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Ann Surg. Jun 1999; 229(6): 860.
PMCID: PMC1420833

Subareolar Versus Peritumoral Injection for Location of the Sentinel Lymph Node

Abstract

Background

Sentinel lymph node (SLN) biopsy is fast becoming the standard for testing lymph node involvement in many institutions. However, questions remain as to the best method of injection. The authors hypothesized that a subareolar injection of material would drain to the same lymph node as a peritumoral injection, regardless of the location of the tumor.

Methods

To test this theory, 68 patients with 69 operable invasive breast carcinomas and clinically node-negative disease were enrolled in this single-institution Institutional Review Board-approved trial. Patients were injected with 1.0 mCi of technetium-99 sulfur colloid (unfiltered) in the subareolar area of the tumor-bearing breast. Each patient received an injection of 2 to 5 cc of isosulfan blue around the tumor. Radioactive SLNs were identified using a hand-held gamma detector probe.

Results

The average age of patients entered into this trial was 55.2 ± 13.4 years. The average size of the tumors was 1.48 ± 1.0 cm. Thirty-two percent of the patients had undergone previous excisional breast biopsies. Of the 69 lesions, 62 (89.9%) had SLNs located with the blue dye and 65 (94.2%) with the technetium. In four patients, the SLN was not located with either method. All blue SLNs were also radioactive. All located SLNs were in the axilla. Of the 62 patients in which the SLNs were located with both methods, an average of 1.5 ± 0.7 SLNs were found per patient, of which 23.2% had metastatic disease. All four patients in which no SLN was located with either method had undergone prior excisional biopsies.

Conclusions

The results of this study suggest that subareolar injection of technetium is as accurate as peritumoral injection of blue dye. Central injection is easy and avoids the necessity for image-guided injection of nonpalpable breast lesions. Finally, subareolar injection of technetium avoids the problem of overlap of the radioactive zone of diffusion of the injection site with the radioactive sentinel lymph node, particularly in medial and upper outer quadrant lesions.

In patients with operable breast cancer, the number of axillary nodes with metastases is an important prognostic factor that allows selection of those who might benefit from adjuvant medical treatment. 1 Historically, nodal involvement was determined by a level I, II, and III axillary lymph node dissection. Recent data suggest that less extensive axillary procedures may provide adequate axillary staging without compromising regional control. 1–3 The sentinel lymph node (SLN) biopsy is a technique used to identify the axillary node most likely to contain tumor cells metastasizing from a primary carcinoma of the breast. This technique provides accurate staging with fewer complications than axillary dissection, and may result in decreased cost. 4–7

Current methods of breast lymphatic mapping in the literature include mapping with isosulfan blue dye and/or technetium-labeled sulfur colloid (filtered and unfiltered) or technetium-labeled albumin. These various materials have been injected in the intraparenchymal tissue, 4,5,7 in the subdermis, 6 or in the skin overlying the tumor or the tumor bed. 8 Preoperative injection has been performed anywhere from 30 minutes to 24 hours before surgery. Although successful localization has varied significantly among the techniques, false-negative rates have not. Problems with the use of blue dye include lower SLN localization rates and the inability to find SLNs outside the axilla (this occurred 8% of the time in a multicenter trial reported by Krag et al 9 ). Problems with technetium include “shine through” and obscuring an axillary SLN in upper outer quadrant lesions and an internal mammary lymph node in medial lesions. In addition, how does one explain the fairly good success rate of localization, even though the actual site of injection varies widely?

The lymphatic drainage of the breast is poorly understood. Injection studies by Turner-Warwick 10 using autoradiographs of surgical specimens have refuted earlier concepts that lymph flows centripetal to the subareolar complex and then to the regional lymph nodes. Rather, lymph flows from superficial to deep and then toward the regional lymph nodes. Further, both the axillary and parasternal lymph nodes receive lymph from all quadrants of the breast. Hultborn et al, 11 using gold injections and autoradiography, likewise found that the breast can drain to any regional lymph node basin, but that most of the drainage was to the axillary lymph nodes but varied with the quadrant of the breast injected. It is thought that there are three interconnecting groups of lymphatic vessels (Fig. 1). The primary and most important channels are within the parenchyma and originate along the lactiferous ducts. The other two groups include the subareolar plexus, which drains the nipple areolar area, and the lymphatics of the deep fascia, which play no important part in the normal drainage of the breast except when normal pathways are obstructed. 12

figure 13FF1
Figure 1. Proposed lymphatic drainage of the breast. (From Romrell LJ, Bland KI. Anatomy of the breast, axilla, chest wall, and related metastatic sites. In Copeland EM, Bland KI, eds. The breast. Philadelphia: WB Saunders; 1998:32. Reprinted with permission.) ...

