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Tc-99m tetrofosmin scintigraphy as an adjunct to plain-film mammography in palpable breast lesions
Clinical Radiology (1998) 53, 17-24
Tc-99m Tetrofosmin Scintigraphy as an Adjunct to Plain-film Mammography in Palpable Breast Lesions H. M. FENLON, N. PHELAN, S. TIERNEY*, T. GOREY* and J. T. ENNIS
Departments' of Radiology and *Surgery, Mater Misericordiae Hospital and the Institute of Radiological Sciences, University College Dublin, Dublin, Ireland Aim: To investigate the use of Tc-99m tetrofosmin as a breast imaging agent and to compare results of Tc-99m tetrofosmin scintimammography with plain-film mammography and pathological outcome. Patients and Methods: Forty-four patients (mean age, 51 years; range 26-79 years) with a palpable breast mass requiring fine needle aspiration biopsy (FNAB) were prospectively studied. All patients had Tc-99m tetrofosmin scintimammography. Patients over 35 years of age had two view mammography performed on the same day. FNAB was performed within 2 weeks of imaging, and patients referred for surgery as appropriate. Results of scintigraphy and plain-film mammography were correlated with pathological outcome. Results: Of the 44 patients, 21 had biopsy proven malignancy while 23 had benign lesions. Of the 21 patients with carcinoma, 20 (95.2%) had positive Tc-99m tetrofosmin scintimammography while 21 (91.3 %) of the 23 patients with benign histology had negative scintigraphy. The sensitivity of scintimammography was 95.24%, the specificity was 91.3%, with a positive predictive value of 90.9% and a negative predictive value of 95.45%. Thirty-eight patients had two view mammography performed (six patients were < 35 years of age). Of these 38 patients, 21 had biopsy proven malignancy while 17 had benign histology (all patients < 35 years of age had benign histology). Of the 21 patients with malignancy, plain-film mammography was suspicious for malignancy in 17 (81%) while four were reported as benign. Of the 17 with benign disease, 14 patients (82.4%) had benign appearances on plain-film mammography while three (18%) had one or more findings suspicious for malignancy. The sensitivity of plain-film mammography in our group was 81%, with a specificity of 82.4%, a positive predictive value of 85% and a negative predictive value of 77.8%. Tc-99m tetrofosmin scintimammography correctly characterized all seven lesions where mammographic evaluation was limited because of dense breast parenchyma or previous surgery and/or radiotherapy. Conclusion: Tc-99m tetrofosmin scintimammography is an accurate, well tolerated and non-invasive method of differentiating benign from malignant palpable breast lesions. Negative Tc-99m tetrofosmin scintimammography excludes malignancy with a high degree of confidence while false-positive scintigraphy can occur in cases of proliferative dysplasia and hypercellular fibroadenoma. Tc-99m tetrofosmin scintimammography is particularly useful when plain-film mammography is indeterminate or limited in patients with dense breasts or a history of previous surgery and/or radiotherapy. Fenlon, H.M., Phelan, N., Tierney, S., Gorey, T. & Ennis, J.T. (1998). Clinical Radiology 53, 17-24. Tc-99m Tetrofosmin Scintigraphy as an Adjunct to Plain-film Mammography in Palpable Breast Lesions Accepted for Publication 21 April 1997
With an incidence of 7.2 per 1000 women, breast cancer is now the leading cause of non-preventable cancer-related death amongst women in the western world [1,2]. Although advanced breast cancer is difficult to treat effectively, patient prognosis has been shown to improve with early diagnosis and treatment [3,4]. Mammography is well established as the imaging modality of choice for breast cancer detection. Although mammography has a relatively high sensitivity for carcinoma, limitations arise in patients with dense fibroglandular tissue and following breast surgery and/or radiotherapy. Moreover, mammography has limited specificity ranging from 30% to 65% [1,5,6]. Although results vary between centres, Correspondence to: Professor J.T. Ennis, Institute of Radiological Sciences, 52 Eccles Street, Dublin 7, Ireland. 9 1998 The Royal College of Radiologists.
published data show that between one-half to two-thirds of women referred for FNAB and/or core biopsy based on a suspicious mammogram has benign histology [1,5-9]. Supplementary techniques including ultrasound (conventional and Doppler ultrasound) and magnetic resonance mammography have been used in association with plainfilm mammography to improve the diagnostic accuracy of imaging [10]. Recent reports suggest that nuclear medicine imaging of the breast (scintimammography) may be an accurate, non-invasive alternative for differentiating benign from malignant breast lesions with quoted sensitivities and specificities similar to contrast-enhanced MR mammography [11-17]. The aim of this study was to investigate the novel use of the myocardial imaging agent, Tc-99m tetrofosmin (Myoview, Amersham International plc, Buckinghamshire, UK),
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(b)
(a)
as a breast imaging agent in patients with palpable breast lesions requiring biopsy. PATIENTS AND METHODS
Study Group A prospective study of 44 consecutive patients presenting to the outpatients department with a palpable breast lesion was performed. All patients had a clinically palpable breast lump suspicious for malignancy that required FNAB. The mean age of the study group was 51 years with a range of 26-79 years. Nine of the 44 patients had a history of previous breast surgery and/or radiotherapy.
Study Protocol All patients over 35 years of age had two view mammography (Mammomat 2, Siemens, Erlangen, Germany). On the same day, Tc-99m tetrofosmin scintimammography was
Fig. 1 - (a) A 58-year-old female with a 3-month history of a palpable mass in the right breast. Mediolateral oblique mammography demonstrates a well circumscribed mass (arrows) with posterior halo effect suggestive of a cyst. (b) Negative Tc-99m tetrofosmin scintimammography. Ultrasound and subsequent needle aspiration confirmed the presence of a simple benign cyst.
performed. FNAB was performed within 1 week after imaging in all cases. Patients with suspicious or clearly malignant cytology proceeded to surgery (lumpectomy, segmentectomy or mastectomy as appropriate) irrespective of radiological findings. Patients with benign cytology on FNAB and plain-film mammographic findings consistent with benignity did not routinely undergo surgery (benign lesions were excised for cosmetic reasons only) but attended for repeat clinical and mammographic follow-up at 1 year. The study protocol was approved by the Hospital's Ethics Committee and fully informed written consent was obtained in all cases.
