The Terminology History of NNEDV

NNEDV are a group of common vulvar non-infectious, benign dermatoses. Characteristic clinical manifestations include vulvar pruritus, pain, dyspareunia, skin depigmentation, rhagadia, adhesion and atrophy. Epidemiological studies showed that NNEDV may be associated with genetic [10-13] and immune factors [14, 15], however, the etiology remained unknown. Initially, NNEDV was named vulvar leukoplakia, neurodermatitis, etc. In 1976, the International Society for the study of Vulvovaginal Disease (ISSVD) used the word dystrophy as a neutral term to substitute previous nomenclature to clearly separate these benign disorders from the premalignant and malignant epithelial conditions. Dystrophy was subdivided into 3 categories: lichen sclerosus, hyperplastic dystrophy and mixed dystrophy [16]. However, the dermatologists and dermatopathologists recommended elimination of the nomenclature because of its imprecision and lack of usefulness. In 1987, ISSVD discontinued the use of the term dystrophy and replaced with NNEDV, which contained 2 specific categories: (lichen sclerosus and squamous epithelial hyperplasia) and 1 general categories (other dermatoses) [17]. And this classification system remained in use to the present. However, NNEDV was misleading in that many of the conditions were not solely, or even primarily, epithelial. Based on pathologic subsets and their clinical correlates, 2006 ISSVD Classification of Vulvar Dermatoses was then issued, which included 8 histologic patterns: spongiotic pattern, acanthotic pattern (formerly squamous epithelial hyperplasia), lichenoid pattern, dermal homogenization/sclerosis pattern, vesiculobullous pattern, acantholytic pattern, granulomatous pattern, vasculopathic pattern and a list of the diseases most commonly demonstrating that pattern. Then, using clinicopathologic correlation, the clinician could almost always determine the most likely diagnosis [18]. To assist clinicians to arrive at a diagnosis based solely on clinical findings, ISSVD published 2011 ISSVD Terminology and Classification of Vulvar Dermatological Disorders: An Approach to Clinical Diagnosis. About 50 of the most commonly encountered disorders along with a few uncommon conditions that are so important (e.g., melanoma) were listed in 8 morphological groups. Notably, it does not supplant the 2006 ISSVD Classification of Vulvar Dermatoses, which remains an important tool where a specific clinical and/or biopsy diagnosis is not possible [19].

HIFU Treatment of NNEDV

Topical corticosteroids are the mainstay of therapy and treatment with a superpotent topical corticosteroid, such as 0.05% clobetasol propionate, has long been considered the standard of care. Approximately 89~95% of patients reported improvement of symptoms [20, 21]. In 1927, ultrasound was first described by Loomis and Wood as having a biologic effect on living tissues [22]. Thermal ablation occurs when the targeted delivery of heat or cold causes a rapid change in temperature >55°C for heat or < -20~50°C for cold in the local tissue environment. The ability of focus ultrasound to induce thermal or mechanical effects at focal locations in living tissue has long been recognized; the earliest exploration of the medical use dates to 1942, when Lynn et al first tested it in the brain. Notably, in the 1950s the Fry brothers developed a clinical focus ultrasound device for treating patients with hyperkinetic disorders such as Parkinson disease [23,24]. HIFU is a completely non-invasive thermal ablation technique, which can accurately localize the target tissue by using ultrasound or MR imaging guidance. In particular, MR imaging guidance and MR imaging thermometry allows for accurate targeting, real-time monitoring, and even control of energy deposition. This disruptive technology can revolutionize the various fields of surgery and has replaced partial surgery in breast, liver, prostate cancer etc. In gynecology, focused ultrasound with ultrasound and MR guidance has been approved to treat uterine leiomyomas in Europe and USA, respectively. In the last 20 years, more reports showed HIFU is safe and effective in NNEDV with effective rate of 90~98% and recurrence rate of 9~36% [3, 4, 8, 25, 26]. The treatment was statistically more effective in younger patients with squamous hyperplasia and smaller lesions than in older patients with lichen sclerosus and larger lesions [8].

 Characteristics and Mechanism of HIFU Treatment

Skin consists of 3 layers: epidermis, dermis and subcutis. The skin thickness of epidermis and dermis (with exception of subcutis) usually varies from 0.5mm to 4mm, depending on different individuals, ages and sites [27,28]. Since NNEDV involve epidermis and dermis on histologic examination, HIFU treated the skin with the focus of 4~6mm and the depth of <8mm without ultrasound or MR guidance (Figure 1). On one hand, treatment is simple, convenient and low cost. On the other hand, without real-time monitoring and control of energy deposition, clinicians have to determine the treatment time and doses by the size and extent of lesions and the degree of skin edema. Different degrees of swelling and congestion may last for 3~7 days in nearly all patients. Scalding change may appear in a few patients due to nonuniform movement of the probe. Since the judgments of degrees of skin edema to stop treatment were different among clinicians, dramatic differences in treatment time existed in literature, ranging from 8 min to 60 min, with scalding, blisters or ulcer in 2~10% of patients and ulcer in 2~3% of patients [8,25,29]. Compared with the previous studies, the treatment time in our experience was shorter with the average time 2 min (113s, ranging from 1~5min), and the incidence of complication was in accordance. Up to now, there have been no reports on the doses of vulvar HIFU treatment, and shortage of safe, effective and quantified therapeutic dose studies. Lack of standardized treatment protocol is an important factor which hampers its clinical application.

Quantified Experience of Hifu Treatment

Photos of patients is shown below in photo(a) to photo(g). Our data in the past decade show that HIFU is an effective treatment of NNEDV, which is consistent with previous reports in efficacy, recurrence and complication rates3, 4, 8, 25, 26. Based on analyzing respective symptoms and signs after treatment, the efficacy in improving the pruritus were higher than skin color and elasticity. Before HIFU treatment, 39 of 93 patients complained severe pruritus (pruritus score 3). They were severely affected by the intolerable pruritus and often could not sleep at night. After treatment, 11 patients (29%) had no pruritus (pruritus score 0); 19 patients (50%) had mild pruritus (pruritus score 1); 7 patients (18%) had moderate pruritus (pruritus score 2) and only 1 patient (3%) still had severe pruritus (pruritus score 3). In our perspective, the therapeutic doses should correlate with the lesion areas. Therefore, treatment areas, doses, time and other parameters in all patients were recorded in order to study the treatment doses per unit area. The results showed that the safe doses per unit area varied to a great extent (8-92 J/cm2). In the safe range, the doses were not linearly correlated to efficacy. That is, a higher dose is not associated with the better effect. The average dose per unit area 41 ± 22 J/cm2 in effective group and 27 ± 12 J/cm2 in the best effect group (pruritus score 3 before treatment and 0 after treatment). Hence, there remains a relatively wide range in effective or curative doses and future studies are in need to investigate more accurate doses within the range.