Uncommon manifestations of paraneoplastic autoimmunity associated with thymic epithelial tumors

Thymic epithelial tumors (TETs) are rare cancers that arise from the epithelial compartment of the thymus and exhibit a spectrum of histological, genomic, and clinical features (1,2). Due to the role of the thymus in development of immunological tolerance, a complex process that is mediated by the interactions between thymic epithelial cells and developing thymocytes (3), TETs, especially thymomas, are often associated with paraneoplastic autoimmune diseases (ADs) (Figure S1) (4-7).

The development of autoimmunity affects the quality-of-life of patients and can substantially increase morbidity (8,9). The presence of paraneoplastic AD in patients with TETs has prognostic implications and influences treatment selection in the era of immunotherapy. ADs are associated with favorable prognostic factors such as younger age, favorable histology (World Health Organization types A, AB, B1 and B2 thymoma), earlier stage, and increased rate of complete resection, but are not an independent prognostic factor in patients with TETs (10). AD is also a contraindication for immunotherapy in most cases due to a high risk for development of immune-related adverse events (11). This issue is especially relevant for patients with TETs since defective immunological tolerance increases the risk for severe or life-threatening immune-mediated toxicity (12).

Given the clinical implications of paraneoplastic ADs in patients with TETs, early recognition of uncommon ADs is crucial in facilitating adequate management and improving quality-of-life. In this review, we describe four rare and often under-recognized TET-associated ADs that affect widely disparate organ systems, which if undiagnosed and inadequately managed, can lead to poor clinical outcomes.

Lymphocytic pneumonitis

Lymphocytic pneumonitis, or lymphoid interstitial pneumonia (LIP), is characterized by lymphocyte infiltration of the interstitial and alveolar spaces of the lungs (13). LIP can occur due to impaired central immune tolerance. Central immune tolerance mechanisms ensure that lymphocytes with self-antigen receptors are deleted at the early stages of development of lymphocyte precursors within the thymus (3). The autoimmune regulator (AIRE) gene regulates the processes of positive and negative selection of T cells in the thymus (14).

Patients with TETs and other AIRE deficient states can develop lymphocytic pneumonitis and present with chronic respiratory symptoms in addition to radiographic and pulmonary function abnormalities (15). These symptoms, if left untreated, can lead to hypoxemic respiratory failure and death. CT findings of lymphocytic pneumonitis include nodular opacities and bronchiectasis (15). Endobronchial biopsies show a submucosal lymphocytic infiltrate and serology can detect autoantibodies to lung-specific bactericidal and permeability-increase fold-containing B1 (BPIFB1) and/or the potassium channel regulator (KCNRG) in approximately 75% of affected patients (15). These clinical, radiological, histologic and serological features are shared with other AIRE deficiency conditions such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and RAG deficiency (15). T and B cell-directed immunosuppressive strategies, such as T cell modulation with azathioprine in combination with B cell-targeting rituximab, can decrease lung inflammation and improve pulmonary function in patients with AIRE deficiency-associated lymphocytic pneumonitis (15).

Large granular lymphocytic (LGL) leukemia

LGL leukemia is a rare clonal lymphoproliferative disease that is T or NK cell-derived and can be associated with neutropenia and ADs (16). T-LGL is often chronic and indolent in nature. Bone marrow biopsies in patients with LGL leukemia show a hypercellular marrow with frequent small lymphoid cells, compact chromatin, and negligible to moderately abundant cytoplasm with azurophilic granules (17).

The pathogenesis of LGL leukemia involves chronic antigenic stimulation that causes polyclonal expansion of T-cells, which evolves into monoclonal expansion that can cause inhibition of erythroid or myeloid precursors and lead to pure red cell aplasia (PRCA) and neutropenia, respectively (18). LGL leukemia has been described in AIRE deficiency states, including both APECED and thymoma, with or without other blood dyscrasias and ADs (19-21). In a series of 327 patients with thymoma, LGL leukemia was diagnosed in 3 (0.9%) cases, with or without concurrent PRCA (20). Methotrexate is often used for treatment of LGL leukemia and can restore bone marrow function in patients with concurrent cytopenias (17).

Anti-PIT-1 antibody syndrome

Pituitary-specific transcription factor-1 (PIT-1) regulates the expression of growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) (22). Anti-PIT-1 antibody syndrome occurs when there is an acquired and combined deficiency of GH, PRL and TSH in the presence of circulating anti-PIT-1 antibodies and PIT-1-reactive cytotoxic T cells (CTLs) (23,24). In patients with thymoma, anti-PIT-1 antibody syndrome was first described in three patients, who were first diagnosed with endocrinopathies and found to have circulating anti-PIT-1 antibodies (24). During follow-up, all patients developed a mediastinal mass, with histological confirmation of thymoma in two out of three cases. Thymectomy resulted in a decrease in anti-PIT-1 antibody titers and diminished reactivity of CTLs toward PIT-1 protein (24). However, at 2 years post-thymectomy, there was no improvement in anterior pituitary function, possibly indicating irreversible immune-mediated damage to pituitary cells (24).

Anticytokine autoantibody-mediated acquired immunodeficiency

Good syndrome is a well-recognized, albeit poorly understood cause of adult-onset immunodeficiency in patients with thymoma that is characterized by hypogammaglobulinemia and an increased risk for developing opportunistic infections (25). However, patients with thymoma can be at increased risk for recurrent infections even in the absence of hypogammaglobulinemia. A less well recognized cause of thymoma-associated acquired immunodeficiency is the presence of circulating anti-cytokine autoantibodies (ACAAs) (26,27). In patients with thymoma, ACAAs are most often directed against interferon-α (IFN-α) and IFNω, and a subset of patients develop chronic mucocutaneous candidiasis, chronic viral infections, recurrent bacterial sinopulmonary disease, including Mycobacterium avium infection, and severe infections, such as disseminated cryptococcosis and severe cytomegalovirus or varicella zoster virus (VZV) infections (26,27). Treatment directed at ACAAs is an area of active research and includes T and B cell-directed immunosuppressive therapies and interventions to deplete ACAAs, such as plasma exchange or the use of high-dose intravenous immunoglobulins (27).

In conclusion, a wide variety of paraneoplastic ADs can occur in patients with TETs due to defects in immunological tolerance. Although predominantly associated with thymoma, ADs can also occur in patients with thymic carcinoma. Early recognition and aggressive treatment of ADs is essential to decrease morbidity and improve quality-of-life. Further research is required to understand the pathophysiology of TET-associated ADs and to develop better immunosuppressive therapies to treat these conditions.

Acknowledgments

Figures were created with BioRender.com.

Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (No. ZID BC 011543).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-2/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-2/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Copyright Information: The authors of this manuscript are U.S. Government employees. Since this manuscript has been prepared within the scope of their employment, it should be considered to be in the public domain in the USA and not require a transfer or license of rights.

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