Molecular Convergence Between Hashimoto's Thyroiditis and Thyroid MALT Lymphoma: A Scoping Review of Shared Lymphomagenic Mechanisms and Pre-Neoplastic Potential

Molecular Convergence Between Hashimoto's Thyroiditis and Thyroid MALT Lymphoma: A Scoping Review of Shared Lymphomagenic Mechanisms and Pre-Neoplastic Potential | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Molecular Convergence Between Hashimoto's Thyroiditis and Thyroid MALT Lymphoma: A Scoping Review of Shared Lymphomagenic Mechanisms and Pre-Neoplastic Potential Luís Jesuíno de Oliveira Andrade, Luís Matos de Oliveira, Gabriela Correia Matos de Oliveira, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9534061/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To systematically map, through a scoping review methodology, the molecular and histological evidence of mechanistic overlap between HT and thyroid MALT lymphoma, examining shared lymphomagenic pathways and the biological plausibility of a pre-neoplastic continuum. Method Scoping review conducted in PubMed/MEDLINE, Embase, and Web of Science (1980–2024), following the Joanna Briggs Institute (JBI) framework for scoping reviews. Studies were included if they reported molecular, immunohistochemical, or genomic data on: (1) B-cell biology in HT tissue; (2) shared molecular markers between HT and thyroid lymphoma; or (3) the epidemiological association between HT and primary thyroid lymphoma. Study selection followed a two-stage screening protocol by two independent reviewers, with disagreements resolved by consensus. Results Forty-two studies met inclusion criteria. Five molecular pillars with documented evidence of overlap between HT and thyroid MALT lymphoma were identified: (1) ectopic germinal center formation with progressive B-cell clonal restriction; (2) BAFF/BLyS-driven NF-κB survival signaling; (3) BCL-2-mediated apoptosis resistance indistinguishable by immunohistochemistry between advanced HT and early MALT lymphoma; (4) sustained AID-dependent mutagenesis; and (5) TNFAIP3/A20 dysregulation in 11–20% of HT-associated primary thyroid lymphomas. A three-step molecular continuum from antigen-dependent oligoclonal expansion to constitutive NF-κB activation is proposed. Conclusion The available molecular and histological evidence supports biological continuity between HT and thyroid MALT lymphoma. This synthesis identifies testable hypotheses for future prospective studies and highlights molecular targets whose pharmacological modulation merits investigation in properly designed clinical trials. These findings do not constitute clinical recommendations, but provide a mechanistically grounded framework for translational research. Endocrinology & Metabolism Immunology Hashimoto's thyroiditis thyroid lymphoma pre-neoplastic state AID mutagenesis scoping review Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Hashimoto's Thyroiditis (HT), first described by Hakaru Hashimoto in 1912, is a chronic autoimmune thyroid disorder characterized by diffuse lymphocytic infiltration of the thyroid parenchyma, progressive destruction of thyroid follicles, ectopic germinal center formation, and eventual hypothyroidism. It represents the leading cause of hypothyroidism in iodine-sufficient regions, affecting approximately 1–2% of the general population, with a marked female predominance (female-to-male ratio of 10–20:1). 1 Beyond its endocrine manifestations, HT is uniquely associated with an exceptionally elevated relative risk for primary thyroid lymphoma. In the landmark Swedish cohort study by Holm, Blomgren, and Löwhagen (829 patients with chronic lymphocytic thyroiditis monitored through the Swedish Cancer Register), the relative risk of primary malignant thyroid lymphoma reached 67-fold (4 observed vs. 0.06 expected cases; P < 0.000001). 2 Subsequent meta-analyses and cohort studies have corroborated this association, with estimated relative risks ranging from 60- to 80-fold. 3 This remarkable epidemiological association has not prompted a systematic molecular investigation of HT from an oncological perspective. Traditionally, HT is classified as an autoimmune disorder, while thyroid Mucosa-Associated Lymphoid Tissue (MALT) lymphoma is regarded as a distinct malignant neoplasm. However, their molecular underpinnings exhibit substantial overlap, raising the hypothesis that the distinction between these two entities may be fundamentally quantitative, relating to clonal dominance and the progressive accumulation of genomic alterations, rather than qualitative in nature. The present scoping review aims to map and synthesize the available evidence on molecular mechanisms shared between HT and thyroid MALT lymphoma, structured around five biological pillars, to articulate the biological plausibility of a pre-neoplastic continuum, and to identify research gaps and testable hypotheses for future prospective studies. METHODS AND RESULTS Overview of Included Studies The initial database search retrieved 847 records. After removal of duplicates (n = 214) and screening of titles and abstracts (n = 633), 127 studies were selected for full-text review. Of these, 42 met all eligibility criteria and were included in the final synthesis. The complete characterization of all included studies by thematic domain is presented in Table 1 . Table 2 presents the key epidemiological studies in detail. Figure 1 displays the PRISMA-ScR selection flow diagram. The 42 included studies comprised: 10 cohort studies or case series on the epidemiological association between HT and primary thyroid lymphoma (refs. 2, 3, 6, 7, 8, 9, 10, 11, 12, 13); 7 systematic reviews, meta-analyses, and clinical guidelines on HT (refs. 4, 5, 37, 38, 39, 40, 41); 9 immunohistochemical or molecular studies characterizing B-cell biology, B-cell lymphoma (BCL)-2, and clonality in HT tissue (refs. 14, 15, 16, 19, 22, 23, 24, 26, 27); 9 translational or experimental studies addressing molecular pathways shared between HT and MALT lymphoma (refs. 17, 18, 20, 21, 28, 29, 30, 31, 32); and 7 studies on molecular oncology of MALT lymphoma and B-cell malignancies relevant to the proposed continuum (refs. 25, 33, 34, 35, 36, 42, 43, 44). Table 1 Classification of the 42 included studies by thematic domain. Reference Ref. No. Thematic domain and primary contribution Domain 1 – Epidemiology of the HT–Thyroid Lymphoma Association (n = 10) Holm et al. (1985) 2 Foundational Swedish cohort (n = 829); RR = 67× for thyroid lymphoma in chronic lymphocytic thyroiditis (P < 0.000001) Travaglino et al. (2020) 3 Systematic review and meta-analysis (n = 1,346); pooled HT prevalence in PTL: 78.9%; pooled RR: 60–80× Watanabe et al. (2011) 6 Largest HT cohort (n = 24,553); 171 PTL identified; 10-year lymphoma risk in HT patients: 0.7% Pavlidis & Pavlidis (2019) 7 Narrative review of primary thyroid lymphoma: molecular factors, diagnosis, and clinical management Kato et al. (1985) 8 Japanese case-control (n = 5,592); chronic thyroiditis as independent B-cell lymphoma risk factor Hyjek & Isaacson (1988) 9 Case series (n = 236 PTL); HT background present in ~ 98% of primary thyroid B-cell lymphomas Derringer et al. (2000) 10 Clinicopathological series (n = 108 PTL); HT in 87%; strong histological overlap with early MALT Thieblemont et al. (2002) 11 Retrospective cohort (n = 70 PTL); HT in 90%; primary thyroid lymphoma is heterogeneous (MALT 60%, DLBCL 40%) Troch et al. (2008) 12 Multi-site MALT cohort; chronic autoimmune thyroiditis in 16% of all-anatomical-site MALT lymphoma cases Hu X et al. (2022) 13 Systematic review and meta-analysis (n = 3,591); elevated cancer risk in HT, including thyroid lymphoma and PTC Domain 2 – Systematic Reviews, Meta-Analyses, and Clinical Guidelines on HT (n = 7) Peters et al. / JBI (2020) 4 JBI Manual for Evidence Synthesis, Chap. 11: Scoping Reviews; methodological framework adopted Tricco et al. (2018) 5 PRISMA-ScR checklist and explanation; methodological reference for scoping review reporting Klubo-Gwiezdzinska & Wartofsky (2022) 37 Evidence-based guide to HT etiology, diagnosis, and treatment; comprehensive clinical reference Jonklaas et al. / ATA (2014) 38 American Thyroid Association guidelines for treatment of hypothyroidism; standard of care reference Huwiler et al. (2024) 39 Systematic review and meta-analysis of RCTs on selenium supplementation in HT; effects on anti-TPO titers Li R et al. (2025) 40 Review of the immune system in HT, potential therapies, and animal model construction Palazzo et al. (2025) 41 Review of lessons from belimumab trials in SLE; pharmacological reference for anti-BAFF strategy Domain 3 – Immunohistochemical and Molecular Studies on HT Tissue (n = 9) Caturegli et al. (2013) 14 Histopathological characterization of HT; ectopic germinal center formation and lymphoid neogenesis Moshynska & Saxena (2008) 15 PCR-based clonality assays in HT tissue; monoclonal/oligoclonal Ig rearrangements without overt lymphoma Chetty et al. (1995) 16 IHC detection of p53 and BCL-2 in HT and thyroid lymphoma; IHC overlap between advanced HT and early MALT Campi et al. (2015) 19 BAFF and BAFF-R expression in HT tissue (IHC); maximal signal in GC and mantle zones of ectopic follicles Kuribayashi-Hamada et al. (2022) 22 A20/TNFAIP3 mutation in primary thyroid lymphoma; all A20 mutations associated with HT background Rodríguez-Sevilla & Salar (2021) 23 Genetic advances in MALT lymphoma including TNFAIP3 inactivation in thyroid MALT (11–20% of cases) Chu et al. (2011) 24 Murine model: B-cell-specific TNFAIP3 deletion induces HT-like autoimmune phenotype with anti-thyroid IgG Vasconcelos et al. (2021) 26 BCL-2 and MCL-1 co-overexpression in HT infiltrates; elevated Ki-67 and low apoptotic rate Stassi et al. (2001) 27 Fas/FasL pathway dysregulation in HT; inverted Fas-FasL axis promotes lymphocytic infiltrate persistence Domain 4 – Translational and Experimental Studies on Shared Molecular Pathways (n = 9) Giordano et al. (2023) 17 BAFF from dendritic cells and neutrophils required for B-cell maturation and autoantibody production in SLE-like disease Kampa et al. (2020) 18 APRIL and BAFF receptors (TACI, BCMA, BAFFR) in oncology; mechanistic and pharmacological review Yang et al. (2014) 20 BAFF/BAFF-R axis in B-cell non-Hodgkin lymphoma; survival signaling and therapeutic targeting Hamoudi et al. (2010) 21 NF-κB target gene expression in MALT lymphoma with and without chromosomal translocation Leeman-Neill et al. (2024) 28 AID on- and off-target activity in non-Hodgkin B-cell