Comprehensive management of vulvovaginal cancers

Abstract

Vulvar and vaginal cancers represent rare malignancies, with an incidence of 2.7 per 100,000 women for vulvar cancer, predominantly affecting women older than 60 years, although rising rates are observed in younger demographics. Approximately 90% of vulvar cancers are squamous cell carcinoma and frequently are associated with human papillomavirus (HPV) infection. Vaginal cancer, constituting less than 1% of all female cancers, similarly exhibit HPV‐related trends. This review delineates the etiology, histopathology, and treatment strategies for carcinomas and vulvovaginal melanomas and sarcomas. Surgical intervention remains the primary treatment modality for vulvar cancer, involving tumor resection and inguinofemoral lymph node staging. For locally advanced vulvar carcinoma, chemoradiation is advised when exenterative surgery would be indicated. Recurrence rates within 2 years after diagnosis range from 12% to 37%. Unfortunately, systemic treatments for recurrent or metastatic disease are limited, with 5‐year survival rates at approximately 20%. Current evidence primarily derives from retrospective studies or small phase 2 trials or otherwise is extrapolated from the treatment of cervical cancer. Enrollment in clinical trials is strongly advocated, along with prompt access to best supportive care to mitigate the effect of locoregional progression on quality of life. Moreover, the psychosocial implications of treatment on body image and sexuality necessitate careful consideration. Future HPV vaccination initiatives may reduce cancer incidence, although significant effects of such vaccination will manifest over decades, underscoring the urgent need to enhance treatment efficacy and minimize morbidity in vulvar and vaginal cancers.

INTRODUCTION

Vulvar and vaginal cancers are rare diseases. The incidence of vulvar cancer is 2.7 per 100,000 women. Although typically considered a disease of older women, ¹ its incidence is notably increasing worldwide, particularly among women younger than 60 years. ¹ The most common type is squamous cell carcinoma (SCC), which accounts for approximately 90% of vulvar malignancies; whereas other types, such as basal cell carcinoma, adenocarcinoma, and melanoma, are much less common.

Two main pathways are believed to contribute to the development of vulvar cancer: there is an increase in human papillomavirus (HPV)‐related cases, ² which are more common in younger women, with HPV playing a role in 18%–52% of all vulvar cancers. ³ Risk factors for this type of vulvar cancer include smoking and immunosuppression, such as in patients who undergo solid organ transplantation or those with human immunodeficiency virus/acquired immunodeficiency syndrome. ¹ Persistent HPV infection can lead to high‐grade squamous intraepithelial lesions (HSIL) of the vulva, with a risk of approximately 5% that high‐grade squamous intraepithelial lesions will progress to cancer. The prognosis for HPV‐related vulvar cancer is better compared with that for HPV‐independent cases, with fewer local recurrences and improved overall survival (OS) rates. ³ , ⁴ The second pathway is associated with chronic skin conditions, such as lichen sclerosis. The estimated risk of developing vulvar cancer in patients with lichen sclerosis is approximately 2.6%. In these cases, differentiated vulvar intraepithelial neoplasia (dVIN) serves as the premalignant lesion, with a risk of progression to vulvar cancer between 33% and 86%. ⁵ , ⁶ HPV‐independent vulvar cancers can be classified as either P53‐mutated or wild‐type P53, and the P53‐mutated form has the worst prognosis. ³

Vaginal cancer is even rarer, representing less than 1% of all female cancer cases globally, with an estimated 17,500 new cases and approximately 8000 deaths annually. ⁷ The estimated 5‐year survival rate for vaginal cancer ranges from 50% to 70%. ⁷ Age‐standardized rates of vaginal cancer are generally less than one case per 100,000 person‐years, although higher rates (from one to three cases per 100,000 person‐years) are observed among Black women in several US states and among Indigenous populations in the United States, Canada, and New Zealand. The incidence trends for vaginal cancer appear stable. ⁸

Approximately 75%–85% of vaginal cancers are associated with HPV infection, with HPV types 16 and 18 the most common high‐risk strains. The highest proportion of HPV‐positive cases occurs in patients with SCC, and the presence of HPV is a favorable prognostic factor for SCC. ⁹ The classification of squamous lesions in the vagina mirrors that of the cervix, with HPV‐associated and HPV‐independent SCC recognized as distinct entities. Although there are currently no major treatment differences between them, it is recommended to document the type of vaginal SCC (HPV‐associated or HPV‐independent) in pathology reports.

This review focuses on the diagnosis and treatment of patients with vulvar and vaginal carcinoma, melanoma and sarcoma, presented in this order; and, given the relatively greater rarity of vaginal cancers, this we focus mainly on vulvar cancer. Advances in reducing treatment‐related morbidity have significantly altered standard treatments, especially for early stage disease. However, morbidity remains a concern, particularly in women who undergo inguinofemoral lymphadenectomy as part of their treatment. Lymphedema affects up to 50% of patients who undergo lymphadenectomy. In addition, the treatment of vaginal and vulvar cancers significantly affects body image and sexuality, a sensitive topic often avoided because of the stigma associated with cancers of intimate areas. ¹⁰ In the future, widespread HPV vaccination may help reduce the burden of these cancers, particularly because it is partially driven by aging of the population. ¹¹ However, the effects of vaccination will not be evident for several decades, and improving treatment efficacy and reducing morbidity in vulvar and vaginal cancer remains a critical priority.

PATHOLOGY

Vulva

According to the World Health Organization (WHO), the following primary sites are considered primary vulvar cancer: labia majora, labia minora, vestibule, clitoris, vaginal introitus, perineum, and urethral meatus (Figure 1). ¹¹

FIGURE 1.

Vulvar anatomy.

SCC is the most common histopathologic subtype, representing approximately 90% of cases ¹¹ (Table 1). The fifth edition of the WHO classification of tumors divides SCCs on the basis of their association with HPV infection: approximately two thirds of vulvar SCCs arise through an HPV‐independent pathway ¹² , ¹³ and behave more aggressively than HPV‐associated carcinomas. ¹⁴ Although several morphologic patterns are associated with each subtype, the two categories cannot be confidently distinguished unless molecular HPV tests are used. ¹¹ , ¹⁵ Immunoreactivity for p16 is a reliable surrogate for HPV‐associated SCCs. ¹⁶ Also, according to the WHO fifth edition, although there are currently no differences in treatment between the two distinct types, the recent recommendation is that the type of SCC (HPV‐associated or HPV‐independent) should be documented on the pathology report.

TABLE 1.

Tumors of the vagina and the vulva.

Tumors of the vagina	Tumors of the vulva
Epithelial tumors	Epithelial tumors
Benign squamous lesions	Benign squamous lesions
Condyloma acuminatum (see Tumors of the vulva)	Seborrheic
Squamous papilloma of the vagina	Condyloma acuminatum
Atrophy of the vagina	Squamous cell tumors and precursors
Tubulosquamous polyp	Squamous intraepithelial lesions, HPV‐associated, of the vulva
Squamous cell tumors and precursors	Vulvar intraepithelial neoplasia, HPV‐independent
Squamous intraepithelial lesions of the vagina a	Squamous cell carcinoma of the vulva, HPV‐associated
Squamous cell carcinoma of the vagina, HPV‐associated a	Squamous cell carcinoma of the vulva, HPV‐independent
Squamous cell carcinoma of the vagina, HPV‐independent a	Squamous cell carcinoma of the vulva, NOS
Squamous cell carcinoma of the vagina, NOS a	Basal cell carcinoma
Benign glandular lesions	Glandular tumors and cysts
Villous adenoma	Mammary‐type glandular lesions
Mullerian papilloma of the vagina	Papillary hidradenoma
Vaginal adenosis	Chondroid syringoma
Endocervicosis of the vagina	Fibroadenoma
Cysts of the vagina	Phyllodes tumor
Glandular tumors	Adenocarcinoma of mammary gland type
Adenocarcinoma of the vagina, HPV‐associated a	Bartholin gland lesions
Endometrioid carcinoma of the vagina a	Bartholin gland cyst
Clear cell carcinoma of the vagina a	Bartholin gland hyperplasia, adenoma, and adenomyoma
Mucinous carcinoma of the vagina, gastric type a	Bartholin gland carcinomas
Mucinous carcinoma of the vagina, intestinal type a	Other cysts of the vulva
Mesonephric adenocarcinoma of the vagina a	Adenocarcinomas of other types
Carcinosarcoma of the vagina a	Paget disease a
Other epithelial tumors	Carcinomas of sweat gland origin a
Mixed tumor of the vagina	Adenocarcinoma of intestinal type a
Adenocarcinoma of Skene gland origin a	Germ cell tumors
Adenosquamous carcinoma of the vagina a	Germ cell tumors of the vulva a
Adenoid basal carcinoma of the vagina a
Mixed epithelial and mesenchymal tumors
Adenosarcoma of the vagina a
Miscellaneous tumors
Germ cell tumors of the vagina a

Note: Data are based on the The World Health Organization Classification of Tumors. 5th ed. Volume 4. Female Genital Tumors. WHO; 2020. ¹¹

Abbreviations: HPV, human papillomavirus; NOS, not other specified.

^a These are malignant tumors within the groups.

Extramammary Paget disease is a rare adenocarcinoma typically found in apocrine‐rich skin of the axilla and anogenital regions. It most often affects older patients aged 50–80 years and often presents as a slow‐growing, ill‐defined, erythematous plaque that mimics common inflammatory dermatoses. ¹¹ , ¹⁷ Basal cell carcinomas are identical to the same lesions at other cutaneous sites, which should guide prognosis, expectations, and management, ¹⁸ and adenocarcinomas are extremely rare, particularly the intestinal‐type variant.

Sarcomas comprise 1%–3% of vulvar cancers, ⁹ , ¹² and vulvar melanoma, although it accounts for only 5.7% of cases, carries a dismal prognosis, even compared with cutaneous melanoma. Because of their particularities, melanomas and sarcomas are analyzed independently in greater depth.

Germline, neuroendocrine, and hematolymphoid neoplasias rarely occur on the vulva, and germline tumors usually are the yolk subtype. ¹¹ Metastases to the vulva are also rare, accounting for 5%–10% of all vulvar malignancies.

