodeoxyglucase in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992; 33: 197221980. T, Amemiya A, Kondo M, Fujiwara T, [441 Kubota K, Matsuzwana Watanuki S, Ito M, Ido T. Imaging of breast cancer with (F-18)-fluorodeoxyglucose and positron emission tomography. J Comput Assist Tomogr 1989: 13: 109771098. [451 Wahl RL, Cody R, Hutchins G, Mudgett E. Positron emission tomographic scanning of primary and the metastatic breast carcinoma with radiolabeled glucose analog 2-deoxy-F-18fluoro-d-glucose. N Engl J Med 1991; 324: 200. G, Mudgett E. Primary and [461 Wahl RL, Cody R, Hutchins metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analog 2-[F-181.fluoro-2-deoxy-Dglucose. Radiology 1991; 179: 7655770. [471 Tse NY, Hoh CK, Hawkins RA. Zinner MJ, Dahlbom M, Choi Y. Maddahi J, Brunicardi FC. Phelps ME, Glaspy JA. The application of PET imaging with fluorodeoxyglucose to the evaluation of breast disease. Ann Surg 1992; 216: 27-34. [481 Nieweg OE, Kim EE. Wong WH. Broussard WF, Singletary SE. Hortobagyi GN, Tilbury RS. Positron emission tomography with fluorine-IS-deoxyglucose in the detection and staging of breast cancer. Cancer 1993: 71: 3920-3925.
of [491 Adler LA, Corwe JP. Al-Kaisi NK, Sunshine JL. Evaluation breast masses and axillary lymph nodes with [F-181.2-deoxy-2fluoro-D-glucose PET. Radiology 1993; 187: 743- 750. [501 Crowe JP, Adler LP, Shenk RR, Sunshine J. Positron emission tomography and breast masses: comparison with clinical, mammographic. and pathological findings, Ann Surg Oncol 1994: l(2): 1322140. [511 Wahl RL, Zasadny K, Helvie M, Hutchins CD, Weber B. Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography using positron emission tomography: initial evaluation. J Clin Oncol 1993: 11: 21012111. ~521 Mintun MA. Welch MJ. Siegel BA, Mathias CJ, Brodack JW. McGuire AH, Katzenellenbogen JA. Breast cancer: PET imaging of estrogen receptors. Radiology 1988: 169: 45-48. [531 Dehdashti F, McGuire AH, Van Brocklin HF. Siegel BA, Andriole DP, Griffeth LK, Pomper MC, Katzenellenbogen JA, Welch MJ. Assessment of 2l-[F-l8]fluoro-l6x-ethyl-l9-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas. J Nucl Med 1991; 32: 153221537. RB. [541 John CS. Vilner BJ, Gulden ME, Efange SMN. Langason Moody TW, Bowen WD. Synthesis and pharmacological characterization of 4-[1-125]-N-(N-benzylpiperidin-4-yl)-4-iodobenzamide: a high affinity g receptor ligand for potential imaging of breast cancer. Cancer Res 1995: 55: 302223027. [551 Bakir MA. Eccles SA. Babich JW. Aftab N, Styles JM, Dean CJ. Ott RJ. c-erbB2 protein overexpression in breast cancer as a target for PET using iodine-124-labeled monoclonal antibodies. J Nucl Med 1992: 33: 2154-2160. [561 van Eijck CH, Krenning EP. Bootsma A. Oei HY. van Pel R, Lindemans J. Jeekel J, Reubi JC, Lamberts SW. Somatostatinreceptor scintigraphy in primary breast cancer. Lancet 1994; 343: 640-643.
RADIOLOGY ELSEVIER
European Journal of Radiology 24 (1997) 2- IO
Scintigraphic imaging of breast tumors Jean Maublant’
Received 5 September 1996: revised 5 September 1996: accepted 5 September 1996
Abstract Technetium-99m-sestamibi
scintigraphy has recently emerged as a new procedure for the imaging of malignant breast tumors. has now been collected and this article reviews the main published results. The major drawback of the procedure appears to be its low sensitivity in detecting lesions smaller than 1 cm. The biological background underlying the tracer accumulation is also described. The stimulating potent applications of this functional imaging technique to non-invasively explore the development, and possibly the reversal, of a multidrug resistance under chemotherapy are discussed. The data related to the use of the positron emitter fluor-l&labeled fluorodeoxyglucose (FDG), a very promising agent for imaging breast as well as other solid tumors, are also reviewed. The situation of specific agents, still under development and such as labeled receptor ligands, is examined. Copyright 8 1997 Elsevier Science Ireland Ltd.
A large clinical experience
Keywords: Breast; Breast neoplasms; Deoxyglucose: P-Glycoprotein; Somatostatin receptors: Technetium
Multiple drug resistance; Fluorine radioisotopes; Tc 99m sestamibi; Thallium radioisotopes
1. Introduction Tracking ganism nuclear
molecules
is an old medicine.
once
dream
administered
that
has
come
into
the
to reality
orwith
But the way has been, and is still, paved with numerous difficulties. As per today, suitand commercially available radiopharable y-emitters maceuticals remain very few. Moreover the imaging technique is still penalized by a poor resolution that makes any scintigram look as a low quality, secondrate medical image. But it contains such a unique information, mostly related to function, that strong specific fields of applications have been developed, and many more are under way. Surprisingly, the recent successful applications are not always the fact of specific radiopharmaceuticals. This is particularly true in oncology with the technetium-99m (Tc-99m) la-
’Tel.: + 33 0473278155: [email protected] 0720-048X/97/$17.00 PII 80720-048X(96)01
fax:
+ 33
0473278078;
e-mail:
I .fr
Copyright
I1 l-4
:C: 1997 Elsevier
Science
Ireland
Mammary
neoplasms;
beled sestamibi and the fluor(F-18) labeled glucose derivative fluorodeoxyglucose (FDG). These two normally intp and others, concentrate agents, metabolically active organs such as the brain for FDG and the heart for sestamibi, but they also concentrate into the metabolically very active malignant tumors, and in particular in breast tumors. The first report of scintigraphic breast imaging dates back from 1946 when the radioactive pure fiemitter phosphorus-32 was demonstrated to concentrate into ulcerating carcinoma of the breast [l]. During the following years, various agents were investigated: potassium-42 and analogs such as rubidium86 and cesium-131, but also strontium-87m, bismuth-206 citrate, iodine- 123, gallium-67, Tc-99mpertechnetate and Tc-99m-labeled phosphate derivatives. The sensitivity for the detection of breast carcinoma was generally high but the specificity was low and these procedures did not leave the research field.