lymphomas; review of oncogenic mechanisms Jiao et al. (2023) 29 Off-target AID effects in carcinogenesis; mutagenic activity at proto-oncogene loci Nishikori et al. (2021) 30 Elevated AID expression in ocular adnexal MALT lymphoma with IgG4-positive cells (autoimmune context) Li L et al. (2025) 31 BAFF system role in autoimmune diseases: mechanisms, disease implications, and therapeutic advances Corneth et al. (2022) 32 Aberrant B-cell signaling in autoimmune diseases including HT; BCR and BAFF pathway dysregulation Domain 5 – Molecular Oncology of MALT Lymphoma and B-Cell Malignancies (n = 7) Li WF et al. (2024) 25 BCL-2 inhibitor-based therapies and emerging resistance in CLL; venetoclax pharmacology reference Lauring & Basu (2024) 33 Somatic hypermutation mechanisms during lymphomagenesis and transformation; AID and clonal evolution Lai et al. (2023) 34 Clinicopathological analysis of primary thyroid non-Hodgkin lymphoma; single-center series Raderer et al. (2023) 35 Clinical relevance of molecular aspects in extranodal marginal zone lymphoma; NF-κB and TNFAIP3 Li X et al. (2025) 36 Genetic alterations and prognostic impact in marginal zone lymphoma; meta-analysis Pal Singh et al. (2018) 42 BTK role in B cells and malignancies; ibrutinib pharmacology and BCR-signaling inhibition Zhu & Almasan (2017) 43 Development of venetoclax for therapy of lymphoid malignancies; BCL-2 inhibition rationale Verma et al. (2022) 44 Dual PI3Kδγ inhibition in DLBCL models; preclinical characterization of PI3K inhibitor HT, Hashimoto’s Thyroiditis; PTL, primary thyroid lymphoma; MALT, mucosa-associated lymphoid tissue; DLBCL, diffuse large B-cell lymphoma; RR, relative risk; IHC, immunohistochemistry; GC, germinal center; CLL, chronic lymphocytic leukemia; SLE, systemic lupus erythematosus; BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; AID, activation-induced cytidine deaminase; PTC, papillary thyroid carcinoma. Table 2 Key epidemiological studies (Domain 1) on the association between HT and primary thyroid lymphoma — detailed summary. Study / Year N HT prevalence in PTL (%) Main lymphoma subtype Key finding Holm et al. 2 (1985) 829 — Thyroid lymphoma (mixed) RR = 67× (P < 0.000001); foundational epidemiological study Travaglino et al. 3 (2020) 1,346 78.9% (pooled) MALT, DLBCL Pooled RR 60–80×; systematic review and meta-analysis Watanabe et al. 6 (2011) 171 PTL / 24,553 HT — MALT, DLBCL 10-year lymphoma risk in HT: 0.7%; largest HT cohort Pavlidis & Pavlidis 7 (2019) Review — PTL (all subtypes) Molecular factors, diagnosis, and management of primary thyroid lymphoma Kato et al. 8 (1985) 5,592 — B-cell lymphoma Chronic thyroiditis as independent lymphoma risk factor Hyjek & Isaacson 9 (1988) 236 ~ 98% MALT / DLBCL Near-universal HT background in primary thyroid lymphoma Derringer et al. 10 (2000) 108 PTL 87% MALT, DLBCL Strong histological overlap between HT and early MALT Thieblemont et al. 11 (2002) 70 PTL 90% MALT (60%), DLBCL (40%) Primary thyroid lymphoma is heterogeneous Troch et al. 12 (2008) MALT cohort 16% of all-site MALT MALT (thyroidal & extrathyroidal) HT-associated MALT lymphoma extends beyond thyroid gland Hu X et al. 13 (2022) 3,591 — Thyroid lymphoma, PTC Elevated cancer risk in HT; meta-analysis HT, Hashimoto's Thyroiditis; PTL, primary thyroid lymphoma; MALT, mucosa-associated lymphoid tissue; DLBCL, diffuse large B-cell lymphoma; PTC, papillary thyroid carcinoma; RR, relative risk. Pillar 1 – Ectopic Germinal Centers and Progressive B-Cell Clonal Restriction In HT, the thyroid parenchyma is progressively replaced by a mononuclear infiltrate organized into mature lymphoid follicles harboring ectopic germinal centers (GCs). 14 This intrathyroidal lymphoid neogenesis recapitulates the structural organization of secondary lymphoid tissues and constitutes a distinctive histologic hallmark differentiating HT from simple lymphocytic thyroiditis. Within these ectopic GCs, B cells undergo persistent stimulation by thyroid autoantigens (predominantly thyroid peroxidase and thyroglobulin), initiating iterative cycles of somatic hypermutation (SHM) and antigen-driven clonal selection. Over time, this process imposes progressive restriction of immunoglobulin (Ig) gene diversity. PCR-based clonality assays performed on thyroid tissue from HT patients have demonstrated monoclonal or oligoclonal Ig gene rearrangements even without histologic evidence of lymphoma, patterns analogous to in situ follicular neoplasia of lymph nodes. 15 Immunohistochemical staining for BCL-2 and p53 fails to reliably distinguish advanced HT from low-grade thyroid MALT lymphoma. Within mantle zones and lymphoepithelial lesions (LELs) of HT, lymphoid cells exhibit uniform BCL-2 expression mirroring the pattern observed in low-grade diffuse thyroid lymphomas. 16 This histologic overlap reflects a genuine biological continuum, rather than a mere diagnostic limitation. Pillar 2 – BAFF/BLyS: A Master Survival Signal Shared by HT and MALT Lymphoma B-cell activating factor (BAFF, encoded by TNFSF13B) is a TNF superfamily member essential for mature B-cell survival. It signals through three receptors (BAFF-R, TACI, and BCMA), activating canonical and non-canonical NF-κB pathways, as well as PI3K/AKT and ERK cascades, promoting B-cell survival, proliferation, and Ig class-switch recombination. 17 , 18 In HT, thyrocytes constitutively release BAFF in response to interferon-γ produced by infiltrating Th1 cells. Immunohistochemical analyses of HT tissue have demonstrated BAFF and BAFF-R expression in both infiltrating lymphocytes and thyrocytes, with maximal intensity in GCs and mantle zones of ectopic follicles. 19 This thyroid-derived BAFF establishes a self-perpetuating survival loop for intrathyroidal B cells, bypassing the requirement for classical nodal support. The same BAFF-dependent survival circuitry defines thyroid MALT lymphoma and other indolent B-cell neoplasms. BAFF overexpression lowers the threshold for malignant transformation by inhibiting activation-induced apoptosis in GC B cells, a checkpoint that would otherwise eliminate premalignant clones. 20 These findings suggest that thyrocyte-derived BAFF in HT may function as a driver of the pre-neoplastic state, a hypothesis requiring prospective validation. Pillar 3 – NF-κB Dysregulation and the TNFAIP3/A20 Axis NF-κB is a central hub for survival and proliferation in B-cell lymphomagenesis, regulating target genes including BCL-2, BCL-XL, XIAP, and MYC. In MALT lymphoma, constitutive NF-κB activation arises from chromosomal translocations and from inactivation of the inhibitor TNFAIP3, which encodes the desubiquitinase A20. 21 Mutations and deletions of A20/TNFAIP3 are documented in MALT lymphomas arising in sites of chronic autoimmune inflammation, including the ocular adnexa, salivary glands, and thyroid. In primary thyroid lymphoma, TNFAIP3 inactivation has been reported in 11–20% of cases; in two independent studies, all identified A20 mutations were associated with pre-existing HT. 22,23 These data establish a direct genetic link between the autoimmune microenvironment of HT and a molecular alteration enabling MALT lymphomagenesis. Murine models further support this relationship: B-cell-specific deletion of TNFAIP3 is sufficient to induce an autoimmune phenotype analogous to HT, characterized by thyroid-directed autoreactive IgG antibody production. 24 These findings demonstrate convergence between A20 loss and HT-like autoimmune disease within the same molecular circuitry. Pillar 4 – BCL-2: The Anti-Apoptotic Block Shared by HT Lymphocytes and MALT Tumor Cells BCL-2 is the paradigmatic anti-apoptotic protein in B-cell neoplasms. In thyroid tissue from HT, infiltrating lymphocytes within mantle zones and LELs exhibit strong, homogeneous BCL-2 expression, with an immunohistochemical pattern indistinguishable from early-stage thyroid MALT lymphoma. 25 Co-overexpression of BCL-2 and MCL-1 in HT lymphocytic infiltrates, alongside elevated Ki-67 indices and a paradoxically low apoptotic rate, has been demonstrated by multiple immunohistochemical and molecular studies. 26 This anti-apoptotic phenotype in HT is sustained by tonic BAFF and BCR signaling, defining an antigen-dependent transcriptional state potentially distinct from the chromosomally fixed BCL-2 overexpression of follicular lymphoma, a distinction with potential translational relevance requiring direct comparative studies. Additionally, the Fas/FasL pathway, responsible for elimination of activated lymphocytes and peripheral tolerance maintenance, exhibits functional dysregulation in HT: thyrocytes aberrantly express FasL, promoting destruction of Fas-expressing thyrocytes rather than elimination of infiltrating lymphocytes. This functional inversion contributes to persistence of the lymphocytic infiltrate. 27 Pillar 5 – Activation-Induced Cytidine Deaminase (AID): The Engine of Mutagenesis in HT AID (encoded by AICDA) drives SHM and class-switch recombination in GC B cells, but also possesses off-target mutagenic activity capable of affecting proto-oncogenes including BCL2, MYC, PAX5, BCL6, and PIM1, inducing point mutations, double-strand DNA breaks, and chromosomal translocations that function as initiating events in B-cell lymphomagenesis. 28 , 29 Within the ectopic GCs of HT, AID activity may persist for years or decades due to chronic autoimmune stimulation. Each recirculation of B cells through GCs, driven by thyroid autoantigens, subjects this population to additional rounds of AID-mediated mutagenesis. This framework provides a mechanistic explanation for the dose-response relationship between disease duration and lymphoma risk, a hypothesis consistent with the available epidemiological data, though requiring direct prospective confirmation. Elevated AID expression has been documented in thyroid-origin MALT lymphoma and in ocular adnexal MALT lymphomas arising in sites of chronic autoimmune inflammation. 