Plain-film Mammography Two view (craniocaudal and latero-oblique) plain-film mammography was performed using a Mammomat 2 unit (Siemens, Erlangen, Germany). Acceptable diagnostic quality of mammography was ensured by daily quality control measurements in accordance with the 1996 9 1998 The Royal College of Radiologisls, Clinical Radiology, 53, 17-24.
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TC-99M TETROFOSMIN SCINTIMAMMOGRAPHY
(b)
(a)
European guidelines and the 1995 NHS guidelines on quality assurance in mammography [18,19]. The mean optical density used for mammography was 1.8.
Tetrofosmin Scintimammography Six hundred MBq of Tc-99m tetrofosmin was administered intravenously in the arm contralateral to the affected breast. Immediate erect lateral oblique views of the affected breast were acquired over a 10-min period using a Siemens ZLC gamma camera (Siemens, Erlangen, Germany) with a high resolution collimator. Following this, an anterior view of the thorax was obtained over a 10-min period to assess the axillary tail of both breasts. Finally, a lateral oblique view of the non-involved breast was acquired.
Image Interpretation The plain-film mammograms were reported by two independent mammographers without knowledge of the clinical 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
Fig. 2 - (a) A 60-year-old female presented with a palpable fight breast lump. Mammography demonstrates a spiculated mass in the upper right breast highly suspicious for carcinoma (arrow). Focal benign secretory calcification is projected over the mass lesion. (b) There is intense accumulation of Tc-99m tetrofosmin by the mass on scintimammography. Biopsy and subsequent mastectomy confirmed a 19mm invasive ductal carcinoma.
or histological findings. The scintimammograms were reported by three independent observers, again without knowledge of the findings on physical examination, plainfilm mammography or histology. Correlation between the observers was close and differences were resolved by consensus. Based on the mammographic findings, lesions were classified as either suspicious for malignancy or benign. The criteria used for malignancy were a dominant or spiculated mass _ microcalcifications and the presence of ancillary signs such as focal architectural distortion, asymmetric breast density, nipple retraction and skin thickening. The scintimammograms were reported by three observers using a subjective, visual assessment of radioisotope accumulation. The scintimammograms were reported as negative when there was bilateral symmetrical distribution of radioisotope of the same intensity as background soft tissues. A positive scintimammogram was reported if a focal area of increased radioisotope activity was identified in either breast.
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(b)
(a)
Following FNAB and/or surgery, the pathological diagnoses were correlated with the findings on plain-film mammography and scintimammography.
Statistical Analysis Based on the pathological outcome, results of plain-film mammography and Tc-99m tetrofosmin scintimammography were classified as true-positive, true-negative, falsepositive and false-negative. Sensitivities, specificities, positive (PPV) and negative predictive values (NPV) were determined for both imaging modalities.
RESULTS Of the 44 patients, 21 (47.7%) had pathologically proven malignancy while 23 (52.3%) had benign lesions. All 21 patients with malignancy underwent surgery - mastectomy (n = 8), segmentectomy (n = 6), and lumpectomy (n = 7). Of the 21 malignant lesions, 20 were invasive ductal carcinomas with one mucinous carcinoma. The average tumour size was 17 mm (range 9-42 mm). Of 23 biopsy-proven (FNAB) benign lesions, 11 were surgically excised. Clinical and radiological follow-up at one year in the remaining 12 patients showed no evidence of malignancy. Eight of the 23 benign lesions (35%) represented fibro-fatty tissue, six (26%) were due to fibrocystic disease, three patients (13%) had proliferative dysplasia,
Fig. 3 - (a) A 39-year-old female with dense fibroglandular breast tissue on mammography. No focal mass lesion or microcalcifications are demonstrated. (b) Tc-99m tetrofosmin scintimammography reveals abnormal focal accumulation of tetrofosmin in the upper right breast. Biopsy and subsequent segmental mastectomy revealed an 18 mm mucinous carcinoma.
three patients (13%) had solitary benign cysts, two patients (9%) had apocrine metaplasia and one patient (4%) had a radial scar resected (Fig. 1). Of the 44 patients, 38 had two view mammography (six patients were < 35 years of age). Of these 38 patients, 21 had biopsy proven malignancy while 17 had benign histology (all patients < 35 years of age had benign histology). Of the 21 patients with malignancy, plain-film mammography was reported as suspicious for malignancy in 17 (81%) (Fig. 2) while four were reported as benign. Of these four falsenegative results, two patients had mammographically dense breasts and two had a history of breast surgery (Figs 3 & 4). Of the 17 with benign disease, 14 patients (82.4%) had benign appearances on plain-film mammography while three (18%) had one or more findings suspicious for malignancy. Of these three false-positive results, two patients had fibro-fatty change on histology (postoperative change in both cases) (Fig. 5) while one patient had a radial scar diagnosed in a radiographically dense breast. The sensitivity of plain-film mammography in our group was 81%, with a specificity of 82.4%, a positive predictive value of 85% and a negative predictive value of 77.8%. Of the 21 patients with biopsy proven malignancy, 20 (95.2%) had positive Tc-99m tetrofosmin scintimammography. There was one false-negative result in a patient with severe rheumatoid arthritis where positioning was suboptimal secondary to immobility. However, focal abnormal radioisotope accumulation was not identified and the scintimammogram was reported as negative. FNAB yielded 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
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TC-99M TETROFOSMIN SCINTIMAMMOGRAPHY
(b)
(a)
malignant cells and subsequent excision revealed a 19 mm invasive intraductal carcinoma. Of the 23 patients with benign histology, 21 (91.3%) had negative scintimammography. There were two falsepositive results - one in a patient with proliferative dysplasia and another in a patient with a hypervascular fibroadenoma. The sensitivity of Tc-99m tetrofosmin scintimammography in this group therefore was 95.24%, the specificity was 91.3%, with a positive predictive value of 90.9% and a negative predictive value of 95.45%.
