Since the introduction of GROINSS-V study in 2008, SLNB of the groin has played a central role in the management of VC. Firstly, SLNB has reduced morbidity and mortality rates, whereas radical IFL has significant side effects.6 Secondly, the necessity for IFL remains controversial in the case of positive unilateral SLNB, as to whether it should be done ipsilaterally or bilaterally.1-8 This is due to the fact that when recurrent groin metastasis occurs, the survival rates of these patients decrease significantly. 9-25, 30-33 The long-term follow-up of GROINSS-V showed that the 10-year disease-specific survival rates in the cases of local recurrence was reduced from 90.4% to 68.7% and in patients with positive SLNB from 77.7% to 44.6%.10
A German study of Woelber et al.7, showed in none of the cases of primary VC with positive unilateral SLN contralateral positive LN in consecutive bilateral IFL (0/28 cases, 0%). A Canadian study (Nica et al.)8 reported that only 1 of 19 patients (5.3%) had a contralateral metastatic LN in IFL following unilateral SLN metastasis. But, two of their patients with positive unilateral SLNB had a groin recurrence (one located unilaterally and the other contralaterally) several months following negative IFL.8 Therefore, they suggest it is reasonable to omit contralateral IFL in patients with unilateral SLN metastasis. Both studies are in contrast to our findings with 4/18 (22.2%) women with unilateral positive SLN diagnosed with contralateral positive LN in IFL. The reason for this discrepancy may be the fact, that in our study, the tumors of these four women were all located in the midline. Unfortunately, Woelber et al. and Nica et al. did not specify the location of the tumors, if they were midline or lateral. 7,8,12
Over the past decade, there has been an increasing trend for midline VC34-37. In our hospital, the overall percentage of VC located in the anterior fourchette area is approximately 60%. Four cases with contralateral IFL metastasis in our study had originated from midline lesions. Therefore, our data suggests if the patient has unilateral SLN metastasis, clinicians should offer radical bilateral IFL in case of midline tumors. This is the current recommendation in German guideline.4 Our retrospective single-center study results with a rate of 22% of contralateral positive LN after unilateral positive SLN confirms that current guidelines are appropriate and should not be amended or changed, because our results suggest, that the risk of groin recurrences will be significant if the contralateral groin resection is omitted, also taking into account that none of the women with ipsilateral IFL only (12/30 women, own wish) developed a groin recurrence in the follow up period.
According to our results, the depth of tumor cells infiltration is also a significant factor in the prediction of contralateral metastasis (p=0.0038). The median depth of tumor infiltration was 3mm in group 1, 6mm in group 2A/B and 8.5mm in group 2C. Nonetheless, the diameter of the tumor is statistically insignificant (p = 0.764) in our evaluation. Our findings related to depth of tumor infiltration is in concordance to the current statement in German guideline with the possibility of groin metastasis depending on depth of tumor infiltration: ≤1mm; 0%; 1.1-2mm, 7.6%; 2.1-3mm, 8.3%; 3.1-5mm, 26.7% and ˃5mm , 34.2%, respectively.4 The depth of tumor has also been proposed to be taken into consideration for the decision on the extent of surgery and further management of VC.25,38 Future research should aim for bigger sample size and evaluate the correlation between the depth of tumor cells infiltration and the risk of contralateral groin metastasis. In addition, perineural invasion (PVI) has been reported to be an unfavorable prognostic factor for the outcome of patients indicating a more aggressive behavior of VC. Therefore, adjuvant treatment has been suggested in those women.39 However, in our study, only 3 of 30 women with unilateral positive SLN had PVI in the primary tumor. One woman was from group 2A (negative bilateral IFL) and 2 women belonged to group 1A (negative unilateral IFL). The follow up of all these women was uneventful up to 60 months suggesting that PVI is not an unfavorable prognostic factor in our cohort.