30 Table 3 Side-by-side molecular and histological comparison of HT and thyroid MALT lymphoma across eleven parameters. Feature Hashimoto's Thyroiditis Thyroid MALT Lymphoma Mechanistic significance Lymphoid infiltration Polyclonal → oligoclonal B cells Monoclonal B cells Quantitative shift in clonality; biological overlap documented by PCR-based assays Germinal center formation Ectopic GC in thyroid parenchyma Persistent GC-derived malignant clones Shared microstructural lymphoid platform BAFF/BLyS expression High; thyrocyte-derived, IFN-γ induced High; tumor microenvironment-derived Shared B-cell survival signal BCL-2 expression Elevated in infiltrating B cells (mantle zones, LELs) Constitutively elevated Anti-apoptotic block indistinguishable by IHC in HT vs. early MALT AID / AICDA activity Active in ectopic GCs; off-target mutagenesis sustained Residual or downregulated post-transformation AID provides cumulative oncogenic mutational load during HT phase TNFAIP3 / A20 status Wild-type (intact NF-κB regulation) Mutated/deleted in 11–20% of PTL A20 loss enables constitutive NF-κB activation NF-κB activation Antigen-dependent; BAFF-R and BCR driven Constitutive; TNFAIP3 loss or chromosomal translocations Same effector pathway; different upstream driver Ig gene rearrangement Polyclonal → oligoclonal by PCR Monoclonal dominant clone Clonal dominance is the diagnostic threshold Antigen dependence Yes — TPO, Tg drive BCR engagement Partial → progressive autonomy via BTK/PI3Kδ signaling Loss of antigen dependence is a key molecular event of malignant transition Driver mutations (MYD88, CARD11) Absent Present in DLBCL-transformation subset Genomic divergence occurs at/after transformation Lymphoepithelial lesions (LELs) Present; T-cell mediated follicular destruction Present; hallmark of MALT diagnosis (WHO criteria) LELs shared by both; morphology alone cannot distinguish HT-associated from early MALT GC, germinal center; BAFF, B-cell activating factor; AID, activation-induced cytidine deaminase; IHC, immunohistochemistry; LEL, lymphoepithelial lesion; Ig, immunoglobulin; TPO, thyroid peroxidase; Tg, thyroglobulin; BTK, Bruton's tyrosine kinase. Proposed Three-Step Molecular Continuum Based on the synthesized molecular evidence, a three-step sequential model of the HT-to-lymphoma continuum is proposed as a conceptual framework to guide future research. This model is not intended as a diagnostic or clinical algorithm, but as a heuristic construct identifying testable transition points. Step 1 – Antigen-Dependent Oligoclonal Expansion (Active HT) Thyroid autoantigens (TPO, Tg) promote chronic BCR activation in intrathyroidal B lymphocytes. Clone survival is sustained by BAFF signaling maintaining BCL-2 overexpression. AID remains active within ectopic GCs, driving SHM and progressive Ig gene restriction. TNFAIP3/A20 continues to exert regulatory function, and NF-κB activation remains antigen-dependent (Fig. 2 ). 31 , 32 Step 2 – Early Clonal Escape (In Situ Lymphoid Neoplasia, Candidate Stage) An AID-mediated off-target mutation in TNFAIP3/A20, BCL2, or MYC confers a competitive survival advantage to a single B-cell clone, enabling partial dissociation from continuous antigenic stimulation. This clone expands dominantly. PCR-based clonality assays reveal a predominant Ig gene rearrangement, while histologically the lesion may still be classified as 'florid' HT or 'indeterminate for lymphoma. Whether this stage consistently precedes overt lymphoma and whether it can be reproducibly detected prospectively remains an unresolved research question requiring NGS-based longitudinal studies (Fig. 3 ). 33 , 34 Step 3 – Overt MALT Lymphoma Constitutive NF-κB activation, mediated by TNFAIP3/A20 inactivation or chromosomal translocations (BCL10-IGH, MALT1-IGH), confers complete antigen-independent survival. Expansion of the malignant clone becomes self-sustaining and invasive, with LEL formation and infiltration beyond thyroid parenchyma, fulfilling WHO histologic criteria for primary thyroid MALT lymphoma (Fig. 4 ). 35 , 36 DISCUSSION The present scoping review synthesizes evidence from 42 studies demonstrating substantial molecular overlap between HT and thyroid MALT lymphoma across five mechanistic pillars. The convergence of ectopic GC formation, BAFF-mediated survival signaling, BCL-2 anti-apoptotic blockade, AID-driven mutagenesis, and TNFAIP3/A20 dysregulation in both conditions is consistent with the hypothesis that these entities may represent a biological continuum rather than dichotomous categories. However, this interpretation requires critical qualification. First, the directionality of many documented associations remains observational. Most included studies are cross-sectional or retrospective, documenting molecular co-occurrence rather than causal or temporal relationships. Prospective longitudinal studies tracking molecular events from HT diagnosis through potential lymphoma development are largely absent from the literature. 45 This represents the most critical methodological gap identified by this review. Second, the epidemiological signal, while unequivocal in terms of relative risk, translates into a modest absolute lifetime risk of lymphoma in HT patients (approximately 0.7% at 10 years in the largest available cohort⁶). This suggests that the shared molecular architecture described herein is common in HT but that additional, yet-uncharacterized events are required for overt neoplastic transformation. 46 Identifying these events represents a priority research agenda. Third, the proposed three-step continuum constitutes a conceptual model rather than a validated pathophysiological staging system. The intermediate stage (in situ lymphoid neoplasia/early clonal escape) lacks a consensus definition, standardized detection methodology, or prospective evidence of predictable progression to overt lymphoma. 47 Its clinical or diagnostic utility cannot be established from the currently available evidence. Molecular Targets as Research Hypotheses – Not Clinical Recommendations The molecular pillars identified in this review, particularly constitutive BAFF overexpression, BCL-2 anti-apoptotic signaling, BTK/PI3Kδ-dependent BCR activation, and TNFAIP3/A20-mediated NF-κB dysregulation, represent pharmacologically actionable pathways in thyroid MALT lymphoma. Several agents targeting these pathways (including anti-BAFF biologics, BTK inhibitors, BCL-2 inhibitors, and PI3Kδ inhibitors) are approved for related B-cell malignancies and autoimmune conditions. 48 This mechanistic convergence generates testable research hypotheses: whether pharmacological modulation of BAFF, BCR, BCL-2, or NF-κB signaling in HT patients could influence the molecular trajectory toward lymphoma is a scientifically plausible question. However, the evidence mapped in this scoping review does not support clinical application of these agents in HT, and no such recommendation is made herein. Evaluation of these interventions would require prospective cohort studies with validated surrogate endpoints followed by randomized controlled trials in clearly, high-risk populations. 49 The identification of such populations itself remains an unmet methodological need. Surveillance Research Agenda The findings of this review suggest that monitoring strategies incorporating NGS-based Ig clonality assays on thyroid fine-needle aspiration specimens and TNFAIP3 mutational screening may have biological rationale in patients with long-standing HT. These approaches have not been validated in prospective studies and cannot be considered standard of care. 50 Future research should prioritize the definition of: (1) validated high-risk HT phenotypes; (2) reproducible molecular thresholds distinguishing reactive oligoclonal expansion from in situ neoplasia; and (3) the natural history of clonal dynamics in HT with and without lymphoma development. LIMITATIONS This scoping review has important limitations. Scoping reviews do not formally assess risk of bias in individual studies; the included literature encompasses heterogeneous study designs, sample sizes, and methodologies, limiting direct comparability. The search, while systematic, was restricted to published literature in three languages, potentially introducing publication bias. The proposed molecular continuum integrates evidence from distinct experimental contexts (immunohistochemistry, PCR-based clonality, murine models, and genomic sequencing), which may not directly translate to the clinical trajectory of any individual patient. Fourth, several key mechanistic claims in the literature, particularly regarding the functional significance of BAFF overexpression and BCL-2 expression in HT tissue, are based on cross-sectional studies that cannot establish causality or predict transformation. The role of follicular helper T cells, regulatory T cells, and the broader immune microenvironment in sustaining intrathyroidal B-cell expansion was not comprehensively captured in the included literature and warrants dedicated investigation. Finally, the potential modulatory effect of levothyroxine therapy, the standard treatment for HT-associated hypothyroidism, on intrathyroidal B-cell biology has not been systematically evaluated, despite evidence that thyroid hormone can modulate lymphocyte function and anti-apoptotic regulator expression. CONCLUSION This scoping review maps substantial molecular and histological evidence of mechanistic overlap between HT and thyroid MALT lymphoma across five biological pillars: ectopic germinal center formation, BAFF-mediated B-cell survival, BCL-2-driven apoptosis resistance, NF-κB dysregulation with TNFAIP3/A20 involvement, and AID-sustained mutagenesis. The available evidence is consistent with a biological continuum hypothesis, but does not permit definitive causal or prognostic conclusions given the observational nature and heterogeneity of included studies. The primary contribution of this review is the systematic identification and organization of research gaps: the absence of prospective longitudinal molecular data, the lack of validated intermediate-stage biomarkers, and the unresolved natural history of B-cell clonal dynamics in HT. These gaps define a translational research agenda whose pursuit, through prospective cohort studies and, subsequently, rigorously designed interventional trials, could ultimately inform whether pharmacological modulation of the identified molecular pathways has a role in lymphoma risk reduction in HT. No clinical recommendations are derived from the present synthesis. Declarations Conflict of interest statement: The authors declare no conflict of interest. 