The curative treatment of vulvar cancer requires consideration of both the primary focus of disease in the vulva and the inguinal lymph nodes, which are the regional lymph nodes of the vulva. In current treatment, surgery is the first choice, and historically there has been a transition away from radiation therapy toward surgical procedures in Japan [4, 5]. The FIGO classifications of stages also consist of classifications of surgical staging, which include detailed histopathological findings on lymph node metastasis. However, radiation therapy remains a frequently chosen option, as patients with vulvar cancer are typically elderly and have a high rate of medical complications and high risk for surgery. For cases with high-risk factors for postoperative recurrence, postoperative adjuvant radiation therapy is performed. As with uterine cancer, concurrent chemoradiotherapy (CCRT) is sometimes tried, and combination chemotherapy may be conducted in advanced cases and cases of recurrence (CQ08, CQ10).
In recent years, efforts have been paid for individualization and reduction of radical treatment with special emphasis on the post-treatment quality-of-life (QOL) of the patients. However, these demands have sometimes led to confusion for the physicians treating vulvar cancer and consistent guidelines for determining the treatment plans are needed (Fig. 1)
(1) Histopathological approaches
Most epithelial tumors of the vulva are derived from squamous epithelium. These are divided into noninvasive vulvar intraepithelial neoplasias (VINs) and squamous cell carcinomas. Human papillomavirus (HPV) is detected in approximately 52–100% of cases of VIN . Formerly, VIN was classified into three categories (VIN 1, VIN 2 and VIN 3) based on the degree of spread of atypical cells. However, in the 2004 classifications of the International Society for the Study of Vulvovaginal Disease (ISSVD), VIN was divided into ‘usual VIN (uVIN), VIN caused by infection with HPV, ‘differentiated VIN (dVIN), and VIN not caused by HPV infection . In the WHO classification (4th edition) published in 2014, VIN related to HPV is called ‘squamous intraepithelial lesion’ (SIL). SIL is itself divided into two types—low-grade SIL (LSIL), thought to be non-neoplastic morphological abnormalities associated with HPV infection, and high-grade SIL (HSIL), neoplastic lesion which carries the risk of carcinogenesis. LSIL corresponds to (HPV-related) VIN 1, and HSIL corresponds to VIN 2 and 3 . Bowenoid papulosis (BP) caused by HPV infection is a black pimple or papule that breaks out repeatedly on the vulva. Although the histological appearance of BP is identical to that of uVIN or HSIL, it disappears spontaneously, so the term BP is not used in histological diagnosis. All these lesions have long attracted attention for their potential to undergo malignant change, and the diagnosis and management of VIN is a matter of importance (CQ01).
Squamous cell carcinoma is divided into five types—keratinizing, non-keratinizing, basaloid, warty and verrucous. The vulvar squamous cell carcinoma seen in young women is frequently caused by infection with HPV and often presents in basaloid or warty form. By contrast, vulvar squamous cell carcinoma in elderly women is rarely caused by HPV infection and is usually keratinizing or non-keratinizing .
(2) Surgical treatment
Historically, the 5-year survival rate for treatment of vulvar cancer improved to 60–70% as a result of the establishment of radical vulvectomy and systemic lymphadenectomy (bilateral inguinal lymphadenectomy, pelvic lymphadenectomy) in the United Kingdom and the United States [10,11,12]. Radical vulvectomy and the continuing series of skin incisions leading to bilateral inguinal lymphadenectomy (en bloc type) have been vital in enhancing the understanding of dissection and other skills necessary for operating on vulvar cancer and are basic procedures in the vicissitudes of subsequent procedures (CQO2). In recent years, as increased focus has been placed on postoperative QOL, efforts have been made to improve QOL through the individualization and reduction of the two components of radical vulvectomy, namely surgery on the vulvar disease and surgery on the lymphatic nodes [13, 14] (CQ03, CQ05). The results of detailed histopathological examinations of metastasis to the inguinal lymph nodes and risk factors for prognosis have provided the theoretical basis for the reduction and individualization of surgical therapies [15,16,17,18]. Moreover, the appropriateness of reduction has been confirmed in meticulous reviews of surgical therapy in early stage vulvar cancer ). In inguinal lymphadenectomy, there have been moves toward reduction to superficial inguinal lymphadenectomy alone, but deep inguinal lymphadenectomy is still thought to be necessary based on the results of a prospective clinical trial and recent research on sentinel lymph nodes (SLNs)  (CQ05).
In the field of gynecology, the first disease adopting the SLN biopsy procedure was vulvar cancer  (CQ06). There have been several reports of prospective clinical trials and reviews [21,22,23,24]. From these results, it has been pointed out that omitting the complete removal of the lymph nodes when no metastasis is observed in the sentinel nodes clearly reduces postoperative complications and prognostic symptoms, thereby contributing to improved postoperative QOL. The problem is that safety must be secured by minimizing failure to detect metastasis. Fortunately, it has been confirmed that the relapse rate is low when the target of the surgery is restricted to tumors that are clinically metastasis-negative and localized to the vulva. In addition, it is emphasized that this procedure must be performed by highly trained surgeons and teams [22,23,24].
The usefulness of extensive surgery resecting surrounding affected organs has long been recognized in cases of advanced vulvar cancer . In advanced cases of vulvar cancer in which the lesion extends from the vagina to the urinary bladder or to the anus and/or rectum, anterior, posterior or total pelvic exenteration is selected. Because of the wide range of defects, various forms of reconstructive surgery must accompany this procedure. Reduced QOL and frequent complications are problems with this procedure, and in recent years reports and reviews have cited the use of preceding radiation therapy and chemotherapy as a means of avoiding extensive surgery, and these have been reported as useful  (CQ04).
