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Annals of Surgical Oncology 10:323-329 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

A New Agent, Blue and Radioactive, for Sentinel Node Detection

Mahmoud El-Tamer, MD, FACS, Rola Saouaf, MD, Ted Wang, PhD and Rashid Fawwaz, MD

From the Departments of Surgery (ME-T) and Radiology (RS, TW, RF), College of Physicians and Surgeons, Columbia University, New York City, New York.

Correspondence: Address correspondence and reprint requests to: Mahmoud El-Tamer, MD, FACS, Department of Surgery, Columbia University, College of Physicians and Surgeons, 161 Fort Washington Avenue, Atchley Pavilion, Room 1019, New York, NY 10032; Fax: 212-305-0727; E-mail: me180{at}columbia.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Although with some disadvantages, combining radiotracer and isosulfan blue facilitates the detection of sentinel lymph nodes. This study was designed to evaluate the use of 99mTc-labeled phthalocyanine tetrasulfonate (99mTc-PCTS) as a single agent for simultaneous blue staining and radiotracer localization of the sentinel lymph node.

Methods: Twelve rabbits were injected into the dermis and subcutaneously in the distal hind limb with 1 mL of blue 99mTc-PCTS (.5 mCi). The popliteal and inguinal fossae were explored between 15 minutes and 24 hours after injection for blue and/or radioactive tissue. Popliteal and inguinal fossae and other lymph nodes and organs were harvested for determination of the concentration of radioactivity and for histology.

Results: Within minutes of 99mTc-PCTS injection, the lymphatic channels were easily identified by the blue color. At 10 minutes, the radioactive count over the popliteal fossa was significantly higher than over other areas. At exploration, a blue and radioactive popliteal node was identified in all animals; inguinal nodes were neither blue nor radioactive. At death, the radioactivity in the popliteal node was 1000 times higher than in other nodes or organs. Although fainter, the blue color in the popliteal node was still visible at 6 weeks. Histological sections of popliteal node identified the dye in the cytoplasmic compartment of the cells.

Conclusions: Technetium-99m PCTS is a single agent that identifies sentinel lymph nodes by color and radioactivity and is retained for an extended period of time without migrating to other tissues.

Key Words: Sentinel node • Phthalocyanine • Radiotracer • Isosulfan blue


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node biopsy is currently used in lieu of complete axillary node dissection in melanoma1–4 and breast cancer5–14 in major centers in North America. The role of sentinel node biopsy is expanding to other malignancies, including colon,15–19 esophageal,20 gastric,20–23 prostate,24 thyroid,25,26 head and neck,27 and others.28 The technique used to detect sentinel nodes has focused on using a vital blue dye, a radioactive tracer, or a combination of both.

Isosulfan blue is the currently the dye of choice in North America; it is injected around the tumor minutes before node biopsy.29 Massaging the injection site and exploring the nodal basin for visual identification of blue lymphatic channels leading to the blue lymph node follow the injection. Vital dyes are poorly retained in the node, and the color fades after 20 to 30 minutes, decreasing the detection rate.30 The radiotracer technique uses a radioactive compound, usually 99mTc, attached to a carrier such as sulfur colloid, albumin, or antimony.31 This tracer is most frequently injected around the tumor 1 to 24 hours before surgery. In the operating room, a gamma probe detector, which emits a high-pitched sound when it detects radioactivity, is used to locate the sentinel lymph node.