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Crit Rev Oncol Hematol 91(2):113–122 Hamoudi RA, Appert A, Ye H, Ruskone-Fourmestraux A, Streubel B, Chott A et al (2010) Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation. Leukemia 24(8):1487–1497 Kuribayashi-Hamada Y, Ishibashi M, Tatsuguchi A, Asayama T, Takada-Okuyama N, Onodera-Kondo A et al (2022) Clinicopathologic Characteristics and A20 Mutation in Primary Thyroid Lymphoma. J Nippon Med Sch 89(3):301–308 Rodríguez-Sevilla JJ, Salar A (2021) Recent Advances in the Genetic of MALT Lymphomas. Cancers (Basel) 14(1):176 Chu Y, Vahl JC, Kumar D, Heger K, Bertossi A, Wójtowicz E et al (2011) B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 117(7):2227–2236 Li WF, Atalla E, Dong J, Konopleva M (2024) BCL2i-Based Therapies and Emerging Resistance in Chronic Lymphocytic Leukemia. Cells 13(22):1922 Vasconcelos JC, Siqueira IB, Maia FFR, Parisi MCR, Zantut-Wittmann DE (2021) Influence of thyroid hormone in the expression of the marker pro-apoptosis BID, in spite of the predominance of anti-apoptosis activation in intrathyroidal lymphocytic infiltration in Hashimoto's thyroiditis. Mol Cell Endocrinol 537:111421 Stassi G, Zeuner A, Di Liberto D, Todaro M, Ricci-Vitiani L, De Maria R (2001) Fas-FasL in Hashimoto's thyroiditis. J Clin Immunol 21(1):19–23 Leeman-Neill RJ, Bhagat G, Basu U (2024) AID in non-Hodgkin B-cell lymphomas: The consequences of on- and off-target activity. Adv Immunol 161:127–164 Jiao J, Lv Z, Wang Y, Fan L, Yang A (2023) The off-target effects of AID in carcinogenesis. Front Immunol 14:1221528 Nishikori A, Nishimura Y, Shibata R, Ohshima KI, Gion Y, Ikeda T et al (2021) Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells. Int J Mol Sci 22(8):4083 Li L, Shen S, Shao S, Dang E, Wang G, Fang H et al (2025) The role of B cell-activating factor system in autoimmune diseases: mechanisms, disease implications, and therapeutic advances. Front Immunol 16:1538555 Corneth OBJ, Neys SFH, Hendriks RW (2022) Aberrant B Cell Signaling in Autoimmune Diseases. Cells 11(21):3391 Lauring MC, Basu U (2024) Somatic hypermutation mechanisms during lymphomagenesis and transformation. Curr Opin Genet Dev 85:102165 Lai Y, Ding C, Shen Y, Zhao L, Li H (2023) Clinicopathological analysis of primary thyroid non-Hodgkin lymphoma: a single-center study. Transl Cancer Res 12(3):515–524 Raderer M, Kiesewetter B, Du MQ (2023) Clinical relevance of molecular aspects in extranodal marginal zone lymphoma: a critical appraisal. Ther Adv Med Oncol 15:17588359231183565 Li X, Lin Y, An L (2025) Genetic alterations and their prognostic impact in marginal zone lymphoma: a meta-analysis. Ann Hematol 104(3):1307–1315 Klubo-Gwiezdzinska J, Wartofsky L (2022) Hashimoto thyroiditis: an evidence-based guide to etiology, diagnosis and treatment. Pol Arch Intern Med 132(3):16222 Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR et al (2014) Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid 24(12):1670–1751 Huwiler VV, Maissen-Abgottspon S, Stanga Z, Mühlebach S, Trepp R, Bally L et al (2024) Selenium Supplementation in Patients with Hashimoto Thyroiditis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Thyroid 34(3):295–313 Li R, He T, Xing Z, Mi L, Su A, Wu W (2025) The immune system in Hashimoto's thyroiditis: Updating the current state of knowledge on potential therapies and animal model construction. Autoimmun Rev 24(6):103783 Palazzo L, Tsoi A, Nikolopoulos D, Parodis I (2025) Lessons Learnt from the Belimumab Trials in Systemic Lupus Erythematosus. Int J Mol Sci 27(1):37 Pal Singh S, Dammeijer F, Hendriks RW (2018) Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer 17(1):57 Zhu H, Almasan A (2017) Development of venetoclax for therapy of lymphoid malignancies. Drug Des Devel Ther 11:685–694 Verma MK, Samant C, Kale R, Patra S, Mahajan N, Gholve MK et al (2022) Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models. Biochem Biophys Res Commun 637:267–275 McLeod DS, Watters KF, Carpenter AD, Ladenson PW, Cooper DS, Ding EL (2012) Thyrotropin and thyroid cancer diagnosis: a systematic review and dose-response meta-analysis. J Clin Endocrinol Metab 97(8):2682–2692 Aozasa K (1990) Hashimoto's thyroiditis as a risk factor of thyroid lymphoma. Acta Pathol Jpn 40(7):459–468 Pedersen RK, Pedersen NT (1996) Primary non-Hodgkin's lymphoma of the thyroid gland: a population based study. Histopathology 28(1):25–32 Bastos DCDS, Chiamolera MI, Silva RE, Souza MDCB, Antunes RA, Souza MM et al (2023) Metabolomic analysis of follicular fluid from women with Hashimoto thyroiditis. Sci Rep 13(1):12497 Zucca E, Arcaini L, Buske C, Johnson PW, Ponzoni M, Raderer M et al (2020) Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 31(1):17–29 Vargas-Uricoechea H, Castellanos-Pinedo A, Urrego-Noguera K, Pinzón-Fernández MV, Meza-Cabrera IA, Vargas-Sierra H (2025) A Scoping Review on the Prevalence of Hashimoto's Thyroiditis and the Possible Associated Factors. Med Sci (Basel) 13(2):43 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9534061","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":629832733,"identity":"366121ab-2fb0-492b-8c4a-3a22071c5393","order_by":0,"name":"Luís Jesuíno de Oliveira Andrade","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPgbGBgYGHiCLGYg/MDAkwGQScOhgYEPWwjiDOC1IgJmHKC0Syc0fGGRs7A2O8x58bNtml8fP3sD44WMOQ555Ay4tiW0SDDxpiRsO8yUb57YlF0v2HGCWnLmNoVjmAG4tQL8cTjA4zGMmndvGnLjhRgIbM+82hsQZOB2WCHQYz397sBbLtnqitDQAHXaAcQNIC2PbYSK08DwE+SU5ceZhHmPDnnPHE2f2HGwG+kWiWAKHFn729McfGHvs7PnOnzF88KOsOrGfvfngh4/bbPJwaQEB5r89UBYjOJpAkcuATwMI/IAx/hBQOApGwSgYBSMSAAAthFHtBhERUQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7714-0330","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":true,"prefix":"","firstName":"Luís","middleName":"Jesuíno de Oliveira","lastName":"Andrade","suffix":""},{"id":629832734,"identity":"96733c4b-fcbc-4d3c-a03a-0470a7c6dbd9","order_by":1,"name":"Luís Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0003-4854-6910","institution":"Department of Health, Santa Cruz 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Vinhaes","lastName":"Bittencourt","suffix":""},{"id":629832737,"identity":"f25c979c-6216-4ecd-9056-dab0c88c61b9","order_by":4,"name":"Osmario Jorge de Mattos Salles","email":"","orcid":"https://orcid.org/0009-0002-1859-0478","institution":"Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Osmario","middleName":"Jorge de Mattos","lastName":"Salles","suffix":""},{"id":629832738,"identity":"3402741b-bb87-4e9b-876f-b2efd4ad30a5","order_by":5,"name":"Ricardo Almeida Sinay Neves","email":"","orcid":"https://orcid.org/0009-0000-4827-1342","institution":"Psychotherapy Clinic, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Ricardo","middleName":"Almeida Sinay","lastName":"Neves","suffix":""}],"badges":[],"createdAt":"2026-04-26 18:54:01","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9534061/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9534061/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107985283,"identity":"d6431c0d-0e46-495c-9f14-70069fe85b8c","added_by":"auto","created_at":"2026-04-28 09:14:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":297213,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart on the selection process of eligible studies\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9534061/v1/a048d5a1eb0e8c6238c25f58.png"},{"id":107985282,"identity":"909725d6-5813-412e-a9b8-5681b39fcff8","added_by":"auto","created_at":"2026-04-28 09:14:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":334128,"visible":true,"origin":"","legend":"\u003cp\u003eAntigen-Driven Oligoclonal Expansion and Intratecal B-Cell Homeostasis in Chronic Autoimmune Thyroiditis\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9534061/v1/31a9eb655adcd90f5ca883fe.png"},{"id":108181131,"identity":"374b7691-3065-4954-9b00-3b532e7ae550","added_by":"auto","created_at":"2026-04-30 08:57:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":382391,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular Emergence of In Situ Lymphoid Neoplasia: AID-Mediated Genetic Alterations and Early Clonal Escape in Autoimmune Thyroiditis\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9534061/v1/2c1b8213972912fa229db538.png"},{"id":107985285,"identity":"05e3963e-c4d0-4bb8-9edf-b66e0d8a4929","added_by":"auto","created_at":"2026-04-28 09:14:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":371803,"visible":true,"origin":"","legend":"\u003cp\u003eAutonomous Clonal Expansion and Lymphoepithelial Lesion (LEL) Formation: The Transition to WHO-Defined MALT Lymphoma\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9534061/v1/45f408f34aedec8c29f86320.png"},{"id":108184212,"identity":"4aaa9d6c-9bbf-447e-8381-4d32090c3b06","added_by":"auto","created_at":"2026-04-30 09:03:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1610320,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9534061/v1/d6773824-cf6d-4005-8679-b86a184a3863.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eMolecular Convergence Between Hashimoto's Thyroiditis and Thyroid MALT Lymphoma: A Scoping Review of Shared Lymphomagenic Mechanisms and Pre-Neoplastic Potential\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHashimoto's Thyroiditis (HT), first described by Hakaru Hashimoto in 1912, is a chronic autoimmune thyroid disorder characterized by diffuse lymphocytic infiltration of the thyroid parenchyma, progressive destruction of thyroid follicles, ectopic germinal center formation, and eventual hypothyroidism. It represents the leading cause of hypothyroidism in iodine-sufficient regions, affecting approximately 1\u0026ndash;2% of the general population, with a marked female predominance (female-to-male ratio of 10\u0026ndash;20:1).\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBeyond its endocrine manifestations, HT is uniquely associated with an exceptionally elevated relative risk for primary thyroid lymphoma. In the landmark Swedish cohort study by Holm, Blomgren, and L\u0026ouml;whagen (829 patients with chronic lymphocytic thyroiditis monitored through the Swedish Cancer Register), the relative risk of primary malignant thyroid lymphoma reached 67-fold (4 observed vs. 0.06 expected cases; P\u0026thinsp;\u0026lt;\u0026thinsp;0.000001).\u003csup\u003e2\u003c/sup\u003e Subsequent meta-analyses and cohort studies have corroborated this association, with estimated relative risks ranging from 60- to 80-fold.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis remarkable epidemiological association has not prompted a systematic molecular investigation of HT from an oncological perspective. Traditionally, HT is classified as an autoimmune disorder, while thyroid Mucosa-Associated Lymphoid Tissue (MALT) lymphoma is regarded as a distinct malignant neoplasm. However, their molecular underpinnings exhibit substantial overlap, raising the hypothesis that the distinction between these two entities may be fundamentally quantitative, relating to clonal dominance and the progressive accumulation of genomic alterations, rather than qualitative in nature.