Japan Society of Gynecologic Oncology guidelines 2015 for the treatment of vulvar cancer and vaginal cancer.

Malignant diseases occurring in the vulva other than squamous carcinoma include cancers and sarcomas originating in the skin, such as Paget’s disease and associated invasive carcinomas, malignant melanomas, cancers originating in the Bartholin’s glands, and basal-cell carcinomas. Malignant diseases occurring in the vagina other than squamous carcinoma include adenocarcinoma, malignant melanomas and sarcomas. Because Paget’s disease and malignant melanomas essentially originate in the skin, detailed guidelines have already been published for their general treatment as diseases of the skin [ 191 ]. However, gynecologists encounter these two diseases relatively commonly as lesions of the vulva and vagina, and conditions peculiar to the vulva and vagina must be taken into account in their treatment. Standard treatment methods for other tumors in the vulva and vagina are not established due to their rarity. Physicians must deal with these diseases on a case-by-case basis according to the characteristics of each tumor and the condition of each patient. (1) Histopathological approaches Vulvar Paget’s disease is characterized by intraepithelial proliferation of large atypical cells other than the squamous epithelium and melanocytes. This disease can be divided into two types—primary Paget’s disease, which originates in the skin of the vulva; and secondary Paget’s disease, which originates from malignancies in surrounding organs such as the rectum, anal canal, urinary tract and uterine cervix. Primary Paget’s disease can be further divided into tumors of intraepidermal origin and those originating from cancer of skin appendages or the Bartholin’s glands [ 192 ]. In secondary Paget’s disease, treatment including the primary organ must be considered. Histologically, Paget’s cells are larger than the surrounding epithelial cells and exist as isolated cells or nests with various sizes. Occasionally Paget’s cells appear in tubular form or as signet-ring cells. Primary and secondary Paget’s disease can be distinguished immunohistochemically. The tumor cells of primary Paget’s disease are positive for cytokeratin (CK) 7 and GCDFP-15 but generally negative for CK20, while the cells of rectal and anal canal carcinomas are CK7-negative, CK20-positive and GCDFP-15-negative. Urothelial carcinoma cells are both CK7- and CK20-positive, and GCDFP-15-negative [ 193 , 194 ]. Malignant melanomas are malignant tumors of melanocytes. Malignant melanomas originating in the vulva and vagina are histologically classified into three categories—mucosal, superficial-spreading and nodular. In the vulva, the mucosal and superficial-spreading types are dominant, while the nodular type is common in the vagina [ 195 , 196 ]. In histological diagnosis, positive result in immunostaining for S-100 protein, HMB-45, and melan-A support the confirmation of melanocytic features. Stage is determined by the staging system of cutaneous melanomas [ 197 ]. (2) Surgical therapy Paget’s disease Vulvar Paget’s disease presents in several forms as previously mentioned in histological approaches. Physicians need to be thoroughly familiar with these various types of Paget’s disease when providing treatment (CQ15). The first choice in treatment of vulvar Paget’s disease without invasive carcinoma is wide local excision in due consideration of the excision range. The local relapse rate after excision is high (32–37%) [ 198 , 199 ] for at least three reasons. First, this disease tends to present with multiple foci of disease. Second, foci of disease are sometimes present at sites that appear normal at the gross (visible) level. Third, the boundaries of tumors can be difficult to distinguish in the vulva, due to the region’s natural pigmentation as well as conditions such as eczema and inflammation. Fortunately, while the high relapse rate often requires repeated treatment, intraepithelial lesions transition gently, and prognosis tends to be exceptionally favorable [ 198 – 201 ]. Some researchers variously advocate performing a biopsy (mapping biopsy) on areas around the focus of disease that appear normal preoperatively [ 202 ] or performing a frozen section examination during surgery [ 203 , 204 ], to confirm that no focus of disease remains in the excision stump. However, other reports argue that these procedures are not necessarily effective [ 205 , 206 ]. Surgery is performed in accordance with procedures for invasive vulvar cancer if Paget’s disease is accompanied by invasive carcinoma. The vulva is the most common site (82%) for invasive extramammary Paget’s disease in women according to a report on a cohort study [ 207 ]. In 1439 cases of invasive extramammary Paget’s disease, the disease-specific 5-year survival rate was 95% in cases with localized lesion, 85% for lesions advanced to adjacent organs and 53% for distant metastasis. The prognosis was reported to be