DISCUSSION The sensitivity of mammography for carcinoma in the fatty breast approaches 100%. Despite continuing improvements in mammographic equipment and technique, the radiographically dense breast remains difficult to image, Even palpable masses can be difficult to detect in patients 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
Fig. 4 - (a) A 55-year-old female with a history of right segmental mastectomy for intraductal carcinoma 2 years previously presented with increasing induration and ill-defined mass in the upper right breast on clinical examination. Serial mammography over the 2-year period demonstrated no change with persistent architectural distortion secondary to previous surgery (arrows). (b) Tc-99m tetrofosmin scintimammography reveals a focal 'hot spot' posteriorly in the fight breast abutting the right pectoral muscles (arrow). Biopsy and surgery confirmed tumour recurrence corresponding to the scintigraphic abnormality.
with dense breast parenchyma and in those with a history of breast surgery and/or radiotherapy [20-23]. Moreover, benign lesions such as radial scars, post-traumatic haematoma, and fat necrosis may demonstrate the 'classic' radiographic signs of malignancy on mammography [1]. Although the positive predictive value of mammography (the number of cancers diagnosed per number of biopsies recommended) varies considerably between centres, it is estimated that between one-half to two-thirds of women referred for fine needle aspiration and/or core biopsy on the basis of a positive mammogram has benign histology [1,5-9]. Triple assessment with clinical examination, imaging (mammography and ultrasound), and fine needle aspiration and/or core biopsy is diagnostic in over 70% of cases. Ultrasound is valuable in assessing mammographically occult, palpable breast masses and in guiding biopsy in such cases. Since mammographically dense tissue is usually echogenic and most carcinomas are hypoechoic, ultrasound can be used to confirm a palpable malignancy within a
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(b)
(a)
Fig. 5 - (a) A 53-year-old female with a history of fight lumpectomy (intraductal carcinoma) presents 4 years following surgery with a palpable mass in the upper fight breast. Mammography reveals a spiculated mass and architectural distortion in the upper fight breast suspicious for tumour recurrence (arrows). (b) Negative Tc-99m tetrofosmin scintimammography. Multiple biopsies and clinical follow-up over an 18-month period show no evidence of tumour recurrence.
mammographically dense breast. However, since some malignancies, especially non-invasive and diffusely growing carcinomas, may not be visible sonographically, ultrasound cannot be used to confidently exclude cancer. Furthermore, the sensitivity of ultrasound decreases with lesion size. Even with a combination of mammography, ultrasound and FNAB and/or core biopsy, difficulties may arise in diagnosing cancer in patients with mammographically dense breasts, extensive scarring, silicon implants, or after lumpectomy or radiotherapy. A variety of adjunctive techniques have been developed including colour Doppler and power Doppler ultrasound, contrast-enhanced MR mammography, MR spectroscopy, FDG PET and PET imaging of oestrogen receptors [24-27]. More recently, nuclear medicine imaging of the breast (scintimammography) has been reported as an effective alternative for differentiating benign from malignant breast lesions. A range of radiopharmaceuticals have been evaluated as breast imaging agents and a number of imaging protocols described [11-17].
In a study of thallium-201 (T1-201) scintimammography, Waxman e t al. [11] reported abnormal accumulation of T1-201 in 42 of 44 palpable breast cancers. In 30 patients with both mammographically detected tumours and palpable breast lesions, Lee et al. [12] reported a sensitivity of 80% and a specificity of 96% for carcinoma detection using the same radiopharmaceutical. Similar results were reported by Sehweil e t al. in 1990 in 20 patients with palpable breast lesions [13]. In 1992, Campeau et al. [14] were the first to describe abnormal accumulation of a technetium-labelled pharmaceutical in a breast tumour. In their study, an unsuspected breast cancer was detected on a radionuclide stress test done for suspected ischaemic heart disease. In an investigation of Tc-99m sestamibi scintimammography, Khalkali e t al. [15] reported a sensitivity and specificity of 95.8% and 86.8%, respectively, for carcinoma. In 1996, Palmedo et al. [16] studied Tc-99m sestamibi scintimammography in 54 patients (40 patients with palpable breast masses and 14 with mammographically detected lesions) and reported a 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
TC-99M TETROFOSMIN SCINTIMAMMOGRAPHY
sensitivity of 88% and specificity of 83% for carcinoma. In women attending for routine bone scintigraphy prior to breast surgery, Piccolo et al. [17] described abnormal accumulation of Tc-99m methylene diphosphonate (MDP) in 158 of 172 (92%) carcinomas. Tc-99m MDP scintimammography correctly characterized 43 of 53 lesions (81%) where mammography was indeterminate. We report the novel use of the lipophilic, cationic myocardial imaging agent, Tc-99m tetrofosmin, as a breast imaging agent. Although Tc-99m tetrofosmin has not been previously studied in breast disease, Atasever et al. [28] have described abnormal accumulation of Tc-99m tetrofosmin in 19 of 21 primary lung cancers. The mechanism of tumoral uptake of tetrofosmin is uncertain but it is likely that it behaves in a similar manner to sestamibi as both are lipophilic cations and have a similar mechanism of action in myocardium. Tumoral concentration of sestamibi is related to a combination of factors including rapid cell growth and division (increased mitochondrial activity), increased vascularity (neoangiogenesis), enlargement of the interstitial space, cell wall damage and increased capillary permeability [29,30]. Whatever the mechanism of action, the results of this study indicate that Tc-99m tetrofosmin is an effective breast imaging agent. Twenty of 21 patients with histologically proven breast carcinoma had positive Tc-99m tetrofosmin scintimammography. One false-negative result occurred in a patient with a 19 mm tumour. False-negative scintimammography using sestamibi has been described and attributed to expression of the membrane glycoprotein Pgp-170, a product of the multidmg resistance (MDR) gene, that causes reduced accumulation of radioisotope in turnouts when elevated [30,31]. This factor was not measured in our patients. False-positive results were observed in two of our patients. One of these patients had benign proliferative dysplasia in whom concentration of Tc-99m tetrofosmin was non-focal and diffuse. The second patient had focal accumulation of radioisotope in a hypercellular fibroadenoma. False-positive results have been reported for scintimammography using both Tc-99m sestamibi and T1201 and contrast-enhanced magnetic resonance mammography in both of these conditions [24,30,32,33]. With a sensitivity of 81% and a specificity of 82.4%, the diagnostic accuracy of plain-film mammography in our study compares favourably with published data. Lesion detection on mammography was, however, adversely affected by breast density. Two of four patients with falsenegative mammography and two of three patients with false-positive mammography had dense breast parenchyma. Conversely, results of Tc-99m tetrofosmin scintimammography were not affected by breast density. Scintimammography correctly characterized lesions in 13 of 13 patients with mammographically dense breasts. Similarly, results of plain-film mammography were limited in the postoperative breast. Nine of our group had a history of previous surgery and/or radiotherapy of whom four had histological evidence of tumour recurrence. In two of these four cases plain-film mammography failed to accurately predict recurrent carcinoma while mammographic findings suggested tumour recurrence in two of five patients with postoperative fibrosis alone. Tc-99m tetrofosmin scintimammography was positive in all four patients with recurrent disease and negative in all five cases of benign scar tissue. Compared with other radiopharmaceuticals, there are technical advantages to using Tc-99m tetrofosmin as a 9 1998 The Royal College of Radiologists, ClinicalRadiology, 53, 17 24.
