As a result of the limitations inherent in mammographic diagnosis of breast cancer, researchers have begun to explore the possibilities that radiopharmaceuticals offer in breast examination. This report focuses on the role of Tc-99m-sestamibi as a complementary technique in the evaluation of suspected breast abnormalities.
Breast cancer is the most common invasive malignancy in women in
the United States and is the second most common cause of cancer
death in women. The lifetime risk of a woman developing breast
cancer has been estimated at one in eight.1
Early detection of breast cancer is considered the best means of
reducing mortality from the disease. Mammography and physical
examination are the mainstays of breast cancer detection. However,
the mammographic diagnosis of breast cancer is imperfect.
In U.S. trials, mammography has had a positive predictive value
for the detection of breast cancer on the order of 20 to 30%. The
majority of biopsies, therefore, are unnecessary.2 One of the major
reasons for the low positive predictive value of mammography is its
difficulty in lesion detection in densely fibroglandular breasts.
Approximately 25% of women have dense breasts.3
Recently, additional imaging techniques such as
scintimammography have been investigated for their role in the
detection of breast cancer. The first report of a
radiopharmaceutical concentrating in breast cancer was in 1946,
when the beta-emitter phosphorus-32 was demonstrated to concentrate
in an ulcerating carcinoma of the breast.4 Since that report,
various agents have been investigated including thallium-201,
technetium-99m MIBI, technetium-99m methylene diphosphonates,
technetium-99m tetofosmin, indium-labeled somatostatin analogs, and
monoclonal antibodies. Of these, the most widely investigated
radiopharmaceutical is Tc sestamibi. This report focuses on the
role of Tc-99m-sestamibi (MIBI) as a complementary technique in the
evaluation of suspected breast abnormalities.
Tc-99m-sestamibi is widely available as a myocardial blood flow
imaging agent. Labeling with Tc-99m affords low cost, favorable
energy emission characteristics, and accessibility.
The exact mechanism by which MIBI is taken up by tumors is under
investigation. A cationic lipophilic agent, sestamibi is
transferred across the cell membrane and taken up by mitochondria.
In their investigation, Piwnica-Worms et al demonstrated that the
cellular uptake of sestamibi closely follows the mitochondrial
transmembrane electrical potential in tissue culture cells.5 It
also has been found that nearly 90% of cellular activity is
concentrated in the mitochondria.6,7 Electron probe x-ray
microanalysis has determined that the mitochondrial inner matrix is
the intracellular target for sestamibi.8
The first report of Tc-99m-sestamibi in tumor imaging was in
1987, by Muller et al;9 uptake in breast cancer was first reported
in 1992.10,11 In 1993, abstracts described prospective studies in
which MIBI accumulated in breast cancers.12,13
The first published series of breast cancer detection using MIBI
was in 1994, by Kao et al. Thirty-eight patients with palpable
lesions (32 cancers and 6 benign masses) were studied; sensitivity
was found to be 84%, specificity was 100%. The smallest cancer
detected was 2 ¥ 1 ¥ l cm. In this study, lateral images were
acquired with the lateral side of the breast positioned against the
table, with inclusion of the chest and abdomen in the field of
In 1992, Khalkhali et al described prone-dependent breast
imaging in which patients were imaged prone using a plastic table
overlay which allowed the breast to be freely dependent from the
table (figure 1). Use of an acquisition zoom factor of two provided
for exclusion of most of the activity from the chest and abdomen.
Anterior images also were acquired with the patient's arms raised
(for visualization of the axillae).15
In 1995, Khalkhali et al used Tc-99m-sestamibi scintimammography
prone breast imaging in a series of 147 women with 153 lesions (of
which 113 were palpable and 40 were non-palpable) that were
detected mammographically. In this series, 51 carcinomas were
detected. The sensitivity of scintimammography in this population
was 92%; the specificity was 89%. The false-negative results
consisted of three palpable infiltrating ductal carcinomas that
measured approximately 5, 8, and 8 mm, respectively, and one
non-palpable cluster of microcalcifications not associated with a
mass which contained a microscopic focus of infiltrating ductal
In their series of 65 patients, including 44 palpable and 21
non-palpable lesions, Taillefer et al achieved a sensitivity of 84%
and a specificity of 92%. The high sensitivity in this study may be
partially related to a high incidence of breast cancer in the study
population (47 cancers, 18 benign lesions). Of the patients with
false negative determinations, one had a cluster of calcifications
seen by mammography and three had small infiltrating ductal
carcinomas, all of less than 8 mm in diameter. The single false
positive in their study was found to be fibrocystic disease.17
A greater sensitivity for MIBI in detection of palpable vs
non-palpable cancers has been confirmed by multiple studies.18-20
Palmedo et al found 100% sensitivity for tumors of greater than 1.5
cm and 75% sensitivity for tumor size 1.0 to l.5 cm; no cancers
0.9 cm were detected by MIBI in this study. Scopinaro correlated
lesion size with MIBI detectability in 85 patients with
mammographic results of suspected or highly suspected breast
cancer. Of the 91 lesions, 52 were cancerous and 29 were benign.
