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Nuclear Medicine |
1 From the Departments of Radiology (R.L.B., B.J.B., D.M.I., H.W.S.), Health Research and Policy Division of Biostatistics (B.J.B.), and Surgery (K.L.S., S.S.J.), Stanford University Medical Center, 300 Pasteur Dr, H-1307, Stanford, CA 94305-5105. Received June 20, 2000; revision requested August 29; final revision received January 3, 2001; accepted January 9. Address correspondence to R.L.B. (e-mail: birdwell@stanford.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: One hundred thirty-six patients who had breast cancer underwent preoperative lymphoscintigraphy before SLN biopsy. Patients with visualized and nonvisualized SLNs were compared for age; tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; interval between biopsy and lymphoscintigraphy; intraoperative identification method; and surgical identification rate. Visualized SLN drainage basins were noted.
RESULTS: Ninety-nine patients had visualized and 37 had nonvisualized SLNs, without statistically significant differences in tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; and interval between biopsy and lymphoscintigraphy. Ninety-nine (73%) of the 136 SLNs were visualized at lymphoscintigraphy; 30 (81%) of the 37 nonvisualized SLNS were identified at surgery. Of the seven SLNs not identified at surgery, five were mapped with radiocolloid only. Patients with nonvisualized SLNs were older than those with visualized SLNs. Eleven (46%) of 24 tumors with internal mammary drainage were in the outer part of the breast.
CONCLUSION: Patients with and those without visualization differed in age, SLN identification at surgery, and surgical identification method. Nonvisualized status does not preclude axillary metastasis. In older patients with nonvisualized SLNs, blue dye may aid in SLN detection, as compared with isotope-only localization.
Index terms: Breast neoplasms, metastases, 00.30, 00.33 • Breast neoplasms, radionuclide studies, 00.1216 • Breast neoplasms, staging, 00.1216, 00.1261 • Breast neoplasms, surgery, 00.327, 00.329
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Data collected per patient included age; tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; interval between biopsy and lymphoscintigraphy; intraoperative identification method; and surgical identification rate.
Preoperative lymphoscintigraphy was performed in the department of nuclear medicine. The breast was injected around the periphery of the tumor or biopsy cavity with 29.6–37.0 MBq (800–1,000 µCi) of filtered technetium 99m sulfur colloid divided into four equal doses and injected at the 12-, 3-, 6-, and 9-o’clock positions within 1 cm of the tumor or biopsy cavity edge. Injection was guided either with tumor or biopsy cavity palpation or with imaging (ultrasonography [US] and/or radiography). Initially, real-time US was performed to direct radiocolloid injections into nonpalpable tumors or biopsy cavities. Later, US guidance was changed to outpatient examination 1 day prior to surgery.
The skin overlying the tumors or biopsy cavities was marked at the 12-, 3-, 6-, and 9-o’clock positions by using a felt-tip marker. The measured depth from the skin surface to the midportion of the mass or biopsy cavity was recorded, and the marked skin was covered with a clear adhesive (OpSite Flexigrid; Smith & Nephew Medical, Hull, England). In cases of calcifications or masses that could not be identified at US, grid-coordinate radiography was performed to mark the overlying skin on the day of surgery. This method was particularly useful in patients who had extensive ductal carcinoma in situ, in whom radiocolloid injection was directed into rather than around the abnormal tissue.
After injection, the patient gently massaged the whole breast to increase afferent lymphatic flow. Lymphoscintigraphy was performed with a large–field-of-view dual-head gamma camera equipped with a low-energy high-resolution collimator (ECAM; Siemens Gammasonics, Hoffman Estates, Ill) ; a 20% window around the 140-keV photopeak was used. A transmission scan was obtained to depict the body contour by using a cobalt 57 flood source that was placed behind the patient at the conclusion of emission scanning. Data were recorded from the anterior and lateral views that were acquired immediately following injection and up to 6 hours afterward, with a majority showing an SLN within 2.5 hours after radiocolloid injection. A visualized SLN was defined as an area of increased uptake in the axilla, internal mammary chain, both the axilla and internal mammary chain, or another site within the breast (intraparenchymal). A lymphoscintigram with nonvisualization showed no focus of uptake in the axilla, internal mammary chain, or other location at 3–6 hours after injection. The prospective nuclear image interpretations by three nuclear medicine specialists (including H.W.S.) were considered the final interpretations in a majority of cases. When patient chart review led to interpretation discrepancies, individual cases were reviewed by one of the nuclear medicine experts (H.W.S.).
