Vulvar cancer is a rare malignancy that accounts for about 5% of all gynecologic cancer cases, with more than 6,100 newly diagnosed cases yearly in the United States, leading to nearly 1,400 deaths (1). Ninety percent of vulvar cancers are squamous cell carcinomas (VSCC) (2, 3). Currently, the primary treatment for VSCC is surgical resection and radiotherapy (with or without chemotherapy) if necessary (2, 4).

Vulvar cancer usually spreads to regional lymph nodes, such as the inguinal, femoral, or pelvic lymph nodes. The more the regional lymph nodes were involved, the worse the long-term survival was (5, 6). Therefore, regional lymph nodes dissection (RLND), covering inguinal and femoral lymph nodes, was usually performed to remove lymph nodes for work-up or therapy intent. However, RLND has a high probability of short- and long-term complications that are the leading cause of death after surgical treatment, such as wound breakdown, wound infection, lymphoceles, lymphedema, cellulitis, and erysipelas (7). After implementing several new surgical techniques of lymph nodes dissection procedure, the morbidity of complications after RLND decreased in recent years but remains high and clinically meaningful (8). Thus, sentinel lymph nodes biopsy (SLNB) was preferred to replace RLND for selected VSCC patients because of its less aggressiveness and lower probability of surgery complications (9). Moreover, SLNB has been proven to have high sensitivity of more than 95% to indicate positive regional lymph nodes and a specialty of as high as 100% (9, 10). However, more than 50% of VSCC patients still received RLND alone because of the limited application of SLNB (7), which was led to by the limited evidence on the safety and effectiveness of SLNB because of the rarity of vulvar carcinoma.

Thus, it is urgent to identify the safety and efficacy of SLNB in VSCC surgery patients, especially in those with negative regional lymph node findings. Therefore, we compared the long-term survival between patients who underwent SLNB and those who underwent RLND or NA in a large real-world cohort, controlling for several factors.

This study’s key findings were that SLNB led to significantly prolonged survival outcomes in VSCC surgery patients with no distant metastasis and adjacent organ invading compared to RLND and NA. To our knowledge, this study is the first retrospective study comparing SLNB with RLND in VSCC surgery patients who had no distant metastasis and adjacent organ invading, with 287 patients treated with SLNB and a sample size of 3,161 patients. This study controlled for diverse confounding factors, such as surgery type, tumor size, invasion depth, radiotherapy, and positive lymph nodes findings. IPW adjustment was carried out to minimize the imbalance of variables between groups. This study adds to the supportive evidence of the beneficial effect of SLNB on the survival of VSCC surgery patients and extends the application scope of SLNB.

In this study, the beneficial effect of SLNB compared to RLND on CSS was larger in the LN+ cohort(sHR [95% CI]=0.29 [0.16–0.54]) than in the LN− cohort (sHR [95% CI]=0.42 [0.19–0.93]). Similar larger effect of SLNB was also present for OS in the LN+ cohort (TR [95% CI]=2.68 [1.73–4.14]) than in the LN− cohort (TR [95% CI]=1.38 [0.82–2.32]). Thereby, this study demonstrates that patients in the LN+ cohort could benefit more from SLNB than those in the LN− cohort. To explore the non-inferior effect of SLNB, we carried out a comparison between patients treated with SLNB with those with no regional lymph nodes removed, and the result was very promising. Patients treated with SLNB has significantly improved CSS (sHR [95% CI]=0.40 [0.23–0.70]) and similar OS (TR [95% CI]=1.15 [0.76–1.73]) compared with those in the NA group, which indicates that patients in the NA group might have missing detection of microscopic positive lymph nodes. So the extended application of SLNB was feasible.

Because of vulvar carcinoma’s rareness, there have been no random control trials, which may not be feasible because of methodological and ethical issues, providing high-level evidence about the safety and efficacy of SLNB compared with that of RLND (16). This sizable retrospective study confirmed the significantly superior role of SLNB versus RLND in VSCC surgery patients within both the LN− and LN+ cohorts. This study found that surgery type, tumor size, and invasion depth did not limit the applying of SLNB, contrary to the previous study’s finding that SLNB should be limited to tumors with size ≤4 cm and invasion depth >1 mm (17). Our study provides evidence for extending the indication of the application of SLNB patients with any tumor size and invasion depth, irrespective of surgery type and regional lymph nodes findings. In contrast, age should be taken into account because of its statistically significant association with survival. Together with the cost-efficacy of SLNB, more VSCC surgery patients will benefit from SLNB (17, 18).

The explanation of the promising survival outcome associate with SLNB may lie in that several innovation techniques of SLNB, including imaging tracer agent (ranging from blue dye to indocyanine green and Technetium-99m colloid albumin as well as their combination) and imaging equipment (from lymphoscintigraphy, single-photon emission computed tomography or computed tomography [SPECT/CT] to a fusion of SPECT/CT and ultrasound), have dramatically progressed the precision of lymph node localization (17, 19, 20). SPECT/CT could currently personalize lymphatic mapping and provide detailed information about the number and anatomical location of sentinel lymph nodes for adequate surgical planning in the groin (21). However, it is still essential to standardize the acquisition principles of SPECT/CT images and centralize SLNB performing in experienced centers for a personalized approach (17).

This study has some limitations. 1) Detailed information about surgery was not available in SEER, for example, hospital’s care quality, imaging equipment, tracer agent for imaging, surgeon’s professional experience. Thus, we could not profoundly control those factors’ impact and handle the heterogeneity of those factors between groups. Moreover, margin status was not reported in the SEER, so it could not be controlled, although margin status was proven to be not a significant prognostic factor of survival in early studies (22–25). 2) This study covered so long a period from 2004 to 2016 that some missing factors may bias the findings, despite the year of diagnosis was grouped into two intervals at 2010 and controlled in IPW calculation and multivariate regression, and no significant survival difference was found to be associated with the year of diagnosis. 3) As the retrospective study’s nature, there might be missing confounders that may be important for analysis, which would lead to bias in our findings. For example, we did not know where the exact location of the tumors. Although we had adjusted for the primary site of the tumor, that might not be adequate to account for the bias caused by tumor location. 4) Despite IPW techniques, residual confounding may exist. 5) The pathological result of SLNB and RLND during the surgery process was unavailable in the SEER database, and only the final pathological histology results were given. Thus the false negatives and false positives that were of great interest could not be calculated.

Although our study had some limitations, it was the first retrospective study investigating SLNB in VSCC surgery patients without distant metastasis and adjacent organ involvement until now. Our study extends the scope of SLNB performing on this rare cancer. Our findings will make clinicians preferentially consider performing SLNB in VSCC surgery patients irrespective of surgery type, invasion depth, and positive lymph node findings so that more patients will benefit from SLNB.

SLNB results in significantly prolonged survival in VSCC surgery patients without distant metastasis and adjacent organ invading, irrespective of tumor size, surgery type, invasion depth, and positive lymph node findings. SLNB could be carried out preferentially in VSCC surgery patients. Further prospective clinical controlled trials are warranted to confirm the superior efficacy of SLNB.

Publicly available data sets were analyzed in this study. This data can be found here: https://seer.cancer.gov/.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

WLZ: Conceptualization, Data curation, Formal analyses, Supervision, Writing-Original draft preparation, Writing-Reviewing, and Editing. YB: Conceptualization, Methodology, Software. YYY: Conceptualization, Formal analyses, Methodology, Software, Supervision, Visualization, Writing-Original draft preparation, Writing- Reviewing, and Editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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