Ultrasound-guided intratumoral indigo carmine injection for intraoperative, surgeonperformed

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1 ORIGINAL ARTICLE Ultrasound-guided intratumoral indigo carmine injection for intraoperative, surgeonperformed tumor localization Dongbin Ahn, MD, 1 Jin Ho Sohn, MD, PhD, 1* Junesik Park, MD, PhD, 2 Jeong Eun Lee, MD, PhD 3 1 Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, Korea, 2 Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Catholic University of Daegu, Daegu, Korea, 3 Department of Radiation Oncology, School of Medicine, Kyungpook National University, Daegu, Korea. Accepted 12 August 2013 Published online 12 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to evaluate the feasibility of indigo carmine injections for intraoperative localization of small head and neck tumors and to introduce our surgeon-performed technique. Methods. In total, 23 patients who had tumors 1.5 cm that were not palpable by 2 head and neck surgeons were enrolled in this prospective study. Results. Ultrasound-guided intratumoral indigo carmine injections successfully targeted tumors in 22 patients (95.7%). The mean preinjection target tumor size was 0.8 cm. After an average injection of 0.7 ml indigo carmine, the mean target tumor size increased to 1.0 cm, which enhanced visual demarcation because of the increased tumor size. In these patients, we successfully and uneventfully resected the target tumors with indigo carmine injection assistance. Conclusion. Ultrasound-guided intratumoral indigo carmine injections were technically feasible as an intraoperative procedure and were performed safely by a head and neck surgeon to facilitate localization of small head and neck tumors, even in revision cases. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: ultrasound, indigo carmine, thyroid cancer, recurrence, localization INTRODUCTION The identification and removal of small, nonpalpable tumors that have been identified in imaging studies is challenging, time consuming, and may be associated with increased risk. Even if the information from several preoperative imaging modalities, such as CT, MRI, positron emission tomography, and/or ultrasound, is integrated to localize the tumor, the true location may be dynamic and dependent on the patient position, the rotation of the head, and traction after skin incisions within the actual surgical field. Furthermore, upon the identification of a tumor within a surgical field, the surgeon might wish to confirm that the tumor was designated for removal by preoperative imaging; additionally, the surgeon might be uncertain whether the apparent tumor is that which was biopsied using fine-needle aspiration (FNA), particularly if the tumor was small or located within the scar tissue of a previous surgical field. Therefore, a simple and accurate intraoperative tumor localization procedure is required to improve surgical success rates and to reduce related morbidities. In order to help surgeons identify small tumors *Corresponding author: J. H. Sohn, Department of Otolaryngology Head and Neck Surgery, Kyungpook National University Medical Center, 807 Hogukno, Buk-gu, Daegu , Korea. entgodlikeu@gmail.com Additional Supporting Information may be found in the online version of this article. in the operating room, several methods have been proposed, including ultrasound-guided hook-needle localization, charcoal injection, and radioactive substance injection. 1 5 More recently, ultrasound-guided dye injection with methylene blue was reported for the localization of recurrent thyroid carcinomas and was found to be safe and effective. 6 However, in most of the previous studies, ultrasound and ultrasound-guided injection techniques were performed by radiologists instead of surgeons. 2 4,6 Moreover, with regard to dye injection methods, only methylene blue has been used as an injection material despite the possible risks of tissue necrosis and neural toxicity. 4,6 9 Since the inception of the head and neck cancer center at our institution in 1997, we have established a training course for ultrasound examination of head and neck lesions. Since then, all ultrasound procedures and ultrasound-guided FNA of the head and neck have been performed by head and neck surgeons from our department. Since 2010, we have used intraoperative indigo carmine injections, based on the ultrasound-guided FNA technique, to localize small tumors and thus have designed this prospective study. The purpose of the present study was to evaluate the feasibility of intraoperative indigo carmine injections to facilitate the localization of target tumors and to introduce our surgeon-performed technique. HEAD & NECK DOI /HED SEPTEMBER

