NCCN临床实践指南：外阴癌（2025.V1）

指南妇产科· 妇科疾病 · 2025

Abstract

Table of Contents Discussion Vulvar Cancer (Squamous Cell Carcinoma and Adenocarcinoma) VULVA-8 • Surveillance 5th bullet revised: Patient education regarding symptoms of potential recurrence and vulvar dystrophy, periodic self-examinations, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers), smoking cessation, nutrition counseling, and Clinical evaluation and management of potential long-term and late effects of treatment (Also see Principles of Gynecologic Survivorship (VULVA-F), NCCN Guidelines for Survivorship and NCCN Guidelines for Smoking Cessation) • Footnote u revised: Principles of Gynecologic Survivorship (VULVA-F). Patient education should include symptoms of potential recurrence and vulvar dystrophy, periodic self-examinations, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers, local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling. VULVA-9 • Site of Recurrence revised: Vulva-confined recurrence (nodes clinically negative), not previously irradiated (nodes clinically negative) EBRT ± brachytherapy ± concurrent chemotherapy changed to EBRT ± brachytherapy + concurrent chemotherapy • Footnote i added: The management of positive margins for HSIL (noninvasive disease) should be individualized. VULVA-10 • 2nd column; Bottom pathway revised: Multiple pelvic nodes or Distant metastasis or Prior pelvic EBRT • Therapy for Recurrence, No prior EBRT: EBRT ± concurrent chemotherapy changed to EBRT + concurrent chemotherapy VULVA-A 2 of 4 • Pathologic Assessment for Squamous Cell Carcinoma Additional molecular testing and biomarkers is a new bullet ◊ Sub-bullets revised -Recommend ancillary testing to determine HPV status either by p16 IHC or RNA sequencing or HPV in situ hybridization (ISH) if available, or DNA sequencing -Recommend p53 IHC to determine p53 status in HPV-negative tumors (NGS acceptable alternative) ◊ New sub-bullets added -Consider programmed death ligand 1 (PD-L1) testing for patients with recurrent, progressive, or metastatic disease -HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for advanced or recurrent/metastatic disease. -Consider comprehensive molecular profiling by an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory including at least mismatch repair (MMR)/microsatellite instability (MSI), tumor mutational burden (TMB), and NTRK testing for predicting rare pan-tumor targeted therapy opportunities. ◊ Bullets removed and recommendations incorporated into the new arrow sub-bullets noted above -Consider mismatch repair (MMR)/microsatellite instability (MSI), programmed death ligand 1 (PD-L1), and/or NTRK gene fusion testing for patients with recurrent, progressive, or metastatic disease -Consider tumor mutational burden (TMB) testing as determined by an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory UPDATES CONTINUED

b Principles of Imaging (VULVA-B). c Consider HIV testing, especially in younger patients suspected of having SCC of the vulva or other HPV-related disease. Patients with vulvar cancer and HIV should be referred to an HIV specialist and should be treated for vulvar cancer as per these guidelines. Modifications to cancer treatment should not be made solely on the basis of HIV status. d Histologic high-grade squamous intraepithelial lesion (HSIL; formerly defined as carcinoma in situ [CIS] and incorporates vulvar intraepithelial neoplasia 2 and 3

[VIN2/3]) can be treated with wide local excision. (Squamous Cell Carcinoma and Adenocarcinoma) NCCN e Principles of Surgery (VULVA-C).

i The management of positive margins for HSIL (noninvasive disease) should be individualized. j Principles of Radiation Therapy (VULVA-D).

k Other primary risk factors include: close tumor margins, lymphovascular invasion (LVSI), tumor size, depth of invasion, and pattern of invasion (spray or diffuse). Nodal involvement (as an indicator of LVSI) may also impact selection of adjuvant therapy to the primary site. (Squamous Cell Carcinoma and Adenocarcinoma)

# PRIMARY TUMOR RISK FACTORS ADJUVANT THERAPY TO THE PRIMARY SITE

PRIMARY TUMOR RISK FACTORS ADJUVANT THERAPY TO THE PRIMARY SITE

# NCCN Guidelines Index Table of Contents Discussion

NCCN Guidelines Index Table of Contents Discussion

VULVA-4 j Principles of Radiation Therapy (VULVA-D).

l If ipsilateral groin is positive, the contralateral groin should be evaluated. In select cases of a single, small-volume, unilateral, positive inguinal node with a well-lateralized small primary tumor and depth of invasion ≤5 mm and with a clinically negative contralateral groin examination, a contralateral inguinofemoral lymphadenectomy or radiation may be omitted (Gonzalez Bosquet J, et (Squamous Cell Carcinoma and Adenocarcinoma)

VULVA-8

b Principles of Imaging (VULVA-B).

s Regular cytology can be considered for detection of lower genital tract dysplasia, although its value in detection of recurrent genital tract cancer is limited. t The accuracy of cytology results may be affected in patients who have received pelvic radiation. u Patient education should include symptoms of potential recurrence and vulvar dystrophy, periodic self-examinations, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers, local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling. (Squamous Cell Carcinoma and Adenocarcinoma)

VULVA-9

e Principles of Surgery (VULVA-C).

o Systemic Therapy (VULVA-E). q Consider pelvic exenteration for select cases. (Squamous Cell Carcinoma and Adenocarcinoma)

Procedure: Vulvectomy

General Principles

• Histologic grading of SCC is not well-defined and can be subjective. Two pathways of vulvar intraepithelial neoplasia (VIN) and SCC have been identified in the vulva: HPV-associated and HPV-independent. • A meta-analysis showed that HPV-associated SCC had a better prognosis than HPV-independent SCC. (Squamous Cell Carcinoma and Adenocarcinoma)

HPV-Associated

a In situations where SLN metastases are < 2 mm, the size of greatest metastasis should be reported (VULVA-4). b Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple hematoxylin and eosin (H & E)-stained sections with or without cytokeratin IHC for all blocks of SLNs. There is no standard protocol for LN ultrastaging. c Report on the number of LNs with metastases of the following sizes: < 2 mm; 2-5 mm; and > 5 mm. The 2-mm threshold is used to inform treatment selection and 5-mm threshold is used to inform staging. (Squamous Cell Carcinoma and Adenocarcinoma)

VULVA-

Diagram showing the new International Federation of Gynecology and Obstetrics (FIGO) (A) and previous (B) methods of measuring depth of invasion for vulvar SCC. In the new FIGO method (A), the depth of invasion is measured from the basement membrane of the deepest adjacent dysplastic/noninvasive rete ridge to the deepest point of invasion. The previous method (B) used the distance from the adjacent most superficial dermal papilla to the deepest point of invasion. (Squamous Cell Carcinoma and Adenocarcinoma)

PRINCIPLES OF PATHOLOGY

VULVA-B

PRINCIPLES OF IMAGING

Continued

PRINCIPLES OF SURGERY: TUMOR MARGIN STATUS

References

• Studies suggest a high overall incidence of local recurrence (or new primary lesions) in vulvar carcinoma. 1 Tumor margin of resection has been postulated as a significant prognostic factor for recurrence in SCC of the vulva; however, presence of dVIN and lichen sclerosus may also play a significant role in recurrence or development of new primary carcinomas. 2,3,4,5 • Efforts should be made to obtain adequate gross surgical margins (at least 1 cm) at primary surgery. Recent studies have questioned the traditional (8-mm) pathologic free margin and suggested that a smaller margin may be acceptable, particularly to preserve sensitive areas on the vulva and maintain sexual function. 6,7,8 • The definition of a pathologic close margin has also varied from 1-8 mm for formalin-fixed tissue. 9,10 In the setting of a close margin for invasive cancer at primary resection, observation with regular close follow-up is reasonable. Re-excision should be considered in cases with positive margin for cancer. 9, 11 Adjuvant local radiation therapy (RT) is another alternative. 12 The risk-benefit ratio and morbidity of these approaches must be considered and individualized in each patient. The survival advantage of re-excision and adjuvant vulvar radiation remains to be determined.

• Vulvar cancer is staged using the FIGO staging system (Table ST-1 ). 13 Staging involves complete surgical resection of the primary vulvar tumor(s) with at least 1-cm clinical gross margins and either a unilateral or bilateral inguinofemoral lymphadenectomy or an SLNB in select patients. Inguinofemoral lymphadenectomy removes the LNs along the inguinal ligament, within the proximal femoral triangle, and deep to the cribriform fascia. • LN status is the most important determinant of survival. 14 Historically, en bloc resection of the vulvar tumor and complete bilateral inguinofemoral lymphadenectomy (resection of superficial inguinal and deep femoral nodes) were performed, but this approach was associated with significant morbidity. 15 • The current standard involves resection of the vulvar tumor and LNs through separate incisions. 15 The choice of vulvar tumor resection technique depends on the size and extent of the primary lesion and may include partial or total vulvectomy, and the depth of resection may be superficial/skinning, simple, or radical. 16 The depth of the resection for radical vulvectomy is to the urogenital diaphragm, or median perineal fascia or periosteum of pubic bone. 17 There are no prospective trials comparing the resection techniques above. Retrospective data suggest there is no difference in recurrence outcome between radical partial vulvectomy compared with radical total vulvectomy. • For a unifocal primary vulvar tumor that is < 4 cm in diameter, located ≥2 cm from the vulvar midline and in the setting of clinically negative inguinofemoral LNs, a unilateral inguinofemoral lymphadenectomy or SLNB is appropriate (Principles of Surgery: Inguinofemoral Sentinel Lymph Node Biopsy [VULVA-C 4 of 6]). 18 For a primary vulvar tumor located within 2 cm from or crossing the vulvar midline, a bilateral inguinofemoral lymphadenectomy 18 or SLNB is recommended. • Inguinofemoral lymphadenectomy or SLNB can be omitted in patients with stage IA primary disease with clinically negative groins due to a < 1% risk of lymphatic metastases. 18 Squamous Cell Carcinoma and Adenocarcinoma)

PRINCIPLES OF SURGERY

VULVA-C 3 OF 6

• For patients with stage IB-II disease, inguinofemoral lymphadenectomy is recommended due to a risk of > 8% of lymphatic metastases. 18 A negative unilateral inguinofemoral lymphadenectomy is associated with a < 3% risk of contralateral metastases. 19 Any nodes that are grossly enlarged or suspicious for metastases during the unilateral inguinofemoral lymphadenectomy should be evaluated by frozen section pathology intraoperatively in order to tailor the extent and bilaterality of the lymphadenectomy. • Those with locally advanced disease may benefit from neoadjuvant radiation with concurrent platinum-based radiosensitizing chemotherapy.

