Original article
Diagnostic value of 99mTc-bombesin scintigraphy for differentiation of malignant from benign breast lesions Farzaneh Shariatia, Kamran Aryanaa, Asiehsadat Fattahib, Mohammad N. Forghanib, Azita Azarianc, Seyed R. Zakavia, Ramin Sadeghia, Narjes Ayatia and Keyvan Sadria Objective In this study, we evaluated the diagnostic accuracy of 99mTc-bombesin scintigraphy for differentiation of benign from malignant palpable breast lesions. 99m Tc-Bombesin is a tracer with high affinity for gastrinreleasing peptide receptor, which is overexpressed on a variety of human tumors including breast carcinoma. Materials and methods We examined 33 consecutive women who were referred to our center with suspicious palpable breast lesions but had no definitive diagnosis in other imaging procedures. A volume of 370–444 MBq of 99m Tc-bombesin was injected and dynamic 1-min images were taken for 20 min immediately after injection in anterior view. Thereafter, two static images in anterior and pronelateral views were taken for 5 min. Finally, single-photon emission computed tomography images were taken for each patient. Definitive diagnosis was based on biopsy and histopathological evaluation. Results The scan findings were positive in 19 patients and negative in 11 on visual assessment of the planar and single-photon emission computed tomography images. Pathologic examination confirmed breast carcinoma in 12 patients with positive scans and benign pathology for 18 patients. The overall sensitivity, specificity, negative and positive predictive values, and accuracy of this
Introduction Breast cancer is the most common malignancy in women worldwide. Approximately, 230 000 new cases of breast cancer are diagnosed every year in the USA alone, which result in more than 39 000 deaths yearly. The incidence rate is estimated at 12% of all women and it has been increasing recently [1]. Therefore, early detection of malignant breast lesions is necessary for proper management and treatment, which in turn results in a better and more favorable patient outcome [2]. Routine diagnostic tools for evaluation of breast lesions include physical examination, mammography, and ultrasonography. If the results of these procedures are equivocal and indeterminate, depending on the clinician’s opinion, other noninvasive imaging procedures such as MRI, mammoscintigraphy, and positron emission mammography can be used [3,4]. In mammoscintigraphy, different radiopharmaceuticals including 201Tl, 99mTc-sestamibi, 99mTc-tetrofosmin, 99m Tc-thymine, and 99mTc-bombesin are used [5–10]. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0143-3636
radiotracer for diagnosis of breast cancer were 100, 66.1, 100, 63, and 76%, respectively. Semiquantitative analysis improved the specificity of the visual assessment from 66 to 84%. Conclusion Our study showed that 99mTc-bombesin scintigraphy has a high sensitivity and negative predictive value for detecting malignant breast lesions, but the specificity and positive predictive value of this radiotracer for differentiation of malignant breast abnormalities from benign ones are relatively low. Nucl c 2014 Wolters Kluwer Health | Med Commun 35:620–625 Lippincott Williams & Wilkins. Nuclear Medicine Communications 2014, 35:620–625 Keywords: benign, breast cancer, malignant, single-photon emission computed tomography, 99mTc-bombesin scintigraphy a Nuclear Medicine Research Center, bMinimally Invasive and Endoscopic Surgery Research Center and cDepartment of Radiology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Correspondence to Kamran Aryana, MD, Nuclear Medicine Research Center, Ghaem Hospital, Ahmad Abad St, Mashhad 99199-91766, Iran Tel: + 98 511 801 2781; fax: + 98 511 893 3186; e-mail: [email protected] Received 15 November 2013 Revised 7 February 2014 Accepted 25 February 2014
Bombesin is a gastrin-releasing peptide receptor analogue that is overexpressed on several human tumors including lung, prostate, ovarian, colon, stomach, exocrine pancreatic, and breast. This peptide acts as a mitogen, morphogen, growth, and antiapoptotic factor and also as a neurotransmitter in both normal and tumoral cells [11–18]. Bombesin-like peptides can be labeled with g rayemitting radioisotopes and also with b emitter radionuclides for cancer imaging and treatment goals, respectively [19]. The main aim of this study was to evaluate the diagnostic value of 99mTc-labeled bombesin scintigraphy in differentiation of benign from malignant breast lesions.
