Tumor-infiltrating lymphocyte therapy in metastatic vulvar melanoma: A case report and review of the literature

Highlights

• •Vulvar melanoma is rare, aggressive, and hard to treat.
• •Limited response to checkpoint inhibitors in mucosal disease.
• •TIL therapy shows promise after immunotherapy failure.
• •Case achieved meaningful partial response with manageable toxicity.
• •Supports expanding TIL use in refractory gynecologic melanoma.

Abstract

Background: Vulvar melanoma is a rare and aggressive malignancy comprising less than 1% of all melanomas in women. Despite advances in immune checkpoint blockade, durable responses remain limited, and treatment of refractory disease poses a major challenge. Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a promising option for patients with metastatic mucosal melanoma resistant to standard immunotherapy.

Case: We report a 48-year-old woman diagnosed with multifocal, unresectable vulvar melanoma who initially received ipilimumab and nivolumab, but discontinued due to immune-related colitis and progression of disease. She subsequently developed pulmonary, hepatic, and nodal metastases and underwent palliative vulvectomy for symptomatic relief. Following left inguinal lymph node harvest and autologous TIL expansion, she received lymphodepleting chemotherapy, TIL (lifileucel) infusion, and adjuvant interleukin-2 therapy. Her treatment course was notable for transient transaminitis, rash, and reversible encephalopathy. Follow-up PET-CT demonstrated a partial metabolic response with resolution of hepatic lesions and decreased pulmonary nodularity.

Conclusion: This case highlights the potential clinical benefit of TIL therapy in metastatic vulvar melanoma following checkpoint inhibitor failure, supporting its consideration as an emerging therapeutic option in this rare gynecologic malignancy.

1. Introduction

Vulvar melanoma is an uncommon subtype of mucosal melanoma, accounting for less than 1% of all melanomas in women (Wohlmuth and Wohlmuth-Wieser, 2021). Its incidence is estimated at approximately 0.1 cases per 100,000 women per year, with five-year survival rates ranging from 10% to 60% (Falcicchio, et al., 2022). The disease is characterized by late presentation, early metastatic spread, and unique molecular alterations, all of which contribute to its poor prognosis (Wohlmuth and Wohlmuth-Wieser, 2021, Falcicchio, et al., 2022).

Management is largely extrapolated from cutaneous melanoma and typically involves wide local excision with lymph node assessment (Wohlmuth and Wohlmuth-Wieser, 2021). However, achieving negative surgical margins is often difficult due to anatomic constraints, and recurrence is frequent even after apparently adequate resection. For patients with advanced or metastatic disease, or lesions not amenable to primary resection, immune checkpoint inhibitors targeting PD-1 or CTLA-4 are considered standard first-line therapies (Tsai et al., 2014). Nonetheless, mucosal melanomas—including vulvar primaries—demonstrate lower response rates compared to their cutaneous counterparts.

Emerging cell-based immunotherapies, such as tumor-infiltrating lymphocyte (TIL) therapy, have shown promise for patients with refractory metastatic melanoma, including mucosal subtypes (Monberg, 2025, Skok, 2025). We describe a case of multifocal vulvar melanoma refractory to dual checkpoint inhibition that achieved a partial metabolic response following TIL therapy, highlighting the potential role of adoptive cell transfer in treatment-resistant mucosal melanoma.

2. Case presentation

A 48-year-old woman presented in October 2024 with vulvar swelling and intermittent vaginal bleeding. She first noticed a lump on her left labia in May 2024, which progressively enlarged, became painful, and began bleeding. Examination revealed a 4 × 2 × 1 cm multilobulated, friable mass on the left inner labia minora with necrosis, tenderness, and scattered hyperpigmented macules on both labia minora. The urethral meatus appeared uninvolved.

A vulvar biopsy of the left labia minora performed in October 2024 revealed invasive malignant melanoma. Histologic sections showed fragmented sheets of tumor with extensive ulceration and frequent mitotic figures, up to 16 per mm². Immunohistochemical staining was positive for Melan-A and SOX10 and negative for cytokeratin AE1/AE3, CK7, CK8/18, CK20, chromogranin A, INSM1, synaptophysin, p40, and TTF-1. The lesion demonstrated high nuclear-to-cytoplasmic ratios, nuclear pleomorphism, and cellular atypia. The tumor was estimated to have a Breslow thickness of at least 3.5 mm, was ulcerated, and was present at all tissue edges. No lymphovascular invasion, neurotropism, or microscopic satellitosis was identified, and tumor-infiltrating lymphocytes were present but non-brisk. Regression was not identified. Based on these findings, the pathologic stage was designated at least pT3b (AJCC 8th edition).

Molecular profiling revealed BRAF wild-type disease with NRAS and PTEN mutations and a low tumor mutational burden. MRI of the pelvis and PET-CT imaging in early November 2024 showed no evidence of regional or distant metastasis. Due to the multifocal and rapidly progressive nature of the lesions, the disease was deemed unresectable.

