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10.1245/ASO.2005.07.014
Annals of Surgical Oncology 12:533-538 (2005)
© 2005 Society of Surgical Oncology
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Original Article

The Impact of Nonvisualization of Sentinel Nodes on Lymphoscintigraphy in Breast Cancer

C. Rousseau, MD1, J. M. Classe, MD2, L. Campion, MD3, C. Curtet, PhD1, F. Dravet, MD2, R. Pioud, MD2, C. Sagan, MD4, B. Bridji, MD1 and I. Resche, MD1

1 Service of Nuclear Medicine, René Gauducheau Cancer Center Nantes-Saint Herblain, Boulevard Monod, 44805, Saint Herblain Cedex, France
2 Service of Surgery, René Gauducheau Cancer Center Nantes-Saint Herblain, Boulevard Monod, 44805, Saint Herblain Cedex, France
3 Service of Statistics, René Gauducheau Cancer Center Nantes-Saint Herblain, Boulevard Monod, 44805, Saint Herblain Cedex, France
4 Service of Pathology, René Gauducheau Cancer Center Nantes-Saint Herblain, Boulevard Monod, 44805, Saint Herblain Cedex, France

Correspondence: Address correspondence and reprint requests to: C. Rousseau, MD; E-mail: c-rousseau{at}nantes.fnclcc.fr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: This study aimed at evaluating the relationship between the nonvisualization of sentinel nodes (SNs) at lymphoscintigraphy and the intraoperative detection rate, radioactive counts in vivo, and histological status of SNs.

Methods: Two hundred eighty patients with infiltrating breast carcinoma (T0, T1/T2) underwent preoperative lymphoscintigraphy before gamma probe–guided SN biopsy.

Results: The surgical identification rate with a gamma probe was 84.6% (56 of 280) in lymphoscintigraphy-negative patients and 93.2% (224 of 280) in lymphoscintigraphy-positive patients (P < .05) after two subdermal periareolar injections. The average number of SNs per patient was 1.7 in lymphoscintigraphy-negative patients and 2.2 in lymphoscintigraphy-positive patients (P < .01), as assessed by gamma detection. The mean age of lymphoscintigraphy-negative patients was 62 ± 10 years, versus 55 ± 13 years for lymphoscintigraphy-positive patients (P < .001). The median radioactive count in dissected SNs identified by gamma detection was 204 cps (range, 4–618 cps) in lymphoscintigraphy-negative patients, versus 606 cps (range, 43–16,928 cps) in lymphoscintigraphy-positive patients (P < .001). The rate of macrometastatic SNs was 40% in lymphoscintigraphy-negative patients, versus 30% in lymphoscintigraphy-positive patients (not significant), whereas the size of involved SNs was 16.6 mm in lymphoscintigraphy-negative patients, versus 13.1 in lymphoscintigraphy-positive patients (P < .05). The micrometastasis detection rate in SNs from lymphoscintigraphy-negative patients was 6.25%, versus 23.3% in lymphoscintigraphy-positive patients (P < .01).

Conclusions: Negative lymphoscintigraphy was observed in 20% of patients and was more frequent in elderly patients. Negative lymphoscintigraphy was predictive of a lower surgical identification rate and fewer detected SNs. These SNs had fewer micrometastases, were fairly large, and tended to harbor metastases.

Key Words: Sentinel lymph node • Breast cancer • Lymphoscintigraphy • Probe


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Sentinel node (SN) biopsy is an alternative to standard axillary lymph node dissection in breast cancer staging.1 The significance of the nonvisualization of SNs at lymphoscintigraphy is still unclear. The multiplicity of approaches and the fact that lymphoscintigraphy has evolved over time have contributed to raise a number of controversial issues regarding the visualization of SNs by lymphoscintigraphy.2,3 These include the choice of mapping agents, the site of injection, the type of image guidance, and the necessity for preoperative lymphoscintigraphy. This study, involving patients for whom SNs were visualized or not at lymphoscintigraphy, assessed the effect of a nonvisualization on the detection rate at operation, radioactive counts in vivo, and the histological status of SNs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
Two hundred eighty patients were included in the study between January 2001 and June 2003. SN biopsy was offered to patients who met all inclusion criteria, and lymphoscintigraphy was performed as an accepted routine practice. The criteria were the following: preoperative diagnosis of invasive breast carcinoma, indication for conservative surgery (T0, T1, T2 ≤ 2 cm), and clinically negative axillary lymph nodes (N0). Exclusion criteria included pregnancy, suspicious palpable axillary lymph nodes (N1, N2), neoadjuvant treatment (diagnostic surgery, neoadjuvant chemotherapy), and indication for radical surgery. Diagnosis of invasive carcinoma was established on the basis of preoperative microbiopsy.