significantly better for the surgery group compared to the non-surgical group. Malignant melanomas Vulvar and vaginal malignant melanomas are mucosal. They are distinct from cutaneous malignant melanomas, which comprise >98% of malignant melanomas. Cutaneous malignant melanomas have been treated by surgical therapy and pharmacotherapy, based on their clinical and histopathological characteristics. Similarly, thorough surgical excision is a principle for malignant melanomas of the vulva and vagina, but restrictions exist concerning anatomical difficulties and postoperative QOL. Currently, pharmacotherapy is also used, following the practice for cutaneous malignant melanomas (CQ16). A margin of ≥2 cm of normal tissue is generally mandatory in excision of vulvar malignant melanomas, but if tumor infiltration is ≤1 mm, a margin of ≥1 cm is regarded sufficient [ 208 – 210 ]. Radical vulvectomy is not necessarily required, and radical local excision may be applicable, as is the case with squamous carcinoma. Even in such cases, the subcutaneous adipose tissue should be totally resected just above the fascia. Conversely, in cases with more tumor infiltration and/or spread, wider excision is usually performed. Inguinal lymph node metastasis is a definite poor prognostic factor for vulvar malignant melanomas. Lymphadenectomy (biopsy) is required to confirm the presence of metastasis, but as the therapeutic significance of this procedure is obscure [ 211 ], SLN biopsy has recently been applied to avoid systemic node dissection. This approach is proclaimed to have >85% negative predictive value, but the procedure remains at the research stage and should be performed only by highly experienced teams [ 212 , 213 ]. Most vaginal malignant melanomas are diagnosed at an advanced stage, rendering prognoses extremely poor. Extended surgeries such as radical vaginectomy, pelvic exenteration, and inguinal and pelvic lymphadenectomy have been performed, but the significance of these procedures is not conclusive [ 214 , 215 ]. In small localized cases with shallow infiltration, local excision with sufficient margin followed by postoperative treatment may provide favorable outcomes [ 216 ]. Other vulvar cancers For other vulvar cancers, the most commonly chosen treatment option is surgery, but the procedure needs to be determined based on the clinical characteristics. For example, as tumors originating in Bartholin’s glands tend to infiltrate deeper than ordinary vulvar cancers, excision must extend deeper in order for curative surgery to be effective [ 217 , 218 ]. Because the excision stumps have a high positive rate for foci of disease, addition of preoperative and postoperative radiation therapy has been reported, but prognosis is still poor [ 218 , 219 ]. For basal-cell carcinoma, local excision is usually judged sufficient because metastasis is rare. However, a local relapse rate of 10–22% is reported, and caution is in order [ 220 ]. (3) Radiation therapy In vulvar Paget’s disease, radiation therapy is applied in elderly patients or patients with medical complications rendering the condition inoperable, or in advanced disease rendering surgery inappropriate, and in cases of postoperative recurrence. The only reports on the effectiveness of this therapy are retrospective studies of a small number of cases and case reports. The study with the largest number of cases was reported from Japan, consisting of 22 cases of radiation therapy for external genital Paget’s disease, including 12 cases of vulvar Paget’s disease. The treatment results consist of 10 cases of definitive radiation therapy, eight cases of postoperative irradiation and four cases of postoperative recurrence. The 5-year local control rate for these cases was 84%, the disease-specific survival rate was 73%, and the overall survival rate was 53%, with no serious radiation morbidity [ 221 ]. Definitive radiation therapy is rarely the first choice for malignant melanomas as their sensitivity to irradiation is low. However, heavy-particle radiation therapy has been conducted on malignant melanomas on a trial basis in the gynecology field, as it has a stronger biological effect than conventional radiation therapy. Some effectiveness has been reported [ 222 ]. As an adjuvant treatment to surgery, postoperative irradiation has been conducted in cases of lymph node metastasis, for which the risk of recurrence is high. This procedure has been shown to improve the control rate in the lymph node area [ 223 , 224 ]. However, its contribution to improvement of prognosis has not been established, and problems of increasing late radiation morbidity have been pointed out. The decision on whether to apply these procedures must be judged on a case-by-case basis. CQ 15: What treatments are recommended for primary vulvar Paget’s disease? (Fig.  5 ) Fig. 5 Primary vulvar Paget’s disease Primary vulvar Paget’s disease Objective The objective is to examine treatment methods for primary vulvar Paget’s