CANCER BIOTHERAPY & RADIOPHARMACEUTICALSVolume 16, Number 2, 2001Mary Ann Liebert, Inc.

The Role of Technetium-99m Methoxyisobutyl isonitrile Scintigraphy in Suspected Recurrent Breast Cancer

Akin Yildiz,1 Melahat GaripagÆ aogÆ lu,2 Firat Güngör,1 Adil Boz,1 and Gamze Dalmaz2

1Department of Nuclear Medicine, Akdeniz University Faculty of Medicine, Antalya, Turkey and2Department of Radiation Oncology, Akdeniz University Faculty of Medicine, Antalya, Turkey

The aim of this study was to determine the role of technetium-99m methoxyisobutyl isonitrile (99mTc-MIBI)scintigraphy in the evaluation of recurrence and metastases in breast cancer patients with mastectomyand/or radiotherapy. A prospective study was designed to assess the accuracy of 99mTc-MIBI scintigra-phy in 36 patients (mean age 49 years) with suspected recurrent breast cancer. The scintigraphic studieswere correlated with radiological findings and/or with histopathology. At 10-15 min after 740MBq 99mTc-MIBI injection, standard planar images were obtained in prone lateral and anterior supine views andthen single-photon emission computed tomography (SPECT) imaging was performed. A whole body imag-ing was also performed to demonstrate distant metastatic lesions. Totally 52 lesions were evaluated which19 of them in 9 patients were malignant, while 33 lesions in 27 patients were benign. The sensitivity was33%, 88% and the specificity was 96%, 93% for planar and SPECT imaging, respectively in loco-regionallesions. Overall, the sensitivity and the specificity of MIBI imaging including whole body were 89%, 81%,in other conventional radiological imaging methods were 95%, 65%, respectively. 99mTc-MIBI scintigra-phy using SPECT imaging may provide useful complementary information in patients with suspected re-currence breast cancer.

Key words: Recurrent breast cancer, technetium-99m methoxyisobutyl isonitrile, single-photon emissioncomputed tomography, scintigraphy.

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INTRODUCTION

The goal of follow-up imaging of breast canceris the early recognition of tumor recurrence.However, there is no reliable diagnostic imagingmethod for detecting loco-regional recurrencesafter mastectomy and/or radiotherapy. Local re-currence of breast cancer, defined as the reap-pearance of cancer in the mastectomy scar, chestwall, or ipsilateral regional lymph nodes, has an

incidence of 5% to 30% according to stage.1,2 Forlocal and regional recurrences, repeated historyand physical examination and mammography arethe only follow-up procedures that need to be per-formed.3 However, any history of symptoms orsuspicious metastases or recurrence detectedupon physical examination should be confirmedby further tests as indicated by the character oftheir medical problem.4 The signs and symptomsof local-regional recurrence of breast cancer of-ten overlap with the side effects of treatment, in-cluding peripheral neuropathy, brachial plexopa-thy, arm pain, postoperative fluid collections,scarring, edema, skin thickening, and calcifi-cations.5,6 Physicians should be alert to thesechanges to avoid unnecessary biopsies. The sen-

Address reprint requests to Dr. Akin Yildiz, Akdeniz Uni-versity Faculty of Medicine, Department of Nuclear Med-icine, 07070, Antalya, Turkey. Telephone: 190 2422274343 ext. 55273 Fax: 190 242 2274490 e-mail : ay-ildiz@med.akdeniz.edu.tr

sitivity of mammography in this populationranges from 55% to 68% in various studies.6-8

Tumor markers have been proposed for follow-up of breast cancer after therapy. However, 30%of patients with a documented recurrence do nothave elevated CA 15-3 levels.9 In patients witha breast cancer recurrence, appropriate stagingfor distant metastases should also be performedbefore definitive therapy.10

A large number of studies have demonstratedhigh diagnostic accuracy of technetium-99mmethoxyisobutyl isonitrile (99mTc-MIBI) for de-tection of breast cancer and axillary metasta-sis.11-14 The reported overall sensitivity andspecificity of these studies are 84%-94% and83%-94%, respectively.11-15 It was also reportedthat 99mTc-MIBI scintigraphy might contributeto the detection of local recurrence or distant me-tastasis. However, there are only a few observa-tions about the use of 99mTc-MIBI scintigraphyin the treated breast.16-20 We aimed to investi-gate the role of 99mTc-MIBI scintigraphy in sus-pected recurrences and distant metastases inbreast cancer patients.

