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The Role of Lymphoscintigraphy in the Management of the Patient With Breast Cancer

From the Comprehensive Breast Cancer Program, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida, and DOD Breast Lymphatic Mapping Trial Member Institutions.

Correspondence: Correspondence to: Elisabeth L. Dupont, MD, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612-9497; Fax: 813-979-3984; E-mail: dupontel{at}moffitt.usf.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Introduction: Regional nodal status is the most powerful predictor of recurrence and survival in women with breast cancer. Lymphatic mapping and sentinel lymph node (SLN) biopsy have been found to accurately predict the regional nodal status. Preoperative lymphoscintigraphy has been used in melanoma patients to identify the basins at risk for metastases when primary sites are located in watershed areas of the body. This study was performed to define the role of lymphoscintigraphy for axillary nodal staging in women with breast cancer. Specifically, can preoperative lymphoscintigraphy define a population of women with breast cancer who have multidirectional drainage or who do not drain to the axilla and need no axillary dissection?

Methods: 516 patients with invasive breast cancer were accrued in a national breast lymphatic mapping trial sponsored by the U.S. Department of Defense. Preoperative lymphoscintigraphy images were produced using filtered technetium-99 sulfur colloid. Lymphatic drainage to axillary and internal mammary sites was noted.

Results: Drainage to an axillary SLN was found in 335 (65%) patients, and internal mammary or extra-axillary drainage was noted in 52 (10%) patients. By using sensitive hand-held probes and vital blue dye intraoperatively, the overall success rate of finding an axillary SLN was 85%. Of the 335 patients who had an axillary SLN identified with imaging, all had successful SLN biopsy procedures. Although no SLNs could be imaged in 181 patients, 153 (85%) of these patients had an axillary SLN identified with intraoperative mapping. For 28 patients in which lymphoscintigraphy was negative and intraoperative mapping was unsuccessful, complete axillary node dissection was performed, and 13 (46%) of these patients were found to have metastatic disease in the basin.

Conclusions: Preoperative lymphoscintigraphy can identify those women with primary breast cancers who have extra-axillary regional basin drainage such as internal mammary. The ability to image an axillary SLN was associated with a high success rate of being able to find the node intraoperatively with a combination mapping technique. In a high percentage of patients with negative lymphoscintigraphy, the SLN was identified with more sensitive hand-held probes. Therefore, patients who have a negative preoperative lymphoscintigraphy and intraoperatively are found to have no "hot" spot in the axilla with the hand-held probe still need an axillary node dissection, because 46% of these patients contain metastatic disease in the axilla.

	INTRODUCTION

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Radioguided surgery techniques have the potential to change the standard of surgical care for patients with breast cancer. Lymphoscintigraphy has been useful in predicting the lymphatic drainage patterns of melanoma patients.¹ The use of lymphoscintigraphy and lymphatic mapping with sentinel lymph node (SLN) biopsy allows full nodal staging information with a minimally invasive procedure.² Alternatively, axillary nodal dissections bear a significant morbidity risk and cost despite being an established component of surgical treatment in breast cancer. Although lymphoscintigraphy (imaging) offers few complications, this procedure is not uniformly performed in patients with breast carcinoma, particularly if nodal staging is confined to the axilla.

Speculation regarding radioguided surgery has led to national trials³ investigating this technique as a viable surgical strategy for women with invasive breast cancer. The Department of Defense has funded a national prospective multicenter study of breast lymphatic mapping. Information from this prospectively accrued database was used in an attempt to define the limits of preoperative lymphoscintigraphy with the intraoperative breast mapping techniques. The specific question addressed was whether localizing details can be obtained with this nuclear medicine study in light of the fact that mapping is preformed to the axillary basin as a standard. Could preoperative lymphoscintigraphy be used to define a subset of women who have multidirectional drainage or who do not drain at all to the axilla and need no axillary dissection?

	MATERIALS AND METHODS

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The population of this study was a group of 961 women with breast cancer who were enrolled in a national, multi-institutional Department of Defense (DOD) clinical trial led by the H. Lee Moffitt Cancer Center at the University of South Florida. The DOD breast lymphatic mapping trial was composed of 41 institutions (see Appendix A) across the country, 12 of which were university centers with the remainder being from community-regional hospitals. One of the goals of the trial was to document whether lymphatic mapping and sentinel lymph node (SLN) biopsy was a viable surgical technique in the community-regional hospital and 70% of the hospitals were considered in this category. Of the 961 patients in the study, 516 (53.3%) underwent preoperative lymphoscintigraphy with intraoperative lymphatic mapping and were evaluated as a part of this study.