2 AHN ET AL. FIGURE 1. Representative 1-mL syringe with a 25-gauge needle that was used in the study. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] MATERIALS AND METHODS Study design and patients This study was designed as a prospective case series. The institutional review board of our institution approved the study protocol (registration number ), and written informed consent for the procedures was obtained from all patients. From January 2012 to November 2012, a total of 23 patients with tumors were enrolled in the study. Preoperative diagnostic impressions of the tumors were as follows: metastatic papillary thyroid carcinomas in 15 patients, recurrent lymphomas in 3 patients, recurrent lymph node tuberculosis in 3 patients, metastatic medullary thyroid carcinoma in 1 patient, and parathyroid adenoma in 1 patient. All patients had undergone a preoperative FNA that was performed by the same head and neck surgeon (D.A.), but the diagnoses were not confirmed in some of the patients. None of the target tumors in the study patients were palpable by 2 head and neck surgeons; these tumors were only detectable with preoperative imaging modalities such as ultrasound, CT, and/or positron emission tomography. To evaluate the absolute usefulness of indigo carmine injections, tumors that had ultrasound-determined maximum diameters >1.5 cm were excluded, even if such tumors were not externally palpable. Tumors that were preoperatively palpable were also excluded, regardless of size. Technique All intraoperative indigo carmine injections and subsequent surgeries were performed by a single head and neck surgeon (D.A.). For indigo carmine injections, we used the following equipment: an ultrasound machine (HD3; Philips Healthcare, Ridgefield Park, NJ) with a high-frequency transducer (7 12 MHz), 0.8% undiluted indigo carmine, and a 1-mL syringe fitted with a 25- gauge needle (Figure 1). All indigo carmine injection procedures were performed in the operating room before the surgical skin incisions. In almost all cases, the indigo carmine injection was also performed with the patient under general anesthesia; however, in some patients who were enrolled into the beginning of the study, ultrasoundguided intratumoral indigo carmine injection was performed with the patient under local anesthesia before general anesthesia was administered to avoid a prolonged duration of general anesthesia. After adjusting the patient to a suitable position for each surgical case, the surgeon performed an ultrasound scan of the neck. The surgeon could easily find the target tumor that was observed on imaging studies, including ultrasound scans, which were previously documented when the patients visited the outpatient clinic. After preparing the skin with an alcohol wipe, 0.8% indigo carmine was injected into the target tumor using a 1-mL syringe fitted with a 25-gauge needle in a parallel fashion under ultrasound guidance. Once the needle tip location was confirmed to be inside the tumor, indigo carmine was injected slowly (Figure 2). An assistant carefully performed the injections to avoid dislocation of the needle tip that might occur during the injection procedure, especially for small tumors. A hyperechoic blush of the injected fluid was visualized on real-time ultrasound. The indigo carmine injection amounts were adjusted according to the tumor size; larger amounts of indigo carmine were injected into larger tumors, and smaller amounts into smaller tumors. However, the injected volumes did not exceed 1 ml in any cases. After the injection, the injection site was compressed gently for 3 minutes to prevent hematoma and the immediate leakage of indigo carmine from the tumor. All ultrasoundguided intratumoral indigo carmine injection procedures were completed within 10 to 15 minutes. Subsequent surgeries were performed immediately after ultrasoundguided intratumoral indigo carmine injections under 2.53 magnified loupes. Assessment parameters Because we noted changes in tumor size and shape after indigo carmine injections before this prospective FIGURE 2. The needle (arrow) tip is inserted into the 0.9-cm lymph node located at the left level III region of a patient with recurrent papillary thyroid carcinoma HEAD & NECK DOI /HED SEPTEMBER 2014

3 ULTRASOUND GUIDED INTRATUMORAL INDIGO CARMINE INJECTION intratumoral indigo carmine injections targeting accuracy was graded simultaneously using real-time ultrasound monitoring for each procedure. For the objective assessments of surgical and indigo carmine injectionrelated complications, cranial nerve examinations, laryngoscopic examinations with a stroboscope, and laboratory studies for parathyroid hormone and serum calcium concentrations were performed preoperatively and postoperatively, depending on the target tumor location. To evaluate the effectiveness of ultrasound-guided intratumoral indigo carmine injections, surgical success was defined as the successful indigo carmine injection-assisted retrieval and removal of the target tumor without any adverse