Based on the above observations, the objective of this report was to test the hypothesis that central subareolar parenchymal injection of technetium-99 sulfur colloid (unfiltered) is as accurate as peritumoral injection of blue dye, regardless of tumor location.

PATIENTS AND METHODS

Patients

Patients diagnosed with breast cancer were evaluated for enrollment into this clinical trial between October 1997 and November 1998 at the Arkansas Cancer Research Center at the University of Arkansas for Medical Sciences. The study was approved by the Institutional Review Board at the University of Arkansas for Medical Sciences. Enrollment criteria included operable invasive breast cancer documented by fine-needle aspiration, core biopsy, or excisional biopsy and clinically negative axillary lymph nodes by physical examination. Patients with prior axillary surgical procedures, multiple primary tumors, and/or pregnancy were excluded.

Study Procedure

Patients were injected in the nuclear medicine department on the morning of the surgery. Each patient received an injection of 4.0 ml containing 1.0 mCi of technetium-99 sulfur colloid (unfiltered) in the subareolar area of the tumor-bearing breast. Patients came to the operating room 30 minutes to 8 hours after injection. In the operating room, each patient received an injection of 2 to 5 ml of 1% isosulfan blue around the tumor, but not into the tumor or the biopsy cavity, 10 to 15 minutes before the surgical procedure. A hand-held gamma probe (Neoprobe, Dublin, OH, or C-Trak, Morgan Hill, CA) was used before making a skin incision to identify the area of greatest activity (in counts per second) separate from the injection site zone of diffusion. Areas of radiolocalization apart from this zone were named “hot spots” and corresponded to the underlying radiolabeled nodes. The right lobe of the liver, the supraclavicular fossa, and the internal mammary chain were also scanned for increased uptake. A skin incision was made so as to achieve the radiolabeled lymph node biopsy, followed by a conventional lymphadenectomy in case the lymph node tested positive for metastatic disease. After localization of the radiolabeled node with the gamma detector, a dissection of the radiolabeled node was performed. Careful dissection was performed so that identification of the blue-stained afferent lymphatic vessels could be made and followed to the SLN. The gamma-detection device was used to confirm the location of the SLN and to guide the dissection in cases where the afferent lymphatic vessels were difficult to identify. Criteria for identification of the SLN included blue staining and/or counts >10% of background. 13 The wound was reexamined after SLN removal to ensure that all radiolabeled LNs and blue-stained LNs were removed. Any remaining radiolabeled LNs >10% of background or any blue-stained LNs were removed using the same technique. Ex vivo radioactivity of the removed LN was measured to confirm that it was indeed the hot spot. The patient then underwent routine modified radical mastectomy or lumpectomy. If the lymph node had metastatic disease, then an axillary lymph node dissection was performed at the same setting.

Pathologic Examination

The SLNs were sent to pathology separately. Touch preps (TP) as well as permanent sections were performed on all SLNs. A single pathologist blinded to the patient diagnosis read all specimens. The SLNs were bisected with a clean blade and touched to a slide. The TP method consisted of simply touching the specimen onto a glass slide, similar to pressing a rubber stamp onto paper, as previously described. 14,15 The principle is that tumor cells, if present, will adhere to the slide. The material was immediately fixed in 70% ethanol. Slides were then stained with hematoxylin and eosin and examined for cytologic features of malignancy. These included cellular smears, loosely cohesive and individually scattered malignant cells, malignant epithelial cells arranged in three-dimensional clusters, syncytial grouping and occasional acinar pattern, tumor diathesis, and nonpolar naked nuclei. 16 Diagnostic categories in reporting cytologic findings included negative or malignant. Each SLN was labeled separately and processed routinely for permanent sections. Any axillary lymph node dissection specimens were dissected fresh using routine surgical pathology techniques for isolation of lymph nodes and were submitted for permanent sections as above.

Statistical Analysis

Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values were calculated using the definitions given in Greenberg. 17 Statistical analyses were performed using StatView II (MacIntosh Iici Computer/Apple Computers, Inc./Abacus Concepts, Inc., Berkley, CA).

RESULTS

A total of 68 patients with clinically node-negative breast cancer were enrolled in the study after signing an informed consent. One patient had bilateral synchronous tumors. The diagnosis was made by fine-needle aspiration or core biopsy (stereotactic or ultrasound-guided) (58%) or excisional biopsy (42%). The average age of the patients was 55.2 years ± 13.4 (range 28 to 86) (Table 1) . Most of the women were white (78.6%); 21.4% were black.

