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Original research
Sentinel lymph node mapping with indocyanine green using SPY-PHI in open radical hysterectomy or trachelectomy
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  1. Maria A Fernandez1,2,
  2. Helen D Clark3,
  3. Maria D Iniesta4,
  4. Mark F Munsell5,
  5. Michael Frumovitz4 and
  6. Pedro T Ramirez6
  1. 1 Medicine Department, Universidad del Norte, Barranquilla, Atlántico, Colombia
  2. 2 Executive and Continuing Professional Education (ECPE) – Principles and Practice of Clinical Research (PPCR), Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
  3. 3 Department of Obstetrics and Gynecology, Columbia University, New York, New York, USA
  4. 4 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6 Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, Texas, USA
  1. Correspondence to Dr Maria A Fernandez, Universidad del Norte, Barranquilla, Atlántico, Colombia; mfernandezc23{at}gmail.com

Abstract

Objective To evaluate the detection rate of at least one sentinel lymph node (SLN) in patients with early cervical cancer who underwent open radical hysterectomy or trachelectomy using indocyanine green (ICG) with the SPY Portable Handler Imager (SPY-PHI) system.

Methods We retrospectively reviewed patients with cervical cancer FIGO 2018 stage IA1 with lymphovascular invasion up to stage IIIC1p who underwent SLN mapping and open radical hysterectomy or trachelectomy from March 2018 through August 2022 at The University of Texas MD Anderson Cancer Center. ICG was the only tracer used with the SPY-PHI system. Patient demographics, surgical approach, and tumor factors were analyzed. Overall detection, bilateral detection, and empty lymph node packet rates were determined.

Results A total of 106 patients were included. Ninety-four (88.7%) patients underwent open radical hysterectomy and 12 (11.3%) open radical trachelectomy. Median age was 40 years (range, 23–71). Median body mass index was 28.8 kg/m2 (range, 17.6–48.4). The most common FIGO 2018 stages were IB1 (35%) and IB2 (30%). The most common histologic subtypes were squamous cell carcinoma (45%) and adenocarcinoma (45%). Most patients had grade 2 disease (61%) and no lymphovascular invasion (58%). Median tumor size was 1.8 cm (range, 0.3–4). Median number of detected SLN was 4 (range, 0–12). An SLN was identified during surgery in 104 patients (98%), with bilateral mapping in 94 (89%) and unilateral mapping in 10 (9%). The empty lymph node packet rate was 4 (3.8%). The external iliac (73%) was the most common site of SLN detection. Fourteen patients had positive lymph nodes (13.5%); 3 (21.4%) had macrometastases, 9 (64.3%) had micrometastases, and 2 (14.3%) had isolated tumor cells.

Conclusion SLN mapping using ICG with the SPY-PHI system in open radical hysterectomy or trachelectomy is reliable and results in high overall and bilateral detection rates in patients with early cervical cancer.

  • Sentinel Lymph Node
  • Cervical Cancer
  • Hysterectomy

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/ijgc-2023-004787

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Sentinel lymph node (SLN) mapping with indocyanine green (ICG) in early cervical cancer has been evaluated in several studies in minimally invasive surgery. Following the LACC trial, there is a paucity of data on the SLN detection rates in the setting of the open approach using ICG and the SPY-PHI system.

    WHAT THIS STUDY ADDS

    • SLN mapping using ICG with the SPY Portable Handler Imager (SPY-PHI) system in open radical hysterectomy or radical trachelectomy in early cervical cancer had an overall and bilateral detection rate of 98% and 89%, respectively.

    HOW MIGHT THIS STUDY AFFECT RESEARCH, PRACTICE OR POLICY

    • Our results show that SLN mapping using ICG with the SPY-PHI system is associated with high detection rates in patients with early cervical cancer who undergo open surgery. Prospective trials are needed to corroborate the results of this approach.

    Introduction

    Cervical cancer remains the fourth most common cancer in women worldwide, diagnosed mainly in women from low-income countries.1 In 2020, approximately 604 000 new cases and 342 000 deaths were reported globally.1 Of the 13 328 new cases diagnosed in the United States in 2019, 44.2% had a disease localized to the cervix.2 According to the 2023 National Comprehensive Cancer Network (NCCN) guidelines,3 the current standard treatment for early cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2018 IA to IIA) consists of open radical hysterectomy or radical trachelectomy for women who desire to preserve fertility and bilateral pelvic lymph node evaluation with or without sentinel lymph node (SLN) mapping in the open setting.

