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.

Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis

“…PNP is an obligate PD usually associated with B-cell lymphomas and hematological malignancies [7]. In 2001, Nguyen et al suggested the term "paraneoplastic autoimmune multiorgan syndrome" (PAMS) as several organs are affected and autoantibodies bind several tissues [8,9]. PNP usually affects patients aged between 45 and 70 years [7,10,11].…”

“…Nearly 84% of all PNP are found in association with hematologic neoplasms or disorders. Among these, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease, and thymoma are mostly reported, accounting respectively for 38.6%, 18.4%, 18.4%, and 5.5% of all PNP cases [7,9,11]. Usually, the neoplasm is detected before the onset of PNP, but in about 30% of cases, the skin manifestations lead to the detection of an occult neoplasia [7,11].…”

“…Therefore, it is important to evaluate accurately the respiratory symptoms in patients with positive anti-Dsg3 IgG. However, PNP cases associated with benign tumors, such as localized Castleman disease and benign thymoma, usually improve or achieve a complete remission after tumour resection [7,9].…”

Immune-Mediated Dermatoses in Patients with Haematological Malignancies: A Comprehensive Review

“…5). Besides acantholysis, PNP shows a lichenoid lymphocytic infiltrate along the dermal-epidermal junction by histopathology [136,137]. Serologically, PNP is only rarely associated with IgG antibodies against desmoglein 3 and desmoglein 1, which are the main antigenic targets of pemphigus vulgaris and foliaceus respectively, whereas IgG autoantibodies against envoplakin, periplakin and the protease inhibitor, alpha-2-macroglobulin-like antigen-1 are more frequently detected.…”

“…Based on the evidence of increased levels of IL-6 in PNP sera and the crucial role of IL-6 in Castleman's disease [157,158], tocilizumab, a monoclonal antibody targeting IL-6, has been successfully applied as a treatment for PNP in this context, but seems to have limited effect in preventing bronchiolitis obliterans [159,160]. Rituximab, with or without chemotherapy, represents an effective therapeutic option for PNP [146,161]; thymoma-associated PNP or multi-organ syndrome also respond well to rituximab treatment, but a significant proportion of these patients still die as a result of infections and sepsis [137].…”