Materials and methods Thirty-three consecutive female patients, who were between 17 and 65 years of age with an average of 40±12 years, with a suspected breast lesion on mammography (BIRAD category III or IV) or with an inconclusive sonography report between October 2012 and August DOI: 10.1097/MNM.0000000000000112
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
99m
Tc-Bombesin scan for breast lesions Shariati et al. 621
2013 were selected and included in the study. All patients signed a specific written informed consent form for participation in the study, and the study was approved by the local ethics committee. Inclusion criteria were the presence of mammographic or sonographic breast abnormality that was suspicious and equivocal for malignancy with a palpable mass and being a candidate for histopathological examination. Exclusion criteria were pregnancy, lactation, prior surgery or manipulation of the breast, history of breast radiotherapy, and reluctance of the patient to undergo biopsy and pathologic assessment. Twenty-two patients were premenopausal, three were perimenopausal, and five were postmenopausal. Thirtyone patients had palpable breast masses and 22 had suspicious findings on mammographic evaluation. All had indeterminate sonographic reports. All patients underwent core needle or excisional biopsy and histopathologic examinations after scintigraphy. Two of the patients were excluded because of technical mistakes on the part of the technicians in their scintigraphy and one patient was excluded because of refusal to undergo surgical biopsy.
Imaging procedure
A dose of intravenous 370–444 MBq 99mTc-bombesin was injected into each patient. The radiopharmaceutical purity was controlled before each injection by means of thin-layer chromatography with 75% methanol and 2-butanone as the mobile phases and was greater than 98% in all cases. First, anterior-view dynamic images were taken immediately after injection of the tracer for 20 min with an interval of 1 min/frame and a matrix size of 64 64 using a dualhead variable-angle gamma camera (E.CAM Siemens, Siemens Medical Solutions Inc., Malvern, Pennsylvania, USA). The camera was equipped with a low-energy highresolution collimator and all images were taken using the 99m Tc photopeak. Thereafter, two static images in anterior and prone-lateral views were taken for 5 min with a matrix size of 256 256 pixels. Finally, the single-photon emission computed tomography (SPECT) protocol, with a 120 20 s acquisition time over 3601 and a matrix size of 128 128 pixels, was performed for each patient and the images were then reconstructed iteratively. The images were independently interpreted qualitatively by two nuclear medicine physicians who were blinded to the pathology results but had access to clinical and radiologic reports. On visual assessment, one or more focal regions of increased tracer uptake, as compared with the surrounding breast background and the mirror image on the contralateral side, were considered positive scintigraphic findings. Then, for a semiquantitative analysis, regions of interest were drawn over the area of tracer accumulation corresponding to the palpable breast mass or abnormal findings on radiologic evaluation. Thereafter, the ratios of tumor uptake in 1–5- and
1–15-min time frames in dynamic images and the tumor to normal tissue in the contralateral breast (target/ nontarget) ratio in static and SPECT images were calculated. The time–activity curve for each patient was plotted with curve analysis software and was evaluated carefully. All patients underwent core needle or excisional biopsy and histopathologic examinations after scintigraphy. Quantitative variables are expressed as mean±SD. To compare these variables, the independent sample t-test was used. The diagnostic accuracy of the semiquantitative analyses was evaluated using receiver operating characteristic (ROC) curve analysis and the area under the curve. Statistical analyses were carried out with SPSS 16 software (SPSS Inc., Malvern, Pennsylvania, USA) with a statistical significance of observed differences at a P value less than 0.05.
Results Out of the remaining 30 patients, the scan findings on visual assessment were positive for malignant lesions in 19 patients and negative for 11 patients. Histopathological evaluations confirmed breast carcinoma in 12 patients with positive scans and benign pathology for the remaining 18 patients (Fig. 1). There were seven false-positive cases on bombesin scintigraphy, which were proved to be benign lesions on pathological analysis. Among patients who were correctly diagnosed as having breast carcinoma on bombesin scan, 11 had ductal carcinoma and one patient had high-grade B-cell lymphoma. The mean age of the patients with false-positive results was 36 years, whereas the mean age of the true-positive group was 46.8 years. Eight of the patients with malignant pathologies had axillary lymph node involvement, and visual assessment of the axilla on the scintigraphy images was positive in seven patients, which means that this procedure has a sensitivity of 87.5% in the detection of axillary lymph node involvement. None of the patients with negative scan results had breast carcinoma. Histopathologic assessments of these patients in correlation with their scan results and their mean age are shown in Table 1. The sensitivity, specificity, and positive and negative predictive values for visual assessment of the images were 100, 61, 63, and 100%, respectively. Semiquantitative analyses are shown in Fig. 2. The mean target/nontarget ratios in static and SPECT images for benign and malignant lesions were 1.2±0.2, 1.5±0.3, 1.6±0.5, and 2.3±0.7, respectively, which were significantly higher in tumoral lesions. Uptake ratios at 1–5 and 1–15 min on dynamic images were not significantly related to the final diagnosis confirmed by pathologic evaluation (P = 0.8 and 0.5, respectively). ROC curve analyses for semiquantitative assessments are shown in Fig. 3. Area under the curve for planar and
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622 Nuclear Medicine Communications 2014, Vol 35 No 6
Fig. 1
Examples of negative (left images) and positive (right images) 99mTc-bombesin scintigraphy. Upper rows show dynamic images of the patients and the lower row shows the reconstructed single-photon emission computed tomography images.
