10.1245/ASO.2004.03.057
Annals of Surgical Oncology 11:21-26 (2004)
© 2004 Society of Surgical Oncology
Lymphazurin 1% Versus 99mTc Sulfur Colloid for Lymphatic Mapping in Colorectal Tumors: A Comparative Analysis
Sukamal Saha, MD,
Adrian G. Dan, MD,
Blake Berman, MD,
David Wiese, MD,
Elie Schochet, MD,
Kimberly Barber, PhD,
Sharan Choudhri, MD,
Sunil Kaushal, MD,
Balvant Ganatra, MD,
Delip Desai, MD,
Marigowda Nagaraju, MD and
S. Mannam, MD
From the McLaren Regional Medical Center, Michigan State University Department of Surgery, Flint, Michigan.
Correspondence: Address correspondence and reprint requests to: Sukamal Saha, MD, Department of Surgery, McLaren Regional Medical Center, Michigan State University, 3500 Calkins Road, Suite A, Flint, MI 48532; Fax: 810-230-9607; E-mail: ssahadr{at}aol.com
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ABSTRACT
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Background: The combination of isosulfan blue (Lymphazurin) 1% and 99mTc sulfur colloid (TSC) may improve the feasibility and accuracy of lymphatic mapping for colorectal cancer.
Methods: At laparotomy, 1 to 2 mL of isosulfan blue and 1 mCi of TSC were injected subserosally. Sentinel lymph node (SLN) designation was based on blue staining for isosulfan blue and increased radioactivity for TSC. Focused pathologic analysis of the SLNs and standard pathologic examination of the remaining specimen were performed.
Results: A total of 57 consecutive patients were studied (median age, 71 years; 27 men and 30 women). Mapping was successful in 100% of patients with isosulfan blue and in 89% with TSC (P = .47). Lymphatic mapping was accurate in 93% of patients with isosulfan blue versus 92% with TSC (P = .53). The combined accuracy was 95%. A total of 709 lymph nodes were found (12.4 per patient): 553 non-SLNs (5.6% nodal positivity) versus 156 SLNs (16.7% nodal positivity; P < .0001). Isosulfan blue detected 152 SLNs, TSC detected 100, and both modalities detected 96. Of the SLNs detected by isosulfan blue only, 10.7% had nodal metastases, whereas 19.8% of SLNs detected with both modalities had nodal metastases (P = .028). Nodal disease was detected in 41% of patients with invasive carcinoma. Metastases were detected only in the SLNs in 26% and only by micrometastases in 11% of these patients.
Conclusions: These data confirm the efficacy of isosulfan blue and TSC for SLN mapping in colorectal tumors. No significant difference with respect to feasibility or accuracy exists between isosulfan blue and TSC. The metastatic yield is significantly higher in SLNs identified by both modalities compared with isosulfan blue only.
Key Words: Sentinel lymph node • Lymphatic mapping • Colorectal cancer • Technetium • Lymphazurin
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INTRODUCTION
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Sentinel lymph node (SLN) mapping has been successfully applied for accurate staging of melanoma and breast cancer.1,2 More recently, several authors have validated the use of SLN mapping as a staging technique for colorectal tumors.3–6 This method has been shown to be highly feasible and accurate in predicting the histological status of the nodal basin. SLN mapping for colorectal tumors has been shown to upstage a significant percentage of patients whose nodal metastases would not have been detected by conventional surgery and standard pathologic examination. This upstaging is made possible by focusing the attention of the pathologist and by the use of highly sensitive pathology techniques on the SLNs, which are assumed to be the lymph nodes with the highest likelihood of harboring metastatic disease. The cost, labor, and time requirements associated with these advanced pathology techniques prohibit their indiscriminate use in all of the lymph nodes of a specimen.
Isosulfan blue (Lymphazurin; US Surgical Corp., Norwalk, CT) has traditionally been used in the detection of SLNs for melanoma, breast cancer, and colon cancer. The addition of radioactive tracer as an adjunct to isosulfan blue in lymphatic mapping for melanoma has been shown to increase the accuracy of predicting the status of the nodal basin.7 In the United States, 99mTc sulfur colloid has been used along with a gamma probe for the detection of radioactivity levels within the lymph nodes during SLN mapping. The first use of radioactive tracer in SLN mapping for colorectal tumors was reported by Kitagawa et al.5 (Japan) in 2000; they used 99mTc tin colloid. In this initial series, the success rate for SLN mapping was 85%, and the status of the nodal basin was accurately predicted in 93% of those patients. A prospective study was undertaken that compared the use of isosulfan blue 1% and TSC for lymphatic mapping in colorectal tumors with respect to success rate, accuracy, number of lymph nodes identified, and histological yield of the lymph nodes identified by the various techniques.