Intraoperative mapping of the radiolabeled SLN was accomplished with a hand-held gamma probe (models 1500 and 2000, Neoprobe, Dublin, Ohio; or Navigator Probe, U.S. Surgical, Norwalk, Conn). Intraoperative SLN mapping with vital blue dye followed the injection of 4–5 mL of 1% isosulfan blue dye (Lymphazurin; U.S. Surgical) around the margins of the tumor or prior biopsy cavity. The SLN was identified from its radioactivity by using the gamma probe, with visualization of a bright blue node, a blue lymphatic track leading directly into a lymph node, or both radioactivity and blue dye. After SLN excision, the probe was reinserted into the axilla to assess any residual radioactive foci. In three patients who underwent internal mammary nodal biopsy after informed consent was obtained, only one internal mammary SLN was visualized in each. The node site was marked during preoperative lymphoscintigraphy and verified intraoperatively with the gamma probe. In the first two patients, the node was excised by means of a direct parasternal cutdown through the intercostal muscles. In the third patient, the internal mammary SLN was endoscopically excised.
Pathologic assessment of all SLNs (axillary and internal mammary) included serial sectioning, staining with hematoxylin and eosin, and, if results were negative, cytokeratin immunostaining. No frozen-section SLN analyses were performed. The remainder of the axillary lymph nodes were processed in a standard bivalved fashion, without serial sectioning or immunostaining.
All data were entered into a database by a dedicated research coordinator and cross-checked against the original medical records (R.L.B. and K.L.S.). The data were analyzed by performing two-sample t tests and 
2 tests. The Fisher exact test was performed to test contingency tables with small observed cell frequencies.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intraoperative SLN identification was successful in 128 (94%) of the 136 patients (Table 4). There was no difference in SLN identification rate between 85 (94%) of the 90 patients who received a diagnosis with either fine-needle aspiration or core-needle biopsy and 43 (93%) of the 46 patients who underwent excisional biopsy. However, there was a difference in SLN identification rate between visualized- (99% [98 of 99]) and nonvisualized-SLN (81% [30 of 37]) groups.
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However, in patients 70 years of age or older, the identification rate with the gamma probe alone was 57% (four of seven), as compared with 100% (14 of 14) with the two mapping agents. No woman older than 70 years underwent SLN biopsy with blue dye as the single mapping agent. In women younger than 70 years, the identification rate with the gamma probe alone was 93% (27 of 29) and with both mapping agents was 96% (72 of 75).
There was a statistically significant difference between the visualized and nonvisualized cases in which SLN identification failed. One (1%) of the 99 cases in the visualized-SLN group was not identified at surgery, as compared with seven (19%) of the 37 in the nonvisualized-SLN group. In two (one in the visualized-SLN group, one in the nonvisualized-SLN group) of these cases of failure, axillary dissection findings were positive for metastases. There was a difference in the number of visualized SLNs that were positive for metastatic disease (40 [41%] of 98), as compared with the nonvisualized SLNs (six [19%] of 30). Of the 136 total patients, 52 (38%) had positive findings of axillary metastases, 50 of whom had an SLN identified. Of these, four patients had negative SLNs and metastatic axillary disease in nonsentinel lymph nodes, for an overall false-negative rate of 8% (four of 50 patients) (Table 4).
Table 5 shows that a majority of visualized SLNs drained to the axilla alone (73 [73%] of 99 cases) (Figs 2, 3), with 18 (18%) of 99 cases draining to the axillary and internal mammary nodes and six (6%) of 99 to the internal mammary nodes only (Fig 4). Biopsy was performed on three of the internal mammary SLNs, and all three were negative for metastatic disease. However, one of these three cases had positive axillary nodes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Preliminary assessment of our first 74 patients found no statistically significant difference in age between women who had visualized SLNs and those who did not (5). More recently, Ng et al (6) reported an increase in failure to identify SLNs in women older than 50 years of age. This is similar to our experience in the current study, in which a statistically significant difference was found in patient ages: Patients with nonvisualized SLNs were older than patients with visualized SLNs. Also, of the eight patients in the current study in whom an SLN was not identified at surgery, five (63%) were 50 years of age or older. Speculation as to why lymph nodes are not identified as often in older women may be related to a decrease in tissue turgor, with a resultant decrease in the hydrostatic intralymphatic pressure that drives the mapping agent into the node. Even if the agent is delivered successfully to the node, it may not be concentrated because of the limited sinusoidal space that remains in a fat-replaced node, another feature found more commonly in older patients.