SPECT semiquantitative analyses was 0.8 (95% confidence interval: 0.6–0.93) and 0.78 (95% confidence interval: 0.62–0.95), respectively. Target to nontarget cutoff value of 1.45 for static images yielded a sensitivity of 75% and a specificity of 84%. Target to nontarget cutoff value of 1.97 for SPECT images yielded a sensitivity of 66% and a specificity of 84%. Time–activity curve analysis of the dynamic images did not show any distinctive pattern (increasing, decreasing, or stable uptake with time) for differentiation of malignant from benign breast lesions. Mean time to peak activity of the curves was 14±7.12 for benign lesions and 4.8±3.2 and 5.25±1.89 min for malignant lesions with and without axillary involvement, respectively. Five patients with false-positive scan results had fibroadenoma and all of them had dense breasts on mammography. Their mean age was 29.5 years. It seems that in young women with dense breasts 99mTc-bombesin scintigraphy cannot provide useful additional diagnostic information. The final diagnosis of two other patients who had false-positive scan results was ductal hyperplasia,
which is an important risk factor for progression to ductal carcinoma and close follow-up is essential. We believe that the greater uptake in bombesin images of these two patients in comparison with others was the result of this specific pathology. The mean age of these two patients was 53 years, which is significantly higher than that of other patients with false-positive results.
Discussion Selecting a proper imaging procedure for early detection of breast cancer is necessary for successful treatment and management. If the two conventional radiologic procedures (mammography and ultrasonography) are inconclusive for differentiating between benign and malignant breast lesions, the clinician can use another noninvasive imaging modality or consider surgical biopsy. Our study showed 100% sensitivity and 61% specificity for detection of malignant breast lesions by visual assessment of the 99mTc-bombesin scintigraphy images. To improve the accuracy of the test, we used semiquantitative analysis and SPECT images. As a three-dimensional tomographic
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99m
Tc-Bombesin scan for breast lesions Shariati et al. 623
method, SPECT imaging has been used to increase the accuracy of the planar images [20,21]. However, our results showed lower accuracy of SPECT when compared with planar images of the 99mTc-bombesin scintigraphy (Fig. 3). This is most likely due to nonhomogenous activity of the normal breast tissue on the SPECT images. Actually, nonsignificant uptake of the tracer in normal breast tissue is more prominent on SPECT images, which can decrease the accuracy of the test. In the present study, because all patients had palpable lesions, the size of the tumor was an important issue as it is the most important reason for 100% sensitivity for the detection of malignant lesions. If we had included the nonpalpable tumors in our study, we would have had a much lower sensitivity. Although our study showed Pathological diagnosis of the breast lesions in correlation with scan results and the patient mean age
Table 1
Number of patients
Mean age of patients
11
48
High-grade B-cell lymphoma Fibroadenoma
1 5
37 36.4
Fibrocystic changes Adenosis and severe intraductal hyperplasia Granolumatous mastitis Ductal ectasia with abscess formation Fibroadenoma
3 1
35.6 52
1 1
32 17
5
29.5
1
41
1
65
–
–
Scan results
Pathologic diagnosis
True positive (12/19 patients) True negative (11/18 patients)
False positive (7/19 patients)
Intraductal carcinoma
Focal adenosis and intraductal hyperplasia Ductal hyperplasia and fat necrosis None
False negative (0 patient)
minimal efficacy of the SPECT images for interpretation, the SPECT technique can be useful in the detection of small lesions by increasing its sensitivity. In contrast to visual assessment of the planar and SPECT images, semiquantitative evaluation increased the specificity of our study. Target to nontarget cutoff value of 1.97 for SPECT images yielded a sensitivity of 66% and a specificity of 84%. However, the sensitivity for detection of malignant breast lesions decreased despite considerable increase in specificity, which can reduce the utility of semiquantitative methods. In addition to 99mTc-bombesin, other radiotracers have been used for differentiation of benign from malignant breast tumors. In a meta-analysis published by the Agency for Healthcare Research and Quality the pooled sensitivity and specificity of mammoscintigraphy and PET were 84.7 and 77% and 83 74%, respectively [22]. The sensitivity of 99mTc-bombesin in our study was much higher, which, as mentioned before, is due to recruitment of only palpable breast tumors. In contrast, the specificity of our study (especially in semiquantitative methods) was comparable to that of other nuclear medicine techniques. Several other groups also reported the results of Tc-bombesin scintigraphy in breast lesions [23]. In a preliminary study, Scopinaro et al. [16] compared the imaging results of 99mTc-MIBI and 99mTc-bombesin in three patients with breast cancer. They reported high tumor to background ratios for these three patients with both radiotracers. More importantly, the ratio was higher on the 99mTc-bombesin images as compared with the 99m Tc-MIBI images. They concluded that 99mTc-bombesin scintigraphy can be used for breast tumor imaging. Another study by the same group reported the kinetics of 99m Tc-bombesin in malignant tumors. They reported that 99m