When large parts of the vulva and surrounding area are lost as a result of vulvar surgery, it is useful to accompany with reconstructive surgery. By making proactive use of cosmetic reconstructive surgery, it has become possible to reduce postoperative complications, improve QOL and limit impairment of the patient’s appearance. A wide range of methods of reconstructive surgery are available, and reconstruction can be tailored to each excision wound, so careful examination is in order before proceeding with surgery .
Most patients are elderly and medical complications are frequent. Surgeons preparing to proceed with vulvar surgery must become experts in postoperative management and management of the possible complications, particularly excision infection and dehiscence of operative wounds.
(3) Radiation therapy
The principal role of radiation therapy is as adjuvant therapy to surgery (CQ07). In GOG37, postoperative irradiation of the groin and pelvis is reported to be effective if lymph node metastasis is clinically recognized, if metastasis to the inguinal lymph nodes is combined with fixation or ulceration, or if two or more lymph node metastases are recognized histopathologically . Retrospective research also reports that postoperative irradiation is effective against vulvar primary lesions in cases with positive or close margins .
Because patients with vulvar cancer are typically elderly, surgery is not applied in some cases because of medical complications. Definitive radiation therapy is applied in these cases, as well as in inoperable cases with locally advanced cancer (CQ07) [30,31,32].
Clinical trials have been conducted using preoperative irradiation on locally advanced vulvar cancer (CQ07). In four phase II trials examining the efficacy of preoperative irradiation in cases of stage II−IVa disease and in cases of local recurrence, clinical complete remission was observed in 27–64% of cases, while histopathological complete remission was obtained in 31–70% of cases [30, 33,34,35]. While these results indicate the effectiveness of multidisciplinary therapy aiming to preserve the function of adjacent organs, problems of consistency still remain. The treatment method is not uniform and criteria for evaluating operability have not been demonstrated. At present, clear evidence is still lacking to support the application of preoperative irradiation to locally advanced vulvar cancer as a standard method.
Three-dimensional conformal radiation therapy (3D-CRT) is a standard method of the external beam radiation therapy. However, intensity-modulated radiotherapy (IMRT) is a more useful treatment that can deliver a conformal radiation dose to a target extending from the vulva to the inguinal region and pelvic lymph nodes.
Reports of chemotherapeutic treatment of vulvar cancer have increased in recent years. However, all the studies were at the phase II trial level, and no standard treatment has been established (CQ08, CQ10). Chemotherapy is selected in the following situations including preoperative chemotherapy, CCRT, postoperative adjuvant chemotherapy, and chemotherapy against progression and relapse.
Clinical questions and recommendations
CQ 01: What treatments are recommended for VIN?
The objective is to determine a treatment method for VIN.
(1) Periodic follow-up is recommended for LSIL (Grade A).
(2) Wide local excision, simple vulvectomy, or laser vaporization may be considered, depending on the case, or laser vaporization may be combined with either of the first two for HSIL or dVIN (Grade C1).
Many reports about VIN have been published in accordance with the stage categories VIN 1 to VIN 3, advocated in the WHO classification 2003 (3rd edition). However, the latest WHO classification identifies three new categories as mentioned in general consideration. LSIL and HSIL occur in relatively young patients, have been increasing in recent years, and represent the majority of VIN cases. Although most cases of LSIL regress spontaneously, 6% of HSIL cases have been shown to progress to squamous carcinoma [36, 37]. BP, which most commonly occurs in patients in their late teens and 20s, presents histopathologically as HSIL, but frequently regresses spontaneously without any treatment [38,39,40,41,42]. On the other hand, dVIN, which is related to lichen sclerosis and lichen planus, corresponds to simplex VIN in the old WHO classification. Simplex VIN often occurs in elderly patients and clinically presents as leukoplakia vulvae. It has been pointed out that simplex VIN progresses to squamous carcinoma in 33% of cases, and is more malignant than LSIL or HSIL [37, 43]. Because LSIL, HSIL and dVIN differ in pathogenesis and malignancy, it is preferable that each be managed differently.
Most cases in the old VIN 1 category are LSIL, and doubt exists as to their significance as neoplastic lesions. However, the old histopathological definition of VIN 1 includes dVIN which, unlike LSIL, is a neoplastic lesion and must be separated from VIN 1 even though the frequency of dVIN occurrence is very low . On that understanding, it is preferable to avoid invasive treatment for LSIL and to follow-up periodically. On the other hand, HSIL and dVIN are neoplastic lesions which require treatment. In a systematic review of the literature, it was found that 9% of untreated cases of VIN 3 progressed to invasive carcinomas, and 3% of cases that are surgically excised had occult invasive carcinoma , indicating that biopsy under colposcopy is important to exclude invasion . Clinically the evidence for a clear distinction between VIN 2 and VIN 3 has not been demonstrated, and HSIL, which includes both VIN 2 and VIN 3, must be managed with the same due consideration [7, 36]. Because HSIL is caused by HPV infection, multiple foci of disease can appear in a wide-ranging area of the vulva and can also appear, simultaneously or allochronically, in and around the uterine cervix, vagina and anus. Careful examination of all of these areas is required.
When part of a VIN lesion is suspicious for invasion on the appearance of ulceration or irregular surface, it is necessary to move proactively to carry out a wide local excision or simple vulvectomy and conduct a histopathological examination on excised specimens, even if biopsy results do not identify the invasion. In particular, dVIN is often complicated with, or progresses to, invasive carcinoma, and surgical excision is the first choice of treatment that should be considered. In surgical procedures, physicians should consider the patient’s QOL and carry out shallow excision, avoiding deep excision of the vulva, and take care in preserving the clitoris [47, 48]. If the range of excision is very wide, cosmetic surgery of the vulva using skin grafts may be added .