Our experience resulted in successful intraoperative SLN identification rates of 86% (32 of 37 cases) with radiocolloid alone, 100% (11 of 11 cases) with blue dye alone, and 97% (85 of 88 cases) with both mapping agents. By using radiocolloid alone, however, our SLN identification success rates for the visualized-SLN and nonvisualized-SLN groups varied, with 100% (30 of 30) of the visualized cases identified at surgery, as compared with 29% (two of seven) of the nonvisualized cases. Our results are comparable to those of Alazraki et al (7), who compiled results from different investigators studying the various methods of SLN mapping to get a weighted average that was based on the number of published studies. They reported weighted average SLN identification rates of 92%, 76%, and 94% with radiocolloid alone, blue dye alone, and both mapping agents, respectively. In the current study, because five of the eight cases in which there was failure to identify a SLN at surgery were mapped with radiocolloid alone and were nonvisualized, our findings suggest that if preoperative lymphoscintigraphy does not depict an SLN, then blue dye should be used with the radiocolloid as an intraoperative mapping agent.
We found that patients with nonvisualized SLNs had a significantly lower rate of SLN identification at surgery, as compared with those with visualized SLNs. Of the 37 patients with nonvisualized SLNs, 30 (81%) had a SLN identified at surgery. This was in contrast with intraoperative SLN identification in 98 (99%) of the 99 patients with visualized SLNs. Burak et al (8) reported that of seven patients who did not have an SLN visualized at preoperative lymphoscintigraphy, five (71%) had an SLN identified at surgery.
Factors not addressed in the current study may also relate to whether a case is visualized. These factors include the various radiocolloid injection guidance methods; the number of nuclear medicine physicians performing injections, particularly at a teaching hospital; patient positioning for gamma camera imaging; and time from injection to imaging and from imaging to surgery.
Important techniques for successful preoperative lymphoscintigraphy include avoiding injection into the pectoral muscle deep to the tumor or directly into the tumor or the biopsy cavity. Also, to optimize SLN visualization at lymphoscintigraphy, Alazraki et al (7) advise "moving the breast to optimally clear the axillary and internal mammary regions of the overlying breast soft tissue...[as] the soft tissues of the breast attenuate and can mask visualization of a lymph node that likely contains less than 1% of the injected activity."
Our success in SLN identification in women who had undergone prior excisional biopsy is similar to that reported by other investigators (9–12) in that we found no difference between SLN identification in women who underwent prior surgical biopsy versus that in women who underwent percutaneous biopsy diagnosis. Our findings differ from those of Borgstein et al (13), in which six (75%) of eight failed SLN identifications were in women who had undergone prior excisional biopsy. Of note in the Borgstein et al study (13) is that of the six cases in which the SLN was not identified, three had undergone radiocolloid injection directly into the biopsy cavities.
Dauway et al (14) reported on 25 patients with nonvisualized SLNs in whom an SLN was not identified at surgery by using blue dye or a gamma probe and in whom subsequent axillary dissection was performed, without findings of axillary metastases. The findings suggest that this subgroup may not have required axillary dissection. We found a statistically significant difference in the number of positive SLNs between visualized- and nonvisualized-SLN groups, 41% and 20%, respectively. However, one of the seven patients with a nonvisualized SLN and no SLN identified at surgery had axillary metastasis; this finding serves as caution that larger studies are necessary before axillary dissection is omitted in patients with nonvisualized SLNs.
If tumors are medial, some investigators (15) perform lymphoscintigraphy to evaluate possible internal mammary drainage. The findings of both our preliminary data assessment (5) and the present study refute this selective practice and agree with the finding that tumor drainage pathways are not predictable on the basis of tumor location, as reported in the classic study by Turner-Warwick (16). Of the 24 visualized cases with internal mammary drainage in our series, 11 (46%) were in the outer portion of the breast. Of the 55 outer-portion breast tumors, eight (15%) drained to the axilla and internal mammary nodes, and three (5%) drained to internal mammary nodes only. Of the 24 inner breast tumors, 21 (88%) drained to the axilla, 15 (63%) drained to the axilla alone, six (25%) drained to the axillary and internal mammary nodes, and two (8%) drained to the internal mammary nodes only. Thirty-two (32%) of the 99 visualized cases demonstrated drainage pathways that crossed the center of the breast. Uren et al (17) and Borgstein et al (13) reported similar findings, with 11 (32%) of 34 and 35 (27%) of 130 cases, respectively, draining across the center of the breast to either the axilla or internal mammary nodes. Our findings are of clinical importance in identifying tumor drainage crossover rates and dispelling the myth that lymphoscintigraphy should be performed for only medially located tumors. Therefore, if one chooses to perform lymphoscintigraphy to identify internal mammary nodes, then it should be performed irrespective of tumor location.
A more basic question is whether preoperative lymphoscintigraphy should be performed as part of the SLN procedure. Specific to the question of SLN identification rate, Burak et al (8) and, in a larger study, McMasters et al (18) found no significant difference between women who underwent preoperative lymphoscintigraphy and those who did not. Our overall SLN identification rate of 94% (128 of 136) with preoperative lymphoscintigraphy is comparable with the 92% and 90% reported by McMasters et al (18) and Burak et al (8), respectively, for those women who did not undergo preoperative lymphoscintigraphy.
