INTRODUCTION:

In recent years nuclear oncology has played a significant role to the study and management of patients with malignant diseases. Newly acquired information has lead to better diagnostic and therapeutic uses of nuclear medicine, has had the greater availability of radiopharmaceuticals with unique features to detect a variety of cancers. Many advances in nuclear medicine evolved from efforts to improve the management of a particular type of tumor-related problem. Anatomical imaging such as CT and MRI, when was not yet fully developed, neurosurgeons and many other specialists looked for help in defining the extent of certain cancers by nuclear medicine imaging techniques. It was soon appreciated, the in the case of brain tumor for example, that a radiolabeled dye and hand-held probe might provide a more sensitive method to estimate the extent of tumor involvement.

IMPACT OF NUCLEAR MEDICINE IN PATIENTS WITH BREAST CARCINOMA

Mammographic evaluation of the breast is the only imaging technique for detection of breast cancer. Mammography however as a "diagnostic" test is still in question. With the exception of some classic lesions, namely calcified fibroadenomas, lypomas, some forms of fat necrosis, and spiculated carcinomas-mammography is not "diagnostic" and therefore, cannot be used alone to reliably differentiate between benign and malignant lesions.

In the past decade several complimentary techniques have been developed to help the radiologists and their patients to characterize some abnormalities that are seen on mammography and therefore, hopefully, reduce the number of unnecessary breast biopsies in the future. One such technique includes the use of nuclear medicine imaging of the breasts to improve the specificity of mammography. Although, there is still a critical need for more research and data collection, it seems that Tc99m Sestamibi breast imaging can offer some benefits in certain groups of patients who have ambiguous mammograms. These include women with dense breasts, patients with residual scar as a result of prior biopsy and perhaps in women with low suspicious mammographic lesions that breast biopsy is not warranted. Finally, in a large group of patients (20% of all breast cancers) who present with advanced disease and preoperative chemotherapy is indicated, combination of mammography and breast physical examination cannot determine the progression or regression of the disease. It has been demonstrated in at least 3 major manuscripts that the use of Tc99m Sestamibi breast imaging has been extremely beneficial to monitor the disease process and effect of therapy.

Among different radiopharmaceutical that has been tested for breast imaging, Tc99m Sestamibi is the only drug that is approved in the U.S. by the Food and Drug Administration for breast imaging. However, the result of this test is not favorable in patients with small cancers (1-1.5 cm in diameter). Research at several institutions including ours, has shown that the development of small size nuclear medicine detectors can improve the resolution of this technique.

BREAST CANCER STAGING

Axillary lymph node dissection has been shown to be the most commonly performed at Level 1 lymph nodes (i.e. those lateral to the pictoralis minor are the nodes involved with tumor spread. In one report, in 539 patient with positive axillary lymph nodes, 96% had Level 1 lymph nodes involved, 58% of these patients showed only Level 1 nodes with tumor. Other series have shown Level 2 involvement in the absence of Level 1 involvement in 2%-5% of the patients. In earlier experiences, sites of much higher prevalence of "Skip" metastases defined as metastases to Level 2 and 3 axillary nodes without involvement of Level 1 nodes. In one report, 10% of all women with carcinoma of the breast would be understaged by an axillary node sampling procedure. Based on a retrospective view of 72 patients, 25% had metastatic involvement confined to the other axillary nodes, of whom 14% had primary lesions less than 2 cm in diameter. It is a fact that no data thus far available about clinical or pathologic correlation of the "Skip" metastases. However, based on data from several sources, the risk of a "false negative" dissection with only Level 1 and 2 lymph nodes are removed is very low.

BREAST LYMPHATIC MAPPING TECHNIQUES

Blue Dye has be advocated for the use of preoperative lymphatic mapping prior to sentinel node biopsy. As opposed to using only a Blue-Dye intraoperative approach to finding the sentinel lymph node, some advantages of lymph scintigraphic sentinel node identification preoperatively followed by biopsy are as follows:

1. The location of the sentinel node (s) can be identified before any incisions.
2. A small incision can be made to excise the sentinel node rapidly and easily.
3. Staging may be improved over axillary node dissection staging.
4. Successful identification and excisional biopsy of the sentinel node (S) in the axilla minimizes the morbidity.

All these, except 1 and often 2, can be achieved by either Blue-dye or lymphoscintigraphic and gamma probe techniques. A long learning curve has been experienced and reported by proponents of the Blue-dye techniques such that initially, there is failure to find a sentinel node in as many as 35% of cases. Giuliano et al. Reported 174 patients in whom Vital dye lymphatic mapping was performed, injecting the dye at the primary breast cancer site intraoperatively (no radioactive tracer or imaging component were included in this study). Axillary lymphatics were identified and followed to the first node (sentinel node), which was excised before an axillary lymph node dissection. In 65.5% (114/174) sentinel nodes were identified. All the missed sentinel nodes occurred among the first 87 procedures. The authors discussed the learning curve and the fact that surgeons rate of sentinel node detection increased with experience. Albertini et al. reported a prospective trial of 62 patients with newly diagnosed invasive breast cancers in which patients underwent intraoperative mapping using both Vital Blue Dye and filtered Tc-99m sulfur colloid to identify sentinel lymph nodes. After the removal of axillary sentinel lymph nodes, and axillary lymph node dissection and definitive removal of the primary tumor where performed, their results showed in 97% of patients, a sentinel lymph node was found and excised, 18 of 62 patients had metastases, and all of their sentinel nodes were tumor positive. They concluded that axillary sentinel lymph node and breast cancer indeed probably reflect the histology of the remaining axillary lymph nodes. Furthermore, the authors emphasized that this procedure allows the pathologist to focus on one or two nodes, thereby perhaps increasing the yield of micrometastases and the accuracy of staging.

