https://orcid.org/0000-0003-2375-6268
Abstract
Objective
This study aimed to compare the efficacy and safety of focused ultrasound (FU) at different focal depths in treating vulvar lichen sclerosus (VLS).
Methods
A retrospective study was conducted on 84 patients with VLS. Among them, 43 cases were treated with FU at a focal depth of 2.5 mm and 41 cases at a focal depth of 4.0 mm. Therapeutic time, treatment energy, postoperative efficacy, complications and recurrence rates were compared.
Results
No statistically substantially differences in age, disease course, history of immune system diseases, lesion size and severity of symptoms were found between the two groups. All patients successfully received FU therapy. No significant difference in curative rate was observed between the two groups at 3, 6 and 12 months after FU therapy. At 12 months after FU therapy, the recurrence rate of the experimental group (FU treatment at 2.5 mm focal depth) was lower than the control group (FU treatment at 4.0 mm focal depth) (7.0% vs 24.4%, p = 0.027). The experimental group was treated for a shorter period of time [22.69 ± 0.64 (min) vs 24.93 ± 0.72(min), p = 0.022] and at a lower dose[5,026.05 ± 148.00(J) vs 5,484.26 ± 160.60(J) p = 0.039].
Conclusion
Compared with that at the routine focal depth (4.0 mm), FU therapy at a low treatment depth (2.5 mm) can achieve a similar therapeutic effect but lower recurrence rate, therapeutic time and treatment energy. This work provides insight into the optimization of clinical protocols.
1. Introduction
Vulvar lichen sclerosus (VLS), a common chronic inflammatory non-neoplastic skin lesion of the vulva [Citation1], is characterized by vulva and perianal skin thinning, chronic progression and recurrent attacks. Without timely and standardized treatment, VLS can lead to vulvar atrophy, adhesions, scarring, loss of normal anatomy and function of the vulva and a high risk of focal cancer [Citation2]. Differentiated vulvar intraepithelial neoplasia (dVIN) caused by VLS is more likely to develop into vulvar carcinoma than high-grade squamous intraepithelial lesion caused by HPV infection (32.8% vs. 5.7%) [Citation3]. The overall malignancy rate of dVIN is estimated to be 3.5%–7% [Citation4–6]. VLS is easy to diagnose but difficult to treat. Early diagnosis and intervention can improve the long-term prognosis of patients. Owing to special clinical manifestations and possible malignant changes, patients with VLS may suffer from more psychological and mental distress than patients with other diseases [Citation7]. For this reason, patients with VLS are eager to achieve remission through treatment. To date, the pathogenesis of VLS remains unclear. Glucocorticoid therapy is the main treatment for VLS, and photodynamic therapy (PDT), fractional CO2 lasers (FxCO2) therapy, local injection and surgical intervention are also used [Citation2,Citation8,Citation9]. Regardless of treatment, patients with VLS are prone to relapse. Focused ultrasound (FU) features precise localization, tissue penetration, and energy deposition and can produce thermal, mechanical and cavitation effects on the lesion that cause cellular degeneration and necrosis of the diseased tissues. Over time, the devitalized tissues will be replaced by the surrounding healthy tissues, thus completing the targeted destruction of lesions [Citation10,Citation11]. FU can also promote cell proliferation, protein synthesis and revascularisation and accelerate tissue reconstruction to achieve therapeutic effect [Citation12].
To date, FU surgery has achieved certain efficacy as a viable treatment modality. The main pathological manifestations of VLS include the hyperkeratosis of the epidermis, epidermal atrophy with loss of rete ridges, homogenization of collagen in the dermal papillary layer and lichenoid (band-like) inflammatory infiltration in the dermis [Citation9,Citation13]. The curative rate in patients with VLS is significantly lower than that in patients with lichen simplex chronicus (LSC) [Citation14]. In terms of pathological difference, VLS is the thinning of the epidermis and LSC is the thickening of the epidermis. Therefore, FU must be performed at a low depth to easily concentrate the energy on the VLS lesion site to achieve effective treatment and improve the patients’ clinical symptoms and psychological problems. The therapeutic time, treatment energy, safety, efficacy and recurrence rate in the treatment of VLS at different focal depths have not been investigated yet. Using the pathological feature of thinning as basis, this study aimed to evaluate whether a low treatment depth is more favorable to the FU therapy of VLS than the routine focal depth.
