Vulvar Cancer
Squamous cell carcinoma of the vulva and vulval intraepithelial neoplasia
DefinitionClick to collapse
EpidemiologyClick to collapse
SubtypesClick to collapse
Molecular PathogenesisClick to collapse
Risk FactorsClick to collapse
Clinical FeaturesClick to collapse
Typical Presentation
Vulvar cancer typically presents in the labia majora, labia minora, clitoris, mons pubis, or perineum. In HPV-independent (p53 abnormal) tumors, the classic presentation is a single mass or ulcer on the labia majora or minora, often in older patients (median age 68 years) with chronic vulvar inflammatory disorders such as lichen sclerosus. In HPV-associated tumors, multifocal lesions and concurrent cervical neoplasia are more common, and patients are frequently younger. Many patients are asymptomatic at early stages, but when symptoms occur, pruritus and pain/irritation are most common; vulvar bleeding or discharge may also occur. A majority of patients present with early-stage localized disease (stage I/II), with 5-year survival of 85.7% for localized disease based on SEER data (2015–2021).
Symptoms
Pruritus
Itching is a common presenting symptom, often chronic and localized to the vulvar area.
Pain/irritation
Localized pain, burning, or irritation of the vulva, often associated with ulceration or advanced disease.
Vulvar bleeding or discharge
Spontaneous bleeding or serosanguinous discharge from a visible lesion.
Palpable mass
A single lump or nodule, often on the labia majora, sometimes ulcerated.
Signs
Visible vulvar lesion
May appear as an exophytic mass, ulcer, or area of leukoplakia/erythroplakia. In HPV-associated cases, multiple lesions often present.
Inguinal lymphadenopathy
Palpable enlarged groin lymph nodes, may be fixed or ulcerated in advanced disease.
Lichen sclerosus or differentiated VIN
Signs of chronic inflammatory vulvar conditions, especially in HPV-independent disease; may appear as white plaque or atrophic skin.
Multifocal lesions
Multiple separate lesions suggest HPV-associated disease; may involve vagina and cervix.
Red FlagsClick to collapse
Persistent vulvar pruritus or pain lasting more than 4 weeks despite conservative therapy
Any visible vulvar mass, ulcer, or area of mucosal irregularity that fails to heal within 2–3 weeks
Palpable inguinal or femoral lymphadenopathy, especially if firm, fixed, or >1.5 cm
Unexplained vulvar bleeding or discharge in a postmenopausal patient
Rapid growth of a vulvar lesion
Multiple vulvar lesions, particularly with history of cervical or vaginal HPV-related neoplasia
History of lichen sclerosus with new or changing lesion
Symptoms of urinary obstruction or tenesmus from locally advanced disease
InvestigationsClick to collapse
Diagnostic
History and physical examination (H&P)
Comprehensive evaluation of vulvar, vaginal, cervical, and inguinal regions; assess for multifocal disease and nodal involvement.
Biopsy and pathologic review
Definitive diagnosis; must include adequate sampling of suspicious areas, preferably with punch or excisional biopsy.
Complete blood count (CBC)
Baseline assessment for anemia, infection, or thrombocytosis; part of routine workup.
Liver function tests/renal function studies
Baseline for chemotherapy planning and assessment of metastatic disease.
Cervical HPV and cytology testing
Due to multifocal lower genital tract neoplasia risk; HPV testing helps identify HPV-associated vulvar disease.
HIV testing (consider)
Recommended especially in younger patients with vulvar SCC or other HPV-related disease; HIV status affects management but cancer treatment should not be modified solely based on HIV.
Examination under anesthesia (EUA) with cystoscopy or proctoscopy
Indicated when tumor involves or is near urethra, bladder, or anus; helps delineate extent for surgical planning.
Distress assessment (NCCN Distress Thermometer)
Recommended at all stages to identify psychosocial needs including social determinants of health.
Staging
Pelvis MRI (with and without contrast)
Consider to aid in surgical and/or radiation treatment planning; best for assessing local tumor extent, depth of invasion, and involvement of adjacent structures (urethra, vagina, anus).
FDG-PET/CT (neck, chest, abdomen, pelvis, groin) or chest/abdomen/pelvis CT with contrast
Assess for nodal and distant metastases; PET/CT more sensitive for detecting metastatic disease and aids in radiation planning.
Chest x-ray (consider)
Baseline for pulmonary metastases; if abnormality seen, proceed to chest CT without contrast.
Imaging based on symptomatology
Additional imaging as clinically indicated for symptoms suggestive of metastases (e.g., bone scan for pain, brain MRI for neurological symptoms).
Fine-needle aspiration (FNA) of radiographically suspicious lymph nodes
Confirm nodal metastasis when inguinofemoral lymphadenectomy not performed or to guide treatment planning.
Intraoperative frozen section of suspicious nodes
During inguinofemoral lymphadenectomy, to tailor extent and bilaterality of lymphadenectomy.
Biomarkers
HPV status determination (p16 IHC or RNA sequencing or HPV ISH or DNA sequencing)
Classify tumor as HPV-associated vs. HPV-independent; HPV-associated has better prognosis.
p53 IHC (or NGS for TP53 mutations)
Determine TP53 status in HPV-negative tumors; p53 abnormal SCC has worst clinical outcomes among three molecular categories.
PD-L1 testing
Assess eligibility for pembrolizumab in recurrent, progressive, or metastatic disease (tumors with CPS ≥1).
HER2 IHC with reflex to FISH for equivocal (2+)
Identify HER2-positive tumors (IHC 3+ or 2+ with FISH positive) for potential treatment with fam-trastuzumab deruxtecan-nxki.
Comprehensive molecular profiling (FDA-approved or CLIA-validated test including MMR/MSI, TMB, NTRK)
Identify rare pan-tumor targeted therapy opportunities: MSI-H/dMMR (pembrolizumab), TMB-H (pembrolizumab), NTRK fusions (larotrectinib, entrectinib, repotrectinib).