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MATERIALS AND METHODS
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Patients were entered prospectively under an institutional review board–approved protocol over 2 years (February 14, 2001, to February 6, 2003). Every patient underwent a standardized work-up that included computed tomography of the abdomen and pelvis, as well as colonoscopy. Patients had a biopsy-proven tumor of the colon or rectum. All patients underwent a standard oncological resection. The patients who underwent complete endoscopic polypectomy also received a preoperative endoscopic injection of TSC along with a lymphoscintigram (Fig. 1). Before resection, the bowel containing the tumor was mobilized into the working field with great care to avoid violating the lymphatics of the mesentery. After this, 1 to 2 mL of isosulfan blue 1% and .5 to 1 mCi of TSC were injected circumferentially into the subserosal layer of the bowel by using a tuberculin syringe and a 30-gauge needle. Great care was taken to avoid spillage of the materials onto the field. To prevent spillage, negative pressure was maintained on the syringe every time the needle was withdrawn from the subserosal space. After injection of the radioactive tracer, the radioactive material, as well as contaminated sponges, syringes, and gloves, should be discarded according to radiation safety guidelines. The isosulfan blue–designated SLNs were those nodes in which a blue hue was detected within the first 5 to 10 minutes after injection of the isosulfan blue dye (Fig. 2). The TSC-designated SLNs were those identified by increased radioactivity—twice that of the baseline readings—by using a gamma probe (Fig. 3). All SLNs were immediately marked with a suture to facilitate their identification by the pathologist. Unlike in breast and melanoma, SLNs were not dissected out as soon as they were identified. This was followed by the completion of the standard en-bloc oncological resection of the tumor-bearing area and adjoining mesentery. In patients with mid to low rectal tumors, both TSC and isosulfan blue were injected submucosally via rigid proctoscope by using a spinal needle before the operation. At laparotomy, if no SLNs were seen outside the total mesorectal excision margin, the specimen was examined ex vivo immediately after the resection. The dye-stained nodes were dissected within the mesorectum ex vivo and marked with suture as SLNs. In a few colon patients, when preoperative polypectomy was performed, the TSC was injected via colonoscope before surgery into the submucosal layer. Multilevel microsections with hematoxylin and eosin and cytokeratin immunohistochemistry were then performed on all SLNs. The remainder of the specimen was examined with standard pathology techniques. The data were collected and analyzed by using computer spreadsheet software. The SLNs were separated into subsets depending on the method by which they were identified. The likelihood of yielding a histologically positive result was compared among the subset of SLNs identified by isosulfan blue only, the subset of SLNs identified by TSC only, and the subset of SLNs identified by both modalities. This was statistically analyzed by performing a two-sample t-test between proportions to determine whether there was a significant difference between the two subsets with respect to the percentage of histological positivity. The t-statistic was set as significant at a P value of <.05 and as a two-tailed probability. In a similar manner, a two-sample t-test between proportions was also used to determine whether a statistically significant difference between isosulfan blue and TSC existed with respect to success rate, accuracy, and number of SLNs identified.
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FIG. 1. Lymphoscintigram in a patient with complete polypectomy. SLN, sentinel lymph node. RT, right, LT, left.
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RESULTS
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A total of 57 consecutive patients (27 men and 30 women) were prospectively entered onto the study over 2 years (February 14, 2001, to February 6, 2003). The median age was 71 years, and the mean age was 70 years. The anatomical distribution of the tumors was as follows: cecum, n = 11 (19.3%); ascending colon, n = 16 (28.1%); hepatic flexure, n = 4 (7.0%); transverse colon, n = 5 (8.8%); descending colon, n = 2 (3.5%); sigmoid colon, n = 14 (24.6%); and rectum, n = 5 (8.8%; Fig. 4). The T-stage distribution of the population was as follows: Tis, n = 11 (19.3%); T1, n = 8 (14.0%); T2, n = 6 (10.5%); T3, n = 30 (52.6%); and T4, n = 2 (3.5%; Table 1). The lymphatic mapping was successful in 100% (57 of 57) of patients with isosulfan blue dye versus 89% (51 of 57) with TSC (P = .47). The status of the nodal basin was accurately predicted in 93% (53 of 57) of patients with isosulfan blue dye versus 92% (47 of 51) with TSC (P = .53). When isosulfan blue and TSC SLNs were used in combination, the accuracy increased to 95% (54 of 57).