Detection Method
Surgical biopsy and lymphoscintigraphy were used for detection. Agents used to detect SNs included unfiltered rhenium sulfur colloid labeled with technetium and with a mean diameter of 100 nm (Nanocis; Schering-Cis Bio International, Paris, France) and patent blue dye. Two subdermal .1-mL injections of radiocolloid were made at the periareolar site corresponding to the tumor quadrant. A dose of 30 to 40 MBq was injected the day before surgery. A 3- to 5-minute postinjection massage of the entire breast was performed to increase afferent lymphatic flow, which is thought to increase clearance of the radiocolloid. Lymphoscintigraphy was performed 2 hours after injection. A visualized SN was defined as an area of increased uptake in the axilla, internal mammary chain, or any other site within the breast. Nonvisualization was characterized by the absence of uptake at lymphoscintigraphy in these same nodal basins. Breast images (including the axillary, internal mammary, and supraclavicular lymph nodes) were obtained by using a Millenium Hawk-Eye dual-head gamma camera (General Electric, Haifa, Israel) equipped with a low-energy high-resolution collimator. Acquisition time was 10 minutes. Anterior and external lateral views (matrix size 128 x 128) of the imaged breast were obtained. No shielding was used at injection sites. No skin markers were used. All surgical procedures were performed by three surgeons with extensive experience in SN biopsy. Two intraparenchymal 1-mL injections of patent blue dye were performed. These injections were performed in the operating room with patients under general anesthesia, 10 minutes before axillary incision. The blue dye method was never performed alone. Intraoperative detection of the radioactive colloid was performed using a Modelo2 gamma probe with a BgO scintillator (DAMRI, CEA, Paris, France). Back ground radioactivity was defined as the count rate in the contralateral chest wall. SNs were stained blue and/or radioactive (i.e., in vivo counts were at least twice as high as the background). The anatomical localization (based on Berg’s classification) of all detected SNs was recorded.

Histology
No frozen sections were performed. All lymph nodes were embedded. Blocks were sectioned perpendicularly to their longest axis. Ten 4-µm-thick sections were prepared for each SN. Sections 1, 4, and 7 were stained with hematoxylin and eosin. When metastases were not detected in hematoxylin and eosin–stained sections, immunohistochemical staining was performed on three intermediate sections by using a keratin-specific antibody. A micrometastasis was defined as a metastasis <2 mm.4

Statistical Analysis
Age, type of tumor, location of the primary lesion, number of detected SNs, radioactivity content of SNs, surgical identification rate, intraoperative detection method, and SN status were recorded for each patient.

Statistical analysis was performed by using the {chi}2 test or Fisher’s exact test for qualitative variables and small numbers of patients. Quantitative variables were analyzed with Student’s t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
SNs were not visualized (group 1) in 21.5% of patients (60 of 280) and were visualized (group 2) in 78.5% of patients (220 of 280). No difference was observed between groups regarding the location of the tumor and the type of cancer (Table 1Go). One hundred forty-six (52%) of the 280 tumors analyzed were located in the outer quadrant of the breast, and 80 (28.5%) were T0 tumors, 147 (52.5%) were T1 tumors, and 53 (19%) were T2 tumors. One site of injection was used: periareolar injection. Patient age ranged from 34 to 85 years (mean age, 58 years). The age of patients from group 1 (nonvisualized SNs) was significantly higher (range, 34–85 years; mean, 62 years) than that of patients in group 2 (range, 42–85 years; mean, 55 years; Table 1Go). The age distribution of patients with visualized and nonvisualized SNs showed that nonvisualization of SNs most often occurred in patients aged ≥ 70 years (Fig. 1Go).