The broad range of the cited subtypes underscores the complex nature of vulvar cancer, with SCC remaining the dominant form. Figure 2 depicts the common differential diagnosis of vulvar SCC.

FIGURE 2.

(A) Basocellular carcinoma, (B) Lichen sclerosus associated with a squamous cell carcinoma, (C) vulvar Paget disease, (D,E) Clinical aspect of a stage II squamous cell vaginal carcinoma in vaginal upper one third with a normal cervix.

Vagina

Vaginal cancer is a rare malignancy with distinct histopathologic subtypes, each varying in incidence and clinical characteristics. The most common subtype is SCC, which constitutes approximately 80%–90% of primary vaginal cancer cases, although there is a recent tendency toward a decline in its incidence. ¹¹ The classification of squamous lesions of the vagina parallels that of the cervix and vulvar carcinomas, with HPV‐associated and HPV‐independent SCCs, although almost 80% of the cases of are linked to HPV infection. According to the WHO, the following criteria are essential for a vaginal SCC diagnosis: no previous (≤5 years) or concomitant SCC of the cervix or vulva; infiltrating, angulated, irregularly sized and shaped nests, anastomosing cords, and solid sheets; nuclear pleomorphism and increased mitotic count; a desmoplastic or inflammatory stroma; and the overexpression of p16 as an acceptable surrogate marker of HPV association. HPV testing is a desirable criterion, but it is not essential according to the WHO. ¹¹ Importantly, whether vaginal SCC is HPV‐associated or HPV‐independent should be documented on the pathology report. ¹¹

Adenocarcinoma represents approximately 5%–0% of vaginal cancer cases, including clear cell adenocarcinoma, which is classically linked to in‐utero exposure to diethylstilbestrol. Adenocarcinomas include HPV‐associated neoplasms, various HPV‐independent tumors, and a newly described primary vaginal gastric‐type adenocarcinoma. ¹²

Melanoma and sarcomas are rare and aggressive subtypes of vaginal cancer. Vaginal melanoma, which accounts for a small percentage of cases, has a particularly poor prognosis, with a 5‐year survival rate of only 14%. Sarcomas, including leiomyosarcoma and rhabdomyosarcoma (RMS), also occur. ¹² Other rarer subtypes, such as adenosquamous carcinoma, carcinosarcoma, and mucinous adenocarcinoma, contribute to the diverse histologic spectrum of vaginal cancer.

STAGING

Vulvar cancer

The vulvar cancer staging system was last reviewed in 2021 by the International Federation of Gynecology and Obstetrics Committee on Gynecologic Oncology (Table 2) and has been aligned with the eighth edition of the American Joint Commission on Cancer (AJCC) tumor‐node‐metastasis (TNM) classification. Vulvar cancer is characterized by local growth and invasion, with subsequent dissemination to the inguinofemoral lymph nodes (ILNs) and, potentially, to the pelvic lymph nodes (LNs). A comprehensive diagnostic work‐up includes a thorough clinical examination, which involves meticulous inspection of the urethra, anus, vagina, and clitoris, as well as biopsies and various imaging modalities. Given the multifocal nature of lower anogenital squamous cell intraepithelial lesions, a full examination of the vagina, cervix, and anus is also recommended. ¹⁸ The primary tumor's location (Figure 1) and any LN metastases should be precisely documented through structured reporting and clinical diagrams.

TABLE 2.

International Federation of Gynecology and Obstetrics staging for vulvar cancer.

Stage	Description
I	Tumor confined to the vulva
IA	Tumor size ≤2 cm and stromal invasion ≤1 mm a
IB	Tumor size >2 cm or stromal invasion >1 mm a
II	Tumor of any size with extension to lower one third of the urethra, lower one third of the vagina, lower one third of the anus with negative nodes
III	Tumor of any size with extension to the upper part of adjacent perineal structures or with any number of nonfixed, nonulcerated lymph nodes
IIIA	Tumor of any size with disease extension to upper two thirds of the urethra, upper two thirds of the vagina, bladder mucosa, rectal mucosa, or regional lymph node metastases ≤5 mm b
IIIB	Regional lymph node metastases >5 mm b
IIIC	Regional lymph node metastases with extracapsular spread b
IV	Tumor of any size fixed to bone; or fixed, ulcerated lymph node metastases; or distant metastases
IVA	Disease fixed to pelvic bone or fixed or ulcerated regional lymph node metastases
IVB	Distant metastases

^a Depth of invasion is measured from the basement membrane of the deepest, adjacent, dysplastic, tumor‐free rete ridge (or nearest dysplastic rete peg) to the deepest point of invasion.

^b Regional refers to inguinal and femoral lymph nodes.

Local extension of vulvar cancer is best evaluated by magnetic resonance imaging (MRI) because of its excellent soft tissue resolution, which enables precise assessment of deep infiltration into the vagina, urethra, and anus. ¹⁹ For ILN evaluation, imaging is essential, except in cases of T1a tumors. The preferred imaging modality for preoperative assessment of ILNs is ultrasound, which provides detailed information on LN morphology and vascular architecture. Ultrasound has a sensitivity ranging from 76% to 90% and a specificity between 60% and 96%, ¹⁹ and it also can guide core‐needle biopsy. MRI is an alternative to groin imaging but generally exhibits lower sensitivity, between 40% and 89%. Computed tomography (CT) scans are less effective for detecting groin metastases. For women who have suspected inguinofemoral metastases or advanced tumors (≥T3), it is crucial to exclude pelvic LN involvement and distant metastases using either a CT scan with intravenous contrast or ¹⁸F‐fluorodeoxyglucose–positron emission tomography (¹⁸FDG‐PET)‐CT. ¹⁸

Vaginal cancer

Vaginal cancers are distinguished by their propensity for local invasion and dissemination to adjacent anatomic structures, including the paravaginal tissues, paracervix, bladder, urethra, vulva, and rectum. The lymphatic drainage of the vagina is notably intricate, involving a comprehensive network within the submucosa and muscularis layers. In the upper one third of the vagina, lymphatic vessels align with the uterine vessels; whereas, in the lower two thirds, lymphatic vessels correspond with vaginal vessels. Typically, lymphatic dissemination from the upper one third of the vagina initially progresses to the pelvic LNs and only rarely extends to the para‐aortic LNs. Conversely, the lower one third of the vagina disseminates predominantly to the groin nodes, with potential spread to the femoral LNs. Tumors situated in the middle one third of the vagina may follow either or both of these lymphatic pathways.

A thorough vaginal examination and comprehensive inspection of the vaginal walls are essential to ensure that no lesions are overlooked. Any suspicious lesions identified during the examination should be subjected to biopsy because these may manifest as tumors, ulcers, or plaques. For cases in which no macroscopic lesions are visible and the Papanicolaou test results are abnormal, a colposcopy should be performed. The assessment of local primary disease within the vagina, including the size and macroscopic characteristics of the lesions (whether ulcerative or exophytic), should be meticulously conducted through a gynecologic physical examination. In addition, any suspicious ILNs should be carefully documented.

Vaginal cancer staging is defined using the 2021 International Federation of Gynecology and Obstetrics staging system (Table 3) rather than the AJCC TNM system. Accurate staging is established through a comprehensive diagnostic work‐up, which encompasses clinical examination, biopsy, and various imaging modalities.

TABLE 3.

International Federation of Gynecology and Obstetrics staging for vaginal cancer.

Stage	Description
I	Limited to the vagina
II	Invading paravaginal tissues, but not to pelvic sidewall
III	Extending to the pelvic wall and/or the lower one third of the vagina and/or causing hydronephrosis or nonfunctioning kidney; with or without metastases to inguinal lymph nodes
IV	Extending beyond the true pelvis and/or involving the bladder or rectal mucosa and/or distant metastases (lung or bones); with or without metastases to nearby lymph nodes

MRI is particularly valuable for assessing tumor size and locoregional involvement in vaginal cancer. MRI exhibits superior sensitivity compared with physical examination for detecting paravaginal or parametrial involvement, a characteristic that also may apply to vaginal cancer. ²⁰ Vaginal tumors are optimally visualized on T2‐weighted MRI images, in which they typically present as low‐to‐intermediate signal intensity on T1‐weighted images and intermediate‐to‐high signal intensity on T2‐weighted images. ²¹ , ²² , ²³ The use of vaginal gel to distend the vaginal walls can enhance the assessment of tumor details and the surrounding tissues. ²⁰

In stage I vaginal cancer, when the tumor is confined to the vagina, the paravaginal fat appears with high signal intensity on T1‐weighted images. In contrast, stage II tumors result in the loss of the normal low signal intensity of the vaginal wall, and the paravaginal fat exhibits an abnormal low signal intensity on T1‐weighted images. The high soft tissue resolution of MRI provides an accuracy rate of 92% for detecting metastatic tumors involving the vagina. ²⁰ Although MRI is the standard modality for evaluating locoregional extent, expert pelvic ultrasound may serve as a complementary tool. ²⁴ CT is useful for assessing nodal and distant metastatic spread, ²⁰ whereas ¹⁸FDG‐PET‐CT is a reasonable choice for evaluating node‐positive and locally advanced disease requiring chemoradiation or pelvic exenteration with curative intent.

In summary, physical examination and pelvic MRI are crucial for the work‐up of vaginal cancer. Given the potential for distant metastasis, particularly in stage II or greater disease, PET‐CT should be used when feasible to assess for metastatic spread. If PET‐CT is not available, a CT scan can be used to evaluate distant metastases.