complications related to the surgical procedure. RESULTS Table 1 summarizes the patients characteristics and indigo carmine injection results for 23 tumors in 23 patients. With regard to location, the target tumors were at level II in 4 patients, at FIGURE 3. Representative example of a lesion for which targeting accuracy was classified as well-targeted without dye leakage. (A) A metastatic lymph node, 0.7 cm in size, was identified at the right level IV region of a patient with recurrent medullary thyroid carcinoma. (B) The lymph node was expanded to approximately 0.9 cm after an intratumoral injection with 0.7 ml of indigo carmine. study, in the present study, we attempted to determine whether certain injection amounts could induce tumor expansion. To evaluate this, we measured the injected indigo carmine volumes for each indigo carmine injection procedure and the target tumor sizes on ultrasound before and after the injections. To evaluate technical feasibility, we graded the targeting accuracy of indigo carmine injections into 3 categories: well-targeted without dye leakage, well-targeted with dye leakage, and failed to target. Well-targeted without dye leakage was defined as the injection of indigo carmine into the target tumor and accompanying changes in size or shape, with no evidence of dye leakage (Figure 3). Well-targeted with dye leakage was defined as a tumor that was well-targeted by indigo carmine injections with accompanying changes in size or shape, but with identified indigo carmine leakage as documented by a hypoechoic halo around the tumor (Figure 4). Failed to target was defined as an unintentional injection of indigo carmine outside the target tumor, possibly because of an incidental dislocation of the needle tip that resulted from vague visualization of the needle tip. In such cases, accurate targeting was attempted again. The ultrasound-guided FIGURE 4. Representative example of a lesion for which targeting accuracy was classified as well-targeted with dye leakage. (A) A metastatic lymph node (arrow), 0.6 cm in size, was identified at the right level IV region of a patient with recurrent papillary thyroid carcinoma. (B) After an intratumoral injection with 0.6 ml of indigo carmine, the lymph node became more rounded in the absence of a significant change in the maximal diameter. A hypoechoic halo (arrow head) was observed around the tumor, which suggested leakage of the injected indigo carmine. HEAD & NECK DOI /HED SEPTEMBER

4 AHN ET AL. TABLE 1. Patients characteristics and the results of ultrasound-guided intratumoral indigo carmine injection. Variables No. of patients, N 5 23 Male:female 8:15 Age, y (range, 21 80) Location of target tumors, neck level II 4 (17.4%) III 6 (26.1%) IV 7 (30.4%) V 2 (8.7%) VI 4 (17.4%) Mean size of target tumors before the (range, ) indigo carmine injections, cm Mean volume of injected (range, ) indigo carmine, ml Targeting accuracy of indigo carmine injections Well-targeted without dye leakage 20 (87.0%) Well-targeted with dye leakage 2 (8.7%) Failed to target 1 (4.3%) Mean size of target tumors after (range, ) indigo carmine injections, cm Mean change of tumor size after (range, ) indigo carmine injections, cm Data are presented as mean 6 SD. level III in 6 patients, at level IV in 7 patients, at level V in 2 patients, and at level VI in 4 patients. Fifteen tumors (65.2%) were located within the previous surgical scar tissue. The average number of previous neck dissections in these patients was 2.2 (range, 1 4). The injections were well-targeted without dye leakage in 20 patients (87.0%), were well-targeted with dye leakage in 2 patients (8.7%), and failed to target the tumor in 1 patient (4.3%) who presented with a 0.4-cm parathyroid adenoma. The mean size of the target tumors was 0.8 cm (range, cm) on preoperative ultrasound, and the mean volume of injected indigo carmine was 0.7 ml (range, ml). After indigo carmine injections, the mean size of the target tumors were 1.0 cm (range, cm), which indicated a mean increase in size of 0.2 cm (25.0%; range, cm) compared to the initial size. In 22 of the 23 patients (95.7%), we observed bluecolored target tumors in the surgical fields that increased visual distinction from the surrounding tissues; the target tumors were successfully removed surgically in these patients with indigo carmine injection assistance (Figure 5). The targeting accuracy in all 22 patients was classified as well-targeted with or without dye leakage. In the 20 patients in whom the targeting accuracy was graded as well-targeted without dye leakage, the boundaries of the target tumors were well-demarcated by the infiltrating indigo carmine and were completely distinguishable from the adjacent tissues (Figure 6). In the 2 patients in whom the targeting accuracy was graded as well-targeted with dye leakage, we experienced some anatomic confusion because of