Fig. 2
(a)
(b) 4.00
Target to nontarget ratio
2.50
o17
2.00
3.00
1.50
P = 0.002
2.00 P = 0.005
1.00 1.00
0.50 0.00
o7 Benign Malignant Pathological results
0.00
o7 Benign malignant Pathological results
Box plots of target to nontarget ratios of the planar (a) and single-photon emission computed tomography (b) images. The mean target to nontarget ratios were statistically higher in the malignant tumors on both planar and single-photon emission computed tomography images.
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624 Nuclear Medicine Communications 2014, Vol 35 No 6
Fig. 3
ROC curve
Sensitivity
(a) 1.0
ROC curve
(b) 1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0 0.0
0.2
0.4 0.6 0.8 1−specificity Diagonal curves are produced by ties
1.0
0.0
0.2
0.4 0.6 0.8 1−specificity Diagonal curves are produced by ties
1.0
Receiver operating characteristic analyses of the target to nontarget ratios of the planar (a) and single-photon emission computed tomography (b) images.
23 of 26 included cancer patients had rapid increase of radioactivity inside the tumor, followed by a radioactivity plateau on dynamic imaging. More importantly, they reported faster uptake of 99mTc-bombesin in the nodepositive (N +) tumors as compared with the node-negative ones (3.62±0.75 vs. 5.5±0.88 min for patients with breast cancer). Our study showed similar findings as time to peak activity was the lowest in node-positive breast cancer patients. Scopinaro et al. [24] concluded that this time difference depended on gastrin-releasing peptide receptor density on tumoral tissue and regional blood flow. One of the reasons for our high false-positive scan results could be the abundance of these receptors in some of the benign breast pathologies, and further investigations seem to be necessary.
Another finding of our study was a sensitivity of 87.5% for detection of axillary lymph node involvement. In accordance with our results, Van de Wiele et al. [26] in 2008 showed that 99mTc-RP527 (one of the bombesin analogues) had high sensitivity (B88%) for detecting breast cancer and involved lymph nodes and part of the bone metastases, but had false-negative results in tamoxifen-resistant patients.
Although Scopinaro and colleagues reported three decreasing patterns of time–activity curves after reaching maximum activity in their patient series and attributed them to technical problems and suboptimal background subtraction, in our study no specific pattern of time– activity curve was observable. Therefore, these curves had limited value for distinguishing malignant from benign lesions.
Conclusion
Another study by Soluri et al. [25] evaluated 99mTcbombesin in five patients suspicious of having breast carcinoma. The probability of malignancy was closely related to uptake value in suspected lesions. Their findings are consistent with our results. In our study, lesions with high uptake were most likely to be malignant, whereas negligible or low tracer accumulation was almost always related to benign pathology.
Because of inconclusive results in our young patients, we are inclined to conclude that, at least in this age group, dense breasts can cause false-positive 99mTc-bombesin scintigraphy results, which is a major limitation of this imaging method compared with other noninvasive imaging procedures.
According to our findings, 99mTc-bombesin scintigraphy had a high sensitivity and negative predictive value for diagnosis of malignant breast lesions. However, the specificity and positive predictive value of this radiotracer for differentiating malignant from benign breast abnormalities are relatively low, especially in young women and in those with dense breasts. Therefore, it cannot eliminate the necessity of surgical biopsy and histopathologic examination.
Acknowledgements The study was financially supported by the vice chancellery of research of Mashhad University of Medical Sciences and is the result of a residency thesis under approval number 900790.
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99m
Tc-Bombesin scan for breast lesions Shariati et al. 625
Conflicts of interest
14
There are no conflicts of interest.