TREATMENT

Vulvar cancer

Early stage vulvar carcinoma

Surgery remains the cornerstone of treatment for vulvar cancer, encompassing both primary tumor resection and ILN staging. For patients with primary tumors <2 cm in greatest dimension and a depth of invasion <1 mm (stage IA), LN staging may be omitted because of the very low risk of involvement. For larger tumors, however, surgical staging of the ILNs is necessary. In addition, primary groin radiotherapy in patients with clinically negative LNs has been associated with higher groin recurrence rates and poorer survival outcomes compared with surgical staging. ²⁵

In an important study, de Hullu et al. observed a significantly lower prevalence of fatal groin or skin bridge recurrences with en bloc surgery (1.3%) compared with separate incisions (6.3%). ²² , ²⁶ However, there was no observed impact on survival. Other studies, however, have reported low groin recurrence rates after en bloc inguinofemoral lymphadenectomy, ²⁷ whereas some have noted skin bridge recurrences even in patients with negative LNs. ²⁶ , ²⁸ , ²⁹ , ³⁰ Nevertheless, primary tumor resection and inguinofemoral lymphadenectomy performed using separate incisions have emerged as a viable alternative to en bloc resection, with reduced complication rates. This approach is based on the understanding that LN dissemination may occur through lymphatic embolization rather than lymphatic continuity. ¹⁹ , ³¹ The overall risk of skin bridge recurrence is low, and no conclusive evidence suggests that this technique compromises outcomes. Furthermore, a Cochrane review indicated a skin bridge recurrence rate <1% in patients without LN metastasis and suggested that separate incisions could be considered a safe procedure. ³²

Given the higher complication rates associated with the en bloc technique and the limited strength of studies linking triple‐incision surgery to increased recurrence rates, the use of separate incisions is currently the preferred surgical approach for vulvectomy and inguinofemoral lymphadenectomy (Figure 3).

FIGURE 3.

(A) Clinical presentation of a vulvar carcinoma, 5.5 cm in size, human papillomavirus‐positive with metastatic right inguinofemoral lymph node, submitted to radical vulvectomy and bilateral inguinofemoral lymphadenectomy (triple incision technique). (B) Surgical aspect after radical vulvectomy. (C) Surgical specimen of primary tumor. (D) Surgical aspect of right inguinofemoral lymph nodes before resection. (E) Surgical aspect after bilateral inguinofemoral lymphadenectomy with cribriform fascia and saphena preservation at the left side. (F) Clinical aspect of a vulvar wound dehiscence. (G) Inguinal skin necrosis and dehiscence.

Notably, the most common early complications of surgical treatment include wound breakdown (ranging from 17% to 31%), wound cellulitis (25%–39%), and lymphocyst formation (40%). ²⁸ , ³³ , ³⁴ In addition, the most common late complication is lower limb lymphedema, which ranges from 16% to 49%, ³⁵ , ³⁶ with a higher incidence in women who have received adjuvant radiotherapy after ILN dissection.

Although radical vulvectomy confers a potentially curative treatment, wide local excision has become an acceptable option, particularly for early stage disease. Whereas no randomized trials have directly compared radical vulvectomy with wide local excision, safety and outcomes appear to be comparable. ²⁷ , ³⁷

The optimal resection margins after wide local excision remains a topic of debate. Heaps et al. ³⁸ first reported that pathologic margins <8 mm were associated with a 50% local recurrence rate. Similarly, de Hullu et al. ³⁹ identified no local recurrences with pathologic margins >8 mm, whereas a 22.5% recurrence rate was observed in patients who had margins ≤8 mm or (p = .002). However, Chan et al. ⁴⁰ reported no local recurrence with margins ≥8 mm and a 23% recurrence rate with margins <8 mm. Given the importance of the pathologic margin, Palaia et al. ⁴¹ prospectively evaluated the correlation between macroscopic and microscopic margins. They observed that a microscopic margin of 8 mm was achieved in 83% of cases when the macroscopic measurement was 1 cm, in 91% when it was 1.5 cm, and in 98% when it was 2 cm. These results support the recommendation from de Hullu et al. ³⁹ of a 2‐cm macroscopic margin. However, this approach can result in significant mutilation, particularly when the primary tumor is near the clitoris, affecting up to 25%–37% of cases. ⁴²

Contemporary data, however, suggest no significant difference in local recurrence rates between margins ˂8 mm and those ≥8 mm. Woelber et al. ⁴³ reported on 102 patients, observing that margin distance had no significant effect on progression free survival (PFS) when analyzed as either a continuous variable or divided into groups (<3 mm, ≥3 to <8 mm, and ≥8 mm). Furthermore, the vulvar recurrence rate did not differ significantly between margins <8 mm (11.1%) and those ≥8 mm (10%). These findings were corroborated by Baiocchi et al., ⁴⁴ who observed local recurrence rates of 16.7% for margins <3 mm, 24.6% for margins between 3 and <8 mm, and 22.2% for margins of ≥8 mm.

Similarly, the Arbeitsgemeinschaft Gynaekologische Onkologie CaRE‐1 study reported vulvar recurrence rates of 12.6% in patients with margins <8 mm and 10.2% in those with margins ≥8 mm, with no significant difference in disease‐free survival between these groups. ⁴⁵ These findings were confirmed by a Dutch study of 287 patients, ⁴ which, after a follow‐up period of 80 months, reported a 10‐year recurrence rate of 42.5%. Although the pathologic tumor‐free margin did not influence the risk of local recurrence, a higher recurrence rate was noted in patients with concurrent dVIN and lichen sclerosus. There were no differences in local recurrence rates between those who did and did not receive adjuvant radiotherapy. The authors recommend aiming for a surgical tumor‐free margin of 10 mm and considering re‐excision if dVIN is present at the pathologic margin or if margins range from 0.1 to <3.0 mm.

It is also important to recognize that many recurrences may actually be second primary tumors rather than recurrences because most local recurrences occur after 2 years of follow‐up and at sites different from the original tumor. ²¹ These findings underscore the need for more rigorous and lifelong follow‐up for patients who have vulvar cancer with a history of lichen sclerosus or dVIN.

Despite ongoing debate, we recommend radical or wide local resection as the primary treatment approach for vulvar tumors. In cases with additional suspicious lesions or multifocal disease, radical vulvectomy is advised. We aim for a tumor‐free resection margin of 1 cm. However, for specific cases in which margins are near the urethra, anus, or clitoris, a final pathologic margin of at least 3 mm may be acceptable (Figure 3).

ILN metastases are observed in approximately 25%–30% of women with vulvar cancer, leading to potential overtreatment with radical groin lymphadenectomy for many. ⁴⁶ Therefore , sentinel LN (SLN) biopsy has become the preferred approach for patients with clinically negative LNs. A systematic review by Selman et al. ⁴⁷ reported detection rates with technetium‐99m of up to 100%, with pooled sensitivity and specificity of 97% and 100%, respectively. This high detection rate is especially achievable with the combined technique.

False‐negative results in SLN biopsy may occur when positive groin metastases disrupt lymph flow, causing bypassing of the SLN. ²² Preoperative imaging can help identify gross LN involvement. Patients with enlarged or suspicious groin LNs should undergo core‐biopsy or fine‐needle aspiration cytology to exclude metastatic involvement. All enlarged LNs should be resected during the surgical procedure, even if they are not SLNs. ²³ , ⁴⁶

In 2008, van der Zee et al. ⁴⁸ published the seminal prospective multicenter trial Groningen International Study on Sentinel Nodes in Vulvar Cancer‐V (GROINSS‐V) involving 403 patients with tumors <4 cm, stromal invasion >1 mm, and clinically negative ILNs. All patients underwent SLN biopsy using a combined technique (radioactive tracer and blue dye). For those with negative SLNs, systematic lymphadenectomy was omitted. After a median follow‐up of 35 months, the groin recurrence rate was only 2.3% for unifocal disease, which was comparable to the rates reported for patients who had early stage vulvar cancer treated with groin lymphadenectomy. ⁴⁹ , ⁵⁰ SLNs were analyzed using an ultrastaging technique (three sections per mm and cytokeratin AE1/AE3 immunostaining), detecting 41.7% of metastases.

In the GROINSS‐V study, non‐SLN involvement occurred in 21% of patients with metastatic SLNs. Oonk et al. ⁵¹ observed that isolated cells in SLNs had a non‐SLN metastasis rate of 4.1% (one of 24); and, in cases with metastases <5 mm, the rate was 11.7% (four of 34).

The results of GROINSS‐V were confirmed by the Gynecologic Oncology Group (GOG) 173 trial (ClinicalTrials.gov identifier NT00003325), ⁵² a prospective, multi‐institution study involving 452 patients with tumors up to 6 cm who underwent SLN biopsy followed by inguinofemoral lymphadenectomy. No skill verification for surgeons was required. After nearly 10 years, 23% of positive SLNs were detected by ultrastaging, with an overall false‐negative predictive value of 3.7%, decreasing to 2.0% for tumors <4 cm, consistent with the GROINSS‐V study. ⁴⁸ , ⁵¹ These findings support the use of SLN biopsy for selected patients, emphasizing the need for well trained gynecologic oncologists.

The safety of unilateral SLN biopsy was also addressed. Coleman et al. ⁵³ analyzed data from 234 patients in the GOG‐173 trial and identified no contralateral metastasis in patients who had tumors located within 2 cm of the midline on unilateral lymphoscintigraphy. However, contralateral metastasis was observed in 12.5% of patients who had midline tumors. Thus unilateral SLN biopsy may be safely performed in patients who have tumors located within 2 cm of the midline or those who have unilateral drainage on lymphoscintigraphy.

Recent analyses from the GROINSS‐V I and GROINSS‐V II studies, which included 366 patients with unilateral groin metastasis, demonstrated a 2.9% rate of contralateral non‐SLN metastases or groin recurrences, similar to the expected recurrence rates in patients with negative SLNs. For patients in whom adjuvant radiation was applied to both groins, the risk of contralateral groin recurrence was 0.8%. ⁵⁴

In summary, women with unifocal vulvar cancer, tumor size <4 cm, and clinically negative groins should undergo SLN biopsy performed at centers with an experienced multidisciplinary team. SLNs should be analyzed using ultrastaging (Figure 4).

FIGURE 4.