If a case of HSIL or dVIN has been comprehensively confirmed not to be associated with invasion, it is possible to choose laser vaporization instead of surgical excision . If the focus of disease is wide, or if there are multiple foci, it is possible to treat the condition on a case-by-case basis with a combination of vaporization and surgical excision. However, lesions clinically judged to be BP have been reported to regress spontaneously over a period of 3–30 months (median period 9.5 months) . If the focus of disease is not seen to regress under strict periodic follow-up, treatment should be administered.
Recently imiquimod ointment has been used to treat LSIL and HSIL to stimulate local immune response [40, 50,51,52,53,54]. Effectiveness for this approach has been indicated by prospective controlled trials and meta-analyses. However, no randomized trial has compared imiquimod treatment to standard treatment, and the evidence remains insufficient due to the small number of cases. Imiquimod treatment is not a standard treatment at present and is not listed as an insured treatment in Japan.
Currently, a preventive vaccine for HPV is expected to show effectiveness against HPV-related lesions, and a decline in cases of LSIL and HSIL is anticipated as adoption of the vaccine spreads .
Because of the high frequency of recurrence and the possibility of transition into vulvar cancer, periodic follow-up is an important component of management of intraepithelial lesions .
CQ 02: How should radical vulvectomy be applied? What techniques should be used?
The objective is to examine how radical vulvectomy should be applied as a curative excision and the techniques that should be used.
(1) Radical vulvectomy is recommended in cases where the focus of disease is localized to the vulva or perineum when the diameter of the tumor is >2 cm and the stromal invasion is >1 mm deep (Grade B).
(2) Resection of vulvar tumors and inguinal lymph nodes through separate incisions is recommended (Grade B).
Until the first half of the 20th century, surgical methods for vulvar cancer (squamous carcinoma) were limited to vulvectomy in advanced cases. In those days, the 5-year survival rate was 20–25%. Later, the survival rate improved to >60% with the introduction of en bloc incision, in which excision was applied to a continuous mass incorporating the skin and subdermal tissue of the vulva and the adipose tissue of the groin, including the inguinal lymphatic nodes, and combined sometimes with removal of the pelvic lymphatic nodes [10, 11]. This combination of radical vulvectomy plus inguinal and pelvic lymphadenectomy became the standard surgical procedure. However, many cases were accompanied by special site characteristics, very elderly patients, or various medical complications. As a result, the surgery was associated with significant morbidity, including wound dehiscence and infection . In the 1980s, it was reported that postoperative complications could be reduced through conservative surgery, and the focus began to shift toward individualized treatment. However, because of the many sites of occurrence and foci of diseases in individuals of vulvar cancer and the low frequency of occurrence, many reports gathered cases over a period of >20 years. There were no randomized controlled trials of incision methods, and clear evidence of the effect of conservative surgery on vulvar cancer was limited. Complicating matters further was the lack of reports based on the new FIGO classifications; the existing literature was based entirely on the 1988 FIGO classifications. Therefore, radical vulvectomy should be applied in cases where application of conservative surgery was not clearly indicated, i.e., the tumor is on the median, on the side of the pubic bone, the tumor is on both the left and right sides, and multiple foci of disease are present.
As an improvement to radical vulvectomy, separate incision (or triple incision) was reported in 1962. In this approach, the excision of vulvar neoplasia is separated from inguinal lymphadenectomy . Later, in the 1980s, a method was developed to leave the suprapubic skin intact as a skin bridge. The prognosis for this procedure was found to be commensurate with historical data in stages I–IV in the old (1988) FIGO classifications, and the frequency of wound complications decreased dramatically [59,60,61,62]. In particular, a comparative matched study was conducted on 32 patients per group with squamous cell carcinoma localized to the vulva and perineum, where the tumor was ≤2 cm in diameter and with lesions >2 cm,in which either en bloc incision or separate incision was performed. While overall survival and disease-free survival rates were similar for the two groups, the dehiscence rate for vulvar and inguinal wounds decreased significantly in the case of separate incision . Separate incision was shown to be clearly less surgically invasive than en bloc incision. Although skin bridge recurrence between the vulva and groin was higher for separate incision than for en bloc incision, the survival prognosis after re-excision was good [64, 65]. Furthermore, cases of skin bridge recurrence between the vulva and groin are <1% where no gross lymph node metastasis is present. Although recurrence in lymph nodes is lower for en bloc incision, no difference in survival prognosis is found. Currently, even when the frequency of recurrence in lymph nodes and skin bridge recurrence between the vulva and groin is considered, separate incision is recommended, due to the lesser degree of impairment caused by the treatment .
When vulvar disease invades the urethral opening or lower urethra, it is possible to excise the urethra in a way that preserves the urethral sphincter and does not cause incontinence . Invasion to the vagina as far as the lower third of the vaginal wall can also be excised at the same time as vulvectomy.
The term ‘radical vulvectomy’ also includes the modified radical vulvectomy which preserves part of the healthy vulva.
CQ 03: How should conservative surgery be applied for invasive vulvar cancer?
The objective of this section is to consider methods of conservative surgery planned for early stage vulvar cancer and how to apply them.
(1) Wide local excision is recommended in cases where the diameter of the tumor is ≤2 cm and the stromal invasion is ≤1 mm deep (Grade B).
(2) Radical local excision can be considered with an excision margin of 2 cm in cases where the diameter of the tumor is ≤2 cm but the stromal invasion is >1 mm deep; or the diameter of the tumor is >2 cm but the lesion is localized laterally to the vulva or to the perineum (Grade C1).