Increased sensitivity of SLN detection is observed when both radiocolloid and blue dye are used. 23, 24, 25 The radiocolloid most commonly injected into the vulvar tumors is technetium-99m sulfur colloid. It is most commonly injected 2-4 hours prior to the vulvectomy and lymphadenectomy procedure. A preoperative lymphoscintigraphy may be performed to aid in anatomically locating the sentinel node. The blue dye most commonly used is Isosulfan Blue 1%. Approximately 4 cc of dye is injected peritumorally using a four-point injection technique at 2, 5, 7, and 10 o'clock. The blue dye is injected in 4 quadrants intradermally around the leading edges of the tumor. • It is recommended that the SLN procedure is performed prior to the excision of the vulvar tumor, so as not to disrupt the lymphatic network between the primary vulvar tumor and the inguinofemoral LN basin. Additionally, the injected blue dye will only transiently localize (ie, for 30-60 minutes) in the first group of nodes that correspond to the primary vulvar tumors. Indocyanine green (ICG) with technetium has also been used for SLN mapping in vulvar cancer with encouraging results. • Use of a gamma probe to detect the injected radiocolloid within the inguinofemoral region is recommended prior to making the groin incision in order to tailor the location and size of the incision. • A side-specific complete inguinofemoral lymphadenectomy is recommended if an ipsilateral SLN is not detected.

• Completion inguinofemoral lymphadenectomy is the preferred approach in the presence of metastases > 2 mm in diameter in the SLNs. 28 For lateralized and near-midline tumors with unilateral SLN metastasis, unilateral groin treatment by either inguinofemoral lymphadenectomy or RT is acceptable. • For midline tumors with unilateral SLN metastasis, unilateral groin treatment can be performed if the contralateral groin has negative sentinel node or negative inguinofemoral lymphadenectomy. (Squamous Cell Carcinoma and Adenocarcinoma) (Squamous Cell Carcinoma and Adenocarcinoma)

Continued References

PRINCIPLES OF RADIATION THERAPY

PRINCIPLES OF RADIATION THERAPY Treatment Information • Target Volumes

The (Squamous Cell Carcinoma and Adenocarcinoma) (Squamous Cell Carcinoma and Adenocarcinoma)

• Adjuvant Therapy (Postoperative RT)

May be considered for close or positive margins where re-resection may be too morbid. Interval from surgery to RT is ideally < 6 weeks unless adjuvant systemic therapy is given first, or for delayed wound healing. Elective nodal radiation may be considered for any LN > 3 cm, ENE, or ≥3 positive nodes.

• Dosing Regimens

More hypofractionated regimens may be chosen for smaller volume radiation. If primary and nodal volumes are targeted, then the more protracted courses will give less long-term toxicity, particularly for vulvar disease.

EBRT alone

Recommend doses on lower range (45-55 Gy) for elective nodal basins, middle range (50-55 Gy) for close margins, and higher range (55-65 Gy) for positive margins/ECE.

• Simultaneous integrated boost (SIB) to nodes may be used to achieve an EQD2 of 66-70 Gy to gross disease.

• Stereotactic body radiotherapy (SBRT) is often used in the treatment of melanoma given its relative radioresistance, however, is typically not a favored approach for a primary vulva site due to concern for toxicity.

• In non-melanoma vaginal cancers, brachytherapy with either interstitial or intracavitary techniques is the preferred approach to escalate dose to the gross vaginal disease and can similarly be used in vaginal melanoma when surgical resection is deemed too morbid, though data are limited.

For definitive therapy dosing regimens, see VM-A (3 of 7).

◊ For OAR Constraints for Cumulative EBRT + Brachytherapy dosing, see VM-A (4 of 7).

May be considered for close or positive margins where re-resection may be too morbid.

Interval from surgery to RT is ideally < 6 weeks unless adjuvant systemic therapy is given first, or for delayed wound healing.

Elective nodal radiation may be considered for any LN > 3 cm, ENE, or ≥3 positive nodes. 8 or adjuvant therapy dosing regimens, see VM-A (5 of 7).

Note: All recommendations are category 2A unless otherwise indicated.

• 54-63 Gy (1.8 Gy/fraction), 9 a Prescribing to the surface or 5-mm depth is a general institutional preference. When comparing regimens, for cylinders ~2.5-3 cm, the surface dose is ~30% higher than the 5-mm dose.

ST-1

Staging-Vulvar Cancer

NCCN Guidelines Version 1.2025 Vulvar Cancer

CAT-1

NCCN Categories of Evidence and Consensus Category 1

Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate. Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate. Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but < 85% support of the Panel) that the intervention is appropriate.

Category 3

Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.

Other recommended intervention

Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.

Useful in certain circumstances

Other interventions that may be used for selected patient populations (defined with recommendation).

All recommendations are considered appropriate.

Overview

In 2023, an estimated 6470 individuals will be diagnosed with vulvar cancer, and 1670 deaths are expected from the disease. 1 Vulvar cancer accounts for 5% to 8% of gynecologic malignancies and median age of diagnosis is 68 years. Based on data from the SEER database, 5-year survival rates range from 85.6% for localized disease (stages I/II), to 47.5% for regional or locally advanced disease (stages III/IVA), and finally to 23.3% for patients with stage IVB (which includes patients with pelvic nodal disease). 2 Studies of the SEER database and the National Cancer Database (NCDB) have shown that treatment approaches/modalities vary considerably with sociodemographic factors such as race/ethnicity, age, and non-private insurance, particularly for individuals with advanced disease. 3, 4 nety percent of vulvar cancers are of squamous cell carcinoma (SCC) histology. 5 Risk factors for the development of vulvar neoplasia include increasing age, infection with human papillomavirus (HPV), cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. 6 arer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. 7 e International Society for the Study of Vulvovaginal Disease (ISVVD) has revised the terminology used to characterize vulvar lesions over the years. In 2004, vulvar intraepithelial neoplasia (VIN) terminology was refined to include two types of lesions, usual-type VIN and differentiated VIN (dVIN). 8 Usual-type VIN was linked to persistent infection with carcinogenic strains of HPV, while dVIN was commonly associated with vulvar dermatologic conditions such as lichen sclerosus. In 2015, the ISVVD updated the description to three classes of vulvar lesions: 1) lowgrade squamous intraepithelial lesion (LSIL) due to flat condyloma or HPV effect; 2) high-grade squamous intraepithelial lesions (HSIL, formerly considered usual-type VIN); and 3) dVIN. 9 The 2020 WHO Classification of Female Genital Tumors, VIN is now classified as HPV-associated or HPV-independent. HPV-associated VIN corresponds to low-and highgrade squamous intraepithelial lesion (SIL) similar to other anatomic sites in the anogenital tract. 10 HPV-independent VIN is associated with a faster rate of progression to invasive SCC. It is the less common form of VIN and is often associated with lichen sclerosus.

The histologic grade of SCC is not well-defined and can be subjective. HPV-associated SCC has a better prognosis than HPV-independent SCC. HPV-associated SCC frequently occurs in younger patients, is multifocal, is associated with classic VIN, and can be seen in conjunction with additional sites of lower genital tract squamous neoplasia. Immunohistochemistry (IHC) shows strong, diffuse, block-like positive nuclear and cytoplasmic staining with p16 and wild-type p53 (heterogeneous staining pattern). HPV-independent SCC is split into two main groups: those associated with TP53 mutations and those with wildtype TP53 status. 11 The p53 abnormal, HPV-independent SCC usually occurs in older patients, is unifocal, and is associated with dVIN by histological evaluation. IHC usually shows aberrant p53 staining and negative or weak p16 staining. The p53 abnormal SCCs have the worst clinical outcomes of the three molecular categories (HPV positive, HPVnegative/p53 mutant, and HPV-negative p53 wild type). Assessing the presence and depth of invasion in vulvar SCC can be challenging.

Estimates of the percentage of vulvar cancers attributable to HPV infection range from conservative estimates of 30% to up to 69%, with a metaanalysis reporting an HPV prevalence of 39.7%. 12-15 A recent metaanalysis showed the prevalence of HPV in vulvar cancer and VIN to be 39.1% and 76.1%, respectively. Of the HPV-positive disease, 78.1% were HPV-16, followed by HPV-33 in vulvar cancer. A similar trend was NCCN Guidelines Version 1.2025 Vulvar Cancer

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observed in VIN. The prevalence of p16-positive vulvar cancer was 34.1% while it was 65.7% in VIN. 16 However, HPV infection is detected in 80% to 90% of patients with SIL. Historically, VIN has been diagnosed in younger patients (median age 45-50 years) while vulvar cancers have been diagnosed in older patients (median age 65-70 years). 17, 18 Because a large majority of HPV-related vulvar cancers are associated with HPV-16 and HPV-18 strains, vaccination with currently available HPV vaccines may reduce the burden of HPV-related vulvar cancers in the future. 12, 17 definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. "Many exceptions to the rule" were discussed among the members of the panel during the process of developing these guidelines. Recommendations in the NCCN Guidelines are category 2A unless otherwise noted.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, antimisogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

MS-4

Diagnosis and Workup

1] [22] [23] The updated FIGO system has included a revised definition for depth of invasion, lymph node (LN) metastases definition, and allows the incorporation of findings from crosssectional imaging.