23
breast imaging agent. Tc-99m labelled radiopharmaceuticals emit more abundant photons in a suitable energy range for gamma camera imaging than T1-201, with less scatter and photon attenuation, superior image resolution with increased counting rates, and reduced patient radiation dose. Compared with Tc-99m sestamibi, Tc-99m tetrofosmin is more convenient to prepare. Tc-99m sestamibi requires boiling and subsequent cool-down prior to use. This step is time consuming and potentially increases the radiation exposure of medical personnel. Tetrofosmin, on the other hand, is a freeze-dried formulation, ready to use and requiring no additional preparation. A significant limitation of this study is tumour size. All patients had palpable breast lesions with a mean tumour size of 17mm (range 7 - 42ram). There was no case of ductal carcinoma in situ (DCIS). Although a 7-mm tumour was successfully demonstrated, the limited resolution of gamma camera imaging may prevent detection of smaller lesions. This may improve with the use of small field-of-view gamma cameras specifically designed for breast scintigraphy. Although the high sensitivities and specificities attributed to scintimammography in this and other series may not apply to larger groups of healthy women attending for screening, the proposed application of scintimammography is not as a screening technique but as an adjunct to plain-film mammography in indeterminate cases. Further work to determine the sensitivity of scintimammography in nonpalpable, mammographically detected lesions is ongoing in our department.
CONCLUSION Tc-99m tetrofosmin scintimammography is an accurate, well tolerated and non-invasive method of differentiating benign from malignant breast lumps. Negative Tc-99m tetrofosmin scintimammography excludes malignancy with a high degree of confidence while false-positive scintigraphy can occur in cases of proliferative dysplasia and hypercellular fibroadenoma. Tc-99m tetrofosmin scintimammography is particularly useful when plain-film mammographic assessment and biopsy are difficult due to breast density, radiotherapy or previous surgery. Further work to compare the accuracy of Tc-99m tetrofosmin scintimammography with contrast enhanced MR mammography, and to determine the accuracy of scintimammography in characterizing non-palpable, mammographically detected lesions is ongoing.
REFERENCES 1 Kopans DB. The positive predictive value of mammography. American Journal of Roentgenology 1992;158:521 526. 2 Kelsey JL, Gammon MD. The epidemiology of breast cancer. Cancer 1991;41:146-165. 3 Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O. Update of the Swedish two-county programme of mammographic screening for breast cancer. Radiologic Clinics of North America 1992;30:187-210. 4 Habbema JDF, van Oortmarssen GV, van Putten DJ, Lubbe JT, van der Maas PJ. Age-specific reduction in breast cancer mortality by screen: an analysis of the results of the Health Insurance Plan of greater New York study. Journal of National Cancer Institute 1986;77:317-320. 5 Sickles WA. Mammographic features of 300 consecutive nonpalpable breast cancers. American Journal of Roentgenology 1986;146:661663. 6 Meyer JE, Eberlein TJ, Stomper PC, Sonnenfeld MR. Biopsy of occult breast lesions: analysis of 1261 abnormalities. Journal of American Medical Association 1990;263:2341-2343.
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7 Kopans DB, Swann CA. Observations on mammographic screening and the false-positive mammograms. American Journal of Roentgenology 1988;150:785-786. 8 Tinnemans JGM, Wobbes T, Lubbers EC, van der Sluis RF, de Boer HHM. The significance of microcalcifications without palpable mass in the diagnosis of breast cancer. Surgery 1986;99:65-67. 9 Tabar L, Gad A. Screening for breast cancer: the Swedish trial. Radiology 1981;138:21-22. 10 Heywang-Kobrunner SH. Nonmammographic breast imaging techniques. Current Opinions in Radiology 1992;4:146-154. 11 Waxman AD, Ramanna L, Memsic LD et al. Thallium scintigraphy in the evaluation of mass abnormalities of the breast. Journal of Nuclear Medicine 1993;34:18-23. 12 Lee VW, Sax EJ, McAneny DB et al. A complementary role for thallium-201 scintigraphy with mammography in the diagnosis of breast cancer. Journal of Nuclear Medicine 1993;34:2095-2100. 13 Sehweil AM, McKillop JH, Milroy R et al. Thallium-201 scintigraphy in the staging of lung cancer, breast cancer and lymphoma. Nuclear Medicine Communications 1990;11:263-269. 14 Campeau RJ, Kronemer KA, Sutherland CM. Concordant uptake of Tc99m Sestamibi and T1-201 in unsuspected breast tumour. Clinical Nuclear Medicine 1992;17:936-937. 15 Khalkali I, Mena I, Jouanne E et al. Prone scintimammography in patients with suspicion of carcinoma of the breast. Journal of American College of Surgeons (United States) 1994;178:491-497. 16 Palmedo H, Schomburg A, Grunwald F, Mallmann P, Krebs D, Biersack H-J. Technetium-99m-MIBI scintimammography for suspicious breast lesions. Journal of Nuclear Medicine 1996;37: 626-630. 17 Piccolo S, Lastoria S, Mainolfi C, Muto P, Bazzicalupo L, Salvatore M. Technetium-99m-methylene diphosphonate scintimammography to image primary breast cancer. Journal of Nuclear Medicine 1995;36:718-724. 18 Commission of European Communities. European Guidelines for Quality Assurance in Mammographic Screening, Version 2. Commission of European Communities, 1996. 19 NHS BSP. Quality Assurance Guidelines for Quality Control in Mammography. NHS BSP Publication No. 33, 1995. 20 Kopans DB. Conventional wisdom: observation, experience, anecdote