disease. Recommendations (1) Wide local excision with sufficient excision margin is recommended for intraepithelial lesions unaccompanied by invasive carcinomas (Grade B). (2) A mapping biopsy may be considered for lesions without a clear gross boundary (Grade C1). (3) Surgery following the practice for ordinary invasive vulvar cancer is recommended for lesions accompanied by invasive carcinomas (Grade B). (4) Radiation therapy may be considered in inoperable cases, or in cases of recurrence (Grade C1). Comments For intraepithelial vulvar Paget’s disease without invasive carcinoma, the recommended treatment is wide local excision, giving careful consideration to the excision range. The local recurrence rate after excision is reported to be as high as 32–37%. However, progression in intraepithelial Paget’s disease is gentle, and its prognosis is extremely favorable [ 198 , 199 ]. No highly reliable evidence exists concerning the excision range (excision margin) required for the complete excision of vulvar Paget’s disease. According to the discussion of extramammary Paget’s disease in Treatment Guidelines of Malignant Skin Tumors, Japan, excision may be conducted with a margin of about 1 cm if the focus of disease has a clear gross boundary or the site is judged negative for metastasis in a mapping biopsy. If the gross boundary is not clear, an excision margin of about 3 cm is recommended [ 191 ]. These recommendations are based on the findings of two studies. First, according to data from mapping biopsies of extramammary Paget’s disease and from implementation of Mohs surgery (surgery in which the entire excision stump is confirmed during surgery using frozen sections), an excision margin of ≥3 cm is required for extramammary Paget’s disease. Second, in a study of 46 cases in which a margin of 1 cm was obtained for lesions with clear gross boundaries on ordinary skin, the difference between the gross boundary and the histological boundary was small [ 225 , 226 ]. In a report on 33 cases of vulvar Paget’s disease in which frozen section diagnoses were conducted during surgery to determine excision range, the excision stump was positive in 44% of cases, while in cases where these intraoperative diagnoses were not conducted, the positive rate was 56% [ 199 ]. Another study, reporting on 30 cases of vulvar Paget’s disease, found that in nine cases where the excision range was decided on gross appearance, the positive rate for the excision stump was 67%, but in 18 cases where the excision range was decided based on mapping biopsies and intraoperative checks during surgery, the positive rate declined to just 39% [ 202 ]. Furthermore, in a single-facility retrospective study in Japan of 18 cases where the excision margin was determined so as to ensure a negative mapping biopsy, the stump was negative in postoperative histopathological diagnosis and no recurrences were confirmed [ 227 ]. These results testify that mapping biopsies and frozen section checks during surgery reduce the positive rate in excision stumps. However, other studies found that in cases where excision stumps were positive, the recurrence rate was 31–70%, and even when it was negative, recurrence was confirmed in 18–38% of cases, indicating that recurrence can happen regardless of the condition of excision stumps [ 197 , 228 , 229 ]. The depth of the excision is sufficient to extend through all dermal layers and slightly into the subcutaneous fat in cases of intraepithelial lesion because the tissue of the vulvar appendages of the skin is only ≤4 mm thick. For intraepithelial lesions without invasive carcinomas, inguinal lymphadenectomy should not be conducted, as lymph node metastasis is absent. Because vulvar Paget’s disease can progress into adjacent structures such as the urethra, vagina and anus, it is necessary to confirm sufficiently that such progression has not occurred when setting the excision range. These mucous membrane adjacent organs must also be excised as far as possible if such progression is confirmed. Within the anus, excision is possible as far as the pectinate line. Although the prognosis for intraepithelial vulvar Paget’s disease is favorable, postoperative local recurrence is frequent. According to a report on 17 cases of recurrence out of 28 initial surgery cases, one to three additional excisions were performed in 14 of the 17 recurrence cases, and the lesions were eliminated in 80% of these cases [ 229 ]. Whether for initial treatment or for recurrence treatment, surgical excision should be considered first. However, as patients are typically elderly, averaging 68–70 years of age at the time of diagnosis, the focus of disease is often wide. For this reason, a less invasive treatment has come to be adopted, in which photodynamic therapy (PDT), external use of imiquimod, or laser vaporization, are tried alone or in combination [ 230 – 232 ]. However, the reports on these treatment methods consist mainly of retrospective studies and case reports, and