Incidence and etiology: HPV association coexists with independent pathways
The global incidence of vulvar cancer is about 2.7 per 100,000 women, more common in women over 60 years of age, but is on the rise in younger populations. About 90% are squamous cell carcinomas, and their occurrence is mainly related to two pathways: one is human papillomavirus (HPV) infection, which accounts for 18%-52% of all vulvar cancers, more common in young women, and has a relatively good prognosis; the other is associated with chronic skin diseases (such as lichen sclerosus), whose precancerous lesions are differentiated vulvar intraepithelial neoplasia (dVIN), with a risk of progression to cancer of 33%-86%, and usually have a poor prognosis. Vaginal cancer is even rarer, accounting for less than 1% of all female cancers, of which 75%-85% are associated with HPV infection, and HPV positivity is also a favorable prognostic factor for squamous cell carcinoma.
Pathological classification: Squamous cell carcinoma is dominant, and type subdivision is crucial
According to the World Health Organization (WHO) Fifth Edition classification, vulvar and vaginal squamous cell carcinoma (SCC) should be differentiated according to their association with HPV, and although there is no difference in treatment at present, the pathology report must indicate whether it is HPV-associated or HPV-independent. p16 immunostaining is a reliable surrogate marker for HPV-associated SCC. In addition, vulvar cancer also includes rare extramammary Paget's disease, basal cell carcinoma, adenocarcinoma, etc. Although melanoma and sarcoma account for a small proportion (about 5.7% of vulvar melanoma and 1% to 3% of sarcoma), they are highly aggressive and require separate in-depth analysis. In addition to SCC, vaginal cancer also has rare subtypes such as adenocarcinoma, melanoma, and sarcoma (such as leiomyosarcoma and rhabdomyosarcoma).
▲Table: Tumor types of vagina and vulva
Precise staging: Imaging is combined with clinical examination
Vulvar cancer staging was carried out using the 2021 International Federation of Obstetrics and Gynecology (FIGO) system. Magnetic resonance imaging (MRI) is the preferred choice for assessing the depth of local tumor invasion (e.g., vagina, urethra, anus) due to its excellent soft tissue resolution. Ultrasound is preferred for inguinal lymph node evaluation, with a sensitivity of 76% to 90%. For suspected advanced cases (≥T3), CT or 18F-FDG PET-CT should be used to rule out pelvic lymph nodes and distant metastases.
▲Table: International Union of Obstetrics and Gynecology Vulvar cancer stage
Vaginal cancer staging is also based on the 2021 FIGO system instead of the AJCC TNM system. A comprehensive colposcopy and tissue biopsy are essential. MRI is superior to physical examination in assessing tumor size, paravaginal or parauterine invasion, and is the standard means of local staging. For stage II and above disease, PET-CT is recommended to evaluate distant metastasis.
▲Table: International Union of Obstetrics and Gynecology Vaginal Cancer Staging
Early vulvar cancer treatment: surgery is the main focus, tending to be minimally invasive and precise
Surgery remains the cornerstone of early-stage vulvar cancer, including resection of the primary tumor and inguinal lymph node staging. For tumors < 2 cm and invasion depth < 1 mm (stage IA), the lymph node stage may be omitted.
Resection of primary lesion: Extensive local resection has become an acceptable option for early disease, with a safety profile comparable to radical vulvectomy. The debate over surgical margins continues, with the traditional belief that a pathological margin > 8 mm reduces local recurrence rates, but recent studies (e.g., the CaRE-1 study) have shown no significant difference in local recurrence rates (approximately 12.6% vs. 10.2%) between margins < 8 mm versus ≥8 mm. The current recommended goal is to obtain a macroscopically visible 1 cm tumor-free margin, but a final pathological margin of at least 3 mm is acceptable for tumors close to the urethra, anus, or clitoris.
Lymph node management: Sentinel lymph node (SLN) biopsy has become the preferred method for clinically negative lymph node patients. Pivotal studies (GROINSS-V and GOG-173) confirmed that SLN biopsy combined with hyperstaging is safe and reliable in single-focal patients with tumor < 4 cm and negative clinical inguinal lymph nodes, and the inguinal recurrence rate is low (approximately 2.3%). Unilateral SLN biopsy can be performed for tumors within 2 cm of midline or with unilateral drainage on lymphoscintigraphy.
Adjuvant radiotherapy: recommended for patients with positive surgical margins. For SLN micrometastases (≤2 mm), adjuvant radiotherapy can be used as an alternative to complete inguinal lymph node dissection; for SLN macrometastases (>2 mm), complete inguinal lymph node dissection is required, and radiotherapy is considered after surgery. If there is more than one lymph node metastasis, adjuvant radiotherapy is recommended. The interval between radiotherapy and surgery should not exceed 8 to 10 weeks.
▲Figure: Surgical examples of radical vulvectomy and bilateral inguinal lymph node dissection
▲Figure: Extensive local resection of midline vulvar cancer and sentinel lymph node mapping process
▲Figure: Flow chart of early vulvar cancer management
Locally advanced vulvar cancer treatment: chemoradiotherapy helps organ preservation
For locally advanced vulvar cancer requiring organ resection (eg, involving the anus, rectum, bladder), concurrent chemoradiotherapy is preferred for down-staging and organ preservation. Studies have shown that concurrent chemoradiotherapy can significantly improve the 5-year overall survival rate of inoperable patients (49.9% vs 27.4%) compared with radiotherapy alone. The GOG-279 phase II trial reported that the complete response rate of pathology with cisplatin and gemcitabine combined with concurrent radiotherapy was 73%. Efficacy should be evaluated 12 weeks after the end of treatment, and surgery should be considered if residual disease is present.