The patient began systemic immunotherapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) on November 22, 2024, with subsequent cycles on December 13, 2024, and January 3, 2025. The third cycle was dose-reduced due to weight loss. Therapy was discontinued after the third cycle due to suspected immune-mediated colitis.

A PET-CT on February 7, 2025, demonstrated enlargement of the vulvar mass and new hypermetabolic lymphadenopathy above and below the diaphragm, concerning for progression versus sarcoid-like reaction. Because of worsening pain, bleeding, and local growth, she underwent palliative bilateral vulvectomy on March 3, 2025.

Intraoperatively, a large fungating mass (6 × 4 × 3 cm) of the left labia extending to the clitoral hood was noted, with multiple satellite lesions on the right labia and periurethral area (Fig. 1). Pathologic analysis revealed invasive melanoma of at least 25 mm depth on the left vulva and 1.6 mm on the right. The clitoral margin contained melanoma in situ extending to the cauterized edge. Margins were positive for both in situ and invasive disease, confirming that complete oncologic resection was not feasible.

Fig. 1.

Intraoperative view demonstrating a large fungating vulvar mass (6 × 4 × 3 cm) of the left labia extending to the clitoral hood.

Follow-up PET-CT on April 22, 2025, demonstrated new pulmonary nodules and left inguinal and external iliac lymphadenopathy consistent with metastases. On May 15, 2025, she underwent left inguinal lymph node harvest for TIL production. Subsequent PET-CT on June 24, 2025, revealed further progression with hepatic involvement.

She was admitted on June 25, 2025, for lymphodepleting chemotherapy before TIL therapy. She received cyclophosphamide 60 mg/kg on days –7 and –6 and fludarabine 25 mg/m (Falcicchio, et al., 2022) on days –5 to –1. On July 3, 2025, she received autologous TIL infusion (lifileucel, Amtagvi), followed by high-dose interleukin-2 (IL-2) starting 24 h later. She completed five of six planned doses, with the final dose held due to hypoxia, tachycardia, and transient altered mental status.

Her post-TIL course was complicated by transient transaminitis, neutropenic fever, and a maculopapular rash attributed to IL-2, managed with topical corticosteroids and antihistamines. She also experienced transient encephalopathy with normal neuroimaging and reversible hypoxia following IL-2. She recovered fully and was discharged on July 14, 2025, on acyclovir and trimethoprim–sulfamethoxazole prophylaxis with daily follow-up.

A PET-CT on September 19, 2025, demonstrated interval decrease in size and metabolic activity of multiple pulmonary nodules, resolution of hepatic and pelvic lesions, and improvement in left pelvic activity consistent with a partial metabolic response (Fig. 2). A new right lower lobe pulmonary nodule and a subcutaneous chest wall lesion were noted for surveillance. The patient’s rash and functional status improved significantly, and she remains in outpatient follow-up.

Fig. 2.

PET/CT images demonstrating interval response to tumor-infiltrating lymphocyte (TIL) therapy.

3. Discussion

Vulvar melanoma is a rare and aggressive gynecologic malignancy that poses major therapeutic challenges due to its low incidence, complex anatomy, and poor responsiveness to conventional therapies (Wohlmuth and Wohlmuth-Wieser, 2021, Falcicchio, et al., 2022). While immune checkpoint inhibitors (ICIs) have improved survival in cutaneous melanoma, their efficacy in mucosal subtypes remains limited (Falcicchio, et al., 2022, Chłopik, et al., 2018, Nasioudis, Dimitrios et al., 2023). These tumors often carry distinct molecular features such as NRAS, KIT, and PTEN mutations and exhibit lower tumor mutational burden, contributing to reduced immunogenicity and decreased response to ICIs (Wohlmuth and Wohlmuth-Wieser, 2021, Falcicchio, et al., 2022, Chłopik, et al., 2018, Nasioudis, Dimitrios et al., 2023). The current case exemplifies these limitations, with disease progression despite combined CTLA-4 and PD-1 blockade. Given the extent and distribution of disease, surgical resection was not feasible, emphasizing the need for alternative systemic therapies in advanced vulvar melanoma.

For localized disease, surgery remains the mainstay of treatment (Leitao, 2014). Wide local excision with sentinel lymph node biopsy (SLNB) is preferred, as radical vulvectomy does not improve survival and carries significant morbidity, including infection, wound breakdown, and sexual dysfunction (Leitao, 2014, Sinasac, Sarah E et al., 2019). The recommended excision margins for melanoma typically measure 0.5 cm for in situ lesions, 1 cm for tumors up to 2.0 mm thick, and 2 cm for those deeper than 2.0 mm, correlating to pathologic negative margins of 0.4, 0.8, and 1.6 cm, respectively (Leitao, 2014). Achieving negative margins is difficult, and lymph node involvement is an established poor prognostic factor. While SLNB is often recommended for lesions greater than 1 mm in Breslow thickness, its survival benefit in mucosal primaries remains uncertain (Lopez, et al., 2020).

