A rare case and literature review of bullous pemphigoid appearing in the setting of lichen sclerosus: a dermatopathological conundrum and what to expect Tijana Orlić1 ✉*, Igor Kapetanović1*, Vesna Reljić1,2, Snežana Minić1,2, Dubravka Živanović1,2 1Dermatology and Venereology Clinic, University Clinical Center of Serbia, Belgrade, Serbia. 2Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 209 2024;33:209-211 doi: 10.15570/actaapa.2024.30 Introduction Blisters occurring on lichen sclerosus (LS) lesions are often initial- ly considered a bullous variant of LS. However, clinicians should remain vigilant for other potential autoimmune conditions, particularly bullous pemphigoid (BP). Differential diagnoses to consider include lichen planus pemphigoides, cicatricial BP, bullous scleroderma, bullous lichen planus, and circumscribed lymphangioma. Comprehensive diagnostics, including histopa- thology and direct immunofluorescence (DIF) testing, are crucial for distinguishing between these conditions and ruling out alter- native diagnoses. Case report A 69-year-old woman presented to our dermatology clinic with a 10-month history of sclerotic plaques on her back, breasts, thighs, and genital and perianal regions, accompanied by itching and pain. After 9 months, she reported blistering on these sclerotic plaques. Her medical history was significant only for hyperten- sion, managed with bisoprolol and enalapril, and she denied any history of trauma. Physical examination revealed reddish-white indurated plaques with follicular plugging, measuring approxi- mately 25 × 20 cm, symmetrically distributed over the proximal thighs, with multiple erosions and crusts. No new blisters were observed. Similar plaques were found on the abdomen, lower back, anogenital area, and breasts, although without erosions (Fig. 1a, b). Biopsies were taken from an indurated plaque with erosion. Histopathology showed hyperkeratosis, interface dermatitis, and flattened rete ridges in the epidermis. In the dermis, there was hyalinosis in the papillary and upper reticular layers, along with focal infiltrates of lymphocytes and some eosinophils (Fig. 2a). A subepidermal cleft was also noted (Fig. 2b). DIF from perilesional Abstract Co-occurrence of blisters in patients with lichen sclerosus (LS) can raise the question of whether they represent a bullous variant of LS or a concomitant autoimmune disorder. We report a rare case of bullous pemphigoid (BP) occurring on previous LS lesions. To the best of our knowledge, this is also the first BP180-negative case reported in literature. Here, we propose alternative mecha- nisms, independent of BP autoantibodies, that may lead to development of BP on skin affected by LS. In addition, we provide a literature review that explores the underlying pathophysiology and offers practical treatment insights, equipping clinicians with valuable guidance for similar complex cases. Keywords: autoimmune diseases, BP180 antigen, bullous pemphigoid, lichen sclerosus, dermatopathology Acta Dermatovenerologica Alpina, Pannonica et Adriatica Acta Dermatovenerol APA Received: 27 June 2024 | Returned for modification: 27 September 2024 | Accepted: 22 October 2024 ✉ Corresponding author: tijanaorlic94@gmail.com *Co-first authors, these two authors contributed equally to this article. Figure 1 | (a, b) Reddish and whitish indurated plaques with follicular plugging and solitary erosions with hyperkeratosis and crusts. 210 Acta Dermatovenerol APA | 2024;33:209-211T. Orlić et al. skin demonstrated linear deposition of immunoglobulin (Ig) G and complement component (C) 3 along the basement membrane zone (Fig. 2c). Based on these histopathological and DIF findings, a diagnosis of localized BP superimposed on LS was established. Further testing with indirect immunofluorescence (IIF) was negative. Enzyme-linked immunosorbent assay (ELISA) showed no elevated levels of antibodies to BP180, BP230, desmoglein 1, desmoglein 3, envoplakin, or type VII collagen. Routine labora- tory tests were within normal limits. Treatment with methotrex- ate 15 mg weekly and topical 0.05% clobetasol propionate oint- ment was initiated. A positive clinical response was observed after only four doses of methotrexate, with no new blister formation throughout follow-up. Discussion LS is a chronic inflammatory disorder that usually affects the skin of the anogenital area, but it can also affect any other body region. Multiple etiopathological theories have been suggested, primarily, genetic background combined with triggering factors (1, 2). In the latest review by De Luca et al., pathogenesis involved immune- mediated T helper (Th) 1-specific interferon (IFN) γ-induced phe- notype and infiltrate (3). They also highlighted distinct expression of tissue remodeling–associated genes as well as microRNAs, oxi- dative stress with lipid and DNA peroxidation providing an ena- bling microenvironment for autoimmunity, carcinogenesis along with abnormal fibroblast growth, and collagen synthesis leading to hyalinization and sclerosis of the dermis (1, 3). Finally, circulat- ing IgG autoantibodies against extracellular matrix protein 1 and hemidesmosome have been mentioned as potential contributors to progression of LS or simply representing an epiphenomenon (1–3). The role of hormonal factors has also been considered, among them hypoestrogenism, due to the typical onset of LS be- fore puberty and after