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Original research
Evolution and outcomes of sentinel lymph node mapping in vulvar cancer
  1. Vance Broach1,2,
  2. Nadeem R Abu-Rustum1,2,
  3. Yukio Sonoda1,2,
  4. Carol L Brown1,2,
  5. Elizabeth Jewell1,2,
  6. Ginger Gardner1,2,
  7. Dennis S Chi1,2,
  8. Oliver Zivanovic1,2 and
  9. Mario M Leitao Jr
  1. 1 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, New York, USA
  2. 2 Weill Cornell Medical College, New York, New York, USA
  1. Correspondence to Dr Vance Broach, Memorial Sloan-Kettering Cancer Center, New York City, NY 10065, USA; broachv{at}mskcc.org

Abstract

Objectives To characterize our institutional experience with sentinel lymph node (SLN) biopsy in patients with vulvar cancer. We describe the oncologic outcomes of these patients and the utilization of SLN detection techniques over time.

Methods A retrospective analysis of all patients who underwent inguinofemoral SLN biopsy as part of their treatment for vulvar cancer at Memorial Sloan Kettering Cancer Center from January 1, 2000 to April 1, 2019. Patients were included in this analysis if they underwent inguinofemoral SLN biopsy for vulvar cancer, irrespective of presenting factors such as histology, tumor size or laterality. An “at-risk groin” was defined as either the right or left groin for which SLN biopsy of inguinofemoral lymph nodes was performed.

Results A total of 160 patients were included in our analysis, representing 265 at-risk groins. 114 patients had squamous cell histology representing 195 at-risk groins. Of the 169 negative groins in patients with squamous cell carcinoma, the 2 year isolated groin recurrence rate was 1.2%. SLN detection rate, irrespective of modality, was 96.2%. Technetium-99 (TC-99) + blue dye detected SLNs in 91.8% of groins; TC-99 + indocyanine green detected SLNs in 100% of groins (p=0.157). Among the 110 groins that underwent mapping with TC-99 and blue dye, 4 patients had failed mapping with blue dye and mapped with TC-99 alone (3.6%). Among the 96 groins that underwent mapping with TC-99 and ICG, 14 patients failed to map with TC-99 and mapped with indocyanine green alone (14.6%).

Conclusions SLN mapping in vulvar cancer is reliable and oncologically effective. The utilization of indocyanine green for mapping has increased over the past decade and is associated with high rates of SLN detection.

  • vulvar and vaginal cancer
  • sentinel lymph node
  • lymph nodes
  • melanoma
  • surgical procedures, operative

https://doi.org/10.1136/ijgc-2019-000936

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    • Vulvar cancer is a rare malignancy

    • Sentinel lymph node biopsy has been used to reduce morbidity and improve detection of disease

    • Indocyanine green dye and near infrared imaging reliably identifies sentinel lymph nodes

    Introduction

    Vulvar cancer is a rare malignancy accounting for an estimated 6070 cases and 1280 deaths in the USA in 2019.1 Globally, 44 235 new cases and 15 222 deaths were attributed to vulvar carcinomas in 2018.2 The treatment of early-stage vulvar cancer has traditionally involved radical resection of the primary tumor and full inguinofemoral lymph node dissection. While this treatment was oncologically effective, the surgical morbidity—including wound breakdown, infection, and lymphedema—was considerable. In an effort to reduce surgical morbidity, the operative approach has evolved from the traditional “longhorn” resection, which includes en-bloc resection of the primary tumor as well as the inguinofemoral lymphatics, to a “triple incision” approach in which the primary tumor is resected separately from the lymphatics.3–6 While this reduces surgical morbidity considerably, it does not reduce lymphadenectomy-related complications such as lymphedema.