the leakage of blue dye into the surgical fields around the target tumors. However, the differences in color between the tumor and surrounding tissues were sufficient to localize the target tumors; irrigation was relatively useful in washing out the blue dye from the surrounding tissue while retaining the infiltrated dye within the tumors. In the single remaining patient (4.3%) with a parathyroid adenoma in whom the targeting accuracy was classified as failed to target, the target tumor was removed surgically without the advantage of ultrasound-guided intratumoral indigo carmine injection assistance to directly locate the lesion because of a lack of a visual difference between the tumor and the blue-tinted surgical field. In this case, we first retrieved the recurrent laryngeal nerve and subsequently resected the blue-dyed tissue because the target tumor, which was not palpable even within the surgical field, was included within the dyed region. The result of frozen biopsy and the decreased levels of intraoperative parathyroid hormone concentrations confirmed target tumor resection. The following structures were at risk during the surgeries: for level II lesions, the marginal mandibular and hypoglossal nerves; for level III lesions, the great auricular and spinal accessory nerves; for level IV lesions, the phrenic and vagus nerves and the thoracic duct; for level V lesions, the spinal accessory nerve and the transverse cervical artery; and for level VI lesions, the recurrent laryngeal nerve and the parathyroid gland. However, no complications, such as simple hematomas, inadvertent parathyroidectomies, or injuries to nerves and vessels, FIGURE 5. The blue-dyed target tumor was easily localized in the surgical field of a patient with metastatic papillary thyroid carcinoma (A) and a complete excision of the target tumor and surrounding nodes was performed (B). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] 1320 HEAD & NECK DOI /HED SEPTEMBER 2014

5 ULTRASOUND GUIDED INTRATUMORAL INDIGO CARMINE INJECTION FIGURE 6. A resected specimen of a level VI lymph node from a patient with recurrent papillary thyroid carcinoma. (A) The infiltrated indigo carmine helped to clearly distinguish between the tumor and surrounding tissue. (B) The cut surface of the same specimen also reveals well-demarcated tumor boundaries by the blue dye, with no diffusion of the blue color to the surrounding tissues. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] occurred in any of the patients in relation to the indigo carmine injection procedures or subsequent surgeries. None of the patients experienced any signs of allergic reaction to indigo carmine and no indigo carmine marks were observed at the skin puncture sites after the surgeries. DISCUSSION With the improvement in the accuracy of preoperative diagnostic modalities, nonpalpable small tumors have been frequently detected on imaging studies of patients with known head and neck cancers during follow-up evaluations, or incidentally in healthy patients who undergo medical evaluations. However, surgical tumor localization still depends primarily on the ability of the surgeon to palpate the tumor within the operating field, a method that is absolutely subjective and dependent on the experience of the surgeon. Several techniques for the intraoperative localization of nonpalpable lesions have been reported, but none of the reported techniques are thought to be as useful and safe as the indigo carmine injection technique that we have introduced in this article. 1 4 Hook-needle localization requires an additional procedure before surgery and has the disadvantages of easy needle slippage and migration and the associated risks of bleeding and hematoma. 1,10 In contrast, indigo carmine injections can be performed intraoperatively just before the skin incision and results in only an additional 5 to 10 minutes for the surgical procedure. Although a vascular needle puncture occurs during indigo carmine injections to target tumors that are adjacent to great vessels, there is little risk of bleeding or hematoma because of the fine needle used (25 gauge), and subsequent surgical explorations of the site provide additional opportunities to confirm this. Radioactive identification has been used in conjunction with gamma probes with limited success because of the poor sensitivities of the probes and the variation in radioactivity uptake by the lymph nodes. 11,12 Such approaches require coordination between the nuclear medicine and surgical teams. In addition, it is often difficult to distinguish a finite site of radioactivity that is distinct from that of the underlying background muscular and vascular blood pool. 13 Therefore, additional intraoperative ultrasound may be needed for target retrieval. 13 Colloidal charcoal injections, administered under ultrasound guidance, have been reported to be safe and effective. 