(A) Clinical presentation of a midline vulvar carcinoma, 3.5 cm in size, human papilloma virus‐negative, associated with lichen sclerosus; suitable for wide local excision and sentinel node mapping (bilateral). (B) Perilesion injection of patent blue dye. (C) Surgical margin marking for wide local excision. (D) Micrometastasis found after sentinel node ultrastaging (immunohistochemistry). (E) Sentinel node biopsy in left groin marked with both technetium and blue dye. (F) Clinical aspect after wound closure. (G) Resected sentinel lymph node with afferent lymphatic channel.

The role of adjuvant radiotherapy in the management of vulvar cancer remains a subject of ongoing debate. The primary objective of adjuvant radiotherapy is to mitigate the risk of locoregional recurrence, which is often fatal. Despite this, up to 40% of patients may experience local recurrence after surgical intervention, frequently attributed to the development of second primary tumors. Currently, adjuvant radiotherapy is recommended in patients who have positive surgical margins and are deemed unsuitable for re‐excision. In addition, other factors, such as lymphovascular invasion, perineural space invasion, close surgical margins, and a depth of invasion exceeding 5 mm, also may be used in the decision‐making process. ¹⁸

In a seminal study conducted by Homesley et al., ⁵⁵ 114 women with positive ILNs were randomly assigned to receive either adjuvant inguinal and pelvic radiotherapy or pelvic lymphadenectomy. The study demonstrated a notable difference in recurrence‐free survival between the two treatment modalities, with inguinal recurrence rates of 5.1% in the radiotherapy group compared with 23.6% in the pelvic lymphadenectomy group. This suggests that adjuvant radiotherapy for metastatic ILNs should encompass not only the inguinofemoral region but also clinically negative pelvic LNs up to the iliac bifurcation. Furthermore, for cases of midline tumors in which the contralateral groin has not been staged, contralateral inguinal radiotherapy should be considered. For cases involving positive pelvic LNs, the radiation field should extend to one level above the involved LN.

A recent, large, multicentric study conducted in Germany, known as Arbeitsgemeinschaft Gynaekologische Onkologie CaRE‐1, included 360 patients with LN‐positive vulvar tumors. The study indicated that adjuvant radiotherapy targeting the primary site, in addition to the groins and pelvis, was associated with a lower rate of isolated vulvar recurrences (15.8%) compared with adjuvant radiotherapy directed to the groins and pelvis (22.8%). ⁵⁶

Given the development of SLN biopsy technique, the GROINSS‐VII study ⁵⁷ explored radiotherapy as an alternative to lymphadenectomy for positive SLNs. Women with unifocal vulvar SCC <4 cm with clinically negative LNs received radiation after the identification of a positive SLN. Radiotherapy should be initiated within 6 weeks after surgery delivering a total dose of 50 grays (Gy; 25–28 fractions of 1.8–2.0 Gy). After interim analysis, the protocol was adjusted: patients with SLN metastasis >2 mm underwent systematic inguinofemoral lymphadenectomy before radiotherapy because there is a 20% groin recurrence rate in this group. The final results demonstrated a 2‐year groin recurrence rate of 1.6% with radiation alone for micrometastases (≤2 mm) versus 11.8% without radiation. For metastases >2 mm, adding inguinofemoral lymphadenectomy to radiation significantly reduced the 2‐year groin recurrence rate from 22% to 6.9%. That study concluded that complete inguinofemoral lymphadenectomy could be omitted only in patients who have micrometastatic disease. However, lymphedema rates were 32% for patients who underwent full lymphadenectomy versus 16.4% for those who received radiation alone. ⁵⁷

A large database study evaluated the benefits of chemotherapy when received alongside radiation (chemoradiation) in a cohort of patients who had LN‐positive disease (n = 2779). That study reported better survival for chemoradiotherapy compared with radiotherapy alone, particularly in patients who had two or more positive LNs. ⁵⁸ The ongoing GROINSS‐VIII study (ClinicalTrials.gov identifier NT05076942) is evaluating the safety of replacing lymphadenectomy with chemoradiation (56‐Gy dose) for patients with macrometastasis (>2 mm) in sentinel ILNs. ⁵⁹

Intensity‐modulated radiotherapy is the preferred approach for delivering adjuvant radiotherapy. The standard radiation dose for the groin and pelvic regions typically ranges from 45.0 to 50.4 Gy and is administered in daily fractions of 1.8–2.0 Gy. For cases involving resected macrometastases or extracapsular extension, a boost to the inguinofemoral region of 54–56 Gy is recommended. When metastatic LNs remain resected, a higher boost dose of 64–66 Gy is advised. In the presence of positive pelvic LNs, a dose of 57–60 Gy should be delivered. Furthermore, for positive resection margins of primary vulvar cancer, a boost of 60–66 Gy is suggested, which may be administered by external‐beam radiation therapy (EBRT) or image‐guided adaptive brachytherapy. ¹⁹ , ⁵⁹

It is important to note that the interval between surgery and the initiation of adjuvant radiotherapy should not exceed 8–10 weeks. Furthermore, the overall duration of radiotherapy should be limited to a maximum of 8 weeks. The total time from the date of surgery to the completion of adjuvant radiotherapy should not exceed 105 days.

In summary, adjuvant postoperative radiotherapy is advised for patients who have vulvar cancer with positive surgical margins. For SLN metastases measuring ≤2 mm, adjuvant radiotherapy represents a viable alternative to inguinofemoral lymphadenectomy. Conversely, for SLN metastases >2 mm, a full inguinofemoral lymphadenectomy is indicated. After inguinofemoral lymphadenectomy, radiotherapy is recommended or considered if there is more than one metastatic LN (algorithm I; see Figure 5).

FIGURE 5.

Algorithm I: Management of early stage vulvar carcinoma. CT indicates computed tomography; IFLND, inguinofemoral lymphadenectomy; LN, lymph node; MRI, magnetic resonance imaging; SLN, sentinel lymph node.

Locally advanced vulvar carcinoma

Exenterative procedures for vulvar cancer typically require en bloc removal of the vulvar tumor, which may include the anus, lower rectum, urethra, and bladder, contingent upon the tumor's anatomic location. ⁶⁰ These surgeries are associated with high morbidity and significant physical and psychological effects (Figure 6). Consequently, primary radiotherapy combined with chemotherapy has emerged as an alternative to (or before) surgery, with the goal to provide organ‐sparing and less radical surgical approaches. This method has demonstrated high response and operability rates, ranging from 63% to 92% (Figure 6). ⁶⁰ Notably, a large, retrospective database study that included 1352 women with unresectable tumor who received radiation or chemoradiotherapy demonstrated better 5‐year OS for the chemoradiotherapy group compared with the radiotherapy‐alone group (49.9% vs. 27.4%; p < .001). ⁶¹

FIGURE 6.

(A) Clinical aspect of locally advanced vulvar squamous cell carcinoma with anal involvement. (B) Urethral, ischiatic bone, and lower rectum invasion. (C) Bladder invasion. (D) Locally advanced vulvar carcinoma with anal involvement. (E) Clinical aspect after chemoradiation with 54 grays. (F,G) intensity modulated radiotherapy planning.

Moreover, the GOG‐279 phase 2 trial provided further insight into this approach. That study enrolled 52 women with locally advanced vulvar cancer who were not candidates for standard radical surgery. Participants received neoadjuvant treatment consisting of radiation (64 Gy to the groin and pelvis) combined with cisplatin and gemcitabine (median, six cycles). The trial reported a 73% complete pathologic response rate, with no one requiring pelvic exenteration. With a median follow‐up of 51 months, the 12‐month PFS rate was 74%, and the 24‐month OS rate was 70%. However, treatment was associated with 34% grade 4 adverse events (mainly myelotoxicity) and one (1.9%) grade 5 adverse event. ⁶²

In conclusion, chemoradiation is recommended for patients with locally advanced vulvar cancer when the disease would otherwise necessitate exenterative procedures for primary resection. Some retrospective studies and institutional series suggest that treatment delays, including prolonged radiotherapy, can negatively affect local control and OS. ⁶³ An evaluation of response to chemoradiation should be conducted 12 weeks after the completion of treatment. In cases where residual disease is identified, surgery should be considered (algorithm II; see Figure 7).

FIGURE 7.

Algorithm II: Management of early stage vulvar carcinoma. ¹⁸FDG, fluorodeoxyglucose F18; CT, computed tomography; MRI, magnetic resonance imaging.

Vaginal carcinoma

Management strategies for vaginal cancer are determined based on the location and stage of the primary tumor. Because of the rarity of this cancer, there are no standard surgical approaches, and multiple methods have been reported. For selected patients with small tumors, wide local excision with disease‐free margins is often used. ⁶² , ⁶³ Options also include partial vaginectomy, total simple vaginectomy, and radical vaginectomy with paravaginal tissue resection ⁶⁴ (Figure 2).

For stage I tumors located in the upper one third of the vagina, colpectomy and LN dissection are considered appropriate. However, optimal surgical margins and the extent of paravaginal resection are not well defined. Colpectomy is usually performed alongside a hysterectomy, with a type B resection (parametrial resection at ureter level) generally being sufficient for clear margins. For tumors >2 cm, a more extensive type C1 resection (parametrial resection lateral to the ureter with a nerve‐sparing technique) may be necessary. ⁶⁵

Surgical intervention for stage I vaginal cancer should balance risks and benefits and, ideally, is reserved for younger patients who have not previously received radiotherapy and do not have adverse factors such as positive LNs. In eight studies involving 174 patients, surgery alone for stage I disease resulted in a 5‐year survival rate ranging from 56% to 90%. ⁶⁵

Radiotherapy alone is also a treatment option for stage I cancer. Twenty‐two studies involving 553 patients have reported 5‐year survival rates between 33% and 100%. ⁶⁶ Typically, a combination of brachytherapy with EBRT is used, especially for patients with high‐risk prognostic factors. EBRT is generally recommended for larger, more invasive, or poorly differentiated tumors that may have a higher risk of LN metastasis. ⁶⁶ A National Cancer Data Base analysis indicated that patients who underwent surgery had better survival outcomes compared with those who received radiotherapy, with a 5‐year survival rate of 90% for surgery versus 63% for radiotherapy (p < .05). For stage II and beyond, treatment should primarily involve radiotherapy, with pelvic exenteration reserved for locoregional persistence or recurrence after radiation. ⁶⁷

Adding chemotherapy to radiotherapy in vaginal cancer is extrapolated from the treatment of locally advanced cervical cancer. The National Cancer Data Base suggests that chemoradiation offers a survival advantage over radiotherapy alone across all stages. For stage I tumors, median survival rates are 109 months with chemoradiation versus 85.3 months with radiotherapy alone (p = .02). ⁶⁸ Tumor size also affects survival for stage I patients, with 5‐year survival rates of 79.2% for tumors ≤2 cm and 66.1% for tumors >2 cm (p = .01). ⁶⁸ , ⁶⁹

LN metastasis in stage I vaginal cancer occurs in 6%–16% of cases. ⁷⁰ Given its rarity, only four published studies have examined SLN mapping in vaginal carcinoma, encompassing 16 cases in stages I and II. ⁶⁴ , ⁶⁵ The overall detection rate was 81% (13 of 16 cases). Despite its rarity, SLN mapping is important for identifying unexpected lymphatic drainage, and further research is needed to define its role in vaginal cancer.

