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Original article Optimization of X-ray mammography and technetium-99m methoxyisobutylisonitrile scintimammography in the diagnosis of non-palpable breast lesions Isabel Uriarte, Jose Manuel Carril, Remedios Quirce, Ceferino Gutiérrez-Mendiguchía, Isabel Blanco, Ignacio Banzo, Alfonso Vega, Ana Hernández Servicio de Medicina Nuclear, Hospital Universitario Marqués de Valdecilla, Santander, Spain &misc:Received 10 November 1997 and in revised form 19 January 1998

&p.1:Abstract. The purpose of this study was to evaluate the contribution of technetium-99m methoxyisobutylisonitrile (MIBI) scintimammography to the early diagnosis of breast cancer in 78 patients with non-palpable breast lesions detected by mammography. In all cases biopsy was indicated and they were classified into three groups according to the mammographic findings: high (28), intermediate (30) and low (20) mammographic probability of malignancy. Histological diagnosis confirmed 37 benign and 41 malignant lesions. In the high-probability group 99mTc-MIBI scintimammography changed the four false-positives into true negatives at the expense of two false-negatives; in the intermediate group it changed nine of the 17 false-positives into true-negatives at the expense of one false-negative, and in the low-probability group it changed five of the 16 false-positives into truenegatives without false-negatives. Applying scintimammography to patients included in the intermediate and low-probability groups together, 14 of the 33 mammographic false-positives were changed into true-negatives with 1 false-negative; thus, 41% of the unnecessary biopsies would have been avoided. When MIBI scintimammography was applied to the low-probability group, the negative predictive value was 100% and the unnecessary biopsies would have been reduced by 31%. &kwd:Key words: Technetium-99m methoxyisobutylisonitrile – Scintimammography – Breast cancer – Mammography Eur J Nucl Med (1998) 25:491–496

Introduction Breast cancer is the leading cause of death among women in developed countries. This high mortality and the increasing incidence [1,2] have meant that a great part of Correspondence to: I. Uriarte, Servicio de Medicina Nuclear, Hospital Universitario Marqués de Valdecilla, Avda. Valdecilla s/n., E-39008 Santander, Spain&/fn-block:

oncological research has been concentrated on the disease in recent years. Early detection and diagnosis are crucial since they allow treatment in the early stages, which improves survival times and reduces mortality [3, 4]. The results of treatment have been shown to be better if breast cancer is diagnosed before the lesion becomes palpable. Therefore, detection and diagnosis of non-palpable lesions of the breast are of paramount importance for the success of treatment [5]. Mammography is the accepted and most widely used technique for the early detection of breast cancer. The mammographic signs of non-palpable lesions will determine the selection of patients for definitive histological diagnosis of the malignant or benign nature of such lesions [6, 7]. However, the value of mammography is limited by its low positive predictive value, with many biopsies revealing benign lesions. This is a matter of concern for those involved in breast cancer management [8–10]. In this context, a high priority is the search for a non-invasive technique allowing a better and more accurate selection of patients who will benefit from biopsy because they are more likely to be harbouring a malignant tumour [8, 10]. Following the pioneering work of Khalkali [11], a number of reports have found technetium-99m methoxyisobutylisonitrile (MIBI) scintimammography to be a valuable technique in the diagnosis of breast cancer because of its high sensitivity and specificity [12, 13]. In a preliminary study of a small number of palpable and non-palpable lesions, the high sensitivity of 99mTc-MIBI allowed us to suggest a potential role for the technique in reducing the number of unnecessary biopsies [14]. With a view to early diagnosis, we have since centered our attention only on non-palpable lesions, classified according to the mammographic probability of malignancy. In this study, we evaluated not only the overall contribution of 99mTc-MIBI scintimammography to the early diagnosis of breast cancer in non-palpable lesions detected on mammography but also the value of the technique in relation to the mammographic probability of European Journal of Nuclear Medicine Vol. 25, No. 5, May 1998 – © Springer-Verlag 1998

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malignancy and to the intensity of uptake. The aim of the study was to assess to what extent 99mTc-MIBI reduces the number of unnecessary biopsies and to optimize the use of mammography and scintimammography.