MATERIALS AND METHODS

Patients

The study group consisted of 36 patients (35 fe-male, 1 male; mean age 49 years, range 24-75years) with suspected recurrent breast cancer inthe breast and/or loco-regional tissues and/or dis-tant metastases. Twenty-nine of the patients havehad modified radical mastectomy (MRM), five ofthem have had breast conserving surgery (BCS),one of them has had radical mastectomy, one ofthem who suspected of new lesions has had bi-opsy. All patients had physical examination, lab-oratory, and radiological and scintigraphic eval-uations. All patients had symptoms and/orphysical examination findings in terms of recur-rence. Thirty-one of 36 had local and regionalsymptoms or findings (29 of chest wall mass, 2had axillary mass) 5 had distant symptoms. Themean time interval between the diagnosis ofbreast cancer and scintigraphy was 23 months (1-43 months).

Imaging

Planar and single-photon emission computed to-mography (SPECT) imaging were performed us-ing a dual head gamma camera with a low en-

ergy all-purpose collimator. The planar imagingwas started ten minutes after the injection of 740-925 MBq 99mTc-MIBI. The injection was per-formed on the arm on the opposite site of thetreated breast. The planar study consisted of twolateral breast images and an anterior view with256 3 256 computer matrix for an acquisitiontime of 10 minutes for all views. After planar im-ages were recorded, SPECT was initiated with a64 3 64 matrix, a 1808 rotation, 68 steps and 30sec / frame. All patients underwent 99mTc-MIBIwhole body imaging. Anterior and posteriorwhole body scanning were acquired after planarand SPECT scanning were completed.

All images were visually interpreted by two nu-clear medicine physicians (AY, FG) who wereblinded of clinical findings. In the visual evalu-ation of scans, all focal or multifocal uptake of99mTc-MIBI higher than the background was con-sidered as positive.

RESULTS

All data were analyzed by lesion-based manner.We established the final diagnosis of 52 lesionsin 36 patients. Final diagnosis was achieved bybiopsy in 7 of 52; by clinical and radiological fol-low up at least one year in 29 of 52 lesions.

Thirty-six of 52 lesions were localized in loco-regional, 16 of 52 were in distant sites. Of the36 loco-regional lesions, 9 were malignant, 27were benign. Of the 16 distant lesions, 10 weremalignant, 6 were benign. All scintigraphicfindings by lesion localization are shown inTable 1.

Overall sensitivity in the detection of loco-re-gional malignancy was 33% for planar imagingand 88% for SPECT, the overall specificity was96% and 93%, respectively. Planar and SPECTfindings in loco-regional lesions are summarizedin Table 2. All other imaging methods used for confirmation including mammography, CT,MRI, and bone scanning had 95% of sensitivity,65% of specificity. Overall statistical data aresummarized in Table 3.

Diffuse increased uptake over the operated sideof the thorax wall was identified in 15 patients(Figure 1, c). This finding was regarded as post-treatment changes. There was statistically signif-icant difference between diffuse increased up-take over the treated thoracic wall (1.64 6 0.48,mean 6 SD) and malignant lesions (2.50 6 0.91)(p 5 0.041).

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Planar and SPECT Imaging

True positives

MIBI imaging identified eight of 9 loco-regionalmalignant lesions. Two of 8 were demonstratedby planar imaging, 7 of 8 were demonstrated bySPECT. SPECT scanning showed focally and in-tensely increased uptake in the sternum in twopatients that regarded as pathological uptake andconfirmed by CT. One of these sternum metas-tases was also identified by planar imaging.SPECT of chest revealed metastatic lesions in thelung in 2 patients and mediastinal metastases in4 patients. One 1.5 cm sized recurrent lesion overthe thorax wall was only revealed by SPECT thatwas confirmed by biopsy (Figure 1). All other

imaging studies including mammography, CTand sonography were negative in this patient. Fig-ure 2 shows multiple skin lesions as well as leftaxillary lesion which is not visualized in planarimaging.

True negatives99mTc-MIBI scintigraphy was truly negative in24 patients who have been suspected for focal re-current lesions in the thorax wall.

False positives

False positive uptake of MIBI was observed in 6lesions. Two of 6 were loco-regional; the otherswere in distant localization. 99mTc-MIBI accu-

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Table 1. Scintigraphic findings by lesion localization

NumberLocalization of lesions TP TN FP FN

Loco-regionallesions

Local 28 3 24 1 2Contralateral breast 2 1 1 2 2Skin 1 1 2 2 2Axillary 4 1 1 1 1Supraclaviculary 1 2 1 2 2Distant lesionsMediastinal 4 4 2 2 2Lung 4 2 2 1 1Bone 8 5 2 3 2Total 16 11 2 4 1OverallMIBI

imaging 52 17 27 6 2

TP: True positive; TN: True negative; FP: False positive; FN: False negative.