Ltd. All rights
reserved
J. Mauhlant
2. Scintimammography
i
European Joumal
with thallium-201
Thallium-201 (Tl-201) has been available since 1975 for the scintigraphic imaging of myocardial blood flow. This cyclotron-produced metallic cation is generally considered, in a first approximation, as a potassium analogue. Its rapid blood clearance makes it favorable for early imaging after injection, but its physical properties are suboptimal for scintigraphy with a too long half-life (73 h) and a too low photonic emission energy (98% in the 69-83 keV range). Uptake of Tl-201 by tumors, first described in a 47-year-old patient with a bronchial carcinoma of the left lung and who was being referred for a myocardial scintigraphy, was initially resented as a pitfall in cardiac scintigraphy [2]. It then emerged as a new potential field of application, especially in lung and thyroid carcinoma [3]. The first series of patients with breast cancer studied prospectively with Tl-201 was reported in 1988 by Sehweil et al. [4]. In 1993, Waxman et al. evaluated the sensitivity and specificity of the method in palpable breast tumors [5]. In a series of 81 patients with a lesion size ranging from 1.3 x 1.1 x 0.9 cm to 3.2 x 3.0 x 2.4 cm, 47 had a proven malignancy and scintigraphy was positive in 96%. Three patients with adenoma (23%) showed an area of increased uptake which could not be differentiated from a malignant lesion. All the scans were normal in a group of 19 patients with fibrocystic changes on biopsy and in 30 patients with no palpable breast abnormalities. Similar results were reported by others [6]. The authors believe that Tl-201 breast imaging could complement the existing diagnosis procedures of palpation, mammography and ultrasonography, especially because of the low rate of false positive results. In the more recent work of Cimitan et al. [7], overall specificity was markedly better for scintigraphy than for mammography and echography (95% versus 40 and 26% respectively). The mechanism of tumor accumulation of Tl-201 is not completely understood. As a myocardial blood flow imaging agent, Tl-201 is always described as a potassium analogue, although around 40% of its cellular accumulation is nonspecific. The uptake of Tl-201 by tumors could be related to the long ago discovered increase of potassium content in carcinoma. The organs and tumor distributions of Tl-201 and K-42 have been found to be highly correlated in VX-2 cancer-bearing rabbits [8]. Ando et al. have suggested that only these monocationic alkali metals with a radius larger than the 133 picometers of potassium can be avidly taken up by tumor cells [9]. In a unique observation [lo], from the measured tumor tissue uptake of Tl-201 and of Tc-99mlabeled microspheres injected into the liver circulation of a patient with hepatic metastases of a colon carcinoma and who was to undergo laparotomy, it could be shown that the distribution of Tl-201 within the
of Radiology
24 (1997) 2-10
3
tumor tissue is not proportional to the regional blood flow or, in other words, that Tl-201 distribution in tumors is not a simple flow dependent process.
3. Scintimammography
with Tc-99m-sestamibi
Scintimammography reached a new dimension when Tc-99m-sestamibi was described as a potent agent for cancer imaging. Multicenter clinical trials have been launched and this technique has been suddenly exposed I to an unexpected wide-scale publicity, especially in the United States of America. The major reasons of this success were probably that sestamibi was already available on the market as a myocardial blood flow imaging agent (Cardiolite, Du Pont-Merck Pharmaceutical, USA) and that it is labeled by Tc-99m, a low-cost single-photon emitter radionuclide available in every nuclear medicine division, providing instant access to scintimammography for everyone (Fig. 1). Tc-99m-sestamibi is a small lipophilic and cationic molecule of the isonitrile family and utilized routinely since the beginning of the 90s in nuclear cardiology. Tumor accumulation of Tc-99m-sestamibi has been first reported in 1987 [ll]. In 1992, its uptake in breast carcinoma was described in a case report [12] and in a series of patients with various types of malignant tumors [ 131. The same year, the prone position imaging technique was introduced by Khalkhali et al. [14]. The first two prospective studies describing Tc-99m-sestamibi concentration into breast tumors were reported in abstract form in 1993 [15,16]. The first journal article presenting a prospective study with sestamibi was authored by Khalkhali et al. in 1994 [17]. Prone position imaging for the lateral projections is described. Fifty-nine patients were presenting with 62 lesions, among which 41 were palpable. A total of 45 tumors were studied with biopsy and 17 with fine needle aspiration cytology. The mean size was 2.3 ? 1.8 by 1.9 f 1.6 cm. There were 23/24 (95.8%) true positive scintigrams and 33/38 (86.8%) true negative. The only false negative was in a patient with a non palpable mass and microcalcifications at mammography. The five false positive cases involved two fibroadenomas and three fibrocystic disease. The subgroup of 21 non palpable lesions consisted of lesions that were suspicious on screening mammography and warranted excisional biopsy. Among these, 14 were fibrocystic disease (12 true negative and two false positive at scintigraphy), three were fibroadenomas and two were normal breast tissue (all true negative), one was a ductal carcinoma in situ comedo type (true positive) and one was a noninfiltrating ductal carcinoma (false negative). The positive and negative predictive values of scintigraphy come to 82.1% and 97.1%, respectively. In its two further publications, which included 106 [18]
4
Fig. I. Examples of scintimammography obtained after injection of 740 MBq of Tc-99m-sestamibi. Top left: normal distribution of Tc-99m-sestamibi in the thorax in the anterior projection; high uptake is observed in salivary glands, thyroid, myocardium, liver and spleen; breast uptake is very faint. Top right: 63-year-old patient with a I cm infiltrating ductal carcinoma of the left breast, clearly seen on the anterior projection. Middle left: 67.year-old patient with a I cm infiltrating ductal carcinoma of the left breast and a small area of moderately increased uptake seen on the left lateral projection. Middle right: 64-year old patient with a 1.5 cm intiltrating ductal carcinoma of the left breast and an area of increased uptake seen on the left lateral projection. Bottom left: 63-year-old patient with an infiltrating ductal carcinoma and calcifications of the right breast. and a large area of intense uptake on the right lateral projection. Bottom right: 56.year-old patient with skin retraction, a lobulated mass at mammography, liponecrosis and non specific granuloma at histology, and multifocal intense uptake on the right lateral projection.