    Lymph node involvement is a major prognostic factor in early cervical cancer, with a 5-year survival rate of 50% in patients with stage IB with positive lymph nodes compared with 80% in patients without lymph node involvement.4 5 Multiple prospective studies have shown that compared with pelvic lymphadenectomy, SLN biopsy is a feasible technique for detecting sentinel nodes in patients with early cervical cancer, as it has demonstrated high detection rates (97.8%) and sensitivity (92%)6 additionally providing a better quality of life and decreased surgical morbidity.7 Even though the 2023 NCCN guidelines3 include mapping as part of the standard treatment, there is still a lack of consensus on the best strategy for SLN mapping.8

    Indocyanine green (ICG) is a near-infrared fluorescent tracer with a safe toxicity profile typically used for SLN mapping in breast, endometrial, and vulvar cancers.9–11 In early cervical cancer, a retrospective study on SLN mapping using different radiotracers in patients undergoing laparoscopic surgery demonstrated that the overall and bilateral detection rates of ICG were superior (95.5% and 95.5%, respectively) compared with the combination of blue dye and technetium-99m (Tc-99m) (83% and 61%, respectively).12 Its detection rate was also assessed in the prospective FILM trial, showing a significantly higher overall and bilateral (96% and 78%) detection rate than blue dye alone (74% and 31%).13

    After the LACC trial14 and the subsequent analysis of the National Cancer Database15 showed inferior survival outcomes and higher loco-regional recurrence rates in patients with early cervical cancer who underwent minimally invasive surgery, open radical hysterectomy became the recommended standard of care. These findings raised concern about the safety of minimally invasive radical trachelectomy and prompted the publication of an international, retrospective study in which oncological safety between open and minimally invasive trachelectomy was assessed, finding no difference in the 4.5-year disease-free survival rates.16 Consequently, interest in gathering information regarding SLN mapping in patients undergoing open surgery has increased. SPY Portable Handler Imager (SPY-PHI; Stryker, Kalamazoo, MI, USA) is a novel, portable fluorescence system that uses ICG as a tracer for SLN mapping in open surgery. Two small retrospective studies have recently shown comparable detection rates between open and minimally invasive surgery in cervical cancer patients.17 18

    Our study primarily aimed to assess the detection rate of SLN using ICG with the SPY-PHI system in women with early cervical cancer who underwent open radical hysterectomy or radical trachelectomy. Secondary outcomes included estimating the empty lymph node packet rate; determining the number and location of SLNs; estimating the rate and type of metastasis; and the detection rate by body mass index (BMI) categories.

    Methods

    This was a single-center, retrospective study to evaluate SLN mapping using ICG with the SPY-PHI system in all patients with early cervical cancer who underwent open radical hysterectomy or open radical trachelectomy between March 2018 to August 2022 at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Institutional Board Review exemption was obtained (Registration No.: 2022–0679). Data were collected from medical records and managed using the REDcap (Research Electronic Data Capture)19 20 database hosted by The University of Texas MD Anderson Cancer Center.

    Eligibility criteria included patients over 18 years of age with a confirmed diagnosis of cervical cancer, with FIGO 201821 stage IA1 with lymphovascular invasion, up to stage IIIC1p (pathological), who underwent SLN detection with ICG by open radical hysterectomy or radical trachelectomy, with squamous cell carcinoma, adenocarcinoma, adenosquamous or carcinoma not otherwise specified, and with histopathological and ultrastaging SLN evaluation included. Those with SLN detection with blue dye or a combination of blue dye and ICG, pre-operative metastatic disease, tumor size >4 cm, histologic type different from that mentioned above, who had received pre-operative chemotherapy or radiation were excluded.

    Study Group

    Patient variables included age, race, ethnicity, BMI, surgical procedure (open radical hysterectomy or open radical trachelectomy), SLN characteristics, FIGO 2018 stage, grade, histology subtype, lymphovascular space invasion (LVSI), and tumor size.

    Patients who did not want to preserve fertility underwent an open radical hysterectomy, and those who desired to preserve fertility underwent an open radical trachelectomy. Following the anesthesia induction, 1 mL ICG was injected at the superficial and deep levels of the cervix at the 6 and 9 o’clock positions. The pelvic retroperitoneal space was then opened, and lymph node basins were examined; SLNs were assessed with the SPY-PHI system. Systematic full lymphadenectomy was performed in case of unilateral mapping, no mapping, or when the nature of the SLN was uncertain.

