Pelvic lymph node dissection using indocyanine green fluorescence lymphangiography in robotic assisted radical prostatectomy for non-lymph node or distant metastasis prostate cancer patients

Yu-Feng Chuang; Yen-Chuan Ou; Yi-Sheng Lin; Li-Hua Huang; Wei-Chun Weng; Yu-Kang Chang; Hung-Lin Chen; Chao-Yu Hsu; Min-Che Tung; Chin-Heng Lu

doi:10.4103/UROS.UROS_96_20

ORIGINAL ARTICLE

Year : 2021 | Volume : 32 | Issue : 1 | Page : 27-33

Pelvic lymph node dissection using indocyanine green fluorescence lymphangiography in robotic assisted radical prostatectomy for non-lymph node or distant metastasis prostate cancer patients

Yu-Feng Chuang¹, Yen-Chuan Ou¹, Yi-Sheng Lin¹, Li-Hua Huang¹, Wei-Chun Weng¹, Yu-Kang Chang², Hung-Lin Chen², Chao-Yu Hsu¹, Min-Che Tung¹, Chin-Heng Lu¹
¹ Division of Urology, Department of Surgery, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
² Department of Medical Research, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan

Date of Submission	01-Jul-2020
Date of Decision	15-Dec-2020
Date of Acceptance	15-Jan-2021
Date of Web Publication	27-Mar-2021

Correspondence Address:
Yu-Feng Chuang
Division of Urology, Department of Surgery, Tungs' Taichung Metroharbor Hospital, No. 699, Sec. 8, Taiwan Blvd., Taichung City 435
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_96_20

Abstract

Purpose: The utility of indocyanine green dye (ICG) has evolved significantly to the robotic operations including Robotic Assisted Radical Prostatectomy (RARP). The technology can help the identification of sentinel lymphatic drainage in lymphadenectomy for the majority of prostate cancer (PCa) patients. We describe the potential indications of ICG for lymphadenectomy assistant in PCa patients without lymph node or distant metastasis. Materials and Methods: We prospectively analyzed PCa patients without lymph node or distant metastasis with clinical pathological stage T1c to T3a received RARP from November 2019 to May 2020. The clinical data and pathological data, including Gleason score, tumor volume, pathological stage, and surgical findings, were described. All lymph nodes were divided into ICG positive or negative. All patients were divided into low, moderate, and high risk according to the European Association of Urology PCa risk stratification. Results: Cystoscope-guided intraprostatic injection was performed successively in 34 localized PCa patients in this study. The mean age was 66.1 ± 7.8 years old. The patients' number of high, moderate, and low risk was 18, 10, 6. A total of 447 lymph nodes were identified. Two hundred and sixty-two lymph nodes were ICG positive and 181 lymph nodes were ICG negative. ICG positive rate higher in high risk patients 158/259 (61.0%) compare to intermediate/low risk patients 104/188 (55.3%). There was no statistic significant result, but lymph node could be identified in all ICG-positive tissues. There were 12 patients revealed higher Gleason grade group after RARP and two patients revealed lower Gleason grade group after RARP. There were 18 patients showed upgrade stage after RARP and 4 patients showed down stage after RARP. Conclusion: Cystoscope-guided intraprostatic ICG injection with fluorescence lymphangiography can help identify pelvic lymph nodes in RARP for PCa patients without lymph node or distant metastasis.

Keywords: Indocyanine green dye, localized prostate cancer, lymphadenectomy, robotic assisted radical prostatectomy

How to cite this article:
Chuang YF, Ou YC, Lin YS, Huang LH, Weng WC, Chang YK, Chen HL, Hsu CY, Tung MC, Lu CH. Pelvic lymph node dissection using indocyanine green fluorescence lymphangiography in robotic assisted radical prostatectomy for non-lymph node or distant metastasis prostate cancer patients. Urol Sci 2021;32:27-33

How to cite this URL:
Chuang YF, Ou YC, Lin YS, Huang LH, Weng WC, Chang YK, Chen HL, Hsu CY, Tung MC, Lu CH. Pelvic lymph node dissection using indocyanine green fluorescence lymphangiography in robotic assisted radical prostatectomy for non-lymph node or distant metastasis prostate cancer patients. Urol Sci [serial online] 2021 [cited 2023 Dec 2];32:27-33. Available from: https://www.e-urol-sci.com/text.asp?2021/32/1/27/312437

Introduction

Prostate cancer (PCa) is the second most prevalent malignancy worldwide and the fifth leading cancer-associated cause of death in men.^[1] There are multiple treatment options currently available for localized PCa; robot-assisted radical prostatectomy (RARP) is commonly used to treat these patients.^[2] The aim of RARP is complete cancer control and staging, while maintaining continence and potency. A comprehensive methodology for reporting the outcomes after RARP is pentafecta. The pentafecta includes surgical margin status and complications, along with trifecta, which includes the three major outcomes classically reported, namely potency, continence, and biochemical recurrence-free survival rates.^[3] Tumor control involves two important components: complete removal of the prostate tumor with complete sparing of the neurovascular tissue and complete removal of malignant lymph nodes.

