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Physiotherapy based on energy as a valuable form of treatment for vulvar lichen sclerosus: a review of the literature

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Abstract

Vulvar lichen sclerosus (VLS) is an inflammatory, non-neoplastic dermatosis affecting individuals of all ages, with symptomatic peaks often observed during puberty and menopause. The primary symptoms of VLS include progressive vulvar itching and pain, which can lead to vulvar scarring and sexual dysfunction in later stages, significantly affecting the quality of life for patients. Currently, despite the availability of numerous therapeutic options, treatment outcomes remain less than satisfactory. Energy-based physical therapies, such as photodynamic therapy, laser therapy and high-intensity focused ultrasound, have demonstrated positive therapeutic effects on VLS in various pioneering studies. This review aims to provide an overview of the research progress and potential mechanisms of these physical therapies in the context of VLS while also comparing related treatment methods to emphasise the advantages of energy-based physical therapy for this condition.

Introduction

Lichen sclerosus (LS) is a chronic inflammatory skin disease that primarily affects the genital and anal regions. The main symptoms of LS include pruritus and pain, which significantly impact the quality of life of affected individuals.1 LS occurs in all age groups and affects both sexes, although it has a higher incidence in women than in men. Among female patients, the prepubertal and postmenopausal periods represent two peaks of incidence, with prevalence rates ranging from 0.1% to 3% in these groups.2 3

It is important to note that patients with vulvar lichen sclerosus (VLS) have an elevated risk of developing genital cancer compared with women without this condition. Research indicates that approximately 5% of women affected by LS progress to vulvar squamous cell carcinoma.4 In addition to the common symptoms of pruritus, burning pain, stinging and discomfort are particularly distressing for patients with VLS, especially during sexual intercourse.5 The chronic inflammation in VLS is thought to contribute to progressive scarring, a core feature of the disease believed to stem from an aberrant wound-healing process, though this mechanism has not been definitively proven. This scarring may result in irreversible alterations to the pudendal structures. The combination of cancer risk, painful symptoms and anatomical changes renders VLS a condition that significantly affects both the physical and psychological well-being of patients.

There is increasing evidence that VLS significantly affects the well-being and quality of life of patients. The bothersome symptoms, chronic nature, sexual dysfunction, disfigurement due to anatomical changes, partial and temporary responses to treatment and the risk of progression to cancer are major factors contributing to the burden associated with VLS. Despite the considerable health impact of VLS, a definitive cure remains elusive, as its precise pathogenesis is still not fully understood.

Corticosteroids are the first-line treatment for VLS, achieving complete symptom relief in approximately 70% of patients. However, this indicates that around 30% of patients with VLS do not respond to corticosteroid therapy.2 The role of energy-based physiotherapy modalities, such as phototherapy, laser therapy and photodynamic therapy (PDT), in the treatment of VLS is particularly noteworthy due to their high efficacy and favourable cosmetic outcomes. This article will summarise the principles of these three energy-based physiotherapy approaches and compare them with other treatment options.

Mechanisms of various energy-based physical therapies

Although the precise aetiology of VLS remains unclear, current evidence indicates that inflammation and immune dysregulation, abnormal collagen synthesis and oxidative stress constitute the primary pathological mechanisms underlying VLS.6 7 While oestrogen status, particularly low oestrogen levels, is considered a potential modulating factor that may exacerbate symptoms, it is not regarded as the central determinant of the disease process. The abnormal activation of the Th1 autoimmune response, coupled with impaired immune tolerance due to decreased function of Treg cells in VLS lesions, can trigger heightened autoimmunity, resulting in a chronic inflammatory state in VLS.8–10 Additionally, oxidative stress in VLS contributes to tissue sclerosis and scar formation and can also lead to damage within the microvascular system and activation of endothelial cells, which further exacerbates tissue damage in VLS.11 Furthermore, the aberrant activation of signalling pathways involved in fibroblast function and collagen metabolism has been identified as a significant factor in the fibrosis of VLS tissues.12 Given these pathological changes, treatment modalities, such as PDT, fractional CO2 laser and high-intensity focused ultrasound (HIFU), may be effective in addressing VLS by improving the chronic inflammatory state, eliminating diseased cells and promoting dermal remodelling(figure 1).