Table 1. Mammographic probability of malignancy in relation to histological diagnosis&/tbl.c:& Mammographic probability of malignancy High

Intermediate

Low

Total

Benigh Malignant

4 24

17 13

16 4

37 41

Total

28

30

20

78

Materials and methods This prospective study included 78 women with an age range of 35–81 years. All patients underwent biopsy as indicated by the mammographic signs, which were used to classify the patients according to the criteria previously published [15]: high probability of malignancy, 28 patients; intermediate probability, 30; and low probability, 20. Image acquisition started 10 min after an intravenous injection of 740 MBq of 99mTc-MIBI into the arm on the opposite side to the lesion. In all cases, labelling efficiency was higher than 97%. Anterior and prone lateral views were obtained with the patient lying on a specially designed bed and after careful positioning of the patient. A gamma camera equipped with a high-resolution collimator was used and counts of 600 s per view were acquired. The images obtained were subjectively assessed by three experienced observers who gave a consensus abnormality rating between 0 (total absence of focal uptake) and 5 (maximum uptake). For analysis and evaluation of the results, only grade 0 was considered normal and, hence, scintimammography was considered negative; all other grades were considered positive. The results obtained were compared with the definitive histological diagnosis established by biopsy. The histological diagnosis revealed 37 benign and 41 malignant lesions. Of the 37 benign lesions, 11 represented fibrocystic disease, ten epithelial hyperplasia, seven fibroadenomas, five adenosis and four fibrosis. Of the 41 malignant lesions, nine were intraductal carcinomas, 21 invasive ductal carcinomas, five invasive lobular carcinomas, five mixed invasive carcinomas and one tubular carcinoma.

Results Table 1 gives the results of histological diagnosis for the groups with different mammographic probability of malignancy. Of 28 lesions with high probability of malignancy, 24 were malignant and four benign; of 30 intermediate-probability lesions, 13 were malignant and 17 benign; and of 20 low-probability lesions, only four were malignant and 16 were benign. Since in practice biopsy would be indicated in all 78 patients, even those in the low-probability group, the most interesting finding is that 37 (47%) of the 78 mammographic studies were false positives, i.e. mammography indicated 37 biopsies that revealed benign lesions. For scintimammography, Table 2 shows that, of 21 MIBI-negative lesions, 18 were benign and only three malignant, whereas of 57 MIBI-positive lesions, 38 were malignant and 19 benign. There were, therefore, 19 false-positives compared to 37 on mammography. The prevalence of malignancy was 53%, and sensitivity, specificity, positive predictive value and negative predictive value were 93%, 49%, 67% and 86%, respectively.

&/tbl.: Table 2. Results of MIBI scintimammography in relation to histological diagnosis&/tbl.c:& MIBI −

MIBI +

Total

Benign Malignant

18 3

19 38

37 41

Total

21

57

78

Prevalence of malignancy = 53%, sensitivity = 93%, specificity = 49%, PPV = 67%, NPV = 86% &/tbl.:

When the same analysis was applied to each of the subgroups, the results were more interesting. Table 3 shows that of the 28 patients in the high-probability group, scintimammography detected 22 of the 24 malignant lesions and was negative in all four benign lesions. Sensitivity, specificity, positive predictive value and negative predictive value were 92%, 100%, 100% and 67% for a prevalence of malignancy of 86%. For the 30 patients in the intermediate-probability group (Table 3), of the 13 malignant lesions, 12 were MIBI-positive and one MIBI-negative, and of the 17 benign lesions, nine were MIBI-negative and eight MIBIpositive. The prevalence of malignancy was 43%, and sensitivity, specificity, positive predictive value and negative predictive value were 92%, 53%, 60% and 90%, respectively. In the low-probability group (Table 3), which included 20 patients, of the 16 benign lesions, five were MIBInegative and 11 MIBI-positive, but all four malignant lesions were detected. The prevalence of malignancy was 20%, and sensitivity, specificity, positive predictive value and negative predictive value were 100%, 31%, 27% and 100%, respectively. When the intermediate- and low-probability groups were taken together (Table 4), of the 50 patients, 33 had benign and 17 had malignant lesions (prevalence 34%). Of the 33 benign lesions,14 were MIBI-negative and 19 MIBI-positive. Scintimammography detected 16 of the 17 malignant lesions. Sensitivity, specificity, positive predictive value and negative predictive value were 94%, 42%, 46% and 93%, respectively. The distribution of benign and malignant lesions in terms of the intensity of MIBI uptake is given in Table 5. Of the 37 benign lesions, 18 (49%) did not take up

European Journal of Nuclear Medicine Vol. 25, No. 5, May 1998

493 Table 3. Results of MIBI scintimammography versus mammographic probability of malignancy&/tbl.c:&

High (n=28)a

Intermediate (n=30)b

Low (n=20)c

MIBI−

MIBI+

MIBI−

MIBI+

MIBI−

MIBI+

Benign Malignant

4 2

– 22

9 1

8 12

5 –

11 4

37 41

Total

6

22

10

20

5

15

78

Total

a

Prevalence of malignancy = 86%, sensitivity = 92%, specificity = 100%, PPV = 100%, NPV = 67% b Prevalence of malignancy = 43%, sensitivity = 92%, specificity = 53%, PPV = 60%, NPV = 90% c Prevalence of malignancy = 20%, sensitivity = 100%, specificity = 31%, PPV = 27%, NPV = 100%&/tbl.: Table 4. Results of MIBI scintimammography in the mammographic intermediate- and low-probability groups&/tbl.c:& MIBI −

MIBI +

Total

Benign Malignant

14 1

19 16

33 17

Total

15

35

50

Prevalence of malignancy = 34%, sensitivity = 94%, specificity = 42%, PPV = 46%, NPV = 93%&/tbl.: Table 5. Histological diagnosis and intensity of uptake&/tbl.c:& Grade of uptake

Total

0

1

2

3

4

Benign Malignant

18 3

11 12

6 14

2 11

– 1

37 41

Total

21

23

20

13

1

78

&/tbl.:

MIBI; 11 (30%) were grade 1; six (16%), grade 2; two (5%), grade 3; and none, grade 4 or 5. Of the 41 malignant lesions, one was grade 4; 11, grade 3; 14, grade 2; 12, grade 1; and three, grade 0. Discussion Since the study only included patients for whom biopsy was indicated by the suspicion of malignancy on mammography, all mammographies were considered positive, with no false-negatives or true-negatives. As a result, the sensitivity of MIBI scintimammography can at best only match the 100% sensitivity of mammography. In addition, the study was designed to focus on two main aspects: first, detection of non-palpable lesions in order to test the ability of MIBI scintimammography to establish an early diagnosis and thus improve survival; and, second, reduction of unnecessary biopsies resulting from the low predictive value of mammography, the technique


