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The role of Tc99m-sestamibi scintimammography in combination with the triple assessment of primary breast cancer
EJSO 2002; 28: 108–112 doi:10.1053/ejso.2001.1217, available online at http://www.idealibrary.com on
The role of Tc99m-sestamibi scintimammography in combination with the triple assessment of primary breast cancer M. H. K. Leidenius∗, E. A. Leppa¨nen†, H. T. Tykka¨‡ and K. A. J. von Smitten∗ ∗Breast Surgery Unit, †Unit of Nuclear Medicine, Maria Hospital, Helsinki University Hospital, ‡Breast Surgery Unit, Maria Hospital, Helsinki City Hospitals, Helsinki, Finland
Aim: The aim of this study was to evaluate if Tc99m-sestamibi scintimammography in addition to the triple assessment consisting of clinical examination, mammography, breast ultrasonography and fine needle aspiration cytology (FNA) enhances the diagnosis of breast cancer and helps in avoiding unnecessary operative biopsies. Methods: Pre-operational scintimammography was performed within 2 weeks of operation to 46 consecutive patients with abnormal findings in clinical breast examination, mammography or ultrasonography. Three patients had abnormalities in both breasts. Histological diagnosis was obtained in all 49 cases. Results: The histological diagnosis was benign in 18 (37%) cases and malignant in 31 (63%) cases. The overall sensitivity of scintimammography was 77% and the specificity was 61%. The sensitivity of scintimammography was 95% in invasive ductal carcinoma, 50% in invasive lobular carcinoma and 25% in ductal carcinoma in situ. Scintimammography showed 100% sensitivity in cases with invasive carcinoma, with highly suspicious findings for malignancy in the other examinations. The sensitivity was 63% in cases with indeterminate or contradictory findings in mammography, ultrasonography and FNA. Conclusions: Adding scintimammography to the triple assessment does not seem to be helpful in the diagnosis of breast abnormalities because of low sensitivity in malignant cases with a challenging diagnosis by mammography, ultrasonography and FNA, and because of low overall specificity. 2002 Elsevier Science Ltd Key words: scintimammography; breast cancer; diagnosis.
INTRODUCTION Detection of carcinoma and avoiding unnecessary operative biopsies of benign lesions are the main challenges in the diagnosis of palpable breast masses or abnormalities detected by mammography or ultrasonography. Scintimammography with technetium-99m methoxyisobutylisonitrile has been proposed as a promising non-invasive method in the diagnosis of breast lesions with high overall sensitivity of 84–94% and specificity of 69–94%.1–9 The sensivity of scintimammography is not affected by the dense structure of the breast of a pre-menopausal patient8,10,11 or by scar tissue from a previous operation or radiotherapy7 unlike mammography. However, scintimammography seems to have certain limitations. The sensitivity has been clearly
Correspondence to: Marjut Leidenius, Breast Surgery Unit, Maria Hospital, Lapinlahdenkatu 16, FIN-00180 Helsinki, Finland. Tel: +358 9 47161005; E-mail: [email protected] 0748–7983/02/020108+05 $35.00/0
lower in non-palpable lesions4,5,9,10 and in lesions with a diameter less than 1 cm.4–10 The diagnostic work-up of patients with breast abnormalities should be performed using the triple assessment consisting of physical examination, mammography, ultrasonography and needle biopsy, fine needle aspiration cytology (FNA) or core biopsy.12 FNA of palpable lesions13,14 or ultrasonographically guided FNA15 has been reported to have excellent sensitivity and specificity in expert hands. Breast ultrasonography enhances the diagnostic accuracy of mammography and is thus a part of standard triple diagnosis in patients with dense breast or those with negative or indeterminate results in mammography.16–18 In addition, it is advisable to perform percutaneous needle biopsy under ultrasonography control, when the lesion is visible in ultrasonography.16 The role of scintimammography combined with mammography and/or ultrasonography and/or FNA has been evaluated in few previous studies.5,9,11,19–21 These studies suggest scintimammography is useful in patients 2002 Elsevier Science Ltd
TC99M-SESTAMIBI SCINTIMAMMOGRAPHY WITH TRIPLE ASSESSMENT
109
Table 1 Findings in mammography
Invasive ductal carcinoma (n=21) Invasive lobular carcinoma (n=6) Ductal carcinoma in situ (n=4) Atypical ductal hyperplasia (n=5) Fibroadenoma (n=3) Benign phyllodes tumour (n=1) Other benign lesions (n=9)
Malignant
Indeterminate
Benign
Not done
17 2 3 0 0 0 0
1 2 0 5 1 0 7
3 1 0 0 2 1 1
0 1 1 0 0 0 1
with indeterminate or normal findings in mammography for lesions greater than 1 cm especially in patients with mammographically dense breasts. None of these studies evaluated scintimammography in combination with all the other examinations. The role of scintimammography combined with the triple diagnosis, i.e. physical breast examination, mammography, ultrasonography and FNA has to be clarified. The aim of this study was to evaluate if the diagnosis of breast malignancies is enhanced and if unnecessary operative biopsies can be avoided by adding scintimammography to the triple diagnosis at a referral hospital.