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Diagnostic value of 99mTc-bombesin scintigraphy for differentiation of malignant from benign breast lesions Farzaneh Shariatia, Kamran Aryanaa, Asiehsadat Fattahib, Mohammad N. Forghanib, Azita Azarianc, Seyed R. Zakavia, Ramin Sadeghia, Narjes Ayatia and Keyvan Sadria Objective In this study, we evaluated the diagnostic accuracy of 99mTc-bombesin scintigraphy for differentiation of benign from malignant palpable breast lesions. 99m Tc-Bombesin is a tracer with high affinity for gastrinreleasing peptide receptor, which is overexpressed on a variety of human tumors including breast carcinoma. Materials and methods We examined 33 consecutive women who were referred to our center with suspicious palpable breast lesions but had no definitive diagnosis in other imaging procedures. A volume of 370–444 MBq of 99m Tc-bombesin was injected and dynamic 1-min images were taken for 20 min immediately after injection in anterior view. Thereafter, two static images in anterior and pronelateral views were taken for 5 min. Finally, single-photon emission computed tomography images were taken for each patient. Definitive diagnosis was based on biopsy and histopathological evaluation. Results The scan findings were positive in 19 patients and negative in 11 on visual assessment of the planar and single-photon emission computed tomography images. Pathologic examination confirmed breast carcinoma in 12 patients with positive scans and benign pathology for 18 patients. The overall sensitivity, specificity, negative and positive predictive values, and accuracy of this
Introduction Breast cancer is the most common malignancy in women worldwide. Approximately, 230 000 new cases of breast cancer are diagnosed every year in the USA alone, which result in more than 39 000 deaths yearly. The incidence rate is estimated at 12% of all women and it has been increasing recently [1]. Therefore, early detection of malignant breast lesions is necessary for proper management and treatment, which in turn results in a better and more favorable patient outcome [2]. Routine diagnostic tools for evaluation of breast lesions include physical examination, mammography, and ultrasonography. If the results of these procedures are equivocal and indeterminate, depending on the clinician’s opinion, other noninvasive imaging procedures such as MRI, mammoscintigraphy, and positron emission mammography can be used [3,4]. In mammoscintigraphy, different radiopharmaceuticals including 201Tl, 99mTc-sestamibi, 99mTc-tetrofosmin, 99m Tc-thymine, and 99mTc-bombesin are used [5–10]. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0143-3636
radiotracer for diagnosis of breast cancer were 100, 66.1, 100, 63, and 76%, respectively. Semiquantitative analysis improved the specificity of the visual assessment from 66 to 84%. Conclusion Our study showed that 99mTc-bombesin scintigraphy has a high sensitivity and negative predictive value for detecting malignant breast lesions, but the specificity and positive predictive value of this radiotracer for differentiation of malignant breast abnormalities from benign ones are relatively low. Nucl c 2014 Wolters Kluwer Health | Med Commun 35:620–625 Lippincott Williams & Wilkins. Nuclear Medicine Communications 2014, 35:620–625 Keywords: benign, breast cancer, malignant, single-photon emission computed tomography, 99mTc-bombesin scintigraphy a Nuclear Medicine Research Center, bMinimally Invasive and Endoscopic Surgery Research Center and cDepartment of Radiology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Correspondence to Kamran Aryana, MD, Nuclear Medicine Research Center, Ghaem Hospital, Ahmad Abad St, Mashhad 99199-91766, Iran Tel: + 98 511 801 2781; fax: + 98 511 893 3186; e-mail: [email protected] Received 15 November 2013 Revised 7 February 2014 Accepted 25 February 2014
Bombesin is a gastrin-releasing peptide receptor analogue that is overexpressed on several human tumors including lung, prostate, ovarian, colon, stomach, exocrine pancreatic, and breast. This peptide acts as a mitogen, morphogen, growth, and antiapoptotic factor and also as a neurotransmitter in both normal and tumoral cells [11–18]. Bombesin-like peptides can be labeled with g rayemitting radioisotopes and also with b emitter radionuclides for cancer imaging and treatment goals, respectively [19]. The main aim of this study was to evaluate the diagnostic value of 99mTc-labeled bombesin scintigraphy in differentiation of benign from malignant breast lesions.