The presentation of vulvar cancer can be widely varied. The majority of vulvar cancers are located in the labia majora. Other possible sites include the labia minora, clitoris, mons pubis, or perineum. In patients with HPVnegative tumors, vulvar cancer often presents as a single mass or ulcer on the labia majora or minora. In HPV-positive tumors, multifocal lesions and concurrent cervical neoplasia are more common. 17, 18, 24 Although many cases may be asymptomatic, pruritus and pain/irritation are common symptoms; vulvar bleeding or discharge may also occur. A majority of patients present with early-stage localized disease. 2 Diagnosis is made through biopsy of all suspicious areas followed by pathologic review. The College of American Pathologists (CAP) protocol for vulvar carcinoma is a useful guide (https://documents.cap.org/protocols/Vulva_4.2.0.2.REL_CAPCP.pdf). This CAP protocol was revised in 2021.

Workup includes history and physical examination, complete blood count (CBC), and liver and renal function tests. In addition to vulva examination, evaluation of the vagina and cervix (including cytologic smears) should be emphasized due to the multifocal nature of squamous cell intraepithelial neoplasia. 6] [27] [28] Examination-under-anesthesia (EUA) cystoscopy or proctoscopy should be considered as indicated. Appropriate patients should receive smoking cessation counseling, cervical HPV testing, and cytology testing. Consider HIV testing, especially in younger patients. Those with vulvar cancer and HIV should be referred to an HIV specialist; modifications to the recommended cancer treatments in these Guidelines should not be modified solely on the basis of HIV status. For patients with vulvar cancer who are ≥65 years, also see the NCCN Guidelines for Older Adult Oncology at www.NCCN.org.

Prognostic Factors

Historically, en bloc vulvectomy with wide margins was combined with complete inguinofemoral (IF) lymphadenectomy to treat vulvar SCC. While effective in promoting survival, this approach was associated with serious short-and long-term morbidity (eg, wound complications, lymphedema, decreased sexual function, adverse impacts on body image). The emergence of data on important prognostic factors in vulvar cancer informed the evolution of surgical staging and primary treatment. 24 Based on a retrospective review of 586 patients enrolled in Gynecologic Oncology Group (GOG) trials through 1984, independent predictors of survival included the presence and number of involved LNs and primary tumor size. 29 7] [38] [39] [40] [41] However, these findings are primarily derived from retrospective analyses. A systematic review of the collective data on prognostic factors for local recurrence in vulvar cancer concluded that the weight of each individual prognostic variable remained equivocal when compared to one another. 42 ognostic data have guided the shift towards more conservative primary tumor resection and regional LN management for early-stage disease. 43 he preferred surgical approach evolved towards vulvar-sparing NCCN Guidelines Version 1.2025 Vulvar Cancer

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techniques with separate incisions for lymphadenectomy in patients who were clinically node negative. 24, 44 Current surgical approaches involve tailored primary tumor resection and LN evaluation based on individual patient characteristics. 45, 46 Data suggest that survival is not negatively impacted by less radical surgical approaches for early-stage cancers. 46

Surgical Staging

Previously, the AJCC and the 2009 FIGO systems staged vulvar cancer according to extent of primary tumor (T), LN status (N), and distant metastasis (M). Clinical staging alone provides inadequate evaluation of LN involvement. Because LN metastasis is a key prognostic factor in vulvar cancer survival, 30, 46 these systems used a hybrid surgical and clinical/pathologic approach for more accurate evaluation of nodal status.

Complete staging using the existing system requires primary tumor resection and full IF lymphadenectomy. However, common practice has increasingly included the use of sentinel LN (SLN) biopsy in lieu of complete lymphadenectomy, as well as diagnostic imaging to determine extent of disease. 47, 48 In the new 2021 staging system, the revisions have been made to allow imaging to be used to assign stage. For stage 1 disease, the new method for measurement of depth of invasion has been added, which is now 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. Stage IIIA now also includes the upper two-thirds of the urethra, upper two-thirds of the vagina, and bladder mucosa or rectal mucosa, which were previously part of stage IVA. Stage IIIA includes any number of LNs less than or equal to 5 mm and no longer includes LN metastasis in a single node greater than 5 mm; this is now considered stage IIIB. Stage IVA includes disease fixed to pelvic bone or fixed or ulcerated regional LN metastases, and stage IVB includes any distant metastases. 19

Pathologic Evaluation

Surgicopathologic factors may be used to guide the extent of surgical staging and treatment decisions. Findings from pathologic assessment of the surgical specimen should be carefully documented, including procedure type (ie, partial or total vulvectomy) and depth of procedure (ie, superficial or skinning, simple, or radical). Important elements of primary tumor evaluation include tumor site; size (in multiple dimensions); number of tumor foci; histologic type and grade; depth of stromal invasion; surgical margin status; and the presence of LVSI. When resected, the number of LNs with isolated tumor cells, micrometastases, and macrometastases should be recorded. If SLN mapping is performed, SLNs should undergo ultrastaging for detection of low-volume metastasis. Other important factors include tumor involvement of tissues/organs such as the vagina, urethra, anus, bladder mucosa, rectal mucosa, and pelvic bone. Mismatch repair (MMR), microsatellite instability (MSI), programmed death ligand 1 (PD-L1), neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and tumor mutational burden (TMB) testing may also be considered for treatment planning purposes in patients with recurrent, progressive, or metastatic disease. Additional testing to determine HPV status is recommended. Various methods can be used to detect HPV including detection of overexpressed p16 via IHC, and HPV-specific polymerase chain reaction (PCR) and in situ hybridization (ISH) techniques (for viral mRNA and DNA detection). The NCCN Guidelines recommend p53 IHC to determine p53 status. Evaluation of p53 IHC in vulvar SCC may be challenging and has unique features compared to p53 staining patterns encountered in ovarian and endometrial cancers. 49

Primary Tumor Resection

Depending on the size and extent of the primary tumor, simple partial/total vulvectomy or radical partial/total vulvectomy may be required. No prospective data are available to compare outcomes between these resection techniques; however, retrospective data suggest no difference in NCCN Guidelines Version 1.2025 Vulvar Cancer

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1] [52] Both surgical approaches involve resection of approximately a 1-to 2-cm radial margin of grossly normal tissue and to the deep fascia or a minimum of a 1-cm deep margin.

Vulvar cancer is associated with significant risk of local recurrence, and data demonstrate tumor margin status to be a significant prognostic factor. 36, 39, 53 A review identified 4-year recurrence-free rates of 82%, 63%, and 37% for patients with negative, close, and positive margins, respectively (P = .005). The highest risk of recurrence was associated with margins less than or equal to 5 mm. 54 The goal of primary tumor resection is complete removal with negative pathologic margins. The definition of a negative margin continues to evolve, and more data confirm the importance of a negative margin but put less emphasis on the actual distance (in mm) of the margin. In the setting of close or positive tumor margins, re-resection to obtain negative margins or adjuvant local radiation therapy (RT) are options. 36, 55 In a study, tumor-free margins of at least 2 mm were associated with lower local recurrence risk. 40 e risk-benefit ratio and morbidity of each approach must be weighed and individualized for each patient. Evidence supports improved recurrence rates and survival with re-resection or adjuvant external beam RT (EBRT) to the primary site. 56 However, for close or positive margins involving the urethra, anus, or vagina, re-resection may incur significant morbidity and negatively impact patient quality of life. Re-resection may also be inappropriate for patients with close or positive margins who have inguinal node involvement requiring adjuvant treatment with EBRT ± concurrent chemotherapy.

Lymph Node Evaluation

Because LN status is the most important determinant of survival in vulvar cancer, careful evaluation and determination of nodal status is paramount. LN resection is performed through a separate incision from the primary tumor and may entail ipsilateral or bilateral IF lymphadenectomy, or SLN biopsy in select cases. IF lymphadenectomy involves removal of superficial inguinal and deep femoral LN. Further emphasizing the importance of adequate IF lymph node (IFLN) evaluation and treatment at initial presentation, it has been widely reported that subsequent groin relapses are rarely amenable to successful secondary treatment.

Lymphadenectomy in patients with clinically negative groin nodes is informed by the size and location of the primary tumor. Because the risk of LN metastasis is less than 1% in patients with stage IA primary disease, 45 lymphadenectomy or SLN evaluation can be omitted in patients with stage IA primary disease with clinically negative groins. However, IF lymphadenectomy is recommended for patients with stage IB/II disease because the risk of nodal metastasis is estimated at greater than 8% for stage IB and even higher for stage II tumors. 45 For primary vulvar tumors less than 4 cm in diameter, located at least 2 cm from the vulvar midline, with clinically negative IFLNs, ipsilateral IF lymphadenectomy or SLN biopsy are appropriate. 57, 58 However, bilateral LN evaluation (IF lymphadenectomy or SLN biopsy, if indicated) is recommended for patients with primary tumors that are within 2 cm of, or crossing, the vulvar midline. 58 Lymphadenectomy for stage III/IV disease is individualized, and integrated with combined modality approaches.

