Background: Vulvar epidermolytic hyperkeratosis (EHK) is an exceedingly rare dermatological condition, often presenting as solitary or multiple lesions in the vulvar region. Due to its clinical resemblance to other vulvar disorders, such as condyloma acuminatum, Bowenoid papulosis, and squamous cell carcinoma, vulvar EHK poses significant diagnostic challenges. While individual case reports and small case series have documented instances of vulvar EHK, comprehensive studies systematically consolidating the clinical, histopathological, and therapeutic aspects of this condition remain lacking. Objectives: To address this gap, this systematic review consolidates all available case reports and case series on vulvar EHK. The review aims to provide a comprehensive analysis of clinical presentations, histopathological features, diagnostic challenges, treatment approaches, and patient outcomes. Methods: We conducted a systematic review following the PRISMA guidelines. We searched multiple databases (PubMed, Web of Science, Scopus) for studies published up to 30 September 2024. Only case reports and case series with histopathologically confirmed vulvar EHK were included, as no higher-level studies (e.g., randomized controlled trials or cohort studies) were available due to the rarity of this condition. Exclusion criteria were male cases, oral EHK or other unrelated conditions, and literature reviews. We extracted and analyzed data on: patient demographics, time to diagnosis, anatomical distribution, clinical presentation, associated symptoms, histopathological features, patient history, risk factors, HPV status, treatment, and outcomes. Risk of bias was assessed using the CARE checklist and JBI Checklist for Case Series. Additionally, original clinical and histopathological images from our department were included to enhance the review. Results: A total of 19 studies, encompassing 30 cases of histopathologically confirmed vulvar EHK, were identified. Most cases presented with hyperkeratotic plaques and papules localized on the labia majora. Histopathological analysis consistently revealed hyperkeratosis, acanthosis, and vacuolar degeneration in the granular and spinous layers. Misdiagnosis was common, with lesions frequently mistaken for condyloma acuminatum or other vulvar neoplasms. Conservative management, including observation and topical therapies, was associated with disease stability in asymptomatic cases, while surgical excision demonstrated complete remission in all cases where it was employed. The rarity of vulvar EHK and reliance on case reports and series limit the generalizability of findings. Conclusions: Vulvar EHK is often misdiagnosed due to its similarity to malignancies and sexually transmitted infections. This review, the first of its kind, highlights the importance of prompt histopathological diagnosis to avoid the psychological impact of a cancer or sexually transmitted disease diagnosis and unnecessary, distressing, or aggressive treatments. Further research is needed to explore the role of HPV in vulvar EHK and to establish standardized diagnostic and treatment guidelines.