2,3 However, because colloidal charcoal consists of large molecular particles, it must be injected through relatively large-bore needles (22 23 gauge); furthermore, unlike dyes, colloid charcoal could not define the boundaries of the target tumor and instead tattooed a portion of the tumor. 3 Theoretically, when charcoal is accidentally injected into a vessel, it induces a serious vascular embolism. 14 Additionally, charcoal injections have been administered up to 2 weeks before surgery, resulting in additional cost and time. 3,7 Therefore, we deem that intraoperative ultrasound-guided dye injection is the best technique with which to localize target tumors in terms of efficacy, safety, and efficiency. In previous reports, only methylene blue was used as a dye material for nonpalpable tumor localization. 4,6,7 However, existing reports indicate that methylene blue can cause tissue necrosis and neurotoxicity. 8,9,15 If these types of injuries were to affect nerves, such as the recurrent laryngeal, spinal accessory, and marginal mandibular nerves, or critical structures, such as the trachea, esophagus, and the great vessels of the head and neck, the consequence would be disastrous for the patients. Thus, the use of a relatively safe dye material is more reasonable and suitable, provided its effects are similar. In contrast to methylene blue, indigo carmine is not reported to induce tissue necrosis or neural toxicity; therefore, dilution of dye is not required. Furthermore, indigo carmine is widely thought to be safer than methylene blue for intravenous injections, because the half-life of indigo carmine is significantly shorter than that of methylene blue. 16,17 This suggests that indigo carmine can be used safely for tumors that are adjacent to vascular or neural structures and in patients with decreased renal function. 16,17 In the present study, we have demonstrated interesting findings that were not addressed in previous studies on dye injection techniques. As indigo carmine is safe, we were able to vary the injected volumes of indigo carmine according to the tumor size up to a maximum amount of 1 ml, which was a relatively larger amount than that HEAD & NECK DOI /HED SEPTEMBER

6 AHN ET AL. FIGURE 7. CT scans of a patient with recurrent papillary thyroid carcinoma who had a history of total thyroidectomy with bilateral neck dissection. A metastatic lymph node (arrow), 0.5 cm in size, was identified at the left level IV region before ultrasound-guided intratumoral indigo carmine injection (A). After ultrasound-guided intratumoral indigo carmine injection, the tumor (arrow) expanded to a maximum diameter of approximately 0.7 cm (B). reported in previous studies on methylene blue ( ml). 4,6,7 After a mean injected dose of 0.7 ml of indigo carmine, we observed a mean expansion of 2 mm in the maximal tumor diameters on ultrasound; we defined this as the increasing size effect. Although the data were not included in the results of this study, this effect was also identified on CT scans that were performed before and after indigo carmine injections in some of the enrolled patients (Figure 7). We suppose that this indigo carmine injection phenomenon, which adds to the visual effect of the blue dye, might facilitate the identification and dissection of small tumors in our study, because changes of 2 mm in diameter were more easily identifiable within the surgical field of vision under magnification with 2.53 loupes. Although, in our experience, target expansion was not generally necessary for target retrieval, it was occasionally helpful, particularly in cases of small target tumors that were located adjacent to large veins, such as the internal jugular vein. In such cases, it was often difficult to identify blue-dyed targets because the color was not distinguishable from the vein, and, thus, we observed that a 2-mm increase in size was beneficial for target tumor retrieval and ease of palpation within the surgical field. However, it is questionable whether this phenomenon was absolutely beneficial to the localization of target tumors when the effects of the blue color were excluded. Future control studies in which colored and uncolored injection materials are studied are required for verification. The most important drawbacks of methylene blue were thought to be easy diffusion and a time-limited visual effect. However, we have not experienced issues of anatomic identification that resulted from the spreading of indigo carmine to adjacent tissues when ultrasoundguided intratumoral indigo carmine injection was performed accurately. In patients from our study in whom targeting accuracy was categorized as well-targeted without dye leakage, the infiltrated dye was well-confined to the tumors. The lymph node is usually well-capsulated, even in tumorous diseases, such as metastatic thyroid carcinoma and lymphoma, and indigo