SLN Biopsy

Reported rates of postoperative morbidity with unilateral or bilateral IF lymphadenectomy are high. 0] [61] Studies have begun to investigate whether complete IF lymphadenectomy could be safely avoided in patients who are determined to have a negative SLN. Several prospective multicenter trials have evaluated the feasibility, safety, validity, and risk of groin recurrences with SLN biopsy in early vulvar cancer. The safety and accuracy of SLN assessment was examined in a multicenter observational study (GROINSS-V I) of 403 females with primary vulvar tumors less than 4 cm. IF lymphadenectomy was omitted if SLN(s) were negative on ultrastaging. With a median follow-up period of 35 months (24-month minimum), groin recurrences were detected among 6 of 259 patients (2.3%) with a unifocal primary tumor and negative SLN. The 3-year survival rate was 97%, leading to the conclusion that a negative SLN in this patient population provided sufficient management of the groin(s). Short-and long-term morbidity was reduced if the SLN only was removed compared with SLN removal followed by full groin lymphadenectomy. 62 GOG 173, 452 females (with vulva-confined primary tumors 2-6 cm, at least 1-mm invasion, and clinically node negative) underwent SLN mapping and biopsy followed by IF lymphadenectomy. SLNs were identified in 418 females, and 132 females were node positive (including 11 false-negative nodes). SLN biopsy had a sensitivity of 91.7%, negative predictive value of 96.3%, and false-negative predictive value of 3.7% overall (2% for primary tumors < 4 cm). 63 subgroup analysis of the AGO-CaaRE-1 study compared outcomes of patients with tumors less than 4 cm who underwent radical groin lymphadenectomy or sentinel node lymphadenectomy with negative findings for LN/SLN metastasis (n = 556). The radical groin lymphadenectomy cohort had larger tumor diameter (20 mm vs. 13 mm; P < .001) and greater depth of invasion (4.0 mm vs. 3.0 mm; P = .002), but isolated groin recurrence rates did not differ between the groups. Multivariate analysis controlling for tumor characteristics such as diameter, depth of invasion, grade, and LVSI revealed no statistical differences in progression-free survival (PFS) and overall survival (OS) between the radical and sentinel node lymphadenectomy cohorts. 64 A systematic review and meta-analysis of the cumulative data on SLN biopsy revealed a per-groin detection rate of 87% when using dual tracers, and a false-negative rate of 6.4%. When comparing IF lymphadenectomy, superficial IF lymphadenectomy, and SLN biopsy, recurrences rates were 1.4%, 6.6%, and 3.4% in patients deemed node-negative by the surgical groin approach used, respectively. 65 The GROINSS-V I observational study also evaluated patients with positive SLNs. Within the 135 of 403 patients who had positive SLNs (33%), investigators examined the relationship between size of SLN metastasis and risk of non-sentinel node disease among 115 patients who underwent IF lymphadenectomy following detection of positive sentinel nodes. Risk of non-SLN involvement increased steadily with the size of SLN metastasis, beginning at 4.2% with detection of isolated tumor cells and increasing to 62.5% with SLN metastases greater than 10 mm, suggesting no disease threshold below which further treatment of an SLNpositive groin could be safely omitted. Disease-specific survival (DSS) was worse among those with SLN metastases greater than 2 mm versus less than or equal to 2 mm (69.5% vs. 94.4%, P = .001). 66 Patients undergoing SLN biopsy reported less treatment-related morbidity compared with those undergoing IF lymphadenectomy. 67 Long-term follow-up of the GROINSS-V I cohort compared outcomes of SLN-positive patients who underwent completion IF lymphadenectomy with those of SLN-negative patients (no IF lymphadenectomy). At a median follow-up of 105 months, the data revealed a 5-and 10-year local vulvar recurrence rate of 24.6% and 36.4% for SLN-negative patients, and 33.2% and 46.4% for SLN-positive patients (P = .03). The isolated groin recurrence rate was 2.5% for SLN-negative patients and 8.0% for SLNpositive patients at 5 years, despite more radical treatment in the latter group. DSS at 10 years was 91% in the SLN-negative group and 65% in NCCN Guidelines Version 1.2025 Vulvar Cancer

MS-9

results in less morbidity than surgical dissection. 76 However, surgical treatment of the groin (followed by tailored adjuvant RT if LN-positive) has been associated with lower groin recurrence rates and remains the preferred approach. 77 Primary radiation may have some benefit for those unable to undergo surgery. 78, 79 nel Recommendations

] [82] [83] Patients should be observed following resection. If surgical pathology reveals greater than 1-mm invasion, additional surgery may be indicated.

In treatment for patients with stage IB ( > 1-mm invasion) or select stage II tumors, primary treatment is dictated by tumor location. Patients with lateralized lesions located greater than or equal to 2 cm from the vulvar midline should undergo radical partial vulvectomy accompanied by ipsilateral IFLN evaluation.

Locally Advanced Disease

Historically, locally advanced vulvar cancers were treated primarily with radical surgeries such as en bloc radical vulvectomy with bilateral IF lymphadenectomy or pelvic exenteration. 6] [87] Additionally, complete resection of locally advanced disease may be complicated by tumor fixed to vital organs or vessels, rendering the disease unresectable. 88 A shift to multimodality treatment was explored to improve organ preservation and reduce surgical treatment morbidity. 89 1] [92] [93] Subsequently, borrowing on experience from advanced cervical and anal cancers, chemotherapy typically has been added as a "radiosensitizer" when radiation is delivered in patients with advanced disease.

Chemoradiation

Research directly comparing treatment approaches for locally advanced vulvar cancers is limited. Data from small patient cohorts have shown a generally high response rate to chemoradiation among most patients with stage III/IVA disease, as well as the feasibility of resection for residual disease following chemoradiation. [101] [102] [103] Primary chemoradiation may confer a survival benefit over primary RT in vulvar cancer. OS after primary chemoradiation was superior to OS following primary RT in a series of 54 patients with locally advanced disease. 104 A similar survival benefit was reported in a study using NCDB data from patients who were not candidates for surgery, comparing cohorts who received primary chemoradiation (n = 999) or primary RT (n = NCCN Guidelines Version 1.2025 Vulvar Cancer MS-10 353). The chemoradiation cohort was younger with more advanced disease based on FIGO staging. Chemoradiation was associated with significantly higher 5-year OS than primary RT (49.9% vs. 27.4%, P < 0.001) and multivariate analysis revealed a reduced hazard of death (hazard ratio [HR], 0.76; 95% CI, 0.63-0.91; P = .003). 105 the GOG 101 study, preoperative chemoradiation was examined in 73 patients with stage III/IV disease. 96 The study investigated whether chemoradiation allowed for less radical surgery in patients with T3 tumors and avoidance of pelvic exenteration in patients with T4 tumors. Only 3% of patients (2/71) had residual unresectable disease following chemoradiation, and preservation of urinary and/or gastrointestinal (GI) continence was possible in 96% of patients (68/71).

Two prospective studies from the GOG more closely examined the benefits of surgery after chemoradiation for patients with locally advanced disease. GOG 101 examined 46 patients with vulvar SCC and N2/N3 nodal involvement. 106 Subsequent surgery was performed on 38 patients with resectable disease after chemoradiation with cisplatin/5-fluorouracil (5-FU). Local control of nodal disease was achieved in 36 of 37 patients and for the primary tumor in 29 of 38 patients. The GOG 205 study examined the feasibility of surgery after chemoradiation with cisplatin in 58 patients with T3/T4 tumors that were initially unresectable by radical vulvectomy. 107 Complete clinical response was noted in 64% of patients (37 of 58), with pathologic complete response (pCR) in 78% (29 of 34) of patients undergoing surgical biopsy. Of the total population, approximately 50% achieved pCR after chemoradiation therapy. The high pCR rates have led many to believe that surgery can be avoided in patients with locally advanced tumors who achieve clinical complete responses.

A phase II, multicenter, prospective trial evaluated treatment feasibility, percentage of locoregional control, survival, and toxicity after locoregional radiotherapy combined with sensitizing chemotherapy with capecitabine in 52 patients with T2/T3 tumors. 108 Of the total patients, 58% had no evidence of disease at a median of 35 months. PFS was 58%, 51%, and 45%, and OS was 76%, 66%, and 52% at 1, 2, and 5 years, respectively. Most acute toxicity greater than or equal to grade 3 reported were related to skin/mucosa (54%) and pain (37%). Late toxicity greater than or equal to grade 3 was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%).

An analysis of NCDB data (2004-2012) compared outcomes of 2046 females with locally advanced vulvar cancer who received primary radiation (RT or chemoradiation), or preoperative radiation (RT or chemoradiation) followed by surgery. Patients who underwent surgery after RT/chemoradiation had longer OS than patients who underwent primary RT/chemoradiation without subsequent resection (57.1% vs. 41.7% at 3 years, respectively; P < .001). However, multivariate analysis revealed a radiation dose-dependent effect, and survival was not significantly worse if the dose exceeded 55 Gy. With sufficient RT dose and concurrent chemotherapy, the primary RT cohort had comparable survival to the group who underwent lower-dose preoperative RT/chemoradiation followed by surgery. 109 2011 Cochrane database review of the existing randomized controlled trial data on 141 females with locally advanced vulvar SCC revealed no difference in OS when comparing primary surgery to primary or neoadjuvant chemoradiation. 110 However, the data did not allow for broad conclusions to be drawn regarding treatment-related quality of life and adverse events. An earlier Cochrane database review of five nonrandomized trials suggested that patients with unresectable primary disease and those requiring exenteration may benefit from neoadjuvant chemoradiation if disease was rendered resectable or requiring less radical surgery. 111

MS-11

The combination regimen used for radiosensitization was most commonly cisplatin/fluorouracil, 96, 97, 99, 101, 102 but also included fluorouracil/mitomycin C 295,98,103 or single-agent therapy. 100, 107 The selection of radiosensitizing chemotherapy is often based on extrapolation of findings from cervical, anal, or head and neck cancer. In addition, if cisplatin or carboplatin are unavailable, the panel has included capecitabine/mitomycin, gemcitabine, and paclitaxel as options that may be considered under the "other recommended regimens" category. [115] [116] Metastasis Beyond the Pelvis

The NCCN Panel recommends primary treatment options for extra-pelvic metastatic disease including EBRT for control of locoregional disease and symptom palliation, and/or systemic therapy. Best supportive care is also an alternative in this setting. 8] [119] Treatment regimens are often extrapolated from agents that are active against advanced cervical cancer. See the section on Systemic Therapy for Recurrent/Metastatic Disease in this discussion for information about specific regimens.

Adjuvant Therapy

Due to the rarity of vulvar cancer, especially advanced disease, prospective randomized trials on adjuvant therapy are extremely limited. Much of the common adjuvant treatment approaches have been drawn from studies describing heterogenous, often-individualized treatment approaches, or extrapolated from effective adjuvant therapies for cervical and anal cancers.