▲Figure: Clinical manifestations of locally advanced vulvar cancer and the effect after radiotherapy and chemotherapy
▲Figure: Flow chart for the management of locally advanced vulvar cancer
Vaginal cancer treatment: individualized selection based on location and stage
Because vaginal cancer is rare, there is no standard surgical option, and treatment options are based on tumor location and stage.
Stage I tumors: For those located in the upper 1/3 of the vagina, radical surgery (such as colposectomy plus lymph node dissection) or external beam radiotherapy (EBRT) combined with brachytherapy can be selected. Analysis of the National Cancer Database suggests that surgery may be better than radiotherapy alone (90% vs 63%). Concurrent chemotherapy is recommended even in stage I. Tumor size affected the prognosis, and the 5-year survival rate of patients ≤ 2 cm (79.2%) was better than that of patients with >2 cm (66.1%).
Stage II and above tumors: radiotherapy (EBRT combined with brachytherapy) is the main treatment. Pelvic organectomy is used only for lesions that persist or recur after radiotherapy. There is limited data on the application of SLN mapping in vaginal cancer, but it is helpful in detecting unexpected lymphatic drainage.
Vulvovaginal Melanoma: Unique Challenges and Treatment Advances
The prognosis of vulvovaginal melanoma is extremely poor, with a 5-year overall survival rate significantly lower than that of cutaneous melanoma (about 35% of vulva and 13%-32.3% of vagina). The principle of treatment favors more conservative surgery.
Surgical treatment: Extensive local resection is recommended, and the recommended margin is 0.5cm, Breslow thickness ≤ 1cm for 2mm, and 2cm for >2mm. Radical surgery has not shown a better local control or survival benefit than extensive resection. In high-risk patients, preoperative therapy (eg, radiotherapy combined with ipilimumab) may help reduce the extent of surgery.
Lymph node management: SLN biopsy is recommended for all patients with newly diagnosed vulvar melanoma, but there is no clear recommendation for vaginal melanoma. In SLN-positive patients, there is a trade-off between whether to complete lymph node dissection, and the MSLT-II trial showed that immediate dissection improved the regional control rate but increased the risk of lymphedema.
Systemic therapy: Adjuvant immune checkpoint inhibitors (eg, pembrolizumab, nivolumab) significantly reduce the risk of recurrence of stage II/III cutaneous melanoma, and this strategy may be considered for vulvovaginal melanoma. Neoadjuvant immunotherapy has also shown advantages in resectable stage III melanoma.
▲Figure: Appearance of clinical and surgical specimens of vulvovaginal melanoma
▲Figure: The appearance of local recurrence
▲Figure: Extensive resection of vulvar melanoma and sentinel lymph node biopsy
▲Figure: Vulvar melanoma management flow chart
Vulvovaginal sarcoma: rare and varied, requiring specialist management
Sarcomas account for 1%-3% of vulvar cancers and about 3% of vaginal cancers. There are various types, including leiomyosarcoma, rhabdomyosarcoma (more common in children), angiosarcoma, etc. Treatment is dominated by complete surgical resection (R0), and the effect of lymph node dissection varies depending on the subtype. For those who require extensive surgery, neoadjuvant therapy should be considered. Given its rarity and histological complexity, it should be managed by a multidisciplinary team in a specialized center.
Patient follow-up and support: focus on recurrence and quality of life
The recurrence rate of vulvar cancer is about 25%, mostly within 2 years after treatment, and 60% are local recurrences. Clinical review is recommended every 3-4 months for the first 2 years after treatment, and then every six months thereafter. Imaging tests (eg, MRI/PET-CT) are often used to assess remission 3 to 4 months after the end of treatment. Long-term follow-up is crucial because the risk of relapse and new primary disease can last 5-10 years.
Treatment-related complications seriously affect quality of life, including lymphedema (up to 50% after inguinal lymph node dissection), wound healing problems, sexual dysfunction, and psychological distress. Management requires the involvement of a multidisciplinary team covering specialized lymphedema treatment, plastic surgery repair, psychological support, and sexual health counseling. Early integration of palliative care plays an important role in symptom control and quality of life improvement in advanced patients.
Future prospects: Exploration of systemic therapy and precision medicine
Systemic treatment options for advanced or recurrent vulvovaginal cancer are limited, and more clinical trials are urgently needed. Based on the implications of cervical cancer data, immune checkpoint inhibitors, such as pembrolizumab, show potential in PD-L1-positive patients. Targeted drugs (such as the anti-EGFR drug erlotinib, the anti-angiogenic drug bevacizumab) and antibody conjugates (such as drugs targeting HER2, TROP2) are also being explored. T-cell receptor-engineered T-cell therapy for HPV-related cancers has shown promise in early-stage clinical trials. Next-generation sequencing helps reveal actionable genetic mutations and provides direction for precision treatments.
Conclusion: The management of vulvar and vaginal cancers is becoming increasingly refined, emphasizing comprehensive treatment based on stage, pathological subtype (especially HPV status), and individual circumstances. Minimally invasive surgery (SLN biopsy, extensive local resection) and organ-sparing strategies (concurrent chemoradiotherapy) are important trends. Multidisciplinary collaboration, active participation in clinical trials, and comprehensive patient support and follow-up are essential for improving the prognosis and quality of life of patients with these rare cancers.
Editor-in-charge:Lucy