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TABLE 1. T-stage distribution in the 57 patients and percentage of patients with nodal metastases for the T-stage groups
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A total of 709 lymph nodes were found (12.4 per patient) in the 57 patients. Of these, 156 (2.7 per patient) were SLNs and 553 (9.7 per patient) were non-SLNs. The number of SLNs varied from 1 to 4 and was distributed as follows for isosulfan blue: one SLN in 21.1%, two SLNs in 22.8%, three SLNs in 31.6%, and four SLNs in 24.6% of patients. In comparison, the SLN number distribution for TSC was as follows: one SLN in 33.3%, two SLNs in 41.2%, three SLNs in 21.6%, and four SLNs in 3.9% of patients with successful mapping. The percentages of histologically positive nodes in these two groups were 16.7% (26 of 156) for the SLNs versus 5.6% (31 of 553) for the non-SLNs (P < .0001). Of these 156 SLNs, isosulfan blue detected 152, and TSC detected 100 (P = .01; Table 2). The overlapping subset consisted of 96 SLNs that were detected by both isosulfan blue and TSC. Fifty-six SLNs were detected only by isosulfan blue, and four were detected only by TSC (Table 3). A given SLN was significantly more likely to be detected by both modalities than by isosulfan blue alone (P = .0009). The histological positivity of each subset of SLNs is listed in Table 3. In the subset of SLNs identified by isosulfan blue only, 10.7% (6 of 56) were positive for metastases, compared with 19.8% (19 of 96) of SLNs in the subset detected by both modalities (P = .028). When considering only the 19 patients with nodal metastases, 51.3% (19 of 37) of SLNs identified by both modalities were positive for metastases, compared with 28.6% (6 of 21) for SLNs detected by isosulfan blue only (P = .10).
Nodal metastases were identified in 41% of patients with invasive carcinoma. The sentinel nodes were the exclusive sites of metastasis in 26% of these patients (5 of 19). In 11 of the remaining 14 patients, metastases were detected in SLNs and non-SLNs. In the other three patients, nodal metastases were detected in the non-SLNs, whereas the SLNs were negative for metastases (skip metastases). The nodal metastatic disease was solely detected by micrometastases in 11% (2 of 19) of patients (Fig. 5).
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DISCUSSION
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The presence of nodal metastases is the most important prognostic factor in a variety of solid tumors, including colorectal cancer. Oncologists have long known of the diminished average length of survival in cancer patients with nodal metastases compared with those patients without nodal disease. Whereas SLN mapping is an avenue for highly accurate staging with minimal associated comorbidities for malignant melanoma and breast cancer, its primary role in colorectal cancer is to increase the accuracy of staging by identifying those lymph nodes with the highest likelihood of harboring metastases.8 The SLNs are believed to be the first lymph nodes in an orderly sequential progression of lymphatic flow from the primary tumor. The use of advanced and highly sensitive pathologic methods can then be focused on these few lymph nodes, resulting in significant upstaging, as has been reported by several authors over the past few years.3,4–6,8 The critical necessity of accurate staging is reflected by the fact that approximately 20% to 30% of patients who initially present without any nodal metastases detected by conventional surgery and pathology examination (American Joint Committee on Cancer stage I and II) go on to develop systemic disease within the next 5 years after the initial operation. It is estimated that 20% to 30% of patients with nodal metastases are upstaged by identifying cancer cells in the SLN only and that 10% to 20% of these patients are upstaged by findings of micrometastasis (size <.2 mm) only. Within this series, 26% of the patients with nodal disease were upstaged by metastases found in the SLN only. These metastases were detected as micrometastatic disease in 11% of these patients. A detailed review of the literature confirms these rates of upstaging. It is reasonable to hypothesize that the subset of patients who initially present with stage I and II disease and progress to systemic disease within the next 5 years may correspond to, and may indeed represent, the same subset of patients who are upstaged by SLN mapping and whose nodal disease would not have been detected by conventional histological analysis.