the observation period is often brief. No randomized controlled trials have been performed to compare the recurrence rate and survival rates of these conservative treatments to those of surgical excision. At present, it is not possible to recommend these procedures for daily practice. When intraepithelial Paget’s disease is combined with invasive carcinoma, surgery is performed as for normal invasive vulvar cancer. Recommended therapies include local excision with securing an excision margin of ≥1 cm, or radical vulvectomy, with inguinal lymphadenectomy. No data exist to suggest that inguinal lymphadenectomy improves survival rate if the condition is combined with invasive carcinoma. However, a report on 76 cases of vulvar Paget’s disease including 22 cases accompanied by invasive carcinoma reported that biopsy or excision of the inguinal lymph nodes was conducted in 19 cases and metastasis to the inguinal lymph nodes was confirmed in nine of these cases, six of which resulted in death [ 200 ]. Because the inguinal lymph nodes are a common site for metastasis, and lymph node metastasis is an important prognostic factor, dissection should be considered in cases with underlying invasive cancer. No standard treatment method is established for invasive vulvar Paget’s disease with metastasis, or recurrent disease. No randomized controlled trials or prospective trials have been reported regarding the use of postoperative radiation therapy in cases of vulvar Paget’s disease combined with invasive carcinoma or metastasis to the inguinal lymph nodes, and the usefulness of the treatment is difficult to assess at this point. Similarly, no regimen of chemotherapy is suitable for recommendation in the case of advanced vulvar Paget’s disease with distant metastasis. A small number of reports exist for single-drug or multi-drug chemotherapy following the practice for breast cancer or gastrointestinal cancer. However, the response rate and survival benefit still remain unclear. If surgery is impossible due to advanced age, medical complications or progressive disease, or if postoperative recurrence occurs and no other treatments are available, radiation therapy may be considered. One report from Japan details the results of radiation therapy in 22 cases of Paget’s disease in the external genitalia as previously cited [ 221 ]. X-rays or electron beams were used for radiation therapy, and effort was made to irradiate the entire focus of disease with a uniform dose. If invasion is confirmed from the dermis to the hypodermis, the danger of lymph node metastasis exists, and preventive irradiation of the lymph node area may be considered [ 233 ]. Although no standard dose fractionation is established, the required total dose is believed to be 50 Gy for non-invasive cases and 55–65 Gy for invasive cases and cases combined with invasive adenocarcinoma, with 1.8–2 Gy fraction [ 221 , 233 ]. For very elderly patients, periodic follow-up alone is another option in vulvar Paget’s disease not accompanied by invasive carcinoma. CQ 16: What treatments are recommended for malignant melanomas? Objective The objective is to exhibit appropriate treatments for vulvar and vaginal malignant melanomas. Recommendations (1) Excision of the primary lesion is recommended if distant metastasis is not confirmed. (Grade B). (2) SLN biopsy with cooperation of dermatologists may be useful for determining the disease stage (Grade C1). (3) Dacarbazine-based chemotherapy may be considered. (Grade C1). Comments The tumor thickness (TT) of the primary lesion is the most significant prognostic factor for vulvar malignant melanomas [ 211 ]. Because the TT is correlated with degree of progression of the tumor, the excision range should be decided in a two-step manner after evaluating the TT. Namely, excisional biopsy is initially performed with entire layers of subcutaneous adipose tissue above the basal fascia taking a 2-mm margin around the primary lesion [ 191 ]. A partial resection is acceptable if the lesion is too large or too close to the urethral opening to suture the wound defect since difference in prognostic outcome exists although the diagnostic accuracy is decreased [ 191 ]. Based on tumor histology and TT, the additional excision range is decided as follows —the margin from the tumor border should be set at 3–5 mm, 1 cm, and 2 cm for in situ lesions, TT ≤ 2 mm, and TT > 2 mm, respectively [ 191 , 234 ]. As survival prognosis cannot be improved even with wider excision [ 195 , 235 ], the excision range should be addressed near to the urethral opening and anus with careful consideration of postoperative QOL. The prognostic outcome is not worsened by the interval between the primary excision and the second excision, and is superior in two-step excision after confirming the TT to one-step wide-area excision [ 191 ]. For vaginal malignant melanomas, curative excision is also preferred; however, a pelvic exenteration is frequently necessary due to the tumor location