The sensitivity of Tc-99m-sestamibi was found to be 97% in lesions
larger than 1 cm and 50% in lesions smaller than 1 cm.
Maffioli et al investigated scintimammography with MIBI in
non-palpable breast cancers which were detected by mammography. In
this series, the majority of lesions consisted of only clustered
calcifications without associated opacity. Sensitivity in this
study was only 50%. MIBI was positive in clustered calcifications
of greater than 20 mm in five of seven cases, but in only two of
seven cases in which the clustered calcifications measured less
than 20 mm.21
The DuPont Merck Pharmaceutical Company in the U.S. recently
conducted two multicenter clinical trials at 42 institutions in the
U.S. and Canada. These two prospective trial studies enrolled 673
patients; one study included 286 patients with palpable
abnormalities and the other included 387 patients with
non-palpable, mammographically detected abnormalities. For palpable
lesions, a sensitivity of 95% and a specificity of 74% were
obtained, whereas for non-palpable lesions, a sensitivity of 72%
and specificity of 86% were obtained.22
False positive diagnoses with MIBI have included fibroadenomas,
fibrocystic disease, and inflammation. Lam et al noted that of the
three fibroadenomas with MIBI uptake, two were in women under age
25.23 The role of patient age in MIBI uptake of breast lesions
requires further investigation.
Khalkhali et al reported that of their nine false positives, all
contained areas of moderate-marked epithelial hyperplasia, compared
with less than 27% of the true negatives. In this series, all
patients with fibroadenomas were true negatives, including four
whose fibroadenomas contained areas of epithelial
Buscombe et al investigated the relationship of Tc-99m MIBI to
tumor type. In 53 tumors, target to background (TBR) ratios were
obtained, drawing regions of interest around the tumor and
surrounding normal breast tissue. Ductal carcinoma demonstrated
significantly higher TBR than did the non-ductal carcinomas. The
TBR of non-ductal carcinomas was comparable to the uptake seen in
benign disease, such as fibroadenomas and phyllodes tumor.
Histological grade of ductal carcinoma had no effect on Tc-99m MIBI
Angiogenesis also has been suggested as a factor in MIBI
accumulation. In a series of 19 patients with breast cancer,
Scopinaro et al found MIBI uptake in all primary tumors which were
node positive and lack of uptake in node negative tumors. The MIBI
positive and node positive tumors demonstrated significantly higher
microvessel density than the MIBI negative tumors.25
The use of Tc-99m-sestamibi for the staging of breast
Axillary lymph node status is considered the most important
prognostic variable in the staging of breast cancer. Traditional
management of breast cancer includes axillary lymph node dissection
in order to assess nodal status. Unfortunately, a significant
of patients experience morbidity as a result of this procedure
(e.g., short-term complications of wound infection and seroma) and
a small percent develop long-term upper extremity lymphedema. A
noninvasive procedure which could accurately evaluate lymph node
metastases would be highly desirable.
The ability of Tc-99m MIBI scintigraphy to detect axillary node
metastasis has been investigated. In a series of 31 patients with
untreated breast cancer, Tolmos et al imaged the axillae by means
of anterior planar imaging with the arms elevated. Twenty axillary
nodes were removed; they were considered positive if any metastatic
tumor was detected. Of the 20 node-positive patients, 15 were
detected by Tc-99m-sestamibi imaging (sensitivity 75%). There were
two false positives by SMM (specificity 82%).26
Taillefer et al evaluated the usefulness of Tc-99m-sestamibi in
the detection of axillary node involvement in breast cancer
patients who underwent axillary node dissection. Metastatic
axillary node involvement was seen in 19 of the 41 patients in
their study, of which SSM detected 16 (sensitivity 84.2%). The two
false positives consisted of sarcoidosic lymphadenitis and
nonspecific chronic inflammation (specificity 90.9%).17
Lam et al compared Tc-MIBI mammoscintigraphy, ultrasound, and
conventional axillary view mammography in the detection of axillary
lymph node breast metastasis. Of the 31 patients with breast cancer
who underwent axillary node dissection, 11 were node-positive and
20 were node-negative. Only 7 of the 11 node-positive lesions were
correctly identified with Tc-99m-sestamibi (sensitivity 68%).