From July 1997 to January 1999, 961 patients with breast cancer were accrued in the DOD breast lymphatic mapping trial. This IRB approved study excluded patients who were pregnant or had clinically positive lymph nodes. All principle investigators participating in the trial had attended a formal training session at the Moffitt Cancer Center (MCC). Of these 961 patients, 516 underwent preoperative lymphoscintigraphy using approximately 450 microcuries of 0.22-µm filtered technetium-99 sulfur colloid. Forty-one centers participated, and imaging was performed when facilities were available to do so at that participating institution. The patients were then imaged in a dynamic fashion starting at 15 minutes post injection. Standard large field gamma camera, a high-resolution collimator and a 10% imaging window at the 140-keV energy peak, which is the technetium peak, were utilized for preoperative imaging. A cobalt flood source or a hot marker was used to outline the body to achieve anatomical landmarks of reference for the imaged SLNs.

Patients with palpable tumors are injected in the nuclear medicine department with six injections around the periphery of the tumor at the depth of the mass. Patients with nonpalpable tumors first undergo mammographic or ultrasound needle localization. Six equal aliquots are injected with ultrasound guidance if necessary, at the correct depth. If the lesion is localized by mammography, six equal aliquots are injected equidistant from the tip of the localization wire, at correct depth. Some patients were studied after an excisional biopsy had been performed. Most have seromas that are palpable and injections are performed as if the seroma were tumor. If the seroma is not readily palpable, ultrasound is used to identify a small residual seroma or area of architectural distortion within the breast so that the mapping agents can be correctly injected to avoid the excisional biopsy cavity.

The breast carcinoma patient was imaged immediately after injection, positioned supine under the gamma camera in the anterior oblique lateral projection. The arm was placed over the head to optimize axillary exposure and distance between the primary site and regional basin (Fig. 1). Various maneuvers were attempted to maximize the separation between the primary site and the regional basin. These include taping the breast out of the field of view, imaging patient in a sitting or standing position, and shielding the injection site. Internal mammary and supraclavicular lymph nodes were noted and tattooed in the anterior projection (Fig. 2), whereas the axillary lymph nodes were tattooed with the patient in the lateral position with the arm above the head. Images were acquired over 8–10 minutes per view to assure high-count density.

View larger version (78K): [in this window] [in a new window]   FIG. 1. Breast lymphoscintigraphy, right anterior oblique (RAO) projection of lesion at 12:00, which drains to axilla.

View larger version (108K): [in this window] [in a new window]   FIG. 2. Anterior chest view breast lymphoscintigraphy with bilateral injections. Right drains to axilla while left tumor drains to left internal mammary.

All patients then underwent intraoperative lymphatic mapping and SLN biopsy. Intraoperative mapping was performed with a combination technique of Lymphazurin blue dye and sulfur colloid injection with a hand-held gamma probe used to localize the migration and concentration of the colloid to the SLN. An intraparenchymal injection of 5 cc of vital blue dye is given in multiple sites around the tumor or biopsy site. Most of the patients were in phase I of the trial (or learning phase) in which a SLN biopsy is performed followed by a level I and II node dissection. Per protocol, if no SLN was found, a complete axillary node dissection was performed as the standard of care.

	RESULTS

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Over an 18-month period, 961 patients were enrolled with 516 (53%) undergoing preoperative lymphoscintigraphy. Of these 516 patients, 335 (65%) had axillary SLN(s) identified on imaging. No axillary nodes were imaged preoperatively in 181 (35%). All patients were taken to the OR and the vital blue dye and hand held probes were used in an attempt to identify an axillary "hot spot" or SLN. In 153 (85%) of the patients that did not image an axillary SLN, one could be identified when the very sensitive probes were used at the level of the nodes with the axilla open. This is possible because the probes are so much more sensitive when placed at the level of the nodes in a surgically opened axilla, than the cameras are in nuclear medicine. An extra-axillary or internal mammary lymph node was found in 52 (10%) patients using preoperative imaging. Of these 52, 45(87%) had drainage to both axillary and IM sites (Fig. 3). Seven patients showed only the IM as the site of drainage. These patients were 2% of the successfully imaged patients. The extra-axillary sites were not routinely removed as this is not the standard of care. There were 28 (15.4%) patients who failed to image an axillary SLN preoperatively and who failed to map by either intraoperative technique. All of these 28 patients (5% of the imaged group) underwent a level I and II axillary node dissection, and 13 (46%) had disease in the axilla.