PATIENTS AND METHODS Patients The study was carried out at Maria Hospital, the Breast Surgery Unit of Helsinki City Hospitals. The project plan was approved by the Ethical Committee of Helsinki City Hospitals. Written informed consent was obtained from each patient. The study population consisted of 46 consecutive patients, who were referred to the hospital because of abnormal findings in clinical breast examination, mammography or ultrasonography from December 1996 to April 1997. The median age of the patients was 58 years (range 46–76) years. Three patients had abnormalities in both breasts so altogether 49 breasts were examined. A palpable tumour or mass was found in 25 (51%) breasts. In addition there was retraction of skin or nipple without a clearly palpable mass in two breasts. Mammography was performed in 46 (94%) cases, ultrasonography in 47 (96%) cases and both examinations in 44 (90%) cases. The imaging was performed in referring units. Mammography showed malignant findings in 22 cases, indeterminate findings in 16 cases and benign findings in eight cases (Table 1). The findings in ultrasonography were highly suspicious for malignancy in 17 cases, indeterminate in 17 cases and benign in 13 cases. Fine needle aspiration cytology (FNA) was performed prior to the operation in 44 (90%) cases. The findings in FNA were positive or suspicious for malignancy in 24, atypical in 11 and benign in eight cases (Table 2).
Stereotactic core biopsy was not available at the hospital during the study period.
Scintimammography Scintimammography was performed 20 min after injection of 20 mCi (740 MBq) of Tc99m-sestamibi (Cardiolite, DuPont) with one anterior and two lateral planar images in all patients using 128×128 matrix (Maxicamera 400AT, General Electric). The lateral images were taken when the patient was lying prone and the breasts hanging freely. The scans were interpreted by an experienced nuclear medicine physician. Focal uptake in the breast was interpreted to represent malignancy. The findings were interpreted as indeterminate when the uptake was atypically weak or the margins were imprecise. All patients were operated on within 2 weeks of scintimammography and histological diagnosis was obtained in all cases.
Statistical methods Fisher’s exact test was used to compare the percentages. The medians were compared using the Mann–Whitney U-test.
RESULTS The histological biopsy results were benign in 18 (37%) cases and malignant in 31 (63%) cases (Table 3). The median histological tumour size (the greatest dimension) was 15 mm (range 5–50 mm) in the malignant cases. When the indeterminate findings in scintimammography were interpreted as positive findings, the sensitivity was 77% and the specificity was 61%. The accuracy was 71%. The positive predictive value was 77% and the negative predictive value was 61%. Sixteen of the palpable (89%) and eight of the non-palpable (61%) malignant lesions were found by scintimammography (P=NS). Scintimammography revealed 19 (79%) of the malignant lesions with tumour size of 1 cm or greater and five (63%) of the malignant lesions with tumour size smaller than 1 cm (P=NS).
110
M. H. K. LEIDENIUS ET AL. Table 2 Findings in fine needle aspiration cytology (FNA)
Invasive ductal carcinoma (n=21) Invasive lobular carcinoma (n=7) Ductal carcinoma in situ (n=4) Atypical ductal hyperplasia (n=5) Fibroadenoma (n=3) Benign phyllodes tumour (n=1) Other benign lesions (n=9)
4 or 5
3
1 or 2
0 or not done
17 3 1 0 1 1 1
2 2 1 3 0 0 3
1 1 1 0 2 0 3
1 0 1 2 0 0 2
FNA: 5=malignant finding; 4=suspicious finding; 3=atypical finding; 2=probably benign; 1=normal finding; 0=insufficient specimen.
Mammography showed microcalcifications without a density or mass in 11 cases including one case with invasive lobular carcinoma, three with ductal carcinoma in situ (DCIS), five with atypical ductal hyperplasia, one with sclerosing adenosis and one with fibrocystic mastopathy. Only one of the four malignant lesions (25%) with microcalcifications was detected by scintimammography compared to 23 (85%) malignant cases with other findings in mammography (P<0.05).
Malignant breast lesions Scintimammography showed true positive findings in 24 (77%) cases with breast cancer. Scintimammography suggested malignancy in 20 (95%) cases with invasive ductal carcinoma, in three (50%) cases with invasive lobular carcinoma and in one case (25%) with DCIS (P<0.05, for invasive ductal carcinoma compared to invasive lobular carcinoma). Scintimammography showed false negative findings with no or uniform uptake in seven (23%) cases with malignant lesions including one invasive ductal carcinoma, three invasive lobular carcinomas and three DCIS (Table 3).
Benign breast lesions True negative findings with no focally increased uptake was found in 11 (61%) cases with benign conditions. Scintimammography was suspicious for malignancy in seven (39%) cases with benign lesions including three cases with fibroadenoma, two with atypical ductal hyperplasia, one with intraductal papilloma and one with fibrocystic mastopathy (Table 3).
The impact of scintimammography on clinical decision-making The findings in mammography, ultrasonography and FNA were clearly malignant in all three examinations or clearly malignant in two and suspicious or indeterminate in one examination in 16 (59%) cases with invasive carcinoma. Scintimammography showed 100% sensitivity in these 16
cases, which were assessed as highly suspicious for malignancy by the other examinations. Mammography, ultrasonography and FNA showed indeterminate or contradictory findings in 11 (41%) cases with invasive carcinoma. The sensitivity of scintimammography was 63% in these cases. When malignant findings in either physical examination, mammography or ultrasonography or malignant, suspicious or atypical findings in FNA are considered as indications for operative biopsy, six operative biopsies would have been omitted when relying on the results of scintimammography. These included one case with invasive lobular carcinoma, one with atypical ductal hyperplasia, one with benign phyllodes tumour and three with fibrocystic mastopathy. Scintimammography would have indicated operation in two cases with fibroadenoma with findings typical to fibroadenoma in all other examinations.