Materials and methods Thirty-three consecutive female patients, who were between 17 and 65 years of age with an average of 40±12 years, with a suspected breast lesion on mammography (BIRAD category III or IV) or with an inconclusive sonography report between October 2012 and August DOI: 10.1097/MNM.0000000000000112
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
99m
Tc-Bombesin scan for breast lesions Shariati et al. 621
2013 were selected and included in the study. All patients signed a specific written informed consent form for participation in the study, and the study was approved by the local ethics committee. Inclusion criteria were the presence of mammographic or sonographic breast abnormality that was suspicious and equivocal for malignancy with a palpable mass and being a candidate for histopathological examination. Exclusion criteria were pregnancy, lactation, prior surgery or manipulation of the breast, history of breast radiotherapy, and reluctance of the patient to undergo biopsy and pathologic assessment. Twenty-two patients were premenopausal, three were perimenopausal, and five were postmenopausal. Thirtyone patients had palpable breast masses and 22 had suspicious findings on mammographic evaluation. All had indeterminate sonographic reports. All patients underwent core needle or excisional biopsy and histopathologic examinations after scintigraphy. Two of the patients were excluded because of technical mistakes on the part of the technicians in their scintigraphy and one patient was excluded because of refusal to undergo surgical biopsy.
Imaging procedure
A dose of intravenous 370–444 MBq 99mTc-bombesin was injected into each patient. The radiopharmaceutical purity was controlled before each injection by means of thin-layer chromatography with 75% methanol and 2-butanone as the mobile phases and was greater than 98% in all cases. First, anterior-view dynamic images were taken immediately after injection of the tracer for 20 min with an interval of 1 min/frame and a matrix size of 64 64 using a dualhead variable-angle gamma camera (E.CAM Siemens, Siemens Medical Solutions Inc., Malvern, Pennsylvania, USA). The camera was equipped with a low-energy highresolution collimator and all images were taken using the 99m Tc photopeak. Thereafter, two static images in anterior and prone-lateral views were taken for 5 min with a matrix size of 256 256 pixels. Finally, the single-photon emission computed tomography (SPECT) protocol, with a 120 20 s acquisition time over 3601 and a matrix size of 128 128 pixels, was performed for each patient and the images were then reconstructed iteratively. The images were independently interpreted qualitatively by two nuclear medicine physicians who were blinded to the pathology results but had access to clinical and radiologic reports. On visual assessment, one or more focal regions of increased tracer uptake, as compared with the surrounding breast background and the mirror image on the contralateral side, were considered positive scintigraphic findings. Then, for a semiquantitative analysis, regions of interest were drawn over the area of tracer accumulation corresponding to the palpable breast mass or abnormal findings on radiologic evaluation. Thereafter, the ratios of tumor uptake in 1–5- and
1–15-min time frames in dynamic images and the tumor to normal tissue in the contralateral breast (target/ nontarget) ratio in static and SPECT images were calculated. The time–activity curve for each patient was plotted with curve analysis software and was evaluated carefully. All patients underwent core needle or excisional biopsy and histopathologic examinations after scintigraphy. Quantitative variables are expressed as mean±SD. To compare these variables, the independent sample t-test was used. The diagnostic accuracy of the semiquantitative analyses was evaluated using receiver operating characteristic (ROC) curve analysis and the area under the curve. Statistical analyses were carried out with SPSS 16 software (SPSS Inc., Malvern, Pennsylvania, USA) with a statistical significance of observed differences at a P value less than 0.05.
Results Out of the remaining 30 patients, the scan findings on visual assessment were positive for malignant lesions in 19 patients and negative for 11 patients. Histopathological evaluations confirmed breast carcinoma in 12 patients with positive scans and benign pathology for the remaining 18 patients (Fig. 1). There were seven false-positive cases on bombesin scintigraphy, which were proved to be benign lesions on pathological analysis. Among patients who were correctly diagnosed as having breast carcinoma on bombesin scan, 11 had ductal carcinoma and one patient had high-grade B-cell lymphoma. The mean age of the patients with false-positive results was 36 years, whereas the mean age of the true-positive group was 46.8 years. Eight of the patients with malignant pathologies had axillary lymph node involvement, and visual assessment of the axilla on the scintigraphy images was positive in seven patients, which means that this procedure has a sensitivity of 87.5% in the detection of axillary lymph node involvement. None of the patients with negative scan results had breast carcinoma. Histopathologic assessments of these patients in correlation with their scan results and their mean age are shown in Table 1. The sensitivity, specificity, and positive and negative predictive values for visual assessment of the images were 100, 61, 63, and 100%, respectively. Semiquantitative analyses are shown in Fig. 2. The mean target/nontarget ratios in static and SPECT images for benign and malignant lesions were 1.2±0.2, 1.5±0.3, 1.6±0.5, and 2.3±0.7, respectively, which were significantly higher in tumoral lesions. Uptake ratios at 1–5 and 1–15 min on dynamic images were not significantly related to the final diagnosis confirmed by pathologic evaluation (P = 0.8 and 0.5, respectively). ROC curve analyses for semiquantitative assessments are shown in Fig. 3. Area under the curve for planar and
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622 Nuclear Medicine Communications 2014, Vol 35 No 6
Fig. 1
Examples of negative (left images) and positive (right images) 99mTc-bombesin scintigraphy. Upper rows show dynamic images of the patients and the lower row shows the reconstructed single-photon emission computed tomography images.