Recently, a number of studies have focused on the importance of pelvic lymph node dissection (PLND). Meticulous PLND is not only a staging procedure but may also have a positive impact on the disease progression and long-term disease-free survival, particularly in conditions of micrometastases.^[4] Furthermore, the number of removed lymph nodes during PLND was correlated with time to disease progression.^[5] Joslyn and Konety reported that patients without lymph node metastasis who underwent PLND with the removal of at least 10 nodes showed a lower risk of cancer-specific death during a 10-year follow-up compared with patients who did not undergo PLND.^[6] In patients with lymph node metastasis, Abdollah et al. reported that extended PLND is beneficial to cancer-specific survival.^[7] Finally, the oncological outcome in patients with aggressive PCa is correlated with accurate PLND, specifically, the extended PLND technique.^[8]

Currently, the indications for PLND vary in terms of recommendation guidelines, such as that of the National Comprehensive Cancer Network (NCCN), American Urologic Association (AUA), and European Association of Urology (EAU).^[9] In the AUA/ASTRO/SUO guideline on clinically localized PCa (2017), pelvic lymphadenectomy can be considered for any patient with localized PCa undergoing radical prostatectomy (RP) and is recommended for those with unfavorable intermediate-or high-risk disease based on expert opinion. Comparatively, the EAU PCa guidelines (2019) indicate that PLND during RP failed to improve oncological outcomes and survival, but extended PLND provides important information for staging and prognosis. Moreover, the NCCN guidelines version 2 (2020) (National Comprehensive Cancer Network, United States) suggest that PLND may have a survival advantage, and the extended technique should be used for complete staging. In the real world, PLND or lymph node sampling is performed with the consideration of the patient's condition or surgeon's experience. Increasing efficiency and accuracy while decreasing the complication rates of lymphadenectomy has become a greatly important issue.

In the present era, fluorescence-guided surgery can help operators identify the structures of interest in the real time. There are currently four fluorochromes approved by the US Food and Drug Administration, including indocyanine green dye (ICG), which has several properties and is useful in pelvic surgery.^[10] ICG, also known as tricarbocyanine, is a water-soluble molecule that is only visualized with near-infrared fluorescence (NIRF) on the da Vinci Surgical Systems equipped with Firefly technology. ICG is bound to albumin and near-instantaneously visualized within the vasculature and target organs after intravenous administration. For urologic applications, ICG is diluted in the sterile water to formulate a 2.5-mg/mL solution, which can be injected intravenously or directly into the target organ.^[11] NIRF imaging using ICG has been used very frequently in robotic surgery, including RARP. ICG can mark the targeted prostate tissue with limited diffusion and act as a lymphangiography agent to visualize sentinel prostatic drainage during prostatectomy. Some studies reported the use of ICG-NIRF to identify sentinel lymph node metastasis in RARP.^[12] However, no study has focused on ICG-NIRF imaging technique in patients with PCa without distant or lymph node metastasis. The present study aimed to describe the potential indication of ICG-NIRF for increasing the efficiency and accuracy of lymphadenectomy.

Methods

We prospectively analyzed patients with PCa with clinical stage cT1c to cT3a who underwent RARP from November 2019 to May 2020. ICG injection was performed 30 min before bilateral pelvic lymphadenectomy. The clinical data included age, body mass index, preoperative prostate-specific antigen (PSA) levels, prostate volume, PSA density, and clinical and pathological stage. The pathological data included Gleason scores, tumor volume (percentage of cancer cells in the whole prostate), pathologic T stage, positive surgical margins, seminal vesicle invasion, total number of resected lymph nodes, organ-confined tumor, extracapsular extension, and perineural invasion. Extensive bilateral PLND was performed in all patients. All lymph nodes were divided into ICG positive or negative. All patients were divided into low-, moderate-, and high-risk groups according to the EAU PCa risk stratification.