DISCUSSION The 77% sensitivity and 61% specificity observed in the present study are somewhat lower than those obtained Table 3 Histological findings and findings in scintimammography (n=49) Malignant findings (n=31) Invasive ductal carcinoma (n=21) Invasive lobular carcinoma (n=6) Ductal carcinoma in situ (n=4)
TP 20 3 1
FN 1 3 3
Benign findings (n=18) Atypical ductal hyperplasia (n=5) Fibroadenoma (n=3) Benign phyllodes tumour (n=1) Fibrocystic mastopathy (n=7) Intraductal papilloma (n=1) Sclerosing adenosis (n=1)
TN 3 0 1 6 0 1
FP 2 3 0 1 1 0
TP, true positive findings in scintimammography; FN, false negative findings in scintimammography; TN, true negative findings in scintimammography; FP, false positve findings in scintimammography.
TC99M-SESTAMIBI SCINTIMAMMOGRAPHY WITH TRIPLE ASSESSMENT in previous studies.1–9 The reason for this may be the small number and selection of the patients. The proportion of palpable lesions (51%) was lower than in previous reports.1,3–5,9,10 The sensitivity of scintimammography is enhanced in palpable tumours (85–97%), but seems to be low (35–60%) in non-palpable lesions.4,5,9,10 This finding was confirmed in the present series: 89% of the palpable and 61% of the non-palpable malignancies were identified by scintimammography. The finding that malignant tumours larger than 1 cm were detected by scintimammography more often than the smaller ones (79% vs 63%) is also in agreement with the previous studies.4–10 Scintimammography was positive in one case of four patients with DCIS. Other investigators have also failed to find DCIS by scintimammography.1,3,7,21,22 Conversely, in a series of 15 patients with DCIS, scintimammography showed encouraging results with 80% sensitivity.23 Microcalcifications without a density or mass is a common finding in mammography in DCIS. The sensitivity of scintimammography in the present series was particularly low (25%) when mammography showed only microcalcifications. Stereotactic core biopsy or even preferable a mammotome biopsy has proven to be essential in the pre-operative diagnosis DCIS.24 Therefore the role of scintimammography in the diagnosis of DCIS seems to not to be remarkable. Scintimammography shows an excellent sensitivity in cases with relatively large, palpable invasive ductal carcinoma according to our findings as well as earlier studies. There are seldom difficulties in the diagnosis of these cases even without scintimammography. On the contrary, the diagnosis of invasive lobular carcinoma is not always easy by mammography of FNA, which both often result in indeterminate or benign findings.25,26 In the present study, the false negative findings in scintimammography were rare in invasive ductal carcinoma (one case, 5%) compared to invasive lobular carcinoma (50% false negative rate). False negative results in invasive lobular carcinoma has also been reported in some earlier series.10,27 Regrettably, we did not find scintimammography to be helpful in the often difficult diagnosis of invasive lobular carcinoma. In fibroadenoma, the finding in mammography is often typical but may be confused with invasive lobular carcinoma presenting often with a density without a spiculated outline.25 The cytodiagnosis of fibroadenoma is sometimes difficult, suspicious or atypical findings are not rare.28 Also scintimammography may give false positive results in fibroadenoma.1,9,10,22 In the present study, scintimammography showed false positive results in all three cases with fibroadenoma. Therefore scintimammography seems not to be indicated when there is a suspicion of fibroadenoma in clinical examination and/or in mammography. Relying on scintimammography, six operative biopsies would have been omitted in this series. These included
111
one case with invasive lobular carcinoma, one case with atypical ductal hyperplasia, one case with benign phyllodes tumour and three cases with fibrocystic mastopathy. There were no malignant cases in which scintimammography would have been of essential diagnostic value. On the other hand, scintimammography warranted operation in two cases with fibroadenoma with probably benign findings in all other examinations. Therefore adding scintimammography to clinical examination, mammography, ultrasonography and needle biopsy does not seem to be helpful in routine evaluation of breast abnormalities at a referral hospital. Our patients were somewhat older than those in the previous studies.1,5,7,8 Only four (8%) patients were under the age of 50 years in the present series. The sensitivity of scintimammography is not adversely affected by the dense structure of the breast in young patients. On the contrary scintimammography seems to work better in dense breast and in young patients.8,11 Therefore, despite our results, scintimammography may have a role in the evaluation of abnormal findings in dense breasts especially in pre-menopausal patients. It may also have a role in strengthening the decision not to operate on tumours that are considered to be benign. In addition, scintimammography may be valuable in detecting local recurrence after breast conserving surgery and radiotherapy7 and should be further evaluated. In conclusion, adding scintimammography to the triple assessment including physical examination, mammography, breast ultrasonography and needle biopsy does not seem to be helpful in the diagnosis of primary breast cancer in post-menopausal patients. The sensitivity of conventional imaging with mammography is relatively good in this patient group compared to pre-menopausal patients with dense breast tissue. Its role in younger women is unproven.
