Objectives: Primary Sjögren’s Syndrome (pSS) carries the highest risk for non-Hodgkin's lymphoma (NHL) development among systemic autoimmune diseases. However, the paucity of data on the long-term survival of those patients and the lack of established predictors for each lymphoma histologic subtype prompted our present study. Methods: We retrospectively analysed 121 patients diagnosed with NHL according to the WHO classification criteria. All patients fulfilled the 2016 ACR-EULAR classification criteria for pSS. Cumulative clinical, laboratory, radiologic, treatment regimens and histologic data were recorded, harmonized and analysed. Overall survival (OS) and event-free survival (EFS) curves were calculated. A mucosa-associated lymphoid tissue lymphoma (MALTL) prediction model was developed by applying innovative data-driven analysis of clinical features present at the time of pSS diagnosis. Results: MALTLs constituted the majority of lymphomas (92/121, 76.0%) followed by diffuse large B-cell lymphomas (DLBCL) (11/121, 9.0%) and nodal marginal zone lymphomas (NMZL) (8/121, 7%). MALTLs show salivary glands localization, limited disease and often bone marrow and nodal involvement. The 10-year OS and EFS rates were 79% and 45.5% for MALTLs, 40.9% and 24.2% for DLBCL and 46% and 31% for NMZL. Cryoglobulinemia, focus score and the total EULAR SS Disease Activity Index (ESSDAI) composite index at pSS diagnosis were proven independent MALTL predictors. Even though MALTLs have a comparatively good survival outlook, they are accompanied by frequent events throughout their clinical course. Conclusions: Common features of pSS, present at diagnosis, can predict future lymphomagenesis meriting a more intensive follow-up plan.

Sjögren’s Syndrome (SS) is a chronic autoimmune disorder characterized by focal mononuclear cell infiltrates that surround the ducts of the exocrine glands, impairing the function of their secretory units. Compared to other autoimmune disorders, SS is associated with a notably high incidence of non-Hodgkin lymphoma (NHL) and more frequently mucosa associated lymphoid tissue (MALT) lymphoma, leading to increased morbidity and mortality rates. High risk features of lymphoma development include systemic extraepithelial manifestations, low serum levels of complement component C4 and mixed type II cryoglobulinemia. The discrimination between reactive and neoplastic lymphoepithelial lesion (LEL) is challenging, probably reflecting a continuum in the evolution from purely inflammatory lymphoid infiltration to the clonal neoplastic evolution. Early lesions display a predominance of activated T cells, while B cells prevail in severe histologic lesions. This strong B cell infiltration is not only a morphologic phenomenon, but it is also progressively associated with the presence of ectopic germinal centers (GCs). Ectopic formation of GCs in SS represents a complex process regulated by an array of cytokines, adhesion molecules and chemokines. Chronic antigenic stimulation is the major driver of specific B cell proliferation and increases the frequency of their transformation in the ectopic GCs and marginal zone (MZ) equivalents. B cells expressing cell surface rheumatoid factor (RF) are frequently detected in the salivary glands, suggesting that clonal expansion might arise from antigen selection of RF-expressing B cells. Abnormal stimulation and incomplete control mechanisms within ectopic lymphoid structures predispose RF MZ like cells to lymphoma development. Immunoglobulin recombination, somatic mutation and isotype switching during B cell development are events that may increase the translocation of oncogenes to immunoglobulin loci or tumor suppressor gene inactivation, leading to monoclonal B cell proliferation and lymphoma development. Concerning chronic antigenic stimulation, conclusive data is so far lacking. However immune complexes containing DNA or RNA are the most likely candidates. Whether additional molecular oncogenic events contribute to the malignant overgrowth remains to be proved.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.