Antiga, Emiliano

D&apos

Giovanni, Bagnoni

Maglie, Roberto

Montefusco, Francesca

Senatore, Stefano

English

Florence Research

20 December 2021Localized pemphigus exacerbation associated with underlying breast cancer / Roberto Maglie, Francesca Montefusco,Stefano Senatore, Angelo Massimiliano D'Erme, Giovanni Bagnoni, Emiliano Antiga. - In: JAAD CASE REPORTS. -.ISSN 2352-5126. - ELETTRONICO. - 6(2020), pp. 1268-1270Original Citation:Localized pemphigus exacerbation associated with underlying breast cancerTerms of use:Publisher copyright claim:(Article begins on next page)La pubblicazione è resa disponibile sotto le norme e i termini della licenza di deposito, secondo quanto stabilito dallaPolicy per l'accesso aperto dell'Università degli Studi di Firenze (https://www.sba.unifi.it/upload/policy-oa-2016-1.pdf)Availability:This version is available at: 2158/1211402 since: 2021-01-20T11:22:05ZQuesta è la Versione finale referata (Post print/Accepted manuscript) della seguente pubblicazione:FLORERepository istituzionale dell'Università degli Studi diFirenzeOpen AccessJournal Pre-proofLocalized pemphigus exacerbation associated with underlying breast cancerRoberto Maglie, MD, Francesca Montefusco, MD, Stefano Senatore, MD, AngeloMassimiliano D'Erme, MD, Giovanni Bagnoni, Emiliano Antiga, MD, PhDPII: S2352-5126(20)30752-9DOI: https://doi.org/10.1016/j.jdcr.2020.10.018Reference: JDCR 1618To appear in: JAAD Case ReportsReceived Date: 14 September 2020Revised Date: 13 October 2020Accepted Date: 13 October 2020Please cite this article as: Maglie R, Montefusco F, Senatore S, D'Erme AM, Bagnoni G, Antiga E,Localized pemphigus exacerbation associated with underlying breast cancer, JAAD Case Reports(2020), doi: https://doi.org/10.1016/j.jdcr.2020.10.018.This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.© 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. This is an openaccess...1  Article type: Case reports 1 Title: Localized pemphigus exacerbation associated with underlying breast cancer 2 Author: Roberto Maglie MD,1 Francesca Montefusco MD,1 Stefano Senatore MD,1 Angelo Massimiliano 3 D'Erme MD,2 Giovanni Bagnoni,2 Emiliano Antiga MD, PhD1. 4 1Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy 5 2Melanoma and Skin Cancer Unit, AVNO (Area Vasta Nord Ovest) and Unit of Dermatology, Livorno 6 Hospital, Livorno, Italy.  7  8 Corresponding author: 9 Dr. Roberto Maglie 10 Department of Health Sciences 11 Section of Dermatology 12 University of Florence 13 Viale Michelangiolo 41 14 50125 Florence, Italy 15 Email: robertomaglie.med@libero.it 16  17 Funding sources: none 18  19 Conflicts of Interest: None declared. 20  21  22  23 Reprint requests: Roberto Maglie 24  25 Manuscript word count: 858 26 References: 9 27 Figures: 3 28 Supplementary figures: 0 29 Tables: 0 30 Supplementary tables: 0 31  32 Keywords: pemphigus vulgaris; malignancy-exacerbated pemphigus; breast cancer; desmoglein 3; 33 desmoglein 1. 34  35  36  37  38 Introduction 39  40 Pemphigus is a rare, autoantibody-mediated, mucocutaneous disease characterized by 41 loss of the adhesion between keratinocytes and intraepidermal blistering [1]. Although idiopathic 42 in most cases, epidemiologic studies suggest an association between pemphigus and 43 Journal Pre-proof2  malignancies, including in particular lymphoproliferative disorders and gastrointestinal tumors 44 [2,3]. Pathophysiologic mechanisms behind this association remain elusive.  45 In the literature, pemphigus occurrence in patients with underlying breast cancer has been 46 reported as a particularly rare association, with most of the published cases occurring after 47 radiation therapy [4]. Here, we describe a patient with a history of oral pemphigus vulgaris (PV) 48 experiencing a severe disease flare predominantly affecting her right breast skin in the setting of 49 underlying ductal carcinoma. 