and 153 lesions [19], respectively, the same group reported values of, respectively, 93.7% and 92.2% for sensitivity, 87.8% and 89.2% for specificity, 76.9% and 81 .O% for the positive predictive value, 97.0% and
95.8%) for the negative predictive value. In the latter study, the false-positive results were associated with epithelial hyperplasia for the eight fibrocystic-disease lesions as well as for the three fibroadenomas. The four
J. Muuhlant / European Journal CI/ Radiology 24 (1997) 2- 10
false negative results were in lesions with their largest diameter equal to or smaller than 8 mm. Ductal carcinoma in situ was correctly identified in eight lesions. The role of scintigraphy was underlined in two interesting subgroups. When the lesions on mammograms were interpreted as indeterminate masses, scintigraphy correctly identified 14 of the benign and three of the malignant lesions. When dense breasts did not allow identification of palpable masses by mammography, scintigraphy correctly identified eight carcinomas and 22 benign lesions, but it was falsely positive in two patients. Other groups have also performed scintimammography, but not always with the prone position for imaging. Kao et al. have studied 38 female patients with palpable breast masses detected by mammography and/ or physical examination [20]. Among the 32 malignant lesions, 27 (84%) were detected, the smallest one being a 1 x 1 x 2 cm adenocarcinoma. Among the five adenocarcinomas that were not visualized, the largest one measured 7 x 4 x 3 cm. The six benign lesions, corresponding to fibrocystic disease, were all negative at scintimammography. From these data, the authors concluded that the likelihood of Tc-99m-sestamibi uptake was not related to tumor size, although they did not have in their series any lesion smaller than 2 cm. Burak et al. [21] have studied 27 patients with malignant breast carcinoma and 14 patients with benign lesions, all with a minimal size of 1.5 x 2 cm. Sensitivity was 93% and carcinomas with a grade of 3 were always lesions greater than 3 x 3 cm. No correlation was found between the pathological diagnosis of the mass and the grade of its tracer accumulation on the scans. Of the two negative studies, one was a 2.5 x 2 cm invasive lobular carcinoma, the other one an occult tubular carcinoma. In the 14 benign lesions, scintigraphy was positive in two showing a high degree of cellularity. The overall sensitivity and specificity of scintigraphy were 93 and 86%, respectively. In comparison, mammography alone or in combination with ultrasound provided values of 100 and 78%, respectively. These authors conclude that mammography and ultrasound remain the basic imaging modalities for screening of the palpable breast masses, but that Tc-99m-sestamibi scintigraphy might provide additional evidence of the differentiation between malignant and benign lesions. It may also improve the specificity in women with a suspect mammogram and who are at high risk of developing breast cancer. A different approach for interpreting the tumor uptake of Tc-99m-sestamibi, based on angiogenesis, has been proposed by Scopinaro et al. [22]. In 19 patients with primary breast cancer, sestamibi images were positive in all N + tumors and negative in all N - . The corresponding microvessel density was 147 _+ 21 and 72 k 12 (p < O.Ol), respectively. This raises the possibil-
5
ity that the development of angiogenesis in breast tumors could trigger some cellular modifications leading to an increase of Tc-99m-sestamibi uptake. Based on the technical approach defined by Khalkahli, the group of Taillefer et al. [23] evaluated the sensitivity and specificity of the procedure in a series of 65 consecutive patients referred for a suspicious breast lesion either at palpation (44 patients) or only at mammography (21 patients) and that required fine needle aspiration cytology or biopsy. The overall sensitivity for detecting primary breast cancer was 91.5% and specificity 94.4%. The four false negative studies were found in a microscopic ductal carcinoma in situ without associated mass and in three lesions of 7 mm or less, two of which were not palpable. The only false positive scan was obtained in a patient with a fibrocystic disease. The authors underline the importance of prone imaging, along with a good chest positioning device and a relatively lengthy acquisition time, in order to be able to detect small and deeply located lesions. The results of a large multicenter study involving 673 patients in North America have recently become available [24]. Overall sensitivity and specificity were 85 and 81%, respectively, while they reached 95 and 74% in the palpable lesions, and 72 and 86% in the non palpable lesions. Since one of the basic limitations of scintimammography is the poor resolution of the scintillation camera which does not allow for detection of lesions smaller than around 7 mm, Maurer et al. [25] have investigated whether an optimized camera could improve detection of small lesions. But the breast imaged under the craniocaudal projection was blurred by an important and variable contribution of scattered counts from the liver, gallbladder and heart. Sensitivity of Tc-99m-sestamibi was 90% (S/10) for the lesions larger than 1.5 cm but unfortunately only one patient with a smaller lesion was evaluated. In the same study, a subgroup of patients received Tl-201. The sensitivity was then 67% (8/12) for the lesions greater than 1.5 cm and only 20% (l/S) for the smaller ones. The specificity was 83% (15jlS) for sestamibi and 93% (28/30) for Tl-201. Most of these studies have included patients with palpable and non palpable lesions, irrespective of the presence of dense breasts at mammography. But recently Khalkhali et al. have studied a group of 48 patients with dense breasts [26]. The sensitivity and specificity of scintimammography was 93.7 and 90.6%, respectively, whereas it was only 82.3 and 45.1%, respectively, for mammography, proving the superiority of scintigraphy over a density-based method of imaging. In conclusion, these clinical studies have demonstrated the good sensitivity and specificity of scintimammography for the detection of malignant breast
6
I
J. Muuhlunt
