The role of nuclear medicine techniques in the evaluation of breast cancer is currently being investigated. In this article, scintimammographic techniques using Tc-99m-MIBI and Tc-99m-MDP are described in detail, and their role in evaluating patients with equivocal mammographic findings is discussed, including their potential to increase the yield of positive biopsies by improving the predictive values, thus reducing management costs. Additionally, lymphoscintigraphy based on the sentinel node concept is presented here as a means of assessment of axillary lymph nodes. Mention is also made of other radiotracers that are available in larger centers, and other adjunctive nuclear medicine techniques that may be of value in the management of breast cancer.

Breast cancer is a common disease that poses many challenges for patients as well as doctors. As a result of its increasing incidence (which may in fact be due to earlier detection of existing disease1), many modalities have been employed to answer clinically relevant issues of evaluation and treatment. This article describes the role that nuclear medicine techniques, in particular scintimammography, can play in certain situations involving breast cancer, with an aim of helping the reader recognize such situations and employ the relevant imaging procedure.

Detection of primary disease

The importance of early detection and staging of breast cancer lies in their impact on survival. The 5-year survival rate is 98% for patients with minimal disease at the time of diagnosis, but only 10% for those with distant metastases. The potential role of mammography was recognized over four decades ago,2 and today it remains the modality of choice for screening due to the good resolution and high sensitivity offered.3 However, a low positive predictive value is a contributor in the low (25%) yield of biopsies, which raises the economic impact of the disease.4 Unfortunately, other anatomic modalities such as ultrasound, CT, and MRI have failed to demonstrate an advantage over

mammography.5

Instead of relying on the structural characteristics of the disease, nuclear medicine exploits the functional differences of lesions from normal tissue to aid in detection. Although a wide variety of radiotracers have been employed for this purpose, this article will concentrate on the following major classes: MIBI, MDP, and antibodies.

MIBI

The role of Tc-99m-MIBI (methoxyisobutylisonitrile) in the detection of breast cancer follows the precedent of myocardial perfusion imaging. Initially, the accumulation of T1-201 was noticed in a wide variety of tumors,6 and was then established in breast cancer.7 This was followed by the use of MIBI in detecting malignant tumors,8 and then, finally, for breast cancer, due to the recognition of potential improvements it could offer over mammography. In one series of 100 patients, the positive predictive value of MIBI imaging was found to be 77% (compared to 15 to 30% for mammography), and it demonstrated a negative predictive value of 97%.9 This improvement has subsequently been confirmed by several groups, including one series of 140 patients that demonstrated a sensitivity of 92% and specificity of 43% for mammography compared to 84% and 85%, respectively, for Tc-99m-MIBI imaging.10

Technique -In order to get the desired results, meticulous attention to detail is essential. To start the procedure, 740 MBq (20 mCi) of Tc-99m-MIBI is injected intravenously in the arm contralateral to the breast with the lesion. If bilateral breast lesions are to be evaluated, injection in the foot should be considered. The patient is positioned prone, 15 minutes after injection, on a special couch and/or cushion with removable breast cutouts to enable the side being imaged to hang freely while the opposite one is compressed. Alternatively, a lead shield can be placed between the breasts to reduce the cross-talk signal. A large field-of-view gamma camera with a rectangular detector and a high resolution or general purpose collimator is set up with a 140 KeV (± 20%) window. At least 3 million counts are acquired in a 256¥256 matrix. An optional 15 to 35 degree posterolateral oblique view is then acquired. Both of these images are repeated for the opposite breast. A supine anterior view is also advisable. The arms are raised above the head for all views.

Criteria -A well-defined focal area of uptake is regarded as abnormal. Diffuse uptake or symmetrical heterogeneities are regarded as normal (figure 1 A,B,C).