Somatic mutational testing for cutaneous vulvar and mucosal vulvovaginal melanoma (BRAF, KIT)
Identify actionable mutations for targeted therapy in melanoma (e.g., BRAF V600 for dabrafenib/trametinib, KIT mutations).
StagingClick to collapse
FIGO 2021 (International Federation of Gynecology and Obstetrics) staging for carcinoma of the vulva; also AJCC 8th edition TNM equivalent.
T Categories
| Stage | Description |
|---|---|
| T1 (Stage I) | Tumor confined to the vulva or perineum. T1a: tumor size ≤2 cm and stromal invasion ≤1 mm. T1b: tumor size >2 cm or stromal invasion >1 mm. |
| T2 (Stage 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. |
| T3 (Stage III) | Tumor of any size with extension to upper part of adjacent perineal structures (upper two-thirds of urethra, upper two-thirds of vagina, bladder mucosa, rectal mucosa) or with any number of nonfixed, nonulcerated lymph node metastases. |
| T4 (Stage IV) | Tumor of any size fixed to bone (pelvic bone) or with fixed or ulcerated regional lymph node metastases, or distant metastases. |
N Categories
| Stage | Description |
|---|---|
| N0 | No lymph node metastasis. |
| N1 (Stage IIIA) | Regional lymph node metastases ≤5 mm (includes micrometastases and isolated tumor cells). |
| N2 (Stage IIIB) | Regional lymph node metastases >5 mm. |
| N3 (Stage IIIC) | Regional lymph node metastases with extracapsular spread. |
| N4 (Stage IVA/IVB) | Fixed or ulcerated regional lymph node metastases (IVA) or distant metastases (IVB); note: N4 is not explicitly used; staging includes N0-3 plus M. |
M Categories
| Stage | Description |
|---|---|
| M0 | No distant metastases. |
| M1 (Stage IVB) | Distant metastases (including pelvic nodal disease beyond inguinofemoral region). |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage I | T1 N0 M0. IA: tumor ≤2 cm and stromal invasion ≤1 mm. IB: tumor >2 cm or stromal invasion >1 mm. | Disease confined to vulva/perineum, node negative. Most common presentation (early stage). | 85.7% for localized disease (SEER 2015–2021, includes stages I and II together). | Curative; primary surgical resection with or without sentinel node biopsy. |
| Stage II | T2 N0 M0. Tumor of any size with extension to lower one-third of urethra, vagina, or anus, node negative. | Locally advanced but still node negative; may require more extensive resection or chemoradiation. | 85.7% for localized disease combined with stage I. | Curative; primary surgery (if resectable) or chemoradiation. |
| Stage III | Any T with N1-N3 M0. IIIA: tumor with extension to upper two-thirds of urethra/vagina/bladder/rectal mucosa OR regional LN metastases ≤5 mm. IIIB: regional LN metastases >5 mm. IIIC: regional LN metastases with extracapsular spread. | Node-positive disease or significant local extension; high risk of recurrence. | 49.71% for regional/locally advanced (SEER stages III/IVA combined). | Curative intent with multimodality therapy (surgery, chemoradiation, adjuvant therapy). |
| Stage IV | IVA: Disease fixed to pelvic bone OR fixed or ulcerated regional LN metastases. IVB: Distant metastases (M1). | Advanced disease with bone fixation or non-resectable nodal disease (IVA) or distant spread (IVB). | 49.71% for stage IVA (combined with stage III in SEER estimate) and 21.9% for stage IVB. | IVA: curative intent with chemoradiation ± resection. IVB: palliative; systemic therapy ± RT. |
Staging Pearls
- Depth of invasion is measured from the basement membrane of the deepest adjacent dysplastic tumor-free rete ridge to the deepest point of invasion (FIGO 2021 method A), not from the most superficial dermal papilla (previous method).
- Stage IIIA includes any number of LNs ≤5 mm; stage IIIB includes any LNs >5 mm. The 5-mm threshold is used for staging, while 2 mm is used for treatment selection.
- Regional nodes are inguinal and femoral (not pelvic); pelvic nodal disease is considered distant metastasis (M1) per FIGO 2021.
- Imaging (MRI, PET/CT) can be used to assign stage when surgical staging is not performed, especially in unresectable disease.
- Stage IIIC (extracapsular spread) is a distinct category with worse prognosis, warranting aggressive adjuvant therapy.
- Stage IVA includes disease fixed to pelvic bone OR fixed/ulcerated regional LNs; note that tumor extension to pelvic bone is T4.
- The 2021 FIGO revision removed stage IVA for upper urethral/vaginal/bladder/rectal involvement (now IIIA) and reclassified single >5 mm node as IIIB.
Management PrinciplesClick to collapse
Vulvar cancer treatment requires a multidisciplinary, individualized approach that integrates surgery, radiation therapy (RT), and systemic therapy, with decisions guided by histology (HPV-associated vs. HPV-independent), stage, tumor location, and nodal status. For squamous cell carcinoma (SCC) and adenocarcinoma, management pathways are stratified into early-stage (Stage I and select Stage II), locally advanced (unresectable without removing proximal urethra/bladder/anus), and metastatic disease beyond the pelvis (Stage IVB). Vulvar and vulvovaginal melanoma are treated separately, following principles from cutaneous melanoma guidelines. The NCCN panel emphasizes clinical trials, smoking cessation, distress assessment, and consideration of HIV and HPV status (VULVA-1). Treatment philosophy balances curative intent with organ preservation and quality of life. For early-stage disease, conservative surgery with sentinel lymph node biopsy (SLNB) is preferred to reduce morbidity. Locally advanced disease is managed with chemoradiation, potentially followed by resection. Metastatic disease focuses on systemic therapy and palliative RT (VULVA-7).