Identification of the sentinel node is crucial for the success of the procedure. Although there is debate about the optimal method for sentinel node detection, many surgeons favor combining the techniques to improve the detection rate and facilitate the procedure.32–36

The combination of techniques may be associated with some disadvantages. The radiotracer is usually injected an hour before surgery and very frequently the night before surgery, creating a logistical inconvenience to patients and surgeons, particularly in busy centers.37,38 Although some have reported 90% of sentinel nodes being blue and radioactive with the combination technique,39 others have shown a concordance rate of blue and radioactive (hot) nodes in only 30% of the nodes.40

The purpose of this article is to explore a new agent for sentinel node detection. We were looking for a single agent that combines both detection methods, travels quickly through lymphatic channels, and is retained in the sentinel node for a significant period of time.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The protocol was reviewed and approved by the Institutional Animal Care and Use Committee. The animal model used was the New Zealand White rabbit. The weight of the animals varied between 5 and 8 pounds. All reagents in this investigation were purchased from commercial suppliers and used as received, unless specified. Porphyrin Products, Inc. (Logan, UT) supplied phthalocyanine tetrasulfonate (PCTS). The 99mTc-sodium pertechnetate (Na99mTcO4) was obtained from an alumina-based molybdenum-99/99mTc generator supplied by DuPont-NEN, Inc. (Boston, MA). Instant thin-layer chromatography-silica gel (ITLC-SG) and Whatman No. 1 paper were purchased from Fisher Scientific (Plainfield, NJ). The gamma probe detector was supplied by US Surgical (Norwalk, CT).

Preparation of 99mTc-PCTS
The Na99mTcO4 solution (1.11 GBq/200 µl of normal saline) was added to a freshly prepared stannous chloride solution (.38 mg, .02 mmol/100 µl of .1 N HCl). The mixture was stirred magnetically at room temperature for 2 minutes. The PCTS solution (100.2 mg, .12 mmol/2 mL, pH 8.2) was added dropwise, and the mixture was stirred at room temperature for another 5 minutes. The reaction mixture was incubated for 30 minutes. The product was passed through a .22-µm filter. The radioactivity yield was 1.081 GBq (97.4%). The pH of the product was 7.8. The proposed chemical structure of 99mTc-PCTS is seen in Fig. 1.



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  		FIG. 1. The proposed chemical composition of 99mTc-PCTS.

 
Quality Control of 99mTc-PCTS
The radiochemical purity of the product was analyzed by radiochromatography with Whatman No. 1 paper and the ITLC-SG system and developed in an acetone system. One drop of sample was spotted on the chromatographic strips (Whatman No. 1 and ITLC-SG), air-dried, and developed in 3 mL of acetone. The Rf value of Na99mTcO4 was 1.0. The Rf value of the product, 99mTc-PCTS, was .0 on both systems.41,42

The chromatographic strips were cut into halves. The radioactivity of the top and bottom portion of the strips was measured in a radioactivity dose calibrator. Thus, by subtracting the amount of Na99mTcO4 from the total activity, the radiochemical purity of the product was determined. The results of radiochemical purity were 97.4% and 97.5% by the Whatman No. 1/acetone system and the ITLC-SG/acetone system, respectively.

The rabbits were put and maintained under general anesthesia with a combination of xylazine (2–5 mg/kg) and ketamine (35–50 mg/kg) intramuscularly. The hair of the medial aspect of the right hind limb, the popliteal fossa, and the groin was shaved. The 99mTc-PCTS was injected into the dermis and subcutaneous tissue at the level of the ankle joint. The amount injected was constant, at 500 µCi in 1.0 mL, with a 27-gauge hypodermic needle. The area of injection was massaged, and the popliteal fossa, the femoral triangle, and the rest of the body were scanned with a gamma probe detector. The skin of the hind limb, as well as the femoral triangle, was examined for blue lymphatic channels. A skin incision was performed over the popliteal fossa and the femoral triangle, and these spaces were explored visually for any blue-colored lymphatic channels or lymph nodes. By using the gamma probe detector, the popliteal and inguinal fossae were scanned through the skin incision, and the amount of radioactivity detected was recorded as counts per 10 seconds. The popliteal fossa and inguinal triangle contents were excised in totality and submitted for gamma radiation counting to determine the radioactive count per minute per gram of tissue. At the completion of identification of the popliteal and inguinal fossa exploration, the abdominal cavity was opened, and the iliac and periaortic lymph nodes, as well as the liver and spleen, were scanned for radioactivity. At the completion of the exploration, the animals were killed, and samples were obtained from blood, lung, heart, liver, spleen, kidney, mesenteric lymph node, rectus femoris muscle, contralateral popliteal lymph node, thyroid, stomach, and intestines. To evaluate the body distribution of 99mTc-PCTS, we measured radioactivity with a gamma counter in all of the organs harvested.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Within 3 to 5 minutes of injection of 99mTc-PCTS into the hind limb, the cutaneous lymphatic channels over the distal hind limb were stained with a distinct blue color and converged toward the popliteal fossa (Fig. 2). No cutaneous blue lymphatic channels were identified above the knee joint. By using the gamma probe detector, the body of the animal was scanned for radioactivity at different time intervals. The injection site had the highest radioactivity, followed by the popliteal fossa. The radioactive count over the popliteal fossa was detected within 5 minutes of injection of the 99mTc-PCTS. The radioactive count over the popliteal fossa varied from 350 to 700 counts per 10 seconds from 5 minutes to 24 hours after injection (Table 1). The radioactive count, detected by the gamma probe, over the rest of the body was similar to the background level. The area over the bladder emitted a slightly higher level than the background level.