REFERENCES 1. Khalkhali I, Cutrone JA, Mena IG, et al. Scintimammography: the complementary role of Tc-99m sestamibi prone breast imaging for the diagnosis of breast carcinoma. Radiology 1995; 196: 421–6. 2. Taillefer R, Robidoux A, Lambert R, Turpin S, Laperriere J. Technetium-99m-sestamibi prone scintimammography to detect primary breast cancer and axillary lymph node involvement. J Nucl Med 1995; 36: 1758–65. 3. Clifford E, Lugo-Zamudio C. Scintimammography in the diagnosis of breast cancer. Am J Surg 1996; 172: 483–6. 4. Mekhmandarov S, Sandbank J, Cohen M, Lelcuk S, Lubin E. Technetium-99m-MIBI scintimammography in palpable and nonpalpable breast lesions. J Nucl Med 1998; 39: 86–91. 5. Arslan N, Ozturk E, Ilgan S, et al. 99Tcm-MIBI scintimammography in the evaluation of breast lesions and axillary involvement: A comparison with mammography and histopathological diagnosis. Nucl Med Commun 1999; 20: 317–25. 6. Danielson R, Bone B, Gad A, Sylvan M, Aspelin P. Sensitivity and specificity of planar scintimammography with 99mTc-sestamibi. Acta Radiol 1999; 40: 394–9. 7. Howarth D, Sillar R, Clark D, Lan L. Technetium-99m sestamibi scintimammography: the influence of histopathological characteristics, lesion size and the presence of carcinoma in situ in the detection of scintimammography. Eur J Nucl Med 1999; 26: 1475–81.
112 8. Tofani A, Sciuto R, Semprebene A, et al. 99Tcm-MIBI scintimammography in 300 consecutive patients: Factors that may affect accuracy. Nucl Med Commun 1999; 20: 1113–21. 9. Prats E, Banzo J, Meroa, Herranz R, Carril J. 99mTc-MIBI scintimammography as a complement of the mammography in patients with suspected breast cancer. A multicentre experience. Breast 2001; 10: 109–16. 10. Palmedo H, Biersack HJ, Lastoria S, et al. Scintimammography with technetium-99m metoxyisobutylisonitrile: results of a prospective European multicentre trial. Eur J Nucl Med 1998; 25: 375–85. 11. Danielsson R, Reihner E, Grabowska A, Bone B. The role of scintimammography with 99mTc-sestamibi as a complementary diagnostic technique in the detection of breast cancer. Acta Radiol 2000; 41: 441–5. 12. Rutgers EJTH for the EUSOMA Consensus Group. Quality control in the locoregional treatment of breast cancer. Eur J Cancer 2001; 37: 447–53. 13. Willis S, Ramzy I. Analysis of false results in a series of 835 fine needle aspirates of breast lesions. Cytol 1995; 39: 858–64. 14. Collaco LM, Silviera di Lima R, Werner B, Bleggi Torres LF. Value of fine needle aspiration in the diagnosis of breast lesions. Acta Cytol 1999; 43: 587–92. 15. Boerner S, Fornage B, Singletary E, Sneige N. Ultrasound-guided fine-needle aspiration (FNA) of nonpalpable breast lesions. A review of 1885 FNA cases using the National Cancer Institutesupported recommendations on the uniform approach to breast FNA. Cancer (Cancer Cytopathol) 1999; 87: 19–24. 16. Perry NM, on behalf of the EUSOMA Working Party. Quality assurance in the diagnosis of breast disease. Eur J Cancer 2001; 37: 159–72. 17. Klaus AJ, Klingensmith WC, Parker SH, Stavros AT, Sutherland JD, Aldrete KD. Comparative value of 99mTc-sestamibi scintimammography and sonography in the diagnostic workup of breast masses. Am J Roentgenol 2000; 174: 1779–83. 18. Rubin E, Mennemeyer ST, Desmond RA, et al. Reducing the cost of diagnosis of breast carcinoma. Impact of ultrasound and
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19.
20. 21.
22.
23. 24. 25. 26. 27. 28.
imaging-guided biopsies on a clinical breast practice. Cancer 2001; 91: 324–32. Lumachi F, Marzola MC, Zucchetta P, et al. Breast cancer detection with 99m-Tc-sestamibi scintigraphy, mammography, and fine needle aspiration cytology: comparative study in 64 surgically treated patients. Ann Surg Oncol 1999; 6: 568–71. Mirzaei S, Zajiek SM, Knoll P et al. Scintimammography enhances negative predictive value of non-invasive preoperative assessment of breast lesions. Eur J Surg Oncol 2000; 26: 738–41. Buscombe JR, Cwikla JB, Holloway B, Hilson AJW. Prediction of usefulness of combined mammography and scintimammography in suspected primary breast cancer using ROC curves. J Nucl Med 2001; 42: 3–8. Tiling R, Khalkhali I, Sommer H, Moser R, et al. Role of tecnetium99m sestamibi scintimammography and contrast enhanced magnetic resonance imaging for the evaluation of indeterminate mammograms. Eur J Nucl Med 1997; 24: 1221–9. Cwikla JB, Buscombe JR, Parbhoo SP, Davidson T, Holloway B, Hilson AJW. Detection of DCIS using Tc-99m MIBI scintimammography. Eur J Cancer 2000; 36 (suppl 5): A126. Silverstein MJ, Parker S, Grotting JC, Cote RJ, Russel CA. Ductal carcinoma in situ (DCIS) of the breast: diagnostic and therapeutic controversies. Am J Coll Surg 2001; 192: 196–214. Hilleren DJ, Andersson IT, Lindholm K, Linnel FS. Invasive lobular carcinoma: mammographic findings in a 10-year experience. Radiology 1991; 178: 149–54. Boerner S, Sneige N. Specimen adequacy and false–negative diagnosis rate in fine-needle aspirates of palpable breast masses. Cancer (Cancer Cytopathol) 1998; 84: 344–8. Tiling R, Sommer H, Pechmann M, et al. Comparison of technetium – 99m-sestamibi scintimammography with contrast-enhanced MRI for diagnosis of breast lesions. J Nucl Med 1007; 38: 58–62. Kline TS. Fine needle aspiration of the breast: Diagnosis and pitfalls: A review of 3545 cases. Cancer 1993; 1: 1499–502.