Curative
Early-stage (Stage I and select Stage II) SCC/adenocarcinoma; resectable cutaneous vulvar melanoma stages 0-II; resectable mucosal vulvovaginal melanoma
Primary surgical resection with inguinofemoral lymph node evaluation (SLNB or lymphadenectomy) for SCC; partial vulvectomy with or without SLNB for melanoma. Adjuvant RT or chemoradiation based on risk factors (positive margins, LVSI, nodal metastases).
Curative
Locally advanced SCC/adenocarcinoma (unresectable without removing proximal urethra/bladder/anus)
Definitive chemoradiation with EBRT plus concurrent cisplatin-based chemotherapy; if complete response, surveillance; if residual disease, consider resection or additional therapy (VULVA-5, VULVA-6).
Palliative
Metastatic disease beyond pelvis (Stage IVB); unresectable or recurrent vulvovaginal melanoma
Systemic therapy (cisplatin/paclitaxel-based, immunotherapy, or targeted agents) and/or EBRT for locoregional control/symptom palliation; best supportive care as appropriate (VULVA-7, VM-1A/VM-2).
Management should involve a multidisciplinary team including gynecologic oncology, radiation oncology, medical oncology, pathology, radiology, and supportive/palliative care. For patients with vulvar cancer who are older, the NCCN Guidelines for Older Adult Oncology should be consulted (VULVA-1). Smoking cessation counseling and intervention are recommended. Distress screening using the NCCN Distress Thermometer is required at all stages.
Performance status (PS) is not explicitly defined but treatment decisions consider surgical candidacy, tolerance of chemoradiation, and ability to undergo lymphadenectomy. For older patients (≥65 years), geriatric assessment is advised (VULVA-1). For patients with unresectable disease, PS guides between curative chemoradiation and palliative approaches.
Management PathwaysClick to collapse
Branching: Tumor location relative to midline (≥2 cm from vulvar midline for lateral), Depth of invasion (≤1 mm vs >1 mm), Nodal status, Margin status
Branching: Tumor location (anterior or posterior near midline/midline), Depth of invasion, Nodal status
Branching: Margin status (negative, positive, unresectable), Other risk factors (close margins, LVSI, tumor size, depth of invasion, pattern of invasion)
Branching: SLN status (negative, positive ≤2 mm, positive >2 mm), Inguinofemoral lymphadenectomy result (negative, positive with number of nodes and ENE), Completion lymphadenectomy performed or not
Branching: Radiographic nodal status (negative, suspicious/pelvic-confined M1), Inguinofemoral lymphadenectomy performed or not, Response to chemoradiation
Branching: Extent of disease, Primary controlled, Number of metastases
Branching: Resectability, Margin status after resection, Nodal status (surgically or clinically/radiographically negative)
Branching: Resectability
Branching: Prior EBRT to region, Isolated inguinofemoral/pelvic LN vs distant metastasis
Branching: Clinical stage (0/IA, IB, II, III), SLNB status, Resectability
Branching: Resectability, Margin status, Nodal status (SLNB optional)
Branching: Biomarkers: TMB-H (≥10 mut/Mb), MSI-H/dMMR, PD-L1 positive (CPS ≥1), HER2 positive (IHC 3+ or 2+), HPV-related, NTRK gene fusion
Branching: Stage ≥ IB
Pretreatment EvaluationClick to collapse
Initial Workup (SCC/adenocarcinoma and Melanoma)
Workup for Suspected Recurrence
SurgeryClick to collapse
Surgery is the primary treatment for early-stage vulvar cancer (SCC/adenocarcinoma and melanoma) and is used for resection of residual disease after chemoradiation in locally advanced cases, as well as for recurrence. It provides critical staging information via lymph node evaluation, which is the most important determinant of survival (Burger et al., Ref 33). The goal is complete tumor resection with negative margins while preserving function and quality of life where possible.
Tumor margin status is a significant prognostic factor for local recurrence. Efforts should be made to obtain gross surgical margins of at least 1 cm at primary surgery. Studies question the traditional 8-mm pathologic free margin; a smaller margin may be acceptable, particularly to preserve sensitive areas and sexual function (VULVA-C 1 of 6). Close margins (1-8 mm) may be observed with regular follow-up; re-excision for positive margins should be considered. Adjuvant local RT is an alternative. Positive margins involving urethra, anus, or vagina may be unresectable without significant morbidity.
For invasive SCC, re-excision of close or positive margins may not be beneficial in patients with inguinal node metastases that require EBRT ± chemotherapy postoperatively (VULVA-C 1 of 6).
Lymph node status is the most important determinant of survival. Staging includes complete surgical resection of primary tumor with at least 1 cm clinical gross margins and either unilateral or bilateral inguinofemoral lymphadenectomy or SLNB in select patients (VULVA-C 2 of 6).
Historically, en bloc resection was performed; current standard involves separate incisions for vulvar tumor and LN resection to reduce morbidity (DiSaia et al., Ref 63).
SLNB is an alternative standard-of-care approach in select patients with SCC (tumor <4 cm, unifocal, clinically negative groin). It results in decreased postoperative morbidity without compromising detection of LN metastases. Dual tracer (radiocolloid + blue dye or ICG) improves sensitivity. SLNB should be performed by high-volume surgeons (VULVA-C 4 of 6).
If SLN is not detected on a side, complete inguinofemoral lymphadenectomy is recommended. For SLN metastases >2 mm, completion lymphadenectomy is preferred. For micrometastases (≤2 mm), RT alone is acceptable if lymphadenectomy not performed (GROINSS-V II, Ref 72).
For lateralized and near-midline tumors with unilateral SLN metastasis, unilateral groin treatment by either lymphadenectomy or RT is acceptable. For midline tumors with unilateral SLN metastasis, unilateral groin treatment is acceptable if contralateral groin negative (VULVA-C 4 of 6, Coleman et al., Ref 61).