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and science in breast imaging. American Journal of Roentgenology 1994;162:299-303. Jackson VP, Hendrick RE, Feig SA, Kopans DB. Imaging of the radiographically dense breast. Radiology 1993;188:297-301. Peters ME, Fagerholm MI, Scanlan KA et al. Mammographic evaluation of the postsurgical and irradiated breast. RadioGraphics 1988;8:873-899. Hassell PR, Olivotto IA, Mueller HA et al. Early breast cancer: Detection of recurrence after conservative surgery and radiation therapy. Radiology 1990;176:731-735. Heywang-Kobrunner SH. Contrast-EnhancedMRlofthe Breast. Basel, Switzerland: Karger, 1990. Harms SE, Flamig DP. MR imaging of the breast. Journal of Magnetic Resonance Imaging 1993;3:277-283. Heywang-Kobrunner SH, Fenzl G, Hahn D et al. MR imaging of the breast: comparison with mammography and ultrasound. Journal of Computer Assisted Tomography 1986; 10:615-620. McGuire AH, Dehdashti F, Siegel BA et al. Positron tomographic assessment of 16 alpha-[aSF]-fluoro-17-beta-estradiol uptake in metastatic breast cancer. Journal of Nuclear Medicine 1991 ;32:1526-1531. Atasever T et al. Evaluation of malignant and benign lung lesions with 99Tcm-tetrofosmin. Nuclear Medicine Communications 1996; 17:577582. Delmon-Moigeon LI, Piwnica-Worms D, Van den Abbeele AD, Holman BL. Uptake of the cation hexakis(2-methoxyisobutyl-isonitfile)-technetium-99m by human carcinoma cell lines in vitro. Cancer Research 1990;50:2198-2202. Maublant J, de Latour M, Mestas D et al. Technetium-99m-sestamibi uptake in breast tumor and associated lymph nodes. Journal of Nuclear Medicine 1996;37:922-925. Piwnica-Worms D, Chiu ML, Budding M, Kronauge JF, Kramer RA, Croop JM. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Research 1993;53:1-8. Stack JP, Redmond RM, Codd MB, Dervan PA, Ennis JT. Breast disease: tissue characterisation with Gd-DTPA enhancement profiles. Radiology 1990;174:491-494. Greenstein Orel S, Schnall MD, LiVolsi VA, Troupin RH. Suspicious breast lesions: MR imaging with radiologic-pathologic correlation. Radiology 1994;190:485-493.
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Tc-99m Tetrofosmin Scintigraphy as an Adjunct to Plain-film Mammography in Palpable Breast Lesions H. M. FENLON, N. PHELAN, S. TIERNEY*, T. GOREY* and J. T. ENNIS
Departments' of Radiology and *Surgery, Mater Misericordiae Hospital and the Institute of Radiological Sciences, University College Dublin, Dublin, Ireland Aim: To investigate the use of Tc-99m tetrofosmin as a breast imaging agent and to compare results of Tc-99m tetrofosmin scintimammography with plain-film mammography and pathological outcome. Patients and Methods: Forty-four patients (mean age, 51 years; range 26-79 years) with a palpable breast mass requiring fine needle aspiration biopsy (FNAB) were prospectively studied. All patients had Tc-99m tetrofosmin scintimammography. Patients over 35 years of age had two view mammography performed on the same day. FNAB was performed within 2 weeks of imaging, and patients referred for surgery as appropriate. Results of scintigraphy and plain-film mammography were correlated with pathological outcome. Results: Of the 44 patients, 21 had biopsy proven malignancy while 23 had benign lesions. Of the 21 patients with carcinoma, 20 (95.2%) had positive Tc-99m tetrofosmin scintimammography while 21 (91.3 %) of the 23 patients with benign histology had negative scintigraphy. The sensitivity of scintimammography was 95.24%, the specificity was 91.3%, with a positive predictive value of 90.9% and a negative predictive value of 95.45%. Thirty-eight patients had two view mammography performed (six patients were < 35 years of age). Of these 38 patients, 21 had biopsy proven malignancy while 17 had benign histology (all patients < 35 years of age had benign histology). Of the 21 patients with malignancy, plain-film mammography was suspicious for malignancy in 17 (81%) while four were reported as benign. Of the 17 with benign disease, 14 patients (82.4%) had benign appearances on plain-film mammography while three (18%) had one or more findings suspicious for malignancy. The sensitivity of plain-film mammography in our group was 81%, with a specificity of 82.4%, a positive predictive value of 85% and a negative predictive value of 77.8%. Tc-99m tetrofosmin scintimammography correctly characterized all seven lesions where mammographic evaluation was limited because of dense breast parenchyma or previous surgery and/or radiotherapy. Conclusion: Tc-99m tetrofosmin scintimammography is an accurate, well tolerated and non-invasive method of differentiating benign from malignant palpable breast lesions. Negative Tc-99m tetrofosmin scintimammography excludes malignancy with a high degree of confidence while false-positive scintigraphy can occur in cases of proliferative dysplasia and hypercellular fibroadenoma. Tc-99m tetrofosmin scintimammography is particularly useful when plain-film mammography is indeterminate or limited in patients with dense breasts or a history of previous surgery and/or radiotherapy. Fenlon, H.M., Phelan, N., Tierney, S., Gorey, T. & Ennis, J.T. (1998). Clinical Radiology 53, 17-24. Tc-99m Tetrofosmin Scintigraphy as an Adjunct to Plain-film Mammography in Palpable Breast Lesions Accepted for Publication 21 April 1997
With an incidence of 7.2 per 1000 women, breast cancer is now the leading cause of non-preventable cancer-related death amongst women in the western world [1,2]. Although advanced breast cancer is difficult to treat effectively, patient prognosis has been shown to improve with early diagnosis and treatment [3,4]. Mammography is well established as the imaging modality of choice for breast cancer detection. Although mammography has a relatively high sensitivity for carcinoma, limitations arise in patients with dense fibroglandular tissue and following breast surgery and/or radiotherapy. Moreover, mammography has limited specificity ranging from 30% to 65% [1,5,6]. Although results vary between centres, Correspondence to: Professor J.T. Ennis, Institute of Radiological Sciences, 52 Eccles Street, Dublin 7, Ireland. 9 1998 The Royal College of Radiologists.