The accuracy of MIBI scintimammography has been described above, but it is also important to bear in mind the causes for the small number of false positive and false negative studies. False positives can be caused by fibrocystic disease and fibroadenomata, as well as focal inflammation such as mastitis and abscesses. It is interesting to note that some patients with false-positive diagnoses may have findings of epithelial hyperplasia, cellular atypia, or sclerosing adenosis, all of which have a two- to five-fold increase in the risk for subsequently developing a carcinoma. False negatives can be due to infiltrating carcinoma (ductal, intraductal, tubular or lobular), particularly if these are smaller than 1 cm in size. Location of the abnormality may also have a bearing, depending on body habitus, with upper, outer lesions being somewhat less likely to be detected.

The evolving consensus seems to be that mammography continues to be the modality of choice for screening asymptomatic women for breast cancer, particularly those over 40 years of age. However, scintimammography with Tc-99m-MIBI is a complementary technique that offers increased specificity.

Additionally, Tc-99m-MIBI is currently of particular value in patients with dense breasts, with architectural distortions from prior biopsy, surgery or radiation therapy, with palpable lesions, and those with indeterminate findings on mammography. This role can, and should, be exploited to reduce the number of unnecessary biopsies, thereby helping to reduce the cost of managing breast cancer. However, its role in the screening process needs to be evaluated further.

MDP

The use of Tc-99m-MDP (methylene diphosphonate) is widespread for the evaluation of skeletal abnormalities. Following early observations of its accumulation in breast cancer,11 its use has received renewed attention as a possible agent for evaluating breast cancer. Various hypotheses have been sought to explain this soft-tissue accumulation, and some have been supported by evidence such as increased vascularization, inflammatory changes, local abnormalities in Ca++, and collagen deposition.12 However, no specific binding of MDP to neoplastic cells has been demonstrated, and nonspecific phenomena are thought to determine uptake and discharge of MDP in breast cancer.

While having an established role in staging of breast cancer by the assessment of skeletal metastases, recent studies have sought to evaluate the role Tc-99m-MDP can play in the evaluation of soft-tissue disease. As many as 92% of primary breast cancers found in an initial study of 200 women were shown to have early MDP uptake, with mean tumor-to-background ratios of 3.8.13 This work has been consolidated further with the demonstration of an overall sensitivity of 92%, specificity of 90%, and accuracy of 91% in a study of over 2000 patients.14 Major advantages were observed in the patients with calcifications without a mass, and in those with indirect mammographic signs, such as distortion and asymmetry.

Technique- A dosage of 740 MBq (20 mCi) of Tc-99m-MDP is injected in the arm contralateral to the affected breast, with the patient seated upright in front of a large field-of-view gamma camera interfaced with a computer. A general purpose parallel hole collimator, a 140 KeV (± 20%) energy window, and a 128 ¥ 128 matrix are used to acquire early dynamic images over 9 minutes (60 ¥ 1 sec frames, 6 ¥ 10 second frames, and 4 ¥ 30 second frames). These are followed by planar views in the anterior and lateral oblique at 10 to 20 and 40 to 60 minutes and at 2 to 3 hours post-injection. This protocol can be modified to exclude the initial dynamic acquisition and start with just the planar views at 10 to 20 minutes, as this time frame has been shown to offer maximal tumor-to-background ratios,13 or to image the patient prone, as described above for MIBI. Of course, a routine bone scan is possible in addition to these images.

Manually drawn regions-of-interest (while avoiding the bony structures seen in the later images) are drawn over foci of increased uptake that may be observed and compared to similar regions that are drawn over corresponding parts of the normal breast.

Criteria -The pattern of MDP uptake is not constant over time, showing substantial early uptake for up to 10 to 20 minutes, followed by a slow decline in accumulation out to 2 to 3 hours. Circumscribed foci are regarded as abnormal, particularly if activity is seen to infiltrate the overlying skin (figure 2 A,B).

The majority of breast lesions are seen in the earlier images. Size (particularly if less than 1 cm), and site (particularly in a peripheral location in the inner quadrants) of the lesions seem to affect detectability and can cause false negative results. It is interesting to note that MIBI, with its higher uptake in the pectoral muscles, is at a disadvantage in the outer quadrants, whereas MDP has a disadvantage in the inner quadrants, closer to the sternum. False positives may be caused by inflammatory processes, but uptake in skin can be a sign of infiltration by the malignancy.