2. Materials and methods
2.1. Patients
From January 2018 to June 2021, 84 eligible female patients with VLS were recruited from Chongqing Haifu Hospital, China. Among them, 43 patients received FU treatment at 2.5 mm focal depth in the experimental group and 41 patients received FU treatment at 4.0 mm focal depth in the control group.
Inclusion criteria were as follows: patients who received FU therapy with complete follow-up data; diagnosed as VLS; had no serious heart, liver or kidney disease or uncontrolled diabetes; had no acute genital inflammation, menstruation, gestation or lactation; and with clinical manifestations of VLS. Exclusion criteria were as follows: patients who were contradicted to general and/or local anesthesia or sedation; with vulvar neoplastic epithelial disease; with uncontrolled diabetes during menstruation, gestation and lactation; and with acute inflammatory infection. Data on the age, number of pregnancies, parity, menstruation, clinical manifestations, previous treatments, physical examination results, vulvar biopsy pathological findings, treatment parameters, efficacy and side effects were collected from a review of electronic medical records and telephone follow-up.
2.2. Treatment
The bladder was emptied at first, and skin was prepared preoperatively. The vulvar skin was routinely disinfected with 0.5% povidone iodine solution before treatment. Propofol and fentanyl were administered intravenously as an anesthetic compound. The patients were treated using the Ultrasound Therapeutic Device (Model-CZF, Chongqing Haifu Medical Technology Co., Ltd., China) with a therapeutic power of 3.5–4 W, a working frequency of 10.4 MHz and an impulse of 1000 Hz. This equipment is composed of a generator, two transducers that can be replaced to achieve two different treatment depths, a central console and a circulating degassed water system. Treatment was performed by one trained and qualified physician. The experimental group was treated with a special 2.5 mm-deep transducer, and the control group was treated with a 4.0 mm-deep transducer (a focal depth commonly used in previous studies). During the treatment, the transducer was placed in close contact with the skin of the lesion site via an ultrasonic coupling agent. The treatment range must exceed the edge of the lesion by approximately 5 mm. Linear scans were performed at a speed of 5–10 mm/s until the treated region showed mild congestion and swelling and the skin temperature reached 39 °C–40 °C. The overall treatment time was 10–40 min. Skin iodophor was used to immediately disinfect the vulva after treatment and every time after urination. A cold compress was then applied for 6–12 h. On the first day after treatment, the patients were given a hip bath with 1/5000 potassium permanganate solution twice a day. After sitz bath, scald ointment was applied to the local skin until the edema subsided completely. After treatment, close and regular follow-up was conducted to observe the effect of the treatment.
2.3. Postoperative follow-up and evaluation of efficacy
Regular follow-up was performed in the 1st, 3rd, 6th and 12th months after the treatment. With changes in symptom severity and local skin signs (lesion size, skin color and elasticity) before and after treatment as the criteria, the treatment effect of each patient was assessed 3 months after the surgery. The overall response rate was calculated according to the score table, and the grade was judged according to the efficacy index. The formula was as follows: efficacy index = (total score before treatment − total score after treatment)/(total score before treatment) × 100% [Citation15]. Recovery: curative effect index ≥90% (vulvar pruritus and other symptoms are eliminated, and vulvar skin color and elasticity of the affected skin return to normal). Effective: curative effect index 20%–89% (symptoms such as vulvar itching and burning pain are palliated, vulvar skin color and elasticity are partially restored). Ineffective: efficacy index <20%, or symptoms such as vulvar itching and local skin signs continue to worsen. Recurrence: the patient has symptoms such vulvar itching and pain, rough vulvar skin, hypopigmentation and decreased elasticity in 6 months after treatment. The curative rate is the ratio of cured patients to treated patients, and the total response rate is the ratio of cured patients plus effective patients to treated patients.
2.4. Statistical analysis
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA). Normally distributed continuous variables were depicted as the mean ± standard deviation, and the mean differences were analyzed using Student’s t-test. Non-normally distributed continuous variables were presented as the median and interquartile range and then analyzed using Mann–Whitney U test. Categorical variables were presented as frequencies and percentages for each group and analyzed using Chi-square test and Mann–Whitney U test.
3. Results
3.1. Treatment dose and complications
No significant differences were observed between the two groups in terms of age, duration of disease, presence of depression, history of immune system disorders, lesion size, and severity of symptoms. The demographic characteristics of the patients with VLS are shown in . FU treatment was successfully completed in both groups.The therapeutic time of the experimental group was 22.69 ± 0.64 min, and that of the control group was 24.93 ± 0.72 min. Statistically significant difference was observed between the two groups (p = 0.022). The total treatment energy of the experimental group was 5,026.05 ± 148.00 J, and that of the control group was 5,484.26 ± 160.60 J. Statistically significant difference was observed between the two groups (p = 0.039) ().