published data show that between one-half to two-thirds of women referred for FNAB and/or core biopsy based on a suspicious mammogram has benign histology [1,5-9]. Supplementary techniques including ultrasound (conventional and Doppler ultrasound) and magnetic resonance mammography have been used in association with plainfilm mammography to improve the diagnostic accuracy of imaging [10]. Recent reports suggest that nuclear medicine imaging of the breast (scintimammography) may be an accurate, non-invasive alternative for differentiating benign from malignant breast lesions with quoted sensitivities and specificities similar to contrast-enhanced MR mammography [11-17]. The aim of this study was to investigate the novel use of the myocardial imaging agent, Tc-99m tetrofosmin (Myoview, Amersham International plc, Buckinghamshire, UK),
18
CLINICAL RADIOLOGY
(b)
(a)
as a breast imaging agent in patients with palpable breast lesions requiring biopsy. PATIENTS AND METHODS
Study Group A prospective study of 44 consecutive patients presenting to the outpatients department with a palpable breast lesion was performed. All patients had a clinically palpable breast lump suspicious for malignancy that required FNAB. The mean age of the study group was 51 years with a range of 26-79 years. Nine of the 44 patients had a history of previous breast surgery and/or radiotherapy.
Study Protocol All patients over 35 years of age had two view mammography (Mammomat 2, Siemens, Erlangen, Germany). On the same day, Tc-99m tetrofosmin scintimammography was
Fig. 1 - (a) A 58-year-old female with a 3-month history of a palpable mass in the right breast. Mediolateral oblique mammography demonstrates a well circumscribed mass (arrows) with posterior halo effect suggestive of a cyst. (b) Negative Tc-99m tetrofosmin scintimammography. Ultrasound and subsequent needle aspiration confirmed the presence of a simple benign cyst.
performed. FNAB was performed within 1 week after imaging in all cases. Patients with suspicious or clearly malignant cytology proceeded to surgery (lumpectomy, segmentectomy or mastectomy as appropriate) irrespective of radiological findings. Patients with benign cytology on FNAB and plain-film mammographic findings consistent with benignity did not routinely undergo surgery (benign lesions were excised for cosmetic reasons only) but attended for repeat clinical and mammographic follow-up at 1 year. The study protocol was approved by the Hospital's Ethics Committee and fully informed written consent was obtained in all cases.
Plain-film Mammography Two view (craniocaudal and latero-oblique) plain-film mammography was performed using a Mammomat 2 unit (Siemens, Erlangen, Germany). Acceptable diagnostic quality of mammography was ensured by daily quality control measurements in accordance with the 1996 9 1998 The Royal College of Radiologisls, Clinical Radiology, 53, 17-24.
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TC-99M TETROFOSMIN SCINTIMAMMOGRAPHY
(b)
(a)
European guidelines and the 1995 NHS guidelines on quality assurance in mammography [18,19]. The mean optical density used for mammography was 1.8.
Tetrofosmin Scintimammography Six hundred MBq of Tc-99m tetrofosmin was administered intravenously in the arm contralateral to the affected breast. Immediate erect lateral oblique views of the affected breast were acquired over a 10-min period using a Siemens ZLC gamma camera (Siemens, Erlangen, Germany) with a high resolution collimator. Following this, an anterior view of the thorax was obtained over a 10-min period to assess the axillary tail of both breasts. Finally, a lateral oblique view of the non-involved breast was acquired.
Image Interpretation The plain-film mammograms were reported by two independent mammographers without knowledge of the clinical 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
Fig. 2 - (a) A 60-year-old female presented with a palpable fight breast lump. Mammography demonstrates a spiculated mass in the upper right breast highly suspicious for carcinoma (arrow). Focal benign secretory calcification is projected over the mass lesion. (b) There is intense accumulation of Tc-99m tetrofosmin by the mass on scintimammography. Biopsy and subsequent mastectomy confirmed a 19mm invasive ductal carcinoma.
or histological findings. The scintimammograms were reported by three independent observers, again without knowledge of the findings on physical examination, plainfilm mammography or histology. Correlation between the observers was close and differences were resolved by consensus. Based on the mammographic findings, lesions were classified as either suspicious for malignancy or benign. The criteria used for malignancy were a dominant or spiculated mass _ microcalcifications and the presence of ancillary signs such as focal architectural distortion, asymmetric breast density, nipple retraction and skin thickening. The scintimammograms were reported by three observers using a subjective, visual assessment of radioisotope accumulation. The scintimammograms were reported as negative when there was bilateral symmetrical distribution of radioisotope of the same intensity as background soft tissues. A positive scintimammogram was reported if a focal area of increased radioisotope activity was identified in either breast.
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(b)
(a)
Following FNAB and/or surgery, the pathological diagnoses were correlated with the findings on plain-film mammography and scintimammography.
Statistical Analysis Based on the pathological outcome, results of plain-film mammography and Tc-99m tetrofosmin scintimammography were classified as true-positive, true-negative, falsepositive and false-negative. Sensitivities, specificities, positive (PPV) and negative predictive values (NPV) were determined for both imaging modalities.