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  		TABLE 1. Patient distribution according to tumor location, type of cancer, cancer stage, and patient age
 

Figure 1
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  		FIG. 1. Age distribution of patients with visualized and nonvisualized sentinel lymph nodes.

 
There was a significant difference in the detection rate at operation between the two groups (Table 2Go). In group 1 (nonvisualized SNs), the rate of surgical identification was 84.6%, versus 93.2% in group 2 (P < .05). The detection rate was thus lower in patients for whom SNs were not visualized at lymphoscintigraphy; however, it increased when the blue dye method was also used.


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  		TABLE 2. Intraoperative identification method, number of detected SNs, SN status, and median radioactivity content in SNs
 
The number of SNs per patient based on gamma detection was 1.7 for group 1 and was 2.2 for group 2 (P < .01). The median radioactivity content in dissected SNs identified by gamma detection was 204 cps (range, 4–618 cps) for group 1 versus 606 cps (range, 43–16,928 cps) for group 2 (P < .001). The lower surgical detection rate observed in group 1 was consistent with the fact that the in vivo median radioactivity content of gamma probe-detected SNs was significantly lower in patients from group 1 than patients from group 2 and also with the fact that the number of SNs detected with the gamma probe was also significantly lower in the former nonvisualized group.

The rate of macrometastatic SNs was 40% in group 1 and 30% in group 2 (P = .14), whereas the size of involved SNs was 16.06 mm in group 1 and 13.01 mm in group 2 (P < .05). The micrometastasis detection rate in SNs from group 1 patients was 6.3%, versus 23.3% in patients from group 2 (P < .01). Regarding SN status, more macrometastases tended to be found in dissected nodes from patients with nonvisualized SNs at lymphoscintigraphy. In summary, the patient distribution according to SN status, rate of SN identification at operation, and patient age in group 1 was statistically different from that in group 2.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
A recent retrospective study showed that a statistical association exists between negative lymphoscintigraphy, unsuccessful axillary mapping, and a high number of metastases in axillary nodes.5 Our results have likely demonstrated that metastatic involvement tends to be associated with negative lymphoscintigraphy. According to the literature, the purpose of lymphoscintigraphy is to determine the number of lymph nodes in the direct drainage pathway of a tumor, differentiate first-tier from subsequent lymph nodes, and locate SNs. Tracers accumulate in lymph nodes, and tracer retention is associated with the presence of macrophages lining the nodal sinuses, whose main function is to clear particulate matter from incoming lymph through an active and saturable phagocytosis process. When massive metastatic node involvement occurs, few normal cells remain in the node, the clearance mechanism is lost, and the node cannot be visualized by lymphoscintigraphy.6 The size of colloid particles7 and the route of administration8 have been thought to affect visualization of lymph nodes. 99mTc-human serum albumin nanocolloid and 99mTc-sulfur colloid are currently the most widely used radiocolloids for SN biopsy.6 Subdermal periareolar injections were performed in all cases in our study. In the literature, this route of administration is associated with high and fast rates of migration of colloid particles from the injection site and high rates of SN visualization by lymphoscintigraphy.9,10 Moreover, the 3- to 5-minute postinjection massage may have enhanced the clearance of radiocolloid because it may have increased dispersion of the injected bolus, interstitial pressure, and uptake of the mapping agent into the breast lymphatics.11 By decreasing the labeling dilution volume twice, Valdes Olmos et al.12 observed a 99% rate of SN visualization without increasing the injection volume; lymphoscintigraphy was positive in almost 90% of patients (78.5% in our study). Moreover, radioactive counts in SNs from patients who were given optimized tracer injections were significantly different (70% vs. 35% with nonoptimized injections). Such an improvement may be accounted for by a more effective transport of the tracer from the injection site, a more extensive distribution of the tracer into SNs, and an increased attachment to and ingestion by macrophages.