    The SLN was defined as the first draining ICG-positive pelvic node in the channel pathway. The number and location of SLNs obtained were recorded. All SLNs were removed, labeled, and sent to our center for histopathological and ultrastaging evaluation by specialized gynecologic pathologists. The histopathological evaluation went as follows: all SLNs were serially sectioned in 2 mm intervals perpendicular to the long axis and entirely submitted for routine histologic processing. SLNs with no metastases detected on the initial hematoxylin and eosin (H&E) slide were subjected to an ultrastaging protocol consisting of five wide intervals spaced at 250 µm. At each level, one H&E slide and two unstained slides were obtained. In the case of no metastases detected in the additional slides of H&E, the first unstained slide from level 1 was submitted to immunohistochemistry for cytokeratin control.22 Positive SLNs were classified as macrometastasis if the deposits were >2 mm, micrometastasis within ≥0.2 to 2 mm, and isolated tumor cells if less than 0.2 mm. When patients were found to have more than one type of metastases in the SLN, the lymph node was categorized according to the highest level of metastases.

    The detection rate for SLN was defined as identification of at least one SLN during surgery with ICG. An empty lymph node packet was defined as an SLN identified at surgery that does not yield a lymph node on pathological analysis.

    Statistical Analysis

    We used descriptive statistics to summarize patients’ demographic and clinical characteristics overall and stratified by surgical procedure. Medians were used to compare continuous variables, and frequencies and percentages were used to compare categorical variables. The Wilcoxon rank sum test was used to compare median scores between groups defined by surgical procedure, and Fisher’s exact test was used to compare groups with respect to categorical variables. P-values <0.05 were considered statistically significant. Outcomes were estimated with exact binomial confidence intervals. All statistical analyses were performed using SAS 9.4 for Windows 2020 (SAS Institute Inc., Cary, NC, USA).

    Results

    A total of 106 patients met the inclusion criteria and were included. Ninety-four (88.7%) patients underwent an open radical hysterectomy, and 12 (11.3%) patients underwent an open trachelectomy. The median age was 40 years (range, 23–71). The median BMI was 28.8 kg/m2 (range, 17.6–48.4), 24 (23%) patients had a BMI <25 kg/m2, 36 (34%) had a BMI of 25–29.9 kg/m2, and 46 (43%) had a BMI ≥30 kg/m2. The most common FIGO 2018 stages were IB1 (35%) and IB2 (30%). The most common histologic subtypes were squamous cell carcinoma (45%) and adenocarcinoma (45%). Most patients had grade 2 disease (61%) and no LVSI (58%). Of the 84 patients for whom tumor size was available, the median tumor size was 1.8 cm (range, 0.3–4) (table 1).

    View this table:
    Table 1

    Demographic and tumor characteristics

    A total of 104 patients (98%) had an SLN identified during surgery. Ninety-four (89%) were bilateral, 10 (9%) were unilateral, and 2 (2%) had no mapping. However, there was one patient who had two SLNs identified by ICG, but zero SLNs identified by pathology; hence, 103 patients (97.2%) had an SLN identified after the pathology analysis. The median number of SLNs identified by ICG was 4 (range, 0–12). The most common SLN identification site was external iliac (73%). An SLN was identified in the para-aortic region in one (1%) patient who also had two SLNs in the external iliac. Only 4 of 104 (3.8%) patients had an SLN identified at the time of surgery that was not confirmed by pathology. Thus, our empty lymph node packet rate was 3.8%. A full lymphadenectomy was performed in 13 (12%) patients; the reasons were failure to map in 2 patients, unilateral mapping in 10 patients, and uncertain nature of a sentinel node in 1 patient. The median number of lymph nodes obtained at lymphadenectomy was 7 (range, 3–17). No non-SLNs were positive in those patients (table 2).

    View this table:
    Table 2

    Sentinel lymph node characteristics

    The overall rate of positive lymph nodes among those patients with successful mapping was 13.5% (14/104) (95% CI 7.6%, 21.6%). Of these 14 patients, 3 (21.4%) had macrometastases, 9 (64.3%) had micrometastases, and 2 (14.3%) had isolated tumor cells. All positive lymph nodes were identified by the initial H&E or the first H&E level of the ultrastaging procedure. Only ine isolated tumor cell case needed ultrastaging by immunohistochemistry for confirmation. Of the 11 patients with positive nodes for whom tumor size was available, 8 (73%) had a tumor size ≥2 cm. Of the 14 patients with positive nodes, 10 (71%) were grade 1 or 2, and 12 (86%) had LVSI (table 3). The results of the SLN detection by ICG and pathology are shown in table 4. The SLN detection data stratified by BMI categories are summarized in table 5.