SPECT semiquantitative analyses was 0.8 (95% confidence interval: 0.6–0.93) and 0.78 (95% confidence interval: 0.62–0.95), respectively. Target to nontarget cutoff value of 1.45 for static images yielded a sensitivity of 75% and a specificity of 84%. Target to nontarget cutoff value of 1.97 for SPECT images yielded a sensitivity of 66% and a specificity of 84%. Time–activity curve analysis of the dynamic images did not show any distinctive pattern (increasing, decreasing, or stable uptake with time) for differentiation of malignant from benign breast lesions. Mean time to peak activity of the curves was 14±7.12 for benign lesions and 4.8±3.2 and 5.25±1.89 min for malignant lesions with and without axillary involvement, respectively. Five patients with false-positive scan results had fibroadenoma and all of them had dense breasts on mammography. Their mean age was 29.5 years. It seems that in young women with dense breasts 99mTc-bombesin scintigraphy cannot provide useful additional diagnostic information. The final diagnosis of two other patients who had false-positive scan results was ductal hyperplasia,
which is an important risk factor for progression to ductal carcinoma and close follow-up is essential. We believe that the greater uptake in bombesin images of these two patients in comparison with others was the result of this specific pathology. The mean age of these two patients was 53 years, which is significantly higher than that of other patients with false-positive results.
Discussion Selecting a proper imaging procedure for early detection of breast cancer is necessary for successful treatment and management. If the two conventional radiologic procedures (mammography and ultrasonography) are inconclusive for differentiating between benign and malignant breast lesions, the clinician can use another noninvasive imaging modality or consider surgical biopsy. Our study showed 100% sensitivity and 61% specificity for detection of malignant breast lesions by visual assessment of the 99mTc-bombesin scintigraphy images. To improve the accuracy of the test, we used semiquantitative analysis and SPECT images. As a three-dimensional tomographic
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99m
Tc-Bombesin scan for breast lesions Shariati et al. 623
method, SPECT imaging has been used to increase the accuracy of the planar images [20,21]. However, our results showed lower accuracy of SPECT when compared with planar images of the 99mTc-bombesin scintigraphy (Fig. 3). This is most likely due to nonhomogenous activity of the normal breast tissue on the SPECT images. Actually, nonsignificant uptake of the tracer in normal breast tissue is more prominent on SPECT images, which can decrease the accuracy of the test. In the present study, because all patients had palpable lesions, the size of the tumor was an important issue as it is the most important reason for 100% sensitivity for the detection of malignant lesions. If we had included the nonpalpable tumors in our study, we would have had a much lower sensitivity. Although our study showed Pathological diagnosis of the breast lesions in correlation with scan results and the patient mean age
Table 1
Number of patients
Mean age of patients
11
48
High-grade B-cell lymphoma Fibroadenoma
1 5
37 36.4
Fibrocystic changes Adenosis and severe intraductal hyperplasia Granolumatous mastitis Ductal ectasia with abscess formation Fibroadenoma
3 1
35.6 52
1 1
32 17
5
29.5
1
41
1
65
–
–
Scan results
Pathologic diagnosis
True positive (12/19 patients) True negative (11/18 patients)
False positive (7/19 patients)
Intraductal carcinoma
Focal adenosis and intraductal hyperplasia Ductal hyperplasia and fat necrosis None
False negative (0 patient)
minimal efficacy of the SPECT images for interpretation, the SPECT technique can be useful in the detection of small lesions by increasing its sensitivity. In contrast to visual assessment of the planar and SPECT images, semiquantitative evaluation increased the specificity of our study. Target to nontarget cutoff value of 1.97 for SPECT images yielded a sensitivity of 66% and a specificity of 84%. However, the sensitivity for detection of malignant breast lesions decreased despite considerable increase in specificity, which can reduce the utility of semiquantitative methods. In addition to 99mTc-bombesin, other radiotracers have been used for differentiation of benign from malignant breast tumors. In a meta-analysis published by the Agency for Healthcare Research and Quality the pooled sensitivity and specificity of mammoscintigraphy and PET were 84.7 and 77% and 83 74%, respectively [22]. The sensitivity of 99mTc-bombesin in our study was much higher, which, as mentioned before, is due to recruitment of only palpable breast tumors. In contrast, the specificity of our study (especially in semiquantitative methods) was comparable to that of other nuclear medicine techniques. Several other groups also reported the results of Tc-bombesin scintigraphy in breast lesions [23]. In a preliminary study, Scopinaro et al. [16] compared the imaging results of 99mTc-MIBI and 99mTc-bombesin in three patients with breast cancer. They reported high tumor to background ratios for these three patients with both radiotracers. More importantly, the ratio was higher on the 99mTc-bombesin images as compared with the 99m Tc-MIBI images. They concluded that 99mTc-bombesin scintigraphy can be used for breast tumor imaging. Another study by the same group reported the kinetics of 99m Tc-bombesin in malignant tumors. They reported that 99m