A key point is the predictive value of negative lymphoscintigraphy with regard to the failure of intraoperative SN biopsy. As in our study, others have reported that even when no axillary SNs are visualized at lymphoscintigraphy, SNs may be detected at operation, although the detection rate is much lower than when lymphoscintigraphy is positive.13,14 Authors have reported SN identification rates at operation of 76% to 81% in patients with negative lymphoscintigraphy, whereas mean SN identification rates of 92% and 94% were reported when radiocolloid alone and both mapping agents were injected, respectively, in patients with positive lymphoscintigraphy. We, conversely, observed a significant difference (approximately 10%) between our two groups of patients, although with a much higher identification rate (88.4%), as reported in the literature (76%–81%), with injection of both mapping agents in patients with nonvisualized SNs at lymphoscintigraphy. This study, however, shows that negative preoperative lymphoscintigraphy is a poor predictor of intraoperative SN biopsy failure. Some studies have excluded patients from SN biopsy on the basis of negative preoperative lymphoscintigraphy.15 Our results suggest that intraoperative SN mapping with a gamma probe is independent of SN visualization at lymphoscintigraphy and that axillary SN biopsy should be attempted regardless of lymphoscintigraphy results. Positive lymphoscintigraphy enables the surgeon to focus gamma detection on the correct spot in the axilla, thereby reducing operation time and increasing the overall accuracy of SN biopsy.16 The surgeon’s skill had a role in the identification rate and improved SN detection.17

Consequently, although failure to detect SNs at lymphoscintigraphy is a disadvantage, our findings suggest that when preoperative lymphoscintigraphy fails to detect SNs, intraoperative detection can be improved by combining the blue dye method and injection of radiocolloid (88.4% vs. 84.6% with radiodetection only), as reported in the literature. In patients with positive lymphoscintigraphy, SN detection with a gamma probe alone may be sufficient, provided that the SN has been accurately located. In addition to the fact that it increases the surgical identification rate, there is an additional interest in using the blue dye method in patients with negative lymphoscintigraphy: although using a gamma probe may enhance intraoperative detection of radioactive lymph nodes, it does not allow identification of SNs, because the probe cannot visualize lymphatic channels, and this makes it impossible to determine which nodes drain into which.18 Actually, even in the procedure of radioguided SN biopsy, the definition of surgical success rate cannot identify whether the node identified as the SN is the true sentinel or not. It should be emphasized that more than one SN is identified in a significant proportion of patients and that reported mean values are on the order of two or more SNs per patient.19

Finally, differences in the detection rate as a function of age should be discussed, because in our study, patients with nonvisualized SLNs were older (approximately 70 years) than patients with visualized SLNs. Birdwell et al.13 hypothesized that the diffusion rate of the tracer is lower in older patients. Indeed, decreased tissue turgor is observed in older women, which leads to lower lymphatic pressure and less efficient delivery of the mapping agent to the nodes. Increased age has recently been associated with a decreased spread of malignancies to axillary lymph nodes.20 Fewer axillary lymph node metastases are found in older patients, and SN biopsy may therefore prove most beneficial for them because the morbidity associated with axillary lymph node dissection can thereby be prevented. It has been reported that the combination of increased age and body mass index increases the odds of mapping failure by approximately 12%.21 Because an increasing proportion of patients is likely to be overweight in the near future, it is important that other factors that decrease the effectiveness of SN detection be identified. A second hypothesis is that the agent may be successfully delivered to the node, although in low concentration due to the limited sinus space left in fat-replaced nodes, which are most commonly found in older patients.22 All other investigated parameters, such as tumor location, type of cancer, and cancer stage, showed no relation to negative lymphoscintigraphy.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In conclusion, this study shows that in 88.5% of patients with nonvisualized SNs at lymphoscintigraphy, a SN is detected at operation. Preoperative lymphoscintigraphy nevertheless increases likelihood of SN detection (a high number of detected SNs). The nuclear medicine physician provides the road map that guides the surgeon.

Even if no SN is detected at lymphoscintigraphy, one cannot exclude the possibility that axillary metastases may be present. These SNs had fewer micrometastases, were fairly large, and tended to harbor metastases. In women ≥ 70 years for whom preoperative lymphoscintigraphy failed to detect SNs, intraoperative detection of SNs may be optimized by using both a radiocolloid and the blue dye method.

Received for publication July 13, 2004. Accepted for publication January 19, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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