Adjuvant RT and Chemoradiation

Although it is commonly accepted that LN involvement is a critical prognostic factor in vulvar cancer, the optimal patient selection criteria and adjuvant therapy regimens to address nodal disease continue to be determined. 120 As previously emphasized, it is crucial to prevent metachronous groin relapses, as these often prove refractory to secondary management and are often ultimately fatal.

MS-12

Early randomized trial data on adjuvant RT were published from GOG 37, which enrolled 114 patients with IF node-positive vulvar cancer after radical vulvectomy and bilateral IF lymphadenectomy. 121, 122 Patients were randomized to receive pelvic lymphadenectomy or adjuvant RT to the groin/pelvis. Two-and 6-year survival were superior in the adjuvant RT group, but the most significant survival benefits were observed among patients with greater than or equal to 2 positive IF nodes or those with fixed ulcerative IF nodes. Long-term follow-up (median = 74 months) revealed higher rates of disease-related death for the group receiving pelvic node resection compared with pelvic/groin RT (51% vs. 29%; HR, 0.49; P = .015). 122 study using SEER-Medicare-linked data examined outcomes for 444 older patients (aged ≥66 years; median age 78) with node-positive vulvar cancer who underwent adjuvant RT. Compared to surgery alone, better disease outcomes were associated with adjuvant RT when the following metrics were met: completion of at least 20 fractions, treatment duration of less than 8 weeks, and less than 1 week of intra-treatment break. However, only half of the cohort that received RT met these treatment benchmarks. 123 ere are conflicting data on the benefit of adjuvant RT in patients with a single positive LN. Some studies in patients with a single positive LN have reported no benefit of adjuvant RT in this setting. 124, 125 However, examination of SEER data from 208 patients with stage III, single nodepositive vulvar SCC revealed significant improvements in 5-year DSS with the addition of adjuvant RT compared with those receiving no RT. 126 The survival benefit was more pronounced among patients who underwent less extensive lymphadenectomy (≤12 nodes excised).

In a case series of 157 patients, disease-free survival (DFS) at 2 years was 88% in node-negative patients, but 60%, 43%, and 29% in patients with 1, 2, and greater than 2 positive nodes. The number of involved nodes negatively impacted prognosis in patients receiving no adjuvant RT, but among patients receiving adjuvant RT to the groin/pelvis, the number of metastatic nodes did not harm prognosis. 127 e large, multicenter, retrospective AGO-CaRE-1 study reported significant survival benefits in node-positive patients receiving adjuvant RT or chemoradiation (3-year PFS of 39.6% vs. 25.9%, P = .004; 3-year OS of 57.7% vs. 51.4%, P = .17). 125 RT coverage most commonly included the groin and pelvis ± coverage of the vulva, with a smaller subset receiving coverage to the groin ± vulvar coverage. Again, the benefits of adjuvant RT were most clear for patients with greater than or equal to 2 positive LNs.

An examination of data from the NCDB supported the addition of chemotherapy to RT in the adjuvant setting. Among 1797 patients with node-positive vulvar cancer, 26.3% received adjuvant chemotherapy in addition to RT after primary surgery. Adjuvant chemotherapy increased survival time and reduced mortality risk (44 months vs. 29.7 months; HR, 0.62; 95% CI, 0.48-0.79; P < .001). 128 Based on SEER data, outcomes of adjuvant RT were examined in 519 patients aged ≥66 years who received primary surgery for node-positive vulvar cancer. Adjuvant RT was associated with improved OS over surgery alone in this cohort of older females (HR, 0.71; 95% CI, 0.57-0.88; P = .002) along with a trend towards improved cause-specific survival (CSS) (HR, 0.79; 95% CI, 0.59-1.05; P = .11). 129 Parameters for delivery of RT were important among this cohort; 3-year OS and CSS were significantly improved in patients who received greater than or equal to 20 fractions (3-year OS: 34% vs. 26%, P = .008; 3-year CSS: 48% vs. 37%, P = .03).

Research has also examined the role of adjuvant RT to the primary tumor site. Studies have indicated that isolated primary site recurrences may be addressed effectively by subsequent surgery, or that late recurrences may actually represent secondary tumors. The benefit of adjuvant RT to the

vulva in patients with close/positive surgical margins has also been investigated. 130 Among patients with close/positive surgical margins at the primary site, 5-year OS was significantly improved by the addition of adjuvant RT to the primary site (67.6% vs. 29%; HR, 0.36; P = .038). Patients receiving adjuvant RT for close/positive margins had a similar 5year OS to those with negative margins. A retrospective study examined the association of RT dose with vulvar recurrence, revealing lower risk of recurrence in patients receiving doses of greater than or equal to 56 Gy compared with those receiving less than or equal to 50.4 Gy. 54

Panel Recommendations

For patients with early-stage disease (stage I) and a depth of invasion less than or equal to 1 mm, observation is appropriate following primary surgery if negative margins are present, and the patient does not have any primary risk factors. Risk factors that may require adjuvant EBRT to the primary site are close tumor margins, LVSI, tumor size, depth of invasion, and pattern of invasion (spray or diffuse). Those with positive margins should undergo re-excision, or if unresectable without removing proximal urethra/bladder/anus, adjuvant EBRT. After re-excision, the panel recommends that patients with negative margins undergo observation or risk-factor-dependent EBRT; those with continued positive margins after re-excision should all undergo EBRT. 130 r patients with stage IB ( > 1 mm invasion) and stage II disease, surgical evaluation of the groin is indicated in addition to primary site surgery. Nodal status is an important determinant of adjuvant therapy recommendations. For patients with a negative SLN or negative IFLNs, observation can be considered.

Surveillance

Most recurrences of vulvar cancer occur within the first 1 to 2 years, although recurrences beyond 5 years have been observed in a significant subset of patients. 135, 136 Accordingly, long-term follow-up is indicated. Definitive data on an optimal surveillance strategy are lacking. 137 However, the panel concurs with the Society of Gynecologic Oncology (SGO) recommendations for post-treatment surveillance. 138 e recommended surveillance is based on the patient's risk for recurrence and personal preferences. History and physical examination are recommended every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, and then annually (see Surveillance in the NCCN Guidelines for Vulvar Cancer). Patients with high-risk disease can be NCCN

assessed more frequently (eg, every 3 months for the first 2 years) than patients with low-risk disease (eg, every 6 months).

Annual cervical/vaginal cytology tests, which may include HPV testing, can be considered as indicated for detection of lower genital tract dysplasia, although its value in detecting recurrent cancers is limited and the likelihood of detecting asymptomatic recurrence is low. In addition, the accuracy of these tests may be affected in patients who have received pelvic radiation as radiotherapy can induce changes in cellular morphology that may result in cytological misdiagnosis. Imaging (ie, chest/abdomen/pelvis CT, neck/chest/abdomen/pelvis/groin FDG-PET/CT, pelvic MRI) and laboratory testing (ie, CBC, blood urea nitrogen [BUN], creatinine) are recommended as indicated by suspicious examination findings or symptoms of recurrence.

Patient education regarding symptoms suggestive of recurrence or vulvar dystrophy is recommended, as well as periodic self-examination. Patients should also be counseled on healthy lifestyle, obesity, nutrition, exercise, and sexual health (including vaginal dilator use and lubricants/moisturizers). For information on these and other issues related to survivorship (ie, pain/neuropathy, fear of recurrence, depression), see the Gynecologic Survivorship section at the end of this document and the NCCN Guidelines for Survivorship (available at www.NCCN.org). Smoking cessation and abstinence should be encouraged; see the NCCN Guidelines for Smoking Cessation (available at www.NCCN.org).

If persistent or recurrent disease is suspected, patients should be evaluated using additional imaging studies and biopsy to confirm local and/or distant recurrence as outlined in the next section.

Treatment for Recurrent Disease

A multicenter case series evaluated the rate and patterns of recurrence among 502 patients, 187 (37%) of who developed a recurrent vulvar SCC.

Just over half of recurrences were vulvar (53.4%), followed by inguinal (18.7%), multi-site (14.2%), distant (7.9%), and pelvic (5.7%). Survival rates at 5 years were 60% for vulvar recurrence, 27% for inguinal/pelvic, 15% for distant sites, and 14% for multiple sites. 31 While localized vulvar recurrences can be successfully addressed with subsequent surgery, some studies have suggested higher risk of cancer-related death.

Given the rarity of primary vulvar cancer, data for treating recurrences are even scarcer and no clear standard of care exists. 139 Treatment approach and patient outcomes depend on the site and extent of recurrent disease. 139, 140 Isolated local recurrences can often be treated successfully with radical local excision, 31, 136, 141 and RT ± chemotherapy provided some degree of DFS in several studies. 92, 93 A retrospective review evaluated patients with locoregional recurrences treated via chemoradiation, neoadjuvant chemotherapy, or RT alone. Five-year DFS and OS were around 20%; however, those with single-site recurrence and lesions less than or equal to 3 cm who received RT dose at or above 64.8 Gy remained disease-free at 5 years. 142 Conversely, another series noted decline in survival with the presence of nodal metastases, tumors greater than 3 cm, or high-grade lesions. 143 For central/large recurrences, pelvic exenteration has been shown to prolong survival when performed on carefully selected patients. 85, 86, 144 Regardless of treatment approach, prognosis for nodal recurrences was very poor. 136, 141, 143, 145, 146 nel Recommendations

If recurrence is suspected, the panel recommends workup for metastatic disease with imaging studies to include chest/abdominal/pelvis CT or neck/chest/abdomen/pelvis/groin FDG-PET/CT. Biopsy can be considered to confirm local and/or distant metastasis. Treatment recommendations for recurrent disease are outlined according to site of recurrence and previous therapies received.