i Europeun Journd of’Radiolog~~ 24 (1997) 2-10
tumors, but some false positive and false negative results are clearly encountered. The discrepancies could originate from the imaging technique or from the tissular uptake of the tracer. In order to clarify this issue, we have measured the actual uptake of Tc-99m-sestamibi in tissue samples collected just after surgery [27]. All the malignant tumors were found to have an increased sestamibi uptake but with a wide range of variations, not related to any of the usual clinically or histologically measured parameters. An interesting point was that four tumors which were presenting a high actual uptake were not seen at scintimammography. Two of these were smaller than 8 mm and the two other, with a size of 10 and 25 mm respectively, were located in the lower internal quadrant of the left breast. So tumor size is certainly a limitation of scintimammography, but an internal location and a possible superimposition with the heart image can also be a cause of false negative results. Of notice is that the two false positive at scintigraphy had benign epithelial hyperplasia. Do we have a biological explanation for the uptake of Tc-99m-sestamibi in malignant cells? This issue has been initially clarified in cardiac cells by the extensive research work of D. Piwnica-Worms and coworkers. By modifying the plasma and mitochondria transmembrane electrical potential of cultured myocytes with metabolic inhibitors and ionophores, they could demonstrate that the total amount of cellular uptake of sestamibi closely follows the value of this potential [28]. Other investigators have shown that nearly 90% of the cellular activity is concentrated into the mitochondria, the reason being that their transmembrane potential is higher than at the plasma membrane level [29]. Eventually, direct localization by electron probe X-ray microanalysis has determined that the intracellular target for sestamibi is the mitochondrial inner matrix [30]. In fact, this property is shared by other molecules of biological interest which have in common to be small lipophilic cations, as for example rhodamine[31]. The original in vitro demonstration of an increased avidity of Tc-99m-sestamibi by carcinoma cells was published by Delmon-Moingeon in 1990 [32]. We have observed with different carcinoma cells lines and several normal cells lines that sestamibi is generally more discriminating than Tl-201 [33]. A potential new field of applications for sestamibi tumor imaging was opened when Piwnica-Worms demonstrated [34] that this molecule is a substrate of the 170-kDa transmembrane P-glycoprotein (Pgp- 170) present in the cells overexpressing the multidrug resistance (MDRI) gene. Pgp-I 70 is an energy-dependent ATP consuming efflux pump which acts as a protective device by extruding a wide range of structurally unrelated amphiphilic hydrophobic molecules such as cytotoxic drugs like adriamycin, vincristine, daunorubicin, as well as sestamibi. It is a rather ubiquitous molecule
but it can reach a particularly high level of expression in many tumor cells that become consequently resistant to chemotherapy. The interesting issue is that sestamibi allows visualization of the A4DRl level of expression in vivo. In vitro, Piwnica-Worms et al. have reported that the content of sestamibi at steady-state is in the ratio of l/40 between the highly resistant LZ cells and the low resistant V79 Chinese hamster lung fibroblasts from which the LZ are derived [34]. Incidentally, it was reported in the same study that the Tl-201 uptake is not modified at various levels of A4DR expression, showing that this agent is not a Pgp transport substrate. Other authors have reported for Tc-99m-sestamibi a ratio of 1/lo-20 between MCF7 cell lines expressing A4DRl and eight other breast cell lines showing no detectable levels of PEP-170 [35]. Evidence that this mechanism also plays a role on the washout rate of Tc-99m-sestamibi has been provided [36]. It remains now to be demonstrated that these results can be extrapolated to in vivo imaging in human. But there are already some difficulties lying ahead since Pgp-170 is not the only protein involved in the multidrug resistance. It can also be related to the overexpression of the multidrug-resistance-associated protein (MRP) gene, encoding for a MRP 190-kDa protein, and of the anionic glutathione-S-transferase (GST) gene, which regulates the intracellular level of glutathione (GSH) through the GST enzyme activity. Preliminary results suggest that Tc-99m-sestamibi is also a substrate for MRP, but not for GST [37]. This would implicate that the presence of sestamibi uptake in a tumor would not necessarily indicate that this tumor is sensitive to chemotherapy. Other investigators have also recently described a non-Pgp and non-MRP rhodamine efflux and anthracycline resistance in a selected cancer cell line [38]. Finally, the MDR phenotype appears as a complex multifactorial phenomenon and it seems likely now that only studies comparing the prognosis with the uptake or rate of release of sestamibi will possibly be able to demonstrate the predictive value of scintimammography. Nevertheless, being able to detect the level of resistance of a tumor by scintigraphy could open an innovative way of testing very quickly the effect of the so-called reversal or modulation agents. These agents can block the activity of Pgp- 170 and could therefore be used as adjuvant to chemotherapy in the chemoresistant patients. They belong to the families of calcium channel blockers as verapamil, calmodulin antagonists, quinine derivatives, synthetic isoprenoids, tamoxifen and cyclosporins. In vitro, the effect of verapamil on sestamibi has been assessed by Piwnica-Worms [34] in cultured V79 and the derived MDR enriched cell lines. The observed increase of the steady-state level of intracellular sestamibi concentration in verapamil treated resistant lines strongly suggests a reversal of the MDR
J. Mauhlanr
1European Journal of Radiology 24 (I 997) 2- IO