carmine is practically insoluble in water, unlike methylene blue, thus, the diffusion of indigo carmine through the capsule of the lymph node is unlikely to be a drawback of ultrasound-guided intratumoral indigo carmine injections. Despite this, it does not seem to be advisable to inject parathyroid tumors with indigo carmine, because parathyroid tumors have extensive venous drainage and tend to permit the efferent flow of dye into the surrounding tissues. When we applied indigo carmine injections to parathyroid adenoma, we hypothesized that, unlike methylene blue, indigo carmine would be relatively stable within the tumor because of its insolubility in water. However, we were disappointed by the result. Since then, we have not applied this technique for parathyroid tumors. We consider charcoal, which is composed of large molecular particles, as a better option with which to target parathyroid lesions because it does not spread. In the 2 cases in which the targeting accuracy was categorized as well-targeted with dye leakage, the nontumor surrounding tissues as well as the tumors themselves were dyed with indigo carmine. Although this leakage caused some challenges in the identification of the surgical planes, there were no difficulties in target tumor identification because the blue color of the target tumors was obviously darker than that of the nontumor surrounding tissues. In these cases, irrigation with 40 to 80 ml of normal saline increased the visual differences between the tumor and surrounding tissues because indigo carmine within the lymph node was unlikely to be washed out by irrigation. To avoid anatomic confusion because of extralesional injection of dye, the use of fluorescence might be considered. Recently, indocyanine green was introduced for sentinel lymph node mapping in various tumor types, such as breast, colon, oral cavity, and oropharyngeal Indocyanine green is not visible to the naked eye and therefore does not contaminate the surgical field. 18 However, it could also be disadvantageous because additional equipment, including a near-infrared fluorescence camera system, is required to enable visual detection. We observed that the duration of the visual effect of at least an hour was sufficient to retrieve and dissect the 1322 HEAD & NECK DOI /HED SEPTEMBER 2014

7 ULTRASOUND GUIDED INTRATUMORAL INDIGO CARMINE INJECTION FIGURE 8. Blue-colored urine appeared in the urine catheter approximately 90 minutes after indigo carmine injection. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] target tumors. Some investigators have reported that diluted methylene blue dye disappeared within a few minutes. 2,4 However, we used indigo carmine without dilution, which is thought to contribute to the relatively long duration of the visual effect. In some of our study patients who had urine catheterization for subsequent radical surgeries after retrieval of the target tumors, we observed a change in the normal urine color to a blue color at 90 to 120 minutes after the ultrasound-guided intratumoral indigo carmine injections (Figure 8). As indigo carmine appears in the urine within 10 minutes after an intravenous injection, we calculated that at least 80 to 110 minutes were required for the infiltrated indigo carmine to flow into the venous system from the lymph nodes. Therefore, intraoperative indigo carmine injections just before the skin incision provide sufficient time to retrieve the target tumor. CONCLUSION Ultrasound-guided intratumoral indigo carmine injections are technically feasible as an intraoperative procedure, with a targeting accuracy rate of 95.7%. A head and neck surgeon safely performed this technique, and the localization of small tumors was facilitated even in revision cases because of the advantages of tissue color differences as well as increased lesion size. In the future, prospective randomized trials that compare indigo carmine to other colorless injection materials could be performed to determine the additional benefits of expansion because of indigo carmine injection over color alone for tumor localization. REFERENCES 1. Triponez F, Poder L, Zarnegar R, et al. Hook needle-guided excision of recurrent differentiated thyroid cancer in previously operated neck compartments: a safe technique for small, nonpalpable recurrent disease. J Clin Endocrinol Metab 2006;91: Hartl DM, Chami L, Al Ghuzlan A, et al. Charcoal suspension tattoo localization for differentiated thyroid cancer recurrence. Ann Surg Oncol 2009; 16: Kang TW, Shin JH, Han BK, et al. Preoperative ultrasound-guided tattooing localization of recurrences after thyroidectomy: safety and effectiveness. Ann Surg Oncol 2009;16: Sippel RS, Elaraj DM, Poder L, Duh QY, Kebebew E, Clark OH. Localization of recurrent thyroid cancer using intraoperative ultrasound-guided dye injection. 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