CONTROVERSIAL ISSUES IN BREAST LYMPHOSCINTIGRAPHY

There are several variable factors that have been reported from different investigators throughout the world in performance and in some cases interpretation of the results of lymphoscintigraphy. None of these differences, have been successfully evaluated in prospective trials so that one can conclude the advantage of one technique over the other. However, it seems that most investigators regardless of their technique, as long as they have passed the "learning curve" they have approached reasonable results with the identification of the sentinel node as well as its sensitivity and specificity with Level 1, 2 and 3 axillary node dissections. These variables are as follows:

RADIOPHARMACEUTICAL

The radiopharmaceuticals which have been most widely used for lymphoscintigraphy includes: Tc-99m sulfur colloid, Tc-99m manocolloid, and Tc-99m human serum albumin. The major differences between these agents is the size of the colloid particles or albumin molecules. Tc-99m sulfur colloid has the largest particle size of 0.1 to 2 micro millimeters (1200 nm). Tc-99m antimony sulfide colloid has a much smaller, more desirable particle size of all 0.003 to 0.03 micro millimeters (3 to 30 nm). Tc-99m manocolloid is a labeled albumin colloid with a particle size of about 0.08 micro millimeters (80 nm). Tc-99m serum albumin has a very small size of up to 4 nm. Since the rate of colloid transport through lymphatics is a function of colloid particle size, this is a critical factor for performance of lymph scintigraphy. Particles less than 4nm may penetrate capillary membranes and if so, would be unavailable to migrate through lymphatic channels. Furthermore, such capillary blood uptake would add undesirable blood background counts to add counts detected by a gamma probe.

ROUTE OF INJECTION

There are several methods described for the injection of radiopharmaceuticals to visualize sentinel node. These include: Peritumoral injection, intratumoral injection, intradermal injection, and finally subareolar injection. It appears that most European trials prefer subdermal injections. In the United States, however peritumoral injection is more common. The method of intratumoral injection has been abandoned since there are many lymphatic channels in different directions arise from the tumor site itself. There is a recent article suggesting that even periareolar injection might give the same results.

In our experience at Harbor-UCLA Medical Center, we prefer subdermal injection since it only requires one injection with a small amount of injected material (approximately 0.4 cc) which contains about 400 microcures of filtrated Tc99m Sulfur colloid. We apply gentle hand message over the injected site to facilitate the drainage through the lymphatic channel. We obtain dynamic flow study imaging following the injection followed by static images up to 30 minutes post injection. In more than 50% of our patients, a single sentinel node is visualized approximately 20 minutes post injection. At this point, we mark the skin under a nuclear medicine detector and instruct the patient not to wash the marker.

Attention to detail protocol to perform these images are mandatory. The entire procedure needs to be explained to the patient prior to the study by a experienced physician or a nuclear medicine technologist who is familiar with the procedure. Collaboration with the surgical team is a must for a successful result. Some centers prefer to perform the procedure a day before surgery. In this situation, the patient is scheduled the last case of the day and the skin is marked and the patient returns for surgery the following day. In about 10-15 percent of our patient's population, we visualize more than one sentinel node (mostly 2 to 3 nodes). Careful evaluation of the images should be obtained not to mistake the sentinel node (the very first node after the injection) with simultaneous visualization of other nodes. In any event, dissection of all nodes that are initially visualized is mandatory. If more nodes visualized on delay images, distal to sentinel nodes, they need not be biopsied.

In summary, the concept of lymphoscintigraphy and visualization of the sentinel node for breast cancer staging is still under tremendous investigation and scrutiny. It is a fairly easy procedure with significant learning curve and requires collaboration between departments of nuclear medicine, surgery, and pathology.

Recently, we have edited a book entitled, "Nuclear Oncology Diagnosis and Therapy". (15) I encourage you to look up this book for more detail about the role of nuclear medicine in other cancer diagnosis and therapy.

REFERENCES:

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The Breast Journal Nov/Dec. 1999.

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6. Ciamiello A, Del Vecchio S, Silvestro P, Potena M, Carriero M, Thomas R et al.
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7. Maini C, Notaristefani F, Tofani A, Iacopi F, Seiuto R, Semprebene A. et al.
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8.Taillefer R, Khalkhali I, Waxman A, Biersack.
"Radionuclide Imaging of the Breast"
Book published: 1998 Marcel Dekker, Inc. - New York, Basel, Hong Kong.

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11. Veronesi U, Correspondence. Lancet 1997;350-809.

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13. Glass EC, Essner R, Morton DL. Kinetics of three lymphoscintigraphic agents in
patients with cutaneous melanoma. J Nucl Med. 39:1185-1190.

14. Glass E, Essner R, Giuliano A. "Sentinel Node Localization in Breast Cancer."
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15. Khalkhali I, Maublant J, Goldsmith S. "Nuclear Oncology; Diagnosis and Therapy"
Lippincott Williams and Wilkens, Philedephia USA 2001