    In an effort to reduce morbidity and improve detection of microscopic metastatic disease in the lymphatics, sentinel lymph node (SLN) biopsy has been utilized. The safety and oncologic efficacy of this approach was confirmed by two prospective studies, the GOG-173 and the GROINSS-V (Groningen International Study on Sentinel Nodes in Vulvar Cancer) study. These studies reported a 3.7% false negative predictive value of inguinofemoral SLNs and a groin failure rate of approximately 2% in appropriately selected patients.7 8

    As utilization of inguinofemoral SLN detection has increased over time, the methods have evolved. Initially, blue dyes, such as lymphazurin and methylene blue, and radiocolloid lymphoscintigraphy were the most commonly utilized means for SLN detection.9 However, since the use of near infrared imaging with indocyanine green injection was first described in 2010, this technique has become more widely adopted as a method for identifying inguinofemoral SLNs.10 The choice of method for SLN detection remains largely dependent on surgeon preference and training.

    In this study we describe our institutional experience with SLN biopsy in patients with vulvar cancer. We aimed to characterize the oncologic outcomes for these patients, and the utilization of SLN detection techniques over time.

    Methods

    This study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center. We performed a retrospective analysis of all patients who underwent inguinofemoral SLN biopsy as part of their treatment for vulvar cancer at our institution from January 1, 2000 to April 1, 2019. Patients were included in this analysis if they had undergone inguinofemoral SLN biopsy for vulvar cancer, irrespective of presenting factors such as histology, tumor size, or laterality. An “at-risk groin” was defined as either a right or left groin for which inguinofemoral SLN biopsy was performed. Patients had subsequent completion lymphadenectomy based on surgeon discretion and clinical factors. SLN detection technique, as well as the success or failure of a specific technique, were determined from operative reports. The decision to use a particular method of SLN detection was surgeon-dependent after discussion of the risks, benefits, and alternatives to each approach with the patient. Pertinent past medical, surgical, demographic, pathologic, and treatment data were abstracted from patients’ medical records. Pearson’s χ2 test was used for comparison of categorical variables. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software (International Business Machines Corporation (IBM), Chicago, IL).

    Results

    Oncologic Outcomes

    A total of 160 patients were included in our analysis, representing 265 at-risk groins. The median age was 63 years (range 19–98 years) and median body mass index was 27.3 kg/m2 (range 18.6–49.2 kg/m2). Demographic and pathologic features are summarized in Table 1. The SLN was positive for metastasis in 39/265 at-risk groins (14.7%), irrespective of histology. One hundred and fourteen (71.3%) patients had squamous cell histology and 38 patients (23.8%) had mucosal melanoma. The remaining eight patients (5%) underwent SLN mapping for Paget’s disease, sarcoma, basal cell carcinoma, and yolk sac tumors.

    View this table:
    Table 1

    Patient demographics

    The 114 patients with squamous cell carcinoma represented 195 at-risk groins. Among patients with squamous cell carcinoma, the median vulvar lesion size was 1.0 cm (range 0.01–11 cm). Of the 195 at-risk groins in this group, 25 (12.8%) were found to have positive SLNs; 17 of these 25 (68%) underwent full lymphadenectomy and 17 (68%) received adjuvant radiation therapy to the groin. Nine of 25 positive groins underwent both radiation therapy and lymphadenectomy (36%). Among positive groins, the 2 year isolated groin recurrence rate was 4%. Among the 169 groins that had negative SLNs, the 2 year isolated groin recurrence rate was 1.2% (two groin recurrences).

    The 38 patients with mucosal melanoma represented 59 at-risk groins. Among patients with mucosal melanoma, the median primary vulvar lesion size was 1 cm (range 0.1–2.1 cm). Of the 59 at-risk groins in this group, nine (15.3%) were found to have positive SLNs. Two of these nine (22.2%) underwent full lymphadenectomy. Among the patients with positive SLNs, two (22.2%) patients received adjuvant imiquimod to the vulva and one patient (11.1%) received adjuvant nivolumab. No patients received immediate postoperative radiation therapy. Among the nine groins which were found to have positive SLNs, one (11.1%) experienced a groin-only recurrence at 13 months after surgery. Among the 50 groins with negative SLNs, there were two groin-only recurrences (4%) which occurred at 25 and 27 months following initial surgery. Neither of these patients received immediate postoperative therapy and neither of these patients had undergone completion lymphadenectomy.