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  		FIG. 2. Cutaneous lymphatic seen within minutes of injection of 99mTc-phthalocyanine tetrasulfonate. The needle marks the knee joint.

 

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  		TABLE 1. Results of exploration of popliteal and inguinal fossae for blue and radioactive nodes
 
The ipsilateral popliteal fossa was explored for any blue lymphatic channel or blue lymph nodes. In all 12 rabbits, the cutaneous lymphatic channels distal to the knee were easily identified. In all cases, the lymphatic channel led to a popliteal lymph node that was stained with dark blue color (Figs. 3–5); that node had a high radioactive count in all animals. The dissection was performed at different time intervals (15 minutes to 24 hours) from the time of injection of 99mTc-PCTS.



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  		FIG. 3. Popliteal fossa dissection 15 minutes after injection. The lymphatic channels are entering into the popliteal node.

 


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  		FIG. 4. Popliteal fossa dissection 25 minutes after injection. The popliteal node is deep blue in color.

 


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  		FIG. 5. Popliteal fossa dissection 24 hours after injection. The popliteal node maintained its deep blue color.

 
The inguinal triangle was explored in every animal. In only 1 of 12 rabbits was a deep blue lymphatic channel identified. We were unable to detect any blue inguinal lymph node or radioactive tissue in any of the 12 rabbits.

The animals were killed at different time points after completion of exploration; tissue was harvested from different organs for measurements of radioactivity. The counts of radioactivity per gram of tissue per minute are listed in Table 2. The injection site was the right distal hind limb. The highest count detected was in the right popliteal lymph node. The right inguinal nodes, the second-echelon nodes of the hind limb, had counts similar to those of the left popliteal nodes and the spleen. Most other tissues, except for the kidney, had counts 1000 times less than the popliteal node. In the kidney, the count increased over 24 hours and reached a value 10 to 100 times that of other organs; however, it remained 20 to 200 times less than the popliteal node counts.


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  		TABLE 2. Radioactivity in body organsa
 
Encouraged by the prolonged retention of the dye in the popliteal node, we injected two separate animals with nonlabeled PCTS and explored them at 6 weeks after injection. The popliteal lymph node was persistently blue, although it was fainter than nodes explored within 24 hours (Fig. 6). The inguinal fossa was similarly explored for blue lymphatic channels or blue lymph nodes in these two animals, and no blue lymph nodes or channels were identified.



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  		FIG. 6. Popliteal fossa dissection 6 weeks after injection. The popliteal node retained a light blue color.

 
The popliteal lymph nodes were sent for histological evaluation. The slides were prepared by using the standard hematoxylin and eosin stain. The 99mTc-PCTS seemed to be contained within the cytoplasm of some of the cells in the lymph nodes at 24 hours after injection (Fig. 7). At 6 weeks after injection, a minimal amount of the dye was identified within the reticuloendothelial cells of the lymph node.