Table 1. Demographic characteristics of patients with vulvar lichen sclerosus (VLS).
Table 2. Comparison of treatment parameters and side effects between the two groups.
Immediately after treatment, the skin in the treated region showed slight redness and swelling but no pain in both groups. The congestion and edema of the vulva peaked 24 h after treatment and completely subsided 5–7 days after symptomatic treatment. The skin gradually returned to normal. Two patients in the experimental group developed vulvar skin ulcers 7 days after treatment (). In the control group, one patient developed blisters in the upper part of the vulva on both sides and lesions in the small and large labia after 12 h of treatment, exhibited ecchymosis under the skin after 48 h and developed ulcers after 10 days. In another patient, the lesion was in the lower part of the bilateral interlabial sulcus and the perineum and blisters appeared after treatment and subsequently developed into ulcers. and showed the side effects after FU treatment at 4.0 and 2.5 mm focal depths. Both groups were cured after symptomatic anti-inflammatory treatment without scarring. No urinary tract injury, infection or other serious complications occurred during or after operation in the two groups.
Figure 1. Side effects after FU treatment at 4.0 mm focal depth and the recovery of symptomatic treatment. (a) one patient’s vulvar lesion before FU treatment, (b) the same patient’s vulvar condition immediately after FU treatment, (c) the same patient’s ulcer 12 days after operation and (d) the same patient’s recovery after symptomatic treatment for 7 months after FU therapy.
Figure 2. Side effects after FU treatment at 2.5 mm focal depth and the recovery of symptomatic treatment. (a) one patient’s vulvar lesion before FU treatment, (b) the same patient’s vulvar condition immediately after FU treatment, (c) the same patient’s ulcer 10 days after operation and (d) the same patient’s recovery after symptomatic treatment for 2 months after FU therapy.
3.2. Efficacy
The efficacy of FU treatment for the two groups is shown in . At 3 months after treatment, pruritus was absent and vulva returned to normal in 11 patients in the experimental group. Meanwhile, pruritus was improved, and vulva returned to normal in 26 patients. No change in pruritus and slight changes in vulvar signs were observed in 6 patients. The total curative and response rates in the experimental group were 25.6% and 86.1%, respectively. For the control group, pruritus was cured in 8 patients and palliated in 28 patients, and the treatment was ineffective in 5 patients. The total curative and response rates of the control group were 19.5% and 87.8%, respectively. No statistically significant difference in curative rate was found between the two groups.
Table 3. Comparison of the efficacy of FU therapy between the two group.
At 6 months after treatment, 13 patients in the experimental group were cured, 23 patients claimed to experience improvement, 7 patients showed no specific change, and 1 patient experienced a relapse. In the control group, pruritus was cured in 10 patients, relieved in 25 patients and recurred in 2 patients. The treatment was ineffective in 6 cases. No significant difference in curative rate was observed between the two groups (p > 0.05).
At 12 months after treatment, symptoms recurred in 3 patients (7.0%) in the experimental group. Among which, one patient had milder symptoms than before treatment, and two patients complained of the same symptoms as before with thin skin, white color and no changes. In the control group, 10 patients (24.4%) had recurrent pruritus, of which 5 cases were milder than before treatment and 5 cases were the same as before. The skin became thinner and lighter in color compared with before treatment. No significant difference in curative rate was found between the two groups, but the recurrence rate of the experimental group was lower than that of the control group (p = 0.027). and showed the changes of the clinical manifestation after FU treatment at 2.5 and 4.0 mm focal depths.
Figure 3. Lesion size changed after FU treatment at 2.5 mm focal depth. (a) one patient’s vulvar lesion before FU treatment, (b) 7 days after FU treatment, (c) 3 months after FU treatment and (d) 6 months after FU treatment.
Figure 4. The lesion changed after FU treatment at 4.0 mm focal depth. (a) Clinical appearance before treatment. (b) The skin elasticity and pigmentation of the vulva were almost normal after 3 months of follow-up.
4. Discussion
VLS is a common chronic inflammatory non-neoplastic skin lesion of the vulva with unknown pathogenesis [Citation16]. Increasing evidence suggests that heredity, autoimmunity, hormones, local infection and stimulation may be involved in the pathogenesis of VLS [Citation17,Citation18].