Traditionally, isosulfan blue has been the dye of choice in most published series for SLN mapping in breast cancer, malignant melanoma, and colorectal cancer. Isosulfan blue is readily available in the United States and is relatively easy to use. It exhibits lymphotropic properties and travels through the lymphatic channels relatively quickly. The infiltrated lymphatics and lymph nodes are easily visualized with the naked eye, and no additional equipment is necessary. Isosulfan blue, however, has been linked to allergic reactions in 1% to 1.5% of cases.9–11 These can range from urticaria and hypotension to life-threatening anaphylactic shock. The use of this dye has also been known to interfere with pulse oximetry readings during the course of surgery.12–15 TSC is also easily available in the United States and has been the radioactive tracer of choice for lymphatic mapping in malignant melanoma and breast cancer. In contrast to isosulfan blue, TSC requires additional instrumentation, such as a gamma probe, to detect the radioactivity level of the tissue. TSC, however, has not been linked to allergic reaction or interference with patient monitoring. The size of the isosulfan blue particles is smaller in comparison to the TSC particles, and the transit time of isosulfan blue through the lymphatic channels is therefore shorter. For this reason, a relatively short window of time (
5–10 minutes) has been described during which the isosulfan blue SLN mapping can be ideally performed in relation to the time of injection.5 It is recommended to first look for blue nodes and perform the isosulfan blue SLN mapping during the aforementioned window of opportunity while also allowing time for the TSC to travel through the lymphatics when injected during surgery. The TSC particles are larger and travel through the lymphatic channels to the lymph nodes at a much slower rate. It is therefore thought that over a similar period of time from the injection, the blue dye may reach more lymph nodes in the sequential progression of the lymphatic pathway. This may explain why isosulfan blue detected more nodes in comparison to the fewer nodes detected by TSC. The TSC-detected nodes, however, are likely the primary nodes in the natural sequential pathway of lymphatic flow away from the tumor and are therefore more likely to contain metastatic disease. This would explain the higher likelihood of the subset of SLNs detected by both isosulfan blue and TSC to yield a histologically positive result when compared with SLNs detected by isosulfan blue only. In their study of the diagnostic utility of SLN mapping in colon cancer, Merrie et al.16 also described more SLNs detected by isosulfan blue compared with the number detected by TSC. They also suggested that the faster transit time of isosulfan blue is the likely reason for the higher number of isosulfan blue–detected SLNs. Similarly, the few SLNs detected by TSC only may also be due to the fast transit time of the isosulfan blue, which may have already passed through the lymph node and progressed down the lymphatic pathway. For this reason, it is highly recommended that blue SLNs be tagged with a suture immediately after their identification.
As previously mentioned, our data indicate that more SLNs are identified by isosulfan blue. The success rate of SLN mapping with TSC only, without the simultaneous use of isosulfan blue, would decrease (100% to 89%), as supported by our data. We believe that even this number is artificially high, because many of the TSC-positive SLNs are identified by measuring the radioactivity of a lymph node that has already been detected by the blue dye. It is likely that without the use of isosulfan blue, the success rate of SLN mapping with TSC only would be well under 89%. However, SLNs identified by TSC are more sensitive for identifying metastatic disease. We propose that the combination of the two techniques may be the ideal method of performing SLN mapping in colorectal cancer, providing a means of visually identifying a good number of nodes with isosulfan blue and homing in on those nodes with the gamma probe. The SLNs with radioactive uptake are those that would more likely contain metastatic disease, because they are presumably the primary nodes in the lymphatic pathway from the tumor. These nodes should be specially designated as primary SLNs and should be the principal focus of attention for the pathologist. Further validation of these techniques should be confirmed by multi-institutional trials.
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ACKNOWLEDGMENTS
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The acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.
The authors thank Dr. Lucille T. Saha, Cynthia Duncanson, Maureen Snyder, Diane Gardner, William Joy, and Ted Klopf.
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FOOTNOTES
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Presented at the Society of Surgical Oncology—56th Annual Cancer Symposium, Los Angeles, California, March 5–9, 2003.
Sentinel lymph node mapping was applied to accurately stage 57 patients with colorectal tumors. Lymphazurin and technetium sulfur colloid were utilized in all of these patients and the efficacies of the two modalities were statistically analyzed and compared.
Received for publication March 8, 2003.
Accepted for publication September 4, 2003.
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ABSTRACT
INTRODUCTION
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