Figure 1

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Mechanisms of various energy-based physical therapies for VLS. (a) The mechanism of PDT for VLS. Intramitochondrial light transforms PS from singlet ground state S0 to excited triplet state 3PS*. The energy released from this reaction converts oxygen into cytotoxic ROS, which plays a therapeutic role in VLS lesion tissue through ROS. These effects include apoptosis or necrosis of diseased cells, activation of immunity, injury of endothelial cells in the blood ring and promotion of collagen production. (b) The mechanism of laser therapy for VLS. FxCO2 can cause microthermal damage and ablation zones in the superficial and deep skin, respectively. Chromophores convert light energy into heat energy through photothermal interactions, thereby causing damage to the diseased tissue of VLS. It also promotes angiogenesis and collagen production in the lesion area. (c) The mechanism of HIFU for VLS. The HIFU transducer focuses the US beam to a focal point, and then passes through thermal heating, inertial cavitation and mechanical effects to form a therapeutic effect. HIFU is able to promote the production of blood vessels, collagen, nerve endings and other proteins. FxCO2, fractional carbon dioxide; HIFU, high-intensity focused ultrasound; PDT, photodynamic therapy; PS, photosensitiser; ROS, reactive oxygen species; US, ultrasound; VLS, vulvar lichen sclerosus.

Mechanisms of PDT for VLS

PDT is a modern and non-invasive treatment modality that has been successfully employed in the management of gynaecological and dermatological diseases. PDT fundamentally requires three distinct components to induce cytotoxicity: a photosensitiser (PS), light of an appropriate wavelength and oxygen dissolved in the target diseased cells13 (figure 1a). These components engage in photochemical reactions that generate cytotoxic reactive oxygen species (ROS), resulting in the destruction of diseased cells and tissues. The production of ROS can be categorised into type I and type II photodynamic reactions. The initial stage of both types involves the conversion of intracellular PS from the singlet ground state to the excited triplet state T1 in the therapeutic process.14 These reactions subsequently generate ROS through electron transfer or direct energy transfer mechanisms.15

There are two primary mechanisms underlying the phototoxic effects of ROS generated by PDT in vascular lesion tissues: cytotoxicity and vascular toxicity.16 17 The direct cytotoxic effect of ROS on diseased cells occurs through both programmed (apoptosis) and non-programmed (necrosis) pathways. Typically, high-intensity light induces rapid and extensive cell necrosis, while low-dose light triggers genetically encoded and energy-dependent apoptosis.16 18 The vascular effects of PDT arise from ROS-induced damage to vascular endothelial cells. This destruction of the vessel wall disrupts the blood supply to the local lesion tissue, leading to ischaemic necrosis of the affected area.19

In addition to its phototoxic effects on target tissues, PDT can stimulate a variety of inflammatory mediators and immune cells, thereby improving the chronic inflammatory state associated with VLS. The cell death induced by ROS can elicit a specific immune response, promoting the production of various cytokines, such as vascular endothelial growth factor (VEGF), interleukin-1 beta (IL-1β), interleukin-2, tumour necrosis factor-alpha (TNF-α) and cyclooxygenase-2.20 21 This transient upregulation of inflammatory mediators is a crucial part of initiating a controlled wound-healing cascade. Rather than perpetuating the pathological state, this acute inflammatory phase serves to clear damaged tissue and actively recruit cells necessary for regeneration. Fibroblasts also secrete matrix metalloproteinases (MMPs) in response to PDT.22 These cytokines and MMPs play crucial roles in skin remodelling. Specifically, the coordinated action of TNF-α and IL-1β helps to break down the aberrant extracellular matrix, while VEGF-driven angiogenesis improves tissue perfusion and nutrient delivery. This process of controlled inflammation, matrix degradation and subsequent reconstruction is central to alleviating the fibrosis and ischaemia that underpin VLS symptoms like itching, pain and skin fragility. Furthermore, PDT exerts an indirect effect on the skin by promoting collagen synthesis, which alleviates the fibrotic condition of the skin presenting with VLS lesions.23 The increase in type I and type III collagen following PDT treatment enhances dermal remodelling, thereby increasing the collagen density in the skin of VLS lesions and correcting epidermal hyperkeratosis.24 25