Table thumbnail
Table 1. Enrollment Results

Pathologically, the mean tumor size was 1.9 ± 1.5 cm (range 0.1 to 9.5 cm). In 52 patients (75.4%), the tumor was staged as T1; in 14 patients (20.3%), it was T2; in 3 patients (4.3%), it was T3. Tumors were located in the upper outer quadrant (50.7%), upper central quadrant (24.6%), lower outer quadrant (7.2%), lower central, inner central, or outer central in 4.3% (three each), and lower inner quadrant, upper inner quadrant, or centrally in 1.4% (one each). Most of the tumors (75.4%) were invasive ductal carcinoma, 14.5% were invasive lobular carcinoma, 2.9% were mixed, 4.3% were tubular, and 1.5% each were medullary and mucinous carcinoma. All patients were scheduled for either breast-conservation surgery (66.6%) or mastectomy (33.4%), depending on the presentation of the tumor and their personal preferences.

The success rate of SLN identification, using peritumoral blue dye injection as the standard, 5 was 89.9% (95% confidence interval [CI], 84.3% to 98.1%), or 62 of 69 tumors (Table 2). All SLNs were localized to the axilla. All blue lymph nodes were radioactive (i.e., were considered hot spots). Sensitivity was 100% (62 of 62; 95% CI, 94.2% to 100%). Three additional patients had SLN located by gamma probe alone and the nodes were not blue, for a total identification rate by central technetium injection of 65 of 69 tumors (94.2%; 95% CI, 88.5% to 99.9%). Of the three patients in whom the nodes were not localized by blue dye but by technetium alone, none had previous biopsies, and the tumors were located in the outer central, upper central, and upper outer quadrant, with an average size of 1.7 ± 0.6 cm. In the four patients in whom nodes did not localize by any method, all had undergone previous biopsies. Of these four, the average tumor size was 2.4 ± 1.1 cm. One lesion each was located in the upper central and upper outer quadrant, and two were located in the lower outer quadrant. All five medially located lesions in this series localized to an SLN.

Table thumbnail
Table 2. Central vs. Peritumoral Injection

In the lesions with successful SLN localization, an average of 1.5 ± 0.7 SLNs were removed. The SLNs were metastatic in 15 of 62 patients (24.2%). None of the nonblue radioactive lymph nodes had metastatic disease. In eight patients (53.3%), the SLN was the only positive lymph node. Among the patients with metastasis, the number of involved nodes ranged from 1 to 11. Including all patients, 13.5% of patient with T1 disease, 42.9% of those with T2, and 100% of those with T3 had positive SLNs. Twenty-eight percent (10/35) of upper outer quadrant lesions, 23.5% (4/17) of upper central lesions, and 33.3% (1/3) of inner central lesions had positive SLNs.

DISCUSSION

The major advance in breast cancer treatment in the last decade has been the development of techniques that reduce the complications and extent of the axillary procedure. There have been multiple studies of lymphatic mapping of the axilla with minimally invasive surgery, totaling >1355 patients, using techniques such as blue dye, radiolabeled technetium-99 (sulfur or albumin, filtered or unfiltered), or both. 9,18 These studies have varied in the technique and timing of injections, including peritumoral, pericavity, skin, or subdermal injection, and whether they have been performed in patients with or without clinically positive lymph nodes. 9,18 Results from a recent metaanalysis demonstrated a successful identification rate among 912 patients of 83.6% and a false-negative rate of 5.1%. Concordance of SLN biopsy with axillary lymph node dissection did not vary significantly among various techniques. 18

In the recent multicenter trial reported by Krag et al, 9 peritumoral injection of technetium-99 sulfur colloid demonstrated that all 13 false-negative SLNs reported were in upper outer quadrant lesions, suggesting several possible etiologies. The first was that the zone of diffusion made accurate identification of the SLN more difficult. For example, the closer the zone of diffusion to the axilla, the harder it would be to detect an axillary SLN. If this were true, one would have expected more nonlocalizations resulting from lesions in this area; this was not the case. The other theory was that most lymphatics converge as they near the axilla and that widely spaced injections around a tumor or tumor cavity bed would miss the important lymphatic.