In summary, for stage I tumors in the upper one third of the vagina, radical surgery with LN staging or a combination of EBRT and brachytherapy is preferred. For tumors in the bottom two thirds of the vagina or stage II and beyond, radiotherapy (EBRT and brachytherapy) is the preferred treatment. Radical surgery, such as pelvic exenteration, may be used for recurrence or persistence after radiation therapy. Chemotherapy should be added to radiation even for stage I tumors, and SLN mapping may be beneficial in identifying unexpected lymphatic drainage (algorithm III; see Figure 8).

FIGURE 8.

Algorithm III: Management of vaginal carcinoma. CT indicates computed tomography; MRI, magnetic resonance imaging.

Recurrent or metastatic vulvar or vaginal carcinomas systemic treatment

Approximately 12%–37% of women with vulvar cancer develop a recurrence within the first 2 years of diagnosis. ⁷¹ For advanced or locally recurrent tumors not amenable to local control with surgery and/or radiotherapy, treatment intention is palliative, and systemic treatment options are limited. There is no established standard of care, and OS at 5 years is currently limited to 20% of patients. ⁷² Therefore, enrolling patients with metastatic vulvar and vaginal cancers in clinical trials is strongly encouraged. Also, an early access to best supportive care is important given the potential effect of locoregional progression on quality of life. ⁷³

Specific data on vulvar and vaginal carcinomas usually come from retrospective studies or small phase 2 clinical trials. Monochemotherapy using cisplatin, paclitaxel, or mitoxantrone have been tested without significant activity. ⁷⁴ , ⁷⁵ In a phase 1 trial, 29 patients with advanced vulvar cancer (>80% chemotherapy‐naive) received paclitaxel with an overall response rate (ORR) of 14% and a median PFS of only 2.6 months. ⁷⁵ Platinum‐based combinations have yielded better disease control: for instance, in a retrospective series, cisplatin plus vinorelbine resulted in an ORR of 40%, a median PFS of 10 months, and an OS of 19 months. ⁷⁶ The combination of bleomycin with mitomycin or methotrexate plus lomustine yielded response rates of 55% and 56%, respectively. ⁷⁷ Unfortunately, there are sparse data on medical treatment of both vulvar and vaginal cancers, and treatments often are extrapolated from algorithms in cervical cancer. Therefore, cisplatin or carboplatin plus paclitaxel is the preferred regimen.

Immunotherapy efficacy has been tested in phase 1/2 trials that included patients with vulvar cancer; the basket trials KEYNOTE‐028 and KEYNOTE‐158 trials (ClinicalTrials.gov identifiers NCT02054806 and NCT02628067, respectively) and the CheckMate‐358 trial (ClinicalTrials.gov identifier NCT02488759) are examples. KEYNOTE‐158 is the largest clinical trial in the advanced vulvar cancer setting and included 101 patients who had recurrent/metastatic disease treated with pembrolizumab. The ORR was 10.9% (9.5% of 84 patients who had programmed death 1 [PD‐1] ligand (PD‐L1)–positive tumors, 28.6% of seven patients who had PD‐L1–negative tumors), with a median duration of response of 20.4 months. Median PFS and OS were 2.1 and 6.2 months, respectively. ⁷⁸ , ⁷⁹ , ⁸⁰ KEYNOTE‐028 included 18 patients who had vulvar cancer progression on or after chemotherapy; the ORR was 6%, the OS rate was 28% at 12 months, and PD‐L1 expression according to the combined positive score was also correlated with ORR and PFS. ⁷⁸ Similarly, the basket phase 1/2 trial CheckMate‐358 trial evaluated nivolumab in virus‐associated tumors, including vulvar cancers. In 24 patients with recurrent/metastatic cervical or vaginal/vulvar cancer in first or second line of treatment, nivolumab produced an ORR of 20% and disease control rates of 80%, regardless of PD‐L1 status, in the group of five patients with vulvar cancer. ⁸¹ Based on these phase 2 data and some cervical cancer data from trials like the EMPOWER‐CERVICAL‐1 phase 3 trial (ClinicalTrials.gov identifier NCT03257267) ⁸² and the KEYNOTE‐826 trial (ClinicalTrials.gov identifier NCT03635567), ⁸³ selected patients with metastatic vulvar and vaginal cancer may benefit from immunotherapy. The EMPOWER‐CERVICAL‐1 phase 3 trial reported longer OS and improved response rates with cemiplimab compared with chemotherapy in recurrent and metastatic settings after first‐line chemotherapy, whereas the KEYNOTE‐826 trial of pembrolizumab in first‐line platinum‐based chemotherapy, with or without bevacizumab, significantly improved PFS and OS. ⁸³ Furthermore, all patients with DNA mismatch‐repair deficiency are eligible for pembrolizumab based on a tumor‐agnostic indication.

Targeted drugs have also been explored in this clinical scenario. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib was studied in a phase 2 trial with 24 patients, demonstrating an overall clinical benefit rate of 67.5%, with 11 (27.5%) partial responses, 16 patients (40.0%) who had stable disease, and seven patients (17.5%) who had progressive disease. However, responses were of short duration. ⁸⁴ There are case reports that support the use of using bevacizumab combined with chemotherapy in advanced vulvar cancer, and the phase 3 trial GOG 240 (ClinicalTrials.gov identifier NCT00803062) demonstrated longer OS when bevacizumab was added to chemotherapy in cervical cancer. Once again, extrapolating from cervical cancer, the data suggest that adding bevacizumab to platinum‐based chemotherapy might add clinical benefit in vulvar cancer, as suggested by preliminary retrospective evidence from the use of bevacizumab in combination with neoadjuvant platinum‐based chemotherapy for locally advanced vulvar cancer. ⁸⁵

Perspectives in the systemic treatment of vulvar and vaginal cancers

There is a significant unmet need for dedicated clinical trials focusing on vulvovaginal cancers. Referral of patients with advanced vulvar and vaginal cancers to clinical trials, whenever possible, and to specialized centers is highly recommended.

Recent developments in next‐generation sequencing have provided deeper insights into the genetic landscape of vulvar and vaginal cancer, revealing actionable mutations that potentially could be targeted with individualized therapies. In vulvar SCC, specific gene mutations/overexpression and peculiar pathway dysregulations, such as those in the EGFR, AMPK, and the PI3K/AKT/mTOR pathways, have been identified, providing a potential roadmap for precision medicine approaches. ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ It is strongly recommend that health care providers consider molecular profiling of these rare tumors to identify patients who may benefit from targeted therapies.

Antibody–drug conjugates (ADCs), designed to target specific antigens expressed on tumor cells and to deliver potent cytotoxic agents directly into the cancer while minimizing damage to normal tissue, represent another emerging strategy in the systemic treatment of vulvar and vaginal cancers. ⁹⁰ Positive human epidermal growth factor receptor 2 (HER2) status in vulvar SCC ranges from 0.9% to 1.9% ⁹¹ , ⁹² and represents a potential target for ADCs, particularly in cases where overexpression or gene amplification is detected, as in the case of vulvar extramammary Paget disease, in which 25% of patients present with an immunohistochemistry score ≥3. ⁹³ , ⁹⁴ Trastuzumab deruxtecan, an ADC that targets HER2, had reported efficacy in a range of seven HER2‐positive cancers and was granted US Food and Drug Administration agnostic approval after reports of the results from the DESTINY‐PanTumor02 phase 2 trial (ClinicalTrials.gov identifier NCT04482309). ⁹⁵ A particularly promising target in vulvar cancer is TROP2, a transmembrane glycoprotein that is overexpressed in various epithelial cancers. In vulvar SCC, TROP‐2 expression is present in approximately 97% of cases, and about 74% display high TROP‐2 expression. ⁹⁶ Tissue factors that have been explored in the context of other solid tumors also could be relevant for vulvar and vaginal cancer as ADC targets. Tisotumab vedotin, a tissue factor‐directed ADCs, has produced improved OS with respect to standard chemotherapy in patients with cervical cancer and could be explored in similar tumor types like vulvar and vaginal cancers. ⁹⁷

Immunotherapy continues to be an area of significant interest, especially given the relation between most of these cancers and HPV infection. Immune checkpoint inhibitors, which target the PD‐1/PD‐L1 pathway, have shown success in treating other HPV‐related cancers and also may represent an opportunity for vulvar and vaginal cancers. ⁹⁸ Indeed, based on cervical cancer data and case series/small phase 2 trials, the off‐label addition of pembrolizumab to platinum‐based chemotherapy in patients who have vulvar/vaginal cancer with PD‐L1 expression based on a combined positive score ≥1 in the front‐line setting of advanced/recurrent disease or as monotherapy in patients who progress to first‐line platinum‐based chemotherapy is suggested by the international guidelines. ⁸⁰ , ⁸¹ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² , ¹⁰³ We encourage the inclusion of patients who have vulvar and vaginal cancer in immunotherapy clinical trials because this could offer a new avenue for those who have limited options. In particular, ongoing clinical trials are investigating the use of anti–PD1/PD‐L1 agents, either alone or in combination with platinum‐based chemotherapy and/or radiotherapy, in locally advanced vulvar cancer (ClinicalTrials.gov identifiers NCT05761132, NCT04192253, and NCT04430699), whereas several immune checkpoint inhibitor‐based strategies are under investigation in the advanced/metastatic setting, including the concurrent inhibition of PD‐1/PD‐L1 and CTLA‐4 or TGFβ (ClinicalTrials.gov identifiers NCT05932212, NCT02834013, and NCT04287868), or the combination of anti–PD1/PD‐L1 agents with antiangiogenics, tyrosine kinase inhibitors, histone deacetylase inhibitors, oncolytic viruses, or cytokines (ClinicalTrials.gov identifiers NCT05903833, NCT05949632, NCT06292689, NCT05000294, NCT04357873, NCT04977453, and NCT02978625).

