Vulvar‐vaginal‐gingival‐otic syndrome

In order to retrospectively analyse the multi‐site involvement pattern of erosive lichen planus patients, we retrospectively reported the clinical and medical data of three patients with erosive lichen planus which involving their vulva, vagina, gingiva, and ear canal. We confirmed the existence of otic lichen planus, and found that it is more common in patients with vulvovaginal‐gingival syndrome of erosive lichen planus. Therefore, we propose ‘vulvovaginal‐gingival‐otic syndrome’ to further describe this rare compound pattern of lichen planus.

Lichen planus (LP) is a chronic, autoimmune and inflammatory skin disease that can affect the skin, mucous membranes, hair and nails.LP has an estimated prevalence of 0.22%-5%. 1,2Erosive LP commonly involves the mucous membranes, presenting as painful erythematous lesions with erosions.The condition is prone to relapse and has a poor prognosis, leading to irreversible damage to structure and function.In this study, we conducted a retrospective analysis of patients with erosive LP involving the vulva and vagina who were treated at our hospital.We discuss the possibility of LP involving the ear canal and propose a new multi-site involvement pattern, which we named the 'vulvovaginal-gingival-otic syndrome'.
In the three reported cases, all patients presented with vulvar itching, pain and recurrent ulceration.Through a systematic specialist examination and histopathological examination, a definitive diagnosis of erosive LP was established.The diagnosis met the criteria for Pelisse's vulvovaginal-gingival syndrome. 3Additionally, all three patients had symptoms of discomfort in the ear and exhibited hearing impairment.This study was approved by the Ethics Committee of Beijing Hospital, Beijing, China (2021BJYYEC-159-01), and all subjects gave written informed consent.In our department during the same period, patients vulvar-vaginal-gingival-otic syndrome accounted for 1.7% (3/1368) of vulvar disease patients, while for 7.5% (3/40) of the female vulvar LP patients.

| C A S E 1
A 53-year-old female patient presented with a 6-year history of gingival redness, swelling and pain, a 3-year history of vulvar pain with vaginal bleeding, and a 2-year history of hearing loss.Multiple biopsies of vulvar and gingival lesions were performed, confirming the diagnosis of LP (Figure 1A).The patient received topical treatment with corticosteroids, tacrolimus and pimecrolimus for vulvar and vaginal lesions, and underwent multiple gingival surgeries with adjunctive topical tacrolimus.Oral medications, including compound glycyrrhizin tablets and hydroxychloroquine, were also used, but the skin lesions were poorly controlled.Two years ago, the patient developed pruritus and a feeling of blockage in the ears, and was diagnosed with 'otitis media'.She received topical treatments with levofloxacin and dexamethasone ear drops, but her symptoms persisted.In the past 6 months, the patient developed stenosis and occlusion of the ear canal, and underwent ear canal reconstruction surgery, but her hearing loss continued to worsen.Physical examination revealed edematous erythema with indistinct borders and scattered erosions on the vulva (Figure 2A).
Vaginal examination showed diffuse bleeding of the vaginal wall, partial adhesion of the vaginal wall and vaginal stenosis (Figure 2B).
The gingiva showed atrophy, hyperplasia, exposed roots and white reticular lines on the gingiva and buccal mucosa, with scattered erosions and multiple loose teeth (Figure 2C).Otoscopy showed abundant secretions and crusts in both ear canals, and perforation of the left tympanic membrane (Figure 2D).

| Treatment
The patient was treated with oral methylprednisolone 30 mg/d, topical glucocorticoid cream on the vulva, and dexamethasone ear drops for symptomatic treatment.Two weeks later, the skin lesions improved significantly and the patient's hearing slightly recovered.

| C A S E 2
A 51-year-old female presented with abdominal rash, genital itching and pain, and gum swelling for over 7 years, as well as hearing loss for over 6 years.She had sought medical attention multiple times for the redness, erosion, and bleeding in the genital area, and the skin biopsy confirmed erosive LP (Figure 1B).The genital rash gradually developed into painful and keratotic papules, some of which merged together.She was treated with topical corticosteroids, tacrolimus and retinoid preparations, but the treatment was ineffective.Six years ago, she experienced itching and a feeling of blockage in her ears, accompanied by progressive hearing loss.She was diagnosed with 'non-specific hearing loss' in an external hospital and treated with topical corticosteroids and antibiotic ear drops, but the effect was unsatisfactory.
Physical examination revealed red keratotic plaques with excessive keratinization on both labia majora and interlabial folds (Figure 3A), scattered flat purple-red keratotic papules on the lower abdomen (Figure 3B), gum swelling, white keratotic plaques on the tongue (Figure 3C), diffuse redness and bleeding on vaginal wall under colposcopy, and increased secretion and occlusion of the ear canal under otoscopy (Figure 3D).