The light of an appropriate wavelength also has a therapeutic effect on VLS lesion tissue. 5-aminolevulinic acid (5-ALA) is the most commonly used photosensitising agent for gynaecological and dermatological conditions. The absorption peak of 5-ALA primarily occurs within the 500–635 nm range, making red light the most effective light source for the clinical treatment of VLS.26 27 Red light promotes the production of type I collagen and improves the quality of diseased skin in patients with VLS. In addition, red light can reduce the release of related inflammatory factors and enhance the phagocytic capacity of leucocytes, which has anti-inflammatory and analgesic effects on VLS lesions.28

It is critical to distinguish between the mere quantity and the quality of collagen. The increase in collagen density reported after PDT likely signifies a qualitative improvement in the dermal architecture. The goal is not simply to add more collagen but to induce its remodelling by breaking down the pathological structure and promoting the formation of a healthier, more elastic matrix, thereby alleviating the fibrosis of VLS.

Mechanisms of laser therapy for VLS

Lasers are devices in which an external energy source stimulates a suitable medium to emit laser beams.29 The three fundamental components of a laser include an excitable medium, a resonator cavity equipped with mirrors to reflect light back and forth and an external energy source. Fractional carbon dioxide (FxCO2) lasers are regarded as the gold standard in dermatology, particularly for vascular lesions.30 31 FxCO2 lasers can be categorised into two types: ablative lasers, which can vaporise the epidermis and papillary layer, creating a microthermal damage zone that ablates both superficial and deeper tissue layers; and non-ablative lasers, which form a coagulation zone while preserving the superficial epidermis29 (figure 1b).

Lasers treat VLS through photothermal interactions with tissues. Chromophores, which are chemical groups within cells that can absorb light, convert this light into heat when stimulated by an external energy source. These chromophore-containing cells subsequently transfer heat to the surrounding lesion tissue, thereby serving a therapeutic role.29 32 The laser is emitted in a pulsed manner to minimise the risk of overheating damage to the tissue. The photothermal effects of laser treatment have both histological and immunological impacts on VLS.33–35 Histologically, this effect is characterised by the formation of new blood vessels and collagen, which is attributed to an increase in the levels of TNF-α, IL-1β, MMPs and other cytokines induced by the laser.36 Additionally, laser treatment can decrease the infiltration of inflammatory cells and lower the production of proinflammatory cytokines, thereby altering the local immune environment of VLS and influencing the vaginal flora.37

Mechanisms of HIFU for VLS

HIFU is a needleless, non-ionising tissue thermal ablation technique. Therapeutic ultrasound (US) intensities fall within the high-intensity range, typically between 100 and 10 000 W/cm² or higher.38 The emitted high-intensity US necessitates the use of a HIFU transducer to focus the US beam to a focal point. Current beam focusing techniques include geometric focusing, acoustic lens focusing and electronic focusing, all of which effectively achieve localised US delivery during HIFU treatment.38 HIFU leverages the physical interaction between US and lesion tissue to exert a therapeutic effect, encompassing thermal heating, inertial cavitation and mechanical effects (figure 1c). When the focused US is absorbed by the tissue, it is converted into thermal energy, which can rapidly elevate the local tissue temperature to over 60 °C within seconds, leading to the coagulation of tissue proteins and subsequent coagulation necrosis.39 Typical thermal lesions are oval in shape, ranging from 50 to 300 mm³.

The second physical effect contributing to tissue damage is inertial cavitation. This phenomenon occurs when the pressure within a bubble formed under high sound intensity surpasses a certain threshold, resulting in a violent collapse of the bubble that generates local heat and strong pressure waves.40 41 In addition to thermal heating and inertial cavitation, the mechanical effects of HIFU include tissue displacement caused by radiation forces and cellular damage due to radiation torque.41

HIFU not only induces tissue necrosis through physical energy but also promotes collagen synthesis, stimulates cell proliferation and accelerates tissue reconstruction.42 43 Relevant studies indicate that HIFU can inhibit the expression of Notch1 and c-Fos protein in the genital skin of female Sprague-Dawley (SD) rats with chronic vulvar lichen simplex while promoting the expression of TGF-β3, thus reducing the density of collagen fibres and inhibiting collagen fibrosis in the superficial dermis.44 Additionally, another study demonstrated that, following HIFU treatment, the vulvar tissue structure of patients with vulvar lichen simplex returned to normal pigmentation, with an increase in the number of microvessels, nerve terminals and fibroblasts in the subdermis.45 Furthermore, HIFU also promotes protein synthesis and revascularisation in VLS lesions, thereby accelerating the generation of new tissue.