Finally, a promising strategy for the systemic treatment of HPV‐associated vulvar and vaginal cancers is represented by the targeting of HPV‐linked tumor antigens. These cancers are frequently associated with high‐risk strains of HPV, which lead to the expression of viral oncoproteins, such as E6 and E7, that play a critical role in the malignant transformation and progression of cancer cells. ⁹⁸ T‐cell receptor (TCR)‐engineered T cells targeting the HPV type 16 (HPV16) E6 or E7 antigens, have shown potential in treating HPV‐positive vulvar carcinoma. ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ A phase 1 clinical trial demonstrated that TCR‐engineered T cells targeting the E7 ⁸⁰ , ⁸¹ , ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ epitope of the HPV16 E7 antigen presented by HLA‐A*02:01 could mediate significant tumor regression in patients with metastatic HPV‐associated cancers, including vulvar carcinoma. ¹⁰⁷ The study enrolled a total of 12 patients with HPV16‐positive tumors and with an HLA‐A*02:01 serotype. In the unique patient with metastatic squamous cell vulvar carcinoma, the investigators observed a partial response lasting 8 months with a notable regression of lung metastases. ¹⁰⁷ The persistence and expansion of TCR‐engineered T cells in peripheral blood was correlated with the observed antitumor activity, indicating the potential for long‐term disease control. As of this publication date, the phase 2 part of the trial is open in patients with metastatic disease (ClinicalTrials.gov identifier NCT02858310), and the same E7 TCR T cells are under investigation as induction therapy before definitive treatment in patients with an HLA‐A*02:01 serotype and locally advanced HPV16‐positive cancers (ClinicalTrials.gov identifier NCT05639972). Another phase1/2 study demonstrated similar antitumor activity using TCR‐engineered T cells targeting the E6 epitope of the HPV16 E6 antigen presented by HLA‐A*02:01. ¹⁰⁸ Among the 12 patients enrolled who had metastatic HPV16‐positive tumors with an HLA‐A*02:01 serotype, one patient had vaginal SCC and achieved a stabilization of disease lasting 6 months. ¹⁰⁸ Other TCR T‐cell therapies in the clinical phase of development for HPV‐positive tumors include SCG142 E7‐specific TCR‐T cells armored with a TGFβRII‐41BB chimeric switch receptor (ClinicalTrials.gov identifiers NCT06505551 and NCT06544720), TT12 HPV16 E6/E7 TCR T cells engineered to be resistant to TGFβ (ClinicalTrials.gov identifier NCT02379520), and HRYZ‐T101 HPV18 E7 TCR T cells (ClinicalTrials.gov identifiers NCT05952947 and NCT05787535).

Therapeutic vaccines designed to target HPV‐associated viral antigens alone or in combination with immune checkpoint inhibitors are also under clinical investigation and could offer a highly specific and potentially effective treatment approach (ClinicalTrials.gov identifiers NCT04432597, NCT03260023, and NCT04287868). ¹⁰⁹

VULVOVAGINAL MELANOMA

Introduction

Mucosal melanomas are not well understood and generally exhibit aggressive behavior compared with cutaneous melanomas. ¹¹⁰ Data from the National Cancer Data Base spanning from 1985 to 1994 indicate that cutaneous melanomas comprised 91.2% of cases, 5.2% of ocular melanomas, 1/3% of mucosal melanomas, and 2.2% of melanomas of unknown origin. ¹¹¹

Vulvar melanoma accounts for 2.4%–10.0% of all vulvar malignancies, with an incidence rate ranging from approximately 0.48 to 1.4 per 1,000,000 women annually. ¹¹² Although the vulvar skin constitutes only 1%–2% of the body's surface area, it represents 3%–7% of melanomas in women. Vulvar melanoma commonly presents during the fifth or sixth decade of life, with a mean and median age of onset ranging from 54 to 76 years. ¹¹³

Vaginal melanoma represents <3% of all vaginal tumors and 0.4%–0.8% of all melanomas in women. ¹¹⁰ Recent literature reports approximately 500 cases of vaginal melanoma, with the largest single‐institution study documenting only 44 cases. The median age at presentation for vaginal melanoma ranges from 57 to 68 years. ¹¹⁰ , ¹¹³ , ¹¹⁴

Vulvar melanoma commonly occurs in the clitoral area and the labia majora, with less frequent involvement of the labia minora and periurethral area. The tumors propensity for multifocality can complicate the identification of a specific site of origin. ¹¹⁰ , ¹¹⁵ , ¹¹⁶

Clinical manifestations of vulvar melanoma are the presence of a vulvar lesion, vulvar pain, bleeding, and itching in 39%, 30%, 24%, and 20% of patients, respectively. Vaginal melanoma typically presents as an irregular pigmented plaque, an ulcerated or polypoid lesion, and is located predominantly on the lower one third of the vulva. ¹¹⁰ , ¹¹⁶ These tumors may be prone to bleeding, and approximately 20% are multifocal. Diagnosis requires a gynecologic examination, colposcopy, and biopsy. ¹¹⁰ , ¹¹⁶

Vulvar melanosis is distinguished by the presence of single or multiple, irregularly pigmented macules or patches, which vary in color from tan to black and have uneven borders. Lesions that exhibit clinical or dermoscopic features suggestive of melanoma should undergo biopsy for further evaluation (Figure 9).

FIGURE 9.

(A) Clinical aspect of a multifocal melanoma in situ. (B) Vulvar melanoma with multifocal pattern. (C) Surgical specimen of vaginal melanoma located in the upper one third of vagina. (D) Vulvar melanoma with a nodular aspect. (E) Vaginal melanoma presented as a large tumor in lower one third of vagina.

The five‐year OS rate for patients with vulvar melanoma is notably low. According to data from the Dutch Cancer Registry, which encompasses 6436 patients who had vulvar cancer from 1989 to 2012, 350 patients were diagnosed with vulvar melanoma. ¹¹⁷ The 5‐year OS rate for these patients was 35% (95% confidence interval, 26.7%–44.4%) versus 50% (95% CI, 40.5%–59.1%) for patients with cutaneous melanoma, reflecting a statistically significant difference (p = .002). ¹¹⁷ In the case of vaginal melanoma, the 5‐year survival rate ranges between 13% and 32.3%. ¹¹⁰ Key predictors of clinical outcomes include tumor size, ¹¹⁸ and positive LN status has been associated with nearly a two‐fold increase in the risk of death in the National Cancer Institute's Surveillance, Epidemiology, and End Results database (Figure 10). ¹¹⁹

FIGURE 10.

(A–D) Clinical aspect of locoregional recurrences.

Pathology

Differentiating melanomas from other pigmented lesions—such as melanosis, lentigo, and dysplastic nevi—is crucial for accurate diagnosis. Moreover, vulvar intraepithelial neoplasia can present with pigmentation, and Paget disease may resemble superficial spreading melanoma because of to its intraepithelial‐type appearance. ¹¹⁵ , ¹²⁰

Among immunohistochemical markers, S100 protein and SRY‐box 10 (SOX10) are highly sensitive for identifying melanocytic lesions, although they lack specificity. Conversely, markers like MART‐1 (melanoma antigen recognized by T cells), MITF (microphtalmia‐associated transcription factor), and HMB‐45 (human melanoma black‐45) have high specificity and frequently are used. ¹²⁰

Histologic prognostic features of vulvovaginal melanoma resemble those of cutaneous melanoma and include several factors: tumor type, size, depth of invasion, presence of ulceration, number of mitoses per square millimeter, presence of perineural and vascular lymphatic invasion, radial growth phase, and the extent of tumor‐infiltrating lymphocytes. Tumor thickness is measured in millimeters according to Breslow criteria. ¹¹⁵

Melanoma subtypes display distinct molecular pathways, with variations in mutation frequencies among different types. Melanomas associated with chronic sun‐induced damage (CSD), acral melanomas, and mucosal melanomas demonstrate lower frequencies of BRAF and NRAS mutations compared with non‐CSD melanomas. Specifically, in vulvar melanoma, BRAF mutations are observed at frequencies ranging from 0% to 9%, and NRAS mutations range from 0% to 27%. In contrast, vaginal melanomas rarely present BRAF mutations, and NRAS mutations occur at frequencies ranging from 13% to 43%. ¹²¹ , ¹²² , ¹²³

c‐KIT mutations in mucosal melanomas, acral melanomas, and CSD‐associated melanomas are reported at rates of 39%, 36%, and 28%, respectively; whereas c‐KIT mutations were not identified in non‐CSD melanomas. ¹²¹ Although c‐KIT mutations are frequently observed in vulvar melanoma, with a range from 18% to 35%, they are seldom reported in vaginal melanomas. ¹²¹ , ¹²² , ¹²³ However, PD‐1 and PD‐L1 are expressed in 75% and 56% of vulvovaginal melanomas, respectively. ¹²³

These observations suggest that vulvar and vaginal melanomas, despite their anatomic proximity, may involve distinct molecular pathways. Given the rarity of these tumors and the limited availability of effective therapies, it is advisable to conduct mutational analysis for c‐KIT, BRAF, and NRAS at both initial diagnosis and recurrence.