effect. This has been confirmed by others with verapamil and a non-immunosuppressive analogue of cyresistant breast closporin A, PSC833, in adenocarcinoma cell lines [36]. Studying the effect of verapamil on two of their 9 breast cancer cell lines, Cordobes et al. [35] have also observed that Tc-99msestamibi uptake was increased by a factor of 2 in the sensitive line and by a factor of 12 in the resistant line. Verapamil is also efficient on MCF7 resistant cells, increasing sestamibi uptake by nearly 30% [37]. Two other compounds labeled by Tc-99m could have potential application for breast imaging. Tc-99m-tetrofosmin is another lipophilic cation utilized for myocardial blood flow imaging. Its biological behaviour seems to be similar to that of Tc-99m-sestamibi and it is consequently not surprising that it shows some degree of tumor uptake. Preliminary results have confirmed its potential in breast tumor imaging [39]. Tc-99m-methylene diphosphonate (MDP) is one of the most widely used agents for skeletal scintigraphy. Extraskeletal accumulation in malignant tumors has been described, in particular in breast tumors. In a series of 200 patients with elevated suspicion or proven diagnosis of breast cancer, imaging during the lo-20 min time interval following injection revealed a sensitivity of 92% and a specificity of 95”/;1 [40]. Although the mechanisms of tissular uptake of MDP in tumors remain unclear, the low cost of this agent and its wide utilization for bone scanning are important factors that should stimulate its validation in that indication. In conclusion, initially sought at being a pure blood flow imaging agent, Tc-99m-sestamibi was demonstrated to be extracted from the circulating blood through mechanisms that are not directly related to the blood flow level but to cellular metabolism. This turned out to be of interest first in the assessment of myocardial viability, and now in tumor imaging, with great promise.
4. Breast tumor positron emission tomography F-1%FDG
with
Among the radiotracers that could, in the future, be useful for breast cancer imaging, a special place should be reserved for the positron emitter F-18-FDG. The overconsumption of glucose in tumor cells has been known since the 30s. Its analogue 2-deoxyglucose can only undergo the first step of glycolysis. The resulting 2-deoxyglucose-6-phosphate is not recognized as a substrate by the second enzyme of the glycolytic pathway, glucose-6-phosphatase. It slowly accumulates inside the cells as long as some 2-deoxyglucose remains available in the circulating blood. FDG is very similar to 2-deoxyglucose, but the missing oxygen in the 2 position is substituted by a fluoride atom. F-l8-FDG is a FDG in
7
which the stable fluor is substituted by the unstable, positron emitter, fluor-18. The accumulation of the non metabolisable derivative of F- 18-FDG, namely F-l 8FDG-6-phosphate, in the cells results in an increased signal, appearing as an area of hyperactivity at scintigraphy. Even if hyperglycolysis of tumor cells has long been recognized, its origin remains poorly understood. However it is linked with the overexpression of glucose transporters, called Glut-l to Glut-5.. It was recently demonstrated that breast cancers express higher levels of Glut-l, usually called the brainerythrocyte type, I than of Glut-2 and Glut-4, but not the Glut-3 nor Glut-5 glucose transporters [41]. These results differ from what has been reported for other localizations, suggesting diversity of overexpression between different tissues. Besides malignancy, ischaema is also a well-known biological cause of increased glucose uptake, even in tumor cells [42]. Parallely, macrophages, neutrophils and lymphocytes infiltrating from blood and resulting into a granulation tissue containing fibroblasts, collagen fibers and neocapillaries also utilize glucose as a substrate, especially the activated macrophages and the young granulation tissue [43], causing possible false positive results in case of inflammation, sarcoidosis and early post-operative scar. Following case reports [44,45], the first clinical study with F-18-FDG in breast cancer was reported by Wahl et al. in 1991 [46]. One particularity of PET imaging is the high tumor/background ratio. In this series, it averaged 8.1/l, with a range between 1.8 and > 800. In 1992, Tse et al. assessed the value of F-18-FDG imaging in 14 patients [47]. Of the 10 patients with breast cancer, eight had a positive FDG study. The smallest detected lesion measured 1.0 x 0.7 x 0.3 cm. There was no false positive. In another study involving 20 patients, the tumors were detected with a median tumor/background contrast of 4.911 in 10 of the 11 patients with primary breast cancer [48]. In 35 suspect breast masses found in 28 patients, Adler et al. have obtained a sensitivity of 96% and a specificity of 100% [49]. It was reported by Crowe et al. in 28 patients, that FDG uptake in the primary tumor was not associated with age, menopausal status, race, tumor size, laterality, histology grade, ploidy, DNA index, estrogen or progesterone receptor value, pathologic stage nor serum glucose level [50]. Overall, the number of breast tumor patients that have been studied with FDG is now rather large but multicenter clinical trials have not yet been conducted. Only these will allow us to compare this promising approach with mammography and single photon emission scintigraphy for the detection of the primary tumor. Moreover, FDG provides a unique and powerful way of detecting the associated metastasis on a whole-
body basis. This method could modify dramatically the management of breast cancer in the future. A very interesting application of FDG imaging is the rapid monitoring of the response to chemohormonotherapy. An initial evaluation in nine patients with a large primary breast cancer in whom the tumor response was sequentially measured during three cycles of treatment demonstrated that a successful treatment is associated with a rapid and significant decrease (8 1% of the basal value) in tumor uptake of FDG that antedates any decrement in tumor size [51]. Finally, the potential role of FDG imaging in breast carcinoma could be for (a) the differentiation between benign and malignant tumors, (b) the staging of a primary lesion, especially by the detection of axillary lymph nodes involvement, and the detection of distant metastasis, (c) the evaluation of response to therapy.