In early stage vulvar cancer, the size of the tumor and depth of invasion are related to metastasis to the inguinal lymph nodes. If the diameter of the tumor is ≤2 cm and the stromal invasion is ≤1 mm deep, wide local excision is an appropriate surgical method that offers low surgical invasiveness, and inguinal lymphadenectomy can be omitted [68,69,70,71].
Radical local excision may be considered in cases where the diameter of the tumor is ≤2 cm but the stromal invasion is >1 mm deep; or the diameter of the tumor is >2 cm but the lesion is secluded (localized laterally to the vulva or to the perineum), with surrounding skin tissue normal. This surgical technique presents a considerably lower frequency of postoperative complications than radical vulvectomy, and while the local recurrence rate is reported to be somewhat elevated, no difference is observed in the survival period [72,73,74,75]. The procedure should be limited to tumors which occur singly and are lateral (defined as ≥1 cm distant from the median line of the lesion).
In this procedure the depth of the excision is similar to that of a radical vulvectomy. The excision margin is closely related to the probability of local recurrence; if the margin is ≤8 mm, the probability of local recurrence is 50%. The local control rate is high when the margin is secured for 8 mm to 1 cm histopathologically [76, 77]. However, even if the excision margin is a gross 1 cm, histopathologically the excision margin is ≤8 mm after fixation in 50% of cases. To ensure sufficient excision margin, a gross distance of 2 cm is required .
CQ 04: What surgical therapies are recommended for locally advanced cases with adjacent organs infiltrated?
The objective of this section is to examine the usefulness of pelvic exenteration in locally advanced cases with deep adjacent organ invasion.
(1) Pelvic exenteration is considered if there is no apparent lymph node metastasis and complete excision is anticipated (Grade C1).
(2) Preoperative CCRT or chemotherapy is also considered in order to avoid QOL decline associated with pelvic exenteration (Grade C1).
In the past, pelvic exenteration was considered as an option for locally advanced vulvar cancers deeply infiltrating adjacent organs, such as the urethra, urinary bladder, anus and rectum. According to a retrospective study on 19 cases of vulvar squamous carcinoma receiving pelvic exenteration, including 11 cases of primary treatment, the 5-year survival rate was 60%. Although no difference was found in overall survival between primary treatment and recurrent cases, lymph node metastasis was significantly associated with overall survival . In a retrospective study of 27 cases of stage III−IV vulvar cancer (FIGO 1994) receiving pelvic exenteration, including 9 cases of primary treatment, the 5-year survival rate was 62% . Although no significant difference in prognosis was found between primary treatment and recurrent cases, cases with negative lymph node metastasis had significantly better prognoses than positive cases. Furthermore, cases of pathologically confirmed complete excision had significantly better prognosis than cases of pathological incomplete excision. These results indicate that the presence/absence of lymph node metastasis and complete excision are the most important prognostic factors .
In recent years, conservative surgery preceded by chemotherapy or CCRT has been tried as an alternative to pelvic exenteration, in order to avoid compromising QOL. According to a retrospective study and Gynecologic Oncology Group (GOG) phase II trials, preoperative CCRT can enable cases that are unresectable or requiring pelvic exenteration to be resectable or to circumvent pelvic exenteration [30, 34, 79]. However, since no phase III trials exist to date, the prognostic impact remains unclear.
CQ 05: How and in what range should lymphadenectomy be applied? (Fig. 2)
Although the superficial inguinal and deep inguinal lymph nodes are the regional lymph nodes affected by vulvar cancer, efforts have been made to reduce the scope of lymphadenectomy according to the disease state. The objective of this section is to examine the usefulness and appropriate scope of lymphadenectomy.
(1) Inguinal lymphadenectomy can be omitted in cases where the tumor is ≤2 cm in diameter and the depth of the stromal invasion is ≤1 mm (Grade B).
(2) Inguinal lymphadenectomy includes resection of both the superficial and deep inguinal lymph nodes (Grade C1).
(3) Ipsilateral lymphadenectomy alone can be considered in cases of a tumor located laterally in which the tumor is ≤2 cm in diameter (Grade C1).
(4) Postoperative radiation therapy for the groin and pelvis is recommended in cases that are positive for metastasis in the inguinal lymph nodes, where radical vulvectomy and inguinal lymphadenectomy have been conducted (Grade B).
(5) It is recommended at a minimum that the enlarged lymph nodes be resected if possible, to conduct a histological examination for possible metastasis (Grade B).
Prognosis is extremely poor with recurrence in the inguinal lymph nodes in cases of vulvar cancer in which inguinal lymphadenectomy was not performed. To ensure elimination of lymph node metastasis (the most important factor in prognosis), it is considered essential to conduct inguinofemoral lymphadenectomy on at least one side during primary radical surgery [80, 81]. In randomized controlled trials (GOG88) of radiation therapy to the groin versus lymphadenectomy (postoperative irradiation of the diseased-side groin and pelvis in cases positive for lymph node metastasis) in cases in which metastasis to the inguinal lymph nodes is not suspected, recurrence was higher in the radiation therapy group than in the lymphadenectomy group. Both progression-free survival time and overall survival time were significantly better for the inguinal lymphadenectomy group, prompting the researchers to discontinue the trials. These trials suggest that lymphadenectomy is more useful than radiation therapy to the groin in the treatment of vulvar cancer with no suspicion of inguinal lymph node metastasis .
However, in cases where the tumor is ≤2 cm in diameter and invasion is ≤1 mm deep (corresponding to clinically stage IA), lymph node metastasis occurs in <1% of cases. Lymphadenectomy is not recommended in these cases, as this treatment is ineffective and in fact harmful . Even in cases where invasion is >1 mm, omission of lymphadenectomy is reported based on considerations, for example, on the presence/absence of lymphovascular space invasion, lesion sites and the degree of histological differentiation . Further evaluation of criteria for omission of lymphadenectomy in these cases is warranted in the future.