Physiotherapy based on energy for VLS

Currently, there is no cure for VLS; however, various treatments have been investigated to alleviate symptoms and slow disease progression. These treatments include topical corticosteroids (TCSs), immunosuppressive agents, fat grafting and physical therapy, with ultrapotent TCSs recognised as the gold standard for VLS management. Additionally, PDT, FxCO2 laser therapy and HIFU may be considered for some patients with VLS who do not respond to conservative treatment or who are drug resistant.6 46 Although these energy-based physical therapies are not highly recommended, they possess distinct characteristics. In the following sections, we will compare these physical therapies with the gold standard treatments to elucidate their advantages, limitations and specificities (table 1).

Table 1

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Characteristics of various energy-based physical therapies for VLS

Characteristics of PDT for VLS

PDT can alleviate both subjective symptoms in patients with VLS. Several studies have demonstrated the efficacy of PDT in reducing pruritus among patients with VLS, with significant reductions observed post-treatment as measured by the horizontal visual analogue scale (VAS) scores.47–51 A randomised controlled trial involving 20 participants compared 5-ALA-PDT to clobetasol propionate for the treatment of VLS. The results indicated that the complete response rate in the PDT group (14 out of 20) was double that of the clobetasol propionate group (7 out of 20), with VAS scores further suggesting that PDT was more effective than clobetasol propionate.52 Another distressing symptom of VLS is sexual dysfunction, for which relevant studies have also indicated that PDT positively impacts sexual function in patients. Relevant studies have also shown that PDT has a good effect on improving sexual function in patients.50 53–56 Notably, Zhang et al conducted a study examining the effect of PDT on sexual function in ten patients with VLS, reporting that nine out of ten patients expressed high satisfaction with the treatment outcomes, while one out of ten patients was satisfied.50 Additionally, a clinical study involving 102 patients with VLS revealed that PDT treatment provided significant relief of clinical symptoms, with an improvement rate of approximately 87.25%.57

Significant improvements in objective signs following PDT treatment have been documented. Notably, Osiecka et al reported that PDT treatment facilitates the healing of superficial erosive tissue.48 55 Additionally, Li et al observed a substantial reduction in objective total scores for signs, such as leukoplakia, erythema, hyperkeratosis, purpuric lesions and pruritus-related exfoliation after PDT treatment.51 A retrospective study involving 42 patients with VLS evaluated the effects of PDT treatment, revealing that after 1 year of ALA-PDT treatment, the clinical effective rate was 64.29% (27/42). Furthermore, ALA-PDT was shown to significantly enhance skin elasticity, improve skin colour and reduce the lesion area.58

Selectivity is a noteworthy characteristic of PDT, as photocytotoxic reactions primarily occur in pathological tissues. This high but not absolute selectivity can be attributed to two main factors: the preferential accumulation of PSs in lesion cells and the production of ROS during PDT, which damages vascular endothelial cells, thereby accelerating the demise of the lesion tissue,27 and the other is that ROS produced by PDT can damage vascular endothelial cells.59 The lesion areas of VLS typically exist in a prolonged state of chronic inflammation. Research indicates that the inflammatory microenvironment can promote the retention or concentration of PSs in these inflammatory regions.60 It is important to clarify that while PDT exhibits a preferential effect on diseased tissues, exposed healthy cells in the treatment field can also be affected, which contributes to its side effects.

Safety is a significant advantage of PDT in the treatment of VLS. As the most commonly used PS for VLS treatment, 5-ALA exhibits a rapid degradation rate in the body and is quickly metabolised after fulfilling its therapeutic role.61 Furthermore, 5-ALA typically demonstrates shallow penetration depth and low toxicity to deeper tissues.62 PDT is a non-invasive treatment that enjoys higher patient acceptance compared with surgical options. However, the systemic side effects of highly potent corticosteroids used in VLS treatment can include weight gain, hyperglycaemia and osteoporosis.63 Additional advantages of PDT include short treatment duration, low cost, good patient tolerance and the capability to address multiple lesions simultaneously.16 27 Moreover, a study investigating the effects of PDT on pregnancy and delivery indicated that PDT treatment did not adversely affect fertility among the subjects.64 Consequently, PDT appears to be a suitable option for patients with fertility considerations; however, further authoritative clinical studies are necessary to validate this conclusion.