MS-15

Vulva-Confined Recurrence

If recurrence is clinically limited to the vulva with clinically negative nodes, and the patient did not receive prior RT, the panel recommends surgical and RT treatment pathways. Surgical recommendations include partial or total radical vulvectomy ± unilateral or bilateral IF lymphadenectomy. Pelvic exenteration can be considered for select cases with a central recurrence. Additional therapy is indicated by margin status and nodal status. Observation or EBRT is appropriate for negative margins and nodes. In patients with positive margins but no evidence of nodal involvement, options include re-excision or EBRT ± brachytherapy and/or concurrent chemotherapy (category 2B for chemotherapy). EBRT ± concurrent chemotherapy is recommended for patients with negative surgical margins but surgically positive IFLNs. In patients with both positive margins and surgically positive IFLNs, the panel recommends EBRT ± brachytherapy, concurrent chemotherapy, and/or re-excision as needed/appropriate.

Nonsurgical therapy for recurrence includes EBRT ± brachytherapy and/or concurrent chemotherapy. Resection can be considered for patients with gross residual tumor. When feasible, partial or total radical vulvectomy is also indicated for patients with vulva-confined recurrence who were previously irradiated. After treatment for recurrence, patients should undergo surveillance.

Confirmed Nodal or Distant Recurrence

For patients with multiple pelvic nodes, distant metastasis, or prior pelvic EBRT, the panel recommends systemic therapy and/or selective EBRT (if feasible) or palliative/best supportive care. If recurrence is limited to IF/pelvic LNs, resection should be considered for clinically enlarged and suspicious nodes. Resection followed by systemic therapy can be considered for select cases of isolated IF/pelvic recurrence that were previously irradiated. If no prior RT was given, then EBRT ± concurrent chemotherapy is appropriate. All patients should undergo surveillance following treatment for recurrence.

Systemic Therapy for Recurrent/Metastatic Disease

No standard systemic therapy regimens exist for treating advanced or recurrent/metastatic disease. Several reports provide anecdotal evidence for various regimens, at times extrapolating from regimens with known activity in advanced cervical and anal cancers and other SCCs. See the review articles by Reade et al and Mahner et al for an overview of systemic therapies that have been utilized to treat vulvar SCC. 112, 139 referred, first-line regimens recommended by the panel for treating advanced, recurrent/metastatic disease include cisplatin/paclitaxel, carboplatin/paclitaxel, and cisplatin/paclitaxel/bevacizumab. Carboplatin/paclitaxel/bevacizumab is included as a category 2B regimen under the preferred, first-line options. Other recommended regimens include single-agents cisplatin and carboplatin.

Cisplatin is a commonly employed radiosensitizing agent in locally advanced vulvar cancer, and is recommended for single-agent or combination chemotherapy for treatment of metastatic disease. 88, 147 isplatin/paclitaxel and cisplatin/paclitaxel/bevacizumab are preferred regimens based on extrapolation of randomized phase III trial data in advanced or recurrent/metastatic cervical cancer. 148, 149 rboplatin is an alternative platinum agent active in metastatic cervical cancer that can be used as a single agent or in combination. A small series in 6 patients with advanced or recurrent/metastatic vulvar cancer noted limited clinical benefit of the combination regimen; 117 however, it has been included in these guidelines based on data from patients with advanced or recurrent/metastatic cervical cancer that suggest noninferiority to cisplatin. 150, 151 CCN Guidelines Version 1.2025 Vulvar Cancer

MS-16

For the second-line or subsequent treatment, the NCCN Panel has listed paclitaxel, erlotinib (category 2B for erlotinib), and cisplatin/gemcitabine (category 2B) as options.

Single-agent paclitaxel was modestly active in a phase II trial of 31 females with advanced, recurrent/metastatic vulvar cancer, generating a response rate of 14% and PFS of 2.6 months. 118 Erlotinib was studied in a phase II trial that included a cohort of females with metastatic disease. Short-duration responses were observed, with partial responses and stable disease noted in 27.5% and 40% of enrolled patients, respectively. 119 Cisplatin/gemcitabine is also included as a category 2B option extrapolating from cervical cancer data; however, findings from case reports have been mixed. 152, 153 the recent Guidelines update, the NCCN Panel also included cemiplimab as a second-line or subsequent therapy option under "other recommended regimens." The recommendation of cemiplimab has been extrapolated from its efficacy shown in cervical cancer and in advanced cutaneous SCC. In a phase 2 trial with patients with metastatic cutaneous SCC, a response was observed in 28 out of 59 patients. 154 Median followup was 7.9 months. The phase 3, randomized, Empower-Cervical-1 clinical trial evaluated the efficacy of cemiplimab or investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in patients with recurrent or metastatic cervical cancer who have progressed on prior therapy. The trial enrolled 608 patients who had previously received one or more lines of systemic therapy for recurrence; they were randomized to either receive cemiplimab or chemotherapy. The median OS and PFS were significantly longer in the cemiplimab arm than in the control arm (12 months vs. 8.5 months; HR, 0.69; 95% CI, 0.56-0.84; P < .001 and 2.8 vs. 2.9 months; HR, 0.75; 95% CI, 0.63-0.89; P < .001, respectively). Sixteen percent of the patients in the test arm achieved an OR (95% CI, 12.5-21.1) as compared to 6.3% (95% CI, 3.8-9.6) in the chemotherapy arm. 155 omarker-directed systemic therapies are an emerging class of treatments that may be useful in patients with advanced or recurrent/metastatic cancer. Monoclonal antibodies that function as programmed cell death protein 1 (PD-1) inhibitors are one such example of these treatments. PD-1 functions as an immune checkpoint protein that promotes antitumor T-cell activity. Many tumors, including vulvar cancer, are known to overexpress PD-L1, which disrupts PD-1 function. 7] [158] An estimated 10% to 50% of vulvar cancers express PD-L1. 159, 160 mbrolizumab is one such PD-1 inhibitor that may be effective in patients with vulvar cancer. A case study was published of a single patient with recurrent vulvar SCC who was treated with single-agent pembrolizumab, as part of a phase II basket clinical trial to evaluate efficacy and safety, 161 and had 30% reduction in tumor lesions before the treatment was discontinued due to grade 3 mucositis. 162 The single-arm phase II KEYNOTE-158 basket trial (NCT02628067) measured response to pembrolizumab monotherapy in patients with advanced solid tumors that progressed after standard-of-care systemic therapy. 163 Among 101 patients enrolled in the vulvar SCC cohort, median follow-up was 36 months. The overall response rate (ORR) was 10.9% overall, 9.5% in the PD-L1-positive population, and 28.6% among the PD-L1-negative population. Median PFS and OS were 2.1 and 6.2 months, respectively. 164 embrolizumab is FDA-approved for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1). The panel has added pembrolizumab as a recommended second-line, useful in certain circumstances option for PD-L1-positive advanced or recurrent/metastatic vulvar cancer.

MS-18

cause acute, short-term, and long-term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. 174, 175 Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers. 176 Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss. RT may cause long-term complications (eg, fibrosis, stenosis, vulvovaginal atrophy) 177, 178 and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field. 179 Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consideration should be given to bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long-term effects of these treatments are unknown. 180, 181 llowing completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases (eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle (eg, promoting exercise, smoking cessation). 182, 183 In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, including prior treatment history, and conduct a thorough physical examination and provide any necessary imaging and/or laboratory testing. 183 As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed.

All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. 184 Post-radiation use of vaginal dilators and moisturizers is recommended. 177, 185 For treatment-related menopause, hormone therapy should be considered. Psychosocial effects may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy). 183 Patients should be referred to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) as needed, based on prior treatment history and assessed risk of developing late effects and/or existing concerns.

Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. 183, 186 Providing survivors with a summary of their treatment and recommendations for follow-up is also recommended. To this end, the SGO has developed templates for gynecologic cancer-specific Survivorship Care Plans to aid survivors and their clinicians in summarizing cancer history, treatments received, possible side effects, and recommended follow-up. 187

|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,20:07在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,20:07在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,20:07在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,20:07在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,20:07在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|| |---|---|---|---|---|---|

||NCCN Guidelines Version 1.2025 Vulvar Cancer|NCCN Guidelines Index Table of Contents Discussion|NCCN Guidelines Index Table of Contents Discussion|NCCN Guidelines Index Table of Contents Discussion|NCCN Guidelines Index Table of Contents Discussion|

|CLINICAL STAGE||PRIMARY TREATMENT|Positive LNs|EBRT j + concurrent chemotherapy o to primary tumor/inguinofemoral LNs/ pelvic nodes|ADDITIONAL TREATMENT|

||Radiographically negative nodes|Inguinofemoral lymphadenectomy e||||

|Locally advanced (Unresectable without removing proximal urethra/ bladder/anus) • Radiologic workup b imaging|||Negative LNs|EBRT j + concurrent chemotherapy o to primary tumor (± selective inguinofemoral LN coverage coverage) ± selective pelvic LN|(VULVA-6)|

|Unresectable nodes regardless of stage|Radiologic imaging to assess extent of disease b Radiographically suspicious nodes (|Inguinofemoral lymphadenectomy not performed|Consider fine-needle aspiration (FNA) for enlarged LN a Consider FNA for enlarged LN a|pelvic nodes tumor/inguinofemoral LNs/ chemotherapy o to primary EBRT j + concurrent||

||||||VULVA-5|

|NCCN Guidelines Index| |---|

|Table of Contents|

|Discussion|

|EVALUATION OF RESPONSE TO EBRT +|

|VULVA-6|

||NCCN Guidelines Version 1.2025 Vulvar Cancer NCCN Guidelines Version 1.2025 Vulvar Cancer|NCCN Guidelines Index Table of Contents Discussion| |---|---|---|

|CLINICAL STAGE|PRIMARY TREATMENT||

|Metastatic disease beyond pelvis (Stage IVB)|EBRT j,r for locoregional control/symptom palliation and/or Systemic therapy o or Best supportive care (NCCN Guidelines for Palliative Care)||

||Positive margins for invasive disease||

|||Consider additional EBRT j and/or Systemic therapy o or Best supportive care (NCCN Guidelines for Palliative Care)|

|||VULVA-7|

|VULVA-C 1 OF 6|

|VULVA-C 2 OF 6|

|a True lateral lesions are rare as 2 cm often extends lateral to the genitocrural fold. b Given limited data regarding management of lesions that do not involve the midline but are not true lateral lesions (lateral ambiguous/near midline), it is reasonable to| |---|

|consider only ipsilateral LN evaluation in patients who have preoperative lymphoscintigraphy that demonstrates ipsilateral drainage only. A contralateral LN evaluation|

|should be performed in patients who do not undergo preoperative lymphoscintigraphy, and in patients where preoperative lymphoscintigram demonstrates contralateral drainage. 30|