Cases have been reported in which no recurrence is confirmed when treatment consists of removal of the superficial inguinal lymph nodes alone, if the tumor is ≤1 cm in diameter and invasion is ≤5 mm deep . Later, retrospective studies were conducted for cases with early stages that were treated with removal of the superficial inguinal lymph nodes alone. Recurrence was confirmed on the same side in only 4% of cases. This result indicates that treatment consisting solely of superficial inguinal lymphadenectomy is effective . However, in a prospective one-arm trial of GOG74, superficial inguinal lymphadenectomy alone was conducted in cases in which the tumor was ≤2 cm in diameter, no vascular space invasion was present, lymph nodes were not swollen and invasion was ≤5 mm deep. In comparison with past research results [81, 84], no difference in survival rate was found, but the recurrence rate was high (16%) and recurrence in the treated lymph nodes side was confirmed in six of 121 cases . According to later, retrospective studies, the recurrence rate was also higher for superficial inguinal lymphadenectomy alone compared with lymphadenectomy as far as the deep inguinal lymph nodes [86, 87]. Another study points out that the SLNs are superficial inguinal lymph nodes in 84% of cases and deep inguinal lymph nodes in 16% of cases, indicating that in some cases the deep inguinal lymph nodes are the SLNs . These findings suggest that lymphadenectomy should be extended as far as the deep inguinal lymph nodes.
On the question of whether bilateral inguinal lymphadenectomy is necessary, the organs in which bilateral lymph flow is observed anatomically consist of the perineum, clitoris, and labia minora near the pubis . Retrospective studies indicate that when the focus of disease is ≤2 cm in diameter and is located on one lateral side, metastasis to contralateral lymph nodes occurs in <0.5% of cases [83, 90]. These findings suggest that lymphadenectomy can be limited to the diseased side in cases where the tumor is ≤2 cm in diameter, has not invaded to the midline structures such as the clitoris, urethra, vagina, perineal body or anus, is 1–2 cm lateral from the median, and no lymph node metastasis is suspected. However, some reports indicate that bilateral lymphadenectomy is necessary if lymph node metastasis has occurred on the diseased side . Another study reports that metastasis to the non-diseased side is possible only in cases where the tumor is ≥2 cm in diameter, invasion is ≥5 mm deep, and ipsilateral lymph node metastasis is confirmed. In these cases, bilateral lymphadenectomy is recommended . On the question of whether bilateral inguinal lymphadenectomy is necessary for all medial lesions, some reports indicate that metastasis to the opposite side is not confirmed in cases where the SLNs are identified on only one side . As with the problems of superficial and deep inguinal lymphadenectomy, the answer would be changed in the future according to the generalization of SLN biopsy.
To examine the question of additional treatment for positive cases of metastasis to inguinofemoral lymph nodes, randomized controlled trials (GOG37) were conducted comparing pelvic lymphadenectomy with radiation therapy to the pelvis and groin after radical vulvectomy and full inguinal lymphadenectomy. It was reported that radiation therapy was superior in terms of 2-year overall survival rate. The addition of radiation therapy significantly reduced local recurrence and cancer-related death, according to follow-up data over a median period of 74 months. As a result, treatment with pelvic lymphadenectomy with no radiation therapy was not recommended . However, some guidelines indicate that all of the swollen inguinal and pelvic lymph nodes may be removed and followed by radiation therapy to the groin and pelvis in cases where imaging revealed swelling of the pelvic lymph nodes. As such, surgery to remove the pelvic lymph nodes is by no means repudiated .
One retrospective comparative study examined how to handle swollen inguinal lymph nodes with suspicion of metastasis, comparing removal of the swollen lymph nodes alone with systematic lymphadenectomy. It was found that the selection of limited surgery had no harmful effect on prognosis, provided it was coupled with appropriate postoperative irradiation . Although the study did not draw any conclusions regarding the necessity of systematic lymphadenectomy, it seems likely that at least the excision of swollen lymph nodes suspected of metastasis should be considered, and the presence/absence of metastasis examined histologically, before considering radiation therapy.
CQ 06: Can SLN biopsy be used to avoid performing a lymphadenectomy?
The objective of this section is to examine whether systemic inguinal lymphadenectomy can be avoided by using SLN biopsy.
SLN biopsy may be performed as a means to avoid an inguinal lymphadenectomy in cases in which metastasis to the inguinal lymph nodes is not suspected clinically. In view of the current status of experience in the procedure in Japan, this action should be considered as an experimental approach (Grade C1).
The identification of SLNs for vulvar cancer is one of the most progressed areas of inquiry in gynecology [96, 97]. In principle, SLN biopsies are used in cases with vulvar cancer localized to the vulva and perineum with no suspicion of lymph node metastasis.
According to numerous reports from individual institutions, there are three methods of identifying the SLNs—the dye method alone, the radioisotope (RI) method alone, and the dye/RI combined method [98, 99]. Isosulfan blue and patent blue are used in the dye method, and technetium-99 m is used in the RI method. Recently, a feasibility study has been reported of a fluorescence method using indocyanin green dye in cases of vulvar cancer . An analysis of the combined method based on 26 journal articles and 1271 cases indicates that this method provides an 86% identification rate and a false negative rate of 5.8%. For the RI method, analysis of seven articles and 116 cases yields an identification rate of 83% and a false-negative rate of 8.8%. For the dye method alone, analysis of three articles and 111 cases provides a low identification rate of 64% and a false-negative rate of 8.7%. Most reports recommend use of the combined method .