generally accepted for detection of non-palpable lesions. This limitation of mammography has led over the last few years to the investigation and development of complementary techniques, such as stereotaxic biopsy [16] and the application of digital computerized techniques to the mammographic images [8], to avoid unnecessary biopsies. The ability of MIBI scintimammography to reduce the number of unnecessary biopsies has been suggested by previous studies based on small selected populations, although a high sensitivity of the technique is required [14, 17]. In a preliminary report on non-palpable lesions, we suggested a possible role for MIBI-scintimammography when evaluated in the context of the mammographic probability of malignancy [18]. In the present study, we have not only classified patients according to mammographic probability of malignancy but we have also considered intensity of uptake. This should allow us to select those patients who will benefit from combined scintimammography and mammography. The overall prevalence of malignancy for non-palpable lesions in our population is among the highest prevalences reported by other authors, which range from 25% to 55% [13, 19–21]. This might be due to the selection criteria for patients entering a study. Moreover, by classifying the population by mammographic probability of malignancy we have shown that the performance of a technique depends on this probability, since almost all the false-positives on mammography fall into the intermediate- and low-probability groups. Our overall sensitivity for scintimammography was 93%, higher than the sensitivity (25%–89%) previously reported by other authors for non-palpable lesions [11, 19–21]. Apart from the technique employed, such a wide variation could be explained by the different prevalence of malignancy, and by the criteria employed to define abnormality of uptake. In our study, the prevalence was high, and any focal uptake, regardless of features, was considered abnormal and, therefore, positive (Figs. 1, 2). It should be highlighted that 37 of the 78 mammographies were false-positive (47%) since the mammographic findings indicated biopsy in all cases. In contrast, the number of false-positives for scintimammography

494

1a

2a Fig. 1. a Mammography shows a well defined non-palpable lesion with a low probability of malignancy. However, MIBI scintimammography b was positive, and the histological diagnosis was intraductal carcinoma&ig.c:/f

b

b

was much lower, 19 of 78 (24%). Thus, scintimammography would have reduced the false-positives from 47% to 24%, avoiding unnecessary biopsies in 18 of the 37 patients (49%). However, this would have been achieved at the expense of three false-negatives. Therefore, although the specificity was low, 49%, scintimammography contributes significantly to improvement of the specificity of X-ray mammography. The specificity would increase to 78% if “0” and “1” abnormality ratings were considered negative, but then the sensitivity would be unacceptably low, 63%. Similar analysis for each of the subgroups provides more interesting results. Thus, in the high-probability group, there were four false-positives (14%) for mammography (Fig. 3)and none for scintimammography, that is a 100% reduction in the unnecessary biopsies, but at the expense of two false-negatives (10%). In the intermediate group, the 17 false-positives (57%) on mammography were reduced to only eight (27%) on scintimammography, which means that nine (53%) of the 17 unnecessary biopsies could have been avoided, at the expense of one false-negative (7.5%). In the low-probability group, scintimammography reduced the 16 false-positives (80%) of mammography to 11 (55%), thus avoiding five (31%) of the 16 unnecessary biopsies.

Fig. 2. a Mammography shows a non-palpable lesion of the left breast (arrows). The microcalcification pattern corresponded to a high probability of malignancy. However, MIBI scintimammography b was negative. The final histological diagnosis was fibrosis&ig.c:/f

The results show that scintimammography would be of great value if the intermediate- and low-probability groups were to be taken together. In these groups, the number of false-positive mammographies is very high, and scintimammography would have avoided 14 of the 33 unnecessary biopsies at the expense of one false-negative (sensitivity 94%). Although Waxman [17] was referring to palpable lesions in his recent review, the author suggested that the reduction in unnecessary biopsies might not itself justify scintimammography because of false-negative results. If absence of false-negatives is a requirement for the use of scintimammography, this criterion would only have been met by our low-probability group, where MIBI-scintimammography showed 100% sensitivity and would have avoided 31% of the unnecessary biopsies. In our study, there were 19 false-positives for scintimammography, all in the intermediate (8) and low (11) probability groups. Histologically, the 19 false-positives were classified as fibrosis (two), fibroadenoma (four), adenosis (five) and fibrocystic disease (six). In addition, there were three false-negatives, two in the high-probability group (one intraductal and one tubular carcinoma) and one in the intermediate group, an invasive ductal carcinoma. The histology of the false-negatives was sim-


