A case of radiotherapy-induced bullous pemphigoid with unusually delayed onset: A case report

Abstract

Bullous pemphigoid is an auto-immune blistering disease that generally affects older patients. Radiotherapy is one of the many triggering factors that have been described. Time to disease onset is variable; cases have been described during the course of radiotherapy while others have occurred up to 9 years later. We report a case of localized bullous pemphigoid on an irradiated site with unusual late presentation, 25 years after radiotherapy for left breast cancer. The pathophysiology of radiation-induced bullous pemphigoid is not clear, but the concept of an immunocompromised district seems to be a plausible explanation for the delayed onset of the disease.

Introduction

Bullous pemphigoid is an auto-immune bullous disease that mainly affects older individuals. ¹ It presents tense bullae and urticarial plaques on the trunk and extremities with significant pruritus. ¹ Skin lesions may be localized or generalized, and mucosal involvement is reported in 10%–30% of cases. ¹ The condition results from the degradation of the basement membrane zone as IgG and IgE auto-antibodies target hemidesmosomal proteins BP180 and BP230. ¹ Association of bullous pemphigoid has been reported with multiple comorbidities, including neurologic conditions, auto-immune diseases, neoplasms, and cardiovascular diseases. ⁴ In addition, several trigger factors have been reported to induce or exacerbate bullous pemphigoid. ⁴ Among them is radiation therapy, for which an association with disease onset has been described by many authors since 1988. ⁵ The most recent review of radiation-induced bullous pemphigoid published in 2022 includes 13 articles published between 2014 and 2021. ² In most cases, irradiated fields were the first site of the appearance of skin lesions, but the disease eventually extended to non-irradiated skin as well. The prognosis was generally favorable with adequate response to topical corticosteroids or systemic treatment with prednisolone or immunosuppressive agents. ² The time interval between radiotherapy and disease onset was extremely variable: some patients developed skin lesions during radiotherapy while others developed lesions up to 9 years after its end. ² A previous review published in 2014 analyzed 29 cases of radiotherapy-induced bullous pemphigoid. ⁶ However, inclusion criteria specified time to disease onset of up to 10 years, based on studies suggesting that immunosuppressive effects of radiation therapy may be present 10 years post-treatment. ⁷ The aim of this paper is to report a case of localized bullous pemphigoid on previously irradiated skin with unusual late presentation.

Case report

A 73-year-old female was referred to the dermatology clinic in February 2020 for suspicion of shingles on the left breast. She had no history of skin disease. Her past medical history included infiltrative lobular carcinoma on the left breast for which she had a total left mastectomy with reconstruction in April 2016, and a cutaneous metastasis on the left breast operated in October 2019. She had a history of breast cancer on the same site treated with radiotherapy back in 1996. Her other medical conditions included diabetes, hypertension, dyslipidemia, and a thyroid nodule. She has been taking letrozole since September 2019, as well as indapamide, perindopril, and esomeprazole for many years. At the first visit in February 2020, the patient had a localized eczematous dermatitis on the left breast with a few erosions, that were treated with topical betamethasone valerate and fusidic acid ointment. The patient returned in July 2020 with two hemorrhagic bullae of 1.5 × 0.5 cm on the left breast, surrounded by multiple milia on an erythematous base (Figures 1 and 2). At this point, localized auto-immune bullous disease was suspected. A biopsy with direct immunofluorescence and salt split was performed. A sub-epidermal bulla containing few inflammatory cells overlying a dermis containing granulation tissue with multiple eosinophils and lymphocytes was seen (Figure 3). Discontinuous linear IgG deposits (++) and granulo-linear C3 deposits (++) were seen at the roof of the basement membrane zone. Anti-basement membrane antibodies were detected at 1/1280. A diagnosis of localized bullous pemphigoid on a previous site of radiotherapy was made. The patient was treated with topical corticosteroids (betamethasone dipropionate then clobetasol propionate) with excellent response. She had a complete resolution of the bullae 2 months later, and a good clinical response was maintained at the last follow-up in April 2021.

Figure 1.

Erosions and milia on an erythematous base on the left breast.

Figure 2.

Close-up view of the left breast.

Figure 3.

Sub-epidermal bulla and dermal infiltrate of eosinophils and lymphocytes. Hematoxylin and eosin stain, magnification power 10.

Discussion

Although the association between radiotherapy and bullous pemphigoid has been well documented, the underlying pathophysiology remains uncertain. ⁶ Multiple hypotheses have been described and partially supported by isolated pieces of evidence. ⁶ One theory is that radiation-induced apoptosis of skin epithelial cells causes them to release BP 180 and BP 230 antigens. ⁶ These endogenous antigens are then recognized by Langerhans cells, which are thought to be resistant to radiation-induced apoptosis, and the production of autoantibodies ensues. ⁶ Another theory is that patients already have circulating low levels of anti-basement membrane antibodies.^6,8 Radiation therapy then enhances the binding of these antibodies to the basement membrane zone on the irradiated skin, in a context of enhanced vascular permeability.^6,8 However, the development of bullous pemphigoid many years after radiation therapy, such as in our case, seems to be better explained by the “immunocompromised district” concept. In fact, Ruocco described a unifying explanation for the occurrence of localized skin diseases secondary to local dysregulated immunity in the context of regional chronic lymphedema, herpes-infected sites, or otherwise damaged areas, which include irradiated skin. ³ These conditions cause an alteration of lymph circulation, potentially impairing the trafficking of immune cells, as well as damage to peripheral nerves, which can alter the signaling of neuromediators. ³ An abnormal neuroimmune interaction results, leading to an altered immune response which can be either defective, leading to infections or neoplasms, or excessive, leading to auto-immune phenomena such as bullous pemphigoid. ³ The secondary disease in the immunocompromised district may occur after an extremely variable time period, ranging from a few days to decades. ³ It seems to be a plausible explanation for cases of localized bullous pemphigoid occurring many years after surgery ⁹ or, as in our case, 25 years after radiotherapy.