Indocyanine green injection protocol

The ICG injection solution was prepared using 2.5-mg/mL solution of ICG (IC-Green; Akorn Pharmaceuticals, Lake Forest, IL, USA) in 10 mL sterile water as suggested.^[12],[13] Intraoperative visualization of ICG-NIRF was performed by the near-infrared visualization system that can detect ICG-NIRF in the real time for all cases. The system used was a built-in da Vinci surgical robot (version Si) (Intuitive Surgical, Sunnyvale, CA, USA) with Firefly technology (Novadaq Technologies, Mississauga, ON, Canada).

Injection optimization

We reviewed current articles and identified three intraprostatic injection techniques: percutaneous robot-guided, transrectal ultrasound-guided (TRUS-guided), and cystoscope-guided techniques.^[12] The pros and cons will be elaborated in the discussion section. Initially, we used the percutaneous approach as tuberculosis as per the study by Manny et al.^[12] We used their protocol of titrating a dose of ICG to 1 mg (0.4 mL) per side and performing robot-guided percutaneous injection with a refined technique. However, lymph node fluorescence was not optimum, and ICG spillage still occurred. Then, we shifted to cystoscopic injection of 0.5 mL of ICG into each prostate lobe at the 5 and 7 o'clock positions at the level of the verumontanum. The ICG solution was injected when 1 cm of the injection needle was inserted into the prostate lobe. Bilateral extensive PLND was performed after 30 min. The lymph node was well fluoresced, and ICG spillage did not occur in the large prostate. To prevent ICG spillage and obtain better lymph node fluorescence, we modified the ICG dose protocol according to the prostate weight. If the prostate weighed ≤20, 20–30, 30–40, or >40 mg, then 0.5, 1, 1.5, or 2 mL of ICG, respectively, was injected into each prostate lobe. The injection needle was only inserted 1 cm deep. The protocol was tested in the first six cases. If the dose of ICG was above that of the protocol, ICG spillage would likely occur. If the dose of ICG was below that of the protocol, the fluorescence of the lymph node would be poor.

Extensive bilateral pelvic lymph node dissection protocol

Extensive PLND includes the removal of the obturator, external iliac, and hypogastric nodes. The anatomy and technique essential in robot-assisted bilateral PLND are similar to that in conventional RP. Lymphadenectomy was performed with a vision field under 0° lens, and dissection was performed using scissors and bipolar forceps. At the beginning, we incised the tissue overlying the external iliac vein and then pushed the lymph node package medially. The direction of dissection was from the lymph node of Cloquet toward the bifurcation of the iliac vessels. The obturator nerve and vessels were carefully preserved. The internal iliac lymph node was posterior to the obturator vessels and anterior to the branches of the internal iliac vessels. The lymph node group was continually dissected along the obturator nerve, levator ani, and iliacus muscles. The external lymph nodes were also dissected. All lymph nodes were divided into ICG positive or negative according to ICG-NIRF imaging technique during PLND. Lymph nodes from both sides and the preprostate fat were transferred to an Endo Catch® for retrieval.

Ethics and informed consent

This study was conducted at Tung's Taichung MetroHarbor Hospital with ethics approval (IRB No. 109007). Patient informed consent was waived by the IRB.

Results

We performed percutaneous robot-guided intraprostatic ICG injection in six patients. Lymph node fluorescence was poor, and ICG spillage still occurred. Then, we shifted to cystoscope-guided intraprostatic injection [Figure 1] that was performed successively in 34 patients with localized PCa. The ICG positive areas included the bilateral lymph nodes [Figure 2], bladder wall, and vessels that feed the prostate. The seminal vesicle was ICG negative. The mean ICG positive time was approximately 25–35 min after ICG injection. The result corroborated with the previous study findings.^[12]

Figure 1: (a and b) Cystoscopically injection with indocyanine green injected into each prostate lobe at the 5 and 7 o'clock positions at the level of the verumontanum

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Figure 2: (a and b) Bilateral lymph nodes with indocyanine green positive (Pic 1. is left obturator lymph nodes and Pic 2. is right obturator lymph nodes)

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Demographic data are shown in [Table 1] and [Table 2]. The mean age was 66.1 ± 7.8 years. The mean PSA level was 39.7 ± 74.8 ng/mL. The mean prostate volume was 44.7 ± 18.7 mL. Moreover, 6, 10, and 18 patients had high, moderate, and low risks, respectively. There were 12 patients with a higher Gleason grade and two patients with a lower Gleason grade after RARP. There were 18 patients whose stages were upgraded and four patients whose stages were downgraded after RARP. Three patients were downstaged from cT3a to pT2a, and one patient was downstaged from cT2c to pT2a. The possible explanation of the result was a discrepancy in image interpretation or androgen deprivation therapy (ADT) use. As shown in [Table 2], 30 patients had clinical stage ≤cT2N0M0 and four had cT3aN0M0 before RARP. Postoperatively, 27 patients had pT2 and seven had pT3 as pathological stage.