Accepted for publication 19 September 2001
The role of Tc99m-sestamibi scintimammography in combination with the triple assessment of primary breast cancer M. H. K. Leidenius∗, E. A. Leppa¨nen†, H. T. Tykka¨‡ and K. A. J. von Smitten∗ ∗Breast Surgery Unit, †Unit of Nuclear Medicine, Maria Hospital, Helsinki University Hospital, ‡Breast Surgery Unit, Maria Hospital, Helsinki City Hospitals, Helsinki, Finland
Aim: The aim of this study was to evaluate if Tc99m-sestamibi scintimammography in addition to the triple assessment consisting of clinical examination, mammography, breast ultrasonography and fine needle aspiration cytology (FNA) enhances the diagnosis of breast cancer and helps in avoiding unnecessary operative biopsies. Methods: Pre-operational scintimammography was performed within 2 weeks of operation to 46 consecutive patients with abnormal findings in clinical breast examination, mammography or ultrasonography. Three patients had abnormalities in both breasts. Histological diagnosis was obtained in all 49 cases. Results: The histological diagnosis was benign in 18 (37%) cases and malignant in 31 (63%) cases. The overall sensitivity of scintimammography was 77% and the specificity was 61%. The sensitivity of scintimammography was 95% in invasive ductal carcinoma, 50% in invasive lobular carcinoma and 25% in ductal carcinoma in situ. Scintimammography showed 100% sensitivity in cases with invasive carcinoma, with highly suspicious findings for malignancy in the other examinations. The sensitivity was 63% in cases with indeterminate or contradictory findings in mammography, ultrasonography and FNA. Conclusions: Adding scintimammography to the triple assessment does not seem to be helpful in the diagnosis of breast abnormalities because of low sensitivity in malignant cases with a challenging diagnosis by mammography, ultrasonography and FNA, and because of low overall specificity. 2002 Elsevier Science Ltd Key words: scintimammography; breast cancer; diagnosis.
INTRODUCTION Detection of carcinoma and avoiding unnecessary operative biopsies of benign lesions are the main challenges in the diagnosis of palpable breast masses or abnormalities detected by mammography or ultrasonography. Scintimammography with technetium-99m methoxyisobutylisonitrile has been proposed as a promising non-invasive method in the diagnosis of breast lesions with high overall sensitivity of 84–94% and specificity of 69–94%.1–9 The sensivity of scintimammography is not affected by the dense structure of the breast of a pre-menopausal patient8,10,11 or by scar tissue from a previous operation or radiotherapy7 unlike mammography. However, scintimammography seems to have certain limitations. The sensitivity has been clearly
Correspondence to: Marjut Leidenius, Breast Surgery Unit, Maria Hospital, Lapinlahdenkatu 16, FIN-00180 Helsinki, Finland. Tel: +358 9 47161005; E-mail: [email protected] 0748–7983/02/020108+05 $35.00/0
lower in non-palpable lesions4,5,9,10 and in lesions with a diameter less than 1 cm.4–10 The diagnostic work-up of patients with breast abnormalities should be performed using the triple assessment consisting of physical examination, mammography, ultrasonography and needle biopsy, fine needle aspiration cytology (FNA) or core biopsy.12 FNA of palpable lesions13,14 or ultrasonographically guided FNA15 has been reported to have excellent sensitivity and specificity in expert hands. Breast ultrasonography enhances the diagnostic accuracy of mammography and is thus a part of standard triple diagnosis in patients with dense breast or those with negative or indeterminate results in mammography.16–18 In addition, it is advisable to perform percutaneous needle biopsy under ultrasonography control, when the lesion is visible in ultrasonography.16 The role of scintimammography combined with mammography and/or ultrasonography and/or FNA has been evaluated in few previous studies.5,9,11,19–21 These studies suggest scintimammography is useful in patients 2002 Elsevier Science Ltd
TC99M-SESTAMIBI SCINTIMAMMOGRAPHY WITH TRIPLE ASSESSMENT
109
Table 1 Findings in mammography
Invasive ductal carcinoma (n=21) Invasive lobular carcinoma (n=6) Ductal carcinoma in situ (n=4) Atypical ductal hyperplasia (n=5) Fibroadenoma (n=3) Benign phyllodes tumour (n=1) Other benign lesions (n=9)
Malignant
Indeterminate
Benign
Not done
17 2 3 0 0 0 0
1 2 0 5 1 0 7
3 1 0 0 2 1 1
0 1 1 0 0 0 1
with indeterminate or normal findings in mammography for lesions greater than 1 cm especially in patients with mammographically dense breasts. None of these studies evaluated scintimammography in combination with all the other examinations. The role of scintimammography combined with the triple diagnosis, i.e. physical breast examination, mammography, ultrasonography and FNA has to be clarified. The aim of this study was to evaluate if the diagnosis of breast malignancies is enhanced and if unnecessary operative biopsies can be avoided by adding scintimammography to the triple diagnosis at a referral hospital.