PDT also offers cosmetic and rejuvenating benefits in the treatment of VLS. Several studies have demonstrated that PDT can improve fine lines, speckle-like hyperpigmentation, tactile roughness and a waxy appearance.23 Maździarz et al conducted a study involving 102 patients with VLS, revealing that PDT did not lead to scar formation and resulted in favourable cosmetic outcomes.57 Importantly, PDT is a therapeutic approach that can address precancerous lesions and malignancies, with the reduction of cancer transformation risk being a vital objective in VLS treatment,2 so PDT meets this expectation.

Like all treatment modalities, PDT has certain limitations. While almost all studies have reported adverse effects associated with PDT, the overall performance of the treatment has been well tolerated, as the adverse effects were generally mild, and none of the studies discontinued treatment due to complications. Among these adverse effects, pain during or after treatment is the most commonly reported issue. The Vano-Galvan study noted that patients experienced significant pain intensity during PDT, which led to the termination of their treatment plan. Additionally, PDT is effective only at the irradiated site, making it less suitable for cases where the affected skin area is extensive.65 However, intravenous PSs are frequently employed in the treatment of tumours and other skin conditions, such as port wine stains.66 67 In cases where vascular lesions are extensive or particularly severe, exploring systemic PDT as a treatment option for VLS represents a promising avenue for future research.

Characteristics of laser therapy for VLS

CO2 lasers have been used for the treatment of LS since 1984, with the US Food and Drug Administration approving lasers for gynaecological applications in 1997 for incision, excision, ablation, evaporation and coagulation of soft body tissues.29 Although the efficacy of laser treatment for VLS has been recognised for many years, and numerous studies have investigated the effectiveness of fractional CO2 lasers in recent years, there remains insufficient evidence to robustly support the use of CO2 lasers for VLS treatment.

Several studies have indicated that laser treatment can lead to improvements in VLS symptoms. Mortensen et al summarised data from 263 patients who underwent vulvar laser treatments (comprising nine CO2, one Eu: YAG and one Nd: YAG lasers). Among these, three randomised controlled trials with a maximum follow-up of 6 months and a total of eight trials demonstrated significant symptom improvement in VLS, with no serious adverse events reported.68 In 2022, Krause et al conducted a randomised controlled trial involving 63 patients with VLS, using low-dose CO2 laser as a placebo, and found that even low energy density lasers could improve LS symptoms without serious adverse events during the study.69 Additionally, another study reported positive histological changes in VLS following CO2 laser treatment, with H&E staining revealing improvements in sclerosis, swelling and telangiectasia, as well as a reduction in sclerotic areas infiltrated by inflammation.70

CO2 laser therapy can be considered a viable alternative to corticosteroid treatment, with numerous studies indicating that it is a promising option for patients who either do not respond to topical glucocorticoids or wish to minimise long-term glucocorticoid use. In one study, 40 patients with VLS were randomly assigned to either the laser treatment group or the control group receiving topical glucocorticoids in a 1:1 ratio. The results demonstrated that symptoms of LS—such as burning, itching, pain and dyspareunia—as well as overall patient satisfaction were significantly better in the laser group compared with the topical hormone group.71 Additionally, another study involving patients with VLS who were refractory to TCS therapy found that fractional CO2 laser therapy resulted in substantial symptom improvement without serious adverse effects, thereby supporting the use of laser therapy as an effective treatment for patients with VLS who have not benefited from long-term, ultrapotent TCSs.72 Furthermore, several other studies have corroborated these findings.73–75