View larger version (73K): [in this window] [in a new window]   FIG. 3. Left anterior oblique (LAO) breast lymphoscintigraphy for lesion at 12:00 demonstrating drainage to both left axilla and left internal mammary.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The confirmation of the SLN concept in oncology has led to the rediscovery of lymphoscintigraphy. Combining preoperative lymphatic mapping with intraoperative probe detection allows these nuclear medicine procedures to be increasingly used to distinguish and identify the SLN in breast cancer.⁵ Lymphoscintigraphy has been an important diagnostic tool for lymphatic mapping in melanoma.^1,6 The question is whether lymphoscintigraphy contributes to lymphatic mapping in breast cancer and whether it should be done at all since most surgeons are concerned with mapping only to the axilla.

As with SLN procedures, lymphoscintigraphy can help to identify the first lymph node in the basin to receive drainage from the primary tumor.^7–9 The two criteria to define what is meant by a SLN with preoperative imaging are the first appearing node or the visualization of an afferent lymphatic vessel from the tumor site to a node. Lymphoscintigraphy then requires dynamic studies with associated lymph-vessel depiction and sustained lymph-node retention.^5,10,11

Although it has been suggested that mammary lymphoscintigraphy increases the accuracy of the SLN procedure by distinguishing between the first and second tier nodes and by detection of lymphatic routes outside the axilla, in some cases, lymph nodes are not discernible.⁵ In addition, the demonstration of extra-axillary lymphatic drainage only becomes important when a treatment decision is to be made based on the finding.⁹ Internal mammary nodal (IMN) drainage, a finding that occurred in 10% of the current study, may be handled by incorporating these nodes in the radiation port in women who have breast preservation. Alternatively, radio-guided SLN biopsies are performed of the IMN in some institutions including MCC.¹² An intraparenchymal injection of the mapping agent will image extra-axillary drainage 10% to 19% of the time.^4,13,14 This is in contradistinction to imaging with intradermal or periareolar injections of mapping agents, where internal mammary nodal drainage is never seen. It is thus unclear from these data that the skin lymphatics communicate all the time with the deep parenchymal lymphatics and dermal injections can be substituted for breast parenchymal injections in performing breast lymphatic mapping.

Lymphoscintigraphy by multiple peritumoral injections is probably the most frequently used process for SLN identification. In breast cancer, its confirmation by various groups^8,14–18 has led, in combination with vital blue dye mapping and the use of the intraoperative gamma detecting device, the gamma probe, to identification of the sentinel node in 75% to 98% of breast cancer patients. Numerous authors^4,10,14,16 using Tc99m–nanocolloid, recommend sequential gamma camera images 2–4 and 18 hours after tracer administration, although in >90% of cases no obvious variations in drainage patterns are evident between early and late static images. This suggests that tracer distribution by peritumoral administration is frequently completed after 2 hours. In our practice, we have found the optimal time for delayed imaging as well as for radio-guided surgery with the hand held gamma probe to be at least 2 hours post injection of the radiopharmaceutical. Surgeons have a window of opportunity to perform the harvest as enough radioactivity is left in the SLN up to 24 hours after the injection of the radiocolloid.

The mapping technique in breast cancer has yet to be standardized. The dispersal of administered particles depends largely on the particle size.¹¹ Factors that affect the performance of colloids injected interstitially include particle size and number of colloid particles injected. Molecules smaller than a few nanometers may leak into capillaries and may be distributed into the vascular system. Alternatively, small particles may not stick in the SLN and "pass through" may be a problem. Particles larger than 100 nm usually become trapped in interstitial space and never enter the lymphatic system.^10,19 Animal studies have suggested that optimal lymph node uptake of colloids should be achieved with particle sizes between 10 and 50 nm.²⁰ Historically, investigators have preferred antimony trisulfide colloid for lymphoscintigraphic studies because its particle size, 3–30 nm, is optimal for transit through lymphatics and localization in nodes without phagocytosis.¹¹ Unfortunately, this radiopharmaceutical is no longer available in the United States but is available and widely used in Australia and Europe. Filtered technetium sulfur colloid has been the radiopharmaceutical of choice in the United States. The colloid used most frequently in the current study was technetium sulfur colloid with a 0.2-µm filter. This was the MCC radiopharmaceutical of choice filtered with a 0.2-µm (20-nm) filter and the compound used most often in the DOD study. Our preference of this agent and preparation stems from its ability to decrease shine-through because more of the substance migrates. The issue of shine-through is one of the biggest problems of breast imaging, and we find that this is one reasonable way to lessen the problem. It is important that the sulfur colloid be freshly prepared within 2 hours of use as over time clumping occurs, which results in a larger particle size and less migration.