The advantage offered by MDP imaging is the high positive predictive value, as the negative predictive value is affected by tumor sizes below 1 cm. However, there is less widespread experience with this than with MIBI. If fully realized, this test may offer advantages over MIBI, including a much lower cost.

Antibodies

The use of radiolabeled antibodies for the detection of breast cancer was first described nearly two decades ago,15 and subsequently has been tried with a wide variety of antibodies based on different types of antigens associated with the disease. However, the main problem has been a low sensitivity that is not offset by its high specificity. When using a particular antibody, it cannot be predicted whether the given tumor expresses the antigen, and this lack of expression is the major cause of negative findings on radioimmunoscintig-raphy.16 The use of this technique has been more successful in the evaluation of lymph node involvement, as described below. Cost, availability, and the high level of experience required continue to limit the use of these promising agents to a few centers.

The remaining radiotracers can be divided into (i) receptor imaging agents, such as estrogen and progestin compounds labeled with I-123 or F-18, and (ii) metabolic markers such as F-18-DG (glycolysis), C-11-methionine (protein synthesis), and F-18-fluorouracil (pyrimidine synthesis). The use of these agents, however, remains limited to major centers, under experimental protocols only.

Assessment of extent

Several strategies have focused on the important issue of involvement of axillary lymph nodes, with 85% survival at 5 years without involved nodes, compared to 55% survival with involvement, coupled to the fact that clinical assessments based on size and palpability are not reliable. Success of MIBI for imaging the primary tumor has raised hopes that it may be well suited to lymph nodes as well, but muscular uptake in the axilla can cause problems. Some initial studies using monoclonal antibodies reported a sensitivity (with BCD-F9) and specificity (with 3C6F9) as high as 93% for assessment of axillary lymph node status.17,18 Other groups, using SPECT imaging19 or a statistical change detection algorithm20 and achieving sensitivities as high as 90%, have developed this approach further.

A more widely available alternative approach relies on the sentinel node concept. Provided that there are no skip metastases, the first level lymph node(s) can be evaluated after injecting Tc-99m sulphur colloid and using a gamma probe intraoperatively to aid localization. Success rates approach 95%.21

Technique -A dose of 37 MBq (1 mCi) of Tc-99m-sulphur colloid is injected around the primary lesion. A large field-of-view gamma camera interfaced with a computer, set up with a general purpose parallel hole collimator, a 140 KeV (± 20%) energy window, and a 128 ¥ 128 matrix is used to acquire planar images of the axilla in the anterior and lateral (or lateral oblique) projections over a course of 30 minutes. Breast massage can be performed to aid transit of the radiotracer. The first lymph node to be visualized is marked on the skin in two projections.

The patient is then prepared for surgery, and a gamma probe is used to aid the surgeon in selecting the site of incision over the previously marked node. This is helpful, as the position of the arm may not be the same as when the skin was marked. Following identification and excision of this node, the bed is probed again to confirm that there is no residual nodal material. Once removed, the sample is counted and marked again to aid the histopathologist.

Conclusion

The main aspects of scintimammography have been briefly discussed above. However, the role of nuclear medicine techniques extends to patients with suspected recurrences or metastatic cancer. This evaluation depends on the site of concern, and may involve either MIBI or MDP imaging as described above, or a conventional bone scan for skeletal disease. While other modalities remain dominant in early management, the use of Sr-89, Sm-153, or Re-186 is effective therapy for palliation of bone pain in the terminal stages of the disease. AR

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Dr. Chengazi is a research fellow in the Division of Nuclear Medicine at Strong Memorial Hospital in Rochester, NY.

Dr. O'Mara is Chief of the Division of Nuclear Medicine at Strong Memorial Hospital; he is also a member of the editorial advisory board of this journal.