    SLN Mapping Techniques

    Patients underwent mapping with either technetium-99 radiocolloid injection (TC-99), blue dye injection, near infrared imaging with indocyanine green injection, or a combination of these modalities. A total of 265 at-risk groins were mapped. Two groins (0.8%) were mapped with TC-99 alone and three (1.1%) were mapped with blue dye alone. Twenty-seven groins were mapped with indocyanine green alone (10.2%). One hundred and ten groins (41.5%) were mapped with a combination of blue dye and TC-99. Ninety-six groins (36.2%) were mapped with TC-99 and indocyanine green. Twenty-five groins (9.4%) were mapped with all three modalities. Three groins (1.1%) were mapped with indocyanine green and blue dye without TC-99. The SLN detection rate by modality is summarized in Table 2.

    View this table:
    Table 2

    Sentinel lymph node detection modalities

    Irrespective of modality, the SLN detection rate was 96.2%. Two groins were mapped with TC-99 alone and both SLNs were identified. Three groins were mapped with blue dye alone and all three SLNs were identified. Of the 110 groins mapped with TC-99 and blue dye, 101 (91.8%) SLNs were identified, compared with 96/96 groins (100%) that were successfully mapped with TC-99 and indocyanine green (p=0.157). The use of indocyanine green alone resulted in one groin with failed mapping, with an SLN detection rate of 26/27 (96.3%).

    Among all modalities, SLN mapping failed in 10 of 265 (3.8%) at-risk groins. Among the 110 groins mapped with TC-99 and blue dye, four patients had failed mapping with blue dye and mapped with TC-99 alone (3.6%). Among the 96 groins mapped with TC-99 and indocyanine green, 14 patients had failed mapping with TC-99 and mapped with indocyanine green alone (14.6%) (Table 2). Among the 148 groins that mapped with indocyanine green, either alone or in combination with another modality, indocyanine green failed to identify the SLN in two groins (1.4%).

    Over a 10 year period (January 1, 2000 to December 31, 2009) a total of 41 patients underwent SLN mapping with a combination of TC-99 and blue dye. Indocyanine green dye was first used at our institution for inguinofemoral SLN mapping in 2012, when it was utilized in 12.5% of cases. By 2014, 100% of inguinofemoral SLN mapping involved indocyanine green; since that time, indocyanine green has been utilized in 85–100% of cases. The utilization of blue dye has decreased over that time, from 100% of cases in 2011 to 16.7% of cases in 2019. The utilization of TC-99 has also dropped over the past 8 years, from 100% of cases in 2012 to 66.7% of cases in 2019.

    DISCUSSION

    SLN mapping of vulvar cancer has become the standard for evaluating lymph node metastasis in appropriately selected patients. Other studies have demonstrated that this technique reduces the morbidity of lymph node dissection while maintaining oncologic safety and efficacy.11 In our study, we demonstrated oncologic safety similar to that of previous prospective studies. Specifically, among patients with squamous cell carcinoma, we found a 2 year isolated groin failure rate of 1.2% in patients with negative SLNs. This is comparable to the 2% groin failure rate reported in the GROINSS-V study.8

    Initially, the use of blue dye and radiocolloid lymphoscintigraphy was the dominant technique in SLN mapping for vulvar cancer. Among patients who participated in GOG-173, all had SLN mapping with a combination of blue dye and radiocolloid lymphoscintigraphy. Similarly, in our cohort, 100% of patients were mapped with blue dye and TC-99 in the early part of the study. In GOG-173, 92.5% of patients had at least one SLN identified at surgery; 61% of these patients had nodes that were both blue dye and TC-99 positive. False negative rates were 7.8% for radiocolloid alone, 2.0% for blue dye alone, and 1.6% for radiocolloid plus blue dye. This is consistent with our findings; in our cohort, 91.8% of groins were successfully mapped with blue dye and T-99. A meta-analysis in 2014 by Meads and colleagues reviewed mapping techniques with radiocolloid lymphoscintigraphy as well as blue dye, reporting SLN detection rates of 94.0% (95% CI 90% to 96%) for radiocolloid lymphoscintigraphy alone and 68.7% (95% CI 63% to 74%) for blue dye alone.