Pelvic exenteration may be considered for select cases with central recurrence (VULVA-9).
Procedures
Simple partial vulvectomy
Stage IA SCC (≤1 mm invasion) (VULVA-2). Also for melanoma in situ if not requiring radical depth.
Radical partial vulvectomy
Stage IB or II SCC; vulvar-confined recurrence; resectable melanoma with clear margins.
Radical total vulvectomy
Extensive or multifocal disease; select recurrences (VULVA-9). Retrospective data show no difference in recurrence vs radical partial vulvectomy (VULVA-C 2 of 6).
Inguinofemoral lymphadenectomy (IFLN)
For patients not meeting SLNB criteria (tumor ≥4 cm, multifocal, clinically positive nodes, prior vulvar surgery). Also as completion after positive SLN >2 mm or when SLN not detected.
Sentinel lymph node biopsy (SLNB)
SCC: unifocal tumor <4 cm, clinically negative groin nodes, no previous vulvar surgery. Melanoma: stage IB and above with clinically negative nodes (VULVA-C 4 of 6).
Pelvic exenteration
Select cases of central recurrence not amenable to less radical surgery, after chemoradiation failure (VULVA-6, VULVA-9).
Radiation TherapyClick to collapse
Radiation therapy is used as adjuvant therapy following initial surgery for SCC/adenocarcinoma (e.g., for positive margins, nodal metastases), as primary therapy (with concurrent chemotherapy) for locally advanced disease, and for palliation in recurrent/metastatic disease. For melanoma, RT is considered for medically inoperable patients, adjuvant in high-risk settings, and for symptomatic control.
Principles
- Radiation technique and doses are critical to maximize tumor control while limiting toxicity. CT-based treatment planning with conformal blocking is standard. IMRT is recommended for better dose delivery to target and sparing of organs at risk; 2D/3D technique reserved for urgent/palliative cases (VULVA-D 1 of 5).
- Target volumes should be defined by physical exam and CT simulation; radio-opaque markers on key landmarks (anus, urethra, clitoris, scars) aid planning. MRI and PET fusion help delineate gross disease. Consensus contouring guidelines (Gaffney et al., Ref 3) are recommended.
- Bolus should be used to ensure adequate dose to superficial targets (vulvar and groin). Dose verification with TLD/OSLD is recommended (VULVA-D 3 of 5).
- Acute effects (diarrhea, bladder irritation, fatigue, mucocutaneous reaction) are expected; aggressive management is needed. Treatment breaks should be avoided. Antifungal treatment for Candida overgrowth can reduce skin reaction. Postoperative adjuvant RT should start within 6-8 weeks after adequate healing (VULVA-D 1 of 5).
- For locally advanced disease, concurrent chemotherapy (cisplatin preferred) is standard based on improved survival vs RT alone (NCDB analysis: 5-year OS 49.9% vs 27.4%, HR 0.76, Ref 108).
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Adjuvant to primary surgical bed (negative margins) | 45-50 Gy | 1.8 Gy | 25-28 | Once daily, 5 days/week | Postoperative, negative margins (VULVA-D 4 of 5). |
| Adjuvant to primary surgical bed (close or positive margins) | 54-60 Gy | 1.8 Gy | 30-33 | Once daily, 5 days/week | Close/positive margins after maximal resection (VULVA-D 4 of 5). |
| Uninvolved inguinofemoral LNs (clinically/radiographically negative) | 45-50 Gy | 1.8 Gy | 25-28 | Once daily, 5 days/week | Elective nodal coverage (VULVA-D 4 of 5). |
| Positive inguinofemoral LNs without ECE or gross residual | 50-55 Gy | 1.8 Gy | 28-30 | Once daily, 5 days/week | Postoperative positive nodes without extranodal extension (VULVA-D 4 of 5). |
| Extranodal extension (ECE) in nodal disease | 54-64 Gy | 1.8 Gy | 30-35 | Once daily, 5 days/week | Postoperative with ECE or unresectable gross nodes (VULVA-D 4 of 5). |
| Gross primary vulvar disease (definitive or boost) | 60-70 Gy | 1.8-2.0 Gy | 33-36 | Once daily, 5 days/week. Consider boost to 70 Gy for bulky/persistent disease. | Definitive chemoradiation for unresectable primary; boost to residual disease (VULVA-D 4 of 5). |
| Melanoma – Definitive (vulvar) - PTV high risk | 65-75 Gy EQD2 | Various (e.g., 66 Gy in 2.2 Gy/fx or 70 Gy in 2 Gy/fx) | Variable | Once daily; more hypofractionated regimens for small volumes. | Primary RT for unresectable vulvar melanoma (VM-A 1 of 7). |
| Melanoma – Adjuvant (vulvar or vaginal) | 45-65 Gy (lower range for elective, higher for positive margins/ECE) | 1.8-2.4 Gy | 25-36 | Once daily; hypofractionated options exist. | Postoperative for close/positive margins or high-risk nodal disease (VM-A 1 of 7, VM-A 5 of 7). |
| Vaginal Melanoma – Definitive (EBRT + brachytherapy boost) | EBRT 44-50 Gy (2 Gy/fx) or 54-63 Gy (1.8 Gy/fx) plus brachytherapy boost (e.g., 4.5-6 Gy x5, 7 Gy x4, 8-9 Gy x3) | Variable | Variable | EBRT once daily; brachytherapy as per institutional protocol. | Unresectable vaginal melanoma (VM-A 3 of 7). |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Adjuvant EBRT (SCC/adenocarcinoma) | 45-50.4 Gy/25-28 fractions (1.8 Gy) for negative margins; 54-60 Gy for close/positive margins; 50-64 Gy for nodes depending on ECE | Yes, often with cisplatin (preferred) or carboplatin if intolerant; other options: cisplatin/fluorouracil, cisplatin/gemcitabine, capecitabine/mitomycin, gemcitabine, paclitaxel (category 2A/B). Concurrent chemo recommended for primary site risk factors? Usually considered for nodal positivity; for primary site alone, RT alone may suffice (VULVA-E, VULVA-D). | Postoperative for positive margins, LVSI, deep invasion, or nodal metastases. For ≥2 positive LNs or ENE, RT is category 1 (VULVA-4). | GOG 37 showed survival benefit for adjuvant RT vs pelvic LN resection in node-positive patients; long-term follow-up: disease-related death 51% vs 29%, HR 0.49 (Ref 125). AGO-CaRE-1: 3-year PFS 39.6% vs 25.9% (P=0.004) for RT vs no RT in node-positive (Ref 128). | Acute skin reactions, diarrhea, cystitis, fatigue. Late effects: fibrosis, vulvovaginal atrophy, stenosis, bone loss, pelvic fractures, secondary malignancy risk. |