What is gained from preoperative lymphoscintigraphy is visualization of internal mammary nodal drainage. We found that in the visualized cases, 24 (24%) of 99 demonstrated internal mammary drainage. No internal mammary drainage was identified at preoperative lymphoscintigraphy in the study by Burak et al (8), whereas McMasters et al (18) identified 27 (12%) of 222 cases with internal mammary drainage.
The significance of internal mammary nodal involvement is controversial. Approximately 6%–10% of patients who have negative axillary nodes have internal mammary metastases (19,20). Investigators in a 10-year follow-up (21) of patients from the prechemotherapy era who were treated with extended radical mastectomy with internal mammary node biopsy found that positive internal mammary node status was a more important prognostic predictor than T stage and was second to only axillary node status in predicting long-term survival. However, in the premammography era of large tumors, no survival advantage was demonstrated with internal mammary node removal at the time of mastectomy, and the procedure, with its attendant morbidity, was abandoned (22,23). However, authors of a recent study (24) found a significantly lower 20-year survival rate in patients with tumors smaller than 1 cm, negative axillary lymph nodes, and positive internal mammary nodes. In this select population of patients who would otherwise not be recommended for systemic treatment, there is a risk of understaging and undertreatment, which resurrects the question of whether biopsy should be performed on internal mammary nodes.
Since most SLNs in our study were identified at surgery whether or not they were visualized at preoperative lymphoscintigraphy, we think that preoperative lymphoscintigraphy is not mandatory for SLN biopsy, particularly if information about internal mammary drainage is not acted on. Although three internal mammary nodes were examined for metastases in patients who had high-grade or large tumors and consented to the procedure, surgeons at our institution do not routinely perform biopsy of the internal mammary nodes. The radiation oncologists at our institution have found that some of the internal mammary nodal chain may be included in their ports when radiation therapy is administered after breast conservation surgery or mastectomy. Whether the inclusion of the internal mammary nodal basin in the radiation therapy field with or without internal mammary biopsy improves survival can be answered only with the results of clinical trials.
In the current study, another area in which preoperative lymphoscintigraphy was helpful was radiocolloid use as a single SLN mapping agent in older women. In patients aged 70 years or older, we found that the identification rate with radiocolloid alone was 57%, as compared with 100% with both radiocolloid and blue dye. In patients aged 70 years or older in whom an SLN was not depicted at preoperative lymphoscintigraphy, the surgical identification rate with radiocolloid alone was zero, as compared with an SLN identification rate of 100% when radiocolloid and blue dye were used in older women in whom an SLN was visualized at preoperative lymphoscintigraphy. We recommend that for institutions that use radiocolloid as a single mapping agent, lymphoscintigraphy be considered in women aged 70 years or older (Figure 1). If the SLN is not visualized, then the addition of intraoperative isosulfan blue dye is recommended to increase the likelihood of SLN identification. Because we included only seven women aged 70 years or older whose SLNs were mapped with radiocolloid alone, we encourage institutions in which larger studies have been performed with only radiocolloid to review their data to confirm or refute our findings.
In conclusion, 73% of lymphoscintigraphic examinations depicted an SLN, and 81% of patients with a nonvisualized SLN had an SLN identified at surgery. Nonvisualization of the SLN does not mean that there are no axillary metastases. Preoperative lymphoscintigraphy is not an integral part of SLN biopsy procedures unless specific information regarding internal mammary nodal drainage is required. If lymphoscintigraphy is performed, it should be performed in all patients, regardless of tumor location, because 32% of tumor nodal drainage crossed the midline of the breast and 24% of visualized cases had internal mammary nodal drainage. In women 70 years of age or older who do not have an SLN visualized at preoperative lymphoscintigraphy, both radiocolloid and blue dye should be used for optimizing intraoperative SLN identification.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, R.L.B., K.L.S., S.S.J.; study concepts and design, R.L.B., K.L.S., S.S.J.; literature research, K.L.S., S.S.J.; clinical studies, D.M.I., R.L.B., K.L.S., S.S.J., H.W.S.; data acquisition, K.L.S., S.S.J.; data analysis/interpretation, R.L.B., K.L.S., B.J.B., S.S.J.; statistical analysis, B.J.B.; manuscript preparation, R.L.B., K.L.S.; manuscript definition of intellectual content, all authors; manuscript editing and revision/review, R.L.B., K.L.S., D.M.I., H.W.S., S.S.J.; manuscript final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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