\u003c/p\u003e \u003cp\u003eThe present scoping review aims to map and synthesize the available evidence on molecular mechanisms shared between HT and thyroid MALT lymphoma, structured around five biological pillars, to articulate the biological plausibility of a pre-neoplastic continuum, and to identify research gaps and testable hypotheses for future prospective studies.\u003c/p\u003e"},{"header":"METHODS AND RESULTS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eOverview of Included Studies\u003c/h2\u003e \u003cp\u003eThe initial database search retrieved 847 records. After removal of duplicates (n\u0026thinsp;=\u0026thinsp;214) and screening of titles and abstracts (n\u0026thinsp;=\u0026thinsp;633), 127 studies were selected for full-text review. Of these, 42 met all eligibility criteria and were included in the final synthesis. The complete characterization of all included studies by thematic domain is presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the key epidemiological studies in detail. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displays the PRISMA-ScR selection flow diagram.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe 42 included studies comprised: 10 cohort studies or case series on the epidemiological association between HT and primary thyroid lymphoma (refs. 2, 3, 6, 7, 8, 9, 10, 11, 12, 13); 7 systematic reviews, meta-analyses, and clinical guidelines on HT (refs. 4, 5, 37, 38, 39, 40, 41); 9 immunohistochemical or molecular studies characterizing B-cell biology, B-cell lymphoma (BCL)-2, and clonality in HT tissue (refs. 14, 15, 16, 19, 22, 23, 24, 26, 27); 9 translational or experimental studies addressing molecular pathways shared between HT and MALT lymphoma (refs. 17, 18, 20, 21, 28, 29, 30, 31, 32); and 7 studies on molecular oncology of MALT lymphoma and B-cell malignancies relevant to the proposed continuum (refs. 25, 33, 34, 35, 36, 42, 43, 44).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClassification of the 42 included studies by thematic domain.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef. No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThematic domain and primary contribution\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDomain 1 \u0026ndash; Epidemiology of the HT\u0026ndash;Thyroid Lymphoma Association (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHolm et al. (1985)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFoundational Swedish cohort (n\u0026thinsp;=\u0026thinsp;829); RR\u0026thinsp;=\u0026thinsp;67\u0026times; for thyroid lymphoma in chronic lymphocytic thyroiditis (P\u0026thinsp;\u0026lt;\u0026thinsp;0.000001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTravaglino et al. (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSystematic review and meta-analysis (n\u0026thinsp;=\u0026thinsp;1,346); pooled HT prevalence in PTL: 78.9%; pooled RR: 60\u0026ndash;80\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWatanabe et al. (2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLargest HT cohort (n\u0026thinsp;=\u0026thinsp;24,553); 171 PTL identified; 10-year lymphoma risk in HT patients: 0.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePavlidis \u0026amp; Pavlidis (2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNarrative review of primary thyroid lymphoma: molecular factors, diagnosis, and clinical management\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKato et al. (1985)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapanese case-control (n\u0026thinsp;=\u0026thinsp;5,592); chronic thyroiditis as independent B-cell lymphoma risk factor\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyjek \u0026amp; Isaacson (1988)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase series (n\u0026thinsp;=\u0026thinsp;236 PTL); HT background present in ~\u0026thinsp;98% of primary thyroid B-cell lymphomas\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDerringer et al. (2000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinicopathological series (n\u0026thinsp;=\u0026thinsp;108 PTL); HT in 87%; strong histological overlap with early MALT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThieblemont et al. (2002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRetrospective cohort (n\u0026thinsp;=\u0026thinsp;70 PTL); HT in 90%; primary thyroid lymphoma is heterogeneous (MALT 60%, DLBCL 40%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTroch et al. (2008)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMulti-site MALT cohort; chronic autoimmune thyroiditis in 16% of all-anatomical-site MALT lymphoma cases\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHu X et al. (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSystematic review and meta-analysis (n\u0026thinsp;=\u0026thinsp;3,591); elevated cancer risk in HT, including thyroid lymphoma and PTC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDomain 2 \u0026ndash; Systematic Reviews, Meta-Analyses, and Clinical Guidelines on HT (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeters et al. / JBI (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJBI Manual for Evidence Synthesis, Chap.\u0026nbsp;11: Scoping Reviews; methodological framework adopted\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTricco et al. (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePRISMA-ScR checklist and explanation; methodological reference for scoping review reporting\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKlubo-Gwiezdzinska \u0026amp; Wartofsky (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEvidence-based guide to HT etiology, diagnosis, and treatment; comprehensive clinical reference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJonklaas et al. / ATA (2014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmerican Thyroid Association guidelines for treatment of hypothyroidism; standard of care reference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHuwiler et al. (2024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSystematic review and meta-analysis of RCTs on selenium supplementation in HT; effects on anti-TPO titers\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi R et al. (2025)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReview of the immune system in HT, potential therapies, and animal model construction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalazzo et al. (2025)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReview of lessons from belimumab trials in SLE; pharmacological reference for anti-BAFF strategy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDomain 3 \u0026ndash; Immunohistochemical and Molecular Studies on HT Tissue (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaturegli et al. (2013)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHistopathological characterization of HT; ectopic germinal center formation and lymphoid neogenesis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoshynska \u0026amp; Saxena (2008)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePCR-based clonality assays in HT tissue; monoclonal/oligoclonal Ig rearrangements without overt lymphoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChetty et al. (1995)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIHC detection of p53 and BCL-2 in HT and thyroid lymphoma; IHC overlap between advanced HT and early MALT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCampi et al. (2015)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBAFF and BAFF-R expression in HT tissue (IHC); maximal signal in GC and mantle zones of ectopic follicles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKuribayashi-Hamada et al. (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA20/TNFAIP3 mutation in primary thyroid lymphoma; all A20 mutations associated with HT background\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRodr\u0026iacute;guez-Sevilla \u0026amp; Salar (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGenetic advances in MALT lymphoma including TNFAIP3 inactivation in thyroid MALT (11\u0026ndash;20% of cases)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChu et al. (2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMurine model: B-cell-specific TNFAIP3 deletion induces HT-like autoimmune phenotype with anti-thyroid IgG\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasconcelos et al. (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBCL-2 and MCL-1 co-overexpression in HT infiltrates; elevated Ki-67 and low apoptotic rate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStassi et al. (2001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFas/FasL pathway dysregulation in HT; inverted Fas-FasL axis promotes lymphocytic infiltrate persistence\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDomain 4 \u0026ndash; Translational and Experimental Studies on Shared Molecular Pathways (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGiordano et al. (2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBAFF from dendritic cells and neutrophils required for B-cell maturation and autoantibody production in SLE-like disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKampa et al. (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAPRIL and BAFF receptors (TACI, BCMA, BAFFR) in oncology; mechanistic and pharmacological review\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYang et al. (2014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBAFF/BAFF-R axis in B-cell non-Hodgkin lymphoma; survival signaling and therapeutic targeting\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHamoudi et al. (2010)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNF-κB target gene expression in MALT lymphoma with and without chromosomal translocation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeeman-Neill et al. (2024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAID on- and off-target activity in non-Hodgkin B-cell lymphomas; review of oncogenic mechanisms\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJiao et al. (2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOff-target AID effects in carcinogenesis; mutagenic activity at proto-oncogene loci\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNishikori et al. (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eElevated AID expression in ocular adnexal MALT lymphoma with IgG4-positive cells (autoimmune context)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi L et al. (2025)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBAFF system role in autoimmune diseases: mechanisms, disease implications, and therapeutic advances\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorneth et al. (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAberrant B-cell signaling in autoimmune diseases including HT; BCR and BAFF pathway dysregulation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDomain 5 \u0026ndash; Molecular Oncology of MALT Lymphoma and B-Cell Malignancies (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi WF et al. (2024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBCL-2 inhibitor-based therapies and emerging resistance in CLL; venetoclax pharmacology reference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLauring \u0026amp; Basu (2024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSomatic hypermutation mechanisms during lymphomagenesis and transformation; AID and clonal evolution\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLai et al. (2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinicopathological analysis of primary thyroid non-Hodgkin lymphoma; single-center series\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRaderer et al. (2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical relevance of molecular aspects in extranodal marginal zone lymphoma; NF-κB and TNFAIP3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi X et al. (2025)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGenetic alterations and prognostic impact in marginal zone lymphoma; meta-analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePal Singh et al. (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBTK role in B cells and malignancies; ibrutinib pharmacology and BCR-signaling inhibition\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhu \u0026amp; Almasan (2017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDevelopment of venetoclax for therapy of lymphoid malignancies; BCL-2 inhibition rationale\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerma et al. (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDual PI3Kδγ inhibition in DLBCL models; preclinical characterization of PI3K inhibitor\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eHT, Hashimoto\u0026rsquo;s Thyroiditis; PTL, primary thyroid lymphoma; MALT, mucosa-associated lymphoid tissue; DLBCL, diffuse large B-cell lymphoma; RR, relative risk; IHC, immunohistochemistry; GC, germinal center; CLL, chronic lymphocytic leukemia; SLE, systemic lupus erythematosus; BCR, B-cell receptor; BTK, Bruton\u0026rsquo;s tyrosine kinase; AID, activation-induced cytidine deaminase; PTC, papillary thyroid carcinoma.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eKey epidemiological studies (Domain 1) on the association between HT and primary thyroid lymphoma \u0026mdash; detailed summary.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy / Year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHT prevalence in PTL (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMain lymphoma subtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKey finding\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHolm et al.\u003csup\u003e2\u003c/sup\u003e (1985)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e829\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThyroid lymphoma (mixed)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;67\u0026times; (P\u0026thinsp;\u0026lt;\u0026thinsp;0.000001); foundational epidemiological study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTravaglino et al.\u003csup\u003e3\u003c/sup\u003e (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,346\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78.9% (pooled)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMALT, DLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePooled RR 60\u0026ndash;80\u0026times;; systematic review and meta-analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWatanabe et al.\u003csup\u003e6\u003c/sup\u003e (2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e171 PTL / 24,553 HT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMALT, DLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10-year lymphoma risk in HT: 0.7%; largest HT cohort\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePavlidis \u0026amp; Pavlidis\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e (2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePTL (all subtypes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMolecular factors, diagnosis, and management of primary thyroid lymphoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKato et al.\u003csup\u003e8\u003c/sup\u003e (1985)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5,592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB-cell lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChronic thyroiditis as independent lymphoma risk factor\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyjek \u0026amp; Isaacson\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e (1988)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e~\u0026thinsp;98%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMALT / DLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNear-universal HT background in primary thyroid lymphoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDerringer et al.\u003csup\u003e10\u003c/sup\u003e (2000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108 PTL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMALT, DLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStrong histological overlap between HT and early MALT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThieblemont et al.\u003csup\u003e11\u003c/sup\u003e (2002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 PTL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMALT (60%), DLBCL (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePrimary thyroid lymphoma is heterogeneous\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTroch et al.\u003csup\u003e12\u003c/sup\u003e (2008)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMALT cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16% of all-site MALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMALT (thyroidal \u0026amp; extrathyroidal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHT-associated MALT lymphoma extends beyond thyroid gland\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHu X et al.\u003csup\u003e13\u003c/sup\u003e (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,591\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThyroid lymphoma, PTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eElevated cancer risk in HT; meta-analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eHT, Hashimoto's Thyroiditis; PTL, primary thyroid lymphoma; MALT, mucosa-associated lymphoid tissue; DLBCL, diffuse large B-cell lymphoma; PTC, papillary thyroid carcinoma; RR, relative risk.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePillar 1 – Ectopic Germinal Centers and Progressive B-Cell Clonal Restriction\u003c/h3\u003e\n\u003cp\u003eIn HT, the thyroid parenchyma is progressively replaced by a mononuclear infiltrate organized into mature lymphoid follicles harboring ectopic germinal centers (GCs).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e This intrathyroidal lymphoid neogenesis recapitulates the structural organization of secondary lymphoid tissues and constitutes a distinctive histologic hallmark differentiating HT from simple lymphocytic thyroiditis.\u003c/p\u003e \u003cp\u003eWithin these ectopic GCs, B cells undergo persistent stimulation by thyroid autoantigens (predominantly thyroid peroxidase and thyroglobulin), initiating iterative cycles of somatic hypermutation (SHM) and antigen-driven clonal selection. Over time, this process imposes progressive restriction of immunoglobulin (Ig) gene diversity. PCR-based clonality assays performed on thyroid tissue from HT patients have demonstrated monoclonal or oligoclonal Ig gene rearrangements even without histologic evidence of lymphoma, patterns analogous to in situ follicular neoplasia of lymph nodes.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eImmunohistochemical staining for BCL-2 and p53 fails to reliably distinguish advanced HT from low-grade thyroid MALT lymphoma. Within mantle zones and lymphoepithelial lesions (LELs) of HT, lymphoid cells exhibit uniform BCL-2 expression mirroring the pattern observed in low-grade diffuse thyroid lymphomas.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e This histologic overlap reflects a genuine biological continuum, rather than a mere diagnostic limitation.\u003c/p\u003e\n\u003ch3\u003ePillar 2 – BAFF/BLyS: A Master Survival Signal Shared by HT and MALT Lymphoma\u003c/h3\u003e\n\u003cp\u003eB-cell activating factor (BAFF, encoded by TNFSF13B) is a TNF superfamily member essential for mature B-cell survival. It signals through three receptors (BAFF-R, TACI, and BCMA), activating canonical and non-canonical NF-κB pathways, as well as PI3K/AKT and ERK cascades, promoting B-cell survival, proliferation, and Ig class-switch recombination.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn HT, thyrocytes constitutively release BAFF in response to interferon-γ produced by infiltrating Th1 cells. Immunohistochemical analyses of HT tissue have demonstrated BAFF and BAFF-R expression in both infiltrating lymphocytes and thyrocytes, with maximal intensity in GCs and mantle zones of ectopic follicles.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e This thyroid-derived BAFF establishes a self-perpetuating survival loop for intrathyroidal B cells, bypassing the requirement for classical nodal support.\u003c/p\u003e \u003cp\u003eThe same BAFF-dependent survival circuitry defines thyroid MALT lymphoma and other indolent B-cell neoplasms. BAFF overexpression lowers the threshold for malignant transformation by inhibiting activation-induced apoptosis in GC B cells, a checkpoint that would otherwise eliminate premalignant clones.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e These findings suggest that thyrocyte-derived BAFF in HT may function as a driver of the pre-neoplastic state, a hypothesis requiring prospective validation.