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  		FIG. 7. Hematoxylin and eosin stain of the popliteal node 24 hours after injection. The dye seems to be retained in the cytoplasm of the cells, explaining the retention of the blue color.

 
To evaluate the tattooing effect over the skin, two separate animals were injected with the dye, and the injection sites were observed over time. The cutaneous discoloration of the dye almost completely resolved by 17 weeks of follow-up.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Sentinel node detection is the cornerstone of sentinel node biopsy. Combining visual (isosulfan blue) and aural (radiotracer) detection methods seems to improve the detection rate and facilitates the procedure.

PCTS is a water-soluble compound with a molecular weight of 834.78. It is a porphyrin-like substance, a family of compound with proven accumulation in the reticuloendothelial cells of the lymph nodes when injected intravenously.43,44 PCTS is inherently blue, with an affinity to metals; it has the capability of combining both detection modalities into one agent. The solubility in water and small molecular weight of PCTS have given the compound the ability to travel quickly from the injection site through the lymphatic channels to the sentinel lymph node. Its accumulation in the reticuloendothelial cells allows the lymph node to retain a blue color for few weeks.

The animal model designed stipulated the sentinel node to be in the popliteal fossa and the second lymphatic basin to be the inguinal lymph nodes. In all animals, the dye and radioactivity were exclusively limited to the popliteal fossa. Although in one of the rabbits a deep lymphatic channel was identified deep in the inguinal fossa, we were unable to detect any blue node in that fossa in any of the animals. With the gamma probe detector, radioactivity was limited to the popliteal fossa only. The samples of tissue harvested from different organs showed relatively low radioactive counts per minute per gram of tissue when compared with the ipsilateral popliteal node. Such data confirm the preferential uptake of the radioactive dye into the sentinel node even 24 hours after injection. The kidney showed a slightly higher radioactive count than other organs, albeit far lower than the ipsilateral popliteal lymph node. The radioactive counts in tissue from different organs raises two points. First, the gradual increase of counts in the kidney over 24 hours is a reflection, perhaps, of the method of metabolism or excretion of the compound. The second point is the absence of any significant increase of radioactivity in the thyroid and stomach. These two organs are preferential sites of distribution for free 99mTc. This lack of significant increases in the thyroid and stomach is an indirect proof of the stability and the strength of binding between PCTS and 99mTc. Furthermore, the only significant radioactivity measured was limited to the injection site and the popliteal lymph node; this allowed us to conclude that 99mTc-PCTS does not seem to travel to any other organ, particularly the liver or spleen. The relatively low radioactivity detected in other organs, except the kidney, is probably the result of a small amount of free 99mTc present in the injected solution. We have not measured the distribution of PCTS beyond 24 hours from injection because of the decay of 99mTc.

This experiment showed a quick transit of the compound from the injection site to the sentinel node. We were able to see the bluish staining of the cutaneous lymphatic within minutes of injection. Furthermore, the popliteal node was visually distinguished from the surrounding tissue within 15 minutes. The compound has a deep blue color not matched by any of the surrounding tissues, allowing easy visual identification of the lymph node. The radioactivity carried by the compound to the lymph node is sufficient to allow identification with a gamma probe detector (aural identification). These characteristics of the new agent—deep blue color, affinity for radioactive metals, and quick transit time—make this agent suitable for sentinel node detection.

Hypothetically, the agent could be injected on the operating table just before preparation and draping in patients. Such an agent may obviate the need for injection of the radioactive substance the day before surgery, particularly when preoperative lymphoscintigraphy is not needed, and still allows sentinel node detection with radioactivity and color in cases performed on the morning of surgery. PCTS may facilitate the flow of patients through the operating room and may obviate a visit to the hospital the day before surgery. An extra hospital visit is a major issue for working patients and particularly for those who live at a distance from medical centers.