According to a meta-analysis, the following factors affect the identification rate for SLNs and the sensitivity for metastasis—method of identification of SLNs, and localization of the focus of disease in the vulva, i.e., whether the focus of disease is located medially or laterally. An increase in false negatives for medial lesions has been reported . A multi-institutional validation study similarly report false negatives for medial lesions . Similarly, one meta-analysis indicated a decrease in identification rate for SLNs in cases with palpable swollen lymph nodes or with large tumors .
In a multi-institutional prospective study, SLN biopsies were used to avoid systemic lymphadenectomy when the SLNs were negative for metastasis. In the trial, 403 cases of tumors <4 cm in diameter and localized in the vulva were examined. The recurrence rate in the inguinal lymph nodes was 3%, indicating the effectiveness of the SLN biopsy. In particular, the recurrence rate was 2.3% in isolated vulvar disease . Complications of SLN biopsies such as wound trouble, cellulitis and lymphedema were rare in the study .
In a cost-effectiveness analysis, omission of lymphadenectomy based on SLN biopsy was compared with systemic inguinal lymphadenectomy. This report found that the most cost-effective approach was to identify SLNs using the combined method (dye plus RI) and perform ultrastaging using immunostaining to search for metastasis . In the multi-institutional trials cited above, the metastasis detection rate was found to increase gradually when immunostaining was combined with multi-section searches (ultrastaging) using ordinary hemotoxylin-eosin (H&E) dye . However, the intervals in which sections were prepared and the number of sections searched were not consistent in the reports.
Frozen section diagnosis during surgery is reported as useful, with a sensitivity of 89% and a negative predictive value of 93% . However, the sensitivity and negative predictive value were both low at 48 and 78%, respectively, in a multi-institutional trial . Opinion differs as to whether this practice should be combined with postoperative ultrastaging or omitted when searching for metastasis in SLNs.
Even though evidence was accumulated for the usefulness of SLN biopsy in vulvar cancer, no results of randomized controlled trials currently exist comparing this approach with standard treatments. In Japan, almost no results are available on vulvar cancer, as health insurance covers SLN biopsies only for breast cancer and malignant melanomas. Under these conditions, the first step should be to conduct clinical trials on the omission of lymphadenectomy on the basis of SLN biopsies. It is also preferable that the omission of systematic lymphadenectomy be carried out not by gynecologists alone but with the cooperation of physicians in other medical fields who are thoroughly trained in SLN biopsies, as well as radiologists, pathologists and others.
Radiation therapy for vulvar cancer
CQ 07: How should radiation therapy be applied and what methods should be used?
Radiation therapy is conducted as an adjuvant treatment to surgery and as a definitive treatment. The objective is to examine how radiation therapy should be applied and the methods that should be used.
(1) Postoperative irradiation of the primary site may be considered if the excision margin is <8 mm, or advanced vascular space invasion is confirmed (Grade C1).
(2) Postoperative irradiation of the groin and pelvis is recommended, if two or more metastases or extracapsular invasion of lymph node metastasis is confirmed in the inguinal lymph nodes (Grade B).
(3) Omission of postoperative irradiation may be considered, when one metastasis alone of the inguinal lymph nodes has occurred without extracapsular invasion (Grade C1).
(4) Definitive radiation therapy may be considered in inoperable cases (Grade C1).
(5) Preoperative irradiation may be considered as a means of preserving the function of adjacent organs in locally advanced cases (Grade C1).
(6) Concurrent chemotherapy with a single platinum-based drug or combination of this drug may be considered (Grade C1).
Postoperative recurrence of vulvar cancer is associated with the degree of tumor invasion and lymph node metastasis [76, 81, 104]. Because the risk of local recurrence appears if excision margins are <8 mm , postoperative adjuvant treatment for the primary site is required. In a retrospective study, postoperative irradiation of the primary site is reported to be effective in cases with close margins or where advanced vascular invasion is recognized . As mentioned in CQ05, randomized controlled trials (GOG37) have demonstrated the superiority of postoperative irradiation to pelvic lymph node dissection when inguinal lymph node metastasis is recognized, when lymph node metastasis has occurred in combination with fixation or ulceration, or when two or more lymph node metastases are confirmed histopathologically [28, 93]. One retrospective study of 208 cases of single lymph node metastasis found that postoperative irradiation was effective in increasing disease-specific survival rate. Unfortunately, this study is problematic as it fails to consider extracapsular invasion in lymph node metastasis, which is a major risk factor for recurrence . Later, a multi-institutional retrospective study was conducted on 75 cases of single lymph node metastasis without extracapsular invasion. This study did not confirm that postoperative irradiation was beneficial . Based on these findings, inguinal and pelvic postoperative irradiation is recommended when two or more metastases are confirmed in the inguinal lymph nodes, or extracapsular invasion is confirmed. In practice, the field of pelvic lymph nodes covers the internal and external iliac lymph nodes and the obturator lymph nodes, and the radiation dose is 45–50.4 Gy in 25–28 fractions.
Definitive radiation therapy is considered in cases where surgery is not applicable, such as in elderly patients or in the case of medical complications, and in cases that are judged inoperable, such as those with advanced local progression or metastasis in inguinal lymph nodes that cannot be removed. When planning radiation therapy, the groin is included in the clinical target volume (CTV) even if no metastasis is clinically confirmed, and the CTV is extended to the pelvic lymph nodes if metastasis is clinically confirmed in the inguinal lymph nodes. After external beam irradiation of 45–50 Gy of a CTV encompassing the lymph node area, the irradiation field is shrunk to the focus of disease and the dose is increased to 60–70 Gy. Because it is necessary to apply a uniform dose to a complex CTV that includes the vulva, groin and pelvic lymph nodes, 3D-CRT combining X-ray and electron beam irradiation is applied. Compared with conventional 3D-CRT, IMRT enables more conformal dose distribution to the target and reduced dose on surrounding normal organs .