5. Other agents for breast scintigraphy Various approaches are under investigation, based on the use of possibly more specific agents. The most promising results are presented below. Scintigraphic imaging of steroid receptors could help to measure non invasively their in vivo concentration, providing a possible gain over the in vitro analysis of the cancer tissue which suffers from an uncertainty due to the heterogeneity of the receptor distribution. It could also provide a way for in situ radiotherapy if highly selective molecules were available. Interesting results are appearing for estrogen receptors. For instance, there was an excellent correlation (r = 0.96) between the uptake of 16x-[F-l 8]-fluoroestradiol-17p within the primary breast tumor and the estrogen-receptor concentration in a series of 13 patients [52]. But in the most significant effort dealing with progesterone21-[F-18]fluoro-l6r-ethyl-19-norreceptor imaging, progesterone appeared suboptimal for a proper quantification of the receptors [53]. The a-receptors are known to be present in human malignant melanoma, glioma cells and non-small cell lung carcinoma cells. But breast cancer MCF-7 cells also express these receptors through a iodine-125 labeled iodobenzamide derivative [54]. Bakir et al. [55] have labeled with the positron emitter iodine-l 24 a monoclonal antibody recognizing the external domain of the human c-erb B-2 proto-oncogen, a transmembrane glycoprotein showing similarities with the EGF-receptor and which can therefore function as an autocrine growth factor receptor in breast cancer. Tumor imaging was successful in nude mice bearing human breast carcinoma xenografts overexpressing the c-erb B-2 gene product. Indium- 111 -labeled octreotide, a commercially available somatostatin analogue for scintigraphic imaging of
carcinoids, islet cells’ tumors and paragangliomas, has been found to concentrate into 75% of 52 primary breasts tumors, most of them being invasive ductal carcinomas [56]. It could help selecting somatostatin-receptor positive tumors or detecting recurrence in these patients.
6. Conclusion Scintigraphic imaging of the primary breast cancer is feasible with several radiopharmaceuticals either currently available or still under investigation. The discovery that Tc-99m-sestamibi, a common agent for myocardial imaging, concentrates into most of the malignant breast tumors has caused a sudden and wide surge of interest for scintimammography. Now that a significant experience has been gained, the main weakness of the method appears to be its low sensitivity in the detection of lesions smaller than 1 cm. But functional imaging of the tumors is possible, a new approach that is not possible with any of the other imaging procedures. The role of Tc-99m-sestamibi in the management of breast cancer has now to be evaluated, comparing its feasibility, reproducibility, availability and cost effectiveness with the other imaging and diagnostic procedures in view of diagnosis but also of staging, prognosis and evaluation of the therapeutic response. The emerging capabilities of other promising agents, as for example the positron emitter F-18-FDG, give hope that functional imaging of the primary breast tumors and of their secondary localizations will soon become a reality.
References [I] Low-Beer
[2]
[3]
[4]
[5]
[6]
[7]
BVA. Surface measurements of radioactive phosphorus in breast tumors as possible diagnostic method. Science 1946; 104: 399. Cox PH. Belfer AJ, Van der Pompe WB. Thallium-201 chloride uptake in tumors, a possible complication in heart scintigraphy. Br J Radio1 1976; 49: 767-768. Hisada K, Tonami H, Miyamae T, Hiraki Y, Yamazaki T, Maeda T, Nakajo M. Clinical evaluation of tumor imaging with thallium-201 chloride. Radiology 1978; 129: 497-500. Sehweil A, McKillop JH, Ziada G, Al-Sayed M, Abdel-Dayem H, Omar YT. The optimum time for tumor imaging with thallium-201. Eur J Nucl Med 1988; 13: 5277529. Waxman A, Ramanna L, Memsic L, Foster CE, Silberman AW, Gleischman SH, Brenner RJ, Brachman MB, Kuhar CJ, Yadegar J. Thallium scintigraphy in the evaluation of mass abnormalities of the breast. J Nucl Med 1993; 34: 18-23. Lee VW, Sax EJ, McAneny DB, Pollack S, Blanchard RA, Beazley RM, Kavanah MT, Ward RJ. A complementary role for thallium-201 scintigraphy with mammography in the diagnosis of breast cancer. J Nucl Med 1993; 34: 2095-2100. Cimitan M, Volpe R, Candiani E, Gusso G, Ruffo R, Borsatti E, Massarut S. Rossi C, Morassut S, Carbone A. The use of
J. Mmhlunt
I European Journal of Rudiology 24 (1997) 2-10