Table 2. Planar and SPECT findings in loco-regional lesions

Numberof lesions TP TN FP FN

Planar and SPECTimaging

Planar 36 2 28 1 5SPECT 36 6 27 2 1Total 36 6 27 2 1

TP: True positive; TN: True negative; FP: False positive; FN: False negative.

mulated in postoperative scar tissue that wasproved histopathologically in one patient. Mam-mography also identified suspiciously positivefindings in this patient. 99mTc-MIBI scintigraphyevaluated as false positive in the axillary regionin the operated side in another patient. The lo-calization of the other 4 false positive uptakewere radiation-induced lung fibrosis in 1 case and

bone in 3 cases (one was anterior costal uptake,the other two were vertebral uptake).

False negatives

Axillary lymphadenopathy in one patient (1 cmsized) and multiple lung metastases with lowerthan 1 cm sized in other patients were not ableto be shown by 99mTc-MIBI scintigraphy.

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Table 3. The statistical data of MIBI imaging and conventional imaging findings

Sensitivity Specificity PPV NPV

Loco-regional lesionsTc99m-MIBI Planar 33% 96% 75% 82%Tc99m-MIBI SPECT 88% 93% 80% 96%OIM 88% 62% 42% 94%OverallMIBI imaging 89% 81% 73% 93%OIM 95% 65% 63% 95%

PPV: Positive predictive value; NPV: Negative predictive value; OIM: Other imaging methods

Figure 1. a. Transaxial (upper), sagittal (middle) and coronal (lower) SPECT slices show focal increased activity, confirmedby biopsy, on the medial side of the right thorax wall. b. Increased density in the corresponding region on the CT slices wasconsidered as post-treatment changes. c. Anterior (left image), right lateral (middle image), left lateral (right image) planar im-ages were regarded as normal. Diffuse asymmetric increased uptake on the right side of the thorax wall and diffuse bone mar-row uptake in the sternum are seen.

ab

c

Whole Body Imaging99mTc-MIBI whole body scan showed accumula-tion in three of five distant metastases. Thesemetastases were one in anterior region of the il-iac bone, one in vertebral, one in femoral local-ization. Whole body MIBI imaging did not iden-tify other two bone metastases that localized atvertebra and proximal humerus.

There was diffuse faint uptake in the sternumas well as vertebral colon in seven of 36 (noneof them was in the malign group) in our patientsconsidered as normal uptake in the bone marrowof 99mTc-MIBI.

DISCUSSION

In this study, it was found that 99mTc-MIBIscintigraphy was useful for differentiation be-tween loco-regional recurrences and post-treat-ment changes. The overall sensitivity of 99mTc-MIBI scintigraphy for the detection of recurrentand metastatic breast cancer was 89% and thespecificity was 81% in our study. When we onlyconsider planar and SPECT imaging for demon-stration of loco-regional recurrence, the sensitiv-ity is 33%, 88%, the specificity is 96%, 93%, re-spectively.

Some other studies performed in a relativelylimited number of patients have shown that MIBIimaging can be used to detect recurrent or meta-

static disease.16-20 MIBI imaging was also pro-posed as cost effective method and recommendedas first investigation of possible breast cancer re-currence.20 However, in one study, the accuracyof 99Tcm-MIBI scintigraphy within the treatedbreast (85%) was found similar to X-ray mam-mography (82%).16

In our study, it was also revealed that SPECTincreased the sensitivity in the demonstration ofloco-regional recurrences. It is not surprising thatplanar imaging had low sensitivity in the detec-tion of recurrence particularly on the thorax wallthat muscular uptake and/or superimposition ofthe heart might adversely effect the detection.However, sensitivity was increased, but at thecost of lower specificity by using SPECT. Thehigher rate of false positive findings at SPECTcompared with planar imaging might be ex-plained by improved spatial resolution. More-over, SPECT identified malignant lesions in themediastinal area and in the lung in our eight pa-tients. One metastatic lesion in the sternum wasalso shown only by SPECT. Palmedo et al. alsoreported that bone and pulmonary metastases ofbreast cancer in post-operative patients wereshown by SPECT.21

There are only a few reports focusing on theuse of SPECT in the detection of breast abnor-malities. Some authors concluded that, althoughsome improvement in lesion detection was no-ticed, SPECT did not provide significant im-provement in breast lesion detection.21,22 Theirpossible explanation for the less diagnostic ac-curacy of SPECT was adverse effect of recon-struction artifacts from high activity organ suchas heart. Another explanation was that breasts inplanar imaging are closer than SPECT to the de-tector.