\u003c/p\u003e\n\u003ch3\u003ePillar 3 – NF-κB Dysregulation and the TNFAIP3/A20 Axis\u003c/h3\u003e\n\u003cp\u003eNF-κB is a central hub for survival and proliferation in B-cell lymphomagenesis, regulating target genes including BCL-2, BCL-XL, XIAP, and MYC. In MALT lymphoma, constitutive NF-κB activation arises from chromosomal translocations and from inactivation of the inhibitor TNFAIP3, which encodes the desubiquitinase A20.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMutations and deletions of A20/TNFAIP3 are documented in MALT lymphomas arising in sites of chronic autoimmune inflammation, including the ocular adnexa, salivary glands, and thyroid. In primary thyroid lymphoma, TNFAIP3 inactivation has been reported in 11\u0026ndash;20% of cases; in two independent studies, all identified A20 mutations were associated with pre-existing HT.\u003csup\u003e22,23\u003c/sup\u003e These data establish a direct genetic link between the autoimmune microenvironment of HT and a molecular alteration enabling MALT lymphomagenesis.\u003c/p\u003e \u003cp\u003eMurine models further support this relationship: B-cell-specific deletion of TNFAIP3 is sufficient to induce an autoimmune phenotype analogous to HT, characterized by thyroid-directed autoreactive IgG antibody production.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e These findings demonstrate convergence between A20 loss and HT-like autoimmune disease within the same molecular circuitry.\u003c/p\u003e\n\u003ch3\u003ePillar 4 – BCL-2: The Anti-Apoptotic Block Shared by HT Lymphocytes and MALT Tumor Cells\u003c/h3\u003e\n\u003cp\u003eBCL-2 is the paradigmatic anti-apoptotic protein in B-cell neoplasms. In thyroid tissue from HT, infiltrating lymphocytes within mantle zones and LELs exhibit strong, homogeneous BCL-2 expression, with an immunohistochemical pattern indistinguishable from early-stage thyroid MALT lymphoma.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCo-overexpression of BCL-2 and MCL-1 in HT lymphocytic infiltrates, alongside elevated Ki-67 indices and a paradoxically low apoptotic rate, has been demonstrated by multiple immunohistochemical and molecular studies.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e This anti-apoptotic phenotype in HT is sustained by tonic BAFF and BCR signaling, defining an antigen-dependent transcriptional state potentially distinct from the chromosomally fixed BCL-2 overexpression of follicular lymphoma, a distinction with potential translational relevance requiring direct comparative studies.\u003c/p\u003e \u003cp\u003eAdditionally, the Fas/FasL pathway, responsible for elimination of activated lymphocytes and peripheral tolerance maintenance, exhibits functional dysregulation in HT: thyrocytes aberrantly express FasL, promoting destruction of Fas-expressing thyrocytes rather than elimination of infiltrating lymphocytes. This functional inversion contributes to persistence of the lymphocytic infiltrate.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePillar 5 \u0026ndash; Activation-Induced Cytidine Deaminase (AID): The Engine of Mutagenesis in HT\u003c/h2\u003e \u003cp\u003eAID (encoded by AICDA) drives SHM and class-switch recombination in GC B cells, but also possesses off-target mutagenic activity capable of affecting proto-oncogenes including BCL2, MYC, PAX5, BCL6, and PIM1, inducing point mutations, double-strand DNA breaks, and chromosomal translocations that function as initiating events in B-cell lymphomagenesis.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWithin the ectopic GCs of HT, AID activity may persist for years or decades due to chronic autoimmune stimulation. Each recirculation of B cells through GCs, driven by thyroid autoantigens, subjects this population to additional rounds of AID-mediated mutagenesis. This framework provides a mechanistic explanation for the dose-response relationship between disease duration and lymphoma risk, a hypothesis consistent with the available epidemiological data, though requiring direct prospective confirmation. Elevated AID expression has been documented in thyroid-origin MALT lymphoma and in ocular adnexal MALT lymphomas arising in sites of chronic autoimmune inflammation.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSide-by-side molecular and histological comparison of HT and thyroid MALT lymphoma across eleven parameters.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFeature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHashimoto's Thyroiditis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThyroid MALT Lymphoma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMechanistic significance\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphoid infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePolyclonal \u0026rarr; oligoclonal B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMonoclonal B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQuantitative shift in clonality; biological overlap documented by PCR-based assays\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGerminal center formation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEctopic GC in thyroid parenchyma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePersistent GC-derived malignant clones\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eShared microstructural lymphoid platform\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBAFF/BLyS expression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh; thyrocyte-derived, IFN-γ induced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh; tumor microenvironment-derived\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eShared B-cell survival signal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCL-2 expression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eElevated in infiltrating B cells (mantle zones, LELs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConstitutively elevated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAnti-apoptotic block indistinguishable by IHC in HT vs. early MALT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAID / AICDA activity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eActive in ectopic GCs; off-target mutagenesis sustained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eResidual or downregulated post-transformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAID provides cumulative oncogenic mutational load during HT phase\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNFAIP3 / A20 status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWild-type (intact NF-κB regulation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMutated/deleted in 11\u0026ndash;20% of PTL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA20 loss enables constitutive NF-κB activation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNF-κB activation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntigen-dependent; BAFF-R and BCR driven\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConstitutive; TNFAIP3 loss or chromosomal translocations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSame effector pathway; different upstream driver\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIg gene rearrangement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePolyclonal \u0026rarr; oligoclonal by PCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMonoclonal dominant clone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClonal dominance is the diagnostic threshold\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntigen dependence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes \u0026mdash; TPO, Tg drive BCR engagement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePartial \u0026rarr; progressive autonomy via BTK/PI3Kδ signaling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLoss of antigen dependence is a key molecular event of malignant transition\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDriver mutations (MYD88, CARD11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePresent in DLBCL-transformation subset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGenomic divergence occurs at/after transformation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphoepithelial lesions (LELs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent; T-cell mediated follicular destruction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePresent; hallmark of MALT diagnosis (WHO criteria)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLELs shared by both; morphology alone cannot distinguish HT-associated from early MALT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eGC, germinal center; BAFF, B-cell activating factor; AID, activation-induced cytidine deaminase; IHC, immunohistochemistry; LEL, lymphoepithelial lesion; Ig, immunoglobulin; TPO, thyroid peroxidase; Tg, thyroglobulin; BTK, Bruton's tyrosine kinase.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProposed Three-Step Molecular Continuum\u003c/h3\u003e\n\u003cp\u003eBased on the synthesized molecular evidence, a three-step sequential model of the HT-to-lymphoma continuum is proposed as a conceptual framework to guide future research. This model is not intended as a diagnostic or clinical algorithm, but as a heuristic construct identifying testable transition points.