Table 1: Preoperative and postoperative demographic data of 34 patients undergoing fluorescence-enhanced robotic prostatectomy

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Table 2: Preoperative clinical stage and postoperative pathological stage

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The performance of lymph node fluorescence during robotic prostatectomy with ICG injection is reported in [Table 3]. A total of 447 lymph nodes were identified, wherein 262 lymph nodes were ICG positive, and 181 lymph nodes were ICG negative. There was a trend that ICG positive rate was higher in high-risk patients (158/259 or 61.0%) compared to that in intermediate-/low-risk patients (104/188 or 55.3%). There was no statistical significance (P = 0.228), but lymph nodes could be identified in all ICG positive tissues.

Table 3: Statistical performance of lymph node fluorescence during robotic prostatectomy with indocyanine green injection

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Discussion

PLND for PCa is evolving over time. Initially, PLND was used for PCa staging. A frozen section of pelvic lymph node was performed intraoperatively. If a positive node was noted, the incurable metastatic disease with RP was considered, and surgery was abandoned.^[14] Therefore, the importance of extensive PLND focused on the diagnostic purpose as one could not truly confirm that there is no lymph node metastasis unless all potential tissues are dissected.^[15] With time, patients with PCa with lymph node metastasis, who underwent RP and PLND, had better disease control outcomes over ADT alone.^[16],[17] With more and more patients receiving this treatment, the role of extensive PLND during RP for high-risk patients was still under investigation.^[18] Currently, many studies report that extensive PLND affected the treatment outcome and is associated with an increase in lymph nodes metastasis detection rates.^[18],[19] In the AUA/ASTRO/SUO guidelines (2017), pelvic lymphadenectomy can be considered in any patient with localized PCa undergoing RP. Extended PLND provides important information for staging and prognosis and is recommended in the EAU PCa guidelines (2019).

To date, besides patients with lymph node metastasis, some studies have demonstrated that the number of lymph nodes removed during extensive PLND is associated with improved oncological outcomes. Extensive PLND has therapeutic benefits in patients without lymph node metastasis.^{[8],[20],[21]} On the contrary, some studies were still unable to find evidence that extensive PLND improves PCa outcomes.^[22],[23] Many nomograms have been developed to assist in deciding what type of patients needed PLND. There were problems encountered in some studies wherein the standard template for PLND was performed rather than extensive PLND. Therefore, the incidence of lymph node disease might be underestimated.^[24],[25]

In this era, with the development of the robotic techniques, RARP has improved and exceeded many aspects of traditional open RP. Yuh et al. reported that robotic PLND had similar surgical and oncologic outcomes compared to traditional RP.^[26] The study results on open RP could be applied to RARP. Besides technical advantages, such as better visualization with stereoscopic views, hand tremor elimination, and “robotic wrist” that can improve surgical maneuver, the ICG-NIRF system has been used in many aspects.^[27] There were some studies that performed PLND with ICG pelvic lymphangiography. Jeschke et al.^[28] and Manny et al.^[12] reported that the best timing for lymphadenectomy was approximately 30 min after ICG injection. They attempted different injection techniques, and 30 min was the relatively reliable time course. Jeschke et al.^[28] demonstrated that fluorescence-guided extensive PLND dissected 120 lymph nodes more than radio-guided extensive PLND alone. However, not all ICG positive tissues contained lymph nodes. Manny et al.^[12] revealed that all metastatic lymph nodes were located in ICG-positive tissues.

In our study, lymph nodes can be found in every ICG positive tissue under the ICG-NIRF system. In high-risk patients, the lymph node detection rate can increase up to 61.0%. The result implies that, when extensive PLND is performed, there is less need to dissect every fluorescent tissue under ICG-NIRF assistance. If standard template PLND was performed, the ICG-NIRF system can help increase the number of dissected lymph nodes. When sampling PLND was performed, one can dissect ICG positive tissues only and avoid unnecessary tissue damage.