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|||Table of Contents|

|||Discussion|

||SYSTEMIC THERAPY a,b,1 (REGIMENS ARE EXTRAPOLATED FROM CERVICAL CANCER)||

|Chemoradiation|Advanced or Recurrent/Metastatic Disease||

||First-Line Therapy c|Second-Line or Subsequent Therapy c|

|Preferred Regimens • Cisplatin • Carboplatin if cisplatin intolerant Other Recommended Regimens • Cisplatin/gemcitabine 2 • Cisplatin/fluorouracil • If single-agent cisplatin or Capecitabine/mitomycin 3 Gemcitabine 4 Paclitaxel 5,6 carboplatin are unavailable:|• Carboplatin • Cisplatin Other Recommended Regimens Preferred Regimens • Cisplatin/paclitaxel/bevacizumab d • Cisplatin/paclitaxel • Carboplatin/paclitaxel • Pembrolizumab + cisplatin/paclitaxel • Carboplatin/paclitaxel/bevacizumab d ± bevacizumab d,e • Pembrolizumab + carboplatin/paclitaxel ± bevacizumab d,e|Other Recommended Regimens • Paclitaxel • Cemiplimab e,7,8 • Erlotinib (category 2B) 9 • Cisplatin/|

|NCCN Guidelines Version 1.2025 Vulvar Cancer NCCN Guidelines Version 1.2025 Vulvar Cancer|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion| |---|---|

|PRINCIPLES OF GYNECOLOGIC||

||References|

||VULVA-E 1 OF 2|

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|||||||||Discussion|

|CLINICAL PRESENTATION a|WORKUP||CLINICAL STAGE d,e|PRIMARY TREATMENT|ADJUVANT TREATMENT||||

|||||Stage 0 or Stage IA|Partial vulvectomy f||||

|Cutaneous vulvar melanoma|• H & P • Biopsy, pathologic review a • Imaging b • EUA cystoscopy or proctoscopy as indicated • Consider somatic mutational testing for vulvar melanoma and mucosal vulvovaginal melanoma as clinically indicated (|Resectable Unresectable/ Residual disease|Stage IB Stage III Stage II|Partial vulvectomy f ± SLNB g Partial vulvectomy f + SLNB g ± RT i Systemic therapy h|Partial vulvectomy f with clear margins If negative SLNB If positive SLNB|See Adjuvant Treatment (ME-3) in the NCCN Guidelines for Melanoma: Cutaneous See Adjuvant Treatment (ME-5) in the NCCN Guidelines for Melanoma: Cutaneous See Adjuvant Treatment (ME-6) in the NCCN Guidelines for Melanoma: Cutaneous|Follow-up/ Surveillance (VM-3)|Follow-up/ Surveillance (VM-3)|

|||||||||VM-1|

|Consider Neoadjuvant Treatment (ME-6) in the NCCN Guidelines for Melanoma: Cutaneous|

|See Principles of Imaging (ME-D) in the NCCN Guidelines for Melanoma:|

|Cutaneous. c See Principles of Molecular Testing (ME-C) in the NCCN Guidelines for|

|Melanoma: Cutaneous.|

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|||||Discussion|

|Mucosal vulvovaginal melanoma|• H & P • Biopsy, pathologic review a • Imaging b • EUA cystoscopy or proctoscopy as indicated • Consider somatic mutational testing for vulvar melanoma and mucosal vulvovaginal melanoma as clinically indicated (ie, BRAF, KIT) c • Full skin assessment|Resectable Unresectable/ Residual disease|Systemic therapy h ± RT i||

|||||VM-2|

|FOLLOW-UP/ SURVEILLANCE|

|• Recommend groin nodal ultrasound for stage ≥ IB l every 3-6 months for first 2 years then every 6-12 months for years 3-5 • Consider: CT scan every 3-12 months|

|FDG-PET/CT|

|TREATMENT FOR RECURRENCE| |---|

|Depending|

|Recurrence|

|VM-3|

||NCCN Guidelines Index| |---|---|

||Table of Contents|

||Discussion|

|VULVAR MELANOMA • Consider RT|PRINCIPLES OF RADIATION THERAPY|

||VM-A 1 OF 7|

|PTV low/intermediate risk|| |---|---|

|• 44-50 Gy (2 Gy/fraction) or||

|• 55-63 Gy (1.8 Gy/fraction)||

|PTV high risk||

|• 66 (2.2 Gy/fraction) or||

|• 70 Gy (2 Gy/fraction)||

|Vulvar Melanoma|Adjuvant Therapy|

|54-63 Gy (1.8 Gy/fraction), or • 44-50 Gy (2 Gy/fraction), or • 27-30 Gy (5.4-6 Gy/fraction) twice per week or every other day (for small volumes), or PRINCIPLES OF RADIATION THERAPY • 48 Gy (2.4 Gy/fraction), NCCN Guidelines Index Table of Contents Discussion VAGINAL MELANOMA • RT (| |---|

|References|

|Continued|

|VM-A 2 OF 7|

|PRINCIPLES OF RADIATION THERAPY|

|VAGINAL MELANOMA (continued)|

|• Dosing Regimens|

|VM-A 3 OF 7|

|Vaginal Melanoma|Definitive Therapy| |---|---|

|EBRT alone (for distal primaries, brachytherapy generally preferred for proximal/apical disease)|PTV low/intermediate risk • 44-50 Gy (2 Gy/fraction) or • 54-63 Gy (1.8 Gy/fraction) PTV high risk • 66 (2.2 Gy/fraction) or • 70 Gy (2 Gy/fraction)|

||EBRT dose|

||• 44-50 Gy (2 Gy/fraction) or|

||• 54-63 Gy (1.8 Gy/fraction)|

||Brachytherapy Dose|

|EBRT + brachytherapy boost|• 4.5-6 Gy x 5 fractions • 7 Gy x 4 fractions|

||• 8-9 Gy x 3 fractions|

|Brachytherapy alone (small primaries or in situ disease)|Potential brachytherapy regimens: • 5 Gy x 10 fractions • 6 Gy x 8 fractions • 8 Gy x 5 fractions|

||Continued|

||||NCCN Guidelines Index| |---|---|---|---|

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||||Discussion|

||PRINCIPLES OF RADIATION THERAPY|||

|RT DOSE CONSTRAINTS FOR BRACHYTHERAPY CUMULATIVE WITH EBRT||||

|VAGINAL MELANOMA (continued) • Brachytherapy (||||

|Rectum|< 65 D2 cc|< 75 D2 cc|< 65 point dose|

|Bladder|75-80 D2 cc|< 90 D2 cc|< 75 point dose|

|Sigmoid|< 70 D2 cc|< 75 D2 cc|-|

|Bowel|< 70 D2 cc|< 75 D2 cc|-|

||||References Continued|

||||VM-A 4 OF 7|

|Note:|

|||PRINCIPLES OF RADIATION THERAPY|

|Vaginal Melanoma|(|Adjuvant Therapy|

|||References|

|||Continued|

|||VM-A 5 OF 7|

|NCCN Guidelines Version 1.2025 NCCN Guidelines Version 1.2025 Vulvar and Vulvovaginal Melanoma PRINCIPLES OF RADIATION THERAPY NCCN Guidelines Version 1.2025 NCCN Guidelines Version 1.2025 Vulvar and Vulvovaginal Melanoma PRINCIPLES OF RADIATION THERAPY NCCN Guidelines Version 1.2025 Vulvar Cancer|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion|

|RT Dosing (Gy) 48-50 30 30-36 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 Fractionation Duration 20 fractions In over 4 weeks 10 10 fractions In over 2 weeks 11 6 Gy/fraction For small fields 5 PALLIATIVE REGIMENS • More References point of invasion. (van den Einden LC, et al. Mod Pathol 2015;28:295-302; Skala SL, et al. J Low Genit Tract Dis 2020;24:265-271).||

||VM-A 6 OF 7|

|FIGO Stage|Description|| |---|---|---|

|I|Tumor confined to the vulva and/or perineum.|Tumor confined to the vulva and/or perineum.|

||IA|Tumor size ≤2 cm and stromal invasion ≤1 mm a|

||IB|Tumor size > 2 cm or stromal invasion > 1 mm metastases ≤5 mm|

||IIIB Regional b lymph node metastases > 5 mm|IIIB Regional b lymph node metastases > 5 mm|

||IIIC Regional b lymph node metastases with extracapsular spread|IIIC Regional b lymph node metastases with extracapsular spread|

|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 b lymph node metastases||

||IVB Distant metastases|IVB Distant metastases|

al. Gynecol Oncol 2007;105:742-746).

Indications may include abnormal physical exam findings such as palpable new mass or adenopathy, or new pelvic, abdominal, or pulmonary symptoms.

An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. c If not used previously, first-line agents can be used as second-line or subsequent therapy as clinically appropriate. For the treatment of patients with unresectable or metastatic TMB-H [≥10 mutations/megabase (mut/Mb)] tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. g Recommended for disease progression on or after chemotherapy in patients whose tumors express PD-L1 (combined positive score [CPS] ≥1) h Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.

See Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME-E) in the NCCN Guidelines for Melanoma: Cutaneous. Based on limited data, topical imiquimod may be helpful in selected cases of vulvar melanoma in situ (MIS) when histologic clearance is not possible surgically. g See Principles of Sentinel Lymph Node Biopsy (SLNB) (ME-F) in the NCCN Guidelines for Melanoma: Cutaneous.