| Definitive Chemoradiation (Locally Advanced SCC/adenocarcinoma) | 59.4-64.8 Gy in 33-36 fractions (1.8 Gy) with boost to 70 Gy for bulky disease | Preferred: cisplatin 40 mg/m2 weekly (or carboplatin AUC 2 if intolerant). Other: cisplatin/fluorouracil, cisplatin/gemcitabine (category 2A). | Unresectable SCC/adenocarcinoma of vulva without removing proximal urethra/bladder/anus (VULVA-5). | GOG 205: pCR 78% in patients undergoing biopsy after chemoradiation with weekly cisplatin (Ref 110). GOG 101: 96% avoided pelvic exenteration (Ref 99). NCDB analysis: chemoradiation improved 5-year OS vs RT alone (49.9% vs 27.4%, HR 0.76, Ref 108). | Grade ≥3 skin/mucosa reactions, pain, diarrhea, hematologic toxicity, late fibrosis, fistulae (less common). |
| Palliative RT (SCC/adenocarcinoma or Melanoma) | Variable: e.g., 30 Gy/10 fractions, 48-50 Gy/20 fractions, or hypofractionated 6 Gy x5 for small fields. | Not routinely used; chemo may be given sequentially. | Symptomatic locoregional or metastatic disease (VULVA-7, VM-A 6 of 7). | SABR-COMET: SABR improved OS in oligometastatic disease (median OS 41 vs 28 months, Ref 150). | Palliation aims to minimize toxicity; depends on site and dose. |
Systemic TherapyClick to collapse
Systemic therapy for vulvar SCC is largely extrapolated from cervical cancer due to limited vulvar-specific data. Chemoradiation regimens use platinum-based radiosensitizers. For advanced, recurrent, or metastatic disease, first-line therapy includes platinum/paclitaxel with or without bevacizumab and/or pembrolizumab. Second-line options include checkpoint inhibitors (pembrolizumab, cemiplimab, nivolumab, ipilimumab+nivolumab) and biomarker-directed therapies (TMB-H, MSI-H, PD-L1, HER2, NTRK). For vulvar and vulvovaginal melanoma, systemic therapy follows the NCCN Guidelines for Melanoma: Cutaneous. Regimens are category 2A unless otherwise noted.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Assessment of Response after Definitive Chemoradiation for Locally Advanced Vulvar Cancer
Timing
At least 3 months after completion of EBRT with concurrent chemotherapy (VULVA-6). For other settings (e.g., adjuvant therapy), response is assessed clinically and via imaging as part of surveillance (VULVA-8).
Response Logic
-
Clinically negative for residual tumor at primary site and nodes: proceed to surveillance. Consider biopsy of tumor bed to confirm pathologic complete response (pCR). If biopsy negative, continue surveillance; if biopsy positive, manage as indicated below (VULVA-6).
-
Clinically suspicious for residual tumor at primary site and/or nodes: perform biopsy and imaging (consider FDG-PET/CT or MRI). If biopsy negative and margins negative, consider additional surgery, additional EBRT, and/or systemic therapy, or best supportive care. If biopsy positive and resectable, resect if deemed operable; if margins positive after resection, consider additional surgery, additional EBRT, systemic therapy, or best supportive care. If unresectable, consider additional EBRT and/or systemic therapy, or best supportive care (VULVA-6).
-
If resection of residual disease is performed and margins are negative, consider observation or additional treatment per risk factors. Pelvic exenteration may be considered for select cases (VULVA-6 footnote s).
Imaging Recommendations
-
After definitive chemoradiation: consider FDG-PET/CT and/or pelvis MRI at 3-6 months to assess treatment response (VULVA-B).
-
During surveillance: imaging as indicated based on symptoms or examination findings suspicious for recurrence. CT chest/abdomen/pelvis or neck/chest/abdomen/pelvis/groin FDG-PET/CT if recurrence/metastasis suspected (VULVA-B).
-
For surveillance of vulvar/vulvovaginal melanoma: CT scan or FDG-PET/CT every 3-6 months, especially for high-risk disease (VM-3).
Biopsy Or Salvage Logic
-
If after definitive chemoradiation there is clinically negative exam, biopsy may be considered to confirm pCR but is not mandatory (VULVA-6).
-
If clinically suspicious or biopsy positive for residual invasive disease, assess resectability. If resectable, proceed with surgery (radical partial or total vulvectomy ± inguinofemoral lymphadenectomy). If unresectable, offer additional EBRT (if feasible), systemic therapy, or best supportive care (VULVA-6).
-
For recurrence after prior treatment, see recurrence pathways (VULVA-9, VULVA-10). For isolated inguinofemoral/pelvic nodal recurrence not previously irradiated, consider resection of clinically enlarged LNs followed by EBRT + concurrent chemotherapy. For distant metastasis or prior EBRT, systemic therapy and/or selective EBRT, with consideration of ablative therapy for 1-5 lesions if primary controlled (VULVA-10, footnote t).