Melanoma staging

A thorough total‐body skin examination, along with an ocular examination to rule out other potential primary sites, is advised. ¹²⁴ , ¹²⁵ Because of the high likelihood of locoregional extension and distant metastasis associated with these melanomas, an extensive staging evaluation is essential. This evaluation should include a chest, abdomen, and pelvis CT or, if available, an ¹⁸FDG/PET‐CT scan, in addition to a brain CT or MRI. Furthermore, pelvic MRI is recommended for accurate assessment of local disease extension. ¹²⁴ , ¹²⁵

For the staging of different types of female genital melanomas, the AJCC staging system should be used for vulvar and vaginal melanomas. ¹²⁵

Melanoma treatment

With the evolving surgical approaches for skin melanomas and vulvar SCCs, the management of vulvar melanoma has transitioned from extensive to more conservative surgical procedures. ¹²⁶ For the treatment of a primary tumor, wide local excision is recommended. Although the optimal minimal excision margin for melanoma is not definitively established, clinical guidelines suggest aiming for a 1‐cm margin circumferentially for melanomas with a Breslow thickness ≤2 mm and a 2‐cm margin for those with greater Breslow thickness. For in situ disease, a margin of 0.5 cm is suggested. ¹²⁶ , ¹²⁷

Vulvovaginal melanomas present distinct surgical challenges because of their typically larger size compared with other cutaneous melanomas and their proximity to critical anatomic structures, including the urethra, bladder, anus, and rectum.

Achieving negative surgical margins sometimes may require exenterative procedures. However, radical surgical approaches have not demonstrated superior locoregional control or improved survival outcomes compared with wide local excision with margins from 1 to 2 cm. ¹¹⁰ , ¹²⁶ , ¹²⁷ Consequently, pelvic exenteration should be offered to highly selected and appropriate patients, with preoperative therapies aimed at potentially reducing the need for extensive surgery recommended to the majority of patients. Standard chemotherapy is generally considered ineffective in this context; however, hypofractionated radiotherapy may be used to potentially limit the extent of surgical intervention. In addition, the integration of radiation with novel agents, such as ipilimumab, has been explored with notable interest. ¹²⁸

SLN mapping has become a standard approach for staging cutaneous melanoma and is most accurate for intermediate‐thickness melanomas (Breslow thickness, 1–4 mm). ¹²⁷ , ¹²⁹ Although SLN mapping is also recommended for thick melanomas with a Breslow thickness >4 mm, the supporting data for this group are less extensive. The utility of SLN mapping for thin melanomas (Breslow thickness, ≤1 mm) is less well defined; however, it may be considered in cases with high‐risk features, such as ulceration or a mitotic rate of 1 mitosis per mm² or higher ¹²⁹ (Figure 11).

FIGURE 11.

(A,B) Clinical aspect of a vulvar melanoma before wide local excision and sentinel node mapping. (C) Example of clitoris preservation. (D) Wide local excision. (E) Surgical aspect after excision and sentinel node biopsy. (F) Clinical aspect after wound closure.

SLN mapping should be considered for all patients undergoing wide local excision for newly diagnosed vulvar melanoma. Conversely, SLN mapping for vaginal melanoma is challenging, and definitive recommendations for vaginal melanoma are not yet established.

Completion lymphadenectomy is not required if the SLN is negative. ¹²⁷ , ¹²⁹ Two large, randomized trials have evaluated SLN mapping and LN management in melanoma: the Multicenter Selective Lymphadenectomy Trials I and II (MSLT‐I and MSLT‐II; ClinicalTrials.gov identifiers NCT00275496 and NCT00297895, respectively). MSLT‐I ¹³⁰ demonstrated the feasibility, accuracy, and low morbidity of SLN mapping. Immediate lymphadenectomy for SLN‐positive cases resulted in reduced lymphedema compared with delayed lymphadenectomy after the development of clinically apparent LN disease. The 5‐year disease‐free survival rate did not differ between groups at 78.3% in the SLN mapping group versus 73.1% in the observation group (p = .009). In addition, patients with positive SLNs who underwent immediate completion lymphadenectomy had a 5‐year survival rate of 72.3%, versus 52.4% in those who underwent delayed lymphadenectomy (p = .004), indicating a potential benefit in local control. However, melanoma‐specific survival did not differ significantly between the groups. ¹³⁰ , ¹³¹

The MSLT‐II trial ¹³² randomized patients with SLN metastases to undergo immediate completion lymphadenectomy versus serial ultrasonography of the LN basin, with lymphadenectomy reserved for cases showing recurrence. The 3‐year rate of melanoma‐specific survival was similar in the dissection group and the observation group. The rate of disease‐free survival was slightly higher in the dissection group than in the observation group (68% vs. 63%, respectively; p = .05) at 3 years, based on an increased rate of disease control in the regional LNs at 3 years (92% vs. 77%, respectively; p < .001). Lymphedema was observed in 24.1% of patients in the dissection group and in 6.3% of those in the observation group. ¹³²

Contemporary evidence underscores the effectiveness of immune checkpoint inhibitors in the adjuvant treatment of stage III cutaneous melanoma. Phase 3 trials evaluating adjuvant therapy with anti–PD‐1 antibodies, specifically pembrolizumab and nivolumab, have revealed substantial improvements in recurrence‐free survival compared with both placebo and ipilimumab. ¹³³

For pembrolizumab, significant enhancements in recurrence free survival have been demonstrated relative to placebo. ¹³⁴ Similarly, nivolumab has produced superior recurrence‐free survival outcomes compared with ipilimumab. ¹³⁵ The data indicate that adjuvant immune checkpoint inhibitors reduce the risk of recurrence by approximately 40% in stage III melanoma and by approximately 35%–40% in stage II melanoma relative to surgical intervention alone. ¹³⁴ , ¹³⁵ , ¹³⁶ These findings highlight the considerable clinical advantage of integrating immune checkpoint inhibitors into the adjuvant treatment protocol for melanoma. ¹³³

For patients with clinically positive LN disease, lymphadenectomy has traditionally been the preferred treatment. However, recent trials have demonstrated that neoadjuvant immune checkpoint inhibition offers benefits in the perioperative setting for resectable stage III cutaneous melanoma compared with using adjuvant treatment alone.

In a phase 2 trial conducted by Patel et al., ¹³⁷ the authors reported that, among patients with resectable stage III or IV melanoma, those who received pembrolizumab both preoperatively and postoperatively experienced a significantly longer event‐free survival compared with those who were treated with adjuvant pembrolizumab alone. Specifically, the 2‐year event‐free survival rate was 72% in the neoadjuvant group versus 49% in the adjuvant group (p = .004).

Similarly, the NADINA phase 3 trial (ClinicalTrials.gov identifier NCT04949113) ¹³⁸ assessed the efficacy of neoadjuvant ipilimumab plus nivolumab followed by surgery and response‐driven adjuvant therapy. This approach resulted in significantly longer event‐free survival compared with surgery followed by adjuvant nivolumab alone, with rates of 83.7% versus 57.2%, respectively (p < .001). Notably, within the neoadjuvant group, 59.0% of patients achieved a major pathologic response, 8.0% had a partial response, 26.4% exhibited no response (with >50% residual viable tumor), and only 2.4% experienced disease progression. Regarding adjuvant radiotherapy, it should be considered for patients with vulvar or vaginal melanoma who are at high risk for regional recurrence, such as those with residual disease, cancer spreading outside LNs, visible cancer in LNs, or involvement of multiple or large LNs. Although adjuvant radiotherapy might help control local disease, its impact on OS is not well established, and potential side effects like lymphedema should be carefully weighed. Common treatment regimens include 60–66 Gy over 25–33 sessions over 5–7 weeks or 48 Gy over 20 sessions in 4 weeks, although the optimal dose is not firmly established. Decisions about radiotherapy should be individualized, considering each patient's specific risks and circumstances, and should involve a multidisciplinary team to ensure the best approach. ⁵⁹ , ¹¹⁰

Vulvar and vaginal melanomas represent a rare and challenging subset of melanoma associated with notably poorer prognoses compared with cutaneous melanomas. These adverse outcomes are largely caused by delayed diagnosis, distinct tumor biology, and variation in treatment responses. Effective management of these tumors involves a multidisciplinary approach at specialized centers with extensive expertise in melanoma. Recent advancements in treatment include novel modalities, such as checkpoint inhibitors and targeted therapies (see algorithm IV; Figure 12).

FIGURE 12.

Algorithm IV: Management of vulvar melanoma. IFLND indicates inguinofemoral lymphadenectomy; LN, lymph node; SNL, sentinel lymph node.

VULVOVAGINAL SARCOMAS

Introduction

Gynecologic sarcomas are rare malignancies, representing about 4% of all gynecologic cancers. The majority of these tumors develop in the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%), and other gynecologic organs (2%). ¹³⁹

Vulvar sarcomas are particularly rare, accounting for only 1%–3% of all vulvar malignancies. The median age of diagnosis is 50 years, and patients often present with symptoms like local discomfort, vulvar mass, chronic itching, or pain. The prognosis is largely influenced by tumor size, involvement of surrounding structures, and mitotic activity or atypia. ¹⁴⁰ , ¹⁴¹

Vaginal sarcomas account for only 3% of vaginal cancers, with leiomyosarcomas the most common type, particularly in adults. In children, RMS is the predominant histology. Symptoms typically include vaginal bleeding, discharge, a palpable mass, and localized pain. ¹⁴¹ , ¹⁴²

For diagnosis, an incisional or image‐guided core‐needle biopsy is recommended.

Pathology

Vulvovaginal sarcomas exhibit significant histologic diversity and arise from subepithelial stromal cells in the mesenchyme. Although these sarcomas share certain morphologic and immunohistochemical features, diagnosis primarily depends on clinical, morphologic, and radiologic findings, with increasing focus on molecular alterations. ¹⁴³

The most common types of vulvar sarcomas include leiomyosarcomas, RMS, angiosarcomas, neurofibrosarcomas, malignant fibrohistiocytomas, and deep angiomyxomas. Among vaginal sarcomas, leiomyosarcomas are the most common type in adults. In children, RMS is the predominant histology.