RESULTS Of the 44 patients, 21 (47.7%) had pathologically proven malignancy while 23 (52.3%) had benign lesions. All 21 patients with malignancy underwent surgery - mastectomy (n = 8), segmentectomy (n = 6), and lumpectomy (n = 7). Of the 21 malignant lesions, 20 were invasive ductal carcinomas with one mucinous carcinoma. The average tumour size was 17 mm (range 9-42 mm). Of 23 biopsy-proven (FNAB) benign lesions, 11 were surgically excised. Clinical and radiological follow-up at one year in the remaining 12 patients showed no evidence of malignancy. Eight of the 23 benign lesions (35%) represented fibro-fatty tissue, six (26%) were due to fibrocystic disease, three patients (13%) had proliferative dysplasia,
Fig. 3 - (a) A 39-year-old female with dense fibroglandular breast tissue on mammography. No focal mass lesion or microcalcifications are demonstrated. (b) Tc-99m tetrofosmin scintimammography reveals abnormal focal accumulation of tetrofosmin in the upper right breast. Biopsy and subsequent segmental mastectomy revealed an 18 mm mucinous carcinoma.
three patients (13%) had solitary benign cysts, two patients (9%) had apocrine metaplasia and one patient (4%) had a radial scar resected (Fig. 1). Of the 44 patients, 38 had two view mammography (six patients were < 35 years of age). Of these 38 patients, 21 had biopsy proven malignancy while 17 had benign histology (all patients < 35 years of age had benign histology). Of the 21 patients with malignancy, plain-film mammography was reported as suspicious for malignancy in 17 (81%) (Fig. 2) while four were reported as benign. Of these four falsenegative results, two patients had mammographically dense breasts and two had a history of breast surgery (Figs 3 & 4). Of the 17 with benign disease, 14 patients (82.4%) had benign appearances on plain-film mammography while three (18%) had one or more findings suspicious for malignancy. Of these three false-positive results, two patients had fibro-fatty change on histology (postoperative change in both cases) (Fig. 5) while one patient had a radial scar diagnosed in a radiographically dense breast. The sensitivity of plain-film mammography in our group was 81%, with a specificity of 82.4%, a positive predictive value of 85% and a negative predictive value of 77.8%. Of the 21 patients with biopsy proven malignancy, 20 (95.2%) had positive Tc-99m tetrofosmin scintimammography. There was one false-negative result in a patient with severe rheumatoid arthritis where positioning was suboptimal secondary to immobility. However, focal abnormal radioisotope accumulation was not identified and the scintimammogram was reported as negative. FNAB yielded 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
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(b)
(a)
malignant cells and subsequent excision revealed a 19 mm invasive intraductal carcinoma. Of the 23 patients with benign histology, 21 (91.3%) had negative scintimammography. There were two falsepositive results - one in a patient with proliferative dysplasia and another in a patient with a hypervascular fibroadenoma. The sensitivity of Tc-99m tetrofosmin scintimammography in this group therefore was 95.24%, the specificity was 91.3%, with a positive predictive value of 90.9% and a negative predictive value of 95.45%.
DISCUSSION The sensitivity of mammography for carcinoma in the fatty breast approaches 100%. Despite continuing improvements in mammographic equipment and technique, the radiographically dense breast remains difficult to image, Even palpable masses can be difficult to detect in patients 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
Fig. 4 - (a) A 55-year-old female with a history of right segmental mastectomy for intraductal carcinoma 2 years previously presented with increasing induration and ill-defined mass in the upper right breast on clinical examination. Serial mammography over the 2-year period demonstrated no change with persistent architectural distortion secondary to previous surgery (arrows). (b) Tc-99m tetrofosmin scintimammography reveals a focal 'hot spot' posteriorly in the fight breast abutting the right pectoral muscles (arrow). Biopsy and surgery confirmed tumour recurrence corresponding to the scintigraphic abnormality.
with dense breast parenchyma and in those with a history of breast surgery and/or radiotherapy [20-23]. Moreover, benign lesions such as radial scars, post-traumatic haematoma, and fat necrosis may demonstrate the 'classic' radiographic signs of malignancy on mammography [1]. Although the positive predictive value of mammography (the number of cancers diagnosed per number of biopsies recommended) varies considerably between centres, it is estimated that between one-half to two-thirds of women referred for fine needle aspiration and/or core biopsy on the basis of a positive mammogram has benign histology [1,5-9]. Triple assessment with clinical examination, imaging (mammography and ultrasound), and fine needle aspiration and/or core biopsy is diagnostic in over 70% of cases. Ultrasound is valuable in assessing mammographically occult, palpable breast masses and in guiding biopsy in such cases. Since mammographically dense tissue is usually echogenic and most carcinomas are hypoechoic, ultrasound can be used to confirm a palpable malignancy within a
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(b)
(a)
Fig. 5 - (a) A 53-year-old female with a history of fight lumpectomy (intraductal carcinoma) presents 4 years following surgery with a palpable mass in the upper fight breast. Mammography reveals a spiculated mass and architectural distortion in the upper fight breast suspicious for tumour recurrence (arrows). (b) Negative Tc-99m tetrofosmin scintimammography. Multiple biopsies and clinical follow-up over an 18-month period show no evidence of tumour recurrence.
mammographically dense breast. However, since some malignancies, especially non-invasive and diffusely growing carcinomas, may not be visible sonographically, ultrasound cannot be used to confidently exclude cancer. Furthermore, the sensitivity of ultrasound decreases with lesion size. Even with a combination of mammography, ultrasound and FNAB and/or core biopsy, difficulties may arise in diagnosing cancer in patients with mammographically dense breasts, extensive scarring, silicon implants, or after lumpectomy or radiotherapy. A variety of adjunctive techniques have been developed including colour Doppler and power Doppler ultrasound, contrast-enhanced MR mammography, MR spectroscopy, FDG PET and PET imaging of oestrogen receptors [24-27]. More recently, nuclear medicine imaging of the breast (scintimammography) has been reported as an effective alternative for differentiating benign from malignant breast lesions. A range of radiopharmaceuticals have been evaluated as breast imaging agents and a number of imaging protocols described [11-17].