In addition to the enhanced therapeutic effects of laser therapy on patients with VLS, there are several other advantages. FxCO2 exhibits minimal collateral damage, with tissues outside the targeted area generally remaining unaffected. Furthermore, FxCO2 is convenient and quick to operate, typically requiring only 5–10 min for completion, with good results achievable after 1–4 sessions.76 Additionally, related studies have indicated that FxCO2 can stimulate the vaginal epithelium to release glycogen and acidic mucin, thereby restoring vaginal mucosal pH, maintaining vaginal health and effectively preventing infection.77

Although numerous studies have shown promising results with FxCO2 in the treatment of VLS, and some have suggested that FxCO2 may serve as a substitute for steroids in managing this condition, there remains insufficient evidence to advocate for lasers as a first-line treatment option. There is a pressing need for larger, longer duration and higher quality randomised controlled trials, alongside improved standardisation of treatment protocols. Only then can lasers be considered for routine treatment of VLS. Currently, several randomised trials investigating FxCO2 are underway globally.78 79 Notably, a trial titled ‘Fractionated CO2 Laser With and Without Clobetasol for Treatment of VLS (VULVIE)’ is being conducted in the USA, which may provide insights into the potential for lasers to be employed as a first-line therapy for certain patients.79 Furthermore, additional studies with long-term monitoring of the effects of laser therapy are urgently required to establish the safety and efficacy of this treatment modality. Viereck et al also presented a randomised trial comparing laser treatment to topical steroids for VLS, featuring a follow-up period of 2 years.80

Characteristics of HIFU for VLS

Like PDT and laser therapy, HIFU represents a non-invasive physical therapy. Currently, there are limited studies on the application of HIFU for the treatment of vulvar dystrophy compared with the other two physical therapies, and there is a notable absence of large-scale clinical trials investigating the efficacy of HIFU in treating VLS. Nonetheless, the safety, simplicity and targeting characteristics of HIFU suggest its potential for addressing vulvar skin lesions.

Currently, several studies have demonstrated the safety and efficacy of HIFU in the treatment and management of adult vulvar skin diseases. One study involving 950 patients with pathologically confirmed non-neoplastic epithelial lesions of the vulva, including VLS, with complete follow-up data, indicated that HIFU was effective in alleviating symptoms and signs associated with vulvar conditions, with no serious complications reported during or after treatment.81 Another retrospective study analysed clinical data from 84 patients with VLS, comparing the efficacy and safety of focused US at different focal depths. The findings revealed that HIFU treatment at both conventional depth (4.0 mm) and low depth (2.5 mm) effectively improved symptoms and signs in patients with VLS; however, the low treatment depth resulted in a lower recurrence rate, reduced treatment time and decreased treatment energy.82 Beyond adult vulvar skin diseases, HIFU has also shown effectiveness in treating VLS in children and adolescents. A retrospective study evaluated the efficacy and safety of high-fidelity US in the treatment of VLS in children and adolescents.83 A retrospective study assessing the efficacy and safety of HIFU for VLS in younger patients reported that the treatment effectively relieved symptoms and improved genital signs, with a cure rate of 42.2%, an effective rate of 56.1% and a low recurrence rate of 9.4%. It is important to note that the vulvar region in children and adolescents is not fully developed, and their skin is relatively fragile. Therefore, excessive output power from HIFU may lead to skin burns and more severe coagulation necrosis due to high-intensity US.

In addition to the limitation that there is no large-scale study providing strong evidence for the efficacy of HIFU treatment of VLS, relevant studies indicate that various factors influence the effectiveness of HIFU in this context. One study demonstrated that the success of HIFU in treating non-neoplastic epidermal diseases of the vulva is associated with age, lesion size and pathological type. Furthermore, the recurrence rate following treatment may be linked to the duration of the disease and its pathological subtype.81 Specifically, HIFU treatment appears to be more effective in younger patients with squamous hyperplasia and smaller lesions, compared with older patients with LS and larger lesions. Additionally, the recurrence rate is significantly higher in patients with a prolonged disease duration or LS, as opposed to those with a shorter disease duration or squamous hyperplasia.

The development of energy-based physiotherapy for VLS

Current studies indicate that PDT, laser treatments and HIFU have demonstrated positive effects in alleviating symptoms and signs, ensuring safety, enhancing patient satisfaction and minimising adverse reactions. When interpreting these findings, especially the high rates of patient satisfaction, the potential for a significant placebo effect must be acknowledged. This is a critical consideration in vulvar disease trials, as subjective symptom perception is highly susceptible to psychosocial influences. Consequently, various combined strategies for the treatment of VLS and new treatment modalities developed from individual techniques have been explored. These strategies encompass laser-assisted hormonal therapy, combinations related to PDT and innovative therapies.