Before the advent of immunotherapy, treatment options for unresectable or metastatic vulvar melanoma were limited to cytotoxic chemotherapy, with response rates between 12% and 26% and minimal impact on overall survival (Wohlmuth and Wohlmuth-Wieser, 2021, Falcicchio, et al., 2022). Interferon-α and interleukin-2 offered marginal improvement in progression-free survival but not in overall outcomes (Leitao, 2014). The introduction of ICIs—ipilimumab, nivolumab, and pembrolizumab—transformed melanoma therapy, though mucosal melanomas continue to demonstrate lower response rates compared to cutaneous disease (Wohlmuth and Wohlmuth-Wieser, 2021). Pooled analyses of six clinical trials report objective response rates of 8% for ipilimumab, 23% for nivolumab, and 37% for combination therapy in mucosal melanomas, significantly lower than response rates in cutaneous melanoma (D'Angelo, Sandra P et al., 2017). Similarly, pembrolizumab has shown a 19% response rate in mucosal melanoma. In one institutional series, patients with vulvovaginal melanoma had response rates of 12.5% with ipilimumab and 33% with PD-1–based regimens, with disease control in approximately two-thirds of cases (D'Angelo, Sandra P et al., 2017).

The tumor microenvironment in vulvar melanoma is characterized by complex interactions among tumor cells, stromal components, and immune infiltrates (Monberg, 2025). Tumor-infiltrating lymphocytes (TILs)—including CD8⁺ cytotoxic and CD4⁺ helper T cells—play a key role in antitumor immunity (Monberg, 2025, Skok, 2025). However, immune evasion through PD-L1 upregulation, metabolic shifts, and recruitment of suppressive macrophages limits their effectiveness. PD-L1 expression in vulvar melanoma is generally low but correlates with higher peritumoral CD8⁺ and FOXP3⁺ lymphocyte density, suggesting an exhausted but active immune response (Monberg, 2025, Skok, 2025, Chłopik, et al., 2018). Low intra-tumoral CD8⁺ TIL density is associated with poor prognosis, underscoring the therapeutic relevance of immune infiltration in these tumors (Tsai et al., 2014, Chłopik, et al., 2018).

TIL therapy builds upon these immunologic insights by isolating and expanding tumor-resident lymphocytes ex vivo before reinfusion after lymphodepleting chemotherapy (Monberg, 2025, Skok, 2025). This approach can overcome checkpoint resistance and restore antitumor function using autologous, tumor-specific immune cells. Studies in cutaneous melanoma have demonstrated durable responses in 36–70% of patients, including complete responses in up to 20% (Rohaan, et al., 2022). A recent phase III trial comparing TIL therapy with ipilimumab in advanced melanoma reported a median progression-free survival of 7.2 versus 3.1 months and objective response rates of 49% and 21%, respectively, even in patients refractory to PD-1 blockade (Rohaan, et al., 2022). Although mucosal melanomas, including vulvar primaries, were not included in these studies, these findings provide a strong rationale for extending TIL therapy to this population.

Although TIL therapy remains limited to specialized centers, it has been implemented at our institution since 2024 using lifileucel (Amtagvi) (AMTAGVI (lifileucel), , 2024). Treatment involves surgical tumor harvest with shipment for centralized ex vivo lymphocyte expansion and cryopreservation, followed by return of a patient-specific cellular product for infusion. Patients at our institution undergo a defined treatment sequence of lymphodepleting chemotherapy, infusion of viable T cells, and subsequent high-dose interleukin-2 administration to support in vivo expansion, all delivered in an inpatient setting with intensive monitoring and multidisciplinary expertise.

To date, no prospective trials have evaluated TIL therapy specifically in vulvar melanoma. However, this case demonstrates its feasibility and potential for durable disease control in checkpoint-refractory mucosal melanoma. The patient achieved a partial metabolic and symptomatic response with manageable toxicity, aligning with data from cutaneous melanoma showing that TIL therapy can induce meaningful remission even after ICI failure. Further research is needed to define predictors of response, optimal sequencing with ICIs, and long-term outcomes in this rare disease. Multicenter collaboration will be essential to expand access to cellular immunotherapy and improve survival in patients with advanced vulvar melanoma.

4. Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Author contributions

Aya Bashi contributed to manuscript writing. Riddhishkumar Shah, Jay S. Lee, Georgia M. Beasley, April K. Salama: contributed to clinical guidance and manuscript review. Haley A. Moss contributed to clinical guidance and critical manuscript review.

CRediT authorship contribution statement

Aya Bashi: Writing – review & editing, Writing – original draft, Conceptualization. Riddhishkumar Shah: Writing – review & editing. Jay S. Lee: Writing – review & editing. Georgia M. Beasley: Writing – review & editing. April K. Salama: Writing – review & editing. Haley A. Moss: Writing – review & editing, Conceptualization.

Funding

The authors received no funding for this paper.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: April Salama reports research funding (paid to institution): Ascentage, Bristol Myers Squibb, Ideaya, Immunocore, Merck, Olatec Therapeutics, Regeneron, Replimune, Seagen. Consultant or advisory role: Bristol Myers Squibb, Pfizer, Natera, Delcath, Ideaya, Immunocore. All remaining authors have no conflicts of to disclose..