Thymoma-Associated Paraneoplastic Autoimmune Multiorgan Syndrome-From Pemphigus to Lichenoid Dermatitis

Abstract

Introduction: Paraneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin. PAMS is occasionally associated with thymoma, in which altered immune surveillance eventually leads to multiorgan autoimmunity which often includes variable cutaneous symptoms. This disorder is associated with a profound disturbance of peripheral immune tolerance against human autoantigens. Objectives: We here present a patient with relapsing thymoma who developed PAMS with several cutaneous and extracutaneous autoimmune disorders. Materials: Peripheral blood mononuclear cells (PBMC), sera, and lesional skin biopsies were obtained at different clinical disease stages. Peripheral T cell subsets were characterized phenotypically and the cytokine profile of the peripheral blood T cellular response against distinct epidermal and dermal autoantigens of the skin was analyzed by ELISpot assay. Serological screening was performed by ELISA and immunoblot analysis. Skin biopsies were subjected to immunohistochemical analysis of distinct T cell subsets. Thymoma tissue was analyzed for the presence of T regulatory cells and compared with adult thymus and indolent thymoma. Results and Conclusions: In the present case, thymoma was the cause of the observed multi-organ autoimmune syndromes as its recurrence and surgical removal was associated with the relapse and regression of the cutaneous symptoms, respectively. Initially, the patient presented with two autoimmune disorders with Th2/Th1 imbalance, myasthenia gravis (MG) and pemphigus foliaceus (PF), which regressed upon immunosuppressive treatment. Months later, the patient developed a lichenoid exanthema with a Th1-dominated skin infiltrate. Further clinical evaluation revealed the recurrence of the thymoma and the lichenoid exanthema gradually regressed upon thymectomy. Our contention that T cell recognition against distinct cutaneous autoantigens, such as desmoglein 1 (Dsg1), shifted from a Th2 to a Th1-dominated immune response could not be fully substantiated as the patient was on a stringent immunosuppressive treatment regimen. We could only observe a decrease of the initially present serum IgG autoantibodies against Dsg1. Phenotypic analysis of the associated thymoma showed a lower number of T regulatory cells compared to adult thymus and indolent thymoma, suggesting that impaired thymus-derived immune surveillance had a direct impact on the outcome of the observed cutaneous autoimmune disorders.

Keywords: GVHD-like disease; PAMS; Pemphigus foliaceous; autoimmunity; myasthenia (myasthenia gravis—MG); thymoma auto-immunity.

Figure 1

(A–D) Clinical manifestations of the patient during clinical observational period. (A) Initially pemphigus foliaceus with involvement of the seborrheic skin areas and ptosis in myasthenia gravis, (B) lichenoid eruption at the time of thymoma recurrence, (C) erythroderma with lichenoid eruption right after thymectomy, and (D) resolution of the lichenoid eruption.

Figure 2

Immune serological characteristics of the patient, (A) direct immunofluorescence (DIF) at time of pemphigus foliaceus, which showed IgG and C3 deposits at the surface of epidermal keratinocytes and (B) DIF at time of GVHD-like dermatitis which showed IgG C3 deposits along the BMZ. (C) positive DIF controls of perilesional BP skin, showing linear deposition of IgG along the BMZ (above), and positive DIF from perilesional PV skin presenting deposits at the surface of epidermal keratinocytes.

Figure 3

(A) Immunohistochemical analysis of T cell subsets in pemphigus foliaceus (PF) and lichenoid skin lesions during the observational period. (A) CD3⁺/Tbet⁺ and CD4⁺/GATA3⁺ T cell skin infiltrate in PF, the lichenoid eruption at thymoma recurrence, and after thymectomy. (B) Percentage of CD4⁺/GATA3⁺, T-Bet+, IL17A⁺, and FoxP3⁺ T cells in PF skin lesions, at thymoma recurrence and after thymectomy, (C) expression pattern of FoxP3+ T cells in adult thymus, indolent thymoma, and in PAMS-associated thymoma (present case).