Some other authors reported that the diagnos-tic accuracy of scintigraphy was improved by us-ing SPECT, particularly in detecting axillarylymph node involvement.23,24 Tiling et al. haveproposed that SPECT imaging contributes infor-mation for localizing and determining the extentof tumors if planar imaging is positive.25 Disad-vantage of SPECT versus planar scintigraphy isthe additional time required. Although it is notgenerally available and requires sophisticatedcomputer and software, SPECT with iterative al-gorithms could be more useful.25

In the current study, it was noticed that diffuseincreased uptake over the treated side of thoraxwas found in 15 of 36 (41%) patients. There wasa statistically significant difference between up-

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Figure 2. Transaxial MIBI SPECT slices show multiplerecurrent skin lesions on the left thorax wall and axillarymetastases on the left axillary region.

take of malignant lesions and uptake of thesechanges in this study. These findings might beresult from postoperative changes and/or modifi-cation of attenuation after surgery.

We observed six false positives that occurredin operation scar, radiation-induced pulmonaryfibrosis, axillary region, and bone. Marked in-creased metabolic activity in and around the op-eration scar could be the explanation of uptake inscar and fibrosis. Deformation of muscles aftertreatment and physiological bone marrow uptakecould be the reasons of false positives for axil-lary region and bone. The positive tracer uptakein mastopathy, sclerosing adenosis, and areas ofrecent breast biopsy, fibrocystic disease, infec-tions, and abscesses has been reported in a largenumber of studies.11-14

There were false negative findings in 2 lesions,which one was in the axillary region (1 cm), an-other one was located in the lung (lower than 1cm). Limited spatial resolution of scintigraphymight be a possible explanation for these falsenegative cases. However, the lack of uptake ofMIBI may not depend on technical factor andspatial resolution. Pathophysiology of the tumormight play an important role in tracer uptake suchas p-glycoprotein expression, desmoplastic ac-tivity, mitochondrial density, and blood flow.26

Although we included only four patients withaxillary metastases, we did not find planar orSPECT imaging as reliable method to show them.Planar imaging did not reveal any of the 3 axil-lary metastases, but SPECT showed positivefindings in 2 axillary regions, which one was falsepositive. Various sensitivity values were reportedacross studies (44%-91%) in the detection of ax-illary metastases.19,24,27 Yutani et al. also re-ported that neither FDG-PET nor MIBI-SPECTwas sufficiently sensitive to rule out axillarylymph node metastasis.28 Inherent low resolutionof scintigraphy for detection of small volume oflymph nodes could be the reason. Furthermore,there is considerably more background tracer up-take from neighboring structures in the axillaryregion than in the normal breast, making it moredifficult to identify small foci of abnormal MIBIuptake. Although, it could not be a disadvantagebecause the information from axillary imaging isconcomitantly obtained from a standard MIBIscintigraphy.

Although whole body MIBI imaging has beenfound as effective imaging modality for wholebody screening of metastatic disease in somestudies such as differentiated thyroid cancer and

malignant melanoma, it has not been used for thedetection of metastases of breast cancer.29,30 Ac-cording to our limited data, whole body MIBIscan identified some of distant bone metastases(3 of 5). Further data are needed to confirm thisresult. Moreover, diffuse faint uptake of the MIBIin the bone in 7 (19%) of our patients was ob-served. Similar findings were reported in somestudies and considered as physiological up-take.29,31 Jonsson et al. reported that diffuse weakskeletal MIBI accumulation was seen in 46%-48% of their heterogeneous group of patients.They suggested that this finding was normal andaccumulation was in red bone marrow that wasconfirmed with experiments on mice.32 It wassuggested that false positive heterogeneous up-take in costal and vertebral areas in three of ourpatients could be due to heterogeneous red mar-row distribution. In two sternum metastases, onewas revealed by planar and SPECT, the other onewas showed by only SPECT.

In conclusion, we suggested that MIBI imag-ing could be particularly useful in differentiationbetween local scar tissue and recurrence withhigher specificity and positive predictive value.SPECT is more sensitive than planar imaging inthese patients. Furthermore, SPECT can confirmor identify intrathoracic metastases and / or bonemetastases over the chest. Although whole bodyMIBI imaging might result in false positive find-ings, it can be used for confirmation of compli-cated lesions in other imaging methods. These re-sults encourage further assessment of MIBIimaging in recurrent suspected breast cancer.

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