    View this table:
    Table 3

    Tumor characteristics by nodal status

    View this table:
    Table 4

    Patients with any sentinel lymph nodes found

    View this table:
    Table 5

    Sentinel lymph nodes stratified by body mass index

    Discussion

    Summary of Main Results

    Our overall and bilateral detection rate of SLN mapping using ICG with the SPY-PHI system was 98% and 89%, respectively. Of the SLNs detected, 13.5% were positive for metastatic disease; of these, 78.6% were either micrometastases or isolated tumor cells. Our empty lymph node packet rate was 3.8%.

    Results in the Context of Published Literature

    SLN biopsy in cervical cancer has been extensively studied since its first description in 1999.23 In the SENTICOL I trial6, 139 patients with FIGO 2009 stage IA1-IB1 underwent SLN biopsy with Tc-99m and patent blue dye, followed by pelvic lymphadenectomy, finding a sensitivity of 92% and an overall and bilateral detection rate of 97.8% and 76.5%, respectively. The SENTICOL II trial7 demonstrated that SLN biopsy alone was associated with reduced lymphatic morbidity compared with SLN biopsy plus pelvic lymphadenectomy (31.4% vs 51.5%; p=0.0046) in patients with FIGO 2009 stage IA2-IIA1. Furthermore, SLN mapping improved the detection of up to 15% more positive lymph nodes through an in-depth pathologic analysis.24

    The Memorial Sloan-Kettering Cancer Center developed an algorithm that incorporated SLN mapping in the management of patients with early cervical cancer. Besides detecting SLNs, a reduced need for bilateral pelvic lymphadenectomy in 75% of patients was found when applying it.25 A retrospective study of 188 patients with early cervical cancer demonstrated that SLN biopsy as a replacement for lymphadenectomy had a sensitivity and negative predictive value of 96.4% and 99.3%, respectively.26

    Due to the LACC trial’s impact on the standard management of early cervical cancer,14 two studies on SLN mapping in open surgery have emerged. Bizzarri et al17 retrospectively compared the SLN mapping detection rate using ICG in 27 patients who underwent open and 58 who underwent minimally invasive surgery. SLNs were assessed with the Visera Elite II or PINPOINT in laparoscopy, Da Vinci Xi in robotic, and SPY-PHI system in open surgery. No significant difference in bilateral detection rates between the two approaches (72.0% in the open vs 84.9% in the minimally invasive surgery; p=0.222) was reported. Of the patients in their laparotomy group, 18.5% had tumors >4 cm. Several studies have shown that large-volume tumors are associated with lower side-specific detection rates and sensitivity than small-volume tumors.27 28 We did not include patients with tumors >4 cm, which might have contributed to our high overall and bilateral detection rate. Muallem et al18 compared the detection rate of SLN mapping with ICG in 38 patients who underwent laparoscopic surgery (PINPOINT system) and 38 who underwent open surgery (SPY-PHI system), finding high bilateral detection rates with no statistical difference between both approaches (92.1% and 94.7%, respectively; p=1.0). They stated that their high detection rates might be due to the resection of SLN in the first and second echelons, thus achieving a median of 5.4 SLN per pelvic sidewall. This should be interpreted with caution as ICG can signal nodes in second and more distant basins that are not ‘true’ SLNs.13

    A meta-analysis that evaluated the clinical significance of low-volume metastasis showed the negative impact of micrometastasis in overall and disease-free survival (HR=4.10, 95% CI 2.71 to 6.20).29 In the study by Bizzarri et al17 of the 18 patients with positive SLN, 13 (72%) had micrometastases. Nonetheless, it is noteworthy that 11% of their patients received neoadjuvant chemotherapy, which could jeopardize the detection procedure since it reduces the number of positive lymph nodes and therefore downstages the disease.30 We excluded patients who previously received chemotherapy or radiotherapy and noted a lower rate of patients with micrometastases than in the mentioned study.