Some reports have examined the usefulness of multidisciplinary therapy using preoperative irradiation on tumors that are inoperable due to invasion of adjacent organs, or in cases of locally advanced vulvar cancer requiring exenterative surgery. In the results of four phase II trials targeting stages II, III, IVA and cases in local recurrence, clinical complete remission was confirmed in 27–64% of cases, 72–97% of cases became operable, and histopathological complete remission was obtained in 31–70% of surgical cases [30, 33,34,35]. Although the scale of the trials was small (41–71 cases), the results of each trial indicated the effectiveness of multidisciplinary therapy aimed at preserving the function of adjacent organs. However, the criteria for application of surgery remain unclear; QOL evaluation is not always performed, and the degree to which histopathological complete remission improves prognosis is not clearly understood . Furthermore, no phase III trials have been conducted indicating the effectiveness of preoperative irradiation on advanced local vulvar cancer . Accordingly, physicians must exercise careful judgment before applying preoperative irradiation, even with the aim of preserving organ function.
Many recent reports indicate the concurrent use of cisplatin (40 mg/m2/week), and adverse events were found to be within the acceptable range [30,31,32]. If the patient’s general condition and organ function meet certain criteria, the use of concurrent chemotherapy based on platinum-based drugs may be considered.
The most common acute radiation morbidity is radiation dermatitis, which occurs in virtually all cases. In some cases this condition becomes serious or is combined with infection, requiring the suspension or termination of treatment . Careful management is required, giving due consideration to protection of the skin and prevention of infection during radiation therapy.
Chemotherapy for the vulvar cancer
CQ 08: How should chemotherapy be applied?
The purpose of this section is to examine the usefulness of chemotherapy as a treatment for vulvar cancer.
(1) Preoperative chemotherapy may be considered for locally advanced cases (Grade C1).
(2) Systemic chemotherapy may be considered for cases of progression or recurrence of distant metastasis (Grade C1).
In contrast to the effectiveness of radiation therapy in the treatment of advanced vulvar cancer, there are few reports for chemotherapy which has been regarded as ineffective. Even so, attempts have been made to use chemotherapy as a preoperative adjuvant treatment for advanced cases to make them operable. Chemotherapy is also expected to be beneficial in advanced cases with distant metastasis and in recurrent cases.
Primary surgery of locally advanced vulvar cancer requires pelvic exenteration or other extended surgical methods. These surgeries result in impaired QOL. To address this problem, efforts have been made to use preoperative chemotherapy in advanced cases of vulvar cancer to avoid extended surgery. Many reports on these attempts have been generated from European organizations such as the European Organization for Research and Treatment of Cancer (EORTC). In these trials, preoperative chemotherapy was tested on locally advanced vulvar cancer using drugs such as bleomycin, methotrexate, lomustine, cisplatin, 5-fluorouracil, paclitaxel and vincristine. The reported response rate and surgical completion rate after chemotherapy were both favorable at approximately 60% and 57–90%, respectively [109,110,111,112,113]. In each report, however, the number of cases examined was small, and no standard treatment regimen was established. Problems remain with respect to the selection of drugs.
In phase II trials, the response rate of preoperative chemotherapy was higher than that of chemotherapy usually applied to advanced and recurrent cases. In most cases of recurrence, the patient has undergone radiation therapy in the past, and the low response rate may be found in advanced and recurrent cases for chemotherapy. The reported response rate for treatment with cisplatin alone , mitoxantrone  and a weekly dose of paclitaxel plus carboplatin  is 0% in each case, while for paclitaxel alone the response rate is 14% . In more encouraging treatment results, the response rate for bleomycin alone or concurrent with mitomycin, reported in 1980, was 50% , while a response rate of 40% is reported for concurrent treatment with cisplatin and vinorelbine . Because no studies have found reproducibly high response rates of chemotherapy, no treatments could be regarded as the standard treatment. However, in advanced cases with distant metastasis and in recurrent cases after radiation therapy, chemotherapy may be the only treatment option. Trials are currently under way using a wide variety of drugs .
Although the most widely used postoperative adjuvant treatment for vulvar cancer is radiation therapy, the use of chemotherapy as a postoperative adjuvant treatment is also reported . In this report, cisplatin was used postoperatively as adjuvant treatment in 14 cases of vulvar cancer with lymph node metastasis, and the recurrence rate was low. However, no other reports of similar results exist, and postoperative adjuvant chemotherapy has not become a standard treatment for vulvar cancer.
Follow-up and treatment for recurrent diseases
CQ 09: How should periodic follow-up be conducted after treatment?
The purpose is to examine the intervals and methods by which appropriate periodic follow-up should be conducted regarding recurrence and complications associated with treatment.
(1) A rough guide for the intervals in periodic follow-up after treatment is as follows (Grade C1):
First and second years: every one to three months
Third to fifth years: every six months
Sixth and subsequent years: once a year
(2) Conduct medical interviews, inspection, palpation, cytology, biopsy, chest X-ray, tumor markers and computed tomography (CT). Monitor not only for recurrence but also for complications (Grade C1).
The purpose of periodic follow-up is to detect recurrence as soon as possible, improve the prognosis, and to mitigate and reduce the loss of QOL caused by treatment. However, no evidence exists that diagnosis of recurrence through periodic follow-up after treatment leads to improved prognosis in vulvar cancer. Moreover, no reliable research has been performed regarding the interval of periodic follow-up and items examined during periodic follow-up after treatment of vulvar cancer, and no consensus can be obtained.