Turner-Warwick 10 demonstrated that the most important determinate of lymph flow is a primary set of vessels that originate as channels within the gland in the interlobular spaces and along the lactiferous ducts. The concordance of SLN biopsies with axillary lymph node dissections, despite the technique used, along with the studies of Turner-Warwick and others suggest that the primary drainage of the breast may be more important in determining the SLN than the primary drainage of the tumor. Because most of the lactiferous ducts are in close approximation below the areola, a subareolar injection would be ideal to determine the primary lymph flow from a given breast to the SLN. We therefore hypothesized that a subareolar injection of material would drain to the same lymph node as a peritumoral injection, regardless of the location of the tumor. We previously performed SLN biopsies using radiolabeled technetium-99 sulfur colloid (unfiltered), based on a technique originally proposed by Krag et al for melanoma 19 and for breast cancer. 7 Our success rate for SLN identification of 96.3% 13 compares favorably with that of other published series, where success rates varied from 65% to 97.5%. 4,5,6,20 In this study, the same technical aspects of technetium injection and detection were used, except that the technetium was injected deep to the subareolar area.

The results of the present study suggest that subareolar injection of technetium-99 sulfur colloid (unfiltered) is as accurate as peritumoral injection of blue dye. All blue nodes were also radioactive (see Table 2). Of 69 breasts, 4 (5.8%) did not localize to an SLN. All four had previous excisional biopsies, consistent with the findings of Krag and colleagues in the multicenter trial. 9 As with other studies, the technetium localized to an SLN more frequently than blue dye. 5 In the three patients with nodes not localized by peritumoral injection of blue dye but localized by central injection of technetium, all were in the 9 to 12 o’clock position of the right breast (upper outer quadrant, upper central, and outer central), similar to the multicenter results and consistent with Krag’s theory of converging lymphatics. In the multicenter study, there was a higher incidence of nonlocalization of medial lesions. All five of our medial lesions localized, with one having a positive SLN. Although not confirmed with completion lymphadenectomy, the percentages of positive SLNs with T stage were consistent with other reports: 13.5% for T1, 42.9% for T2, and 100% for T3 lesions. In marked contrast to the results of the multicenter trial, but not our own previously reported results, all of the SLNs in this study were located in the axilla. 9,13

There are clear benefits to central injection for SLN localization. First, it is easy and requires less expertise than peritumoral injection. It avoids the necessity for image-guided injection with nonpalpable lesions. Central injection also avoids the overlap of the zone of diffusion in lesions in the upper outer quadrant with that of the SLN in the axilla and in medial lesions with the internal mammary lymph nodes. If our theory is correct that the drainage of the breast itself concurs with the drainage of the tumor bed, then central injection may also allow use of the SLN biopsy technique in patients with multicentric breast cancer.

Discussion

Dr. Edward M. Copeland III (Gainesville, Florida): For those of us learning the technique of sentinel lymph node biopsy, standardization of the procedure would be very helpful. Whether to use filtered or unfiltered radiocolloid or blue dye is debated, as is the site of injection and the time interval between injection and operation. If the results of this study by Dr. Klimberg and her colleagues can be confirmed, the technique of lymphoscintigraphy will be greatly simplified. Likewise, the need to use blue dye could be abandoned since, in this study, all blue nodes were radioactive. The blue dye gets all over everything when I use it and is particularly annoying when it covers the entire wound of the segmental mastectomy. In fact, I have quit using blue dye when the preoperative lymphoscintogram reveals an obvious “hot” node.

The questions I have for Dr. Klimberg are as follows:

One, can we abandon blue dye when subareolar injection identifies a hot node, as your data would suggest?

Two, if peritumoral injection of radiocolloid fails to identify a hot node, but subareolar injection does, as has happened in two of my patients to date, can we rely on the results of subareolar injection as having identified a true sentinel node?

Three, a 10% increase in background counts as a definition of a hot node seems to be overly sensitive. This would mean if the background counts were 10 then you would remove all nodes that had 11 counts. Would you elaborate?

Dr. Michael J. Edwards (Louisville, Kentucky): The institutions have reported a large experience with sentinel lymph node biopsy, and I think you have confirmed the reliability of this technique in the staging of breast cancer.

But that pertains primarily to institutions with a large experience. We now are faced with the task of trying to implement what has been proven as an effective way of staging our breast cancer patients in institutions which have a much smaller volume of cases, and sometimes in institutions where surgeons might do 20 or fewer breast cancers on a yearly basis. And in this context, I think it is very important that we develop techniques and define them such that they can be easily and simply implemented and implemented reliably. And in this context I think it is very important to recognize that there are several and multiple pitfalls along the way.

There are problems related to injections done by a nuclear medicine physician, injections done by a breast radiologist using image-guided techniques, and problems related to a surgeon maybe not retrieving the correct lymph node, and problems related to the pathologist analyzing that lymph node. Therein, I think, lies the primary contribution in this manuscript, which is to simplify the technique so that a surgical community with a lower volume can practice the technique very effectively.