PATIENTS AND METHODS Patients The study was carried out at Maria Hospital, the Breast Surgery Unit of Helsinki City Hospitals. The project plan was approved by the Ethical Committee of Helsinki City Hospitals. Written informed consent was obtained from each patient. The study population consisted of 46 consecutive patients, who were referred to the hospital because of abnormal findings in clinical breast examination, mammography or ultrasonography from December 1996 to April 1997. The median age of the patients was 58 years (range 46–76) years. Three patients had abnormalities in both breasts so altogether 49 breasts were examined. A palpable tumour or mass was found in 25 (51%) breasts. In addition there was retraction of skin or nipple without a clearly palpable mass in two breasts. Mammography was performed in 46 (94%) cases, ultrasonography in 47 (96%) cases and both examinations in 44 (90%) cases. The imaging was performed in referring units. Mammography showed malignant findings in 22 cases, indeterminate findings in 16 cases and benign findings in eight cases (Table 1). The findings in ultrasonography were highly suspicious for malignancy in 17 cases, indeterminate in 17 cases and benign in 13 cases. Fine needle aspiration cytology (FNA) was performed prior to the operation in 44 (90%) cases. The findings in FNA were positive or suspicious for malignancy in 24, atypical in 11 and benign in eight cases (Table 2).
Stereotactic core biopsy was not available at the hospital during the study period.
Scintimammography Scintimammography was performed 20 min after injection of 20 mCi (740 MBq) of Tc99m-sestamibi (Cardiolite, DuPont) with one anterior and two lateral planar images in all patients using 128×128 matrix (Maxicamera 400AT, General Electric). The lateral images were taken when the patient was lying prone and the breasts hanging freely. The scans were interpreted by an experienced nuclear medicine physician. Focal uptake in the breast was interpreted to represent malignancy. The findings were interpreted as indeterminate when the uptake was atypically weak or the margins were imprecise. All patients were operated on within 2 weeks of scintimammography and histological diagnosis was obtained in all cases.
Statistical methods Fisher’s exact test was used to compare the percentages. The medians were compared using the Mann–Whitney U-test.
RESULTS The histological biopsy results were benign in 18 (37%) cases and malignant in 31 (63%) cases (Table 3). The median histological tumour size (the greatest dimension) was 15 mm (range 5–50 mm) in the malignant cases. When the indeterminate findings in scintimammography were interpreted as positive findings, the sensitivity was 77% and the specificity was 61%. The accuracy was 71%. The positive predictive value was 77% and the negative predictive value was 61%. Sixteen of the palpable (89%) and eight of the non-palpable (61%) malignant lesions were found by scintimammography (P=NS). Scintimammography revealed 19 (79%) of the malignant lesions with tumour size of 1 cm or greater and five (63%) of the malignant lesions with tumour size smaller than 1 cm (P=NS).
110
M. H. K. LEIDENIUS ET AL. Table 2 Findings in fine needle aspiration cytology (FNA)
Invasive ductal carcinoma (n=21) Invasive lobular carcinoma (n=7) Ductal carcinoma in situ (n=4) Atypical ductal hyperplasia (n=5) Fibroadenoma (n=3) Benign phyllodes tumour (n=1) Other benign lesions (n=9)
4 or 5
3
1 or 2
0 or not done
17 3 1 0 1 1 1
2 2 1 3 0 0 3
1 1 1 0 2 0 3
1 0 1 2 0 0 2
FNA: 5=malignant finding; 4=suspicious finding; 3=atypical finding; 2=probably benign; 1=normal finding; 0=insufficient specimen.
Mammography showed microcalcifications without a density or mass in 11 cases including one case with invasive lobular carcinoma, three with ductal carcinoma in situ (DCIS), five with atypical ductal hyperplasia, one with sclerosing adenosis and one with fibrocystic mastopathy. Only one of the four malignant lesions (25%) with microcalcifications was detected by scintimammography compared to 23 (85%) malignant cases with other findings in mammography (P<0.05).
Malignant breast lesions Scintimammography showed true positive findings in 24 (77%) cases with breast cancer. Scintimammography suggested malignancy in 20 (95%) cases with invasive ductal carcinoma, in three (50%) cases with invasive lobular carcinoma and in one case (25%) with DCIS (P<0.05, for invasive ductal carcinoma compared to invasive lobular carcinoma). Scintimammography showed false negative findings with no or uniform uptake in seven (23%) cases with malignant lesions including one invasive ductal carcinoma, three invasive lobular carcinomas and three DCIS (Table 3).
Benign breast lesions True negative findings with no focally increased uptake was found in 11 (61%) cases with benign conditions. Scintimammography was suspicious for malignancy in seven (39%) cases with benign lesions including three cases with fibroadenoma, two with atypical ductal hyperplasia, one with intraductal papilloma and one with fibrocystic mastopathy (Table 3).
The impact of scintimammography on clinical decision-making The findings in mammography, ultrasonography and FNA were clearly malignant in all three examinations or clearly malignant in two and suspicious or indeterminate in one examination in 16 (59%) cases with invasive carcinoma. Scintimammography showed 100% sensitivity in these 16
cases, which were assessed as highly suspicious for malignancy by the other examinations. Mammography, ultrasonography and FNA showed indeterminate or contradictory findings in 11 (41%) cases with invasive carcinoma. The sensitivity of scintimammography was 63% in these cases. When malignant findings in either physical examination, mammography or ultrasonography or malignant, suspicious or atypical findings in FNA are considered as indications for operative biopsy, six operative biopsies would have been omitted when relying on the results of scintimammography. These included one case with invasive lobular carcinoma, one with atypical ductal hyperplasia, one with benign phyllodes tumour and three with fibrocystic mastopathy. Scintimammography would have indicated operation in two cases with fibroadenoma with findings typical to fibroadenoma in all other examinations.