| Treatment
The patient was treated with oral methylprednisolone at a dose of 30 mg/day combined with topical medications.During close followup, the patient reported an improvement in symptoms, but her hearing did not recover.

| C A S E 3
A 53-year-old female patient presented with red, swollen and bleeding gums for 8 years, as well as painful and itchy external genitalia and vagina with erosion and bleeding for over 7 years.The patient also reported a feeling of blockage in her ear with hearing loss for 6 years.
In early 2014, the patient sought treatment for her gum swelling from the dental department, and was diagnosed with erosive oral LP.
Despite receiving medication rinses, cleaning and surgical treatment, the symptoms were not well controlled.At the end of 2014, the patient sought treatment for her genital itching and pain, and vaginal bleeding in our department.A tissue biopsy confirmed the diagnosis of erosive LP (Figure 1C).The patient was prescribed oral compound glycyrrhizin tablets and topical application of betamethasone, but the treatment was not effective, and the patient stopped the medication on her own.In early 2016, the patient sought treatment for the feeling of blockage in her ear and hearing loss from the otolaryngology department, and was diagnosed with 'otitis media.'She was prescribed cefpodoxime, and received treatment with 3% boric acid ear drops, but the symptoms were not completely relieved, and the patient stopped the medication on her own.In 2018, the patient's symptoms in the genitalia, gums and ear canal worsened significantly, and she was prescribed 24 mg/d of methylprednisolone tablets, which gradually improved the skin lesions in all affected areas.However, the patient stopped the medication again on her own.In 2019, she intermittently took hydroxychloroquine sulfate tablets on her own, but the treatment was not effective.
Physical examination showed atrophy and disappearance of the labia minora, edematous erythema with unclear boundaries around the vaginal orifice, accompanied by several flat white keratinized papules, and tenderness was positive (Figure 4A).The vaginal mucosa showed erythema and scattered erosion and bleeding surfaces, and some parts of the vaginal mucosa were adhered (Figure 4B).The gums were red and swollen, with scattered red patches and white lines on the cheek mucosa (Figure 4C).The external auditory canal was blocked at the near opening and could not be explored.

| Treatment
The patient was prescribed 30 mg/d of methylprednisolone tablets and topical application of medication for symptomatic treatment.
Follow-up after 2 weeks showed that the patient's symptoms improved, but her hearing did not show significant improvement.