SurveillanceClick to collapse
Clinical Follow Up Schedule
| Disease | Schedule |
|---|---|
| SCC/Adenocarcinoma | H&P every 3–6 months for 2 years, then every 6–12 months for 3–5 years, then annually; adjust frequency based on risk of recurrence [VULVA-8] |
| Vulvar/Vulvovaginal Melanoma (stage ≥ IB) | Groin nodal ultrasound every 3–6 months for first 2 years, then every 6–12 months for years 3–5; consider CT or FDG-PET/CT every 3–6 months for high-risk disease [VM-3] |
Imaging Strategy
- Initial post-treatment: Consider FDG-PET/CT and/or pelvis MRI at 3–6 months to assess treatment response after definitive primary treatment [VULVA-B]
- During surveillance: CT chest/abdomen/pelvis or neck/chest/abdomen/pelvis/groin FDG-PET/CT if recurrence/metastasis is suspected based on symptoms or exam [VULVA-B]
- For vulvar melanoma: FDG-PET/CT especially for high-risk disease every 3–6 months [VM-3]; groin nodal ultrasound requires specific radiologic expertise [VM-3, footnote m]
- Imaging should be based on symptomatology and clinical concern; routine surveillance imaging in asymptomatic patients is not recommended
Laboratory Monitoring
- CBC, BUN, creatinine as indicated based on symptoms or examination findings suspicious for recurrence [VULVA-8]
- No routine tumor markers are recommended for vulvar cancer
Supportive Follow Up
- Cervical/vaginal cytology and HPV testing as indicated for lower genital tract neoplasia detection (accuracy may be affected by prior pelvic RT) [VULVA-8]
- Patient education on symptoms of recurrence, periodic self-exams, lifestyle (obesity, exercise), sexual health (dilators, lubricants, local estrogen), and smoking cessation [VULVA-8]
- Referral to survivorship clinics, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy as needed [VULVA-F]
- Distress assessment at all disease stages using NCCN Distress Thermometer [VULVA-1]
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Pruritus, pain/irritation, vulvar bleeding or discharge | Symptom-directed care; biopsy for diagnosis; surgical excision or chemoradiation for definitive treatment |
| Multifocal lesions (HPV-associated) and concurrent cervical neoplasia | Full lower genital tract evaluation including cervical cytology/HPV testing |
Supportive CareClick to collapse
Supportive care in vulvar cancer spans the entire disease trajectory and includes management of acute treatment toxicities, prevention and treatment of long-term effects, psychosocial support, and lifestyle interventions. The NCCN Guidelines provide dedicated sections on gynecologic survivorship (VULVA-F) and cross-reference the NCCN Guidelines for Survivorship, Distress Management, and Smoking Cessation.
General healthy lifestyle and nutrition counseling are recommended for all survivors [VULVA-8, footnote w]. No specific nutritional protocols are detailed for vulvar cancer. Patients undergoing chemoradiation may require dietary modifications for mucositis or gastrointestinal symptoms.
Not specified in the NCCN Vulvar Cancer Guideline. Standard institutional antiemetic protocols for chemotherapy (e.g., cisplatin-based) should be followed; refer to NCCN Guidelines for Antiemesis.
Not specified. Use of granulocyte colony-stimulating factors (G-CSF) for febrile neutropenia prophylaxis is not discussed; standard practice per NCCN Guidelines for Hematopoietic Growth Factors may be applied.
Not addressed specifically for vulvar cancer. Venous thromboembolism prophylaxis should follow standard perioperative and oncologic guidelines.
For radiation-related mucocutaneous pain, aggressive local skin care and symptomatic medications are recommended [VULVA-D 1 of 5]. For chronic pain or neuropathic symptoms, referral to pain specialists may be indicated. Best supportive care (including palliative care) is an option for advanced/metastatic disease [VULVA-7].
All patients should be assessed for distress at every stage using the NCCN Distress Thermometer and Problem List, which includes social determinants of health [VULVA-1, footnote d]. Psychosocial effects include depression, anxiety, fear of recurrence, altered body image, financial concerns, and interpersonal/sexual issues. Referral to appropriate providers (psychotherapy, sexual therapy, social work) is recommended [VULVA-F].
Not specifically addressed. For patients receiving chemotherapy or radiation that may affect oral mucosa, standard dental evaluation and preventive care are advised.