50  51 Case report  52 A 54-year-old woman presented to our department because of a 3-month 53 history of a skin rash localized to her right breast. Six months before presentation, 54 she was diagnosed with oral pemphigus vulgaris (PV). An enzyme- linked 55 immunosorbent assay at this time point showed elevation of both anti-Desmoglein 56 (Dsg) 3 (150 UI/mL) and Dsg1 (100 UI/mL) IgG antibodies. The disease was 57 managed with a short-course of oral and topical corticosteroids, with complete 58 remission on low dose systemic corticosteroids (prednisone 7.5 mg/day) without the 59 need of other immunosuppressive medications. She was suffering from a major 60 depressive disorder, for which she was on treatment with trazodone, sertraline, 61 lamotrigine, and duloxetine. 62 Physical examination showed a significant retraction of the right breast and nipple; initial 63 hardening and retraction of her right breast had appeared since about 18 months, but the 64 patient did not consult her physician until the manifestation of the skin rash. The skin overlying 65 her right breast was covered with multiple confluent erosions, hyperkeratotic scales and crusts 66 (Figure 1). The morphological anatomy and the skin of the contralateral breast appeared 67 normal. Some erythematous-scaling plaques were also noted across the back. Examination of 68 the oral mucosa, conjunctivae and genital mucosa appeared normal. Histopathology 69 examination obtained from an erosion of the right breast’s skin showed suprabasal epidermal 70 acantholysis. Direct immunofluorescence from the perilesional skin showed intercellular 71 deposition of IgG and C3 in the epidermis, while ELISA showed high level of IgG autoantibodies 72 against Dsg1 (101.3 UI/mL) and Dsg3 (148.8 UI/mL). Indirect immunofluorescence (IIF) on 73 monkey oesophagus as a substrate showed intercellular IgG deposition; while IIF on the rat 74 bladder epithelium gave negative results. The above findings were consistent with a relapse of 75 her PV. A computed tomography scan and a subsequent breast biopsy confirmed the presence 76 of an invasive triple negative ductal carcinoma. Surgical removal of the tumor resulted in a 77 marked improvement of the pemphigus flare, with complete resolution of the lesions on the 78 breast skin and persistence of a few residual lesions on the trunk (Figure 2), which did not 79 require an increase in her daily prednisone dose.  80  81 Discussion 82 Malignancies can either induce or exacerbate pemphigus. Paraneoplastic pemphigus 83 (PNP) is a rare pemphigus variant that also potentially occurs in patients with underlying 84 malignancies. Unlike classical pemphigus variants, including PV and pemphigus foliaceus, PNP 85 is characterized by distinct clinical and immunopathological findings, including severe mucositis, 86 internal complications such as bronchiolitis obliterans, and antibodies against other keratinocyte 87 antigens in addition to Dsg3 and Dsg1 [5,6]. While malignancy-induced or exacerbated 88 pemphigus often ameliorates or even resolves following removal of the tumor, PNP intrinsically 89 runs a more severe and possibly life-threatening clinical course. Hence, making a differential 90 diagnosis between those entities is crucial [7].  91 JournalPre-proof3   92 Both PNP and malignancy-associated pemphigus have been rarely reported in the 93 setting of underlying breast tumors. In our patient, clinical examination and immunopathological 94 findings suggested a diagnosis of breast-cancer exacerbated PV. PNP was ruled out due to i) 95 the absence of severe mucosal involvement and internal complications at time of pemphigus 96 relapse, ii) negative results of IIF using rat bladder as a substrate, and iii) no evidence of 97 interface dermatitis at the skin biopsy [8].  Although the breast cancer was likely present before 98 the onset of the first pemphigus manifestation, the causal relationship between the presence of 99 the tumor and the localized pemphigus flare was strengthened by the prompt disease 100 improvement following the surgical removal of the tumor and the lack of recurrence of 101 pemphigus lesions on the post-operative skin.  102  103 Indeed, an unusual, and to our knowledge previously unreported, finding of this case 104 was the localization of most pemphigus lesions in close proximity to the underlying tumor. There 105 may be different factors that have possibly contributed to this phenomenon. First, cancer cells of 106 triple negative ductal carcinoma have been shown to over-express Dsg3 [9]; second, the 107 malignancy-induced alteration of the vascular supply and lymphatic drainage, as well as the 108 abundance of antigens produced by neoplastic cells, may have favoured the accumulation of 109 Dsg3 specific-B cells in the contiguous skin. The excision of the affected skin area might have 110 presumably removed those autoreactive B-cells, explaining the significant reduction of 111 pemphigus activity. Local production of anti Dsg-antibodies by skin-resident B-cells is a recently 112 recognized phenomenon in pemphigus, possibly accounting for local pemphigus exacerbation 113 or resistance to immunosuppressive therapies [10].  