Clinical presentation: Cutaneous vulvar melanoma is defined as lesions that occur on the vulva vestibule outside Hart's line; mucosal vulvovaginal melanoma is defined as lesions that occur on the vulva vestibule inside Hart's line. b See Principles of Imaging (ME-D) in the NCCN Guidelines for Melanoma: Cutaneous. c See Principles of Molecular Testing (ME-C) in the NCCN Guidelines for Melanoma: Cutaneous. d Vulvovaginal melanoma should be staged the same as cutaneous melanoma. Clinical staging for cutaneous vulvar melanoma and vulvovaginal melanoma should be done using the AJCC staging system (TNM staging system). See Staging (ST-1) in the NCCN Guidelines for Melanoma: Cutaneous e See Principles of Biopsy and Pathology (ME-B) in the NCCN Guidelines for Melanoma: Cutaneous. g See Principles of Sentinel Lymph Node Biopsy (SLNB) (ME-F) in the NCCN Guidelines for Melanoma: Cutaneous. h See Systemic Therapy for Metastatic or Unresectable Disease (MELSYS-1) in the NCCN Guidelines for Melanoma: Cutaneous.

Nodal ultrasound assessment for melanoma requires specific radiologic expertise. Criteria concerning for early melanoma nodal involvement include the following: hypoechoic island(s) in the cortex, asymmetrical focal cortical thickening, and peripheral vascularity, particularly when there is detectable perfusion to the area of cortical thickening. Core biopsy or FNA of suspicious LNs should be directed to the atypical area(s) within the cortex identified on ultrasound. • van Akkooi ACJ, et al. Ann Surg Oncol 2010;17:660-662. • Voit CA, et al. J Clin Oncol 2009;27:4994-5000. • Voit CA, et al. Melanoma Res 2016;26;267-271. • Faries MB, et al. N Engl J Med 2017;376:2211-2222. • Bartlett EK, et al. Br J Surg 2020;107:1480-1488.

Lower dose ranges are used for distal disease due to higher radiation sensitivity of the distal vagina.Higher dose ranges are used for apical/proximal disease.For OAR Constraints for Brachytherapy, see table on VM-A (4 of 7)

58, 84 ,80IF node evaluation can be performed through SLN biopsy or ipsilateral IF lymphadenectomy; the latter should be performed if no SLN(s) is/are detected.Adjuvant therapy is informed by primary tumor risk factors and nodal surgical pathology.Patients with anterior or posterior central vulvar lesions should undergo radical partial vulvectomy accompanied by bilateral IF node evaluation consisting of SLN biopsy or bilateral IF lymphadenectomy.51,58,80IF lymphade ctomy is required on side(s) for which sentinel nodes are not detected.Adjuvant therapy is informed by primary tumor risk factors and nodal surgical pathology.For lateralized and near midline tumors with unilateral SLN metastasis, unilateral groin treatment by either IF lymphadenectomy or RT is acceptable.For midline tumors with unilateral SLN metastasis, unilateral groin treatment can be performed if the contralateral groin has negative sentinel node or negative IF lymphadenectomy.58,84

121,125diation is strongly recommended for patients with two or more positive IFLNS or a single IFLN with greater than 2-mm metastasis.121,125For patients with locally advanced disease, adjuvant therapy decisions should be made based on clinical evaluation of treatment response after EBRT with concurrent chemotherapy (potentially preceded by IF lymphadenectomy). These guidelines provide adjuvant therapy recommendations based on whether patients are clinically negative or positive for residual tumor at the primary site and in the groin.

the SLN-positive group (P < .0001), again attesting to the prognostic significance of groin nodal involvement. 68 e GROINSS-V II/GOG 270 observational study (NCT01500512) compared the safety of IF radiotherapy with that of IF lymphadenectomy among patients with SLN metastases. 69 The trial further evaluated the treatment-related morbidity (short and long term) with radiotherapy in these patients. Among 322 patients with metastatic SLN, 160 had micrometastases (≤2 mm) and 162 patients had macrometastases ( > 2 mm). Among 160 patients with SLN micrometastases, 126 received IF radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. In 162 patients with SLN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P =.011). Treatment-related morbidity after radiotherapy was less frequent compared with IF lymphadenectomy.

The ongoing GROINSS-V III/NRG-GY024 phase 2 study is investigating the feasibility and safety of replacing IF lymphadenectomy with chemoradiation in patients with early-stage vulvar cancer with a macrometastasis and/or extracapsular extension in the sentinel node. 70

In the current version of the Guidelines, the section on principles of surgery has been updated to include management of mapping based on tumor location in reference to midline structures of the vulva. For appropriate individuals, the panel considers SLN mapping and biopsy of the IFLN basin to be a reasonable alternative approach to decrease postoperative morbidity while maintaining a low rate of groin recurrences. 62, 63, 66 ndidates for SLN biopsy should have clinically/radiologically negative groin nodes, unifocal primary tumor less than 4 cm, and no history of previous vulvar surgery. 65, 66 Mapping and biopsy should be performed by a high-volume SLN surgeon using dual tracers (ie, radiocolloid and dye) to ensure the best detection rates. 63, 65 The panel recommends complete IF lymphadenectomy if no ipsilateral SLN is detected. If the ipsilateral SLN is positive, completion lymphadenectomy or treatment of the affected groin is warranted. The contralateral groin should be evaluated surgically and/or treated with EBRT. In select cases of a single, small-volume, unilateral, positive inguinal node with a well-lateralized small primary tumor and depth of invasion less than or equal to 5 mm and with a clinically negative contralateral groin examination, a contralateral groin lymphadenectomy or radiation may be omitted. 71

Primary Treatment

For the purposes of primary treatment, these guidelines provide recommendations by clinical stage, separating patients into those with early-stage (stage I; select stage II tumors), locally advanced (unresectable without removing proximal urethra/bladder/anus), and distant metastatic disease beyond the pelvis.

Early-Stage Disease

3] [74] [75] Clinicians should strive for primary tumor resection with oncologically appropriate margins of 1 to 2 cm if feasible. 36, 39, 53, 55 See Primary Tumor Resection and Lymph Node Evaluation in this discussion. Although there are no prospective data comparing radical local incision to radical vulvectomy, existing data from retrospective analyses do not demonstrate a difference in recurrence or survival outcomes. 51, 52 rgical dissection and RT have been evaluated for treatment of the groin in early-stage disease. Limited data suggest that primary groin radiation

MS-17

Monoclonal antibodies targeting the PD-1 pathway may also be effective in tumors that have high TMB (TMB-H) or are deficient in MMR (dMMR)/have high levels of MSI (MSI-H). Of the 71 patients in the KEYNOTE-158 trial with advanced vulvar cancer, 12 had TMB-H tumors. The ORR for TMB-H vulvar cancer was approximately 17%, while the ORR for non-TMB-H disease was 3.4%. 165 The KEYNOTE-158 study authors also analyzed pembrolizumab response in 233 enrolled patients with non-colorectal MSI-H/dMMR tumors, one of which had vulvar cancer. ORR for the entire cohort was 34.3%. Median PFS was 4.1 months and median OS was 23.5 months. 166 Based on these data, the FDA expanded pembrolizumab's approval for treatment of TMB-H and MSI-H/dMMR tumors that progressed after prior therapy, regardless of tumor type. 167, 168 ased on these additional data/FDA approvals, the panel also recommends pembrolizumab as a second-line, useful in certain circumstances option for patients with advanced or recurrent/metastatic vulvar cancer whose tumors are MSI-H/dMMR or TMB-H.

Nivolumab is another PD-1 inhibitor shown to have some efficacy in certain patients with vulvar cancer. The single-arm phase I/II CheckMate 358 trial (NCT02488759) measured response to nivolumab monotherapy in a small cohort of 5 patients with recurrent or metastatic vaginal or vulvar cancer who were HPV-positive or had an unknown HPV status. The 12and 18-month OS rates for the combined cohort were 40% and 20%, respectively; 6-month PFS was 40%. 169 Based on these data, the panel added nivolumab as a second-line, useful in certain circumstances option for HPV-related advanced or recurrent/metastatic vulvar cancer.

NTRK gene fusions lead to constitutively active tropomyosin receptor kinases (TRKs), which in turn promote development and progression of cancer. Approximately 0.3% of solid tumors express NTRK gene fusions, although expression varies widely by cancer type. 170 1] [172] In a primary analysis, the efficacy and safety of larotrectinib was reported in 55 patients enrolled in three clinical studies who had locally advanced or metastatic tumors with NTRK gene fusions and had progressed on standard chemotherapy received previously. 171 The three clinical trials included a phase 1 dose-finding study in adults, phase 1/2 dose-finding study in the pediatric population, and a phase 2, single-arm, basket trial. The ORR of larotrectinib in these patients was 75% (95% CI, 61%-85%), with 22% complete response and 53% partial response with median duration of response and PFS not reached at the time. In a longterm follow-up analysis, out of 153 patients, 121 patients (79%; 95% CI, 72-85) had objective response with 16% having a complete response, 63% having a partial response, and 12% having stable disease. The median duration of response was 35.2 months (22.8-NE) and the median PFS was 28.3 months. 173 Similarly, entrectinib showed a durable and clinically meaningful response in 54 patients with advanced/metastatic NTRK gene fusion tumors enrolled in three phase 1/2 clinical trials with 57.4% ORR, 10.4-month median duration of response, and 11.2-month median PFS. 170 In a long-term efficacy and safety analysis in 121 patients at median follow-up of 25.8 months, 61% reported complete or partial responses, and median duration of response was 20 months (95% CI, 10.1-19.9). Both larotrectinib and entrectinib are FDA-approved for NTRK gene fusion solid tumors for patients who have progressed following treatment or have no satisfactory standard therapy. The NCCN Guidelines for Vulvar Cancer recommend larotrectinib and entrectinib as a secondline or subsequent, useful in certain circumstances option for NTRK gene fusion-positive tumors and recently changed the category of evidence from category 2B to category 2A.

Gynecologic Survivorship

Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy, which may

引用 / 出处

NCCN临床实践指南：外阴癌（2025.V1）. 2025.