and multiple foci. Because no difference in prognosis exists between highly radical surgery and local excision, a combination of local excision with irradiation would be preferred both for less complications and better local control and survival [ 236 ]. In vulvar malignant melanomas, those with regional lymph node metastasis exhibit poor prognostic outcome, but lymph node metastasis does not in itself comprise an independent prognostic factor [ 211 ]. The significance of systematic lymphadenectomy is low as it did not provide better prognostic outcome even with radical vulvectomy compared to wide local excision alone [ 237 , 238 ]. Curative lymphadnectomy may be considered to provide long-term survival for young patients who bear only a couple of lymph node metastasis without extracapsular invasion [ 191 ]. As for vaginal malignant melanomas which are accompanied with lymph node metastasis even at early stages, the significance of systematic lymphadenectomy on prognosis is still unclear. SLN biopsy is so far a case-trial procedure for vulvar and vaginal malignant melanomas [ 239 ]. As an SLN biospy is expected to detect and excise microscopic metastasis, it is already recommended for those bearing cutaneous malignant melanomas with 1–4 mm thickness due to its safety and efficacy [ 191 ]. A phase III trial also exhibited that a 10-year disease-free survival rate for those with TT >1.2 mm was significantly higher if an SLN biopsy was performed [ 240 ]. Thus, the SLN biopsy, supervised by a certified dermatologist with experience in treating malignant skin tumors, would be reasonably applied to the treatment for vulvar and vaginal malignant melanomas. Postoperative adjuvant treatment is widely performed for vulvar and vaginal malignant melanomas although its efficacy has not been well clarified. DAV-Feron therapy is a three-drug combination chemotherapy of dacarbazine (DTIC), nimustine and vincristine combined with a local injection of interferon-beta, and it has been employed in Japan as a prognosis-improving regimen for high-risk cutaneous malignant melanomas [ 241 ]. Postoperative immunotherapy (interferon-alpha and interleukin) can reduce recurrence but its survival benefit is uncertain [ 191 ]. In applying these regimens on vulvar and vaginal malignant melanomas, supervision by well-experienced dermatologists is mandatory. The efficacy of postoperative irradiation to prevent node relapse of cutaneous malignant melanoma is demonstrated not only in retrospective studies [ 223 ] but a randomized controlled trial (ANZMTG 01. 02/TROG 02. 01) [ 242 ]. However, whether to conduct irradiation or not should be determined for each case by evaluating the risk of recurrence since postoperative irradiation is highly accompanied with adverse events such as lymphedema and because its contribution to better survival is not clear. Hypofractionation using brief exposure of high doses per treatment is expected to be safe and effective against malignant melanomas, although there is no standard regimen established to date. The prognostic outcome of patients bearing distant metastasis is so poor that extensive excision should be avoided. Excision of metastasis is preferred only for those bearing a solitary tumor with good performance status. Irradiation to metastases in bones or central nerves relieves symptoms in half of cases, and stereotactic irradiation reduces tumor growth by 90% even for multiple brain metastases without active foci other than the brain [ 191 ]. Systemic chemotherapy using DTIC is applied on those bearing metastasis, but the response rate is only 20% and the long-term CR rate is <2% [ 191 ]. The initial response rate of DTIC is higher with other anti-cancer drugs compared to DTIC alone. However, there is no randomized trial which demonstrates the superiority of survival period of DTIC-combination therapy to DTIC alone. For advanced malignant melanomas, several systemic immunotherapies have been investigated—adoptive cellular immunotherapy, cancer vaccines, and cytokine treatments such as interferon-alpha and interleukin-2. The response rates of these treatments, however, remain at most 10% [ 191 ]. Recently, much attention has been paid to immune-checkpoint targeting drugs (anti-CTLA-4 antibodies and anti-PD-1 antibodies) [ 243 , 244 ] and to molecular-targeting drugs for tumor-specific genetic mutations. An anti-PD-1 antibody, nivolumab, and an anti-CTLA-4 antibody, ipilimumab, would deliver longer survival to cutaneous malignant melanomas, and other immune-checkpoint targeting drugs used overseas are also expected to be available in the near future. However, at present it is well demarcated that pharmacotherapies are tailored to mucosal-type vulvar and vaginal malignant melanomas, in which no standard treatments have been established. A multi-institutional prospective study should be conducted to assess the efficacy of these drugs on rare mucosal malignant melanomas including vulvar and vaginal malignant melanomas.