And I am also pleased to see that there is concordance between what Dr. Klimberg found with the blue dye technique and with the sulfur technetium colloid. That is encouraging. However, with any technique, we must define it according to certain parameters. And I think it is very important, with this particular technology, that we carefully and precisely define the false-negative rate, i.e., the number of women who are going to be said to be node-negative when in fact they are node-positive. And in this study, we did not follow the identification of the sentinel lymph node with an axillary dissection, so we did not identify what the false-negative rate was.

I’d like Dr. Klimberg to respond to that and tell us where do we go from here. Do we repeat the study and do an axillary dissection to confirm the false-negative rate? Or do we simply accept the findings of historical controls?

Dr. V. Suzanne Klimberg (Closing Discussion): I just want to make a few comments. The first one was can we abandon blue dye, as well as the comment by Dr. Edwards, axillary node dissection.

There have been multiple studies. This is a meta-analysis with Mittenberg et al, from Brunicardi group. And there have been multiple studies which they looked at, and they have used a variety of blue dye or hot combined sulfur alone, plus or minus axillary node dissection, invasive or noninvasive, and this is the rest of the studies, including one multicenter trial from Krag, which I participated in, in which we used technetium alone, peritumoral or pericavity. And it does make a difference whether you inject around a cavity or not.

If you ferret out from this group and you look at the 912 from the meta-analysis, the axillary node dissection concordance rate is 98% and, from our multicenter trial, 443 patients is 96%, almost 97%, and then Cox’s data that just was published in Oncology in September also published 700 patients. The concordance rate is very high, missing 2%.

If we look at the axillary node dissection as it was defined by the consensus conference in 1990, a 2% miss rate was acceptable. Not 2% false-negative that everybody always says that the difference between a level 1 and 2 and a level 1, 2, and 3. It’s actually 2% miss rate, which if you look at—statistically, it depends on the prevalence of disease in the population. So if it is 20 to 30% and your miss rate is 2 to 3%, depending on the study you look at, your false-negative rate from those studies can be as high as 10 to 15%. And that was acceptable at that time in 1990 to the consensus conference.

So, in general, looking at these studies, I think that we can accept—and if you ferret out the blue dye studies, the false-negative rate of the biggest studies are 0% but do go as high as 9% from Gunther. But that is false-negative. Again, that would be a 1 to 2% miss rate in comparison to the previous data for the level 1 and 2, compared with the level 3.

We had to use two different methods to compare central with peritumoral, and blue dye would be our best method to put around the tumor, as far as its accuracy. I agree that axillary node dissection and complementary study would be excellent. That would be my one criticism of the study, that we didn’t follow with axillary node dissection, but we wanted to do this pilot study to see if it was even worth doing because of the controversy, to me—or the confusion—over what is the actual lymph drainage of the breast. And I think this confirms that it is very much worth doing.

We had three lymph nodes that were hot but not blue. None of those were positive lymph nodes, so I don’t know the answer to your question. I think we have to follow up a small pilot study looking at axillary node dissection. That is our plan.

So if central injection fails to identify the lymph node, then I think that we need to go ahead and do an axillary node dissection at this time. But I think it is very promising to go ahead and do that, and it certainly would simplify the technique for our purposes.

As far as the definition of a sentinel lymph node, everybody defines it differently. In our study using the C-Trak machine, the definition was actually 25 counts, and anything 10% above that was considered also a sentinel lymph node. So it is still a small number. The C-Trak is much less sensitive than the Neoprobe machine. We use both at this time, and the Neoprobe machine, we get much higher counts than that. I wouldn’t take out a count of 10 on the Neoprobe, and our background counts are usually much higher than that.

Before adopting sentinel lymph node as standard of care, I think we do need to ferret out these variations in methods. I think a central injection makes sense. We do our own injections now, as many institutions do. But if you have to rely on your nuclear medicine people—which some institutions won’t let the surgeon inject—it is very difficult to know that they are injecting exactly where you are. For a nonpalpable lesion or a needle localization, it makes it very difficult. Many people inject right into the needle localization.

We have to define what a sentinel lymph node is across the board, because everybody does define it differently.

The other question that has not been brought up is the pathological evaluation. We use the standard pathological evaluation, which is cutting the lymph node in half and comparing it. And then how to incorporate that into the management. So there are many things that have to be ferreted out.

Footnotes

Correspondence: V. Suzanne Klimberg, MD, Department of Surgery, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 725, Little Rock, AR 72205.

Presented at the 110th Annual Meeting of the Southern Surgical Association, December 6–9, 1998, The Breakers, West Palm Beach, Florida.

Accepted for publication December 1998.

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