Intractable pruritus is the most common clinical manifestation of VLS that usually occurs at night and may affect the sleep and quality of life in severe cases. It is accompanied by other symptoms, such as genital pain, dysuria, urinary pain, sexual dysfunction and sexual intercourse or defecation pain [Citation19].
The skin texture of VLS is usually characterized by wrinkles or cellophane white patches, accompanied by irregular hyperkeratosis. Skin lesions mainly develop on the labia majora and labia minora, clitoral prepuce, perineal body and perianal skin. These lesions are mostly symmetrically distributed and usually do not involve the hair-bearing skin of the labia majora. The affected skin of the vulva is relatively fragile and typically manifests as purpura, erosion and chapping. Without standardized treatment, VLS may lead to changes in genital anatomy, culminating in vaginal opening and/or anal stenosis [Citation20].
Patients with VLS suffer from anxiety, depression, sadness and pain. Pain leads to less frequent sexual activity, which has a serious negative effect on sexual health [Citation7,Citation21]. Owing to the symptoms of the disease itself and patients’ willingness, the development of a suitable treatment is crucial.
Many treatment methods have been applied for VLS and are mainly divided into drug therapy, physical treatment and surgical intervention. Topical glucocorticoids, such as 0.05% clobetasol propionate ointment, are often the first-line drug therapy for VLS, Calcin-phosphatase inhibitors, such as 0.1% tamoxus cream and 1% pimelimus, are the second-line drugs. Current side effects of glucocorticoids include local irritation, vulvar atrophy, telangiectasia and folliculitis, and the main side effects of calphosphatase inhibitors are local irritation and a possible increased risk of cancer. Issues regarding patients’ compliance and worries about hormone would affect their long-term use, resulting in a high recurrence rate.
Physical treatment for VLS includes PDT and FxCO2 therapy. PDT remains a clinical challenge, and no standardized treatment protocol regarding the concentration of aminolevulinic acid, incubation time, light source (power and wavelength), exposure time (energy and power density) and number and frequency of VLS treatment repetitions has been established [Citation22,Citation23]. For FxCO2 therapy, randomized controlled trials with large sample sizes and standardized measurement criteria are still lacking. Recent short-term follow-up studies showed that the recurrence rate of symptoms increases with the prolongation of operative time after treatment, thus requiring repeated treatment. Therefore, further data collection is still needed to investigate the effectiveness and recurrence rate of laser technology for VLS [Citation24].
Among women with anogenital VLS, surgery should be limited to patients with associated vulvar intraepithelial neoplasia or malignancy or to correct scarring that interferes with normal function [Citation25].
Hence, an effective treatment with a low recurrence rate is necessary. FU therapy is a new noninvasive therapeutic technology that does not entail surgical incision, skin destruction or puncture for the treatment of skin and mucosal lesions. In this therapy, ultrasonic waves can penetrate the epidermis or mucosal epithelium and focus on the superficial dermis or submucosal lesion tissue, thus producing a high-energy focal point. In a short time, the lesion tissue in the targeted region absorbs the energy, heats up rapidly and undergoes biological effects. Given that the diseased tissues with vigorous proliferation are sensitive to ultrasound energy, FU therapy can selectively damage the lesion tissue cells and accelerate the reconstruction of tissues and the improvement of microcirculation [Citation26]. After local inflammation is eliminated, the stimulation of the nerve endings is reduced to alleviate the itching or hypopigmentation of the vulva [Citation7]. The recurrence of surgical intervention was about 39% at 1.5 years follow-up [Citation27], and that under FU therapy is less than 10%. Compared with medical therapy, whether it could be used as supplementary therapy or collaborative therapy, It had a higher efficacy, less morbidity, and safety compared with conventional treatment methods, such as UV phototherapy/photodynamic therapy, and surgical intervention.
VLS is epidermal cell degeneration caused by growth disorder and insufficient nutrient supply after the degeneration of local nerves and blood vessels [Citation28]. Thus, the change of the dermis is secondary to the change of the epidermis. The epidermal thickness under VLS is lower than that of normal epidermis and under LSC, and the dermal thickness under VLS is not significantly different from that under LSC [Citation29,Citation30]. When the conventional 4.0 mm-deep transducer is used to treat VLS, the ultrasound beams may not reach the diseased tissue on the superficial dermis, which is located below the superficial dermis of the lesion, through heat energy diffusion. The observed energy attenuation indicated that the treatment effect on VLS is not as good as that on LSC. Under the premise of safety, the use of 2.5 mm-deep ultrasonic transducer allows the ultrasound energy to be easily focused on the diseased tissue in the superficial dermis, thus improving the therapeutic effects.
