Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

Abstract

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

The Vulvar Immunohistochemical Panel (VIP) Project: Molecular Profiles of Vulvar Squamous Cell Carcinoma

“…Moreover, ICIs, such as pembrolizumab, have recently been included in NCCN guidelines as a recommended second-line option for PD-L1-positive advanced or recurrent/metastatic vulvar cancer [ 14 ]. Current opinion is that there might be a place for ICIs in vulvar cancer treatment, especially in combination with radiotherapy [ 55 ]. Results from the KEYNOTE-826 trial, recently published, show that the progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab [ 56 ].…”

“…Therefore, our results seem to further support the use of ICIs in vulvar cancer treatment and, as reported in the KEYNOTE-826 trial for cervical cancer patients, the presence of PD-L1 expression could influence the response to treatment; in any case, this remains an hypothesis to be confirmed in specific clinical trials on VSCC patients. Regarding the correlation between PD-L1 expression and HPV status or prognosis, conflicting data are currently available in the literature [ 55 , 57 , 58 , 59 , 60 , 61 ]. In our study, we observed no statistically significant correlations between PD-L1 and p16 IHC expression.…”

Extramammary Paget’s Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments

“…Although germline mutations in mismatch repair genes, such as MLH1 and MSH2, which may be associated with microsatellite instability, were found in some EMPD patients, previous studies have reported that MSI-H status was not observed in most EMPD cases [86,87]. A review for immune checkpoint inhibitors in vulvar neoplasms including EMPD was recently reported [88].…”

“…Further studies of advanced EMPD cases treated with checkpoint inhibitors are needed to evaluate the efficacy. Currently, a clinical trial of nivolmab and ipilimumab for treatment of rare malignancies, including EMPD (NCT02834013), is ongoing [88].…”

Biomarkers of Central Nervous System Involvement from Epithelial Ovarian Cancer

“…However, regarding gynaecological tumors, the role of immunotherapy has so far been limited [ 93 , 94 , 95 , 96 ]. The efficacy of immunotherapy has been tested in ovarian cancer; however, the results were not as expected: the main phase III immunotherapy trials conducted in ovarian cancer yielded negative results [ 97 , 98 , 99 ].…”