495

a

a

Fig. 3. a Non-palpable lesion depicted mammographically as a radial scar a with high probability of malignancy (arrows). b MIBI scintimammography was negative and histological diagnosis confirmed epithelial hyperplasia&ig.c:/f

b

Fig. 4. a Non-palpable lesion in the right breast detected on mammography. The characteristics of the microcalcification pattern corresponded to an intermediate probability of malignancy (arrows). b MIBI scintimammography was positive. The histological diagnosis was mixed invasive carcinoma (8 mm)&ig.c:/f

b

ilar to that reported by other authors. The size of the smallest lesion detected was an intraductal carcinoma of 7 mm. The detection of intraductal carcinomas is particularly important. In our population, the 41 malignant lesions included nine intraductal carcinomas ranging from 7 to 42 mm. Mammographically, four showed a high probability of malignancy, and three were MIBI-positive. Four were placed in the intermediate group and all were MIBI-positive, while the one lesion in the low-probability group was also MIBI-positive. Interestingly, five of the nine intraductal carcinomas had a microcalcification pattern on mammography, two of high probability (one MIBI-positive) and three of intermediate probability (all MIBI-positive). Analysis of previously reported data on this type of tumour revealed that incidence ranges widely, from 6% to 29%, and that the sensitivity of scintimammography varies from 80% to 100%, the highest figures corresponding to incidences lower than that of this study [13, 19–21]. In all, 29 of the 78 patients showed a microcalcification pattern on mammography. Malignancy was confirmed in 11: five in the high-probability group (all intra-


Table 6. Results of MIBI scintimammography in patients with a microcalcification pattern.&/tbl.c:& MIBI −

MIBI +

Total

Benign Malignant

11 1

7 10

18 11

Total

12

17

29

&/tbl.:

ductal carcinomas), five in the intermediate group (three intraductal, one mixed and one invasive ductal carcinoma), and one in the low-probability group (invasive mixed carcinoma). Scintimammography (Table 6) was positive in 10 of the 11 carcinomas showing a microcalcification pattern (Fig. 4), the one false-negative being an intraductal carcinoma in the high-probability group. When the intensity of uptake was compared with the presence of malignancy, 78% of the benign lesions were found to have an abnormality rating of 0 or 1, and 95% were grades 0, 1 or 2. Moreover, 64% of the malignant lesions were rated as grades 2, 3 or 4. The distribution of the data suggests, therefore, that only the extreme values

496

could be used to discriminate between benign and malignant lesions. Although high uptake of grade 3 or 4 is likely to correspond to malignancy, there is considerable overlapping of benign and malignant lesions for grades 1 and 2, as has been reported previously [21–23]. Since we considered only scans graded 0 as negative, there were only three false-negatives among 41 carcinomas. Had we taken grade 1 as the threshold, there would have been an unacceptable false-negative rate of 36%. One of the aims of the study was to optimize the use of MIBI scintimammography and mammography in the diagnosis of breast cancer. Our results indicate that MIBI scintimammography has only a limited value in the diagnosis of non-palpable lesions with a high probability of malignancy. However, it would be of great value in patients with lesions of intermediate and low probability, reducing unnecessary biopsies by 42% in this study. Applying MIBI scintimammography only to patients in the low-probability group, where sensitivity of MIBI was 100%, would have reduced unnecessary biopsies by 31%. References 1. Cannon-Albright LA, Skolnick MH. The genetics of familial breast cancer. Semin Oncol 1996; 23 Suppl 2: 1–5. 2. Wingo PA, Tong T, Bolden S. Cancer statistics 1995. C A Cancer J Clin 1995; 45: 8–30. 3. Byrne C, Smart C, Chu K, Hartman W. Survival advantage differences by age. Cancer Suppl 1994; 74: 301–310. 4. Kerlikowske K, Grady D, Rubin S, Sandrock C, Ernster V. Efficacy of screening mammography. JAMA 1995; 273: 149–154. 5. Hamblin A, Mason E, Ramshaw B. Twenty-year review of a breast cancer screening project. Ninety-five percent survival of patients with non-palpable cancers. Cancer 1996; 77: 104–106. 6. Harris Jr, Lippman M, Veronesi U, Willet W. Breast cancer. N Engl J Med 1992; 327: 319–327. 7. Kopans D. Early breast cancer detection using techniques other than mammography. AJR 1884; 143: 465–468. 8. Khalkhali I, Cutrone JA, Diggles L, Mishkin F. The role of nuclear medicine imaging for the evaluation of patients with breast abnormalities. In: Freeman L, ed. Nuclear medicine annual. Philadelphia: Lippincott-Raven; 1996: 113–142. 9. Kerlikowske K, Grady D, Barclay J, Sicles E, Ernster V. Likelihood ratios for modern screening mammmography. Risk of breast cancer based on age and mammography interpretation. JAMA 1996; 276: 39–43.