In the real world, extensive PLND was not always performed, such as in patients with low-risk PCa, conditions such as obesity, high bleeding tendency, tissue adhesion, postrenal transplantation, or any condition unsuitable to extensive PLND. Standard template PLND or only lymph node sampling could be performed based on the surgeon's experience. In these conditions, the ICG-NIRF system can help increase lymph node detection rate. Furthermore, such an algorithm could help improve the accuracy of PCa staging, while avoiding greater complication rates of extended PLND.^[12]

There was a 5%–50% occurrence rate of complications when PLND was performed. Complications in RARP were not increased when compared to open RP. Lymphocele was most common, self-limited, and clinically insignificant in most patients. Only few patients required further treatment, such as medication or additional drainage insertion.^[27],[29] There were other complications that developed less frequently, including thrombus, bleeding, adjacent vascular or nerve damage, and ureteral injury. There was a hypothesis that the possibility of complication would increase when a larger range of dissection was made. We reviewed studies on whether complication risk would be affected by extensive or limited PLND. Briganti et al. reported a higher rate of complications with extensive PLND (19.8%) compared to limited PLND (8.2%). Furthermore, lymphocele formation rate was higher in extensive PLND (10.3% and 4.6%, respectively, P = 0.01).^[29] There was a special study conducted by Clark et al. wherein they performed extended PLND on one side and limited PLND on the other side in 123 patients with PCa. The complication rate was threefold higher on the extensive PLND side.^[27] However, not all studies revealed that extensive PLND had higher complication rate. Heidenreich et al. reported similar rates of lymphocele (9% vs. 10.6%, respectively) in 203 patients who received standard PLND (100) or extensive PLND (103).^[15] In addition to lymphocele, patients who underwent extensive PLND might have increased surgical time or increased length of hospital stay. In our study, there were no complications, such as lymphocele, thrombus, and adjacent vascular or nerve damage, nor ureteral injury noted in 34 patients. We considered this as the potential benefit of better lymph node identification owing to ICG injection.

There were three intraprostatic injection techniques in ICG pelvic lymphangiography: percutaneous robot-guided, TRUS-guided, and cystoscope-guided. We reviewed current studies, and these techniques were selected upon evaluating the advantages and disadvantages, including relative ease of use, added cost, operative time, separate preparation, ability to evenly diffuse dye into the prostate, and dye spillage. TRUS-guided prostatic ICG injection appeared effective but required additional operative time, financial expense, and possibly increased infectious risk due to gastrointestinal tract exposure. In addition, TRUS biopsy immediately before prostatectomy might increase the risk of prostatic bleeding, cause an unclear surgical margin, and increase the difficulty of surgery. As TB, Manny et al. reported that the percutaneous robot-guided method has the best added cost, operative time, and dye-spillage benefit and does not need a separate preparation. However, in our study, we could not repeat their finding. ICG spillage was noted in the first six cases where percutaneous robot-guided method was used. There was no ICG spillage where the cystoscope-guided method was performed. The result might be due to the use of a modified ICG injection protocol, and insertion of the injection needle that was only 1 cm deep.

The described cystoscope-guided ICG injection pelvic lymphangiography robotic technique is noteworthy for its efficiency. We observed prostatic parenchymal fluorescence in most patients approximately 30 min after ICG injection. Fluorescence in the bladder wall was also noted in some patients. Periprostatic tissues, including seminal vesicles, vas, and neurovascular bundles, remained nonfluorescent. The phenomenon could be explained by the local dye diffusion within the prostatic parenchyma and diffusion beyond the restriction of the prostatic capsule. This finding could be used in defining the neurovascular bundles adjacent to the prostate and increasing the precision of nerve sparing.

Limitations

The present study has some limitations. First, the relatively small sample size makes underrepresentation bias possible. Second, we focused on patients with PCa without lymph node or distant metastasis. Hence, our study could not determine the relationship of lymph node metastasis and fluorescence lymphangiography. Finally, the proportion of lymph node to the dissected tissue was not determined due to technical difficulty. Overall, additional studies with larger sample size at multiple institutions may be performed to confirm the extent of our encouraging results and verify the reproducibility of this technique.

Conclusions

Cystoscopy-guided intraprostatic ICG injection with fluorescence lymphangiography could help identify pelvic lymph nodes, especially in high-risk patients with PCa without lymph node or distant metastasis when extensive PLND is performed during RARP. There is a potential benefit in decreasing the complications with better lymph node identification owing to ICG injection.

Acknowledgement

We thanks the patients and their families for participate the study. We also express our gratitude to the assistance of Urological Oncology Committee of Taiwan Urological Association in this research.

Financial support and sponsorship

Nil.

Conflicts of interest

Prof. Yen-Chuan Ou, an editorial board member at Urological Science, had no role in the peer review process of or decision to publish this article. The other authors declared that they have no conflicts of interest.

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