Laser-assisted corticosteroid therapy for VLS

Although TCSs are the first-line treatment for VLS, this monotherapy may result in inadequate symptom relief or recurrent episodes in some patients. In recent years, researchers have begun to explore the potential of combining fractional CO2 laser therapy with corticosteroids to enhance treatment efficacy. The FxCO2 can improve the underlying skin condition, thereby making subsequent steroid treatments more effective. Some studies have reported significant symptom improvement following laser treatment, which subsequently increased the effectiveness of steroid therapy.73 74 84 One study used the Likert scale to assess the presence of clinical symptoms and their impact on the quality of life in patients with VLS receiving FxCO2 laser as maintenance therapy alongside TCSs and any exogenous hormones. Additionally, the female sexual function index was employed to evaluate changes in sexual function before and after FxCO2 treatment. The results indicated that fractional CO2 laser therapy led to improvements in major clinical signs and structural changes in patients with VLS who had not responded to TCS therapy.74 Beyond the reported capability of FxCO2 laser to enhance corticosteroid efficacy, other studies have demonstrated that Nd:YAG/Er:YAG dual lasers can also serve as an adjuvant treatment modality for corticosteroids.80 This prospective, randomised, active drug-controlled clinical trial compared the efficacy of the novel Nd:YAG/Er:YAG non-invasive dual-laser therapy with the gold standard treatment for LS and found that dual-laser therapy may offer a new treatment option for VLS. It is critical to state that all energy-based modalities discussed are considered adjuvant, non-first-line therapies for VLS. Their efficacy is not yet firmly established, outcomes can be variable, and they entail potential adverse effects that warrant caution.

PDT-related combinations and novel therapies

Numerous studies have demonstrated that PDT is an effective treatment method for VLS. However, multiple sessions are often required to achieve satisfactory outcomes. Consequently, various combination therapies and novel approaches related to PDT have been explored for patients with VLS. Notably, high-frequency fulgation combined with PDT has shown promising results in a limited number of patients.

A recent study investigated the use of high-frequency electrocauterisation in conjunction with ALA-PDT in seven patients with VLS. The approach involved initially performing high-frequency resection of lesions and leukoplakia, followed by a period of wound healing before administering PDT treatment. Prognostic evaluations were then conducted to assess the severity of pruritus and the presence of pigmentation changes. The results indicated a significant alleviation of pruritus in all patients, with no recurrence of skin lesions observed, suggesting that the combination of high-frequency electrocautery and PDT represents a promising therapeutic strategy for VLS.85 Additionally, another case report described the use of holmium laser therapy alongside ALA-PDT for treating VLS, yielding high patient satisfaction and good tolerance. The combination of holmium laser therapy and ALA-PDT appears to enhance treatment efficacy for patients with VLS.86 Although these studies exploring PDT in combination with other therapies have involved only a limited number of subjects, they have consistently demonstrated encouraging outcomes. To draw more definitive conclusions regarding the effectiveness of these combination therapies, further research involving larger study populations is warranted.

Red light is the preferred light source for the majority of PDT treatments for VLS. However, red light is associated with significant local pain during PDT, which has led some patients to discontinue treatment.87 88 In response, some studies have investigated the use of green light (495–570 nm) as an alternative light source during PDT. Green light has been shown to be effective and less painful in the treatment of precancerous skin lesions.89 Osiecka et al assessed the efficacy and tolerability of green light-based 5-ALA-PDT in 11 patients with chronic VLS characterised by severe pruritus. Following PDT, pruritus was significantly improved in all patients, none of whom reported severe pain during treatment nor did any require interruption of irradiation or topical analgesics. These findings suggest that green light is a promising alternative for PDT in the treatment of VLS, though further studies are necessary to validate these results.48

Tools for predicting the efficacy and recurrence rate of PDT for VLS

VLS is characterised by a chronic and recurrent nature. Due to the efficacy of PDT in treating severe and refractory VLS, several tools have been developed to predict the efficacy and recurrence of PDT in this context. These tools include non-invasive multimodal optical coherence tomography, fluorescent diagnostic methods and high-frequency ultrasound (HFUS).