DISCUSSION The 77% sensitivity and 61% specificity observed in the present study are somewhat lower than those obtained Table 3 Histological findings and findings in scintimammography (n=49) Malignant findings (n=31) Invasive ductal carcinoma (n=21) Invasive lobular carcinoma (n=6) Ductal carcinoma in situ (n=4)
TP 20 3 1
FN 1 3 3
Benign findings (n=18) Atypical ductal hyperplasia (n=5) Fibroadenoma (n=3) Benign phyllodes tumour (n=1) Fibrocystic mastopathy (n=7) Intraductal papilloma (n=1) Sclerosing adenosis (n=1)
TN 3 0 1 6 0 1
FP 2 3 0 1 1 0
TP, true positive findings in scintimammography; FN, false negative findings in scintimammography; TN, true negative findings in scintimammography; FP, false positve findings in scintimammography.
TC99M-SESTAMIBI SCINTIMAMMOGRAPHY WITH TRIPLE ASSESSMENT in previous studies.1–9 The reason for this may be the small number and selection of the patients. The proportion of palpable lesions (51%) was lower than in previous reports.1,3–5,9,10 The sensitivity of scintimammography is enhanced in palpable tumours (85–97%), but seems to be low (35–60%) in non-palpable lesions.4,5,9,10 This finding was confirmed in the present series: 89% of the palpable and 61% of the non-palpable malignancies were identified by scintimammography. The finding that malignant tumours larger than 1 cm were detected by scintimammography more often than the smaller ones (79% vs 63%) is also in agreement with the previous studies.4–10 Scintimammography was positive in one case of four patients with DCIS. Other investigators have also failed to find DCIS by scintimammography.1,3,7,21,22 Conversely, in a series of 15 patients with DCIS, scintimammography showed encouraging results with 80% sensitivity.23 Microcalcifications without a density or mass is a common finding in mammography in DCIS. The sensitivity of scintimammography in the present series was particularly low (25%) when mammography showed only microcalcifications. Stereotactic core biopsy or even preferable a mammotome biopsy has proven to be essential in the pre-operative diagnosis DCIS.24 Therefore the role of scintimammography in the diagnosis of DCIS seems to not to be remarkable. Scintimammography shows an excellent sensitivity in cases with relatively large, palpable invasive ductal carcinoma according to our findings as well as earlier studies. There are seldom difficulties in the diagnosis of these cases even without scintimammography. On the contrary, the diagnosis of invasive lobular carcinoma is not always easy by mammography of FNA, which both often result in indeterminate or benign findings.25,26 In the present study, the false negative findings in scintimammography were rare in invasive ductal carcinoma (one case, 5%) compared to invasive lobular carcinoma (50% false negative rate). False negative results in invasive lobular carcinoma has also been reported in some earlier series.10,27 Regrettably, we did not find scintimammography to be helpful in the often difficult diagnosis of invasive lobular carcinoma. In fibroadenoma, the finding in mammography is often typical but may be confused with invasive lobular carcinoma presenting often with a density without a spiculated outline.25 The cytodiagnosis of fibroadenoma is sometimes difficult, suspicious or atypical findings are not rare.28 Also scintimammography may give false positive results in fibroadenoma.1,9,10,22 In the present study, scintimammography showed false positive results in all three cases with fibroadenoma. Therefore scintimammography seems not to be indicated when there is a suspicion of fibroadenoma in clinical examination and/or in mammography. Relying on scintimammography, six operative biopsies would have been omitted in this series. These included
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one case with invasive lobular carcinoma, one case with atypical ductal hyperplasia, one case with benign phyllodes tumour and three cases with fibrocystic mastopathy. There were no malignant cases in which scintimammography would have been of essential diagnostic value. On the other hand, scintimammography warranted operation in two cases with fibroadenoma with probably benign findings in all other examinations. Therefore adding scintimammography to clinical examination, mammography, ultrasonography and needle biopsy does not seem to be helpful in routine evaluation of breast abnormalities at a referral hospital. Our patients were somewhat older than those in the previous studies.1,5,7,8 Only four (8%) patients were under the age of 50 years in the present series. The sensitivity of scintimammography is not adversely affected by the dense structure of the breast in young patients. On the contrary scintimammography seems to work better in dense breast and in young patients.8,11 Therefore, despite our results, scintimammography may have a role in the evaluation of abnormal findings in dense breasts especially in pre-menopausal patients. It may also have a role in strengthening the decision not to operate on tumours that are considered to be benign. In addition, scintimammography may be valuable in detecting local recurrence after breast conserving surgery and radiotherapy7 and should be further evaluated. In conclusion, adding scintimammography to the triple assessment including physical examination, mammography, breast ultrasonography and needle biopsy does not seem to be helpful in the diagnosis of primary breast cancer in post-menopausal patients. The sensitivity of conventional imaging with mammography is relatively good in this patient group compared to pre-menopausal patients with dense breast tissue. Its role in younger women is unproven.
REFERENCES 1. Khalkhali I, Cutrone JA, Mena IG, et al. Scintimammography: the complementary role of Tc-99m sestamibi prone breast imaging for the diagnosis of breast carcinoma. Radiology 1995; 196: 421–6. 2. Taillefer R, Robidoux A, Lambert R, Turpin S, Laperriere J. Technetium-99m-sestamibi prone scintimammography to detect primary breast cancer and axillary lymph node involvement. J Nucl Med 1995; 36: 1758–65. 3. Clifford E, Lugo-Zamudio C. Scintimammography in the diagnosis of breast cancer. Am J Surg 1996; 172: 483–6. 4. Mekhmandarov S, Sandbank J, Cohen M, Lelcuk S, Lubin E. Technetium-99m-MIBI scintimammography in palpable and nonpalpable breast lesions. J Nucl Med 1998; 39: 86–91. 5. Arslan N, Ozturk E, Ilgan S, et al. 99Tcm-MIBI scintimammography in the evaluation of breast lesions and axillary involvement: A comparison with mammography and histopathological diagnosis. Nucl Med Commun 1999; 20: 317–25. 6. Danielson R, Bone B, Gad A, Sylvan M, Aspelin P. Sensitivity and specificity of planar scintimammography with 99mTc-sestamibi. Acta Radiol 1999; 40: 394–9. 7. Howarth D, Sillar R, Clark D, Lan L. Technetium-99m sestamibi scintimammography: the influence of histopathological characteristics, lesion size and the presence of carcinoma in situ in the detection of scintimammography. Eur J Nucl Med 1999; 26: 1475–81.
