Pathogenetic Mechanisms Linking Sarcoidosis to Lymphoma

Abstract

Sarcoidosis and lymphoma share immunopathological characteristics that suggest a complex, interconnected relationship. This article examines the multi-faceted mechanisms linking sarcoidosis to lymphoma, a phenomenon called sarcoidosis-lymphoma syndrome (SLS). SLS is hard to diagnose, requiring distinct criteria and imaging to differentiate overlapping features and histological differences. The co-occurrence of these diseases may be explained by genetic predispositions, immune dysregulation, and environmental factors that enhance malignancy risk. In active sarcoidosis, chronic inflammation and granuloma formation induce the production of cytokines that can contribute to lymphoma development. The role of macrophage polarization is also discussed. Immunosuppressive treatment prescribed in sarcoidosis patients, particularly corticosteroids and biological agents, may increase the susceptibility to lymphoproliferative malignancies. These common mechanisms emphasize the need for vigilant monitoring of lymphoma in patients with sarcoidosis, as this granulomatous disease can mimic and promote the development of lymphoma.

Keywords: differential diagnosis; genetics; immunopathogenesis; immunosuppression; lymphoma; risk factors; sarcoidosis.

Figure 1

In sarcoidosis, multiple factors trigger the development of lymphoma, as depicted in this figure. The role of cytokines, TAMs, B-cell growth factors (BAFF, IL-2) is highlighted. Decreased immune surveillance and Th17 response may also increase the risk for malignancy, while M1 macrophages seem to have a protective effect. BAFF: B-cell activating factor, IL-2: interleukin 2, M1: M1 macrophages, M2: M2 macrophages, TAM: tumor-associated macrophages.

Figure 2

Genetic factors significantly influence sarcoidosis-lymphoma syndrome, with molecular interactions shaping immune responses. MicroRNAs regulate gene expression, while DNA and histone methylation affect chromatin structure and gene activity. The JAK/STAT pathway drives cytokine-mediated inflammation, and HLA-DRB1 variations highlight its role in antigen presentation. Protein expression and oxidative stress via transcription factors further contribute to immune dysregulation and tissue damage, advancing disease progression.

Figure 3

Sarcoid-like reactions can be the result of various agents, as shown in this figure. Notably, different oncological therapies, such as ICIs, anti-TNF-α, and especially α-interferon can contribute to granuloma formation. Regarding the lymphoma microenvironment, the Th1-mediated hypersensitivity reaction and cytokines (e.g., interferon-gamma) can be involved in granulomatosis. ICI: immune checkpoint inhibitors, SLR: sarcoid-like reactions, TNF-a: tumor necrosis factor a.