OCT uses Photodithazine to evaluate the early histological signs of patients with VLS after systemic PDT treatment and then determines the efficacy of PDT and the recurrence after treatment. The early histological signs of VLS with or without PDT treatment are significantly different. The specific approach of OCT is to visually assess skin composition using structural optical tomography, optical tomography and optical tomography of tissues after 6 months of PDT treatment, and to quantitatively assess the dermis by calculating depth-resolved attenuation coefficients and the density of blood vessels and lymphatic vessels. OCT is beneficial for early non-invasive control of patients with early recurrence after PDT without waiting for new clinical manifestations of recurrence.90

The fluorescent diagnostics method was also applied to evaluate the efficiency of the Alasens PS in the treatment of VLS. Loschenov administered the topical PS Alasens to 70 patients with confirmed VLS, with non-invasive spectral and real-time visual control of drug accumulation by fluorescence diagnostic methods before and after each treatment. The results demonstrate a direct correlation between the PS fluorescence signal and disease regression, and this study illustrates the great potential of fluorescent diagnostic methods in the evaluation of VLS efficacy and the prevention of malignant transformation.91

In addition, HFUS was introduced in one study to assess ALA-PDT outcomes in patients with VLS. In this prospective study, clinical, HFUS and histopathological assessments were performed in patients with VLS treated with ALA-PDT and the parameters before and after treatment were statistically analysed. The thickness of the hypoechoic true belt (HDB) shown by HFUS decreased gradually with the continuous treatment of ALA-PDT, and the degree of HDB thickness reduction was positively correlated with the reduction of inflammatory infiltration depth in histopathology. This result indicates that HFUS can be used as a supplement to PDT treatment monitoring because of its objectivity, quantification and accuracy in the vertical angle.92

Conclusions and perspectives

The standard treatment for VLS currently relies on the long-term administration of TCSs. However, these corticosteroids may not provide optimal results for all patients. Consequently, various energy-based physiotherapy modalities have been explored for the treatment of VLS, including PDT, laser therapy and HIFU. These physical therapies exert therapeutic effects on the affected tissue of VLS through multiple mechanisms. PDT generates cytotoxic ROS via a PS, appropriate wavelength light and oxygen. Laser therapy achieves photothermal conversion through a chromophore, resulting in thermal damage to the surrounding lesion tissue. HIFU employs the interaction of thermal heating, inertial cavitation and mechanical effects between US and VLS lesions to produce its therapeutic effects.

These three energy-based methods possess distinct characteristics in the treatment of VLS. PDT is noted for its high selectivity, safety and non-invasive nature, and it does not impact fertility. FxCO2 is characterised by its objective effectiveness, convenience and minimal collateral damage. HIFU is recognised for its safety, efficacy and targeting capabilities. Collectively, these features underscore the potential of energy-based physiotherapy in managing VLS. However, a common limitation among these approaches is the absence of large-scale clinical studies, which results in a lower recommendation for their use in VLS treatment. Investigations into combination strategies that incorporate physical therapy alongside novel treatment modalities are underway, and we summarise their efficacy in treating VLS.

An emerging dimension of these therapies lies in their potential to remodel the aberrant immune microenvironment of VLS. PDT, laser and HIFU are postulated to initiate an ‘immune reset’ by inducing controlled damage that recruits new immune cells and disrupts the self-perpetuating cycle of chronic inflammation. It is conceivable that the principles of immunomodulation observed in cancer biology extend to the context of VLS. In oncology, RNA modifications, such as m6A, have been established as pivotal regulators of immune responses.93 Thus, rectifying the immune dysregulation via energy-based treatments may be as crucial as their direct effects on cells and collagen. A deeper investigation into this immunomodulatory role represents a compelling future direction.

In conclusion, while physics-based energy therapies are not as prevalent as TCSs in clinical practice, an increasing number of studies have been conducted on these physiotherapy modalities. Additionally, a substantial body of small-scale evidence suggests their effectiveness in treating VLS. We anticipate further large-scale studies on PDT, laser therapy and HIFU to provide more robust treatment options for patients with VLS.