In the case of lateralized lesion, the removal of contralateral LNs in case of unilateral positive SLNB should be discussed with the patients in regards to its benefits, risks and possible side effects. According to our results, it may perhaps be omitted but due to the low number of lateralized lesions in our study (20%), future prospective evaluation of lateralized lesions in VC is warranted. The few cases with lateralized lesions in our cohort of women with unilateral positive SLN (6/30 women) is the limiting factor to draw clear conclusions regarding the impact of contralateral IFL. In comparison, Woelber et al. and Nica et al. did not specify the location of the tumors in their study, as to whether they were midline or lateralized.7,8,12 We suspect that it might be possible that the majority of their study subjects had lateralized tumors. This might explain why their radical bilateral IFL results had not shown any contralateral non-sentinel metastasis in contrast to our findings.
Perhaps there will be an alternative treatment option to avoid morbidity of IFL: According to a recently published study GROINSS V-II, radiotherapy could replace IFL if the tumor diameter is < 4cm and SLNB metastasis is < 2mm. However, in the case of sentinel node metastasis of > 2mm, radiotherapy is not a safe alternative of IFL.33 In addition, there is currently an ongoing nationwide study of VC in Sweden with inclusion criteria primary tumor ≥ 4cm, primary multifocal tumors or local recurrences, being an exclusion criterion so far. The results will be expected at the end of 2021 and this could change the current clinical approach of SLNB in primary VC.40
VC may also be diagnosed in pregnancy, in our center 5 women were diagnosed and treated in pregnancy within the last 15 years. We performed SLNB in collaboration with our department of nuclear medicine also in pregnant women after extensive counseling regarding the advantages and risks of the technique and written consent of the women. According to the current recommondations,41-43 this procedure should be done after the end of the 14th week of pregnancy (first trimester) to be safe for the fetus. In pregnancy, a lower dose of radioactive Tc-99m should be injected using a short-treatment protocol (SLNB can be done two hours following injection with lowest possible dose). The half-life of technetium 99m is six hours. Prompt nodal removal can reduce the chance of systemic exposure, even though fetal exposure is considered low when technetium is injected locally in the peritumoral region.41-43 Moreover, diagnosis of VC in pregnancy is often delayed. A systematic review showed that the time interval from the first medical visit until first diagnosis of VC was more than eight weeks (62.5%). The first reason is low suspicion due to the rare occurrence of VC in younger-aged women (70%), second is noncompliance of patients (30%), and third is potential risk of vulvar biopsy resulting in feto-maternal complications during pregnancy.43 In comparison to all gynecological cancers in pregnancy, VC is in fact considered to have the least possible complications in patients who undergo biopsy and/or operation. 41-43
Our data showed comparable morbidity of IFL with the reported data in the literature in respect of infection, lymph cysts, and lymphedema of the legs being 21.3 - 35.4%, 11 - 40% and 14 - 48.8%, respectively.44
Although the overall survival (OS) of the patients in group 1, group 2 A/B and group 2C with contralateral positive LNs in IFL after negative SLNB is statistically not significant (p=0.623, log rank test with Mantel Cox) (p=0.517, Gehan-Breslow-Wilcoxon test, Figure 1), there is a visible trend towards decreased survival in the women of group 2C with contralateral positive lymph nodes in IFL (Figure 1). Interestingly and also unexpectedly, none of the women of group 1 who received only unilateral IFL due to unilateral positive sentinel lymph nodes developed groin recurrence in the observation time of 60 months. Neither in the contralateral groin nor unilaterally. No comparable survival rates exist in the literature since in the study of Woelber et al.7 and Nica et al.8 patients with negative SLNB were compared to women with metastatic groin LNs.
The limitations of this study are retrospective nature of data analysis, loss of some patients in follow-up examinations beyond 12 months following initial VC diagnosis in our clinic because change of address/phone number or switch to a new local gynecologist. Some patients were initially diagnosed in 2018 resulting in short follow up time. A further weakness is the small sample size of patients with lateralized vulvar tumor location.