menopause. Certain medications may also trigger LS, such as immunotherapy and antiarrhythmics, and even infections (3). Some authors have searched for autoimmune factors. In a study by Meyrick Thomas et al. (4), based on 350 female patients with LS, 21.5% had at least one autoimmune-related disease, and 42% had elevated titers of up to three different autoantibodies. Other studies concluded that LS patients had elevated odds of developing alopecia areata, lichen planus, and atopic dermatitis as well as psoriasis, hypertension, diabetes mellitus, obesity, dys- lipidemia, and even genital warts (5). As of May 2024, only five cases have been reported of localized BP coexisting with LSA (2, 6–9, Table 1). All the patients were fe- male, age range 66 to 77 years old, with blisters appearing on top of sclerotic plaques. Table 1 | Comparative overview of clinical, laboratory, and microscopic characteristics of cases reported in the literature, including the present case, of patients with coexisting lichen sclerosus and bullous pemphigoid. Case Age Sex BP lesion localization LS history prior to BP diagnosis ELISA test DIF test (linear deposits in basal membrane zone) Therapy Response to therapy Leonard N, et al. (2008) (6) 74 F Vulva, abdomen — Not done IgG, C3 Prednisolone, 0.5 mg/kg, azathioprine, local corticosteroids, tacrolimus Partial Walsh ML, et al. (2012) (1) 74 F Vulva, gluteus 10 years Not done IgG, C3 Prednisolone, 0.5 mg/kg Complete Yoshifuku A, et al. (2018) (7) 66 F Vulva, anogenital region, body, extremities 12 years BP180+ IgG Prednisone, 30 mg daily Complete Maglie R, et al. (2022) (8) 77 F Forearms 25 years BP180+ IgG, C3 Methotrexate, 15 mg weekly, prednisone 5 mg daily Complete Boeijink N, et al. (2023) (9) 72 F Vulva, anogenital region — BP180+ IgG, C3 Local corticosteroids Partial Orlic et al. 69 F Thighs 9 months Negative IgG, C3c Methotrexate, 15 mg weekly, local corticosteroids Complete BP = bullous pemphigoid, DIF = direct immunofluorescence, ELISA = enzyme-linked immunosorbent assay, F = female, LS = lichen sclerosus, Ig = immunoglobu- lin, C3 = complement component 3. Figure 2 | (a, b) Interface dermatitis and flattened rete ridges in the epidermis. Dermal hyalinosis with focal lymphocytic and eosinophilic infiltrate. A subepidermal cleft is also present (hematoxylin and eosin, ×400); (c) linear deposition of immunoglobulin G and complement component C3 along the basement membrane zone (direct immunofluorescence). 211 Acta Dermatovenerol APA | 2024;33:209-211 Bullous pemphigoid on lichen sclerosus DIF is considered the gold standard for BP (10). Only three cas- es reported an ELISA panel test: all were BP180-positive and none were positive for BP230. Our case was negative for both. Non-col- lagenous extracellular domain (NC16A) is the major pathogenic epitope in BP, especially in BP180-positive patients (10). However, patients with the non-NC16A regions are not recognized in com- mercial ELISA panels (11). Keller et al. (10) concluded that the use of ELISA for BP is inadequate because a standalone test with sen- sitivity for BP180 alone was only 54%, BP230 alone yielded 48% sensitivity, and a combination of BP180 and BP230 showed 66% sensitivity. Regarding BP autoantibodies in LS patients, Baldo et al. found that 43% of patients (6/14) with LS have the NC16A domain of BP180 as the target for circulating T-cells, whereas none in the smaller control group did (12). Our case is the only BP180-nega- tive case that actually developed bullae with a positive DIF. This could imply that autoantibodies do not correlate with the clinical picture. In previous cases, duration of LS before the occurrence of bullae was over 10 years, and thus plenty of time for autoantibod- ies to form. In our case it took only 9 months. Another possibility is that bullae are induced by different factors and/or autoantibod- ies outside of domains tested with the BP/ELISA panel. It is known that BP might appear on skin sites damaged by physical factors: injections, radiation, burns, or surgery (2, 8). Interestingly, it has been theorized that blisters can occur on normal skin due to epitope dissemination (2). Conclusions To differentiate between various causes of blisters in LS patients, a detailed history should be obtained. Not performing the DIF test might lead to misdiagnosis. An ELISA panel should be used in combination as a supportive diagnostic tool instead of a stan- dalone test. With our case being BP180-negative, we can poten- tially theorize about other potential mechanisms outside of BP autoantibodies that could still lead to BP superimposed on LS lesions. We hope that this case motivates larger studies of patho- physiological mechanisms for this diagnosis. Acknowledgement This study was supported by the Ministry of Education, Sci- ence, and Technological Development, grant no. 451-03-66/2024- 03/200110. References 1. Corazza M, Schettini N, Zedde P, Borghi A. Vulvar lichen sclerosus from patho- physiology to therapeutic approaches: evidence and prospects. Biomedicines. 2021;9:950. 2. Walsh ML, Leonard N, Shawki H, Bell HK. Lichen sclerosus and immunobullous disease. J Low Genit Tract Dis. 2012;16:468–70. 3. De Luca DA, Papara C, Vorobyev A, Staiger H, Bieber K, Thaçi D, et al. Lichen sclerosus: the 2023 update. Front Med (Lausanne). 2023;16;10:1106318. 4. Meyrick Thomas RH, Ridley CM, McGibbon DH, Black MM. 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