10. Kopans D. The positive predictive value of mammography. AJR 1992; 158: 521–526. 11. Khalkhali I, Mena I, Jouanne E, Diggles L, Alle K, Klein S. Tc-99m-sestamibi prone breast imaging in patients (pts) with suspicion of breast cancer (ca). J Nucl Med 1993; 34: 140p. 12. Kao CH, Wang SJ, Liu TJ. The use of technetium-99m methoxyisobutylisonitrile breast scintigraphy to evaluate palpable breast masses. Eur J Nucl Med 1994; 21: 432–436. 13. Khalkhali I, Cutrone J, Mena I, Diggles L, Venegas R, Vargas H, Jackson B, Khalkhali S, Moss J, Klein S. Scintimammography: the complementary role of 99m-Tc-sestamibi prone breast imaging for the diagnosis of breast carcinoma. Radiology 1995; 196: 421–426. 14. Tabuenca O, Quirce R, Gómez-Barquín R, Blanco I, Uriarte I, Vega A, Carril JM. La gammagrafía con MIBI-99m-Tc en el diagnóstico del carcinoma primario de mama en 28 pacientes con criterios mamográficos de malignidad. Rev Esp Med Nucl 1996; 15: 149–153. 15. American College of Radiology. Mammographic data base system (BirdTM). Reston, Va.: American College of Radiology, 1993. 16. Sullivan DC. Needle core biopsy of mammographic lesions. AJR 1994; 17: 1677–1682. 17. Waxman AD. The role of 99m-Tc-methoxyisobutylisonitrile in imaging breast cancer. Semin Nucl Med 1997; 27: 40–54. 18. Carril JM, Gómez-Barquín, Quirce R, Tabuenca O, Uriarte I, Montero A. Contribution of 99mTc-MIBI scintimammography to the diagnosis of non-palpable breast lesions in relation to mammographic probability of malignancy. Anticancer Res 1997; 17: 1677–1682. 19. Villanueva-Meyer J, Leonard M Jr, Briscoe E, Cesani F, Ali S, Rhoden S, Hove M, Cowan D. Mammoscintigraphy with Technetium-99m-sestamibi in suspected breast cancer. J Nucl Med 1996; 37: 926–930. 20. Khalkhali I, Cutrone J, Mena I, Diggles L, Venegas R, Vargas H, Jackson B, Klein S. Technetium-99m sestamibi scintimammography of breast lesions: clinical and pathological followup. J Nucl Med 1995; 36: 1784–1789. 21. Palmedo H, Schomburg A, Grünwald F, Mallman P, Krebs D, Biersack H. Technetium-99m-MIBI scintimammography for suspicious breast lesions. J Nucl Med 1996; 37: 626–630. 22. Tiling R, Sommer H, Pechman M, Moser R, Kress K, Pfluger T, Tatsh K, Hahn K. Comparison of technetium-99m-sestamibi scintimammography with contrast-enhanced MRI for diagnosis of breast lesions. J Nucl Med 1997; 38: 58–62. 23. Burak Z, Argon M, Memis A, Erdem S, Balkan Z, Duman Y, Üstüm E, Erhan Y, Ozkiliç H. Evaluation of palpable breast masses with 99m-Tc-MIBI: a comparative study with mammography and ultrasonography. Nucl Med Commun 1994; 15: 604–612.