Factors such as previous excisional biopsy and scarring, body hydration, and variations in oncotic and hydrostatic pressure may play a role in breast lymphatic uptake.¹¹ The physician making the injections must be able to distinguish the tumor seroma or scar from induration or scar related to the skin incision, which is often placed remote from the tumor to satisfy cosmetic concerns. Injection into the tumor or seroma cavity will result in no or little migration of radiopharmaceutical to the SLN.¹⁰ Localization wires must be avoided as well as the technique of injection through the needle through which the localization wire was passed because it acts as a wick causing some of the dose to taint the skin surface.^9–12 This reduces the dose available for imaging and produces confounding contamination of the skin surface.

It was hypothesized that preoperative lymphoscintigraphy could be used to identify a population of women who do not drain at all to the axilla and do not need any axillary nodal staging procedure. This was not the case because in 85% of patients in whom axillary SLN could not be imaged, successful SLN identification was achieved with the hand held gamma probe intraoperatively. Even in the small percentage of patients in which imaging was negative and the intraoperative mapping was unsuccessful because no blue dye or radiocolloid migrated to the axilla, 46% of these patients obviously had lymphatics from the primary in the breast to the axilla because they had metastatic disease in the axilla. It has been shown that if the SLN is "chalked full of tumor," it may not take up enough blue dye or radiocolloid to color or make "hot" a node to distinguish it as a SLN.⁹ This is the explanation for the inability of the SLN to take up the vital blue dye or colloid in some of the 13 patients in this report. Alternatively, the lymphoscintigraphy and intraoperative mapping may have been performed incorrectly, because most of these cases were from the "early" part of the study where nuclear medicine physicians and surgeons were going through their learning curve.^21,22 A change in lymphoscintigraphy technique over the last 2 years at MCC, consisting of an increased volume of injection,²³ an increase diffuseness of injection,¹² use of ultrasound to avoid injecting into the biopsy seroma cavity, and 5 minutes of massage to injected site has resulted in an increase in ability to image an axillary SLN from 65% to 85%.²⁴ These technical advances evolved during the trial and the axillary imaging rate increased correspondingly. Finally, it should be noted that successful lymphoscintigraphy has the advantages of assuring the surgeon that mapping will be possible and therefore assists in scheduling the case and identifying the 10% of cases that have multidirectional drainage.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
In addition to the documentation of the SLN concept,^2,25,26 the use of lymphoscintigraphy for SLN identification in breast cancer has become a major interest for surgeons.^4,27 The nuclear medicine study provides information on the routes of draining regional lymph node basins and thus possible metastasis, the number of SLNs that need to be harvested and their location in relation to other nodes in the basin.^8,9 The purpose of the present study was to examine the role of lymphoscintigraphy for axillary nodal staging in breast cancer. The traditional finding is that most cancers of the breast are located within the upper outer quadrant of the breast. Therefore, it has been assumed that nodal drainage will be to the axilla and only the most medial tumors will drain to the internal mammary node chain (IMN). However, the multiplicity of SLN and variability of the drainage patterns has been noted in this study as well as others (Fig. 4).^8,9,26 Extra-axillary lymphatic drainage occurs in a significant number of patients. How best to handle these patients need to be addressed with national trials.

View larger version (80K): [in this window] [in a new window]   FIG. 4. LAO view breast lymphoscintigram of lesion at 3:00 showing drainage to left axilla. Note the prominent afferent lymphatic involving medial aspect of peritumoral region which crosses over to drain into the axilla.

Radiocolloid injection and intraoperative mapping are important adjuncts in the reliable performance of SLN biopsy. Although imaging axillary SLN with scintigraphy effectively assures successful SLN identification, negative imaging should not be the sole indicator of mapping failure or success. SLNs are still identified in the majority of image negative patients, and patients who have negative imaging and no blue dye or radiocolloid in the axilla, still need a level I and II node dissection because 46% will have metastatic disease.

APPENDIX A

	Acknowledgments

 
This work was supported by Department of Defense Grant Number BC962362 and NIH Grant Number R21CA66553-01.

	Footnotes

 
Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, March 16–19, 2000, New Orleans, Louisiana.

Received for publication June 21, 2000. Accepted for publication December 4, 2000.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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