thallium-201 in the preoperative detection of breast cancer: an adjunct to mammography and ultrasonography. Em J Nucl Med 1995; 22: 1110~1117. [S] Ito Y, Murankka A, Harada T, Matsudo A, Yokobayashi T, Terashima H. Experimental study on tumor affinity of TI-201. Eur J Nucl Med 1978; 3: 81-86. [9] Ando A, Ando I, Katayama M, Sanada S, Hiraki T, Mori H, Tonami N, Hisada K. Biodistributions of radioactive alkaline metals in tumor bearing animals: comparison with TI-201, Eur J Nucl Med 1988: 14: 3522357. [IO] Sehweil AM, McKillop JH, Milroy R. Wilson R. Abdel-Dayem HM, Omar YT. Mechanism of TI-201 uptake in tumours. Eur J Nucl Med 1989: 15: 3766379. [l I] Muller ST, Guth-Tougelids B. Creutizig H. Imaging of malignant tumors with Tc-99m MIBI SPECT. Eur J Nucl Med 1987; 28: 562 (abstract). [I21 Campeau RJ, Kronemer KA, Sutherland CM. Concordant uptake of Tc-99m sestamibi and TI-201 in unsuspected breast tumor. Clin Nucl Med 1992; 17: 9366937. [I31 Atkolun C, Bayhan H, Kir M. Clinical experience with Tc-99m MIBI in patients with malignant tumors: preliminary results and comparison with Tl-201. Clin Nucl Med 1992: 17: 17lll76. [I41 Khalkhali I, Mena I, Jouanne E, Diggles L, Jackson B, Klein S. Breast cancer detection with Tc-99m-sestamibi prone imaging: its correlation with mammography and pathology. Clin Nucl Med 1992; 9: 761 (abstract). [15] Azaloux H. Baudin J, Chanol MA. Boisseron D. Lefebur S, Kerjean J, Escarmant P, Lemab G, Moretti JL, Vilcoq JR. Facteur pronosScintigraphie du cancer du sein au mibi-Tc-99m. tic‘? Med Nucl 1993; 18: 319 (abstract). [16] de Maesschalck P, Demonceau G. InterPt du Tc-MIBI dans la detection du cancer du sein. Med Nucl 1993; 18: 324 (abstract). [I71 Khalkhali I. Mena I. Jouanne E, Diggles L, Venegas R, Block J, Alle K, Klein S. Prone scintimammography in patients with suspicion of carcinoma of the breast. J Am Coll Surg 1994: 178: 491-497. [I81 Khalkhali I, Cutrone. Diggles L, Venegas R, Vargas H. Jackson B, Klein S. Technetium-99m-sestamibi scintimammography of breast lesions: clinical and pathological follow-up. J Nucl Med 1995: 36: 178441789. I, Cutrone JA. Mena 1. Diggles LE. Venegas RI, [I91 Khalkhali Vargas HI, Jackson BL. Khalkhali S. Moss JF, Klein S. Scintimammography: the complementary role of Tc-99m-sestamibi prone breast imaging for the diagnosis of breast carcinoma. Radiology 1995: 196: 42 I -426. WI Kao CH, Wang SJ. Liu TJ. The use of technetium-99m methoxyisobutylisonitrile breast scintigraphy to evaluate palpable breast masses. Eur J Nucl Med 1994: 21: 4322436. PII Burak Z, Argon M, Memis A. Erdem S. Balkan Z, Duman Y, Ustun EE, Erhan Y, Ozkilic H. Evaluation of palpable breast masses with Tc-99m-MIBI: a comparative study with mammography and ultrasonography. Nucl Med Comm 1994: 15: 604612. m Scopinaro F, Schillaci 0, Scarpini M. Mingazzini PL, DiMacio L. Banci M. DanielIi R. Zerilli M, Limiti MR. Colella AC. Technetium-99m sestamibi: an indicator of breast cancer invasiveness. Eur J Nucl Med 1994: 21: 984- 987. ~31 Taillefer R. Robidoux A, Lambert R. Turpin S. Laperriere J. Technetium-99m-sestamibi prone scintimammography to detect primary breast cancer and axillary lymph node involvement. J Nucl Med 1995; 36: 175881765. J. Edell SL. Hanelin LG. Lugo P41 Khalkhali 1. Villanueva-Meyer CE. Taillefer R. Freeman LM, Neal CE, Scheff AM, Connolly JL. Schnitt SJ. Baum JK. Houlihan MJ, Hale CA, Haber SB. Diagnostic accuracy of Tc-99m-sestamibi breast imaging in breast cancer detection, J Nucl Med 1996: 37: 74P (abstract).
1251 Maurer
9
AH, Caroline DF, Jadali FJ, Manzone TA, Maier WP, Au FC, Schnall SF. Limitations of craniocaudal thallium-201 and technetium-99m-sestamibi mammoscintigraphy. J Nucl Med 1995; 36: 16966 1700. J, Edell SL, Hanelin LG, Lugo WI Khalkhali I, Villanueva-Meyer CE, Taillefer R, Freeman LM, Neal CE, Scheff AM, Connolly JL, Schnitt SJ, Baum JK, Houlihan MJ, Hale CA, Haber SB. Impact of breast density on the diagnostic accuracy of Tc-99msestamibi breast imaging in the detection of breast cancer. J Nucl Med 1996; 37: 74PP75P (abstract). ~271Maublant J, de Latour M, Mestas D, Clemenson A, Charrier S, Feillel V, Le Boudec G, Kaufmann P, Dauplat J, Veyre A. Tc-99m-sestamibi uptake in breast tumors and associated lymph nodes uptake. J Nucl Med 1996; 37: 922-925. D. Effect of mitochonWI Chiu ML, Kronauge JF, Piwnica-Worms drial and plasma membrane potentials on accumulation of hexakis-(2-methoxyisobutylisonitrile) technetium (1) in cultured mouse fibroblasts. J Nucl Med 1990; 31: 164661653. v91 Crane P, Laliberte R, Heminway S, Thoolen M, Orlandi C. Effect of mitochondrial viability and metabolism on technetium99m-sestamibi myocardial retention. Eur J Nucl Med 1993; 20: 20-25. D, Hackett D, Kronauge J, Lieber[301 Backus M, Piwnica-Worms man M, Ingram P, LeFurgey A. Microprobe analysis of TcMIBI in heart cells: Calculation of mitochondrial membrane potential. Am J Physiol 1993; 265: Cl78C187. [311 Davis S, Weiss MJ, Wong JR, Lampidis TJ, Chen LB. Mitochondrial and plasma membrane potentials cause unusual accumulation and retention of rhodamine 123 by human breast adenocarcinoma-derived MCF-7 cells, J Biol Chem 1985; 260: 13844 13850. LI, Piwnica-Worms D, Van den Abbeele ~321Delmon-Moingeon AD, Holman BL. Uptake of the cation hexakis (2.methoxyisobutyl-isonitrile)-technetium-99m by human carcinoma cell lines in vitro. Cancer Res 1990; 50: 219882202. [331 Maublant J, Zhang Z. Rapp M, Oilier M, Michelot J. Veyre A. In vitro uptake of technetium-99m teboroxime in carcinoma cell lines and normal cells: comparison with technetium-99m-sestamibi and thallium-201. J Nucl Med 1993; 34: 194991952. D, Chiu ML, Budding M, Kronauge JF, [341 Piwnica-Worms Kramer RA, Croop JM. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res 1993: 53: 9777984. L, Blanchot C, [351 Cordobes MD, Starzec A, Delmon-Moingeon Kouyoumdjian JC. Prevost G, Caglar M, Moretti JL. Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: correlation with mdr gene expression. J Nucl Med 1996; 37: 2866289. [361 Ballinger JR, Hua HA, Berry BW, Firby P, Boxen I. Tc-99m-sestamibi as an agent for imaging P-glycoprotein-mediated multidrug resistance: in vitro and in vivo studies in a rat breast tumour cell line and its doxorubicin-resistant variant, Nucl Med Commun 1995; I6 (4): 253-257. L, Ozker K, Hayward M, Akansel G, Griffith 0, [371 Kabasakal Isitman AT. Hellman R, Collier D. Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance. Eur J Nucl Med 1996; 23: 5688570. [381 Sandor VA, Robey R, Alverez M et al. Rhodamine efflux and anthracycline resistance by a non-Pgp and non-MRP mechanism in a selected breast cancer cell line. Proc ASCR 1996; 37: 320 (abstract). PF, Mansi L, Procaccini E, Di Gregorio F, Del [391 Rambaldi Vecchio E. Breast cancer detection with Tc-99m tetrofosmin. Clin Nucl Med 1995; 20: 7033705. L, [401 Piccolo S, Lastoria S, Mainolfi C, Muto P, Bazzicalupo Salvatore M. Technetium-99m-methylene diphosphonate scinti-
10
III
J. Mauhlunt ! Europrcrn Journd of’Rcrdiiolog~ 24 (1997) 2-10
mammography to image primary breast cancel. J Nucl Med 1995; 36: 7188724. of Glut-l glucose trans1411 Brown RS, Wahl RL. Overexpression porter in human breast cancer: an immunohistochemica1 study. Cancer 1993; 72: 2979-2985. uptake in ~421 Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose human cancer cell lines is increased by hypoxia. J Nucl Med 1995; 36: 162551632. S, Kubota K, Ishiwata K, Tamahashi N, 1431 Kubota R, Yamada Ido T. Intratumoral distribution of fluorine-IS-fluorodeoxyglucase in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992; 33: 197221980. T, Amemiya A, Kondo M, Fujiwara T, [441 Kubota K, Matsuzwana Watanuki S, Ito M, Ido T. Imaging of breast cancer with (F-18)-fluorodeoxyglucose and positron emission tomography. J Comput Assist Tomogr 1989: 13: 109771098. [451 Wahl RL, Cody R, Hutchins G, Mudgett E. Positron emission tomographic scanning of primary and the metastatic breast carcinoma with radiolabeled glucose analog 2-deoxy-F-18fluoro-d-glucose. N Engl J Med 1991; 324: 200. G, Mudgett E. Primary and [461 Wahl RL, Cody R, Hutchins metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analog 2-[F-181.fluoro-2-deoxy-Dglucose. Radiology 1991; 179: 7655770. [471 Tse NY, Hoh CK, Hawkins RA. Zinner MJ, Dahlbom M, Choi Y. Maddahi J, Brunicardi FC. Phelps ME, Glaspy JA. The application of PET imaging with fluorodeoxyglucose to the evaluation of breast disease. Ann Surg 1992; 216: 27-34. [481 Nieweg OE, Kim EE. Wong WH. Broussard WF, Singletary SE. Hortobagyi GN, Tilbury RS. Positron emission tomography with fluorine-IS-deoxyglucose in the detection and staging of breast cancer. Cancer 1993: 71: 3920-3925.
of [491 Adler LA, Corwe JP. Al-Kaisi NK, Sunshine JL. Evaluation breast masses and axillary lymph nodes with [F-181.2-deoxy-2fluoro-D-glucose PET. Radiology 1993; 187: 743- 750. [501 Crowe JP, Adler LP, Shenk RR, Sunshine J. Positron emission tomography and breast masses: comparison with clinical, mammographic. and pathological findings, Ann Surg Oncol 1994: l(2): 1322140. [511 Wahl RL, Zasadny K, Helvie M, Hutchins CD, Weber B. Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography using positron emission tomography: initial evaluation. J Clin Oncol 1993: 11: 21012111. ~521 Mintun MA. Welch MJ. Siegel BA, Mathias CJ, Brodack JW. McGuire AH, Katzenellenbogen JA. Breast cancer: PET imaging of estrogen receptors. Radiology 1988: 169: 45-48. [531 Dehdashti F, McGuire AH, Van Brocklin HF. Siegel BA, Andriole DP, Griffeth LK, Pomper MC, Katzenellenbogen JA, Welch MJ. Assessment of 2l-[F-l8]fluoro-l6x-ethyl-l9-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas. J Nucl Med 1991; 32: 153221537. RB. [541 John CS. Vilner BJ, Gulden ME, Efange SMN. Langason Moody TW, Bowen WD. Synthesis and pharmacological characterization of 4-[1-125]-N-(N-benzylpiperidin-4-yl)-4-iodobenzamide: a high affinity g receptor ligand for potential imaging of breast cancer. Cancer Res 1995: 55: 302223027. [551 Bakir MA. Eccles SA. Babich JW. Aftab N, Styles JM, Dean CJ. Ott RJ. c-erbB2 protein overexpression in breast cancer as a target for PET using iodine-124-labeled monoclonal antibodies. J Nucl Med 1992: 33: 2154-2160. [561 van Eijck CH, Krenning EP. Bootsma A. Oei HY. van Pel R, Lindemans J. Jeekel J, Reubi JC, Lamberts SW. Somatostatinreceptor scintigraphy in primary breast cancer. Lancet 1994; 343: 640-643.