This study found that among the 84 patients who received FU treatment, no difference in curative rate was observed. However, At 12 months after FU therapy, the recurrence rate of the experimental group (FU treatment at 2.5 mm focal depth) was lower than the control group (FU treatment at 4.0 mm focal depth) (7.0% vs 24.4%, p = 0.027). The experimental group was treated for a shorter period of time [22.69 ± 0.64 (min) vs 24.93 ± 0.72(min), p = 0.022] and at a lower dose [5,026.05 ± 148.00(J) vs 5,484.26 ± 160.60(J) p = 0.039]. These results suggested that FU therapy at a focal depth of 2.5 mm is efficient in directing the ultrasound energy to the diseased tissue with good curative efficacy.
In terms of safety, FU therapy may cause skin burns and even severe skin damage or coagulative necrosis when used improperly. In addition, it may lead to vulva scarring, hyperplasia and adhesion [Citation31]. Skin burn, the main side effect of FU therapy that manifests as blisters or superficial ulcers, is associated with a rapid increase in temperature due to the accumulation of excessive ultrasound energy on the focal skin surface. This study showed that the incidence of side effects was 4.7% in the experimental group and 4.9% in the control group. These values were lower than that in previous studies. This result may be related to the proficiency of physicians. If the speed of probe movement is too slow, then the ultrasound energy deposition on the epidermis will be excessive, inducing blisters or ulcers. According to Li [Citation32], FU therapy was first applied in the treatment of non-neoplastic epithelial disorders of the vulva to explore the mechanism of vascular and nerve ending reduction. In 76 patients followed up for 2 years, the curative rates of LSC and VLS were 71.11% and 54.84%, respectively. No difference was found between the two groups, 8 (10.52%) patients experienced recurrence, and 4 patients (5.26%) had side effects.
Feng et al. [Citation33] investigated the factors affecting the clinical efficacy of FU and found that the curative rate was 35.29% for VLS and 60.38% for LSC. Statistically significant difference was found between the two diseases (p < 0.05). Ye et al. [Citation14] examined 950 patients who underwent FU treatment between 2008 and 2012 and they discovered that the total response rate was 98.3% and the curative rate of lichen sclerosus was 32.0%, which was lower than that of squamous hyperplasia (44.1%, p = 0.012). Both Feng and Ye found that the curative rate of VLS was lower than that of LSC.
In our study, the curative rates in the experimental and control groups were 25.6% and 19.5% at 3 months, respectively, 30.2% and 24.4% at 6 months, respectively, and 32.6% and 26.8% at 12 months, respectively. The curative rate at 12 months in our study was not different from that in Ye’s [Citation14]. Although 2.5 mm focal depth did not improve the curative rate, the 1-year follow-up observation showed that the recurrence rate of the experimental group was lower than that of the control group (p = 0.027), suggesting that 2.5 mm focal depth is favorable for patients with VLS. The recurrence rate of FU therapy at a focal depth of 4.0 mm was similar to that reported by Li [Citation31].
This study has several limitations. First, the sample size is small. In addition, the initial experimental design is not rigorous enough, and the biopsies are difficult to obtain. Second, this study has a retrospective design. If prospective studies are conducted to collect pathology before and after treatment, then reliable conclusions can be obtained from long-term observation. Third, the follow-up time is relatively short. Additional work and long observation times are needed to further verify the differences in the curative and response rates.
5. Conclusion
Compared with that at the routine focal depth (4.0 mm), FU therapy at a low treatment depth (2.5 mm) can achieve a similar therapeutic effect but lower recurrence rate, therapeutic time and treatment dose. This work provides insight into the optimization of clinical protocols.
Ethical approval
Our research fully complied with experimental ethics and had been approved by the ethics committee of Chongqing Haifu Hospital. (Approved protocol number: 2022-008, Date of approval: August 1, 2022). We fully complied with the ICMJE requirements on privacy and informed consent from patients and study participants.
Acknowledgements
The authors thank the staff in Chongqing Haifu Hospital for their support in this study.
Disclosure statement
No potential conflict of interest was reported by the author (s).
Additional information
Funding
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