In a study of thallium-201 (T1-201) scintimammography, Waxman e t al. [11] reported abnormal accumulation of T1-201 in 42 of 44 palpable breast cancers. In 30 patients with both mammographically detected tumours and palpable breast lesions, Lee et al. [12] reported a sensitivity of 80% and a specificity of 96% for carcinoma detection using the same radiopharmaceutical. Similar results were reported by Sehweil e t al. in 1990 in 20 patients with palpable breast lesions [13]. In 1992, Campeau et al. [14] were the first to describe abnormal accumulation of a technetium-labelled pharmaceutical in a breast tumour. In their study, an unsuspected breast cancer was detected on a radionuclide stress test done for suspected ischaemic heart disease. In an investigation of Tc-99m sestamibi scintimammography, Khalkali e t al. [15] reported a sensitivity and specificity of 95.8% and 86.8%, respectively, for carcinoma. In 1996, Palmedo et al. [16] studied Tc-99m sestamibi scintimammography in 54 patients (40 patients with palpable breast masses and 14 with mammographically detected lesions) and reported a 9 1998 The Royal College of Radiologists, Clinical Radiology, 53, 17-24.
TC-99M TETROFOSMIN SCINTIMAMMOGRAPHY
sensitivity of 88% and specificity of 83% for carcinoma. In women attending for routine bone scintigraphy prior to breast surgery, Piccolo et al. [17] described abnormal accumulation of Tc-99m methylene diphosphonate (MDP) in 158 of 172 (92%) carcinomas. Tc-99m MDP scintimammography correctly characterized 43 of 53 lesions (81%) where mammography was indeterminate. We report the novel use of the lipophilic, cationic myocardial imaging agent, Tc-99m tetrofosmin, as a breast imaging agent. Although Tc-99m tetrofosmin has not been previously studied in breast disease, Atasever et al. [28] have described abnormal accumulation of Tc-99m tetrofosmin in 19 of 21 primary lung cancers. The mechanism of tumoral uptake of tetrofosmin is uncertain but it is likely that it behaves in a similar manner to sestamibi as both are lipophilic cations and have a similar mechanism of action in myocardium. Tumoral concentration of sestamibi is related to a combination of factors including rapid cell growth and division (increased mitochondrial activity), increased vascularity (neoangiogenesis), enlargement of the interstitial space, cell wall damage and increased capillary permeability [29,30]. Whatever the mechanism of action, the results of this study indicate that Tc-99m tetrofosmin is an effective breast imaging agent. Twenty of 21 patients with histologically proven breast carcinoma had positive Tc-99m tetrofosmin scintimammography. One false-negative result occurred in a patient with a 19 mm tumour. False-negative scintimammography using sestamibi has been described and attributed to expression of the membrane glycoprotein Pgp-170, a product of the multidmg resistance (MDR) gene, that causes reduced accumulation of radioisotope in turnouts when elevated [30,31]. This factor was not measured in our patients. False-positive results were observed in two of our patients. One of these patients had benign proliferative dysplasia in whom concentration of Tc-99m tetrofosmin was non-focal and diffuse. The second patient had focal accumulation of radioisotope in a hypercellular fibroadenoma. False-positive results have been reported for scintimammography using both Tc-99m sestamibi and T1201 and contrast-enhanced magnetic resonance mammography in both of these conditions [24,30,32,33]. With a sensitivity of 81% and a specificity of 82.4%, the diagnostic accuracy of plain-film mammography in our study compares favourably with published data. Lesion detection on mammography was, however, adversely affected by breast density. Two of four patients with falsenegative mammography and two of three patients with false-positive mammography had dense breast parenchyma. Conversely, results of Tc-99m tetrofosmin scintimammography were not affected by breast density. Scintimammography correctly characterized lesions in 13 of 13 patients with mammographically dense breasts. Similarly, results of plain-film mammography were limited in the postoperative breast. Nine of our group had a history of previous surgery and/or radiotherapy of whom four had histological evidence of tumour recurrence. In two of these four cases plain-film mammography failed to accurately predict recurrent carcinoma while mammographic findings suggested tumour recurrence in two of five patients with postoperative fibrosis alone. Tc-99m tetrofosmin scintimammography was positive in all four patients with recurrent disease and negative in all five cases of benign scar tissue. Compared with other radiopharmaceuticals, there are technical advantages to using Tc-99m tetrofosmin as a 9 1998 The Royal College of Radiologists, ClinicalRadiology, 53, 17 24.
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breast imaging agent. Tc-99m labelled radiopharmaceuticals emit more abundant photons in a suitable energy range for gamma camera imaging than T1-201, with less scatter and photon attenuation, superior image resolution with increased counting rates, and reduced patient radiation dose. Compared with Tc-99m sestamibi, Tc-99m tetrofosmin is more convenient to prepare. Tc-99m sestamibi requires boiling and subsequent cool-down prior to use. This step is time consuming and potentially increases the radiation exposure of medical personnel. Tetrofosmin, on the other hand, is a freeze-dried formulation, ready to use and requiring no additional preparation. A significant limitation of this study is tumour size. All patients had palpable breast lesions with a mean tumour size of 17mm (range 7 - 42ram). There was no case of ductal carcinoma in situ (DCIS). Although a 7-mm tumour was successfully demonstrated, the limited resolution of gamma camera imaging may prevent detection of smaller lesions. This may improve with the use of small field-of-view gamma cameras specifically designed for breast scintigraphy. Although the high sensitivities and specificities attributed to scintimammography in this and other series may not apply to larger groups of healthy women attending for screening, the proposed application of scintimammography is not as a screening technique but as an adjunct to plain-film mammography in indeterminate cases. Further work to determine the sensitivity of scintimammography in nonpalpable, mammographically detected lesions is ongoing in our department.
CONCLUSION Tc-99m tetrofosmin scintimammography is an accurate, well tolerated and non-invasive method of differentiating benign from malignant breast lumps. Negative Tc-99m tetrofosmin scintimammography excludes malignancy with a high degree of confidence while false-positive scintigraphy can occur in cases of proliferative dysplasia and hypercellular fibroadenoma. Tc-99m tetrofosmin scintimammography is particularly useful when plain-film mammographic assessment and biopsy are difficult due to breast density, radiotherapy or previous surgery. Further work to compare the accuracy of Tc-99m tetrofosmin scintimammography with contrast enhanced MR mammography, and to determine the accuracy of scintimammography in characterizing non-palpable, mammographically detected lesions is ongoing.
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