112 8. Tofani A, Sciuto R, Semprebene A, et al. 99Tcm-MIBI scintimammography in 300 consecutive patients: Factors that may affect accuracy. Nucl Med Commun 1999; 20: 1113–21. 9. Prats E, Banzo J, Meroa, Herranz R, Carril J. 99mTc-MIBI scintimammography as a complement of the mammography in patients with suspected breast cancer. A multicentre experience. Breast 2001; 10: 109–16. 10. Palmedo H, Biersack HJ, Lastoria S, et al. Scintimammography with technetium-99m metoxyisobutylisonitrile: results of a prospective European multicentre trial. Eur J Nucl Med 1998; 25: 375–85. 11. Danielsson R, Reihner E, Grabowska A, Bone B. The role of scintimammography with 99mTc-sestamibi as a complementary diagnostic technique in the detection of breast cancer. Acta Radiol 2000; 41: 441–5. 12. Rutgers EJTH for the EUSOMA Consensus Group. Quality control in the locoregional treatment of breast cancer. Eur J Cancer 2001; 37: 447–53. 13. Willis S, Ramzy I. Analysis of false results in a series of 835 fine needle aspirates of breast lesions. Cytol 1995; 39: 858–64. 14. Collaco LM, Silviera di Lima R, Werner B, Bleggi Torres LF. Value of fine needle aspiration in the diagnosis of breast lesions. Acta Cytol 1999; 43: 587–92. 15. Boerner S, Fornage B, Singletary E, Sneige N. Ultrasound-guided fine-needle aspiration (FNA) of nonpalpable breast lesions. A review of 1885 FNA cases using the National Cancer Institutesupported recommendations on the uniform approach to breast FNA. Cancer (Cancer Cytopathol) 1999; 87: 19–24. 16. Perry NM, on behalf of the EUSOMA Working Party. Quality assurance in the diagnosis of breast disease. Eur J Cancer 2001; 37: 159–72. 17. Klaus AJ, Klingensmith WC, Parker SH, Stavros AT, Sutherland JD, Aldrete KD. Comparative value of 99mTc-sestamibi scintimammography and sonography in the diagnostic workup of breast masses. Am J Roentgenol 2000; 174: 1779–83. 18. Rubin E, Mennemeyer ST, Desmond RA, et al. Reducing the cost of diagnosis of breast carcinoma. Impact of ultrasound and
M. H. K. LEIDENIUS ET AL.
19.
20. 21.
22.
23. 24. 25. 26. 27. 28.
imaging-guided biopsies on a clinical breast practice. Cancer 2001; 91: 324–32. Lumachi F, Marzola MC, Zucchetta P, et al. Breast cancer detection with 99m-Tc-sestamibi scintigraphy, mammography, and fine needle aspiration cytology: comparative study in 64 surgically treated patients. Ann Surg Oncol 1999; 6: 568–71. Mirzaei S, Zajiek SM, Knoll P et al. Scintimammography enhances negative predictive value of non-invasive preoperative assessment of breast lesions. Eur J Surg Oncol 2000; 26: 738–41. Buscombe JR, Cwikla JB, Holloway B, Hilson AJW. Prediction of usefulness of combined mammography and scintimammography in suspected primary breast cancer using ROC curves. J Nucl Med 2001; 42: 3–8. Tiling R, Khalkhali I, Sommer H, Moser R, et al. Role of tecnetium99m sestamibi scintimammography and contrast enhanced magnetic resonance imaging for the evaluation of indeterminate mammograms. Eur J Nucl Med 1997; 24: 1221–9. Cwikla JB, Buscombe JR, Parbhoo SP, Davidson T, Holloway B, Hilson AJW. Detection of DCIS using Tc-99m MIBI scintimammography. Eur J Cancer 2000; 36 (suppl 5): A126. Silverstein MJ, Parker S, Grotting JC, Cote RJ, Russel CA. Ductal carcinoma in situ (DCIS) of the breast: diagnostic and therapeutic controversies. Am J Coll Surg 2001; 192: 196–214. Hilleren DJ, Andersson IT, Lindholm K, Linnel FS. Invasive lobular carcinoma: mammographic findings in a 10-year experience. Radiology 1991; 178: 149–54. Boerner S, Sneige N. Specimen adequacy and false–negative diagnosis rate in fine-needle aspirates of palpable breast masses. Cancer (Cancer Cytopathol) 1998; 84: 344–8. Tiling R, Sommer H, Pechmann M, et al. Comparison of technetium – 99m-sestamibi scintimammography with contrast-enhanced MRI for diagnosis of breast lesions. J Nucl Med 1007; 38: 58–62. Kline TS. Fine needle aspiration of the breast: Diagnosis and pitfalls: A review of 3545 cases. Cancer 1993; 1: 1499–502.
Accepted for publication 19 September 2001