Guidelines in countries other than Japan were reviewed. In the United Kingdom, the Royal College of Obstetricians and Gynecologists recommends observation every 3 months during the first year after treatment, every 6 months in the second and third years, and once every 12 months in the fourth and subsequent years . In contrast, the National Cancer Institute (NCI) of the United States has no recommendations regarding periodic follow-up . The recommendations are based on the results of retrospective studies indicating that local recurrences diagnosed at a routinely scheduled follow-up were found to have a smaller greater dimension compared with recurrences detected by chance . However, no significant effect on survival rate was confirmed. In retrospective studies examining the timing, site of recurrence and the prognosis, 55–67% of recurrences occurred within 2 years after the first surgery [125, 126]. The most important predictive factors for recurrence are stage and metastasis to the inguinal nodes [125,126,127]. In cases that are positive for metastasis to the inguinal nodes at the time of initial treatment, recurrence within the first 2 years is common. On the other hand, in cases that are negative for metastasis to the inguinal nodes at the time of initial treatment, the recurrence rate is low, and recurrence sites are mainly local .
Because the common sites of recurrence are the local site and the inguinal nodes, inspection and palpation of these sites are most important. If recurrence is suspected, cytology and biopsy should be conducted. Other useful examination items are chest X-ray, tumor markers, CT, magnetic resonance imaging (MRI) and 2-deoxy-2-[18F]fluoro-d-deoxy glucose-positron emission tomography (FDG-PET). No set criteria are established regarding timing or other aspects of these tests. Detailed medical interviews of the patient’s condition enable the physician to make decisions after considering the risk of recurrence in each case. Although recurrence within the first 2 years is common, recurrence also occurs ≥5 years after initial treatment, which demonstrates the need for long-term follow-up .
The probability of postoperative complications in vulvar cancer is relatively high . The rate of wound complications of the vulva ranges from 9−58%, while frequent urination or urinary incontinence is confirmed in 8–28% of cases. The frequency of inguinal complications following inguinal lymphadenectomy is reported as 21–39% for infection, 17–39% for wound dehiscence, 21–57% for cellulitis, 11–40% for lymphocele and 14–48% for lymphedema. Most cases of lymphedema occur in the legs within the first 12 months after surgery and are chronic. Lymphedema is aggravated by obesity, infection, addition of radiation therapy and deep vein thrombosis after surgery. Furthermore, psychological and social problems frequently occur after surgery for vulvar cancer, including psychological stress, pain during sexual intercourse, decreased libido, frequent urination and incontinence. Because these problems are detrimental to a patient’s QOL, long-term periodic follow-up is necessary.
CQ 10: What treatments are recommended for recurrent disease? (Fig. 3)
The objective of this section is to examine the most useful treatment approaches for recurrence.
(1) Re-excision is considered for postoperative localized recurrence (Grade C1).
(2) CCRT is considered for local recurrence unresectable or infiltrating adjacent organs, if unirradiated (Grade C1).
(3) Systemic chemotherapy is considered for recurrences in the pelvis, with distant metastasis or with multiple lesions (Grade C1).
(4) Best supportive care (BSC) is considered if no other effective treatments are left (Grade C1).
When deciding treatment for recurrence, the site of recurrence, details of previous treatments and performance status must be taken into account . A retrospective study on 502 cases of vulvar squamous carcinoma in 5 institutions in Italy reported that recurrence occurred in 37% and the 5-year survival rate varied by recurrence site—60% for the vulva, 27% for the groin and pelvis, 15% for distant metastasis, and 14% for multiple lesions .
For localized recurrence, re-excision is considered. In a retrospective multi-institutional study of 102 recurrent cases receiving re-excision following radical vulvectomy, the disease-free survival rate was 56% and the 5-year survival rate was 61%. Cases with inguinal lymph node metastasis at recurrence showed significantly poor prognosis . If lymphadenectomy has never been performed, unilateral or bilateral inguinal lymphadenectomy may be performed, depending on the site of recurrence. If the re-excision margin or lymph node metastasis turns out positive, CCRT may be added if radiotherapy has not yet been performed .
For local recurrence to unresectable or infiltrating adjacent organs, CCRT is considered if unirradiated. According to a retrospective study where CCRT was performed for 7 unirradiated cases of postoperative local recurrence of vulvar squamous carcinoma which were unresectable or required pelvic exenteration, 4 yielded complete response (CR), 3 yielded partial response (PR), and the 2-year survival rate was 28% . In another study on 15 unirradiated cases of postoperative recurrence which received CCRT, 8 cases yielded CR, and the 2-year survival rate was 46% .
Prospective trials also confirm that the prognosis for inguinal recurrence is extremely poor. According to an analysis of two prospective trials (GOG74, GOG88), recurrence occurred in 37 out of 143 cases of initial treatment of vulvar squamous carcinoma. Significantly poor prognosis was demonstrated in 12 cases of inguinal recurrence with a median survival of 9.4 months compared to 20 cases of vulvar recurrence with a median survival of 52.4 months . In cases of inguinal recurrence which have not received lymphadenectomy or radiotherapy, bilateral inguinal lymphadenectomy followed by radiotherapy or CCRT is considered. In cases after external irradiation, interstitial irradiation may be considered, but complications are frequent . Re-excision for inguinal recurrence after irradiation also requires caution because of frequent postoperative complications.
In cases of recurrence in the pelvis, with distant metastasis or with multiple lesions, chemotherapy is considered. Several phase II studies reported on the effects of chemotherapy for recurrent diseases [109, 117, 119]. However, no treatment could be regarded as the standard treatment as previously mentioned in CQ08. Chemotherapy is considered only when no other effective treatments are available.
In recurrent vulvar cancer, most patients are advanced in age and not many efficacious treatments are available. Therefore, early introduction of BSC including palliative radiotherapy is considered for the purpose of symptomatic relief and QOL improvement .