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 high 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 must be considered due to the fact that when recurrent groin metastasis occurs, the survival rates of these patients decrease significantly. 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 93.5–68.7% and in patients with positive SLNB from 77.7–44.6%.9–22
A German study, on this issue of Woelber et al.7, showed in none of the cases of primary VC with positive unilateral SLN contralateral positive lymph nodes in consecutive bilateral IFL (0/28 cases, 0%). A Canadian study (Nica et al.)8 showed that only 1 of 19 patients (5.3%) had contralateral IFL metastasis after unilateral SLNB metastasis. But, two of their patients with positive unilateral SLNB had groin recurrence metastasis (one located unilaterally and the other contralaterally) several months following negative IFL.8 Therefore, they suggest for the omission of contralateral IFL in positive metastasis of unilateral SLNB. Both studies are in contrast to our findings with 4/18 (22.2%) women with unilateral positive SLN diagnosed with contralateral positive nodes in IFL. In our study, the tumors of these four women were located in the midline. Unfortunately, Woelber et al. and Nica et al. studies had not specified the location of the tumors, if they were midline or lateral. 7,8,12
Over the past decade, there is an increasing trend for midline vulvar cancer23–26. This was confirmed with the majority cases in our recent study located at anterior fourchette. 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 suggests that current guidelines should not be amended or changed. According to our results, the depth of tumor cells infiltration is a significant factor in the prediction of contralateral metastasis (p = 0.0038). The median depth of tumor infiltration was 3 mm in group 1, 6 mm in group 2AB and 8.5 mm group 2C. Nonetheless, the diameter of the tumor is statistical insignificant (p = 0.764). This finding related to depth of tumor infiltration is also parallel to current suggestion in German guideline as follows: ≤1 mm; 1.1-2 mm; 2.1-3 mm; 3.1-5 mm and ˃5 mm with the possibility of overall groin metastasis of 0%; 7.6%; 8.3%; 26.7%; and 34.2%, respectively.4 The depth of tumor has also been proposed in consideration for extensive management of VC.17,27 Future research should aim for bigger sample size and evaluate the correlation between the depth measurement of tumor cells infiltration and risk of contralateral metastasis.
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, future prospective evaluation of lateralized lesions in VC is warranted. The few sample data with lateralized lesions in our study 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 the contrary 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 < 4 cm and sentinel node metastasis is < 2 mm. However, in the case of sentinel node metastasis of > 2 mm, radiotherapy is not a safe alternative of IFL.21
Young women at premenopausal age may also suffer from VC. If the patient complained of persistent itchiness, burning sensation, pain and/or ulcer, gynecologists should not hesitate to perform a tissue biopsy in case of suspicious lesion. VC may also be diagnosed in pregnancy and if the decision to perform SLNB, this procedure should be done after the end of 14th weeks of pregnancy (first trimester) to be safe for the fetus. In pregnancy, lower dose of radioactive Tc-99m should be injected using short-treatment protocol (SLNB can be done two hours following injection with lowest possible dose). The half-life of technetium 99 m is six hours. The threshold for fetal damage in imaging procedure regarding lymphoscintigraphy is 100 mGy. The fetal radiation exposure (X-rays) is significantly reduced to < 0.1 mGy with the use of an abdominal shield. 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.28 Likewise, delivery mode should then be evaluated on a case-by-case basis; dependent on the probability of vulvar wound dehiscence and/or degree of scar tissue stenosis.28–30 In our study, the pregnant woman with VC delivered her baby via caesarean section.
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 vulvar cancer 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. 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. 28–30
No groin recurrence was reported in Group 2 (bilateral IFL after unilateral SLN metastasis detected) of our study after initial follow-up at 12 months. One woman with positive contralateral LN in IFL in subgroup 2C passed away due to lung metastasis, with history of being immunosuppressed following kidney transplantation. Two patients from Subgroup 2A passed away; the first with lung cancer (adeno-squamous cell) diagnosed 12 months following initial diagnosis of vulvar cancer with metastasis to bone and liver, and the second from relapsed epiglottis cancer (positive p16) at about 12 months following vulvar cancer diagnosis (initial diagnosis of epiglottis cancer was about 12 months before vulvar cancer diagnosis). In addition, one of the women with positive unilateral SLN metastasis with free ipsilateral LNs in subsequent IFL and free pelvic LNs (Group 1A) was diagnosed with lung cancer approximately 15 months later (non-keratinized SCC with negative p16, whereas p16 was positively expressed in her vulvar cancer). She was the only patient with R1 resection histopathologically.
Our data showed comparable morbidity 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% after IFL respectively.31
Although the 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, Fig. 1), there is a visible trend towards decreased survival in the women of Group 2C (Fig. 1). Interestingly and also unsuspectedly, 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 were retrospective nature of data analysis, loss of some patients in follow-up examinations beyond 12 months following initial VC diagnosis in our clinic, some patients were initially diagnosed in 2018 resulting in short follow up time and small sample size of patients with lateralized tumor location.