Similar sensitivity and specificity were obtained with ultrasound
using a high frequency transducer. Two false positives obtained
with MIBI consisted of a synchronous carcinoma in the axillary tail
of the breast, which was misinterpreted as axillary adenopathy, and
histologically-proven reactive hyperplasia. Of the four patients
with false-negative results, three had either one or two lymph
nodes involved. Conventional axillary view mammography yielded very
Given the relatively low sensitivity of Tc-99m-sestamibi in the
detection of axillary node metastasis, the adequacy of this agent
for staging of breast carcinoma has not been established at this
Possible future clinical uses of Tc-99m-sestamibi breast
In the future, the major contribution of SMM may be the ability
to further evaluate the "difficult to interpret" mammogram.
Approximately 25% of women exhibit dense breasts on mammography.3
Recently, Khalkhali et al studied 48 women with palpable
abnormalities who had grades III and IV dense breasts according to
the American College of Radiology classification. The sensitivity
and specificity of mammography for these women were 82.2% and
46.1%, respectively, whereas the sensitivity and specificity for
SMM in this group were 93.7% and 90.6%, respectively.28 Although
further investigation is needed, this report suggests that SMM may
play an important complementary role in the detection of breast
cancer in patients with dense breasts.
The effect of breast density on the diagnostic accuracy of
Tc-99m-sestamibi breast imaging also was studied during the two
multicenter trials sponsored by the DuPont Merck Pharmaceutical
Company. These studies demonstrated comparable sensitivity and
specificity of SMM for women with fatty breasts versus those with
highly dense breasts.28
SMM also may play a complementary role in the evaluation of
women with "lumpy" breasts on physical examination, who often have
to undergo multiple mammographic studies and biopsy procedures. A
single negative scintimammogram in this group can provide
reassurance about the absence of breast carcinoma. Additionally,
SMM may have value in the evaluation of an "asymmetrical density"
seen on mammography.
Another possible indication of this technique is in evaluation
of patients with possible multifocal and/or multicentric breast
carcinoma. Mammography often is unable to identify the presence of
multicentric carcinoma. Further investigation is necessary to
support this indication.
MIBI/prediction of response to chemotherapy
Recent studies have evaluated whether MIBI uptake is predictive
of therapeutic response to chemotherapy in patients with locally
advanced breast carcinoma. In a trial of 14 patients, Mankoff
reported that all but one clinical responder showed a decrease in
MIBI uptake from baseline to 2 months post-chemotherapy. The
non-responders all showed no change or an increase in MIBI
Ciarmiello et al examined efflux rates of MIBI calculated from
time-activity curves in patients who received 4'-epidoxorubicin. A
rapid tumor clearance of MIBI was found in six of eight
non-responding patients (75%), and only one of eight patients (12%)
who did respond to chemotherapy.30
In a series of 29 patients with locally advanced breast cancer,
the accuracy of serial MIBI scintigraphy, clinical evaluation, and
mammography were compared in the assessment of tumor response to
neoadjuvant chemotherapy. Surgery was performed 15 days after the
third cycle of chemotherapy, with response classified as positive
if the tumor was replaced by fibrosis or if only a few cells
remained and as negative if viable invasive carcinoma persisted in
more than 25% of the mass. Sensitivities for residual disease were
as follows: scintimammography 65%, clinical evaluation 35%, and
mammography 69%; specificities were: scintimammography 100%,
clinical evaluation 67%, and mammography 33%. The authors concluded
that although MIBI scintigraphy and mammography were equivalent in
sensitivity, the improved specificity of MlBI scintigraphy rendered
it the method of choice.31
Cwikla et al32 reported that of seven cases of breast cancer in
their study, the three lesions which were judged positive on MIBI
after chemotherapy all demonstrated residual tumor on histologic
examination. In two patients, tumor size increased following
chemotherapy; one of these was reported as negative on SMM.
Tumor-to-background ratio was assessed before and after therapy,
finding a universal reduction after therapy even in patients whose
cancer enlarged. The authors conclude that reduced uptake of MIBI
after chemotherapy may be a non-specific change.
The cause of these discrepant results in unclear. Possible
factors include the type of chemotherapy or duration of therapy, or
the strictness of the criteria applied in judging tumor response on
In conclusion, Tc-99m-sestamibi is the only radiopharmaceutical
approved by the FDA for use in breast imaging. Although this agent
is not sufficiently sensitive to serve as a screening agent, it may
play a useful role in the evaluation of women with difficult breast
exams (i.e., "lumpy" breasts). Tc-99m-sestamibi also shows promise
as an adjunctive imaging agent for the mammographically dense
breast. Development of new nuclear medicine camera detectors is
likely to improve the abil-ity of scintimammography in the
detection and characterization of smaller tumors. AR
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Dr. Rice, Dr. Khalkhali and Ms. Diggles are in the Department of
Radiology at Harbor-UCLA Medical Center in