Although vulvar cancer and vaginal cancer are rare tumors, they actually constitute the fourth and fifth most common cancers in the gynecologic oncology field. However, there are no established treatment principles or guidelines to treat these rare tumors in Japan. The Guideline Committee of Japan Society of Gynecologic Oncology (JSGO) has established the treatment guidelines for cervical cancer and considered further revisions to the Guidelines for the Treatment of Cervical Cancer. However, as the revised version would include new content about treatment guidelines for vulvar and vaginal cancer that had not been made explicit internationally in 2015, it was decided to publish a fourth series of JSGO treatment guidelines, the Guidelines for the Treatment of Vulvar and Vaginal Cancer, 2015 edition. In the course of preparing the guidelines, a period just under 2 years, the Committee searched extensively for data on the treatment of vulvar and vaginal cancer, both in Japan and internationally, and collated the findings. Finally, treatment guidelines that the committee felt were most applicable to treatment situations in Japan were presented in the form of 16 clinical questions. The committee is confident that the guidelines constitute an indispensable resource for healthcare providers engaged in the treatment of vulvar and vaginal cancer, and that their use will lead to the best possible outcomes for cancer patients and their families. The main points of these treatment guidelines are as follows. 1. Clinical questions (CQs) are established with focus on vulvar and vaginal cancer, which are epithelial neoplasias. Rare malignancies that can be treated by gynecologic oncologists, such as vulvar Paget’s disease, as well as malignant melanomas are also included as objects of consideration. To encompass all of these types of cancers, the broad terms ‘vulvar cancer’ and ‘vaginal cancer’ were adopted. 2. The ‘Basic Items Regarding The Guidelines' section provides explanations regarding staging classification, histological categories, methods of surgical therapies, radiation therapies and chemotherapies, to give the reader a better understanding of the contents of the guidelines (supplied as an Appendix in the present article). 3. The ‘Basic Items’ section provides historical background on the classification of staging in vulvar and vaginal cancer. It lists the classifications of staging adopted by the JSOG in 2014 and sets in order the names of lymph nodes and their definitions. In addition, in view of the fact that no unique classifications of staging have been developed for vulvar malignant melanomas, the TNM classifications for cutaneous malignant melanomas are adopted with modifications. 4. In histological classifications, because no classifications unique to Japan exist, the original texts are provided of the long-used 2003 World Health Organization (WHO) classifications and the new, revised classifications of 2014. An explanation is added regarding the differences between these two classification systems as regards intraepithelial neoplasias of the vulva and vagina. 5. In surgical therapy and radiation therapy, the terminology in Japanese and English are presented side-by-side. For surgical therapy, the terminology for generally used excision margins and surgical resection stumps is specified. Following publication of the Japanese guidelines in August 2015, the NCCN Clinical Practice Guidelines in Oncology published the guidelines for vulvar cancer (squamous cell carcinoma) version 1.0 on the website in January 2016. Although the basic principles were almost identical to the JSGO guidelines, differences existed in several points. The major difference is that the JSGO guidelines include vaginal cancer and other diseases in the vulva and vagina, such as Paget’s disease and malignant melanoma, and intend to publish for gynecologists who are not familiar with these rare diseases in Japan. The committee decided to publish the English version of the JSGO guidelines worldwide, and hope it will be a useful guide to physicians in a similar situation in Japan.

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