The WHO classification of tumors of soft tissue and bone recognizes four tumor behavioral categories that are relevant to vulvar cancers: benign, intermediate (locally aggressive), intermediate (rarely metastasizing), and malignant. Intermediate tumors can be either locally aggressive (e.g., desmoid fibromatosis and deep angiomyxoma, which locally infiltrates surrounding tissues) or rarely metastasizing (tumors with a very low [<2%] but definite risk of metastasis; e.g., inflammatory myofibroblastic tumor). Malignant tumors, such as leiomyosarcoma, can recur locally and metastasize. Common histopathologies within the sarcoma category include dermatofibrosarcomas and leiomyosarcomas. ¹²

RMS accounts for 7%–8% of all solid tumors and two thirds of pediatric sarcomas. In the female genital tract, RMS comprises 10% of cases. It responds well to chemotherapy, leading to a preference for conservative treatments, including chemotherapy alone or organ‐sparing surgery combined with brachytherapy or EBRT. Prognosis is favorable, with 5‐year survival rates exceeding 90%. The majority of cases show FOXO1 fusion‐negative embryonal RMS histology. ¹⁴²

Formerly known as aggressive angiomyxoma, deep angiomyxoma is an infiltrative, hormone‐dependent, benign mesenchymal tumor that often presents as a large, painless, slow‐growing mass in the perineal region. MRI typically shows a laminated pattern with homogeneous contrast enhancement. Surgical resection, limited to macroscopically invaded tissues, generally results in low recurrence rates. Hormonal therapy and surveillance may be considered in some cases. ¹⁴⁴

Desmoid‐type fibromatosis is an aggressive, locally infiltrative mesenchymal tumor. Diagnosis is often confirmed by CTNNB1 mutation analysis. Because these tumors can regress spontaneously, an initial conservative, nonsurgical approach is recommended. Systemic treatments, including hormonal therapy, anti‐COX2 inhibitors, and imatinib, may be used. Surgery is reserved for cases of disease progression. ¹⁴⁵

Dermatofibrosarcoma protuberans is a rare soft tissue tumor that affects the dermis and subcutaneous fat. Diagnosis is supported by presence of the t(17;22)(q22;q13) translocation. Wide local excision is typically required, and Mohs micrographic surgery has recently been applied for improved precision in surgical removal. ¹⁴⁶

Staging

MRI is crucial for assessing local tumor spread because of its superior soft tissue resolution. Systemic staging to check for LN involvement (rare, <1%) and distant metastasis can be done using CT or PET‐CT scans. Greater than 50% of leiomyosarcomas show pulmonary metastasis at diagnosis. ¹⁴⁷ In addition, because gynecologic sarcomas may be linked to germline TP53 mutations (such as in Li‐Fraumeni syndrome), germline testing should be advised. ¹⁴⁸

Treatment

Because of their rarity and histologic complexity, the management of gynecologic sarcomas should be performed in specialized centers by multidisciplinary teams. The primary treatment for localized soft tissue sarcomas is complete surgical resection, ensuring the macroscopic removal of adjacent tissues to achieve microscopic‐free margins (R0). In cases requiring extensive surgery, such as pelvic exenteration, neoadjuvant therapy should be considered, with the approach tailored to the tumor's histologic type, location, and size. ¹³⁹ , ¹⁴⁹

The role of LN staging is still debated and should be considered in specific subtypes like clear cell sarcomas, epithelioid sarcomas, and alveolar soft part sarcomas. For patients with long progression‐free intervals and isolated recurrences, metastasectomy may offer better survival outcomes. ¹⁵⁰ Cytoreductive surgery can also be beneficial in cases of peritoneal sarcomatosis, particularly when complete tumor removal is achievable, with the best outcomes seen in low‐grade cases. ¹⁵¹

PATIENT FOLLOW‐UP AND SUPPORT

Follow‐up and rehabilitation strategies for vulvar and vaginal cancers focus on early detection of recurrences and addressing the long‐term physical and psychological effects of treatment. For instance, the recurrence rate for vulvar cancer is approximately 25%, with local and groin relapses accounting for 60% and 30%, respectively. ¹⁵² From an oncologic perspective, follow‐up not only monitors treatment outcomes but also facilitates the early detection of subsequent tumors. Recurrences most commonly appear on the vulva, perineum, and inguinofemoral region, with distant metastases being less frequent. ¹⁵² HPV testing and cervical/vaginal screening should be considered 6–12 months after primary treatment if not done earlier. Regular surveillance can aid in detecting smaller recurrences and facilitating curative interventions. ¹⁵³ However, there is conflicting evidence regarding the benefits of routine versus symptom‐triggered follow‐up visits. ¹⁵⁴ For LN‐negative patients who undergo SLN dissection, the risk of LN recurrence is highest in the first 2 years. In these patients, ultrasound surveillance of the groins may be considered, although its cost effectiveness remains unclear. Long‐term follow‐up is important because the risk of recurrence and new primary diseases persists for 5–10 years posttreatment. ¹⁵⁵

Surveillance includes clinical examinations every 3–4 months for the first 2 years, followed by biannual check‐ups. Imaging, such as MRI or PET/CT, is typically performed 3–4 months after therapy to confirm remission, particularly for advanced cases. After these measures, there is no established consensus on the optimal follow‐up schedule. ¹⁵⁴ Importantly, HPV vaccination has been shown to reduce recurrent cervical intraepithelial neoplasia after surgery, although its role in secondary prevention for vulvar and vaginal cancers remains unclear.

Vulvar and vaginal cancers and their treatments can lead to complications, such as urinary incontinence, lymphedema, sexual dysfunction, and psychosocial issues, all of which negatively affect quality of life. ¹⁵⁶ , ¹⁵⁷ , ¹⁵⁸ Rehabilitation should be holistic, involving expert teams to manage these outcomes and offer psychosocial support. ¹⁵⁸ , ¹⁵⁹ Advances in reducing treatment‐related morbidity have significantly altered standard treatments, especially for early stage disease. In the past, treatment in the 1970s through the 1990s was highly mutilating, often involving radical vulvectomy with en bloc resection of the ILNs. Today, for selected patients with early stage disease, a wide local excision and SLN procedure are often sufficient. However, morbidity remains a concern, particularly in women who undergo inguinofemoral lymphadenectomy as part of their treatment. Lymphedema affects up to 50% of patients who undergo lymphadenectomy. Managing lymphedema, which affects 16.7%–49.2% of patients after ILN dissection, requires access to specialist services. ¹⁶⁰ Patients should also be informed about ways to minimize the risk of developing lymphedema through exercise and weight management. ¹⁶⁰ Rehabilitation research aimed at improving outcomes and addressing long‐term complications should be a priority.

In addition, the treatment of vaginal and vulvar cancers significantly affects body image and sexuality, sensitive topics often avoided because of the stigma associated with cancers of intimate areas. Multidisciplinary care involving plastic surgeons and psychological support can significantly affect the quality of life of patients. Furthermore, after pelvic radiotherapy, younger women may experience premature menopause, necessitating hormone‐replacement therapy, whereas topical estrogens may benefit others. Supportive care must address the physical, emotional, and sexual health effects of cancer, especially after treatment. Structured rehabilitation programs should be available to address these needs.

Palliative care plays a crucial role in cases of distant or inoperable recurrence, helping to manage symptoms and improve quality of life. Early integration of palliative services has been shown to reduce aggressive end‐of‐life care and improve survival in other cancers, and similar benefits may apply to vulvovaginal cancers. Radiotherapy continues to offer effective symptom relief in advanced cases, particularly for pain and bleeding control. ¹⁶¹

CONCLUSION

In conclusion, vulvar and vaginal cancers, although rare, present significant challenges because of their treatment morbidity and high recurrence rates. Current treatment modalities primarily involve surgical intervention and chemoradiation patients with for locally advanced carcinoma, yet options for those with metastatic or recurrent disease remain limited. The importance of clinical trial participation and best supportive care is emphasized to improve patient outcomes and quality of life. Future HPV vaccination efforts are critical to reducing incidence rates, highlighting the need for continued advancements in treatment efficacy and morbidity reduction in these malignancies.

CONFLICT OF INTEREST STATEMENT

Dr. Angélica Nogueira‐Rodrigues reports personal/consulting fees from Abvie, Astra Zeneca, Daiichi, MSD, GSK, Pfizer, Lilly, Novartis, Eisai and Roche outside the submitted work. Domenica Lorusso reports grants/contracts from Alkermes Inc., AstraZeneca, Clovis Oncology, Corcept Therapeutics, Genmab, GlaxoSmithKline, ImmunoGen Inc., Merck Sharp and Dohme, Novartis, and Seagen; personal/consulting fees from Daiichi Sankyo, Merck Sharp and Dohme, and Novartis; support for other professional activities from AstraZeneca, Clovis Oncology, Corcept Therapeutics, Genmab, GlaxoSmithKline, ImmunoGen Inc., Merck Sharp and Dohme, Novocure, PharmaMar, Roche Health Solutions Inc., and Seagen; and travel support from AstraZeneca, Merck Sharp and Dohme, and Menarini International outside the submitted work. Brian Slomovitz reports personal/consulting fees from Aadi, AstraZeneca, EISAI INC., Eli Lilly & Company, Genmab, Incyte Corporation, Karyopharm Therapeutics, Merck, Novartis, Regeneron Pharmaceuticals Inc., and Seagen Inc. outside the submitted work. Mario M. Leitão Jr reports personal/consulting fees from Medtronic and support for other professional activities from Ethicon and Intuitive Surgical outside the submitted work. Glauco Baiocchi reports personal/consulting fees from AbbVie, AstraZeneca, GlaxoSmithKline, and Merck Sharp and Dohme; and travel support from AstraZeneca, Merck Sharp and Dohme outside the submitted work. Maaike H. M. Oonk disclosed conflicts of interest.

Nogueira‐Rodrigues A, Oonk MHM, Lorusso D, Slomovitz B, Leitão MM, Jr , Baiocchi G. Comprehensive management of vulvovaginal cancers. CA Cancer J Clin. 2025;75(5):410‐435. doi: 10.3322/caac.70014