114   115 Conclusion 116 This case provides further evidence for the pathogenetic link between pemphigus and 117 solid tumors. Clinicians should be aware about the possibility of underlying malignancies in 118 pemphigus patients experiencing localized flares.  119  120  121  122  123 References 124  125   [1] Didona D, Maglie R, Eming R, Hertl M. Pemphigus: Current and Future Therapeutic Strategies. 126 Front Immunol 2019;10:1418. https://doi.org/10.3389/fimmu.2019.01418.  127  128   [2] Kridin K, Zelber-Sagi S, Comaneshter D, Cohen AD. Coexistent Solid Malignancies in 129 Pemphigus: A Population-Based Study. JAMA Dermatol 2018;154:435–40. 130 https://doi.org/10.1001/jamadermatol.2017.6334. 131  132   [3] Kridin K, Zelber-Sagi S, Comaneshter D, Batat E, Cohen AD. Pemphigus and hematologic 133 malignancies: A population-based study of 11,859 patients. J Am Acad Dermatol 2018;78:1084-134 1089.e1. https://doi.org/10.1016/j.jaad.2017.11.039. 135  136   [4] Schauer F, Ishii N, Mockenhaupt M, Bruckner-Tuderman L, Hashimoto T, Kiritsi D. Radiation-137 Associated Pemphigus Vulgaris in a Patient With Preceding Malignancy: Treatment With 138 Journal Pre-proof4  Rituximab as a Valuable Option. Front Immunol 2019;10:3116. 139 https://doi.org/10.3389/fimmu.2019.03116. 140  141   [5] Solimani F, Maglie R, Pollmann R, Schmidt T, Schmidt A, Ishii N, et al. Thymoma-Associated 142 Paraneoplastic Autoimmune Multiorgan Syndrome-From Pemphigus to Lichenoid Dermatitis. 143 Front Immunol 2019;10:1413. https://doi.org/10.3389/fimmu.2019.01413. 144  145  [ 6] Ohzono A, Sogame R, Li X, Teye K, Tsuchisaka A, Numata S, Koga H, Kawakami T, Tsuruta 146 D, Ishii N, Hashimoto T. Clinical and immunological findings in 104 cases of paraneoplastic 147 pemphigus. Br J Dermatol. 2015;173:1447-52. doi: 10.1111/bjd.14162.  148  149   [7] Streifel AM, Wessman LL, Schultz BJ, Miller D, Pearson DR. Refractory mucositis associated 150 with underlying follicular dendritic cell sarcoma of the thymus: Paraneoplastic pemphigus versus 151 malignancy-exacerbated pemphigus vulgaris. JAAD Case Rep 2019;5:933–6. 152 https://doi.org/10.1016/j.jdcr.2019.09.009. 153  154   [8] Maglie R, Genovese G, Solimani F, Guglielmo A, Pileri A, Portelli F, et al. Immune-Mediated 155 Dermatoses in Patients with Haematological Malignancies: A Comprehensive Review. Am J 156 Clin Dermatol 2020. https://doi.org/10.1007/s40257-020-00553-9. 157  158   [9] Fei H, Chen S, Xu C. RNA-sequencing and microarray data mining revealing: the aberrantly 159 expressed mRNAs were related with a poor outcome in the triple negative breast cancer 160 patients. Ann Transl Med 2020;8:363. https://doi.org/10.21037/atm.2020.02.51. 161  162   [10] Yuan H, Zhou S, Liu Z, Cong W, Fei X, Zeng W, et al. Pivotal Role of Lesional and 163 Perilesional T/B Lymphocytes in Pemphigus Pathogenesis. J Invest Dermatol 2017;137:2362–164 70. https://doi.org/10.1016/j.jid.2017.05.032. 165  166  167  168 Figure legend 169 Figure 1: Breast-cancer exacerbated pemphigus vulgaris: morphological alteration of right breast 170 anatomy with nipple retraction. The skin of the right breast was covered with multiple erosions, scales 171 and crusts. 172  173 Figure 2: complete resolution of the cutaneous lesion of the breast skin following the surgical removal of 174 the tumor.  175  176 Journal Pre-proofJournal Pre-proofJournal Pre-proof

Localized pemphigus exacerbation associated with underlying breast cancer

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Localized pemphigus exacerbation associated with underlying breast cancer

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