    The relationship between obesity and SLN mapping detection rate is widely described. Jewell et al31 assessed the SLN detection rate using ICG or blue dye plus ICG in 227 patients with endometrial and cervical cancer, finding that patients with unilateral mapping had higher BMIs than those who mapped bilaterally (34.0 vs 29.6 kg/m2; p=0.02). Moreover, a large retrospective study of SLN mapping using ICG or blue dye found that even though higher BMI significantly impacted the detection rate, ICG improved bilateral (p=0.002) and overall (p=0.011) detection rates in all BMI categories.32 Our study found that high BMIs did not significantly affect the SLN detection rate when ICG was used as the only tracer for mapping. This demonstrates that ICG seems more suitable in patients with higher BMIs as it has enhanced visualization of the lymphatic channels and SLNs compared with other tracers.32 However, this study was not designed to detect a difference among BMI groups.

    Our most frequent SLN location was the external iliac. This correlates with published literature showing that approximately 65.5–90% of SLNs are in the external iliac and obturator regions.33 34 Previous studies have described that 3.8–8.7% of SLN are in the para-aortic region.34 35 Notably, in 1% of our patients, an SLN was detected in the para-aortic area. This highlights another advantage of SLN mapping, namely allowing the detection of nodes in regions where cervical cancer involvement is not anticipated. However, focus on the dissection should remain in the pelvis as the likelihood of isolated SLNs in the para-aortic region has been consistently low.

    Compared with previous literature, our SLN detection rate with ICG was similar to others reported in open surgery (92.6–96%).17 18 In most of our patients, the same number of SLNs were identified by ICG as by pathology, but in some, more SLNs were detected by ICG. This finding is consistent with the FILM trial,13 in which 5–6% of ‘presumed SLNs’ identified in the mapping were not detected by pathology as they were dilated lymphatic trunks or fat tissue. The ‘empty lymph node packet’ concept is attributed to SLN dissections that do not yield an actual lymph node on pathology, potentially leaving the hemipelvis’s status unknown and, thus, the patient inadequately staged.36 As ICG may produce an oversampling due to its improved visualization, the surgeon’s experience impacts the successful SLN detection.36 In a retrospective analysis of SLN mapping using ICG in endometrial and cervical cancer patients, at least 27 cases were needed for accurate detection.37 No study has yet addressed cervical cancer’s empty lymph node packet dissection rate, contrary to endometrial cancer, where it has been well-described. Thomaier et al36 recognized that the empty lymph node packet rate went from 20% to 7% after 25–30 cases. Our empty lymph node packet rate was below that reported in endometrial cancer, which might suggest an increased experience of our surgeons with SLN mapping using ICG and the SPY-PHI system.

    Strengths and Weaknesses

    This study includes the largest number of patients who underwent radical hysterectomy or trachelectomy and had SLN mapping detection using ICG with the SPY-PHI system. Additional strengths include the high experience level among surgeons, the high detection rates and sensitivity obtained, and the low number of empty lymph node packets. However, the study has several limitations, including its retrospective nature. It was performed at a single tertiary center, which may result in selection bias, as the patients included do not represent most cervical cancer patients treated at institutions with fewer resources. Another limitation was the low number of patients who underwent radical trachelectomy during the study period. Finally, the learning curve of the ICG procedure using the SPY-PHI system was not measured.

    Implications for Practice and Future Research

    Our study offers data about ICG with the SPY-PHI system for SLN mapping in early cervical cancer patients who underwent open hysterectomy or trachelectomy. Prospective studies comparing ICG using the SPY-PHI system with other tracers in open surgery can provide additional data to corroborate our results and establish a recommendation for a standard technique.

    Conclusion

    In conclusion, SLN mapping using ICG with the SPHI-PHY system in open radical hysterectomy and radical trachelectomy is reliable and results in high overall and bilateral detection rates in patients with early cervical cancer.

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    Supported by the NIH/NCI under award number P30CA016672.

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    Footnotes

    • Twitter @hdaifotisclark, @frumovitz, @pedroramirezMD

    • Contributors MAF contributed to the study design, data analysis, manuscript writing, revision, and editing. HDC contributed to data collection and manuscript editing. MDI contributed to data collection and analysis, manuscript revision, and editing. MFM contributed to data analysis, manuscript revision, and editing. MF contributed to manuscript revision and editing. PTR contributed to study design, data collection and analysis, manuscript writing, revision, and editing and was responsible for the overall content as a guarantor. All authors read and approved the final manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.