| DISCUSS ION
LP is an autoimmune, inflammatory disease mediated by T lympho- Erosive LP can affect multiple mucosal and skin sites simultaneously or successively.In 1937, Guogerot and Burnier 4 described a complex pattern of involvement of the oral cavity, cervix, and stomach as 'plurimucosal LP.' In 1982, Pelisse et al. 3 described LP involving the vulva, vagina, and gingiva as the 'vulvovaginalgingival syndrome' (VVGS).The external auditory canal, as a tiny part of the stratified squamous epithelium, is rarely affected by LP.Firstly, in 1948, LP of tympanic membranes was reported by Warin et al. 5 In 1998, Martin et al. 6 reported a case of erosive LP affecting the perianal and gingival regions that led to progressive bilateral stenosis of the external auditory canal and subsequent hearing loss.In 2007, Hopsu and Pitkäranta, 7 an otolaryngologist, discussed the relationship between idiopathic, inflammatory, fibrotic otitis media and LP, reporting three cases of severe, long-standing oral LP with ear canal involvement.In 2008, Young et al. 8 described a case of genital LP with ear canal and tympanic membrane involvement, with histopathological examination confirming LP-like changes in the ear canal lesion, consistent with the pathological features of LP.In 2013, Sartori-Valinotti et al. 9 from the Mayo Clinic conducted a statistical analysis of LP patients seen over a 10-year period, confirming that LP can indeed affect the stratified squamous epithelium of the external auditory canal and tympanic membrane, and officially proposed the concept of otic lichen planus (OLP).However, the incidence of OLP among LP and VVGS patients is still unknown.However, there have been no reports of OLP in China.Our team's research has found that flat mossy lichen in the ear canal often occurs in women with long-term illnesses, especially those with vulvovaginal gingival syndrome, and mostly in the age range of 40-55 years old.This finding is consistent with the report by Sartori-Valinotti et al., 9 which showed that among 19 patients with ear canal involvement, 79% (15/19) were female, and 10 of the 15 female ear canal involvement patients (67%) also had vulvovaginal gingival syndrome.OLP usually has an insidious onset and can have no obvious symptoms in the early stages.Although early ear canal involvement can be well controlled and stabilised through continuous local steroid therapy, as described by Hopsu et al., 7 the damaged epithelium often loses its regenerative ability by the time patients seek medical attention.Once fibrotic repair occurs, the structural abnormalities will be irreversible.Due to insufficient understanding, delayed medical treatment, and lack of specialty consultation, as well as the fast progression and severe inflammation of OLP, hearing loss often rapidly progresses within months.At the same time, multisite involvement often indicates serious and systemic inflammatory activity.
The mechanism underlying the development of ELP remains unclear, but it may be related to the Koebner phenomenon and is considered a non-infectious, inflammatory change.The findings of Hopsu et al. 7 suggest that once the skin at the bony ear canal and tympanic membrane is completely replaced by fibrous tissue, the inflammatory process ceases immediately, indicating that the inflammatory response is confined to the skin system.Localised LP lesions may occur in the ear canal due to minor injuries or other ear diseases, and these patients often undergo months or even years of ineffective antibiotic ear drops, which may cause toxicity, allergy, or contact dermatitis, leading to further ear damage.These findings confirm our observations that early surgical intervention in the ear canal may not prevent disease progression and may even increase the risk of hearing loss, exacerbating the isomorphic response.

F I G U R E 1
Histopathological examination results.(A-C) represent the histopathological results of skin lesions from three patients, respectively.Under HE staining, typical flat lichenoid changes were observed, with thickening of the epidermis, significant liquefaction degeneration of basal cells, and band-like infiltration of inflammatory cells mainly composed of lymphocytes in the superficial dermis.Vascular dilation and bleeding were observed in some areas.(10 × 20 = 200).F I G U R E 2 Physical examination and examination results of Case 1. (A) Swollen erythema with a small amount of punctate erosion and bleeding on both sides of the vaginal opening; (B) diffuse swelling and bleeding of the vaginal wall; (C) gingival swelling, atrophy, and exposed roots; (D) abundant secretion and scabs in the ear canal, with perforation of the left eardrum.
cytes and commonly affects middle-aged individuals.LP has multiple clinical types.The typical skin lesions are polygonal flat-topped papules with a violaceous colour and Wickham's striae.These lesions F I G U R E 3 Physical examination and examination results of Case 2. (A) Erythema with keratotic thickening on the inner side of both labia minora and interlabial sulcus; (B) purple flat papules with scales on the lower abdomen; (C) white keratotic plaques on the tongue surface; (D) increased secretion and occlusion of the external auditory canal.usually regress within 6 months-1 year. 1 The erosive type of LP is rare and often affects mucous membranes, presenting as painful erythema, erosions and bleeding.It can involve the oral cavity, vulva, vagina, oesophagus, pharynx and conjunctiva, and the disease tends to recur and may not resolve on its own, leading to misdiagnosis or delayed diagnosis.Long-term inflammation can cause irreversible damage to mucosal epithelial structures and functions, resulting in structural deformities and functional abnormalities, severely impacting the patient's quality of life.
Sartori-Valinotti et al.9 found that the histopathological examination of OLP lacks specificity, so the diagnosis of ear canal LP mainly relies on its clinical presentation.Based on our team's diagnostic and therapeutic experience, clinical physicians should consider the possibility of external ear canal LP in the following situations: (1) presence of LP lesions on other parts of the body, especially in patients with long-term poor disease control.Especially female patients with Vulvar-Vaginal-gingival syndrome; (2) symptoms of ear canal itching, increased secretion, ear blockage and foreign body sensation, hearing loss, and deafness; (3) difficulty in controlling disease progression F I G U R E 4 Physical examination and examination results of Case 3. (A) Swollen erythema with indistinct boundaries around the vaginal opening, accompanied by several flat white keratotic papules; (B) erythema and scattered erosion inside the vagina; (C) scattered erythema and white lines on the buccal mucosa.