    SLN biopsy in vulvar cancer is associated with very high rates of mapping, irrespective of the mapping modality. However, preoperative lymphoscintigraphy along with intraoperative radiolocalization requires multiple procedures that often need to be performed a day in advance of surgery. Additionally, intraoperative detection with TC-99 is cumbersome and relies on aural rather than visual cues, necessitating a pause in the procedure at frequent intervals so that TC-99 uptake can be measured with a Geiger counter. The use of blue dye does facilitate visual cues regarding the location of the SLN, but this localization is only useful when the lymphatics and lymph node are identified.

    Indocyanine green with near infrared imaging eliminates these drawbacks by providing visual cues that can be appreciated in real-time during the procedure. In 2010, Crane et al described the use of a bespoke near infrared light source and camera for intraoperative indocyanine green-labeled inguinofemoral SLNs.10 They subsequently reported their experience mapping SLNs for vulvar cancer in 16 groins using TC-99, blue dye, and indocyanine green with near infrared imaging. In this study, 29 SLNs were identified with TC-99, 26 with indocyanine green, and 21 with blue dye.12 More recently, in 2017 Soergel and colleagues13 reported their experience with indocyanine green in 27 patients with vulvar cancer, representing 52 at-risk groins. Importantly, they found eight SLNs that were not identified by TC-99 but were identified by indocyanine green alone.14 In our study, we also found that indocyanine green performed favorably and reliably identified the SLN when used either alone or in combination with another technique.

    Drawbacks of this study include its relatively small sample size and its retrospective nature. Retrospective surgical trials may be particularly problematic as they are uniquely susceptible to selection bias, in this case patient and surgical technique selection. Additionally, this study does not address possible advantages of the use of radiocolloid lymphoscintigraphy. Potential advantages include the localization of the SLN in obese patients, where transdermal visualization of indocyanine green may be challenging. Some surgeons also use lymphoscintigraphy to aid in determining the size and location of their incision in all patients. The retrospective nature of this study limits our ability to determine to what extent radiocolloid localization was utilized for this purpose in these patients.

    Figure 1
    Figure 1

    Utilization of sentinel lymph node (SLN) mapping techniques over time. ICG, indocyanine green; TC-99, technetium-99.

    Current standard practice includes the use of radiocolloid tracer, with or without blue dye or indocyanine green, for identification of the inguinofemoral SLN in appropriately selected patients with vulvar cancer. While the results of this retrospective series specifically pertaining to the performance of near infrared imaging are quite promising, prospective studies examining the efficacy of indocyanine green and near infrared imaging are needed to clarify the role of SLN mapping in this disease.

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    Footnotes

    • Editor's note This paper will feature in a special issue on sentinel lymph node mapping in 2020.

    • Twitter @VanceBroach, @leitaomd

    • Contributors VAB: Conception and design; analysis and interpretation of data; drafting of manuscript; revising manuscript critically for important intellectual content; final approval of version to be published; agrees to be accountable for all aspects of the work. NRA-R: Assistance in conception of design, contribution of patients included in this study, assistance in editing of the manuscript. YS: Contribution of patients included in this study, assistance in editing the manuscript. CLB: Contribution of patients included in this study, assistance in editing the manuscript. EJ: Contribution of patients included in this study, assistance in editing the manuscript. GJG: Contribution of patients included in this study, assistance in editing the manuscript. DSC: Contribution of patients included in this study, assistance in editing the manuscript. OZ: Contribution of patients included in this study, assistance in editing the manuscript. MML: Assistance in conception of design, contribution of patients included in this study, assistance in editing of the manuscript.

    • Funding This study was funded by National Cancer Institute (grant no: P30 CA008748).

    • Competing interests NRA-R reports grants from Stryker/Novadaq, grants from Olympus, grants from GRAIL, outside the submitted work. DSC reports personal fees from Bovie Medical Co, personal fees from Verthermia Inc. (now Apyx Medical Corp), personal fees from C Surgeries, other from Intuitive Surgical, Inc, other from TransEnterix, Inc, personal fees from Biom 'Up, outside the submitted work. EJ is a consultant for Intuitive Surgical and Covidien, outside the submitted work. ML is a consultant for Intuitive Surgical, outside the submitted work.

    • Patient consent for publication Not required.

    • Provenance and peer review Commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article.