PrognosisClick to collapse
Vulvar cancer accounts for 5%–8% of gynecologic malignancies, with an estimated 7480 new diagnoses and 1770 deaths in the United States in 2025 [1-3]. The median age at diagnosis is 68 years [1-3]. Ninety percent of vulvar cancers are squamous cell carcinoma (SCC) [7]. Based on SEER data (2015–2021), 5-year overall survival (OS) for localized disease (stages I/II) is 85.7%, for regional or locally advanced disease (stages III/IVA) is 49.71%, and for stage IVB (which includes pelvic nodal disease) is 21.9% [4]. For vulvar melanoma, the 5-year OS is 47%, significantly worse than cutaneous melanoma (92%) [190]. Within SCC, HPV-associated tumors have a better prognosis than HPV-independent tumors [VULVA-A 1 of 4]. HPV-independent SCC is further subdivided by TP53 status: p53 abnormal SCCs have the worst clinical outcomes among the three molecular categories (HPV-positive, HPV-negative/p53 mutant, HPV-negative p53 wild-type) [6].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| I/II (localized) | 85.7% | SEER 2015–2021 data for vulvar cancer [4] |
| III/IVA (regional/locally advanced) | 49.71% | SEER 2015–2021 data [4] |
| IVB (distant metastasis, including pelvic nodes) | 21.9% | SEER 2015–2021 data [4] |
| Vulvar melanoma (all stages) | 47% | OS for vulvar melanoma compared to cutaneous melanoma (92%) [190] |
Prognostic Factors
- Lymph node (LN) status is the most important determinant of survival [14,33]
- Number of positive LNs and presence of extracapsular extension (ECE) independently predict poorer survival [32,35-38]
- Depth of invasion, tumor size, lymphovascular space invasion (LVSI), and surgical margin distance influence recurrence risk [19,32,39-44]
- HPV-associated SCC has better prognosis than HPV-independent SCC [VULVA-A 1 of 4]
- Within HPV-independent SCC, p53 aberrant (mutant) status portends the worst outcomes; p53 wild-type is intermediate [6]
- For vulvar melanoma, molecular alterations (BRAF, NRAS, KIT) and tumor thickness affect prognosis [191-193]
Follow UpClick to collapse
Post Curative Treatment
After completion of primary curative treatment, all patients with vulvar cancer (SCC/adenocarcinoma and melanoma) should enter a structured follow-up program aimed at early detection of recurrence, management of treatment toxicities, and promotion of health-related quality of life. For SCC/adenocarcinoma, history and physical examination are recommended every 3–6 months for the first 2 years, then every 6–12 months for years 3–5, and annually thereafter (with more frequent visits for high-risk disease) [VULVA-8]. For vulvar melanoma (stage ≥IB), groin nodal ultrasound is recommended every 3–6 months for the first 2 years and every 6–12 months for years 3–5; CT scan and/or FDG-PET/CT may be considered every 3–6 months, especially for high-risk disease [VM-3]. Cervical/vaginal cytology with HPV testing is recommended as indicated for detection of lower genital tract neoplasia, though its value in detecting recurrent vulvar cancer is limited and accuracy is reduced after pelvic radiation [VULVA-8, footnotes u,v]. Imaging (CT chest/abdomen/pelvis or FDG-PET/CT) and laboratory assessment (CBC, BUN, creatinine) are recommended when symptoms or exam findings suggest recurrence [VULVA-8]. Patient education should cover symptoms of recurrence, vulvar dystrophy, periodic self-examination, lifestyle modifications (obesity, exercise, smoking cessation), and sexual health including vaginal dilators, lubricants, local estrogen, and hormone therapy for menopause [VULVA-8, footnote w].
Surveillance Rationale
Most recurrences of vulvar cancer occur within the first 1–2 years, but a significant subset occur beyond 5 years, justifying long-term follow-up [138,139]. Definitive data on optimal surveillance are lacking, but the NCCN Panel concurs with SGO recommendations [141]. LN status at initial diagnosis is the strongest predictor of recurrence risk; patients with positive nodes require closer surveillance. The goal is to detect potentially curable local/regional recurrences while avoiding unnecessary imaging in low-risk patients.
Late Effects Screening
- Bone density testing and prophylactic bisphosphonates for patients with osteoporosis or prior pelvic RT [VULVA-F]
- Assessment for lymphedema (refer to lymphedema specialist if present) [VULVA-F]
- Screening for secondary cancers (skin, subcutaneous tissue, organs in RT field) [VULVA-F]
- Cardiovascular risk factor monitoring, recommended vaccinations, and general chronic disease management [VULVA-F]
- Psychosocial screening: depression, anxiety, fear of recurrence, body image, sexual function, financial toxicity [VULVA-F]
- For treatment-related menopause: consider hormone therapy [VULVA-F]
Recurrence Patterns
A multicenter case series of 502 patients reported that 37% developed recurrent SCC: 53.4% vulvar, 18.7% inguinal, 14.2% multi-site, 7.9% distant, 5.7% pelvic [34]. Survival at 5 years was 60% for vulvar recurrence, 27% for inguinal/pelvic, 15% for distant, and 14% for multiple sites [34]. Nodal recurrence carries a very poor prognosis regardless of treatment approach [139,144,146]. For vulvar melanoma, recurrence patterns follow those of cutaneous melanoma with locoregional (in-transit, nodal) and distant spread.
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| GROINSS-V I | GROningen INternational Study on Sentinel nodes in Vulvar cancer I | 2008 | 403 | SLNB; if negative, no further groin surgery | Prospective observational (no control arm) | Females with primary vulvar SCC <4 cm, clinically negative groins | Groin recurrence rate | Groin recurrence in 2.3% (6/259) with unifocal tumor and negative SLN; 3-year survival rate 97% | SLN positivity rate 33%; DSS worse for SLN metastases >2 mm vs ≤2 mm (69.5% vs 94.4%, P=.001) | Established SLNB as safe and effective management for early-stage vulvar cancer with unifocal tumors <4 cm and negative SLN; reduced morbidity compared to full lymphadenectomy. | Journal of Clinical Oncology |