It is not clear why some authors have reported 30% of sentinel nodes being blue and hot. Whatever method one is using, the sentinel nodes remain the same and ought to be blue and radioactive. There are two possible explanations for this discrepancy. (1) Radioactive substances, when filtered and injected a significant time before the operative procedure, may travel to second- and third-echelon nodes that are not identified by the blue technique. (2) Vital dyes are poorly retained in the node, and the color fades after 20 to 30 minutes, thereby decreasing the detection rate.30

PTCS is a noncolloidal water-soluble substance that is retained in the sentinel node for an extended period of time without traveling to second-echelon nodes (inguinal nodes in the animal model). Use of 99mTc-PCTS has allowed identification of sentinel nodes with visual (blue color) and aural (radioactive) methods in all animals. We postulate that 99mTc-PCTS, when used in humans, would achieve similar results.

The combination of both detection modalities—visual and aural—into one compound given through one injection may be important in cancers in which the injection may not be performed transcutaneously. In colon, gastric, or head and neck cancers, injections may be performed through an endoscope before surgery. Dual injection in such cases may necessitate dual endoscopies when isosulfan blue and 99mTc-labeled sulfur colloid are injected separately; 99mTc-PCTS would obviate dual injections.

This experiment has shown that PCTS is retained in the node for an extended period of time (up to 6 weeks). This characteristic is related to the uptake of the dye into the cytoplasm of reticuloendothelial cells within the popliteal lymph node. This prolonged retention of the 99mTc-PCTS in the node would permit injection 24 hours before the surgery. However, if the PCTS is labeled with another radioactive substance with a longer half-life, such as indium-111, the agent may be injected days before the surgical procedure. This is clearly in contradistinction to isosulfan blue, which is cleared from the node quickly, giving the surgeon a narrow window of time to dissect the node.

Phthalocyanine has been previously used in humans in the nonsulfonated form. Phthalocyanine copper, also known as cyan blue, has been approved by the Food and Drug Administration (FDA) for use as a colorant in suture materials and intraocular lenses.45 In Germany, it is approved as a food colorant.46 Phthalocyanine aluminum has been used as a photosensitizer in humans endobronchially, as an aerosol, and intravenously.47 The tetrasulfonated form is more water soluble and, hence, easier to excrete. We are not aware of any reported adverse effect, allergic reaction, or anaphylaxis from prior use of cyan blue in sutures or intraocular devices. To our knowledge, PCTS has not been used in humans; hence, data on side effects and allergic reactions in humans are lacking. Toxicity studies are available in mice, and tissue distribution has been previously studied in rats.42

The compound has proven its stability in this experiment. Free pertechnetate ions tend to accumulate in the stomach and thyroid; the radioactivity detected in these organs was minimal relative to the popliteal node (Table 2). The kidney had an increased uptake, as previously seen by others with intravenous injection of the compound.42 The dose planned in human studies is far lower than the safe dose of 10 mg/kg. The FDA approved hematoporphyrin as a photosensitizer, that is, Photofrin (Axcan Scandipharm Inc., Birmingham, AL), and from animal studies it seems that phthalocyanine tetrasulfonate has fewer side effects; it may be in the process of being approved by the FDA for human use. We believe that 99mTc-PCTS is a reliable agent for sentinel node detection, provided that its translation to human use is proven safe and reliable.


   Acknowledgments
 
The acknowledgments are available online at www.annalssurgicaloncology.org.


   Footnotes
 
Combination of isosulfan blue and radiotracer is the most common method of sentinel node detection. This article evaluated a single agent, blue and radioactive, drained and retained by the sentinel node for a prolonged period of time.

Received for publication March 28, 2002. Accepted for publication October 23, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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C. Tsopelas, E. Bevington, J. Kollias, S. Shibli, G. Farshid, B. Coventry, and B. E. Chatterton
99mTc-Evans Blue Dye for Mapping Contiguous Lymph Node Sequences and Discriminating the Sentinel Lymph Node in an Ovine Model
Ann. Surg. Oncol., May 1, 2006; 13(5): 692 - 700.
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