Fig. 2
(a)
(b) 4.00
Target to nontarget ratio
2.50
o17
2.00
3.00
1.50
P = 0.002
2.00 P = 0.005
1.00 1.00
0.50 0.00
o7 Benign Malignant Pathological results
0.00
o7 Benign malignant Pathological results
Box plots of target to nontarget ratios of the planar (a) and single-photon emission computed tomography (b) images. The mean target to nontarget ratios were statistically higher in the malignant tumors on both planar and single-photon emission computed tomography images.
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624 Nuclear Medicine Communications 2014, Vol 35 No 6
Fig. 3
ROC curve
Sensitivity
(a) 1.0
ROC curve
(b) 1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0 0.0
0.2
0.4 0.6 0.8 1−specificity Diagonal curves are produced by ties
1.0
0.0
0.2
0.4 0.6 0.8 1−specificity Diagonal curves are produced by ties
1.0
Receiver operating characteristic analyses of the target to nontarget ratios of the planar (a) and single-photon emission computed tomography (b) images.
23 of 26 included cancer patients had rapid increase of radioactivity inside the tumor, followed by a radioactivity plateau on dynamic imaging. More importantly, they reported faster uptake of 99mTc-bombesin in the nodepositive (N +) tumors as compared with the node-negative ones (3.62±0.75 vs. 5.5±0.88 min for patients with breast cancer). Our study showed similar findings as time to peak activity was the lowest in node-positive breast cancer patients. Scopinaro et al. [24] concluded that this time difference depended on gastrin-releasing peptide receptor density on tumoral tissue and regional blood flow. One of the reasons for our high false-positive scan results could be the abundance of these receptors in some of the benign breast pathologies, and further investigations seem to be necessary.
Another finding of our study was a sensitivity of 87.5% for detection of axillary lymph node involvement. In accordance with our results, Van de Wiele et al. [26] in 2008 showed that 99mTc-RP527 (one of the bombesin analogues) had high sensitivity (B88%) for detecting breast cancer and involved lymph nodes and part of the bone metastases, but had false-negative results in tamoxifen-resistant patients.
Although Scopinaro and colleagues reported three decreasing patterns of time–activity curves after reaching maximum activity in their patient series and attributed them to technical problems and suboptimal background subtraction, in our study no specific pattern of time– activity curve was observable. Therefore, these curves had limited value for distinguishing malignant from benign lesions.
Conclusion
Another study by Soluri et al. [25] evaluated 99mTcbombesin in five patients suspicious of having breast carcinoma. The probability of malignancy was closely related to uptake value in suspected lesions. Their findings are consistent with our results. In our study, lesions with high uptake were most likely to be malignant, whereas negligible or low tracer accumulation was almost always related to benign pathology.
Because of inconclusive results in our young patients, we are inclined to conclude that, at least in this age group, dense breasts can cause false-positive 99mTc-bombesin scintigraphy results, which is a major limitation of this imaging method compared with other noninvasive imaging procedures.
According to our findings, 99mTc-bombesin scintigraphy had a high sensitivity and negative predictive value for diagnosis of malignant breast lesions. However, the specificity and positive predictive value of this radiotracer for differentiating malignant from benign breast abnormalities are relatively low, especially in young women and in those with dense breasts. Therefore, it cannot eliminate the necessity of surgical biopsy and histopathologic examination.
Acknowledgements The study was financially supported by the vice chancellery of research of Mashhad University of Medical Sciences and is the result of a residency thesis under approval number 900790.
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99m
Tc-Bombesin scan for breast lesions Shariati et al. 625
Conflicts of interest
14
There are no conflicts of interest.
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