| GROINSS-V II | GROningen INternational Study on Sentinel nodes in Vulvar cancer II | 2021 | 322 | IF radiotherapy for patients with SLN micrometastases; IF lymphadenectomy or RT for macrometastases | Observational comparison between RT and IF lymphadenectomy for macrometastases | Patients with positive SLN (160 micrometastases ≤2 mm, 162 macrometastases >2 mm) | Isolated groin recurrence rate at 2 years | Micrometastases: 2-year isolated groin recurrence 1.6% with RT. Macrometastases: 22% with RT vs 6.9% with IFL (P=.011) | Treatment-related morbidity lower with RT compared to IFL | For SLN micrometastases (≤2 mm), IF radiotherapy is a safe alternative to completion lymphadenectomy. For macrometastases, IF lymphadenectomy remains preferred, though RT is an option for patients unsuitable for surgery. | Journal of Clinical Oncology |
| GOG 173 | Gynecologic Oncology Group Study 173: Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women with Squamous Cell Carcinoma of the Vulva | 2012 | 452 | SLN mapping and biopsy followed by inguinofemoral lymphadenectomy | Reference: full lymphadenectomy | Females with vulva-confined primary tumors 2–6 cm, ≥1 mm invasion, clinically node negative | Sensitivity and false-negative rate of SLNB | SLN detection rate 92.5% (418/452); sensitivity 91.7%; NPV 96.3%; false-negative predictive value 3.7% overall, 2% for tumors <4 cm | Confirmed that SLNB can replace full lymphadenectomy in select patients with tumors <4 cm | Supported SLNB as standard for early-stage vulvar cancer with clinically negative groins and tumors <4 cm. | Journal of Clinical Oncology |
| GOG 279 / NRG-GY024 | Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma (NRG Oncology/GOG Study 279) | 2024 | 52 (evaluable) | Weekly cisplatin (40 mg/m2) + gemcitabine (50 mg/m2) concurrent with IMRT | Single-arm | Patients with locally advanced vulvar SCC not amenable to surgical resection | Pathologic complete response (pCR) rate | pCR 73% (38/52; 90% CI, 61%–83%). 12-month PFS 74% (90% CI, 62.2%–82.7%); 24-month OS 70% (90% CI, 57%–79%) | Median follow-up 51 months; toxicities manageable | Demonstrated high pCR with cisplatin/gemcitabine/IMRT in locally advanced vulvar cancer; provides an effective chemoradiation option. | Journal of Clinical Oncology |
| KEYNOTE-158 (vulvar cohort) | Phase II KEYNOTE-158 Study: Pembrolizumab in Previously Treated Advanced Vulvar Squamous Cell Carcinoma | 2022 | 101 | Pembrolizumab 200 mg IV every 3 weeks | Single-arm | Patients with advanced vulvar SCC that progressed after standard therapy | Overall response rate (ORR) | ORR 10.9% overall; 9.5% in PD-L1-positive (CPS ≥1); 28.6% in PD-L1-negative. Median PFS 2.1 months, median OS 6.2 months | Duration of response, safety | Pembrolizumab is included as a second-line option for PD-L1-positive vulvar cancer (CPS ≥1) and for TMB-H or MSI-H/dMMR tumors based on other cohorts in the same trial. | Gynecologic Oncology |
| Key Trials: GOG 101 and GOG 205 (combined summary) | GOG 101: Preoperative chemoradiation for advanced vulvar cancer; GOG 205: Phase II trial of RT and weekly cisplatin for locally advanced vulvar cancer | 1998, 2012 | GOG 101: 73 (T3/T4); GOG 205: 58 (T3/T4) | GOG 101: Preoperative cisplatin/5-FU + RT; GOG 205: Weekly cisplatin + RT | Single-arm | Locally advanced vulvar SCC | Resectability and pCR | GOG 101: 3% residual unresectable disease, 96% preserved urinary/GI continence. GOG 205: Complete clinical response 64%, pCR 78% among those biopsied | Survival data, toxicity | Established chemoradiation as standard for locally advanced vulvar cancer, allowing organ preservation and avoidance of exenteration. | International Journal of Radiation Oncology, Biology, Physics (GOG 101); Gynecologic Oncology (GOG 205) |
Clinical PearlsClick to collapse
- Pearl 1: Lymph node status remains the most powerful prognostic determinant in vulvar SCC; complete inguinofemoral lymphadenectomy or sentinel lymph node biopsy (SLNB) is mandatory for all patients with stage IB or greater disease.
- Pearl 2: SLNB is an alternative to full lymphadenectomy for carefully selected patients: clinically/radiologically negative groins, unifocal primary tumor <4 cm, no prior vulvar surgery. Dual tracer (radiocolloid plus blue dye) is recommended for optimal detection.
- Pearl 3: HPV-associated and HPV-independent vulvar SCC follow distinct molecular pathways; p53 IHC is recommended to determine TP53 status in HPV-negative tumors, as p53-aberrant tumors have the worst prognosis.
- Pearl 4: For locally advanced vulvar cancer (unresectable without removing proximal urethra/bladder/anus), definitive chemoradiation is the preferred primary treatment. Biopsy at ≥3 months post-treatment can confirm pathologic complete response; if residual disease is resectable, surgery should be considered.
- Pearl 5: Adjuvant RT (category 1 for ≥2 positive LNs or extranodal extension) with or without concurrent chemotherapy improves overall survival in node-positive patients. Chemoradiation is particularly recommended for patients with >2 mm SLN metastasis or >1 positive node.
- Pearl 6: Groin recurrences carry a grave prognosis and are difficult to salvage; therefore, initial adequate surgical staging (SLNB or lymphadenectomy) and appropriate adjuvant therapy are critical.
- Pearl 7: Gynecologic survivorship care must address lymphedema, pelvic floor dysfunction, sexual health (dilators, lubricants, local estrogen), bone health (bone density testing after pelvic RT), and psychosocial distress. Long-term follow-up is needed because recurrences can occur beyond 5 years.
Special SituationsClick to collapse
Vulvar and Vulvovaginal Melanoma
HIV-Positive Patients
Older Adults (≥65 years)
Distress and Psychosocial Needs
Smoking Cessation
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer (Version 2.2026)
NCCN Guidelines for Melanoma: Cutaneous
NCCN Guidelines for Distress Management
NCCN Guidelines for Survivorship
An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies
Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Vulva
FIGO Staging for Carcinoma of the Vulva: 2021 Revision
Protective FactorsClick to collapse
Squamous Cell Carcinoma And Adenocarcinoma
- HPV vaccination: Vaccination with currently available HPV vaccines (targeting HPV-16 and HPV-18) may reduce the burden of HPV-related vulvar cancers in the future [14,19].
- Smoking cessation: Avoidance of smoking reduces risk of vulvar neoplasia [VULVA-1, VULVA-8].