\u003c/p\u003e\n\u003ch3\u003eStep 1 – Antigen-Dependent Oligoclonal Expansion (Active HT)\u003c/h3\u003e\n\u003cp\u003eThyroid autoantigens (TPO, Tg) promote chronic BCR activation in intrathyroidal B lymphocytes. Clone survival is sustained by BAFF signaling maintaining BCL-2 overexpression. AID remains active within ectopic GCs, driving SHM and progressive Ig gene restriction. TNFAIP3/A20 continues to exert regulatory function, and NF-κB activation remains antigen-dependent (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStep 2 \u0026ndash; Early Clonal Escape (In Situ Lymphoid Neoplasia, Candidate Stage)\u003c/h2\u003e \u003cp\u003eAn AID-mediated off-target mutation in TNFAIP3/A20, BCL2, or MYC confers a competitive survival advantage to a single B-cell clone, enabling partial dissociation from continuous antigenic stimulation. This clone expands dominantly. PCR-based clonality assays reveal a predominant Ig gene rearrangement, while histologically the lesion may still be classified as 'florid' HT or 'indeterminate for lymphoma. Whether this stage consistently precedes overt lymphoma and whether it can be reproducibly detected prospectively remains an unresolved research question requiring NGS-based longitudinal studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStep 3 \u0026ndash; Overt MALT Lymphoma\u003c/h2\u003e \u003cp\u003eConstitutive NF-κB activation, mediated by TNFAIP3/A20 inactivation or chromosomal translocations (BCL10-IGH, MALT1-IGH), confers complete antigen-independent survival. Expansion of the malignant clone becomes self-sustaining and invasive, with LEL formation and infiltration beyond thyroid parenchyma, fulfilling WHO histologic criteria for primary thyroid MALT lymphoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present scoping review synthesizes evidence from 42 studies demonstrating substantial molecular overlap between HT and thyroid MALT lymphoma across five mechanistic pillars. The convergence of ectopic GC formation, BAFF-mediated survival signaling, BCL-2 anti-apoptotic blockade, AID-driven mutagenesis, and TNFAIP3/A20 dysregulation in both conditions is consistent with the hypothesis that these entities may represent a biological continuum rather than dichotomous categories. However, this interpretation requires critical qualification.\u003c/p\u003e \u003cp\u003eFirst, the directionality of many documented associations remains observational. Most included studies are cross-sectional or retrospective, documenting molecular co-occurrence rather than causal or temporal relationships. Prospective longitudinal studies tracking molecular events from HT diagnosis through potential lymphoma development are largely absent from the literature.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e This represents the most critical methodological gap identified by this review.\u003c/p\u003e \u003cp\u003eSecond, the epidemiological signal, while unequivocal in terms of relative risk, translates into a modest absolute lifetime risk of lymphoma in HT patients (approximately 0.7% at 10 years in the largest available cohort⁶). This suggests that the shared molecular architecture described herein is common in HT but that additional, yet-uncharacterized events are required for overt neoplastic transformation.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e Identifying these events represents a priority research agenda.\u003c/p\u003e \u003cp\u003eThird, the proposed three-step continuum constitutes a conceptual model rather than a validated pathophysiological staging system. The intermediate stage (in situ lymphoid neoplasia/early clonal escape) lacks a consensus definition, standardized detection methodology, or prospective evidence of predictable progression to overt lymphoma.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e Its clinical or diagnostic utility cannot be established from the currently available evidence.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eMolecular Targets as Research Hypotheses – Not Clinical Recommendations\u003c/h2\u003e \u003cp\u003eThe molecular pillars identified in this review, particularly constitutive BAFF overexpression, BCL-2 anti-apoptotic signaling, BTK/PI3Kδ-dependent BCR activation, and TNFAIP3/A20-mediated NF-κB dysregulation, represent pharmacologically actionable pathways in thyroid MALT lymphoma. Several agents targeting these pathways (including anti-BAFF biologics, BTK inhibitors, BCL-2 inhibitors, and PI3Kδ inhibitors) are approved for related B-cell malignancies and autoimmune conditions.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis mechanistic convergence generates testable research hypotheses: whether pharmacological modulation of BAFF, BCR, BCL-2, or NF-κB signaling in HT patients could influence the molecular trajectory toward lymphoma is a scientifically plausible question. However, the evidence mapped in this scoping review does not support clinical application of these agents in HT, and no such recommendation is made herein. Evaluation of these interventions would require prospective cohort studies with validated surrogate endpoints followed by randomized controlled trials in clearly, high-risk populations.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e The identification of such populations itself remains an unmet methodological need.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSurveillance Research Agenda\u003c/h2\u003e \u003cp\u003eThe findings of this review suggest that monitoring strategies incorporating NGS-based Ig clonality assays on thyroid fine-needle aspiration specimens and TNFAIP3 mutational screening may have biological rationale in patients with long-standing HT. These approaches have not been validated in prospective studies and cannot be considered standard of care.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e Future research should prioritize the definition of: (1) validated high-risk HT phenotypes; (2) reproducible molecular thresholds distinguishing reactive oligoclonal expansion from in situ neoplasia; and (3) the natural history of clonal dynamics in HT with and without lymphoma development.\u003c/p\u003e \u003c/div\u003e "},{"header":"LIMITATIONS","content":"\u003cp\u003eThis scoping review has important limitations. Scoping reviews do not formally assess risk of bias in individual studies; the included literature encompasses heterogeneous study designs, sample sizes, and methodologies, limiting direct comparability. The search, while systematic, was restricted to published literature in three languages, potentially introducing publication bias. The proposed molecular continuum integrates evidence from distinct experimental contexts (immunohistochemistry, PCR-based clonality, murine models, and genomic sequencing), which may not directly translate to the clinical trajectory of any individual patient. Fourth, several key mechanistic claims in the literature, particularly regarding the functional significance of BAFF overexpression and BCL-2 expression in HT tissue, are based on cross-sectional studies that cannot establish causality or predict transformation. The role of follicular helper T cells, regulatory T cells, and the broader immune microenvironment in sustaining intrathyroidal B-cell expansion was not comprehensively captured in the included literature and warrants dedicated investigation. Finally, the potential modulatory effect of levothyroxine therapy, the standard treatment for HT-associated hypothyroidism, on intrathyroidal B-cell biology has not been systematically evaluated, despite evidence that thyroid hormone can modulate lymphocyte function and anti-apoptotic regulator expression.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis scoping review maps substantial molecular and histological evidence of mechanistic overlap between HT and thyroid MALT lymphoma across five biological pillars: ectopic germinal center formation, BAFF-mediated B-cell survival, BCL-2-driven apoptosis resistance, NF-κB dysregulation with TNFAIP3/A20 involvement, and AID-sustained mutagenesis. The available evidence is consistent with a biological continuum hypothesis, but does not permit definitive causal or prognostic conclusions given the observational nature and heterogeneity of included studies.\u003c/p\u003e \u003cp\u003eThe primary contribution of this review is the systematic identification and organization of research gaps: the absence of prospective longitudinal molecular data, the lack of validated intermediate-stage biomarkers, and the unresolved natural history of B-cell clonal dynamics in HT. These gaps define a translational research agenda whose pursuit, through prospective cohort studies and, subsequently, rigorously designed interventional trials, could ultimately inform whether pharmacological modulation of the identified molecular pathways has a role in lymphoma risk reduction in HT. No clinical recommendations are derived from the present synthesis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest statement:\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKhachaturov M, Goulis DG, Perros P (2025) Hashimoto's thyroiditis \u0026ndash; What's in a name? Horm (Athens) 24(2):389\u0026ndash;394\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolm LE, Blomgren H, L\u0026ouml;whagen T (1985) Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 312(10):601\u0026ndash;604\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTravaglino A, Pace M, Varricchio S, Insabato L, Giordano C, Picardi M et al (2020) Hashimoto Thyroiditis in Primary Thyroid Non-Hodgkin Lymphoma. Am J Clin Pathol 153(2):156\u0026ndash;164\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeters MDJ, Godfrey C, McInerney P, Munn Z, Tricco AC, Khalil H (2020) Chapter 11: Scoping Reviews. In: Aromataris E, Munn Z (eds) Editors). JBI Manual for Evidence Synthesis. JBI\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D et al (2018) PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med 169(7):467\u0026ndash;473\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe N, Noh JY, Narimatsu H, Takeuchi K, Yamaguchi T, Kameyama K et al (2011) Clinicopathological features of 171 cases of primary thyroid lymphoma: a long-term study involving 24553 patients with Hashimoto's disease. 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Med Sci (Basel) 13(2):43\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hashimoto's thyroiditis, thyroid lymphoma, pre-neoplastic state, AID mutagenesis, scoping review","lastPublishedDoi":"10.21203/rs.3.rs-9534061/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9534061/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo systematically map, through a scoping review methodology, the molecular and histological evidence of mechanistic overlap between HT and thyroid MALT lymphoma, examining shared lymphomagenic pathways and the biological plausibility of a pre-neoplastic continuum.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eScoping review conducted in PubMed/MEDLINE, Embase, and Web of Science (1980\u0026ndash;2024), following the Joanna Briggs Institute (JBI) framework for scoping reviews. Studies were included if they reported molecular, immunohistochemical, or genomic data on: (1) B-cell biology in HT tissue; (2) shared molecular markers between HT and thyroid lymphoma; or (3) the epidemiological association between HT and primary thyroid lymphoma. Study selection followed a two-stage screening protocol by two independent reviewers, with disagreements resolved by consensus.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eForty-two studies met inclusion criteria. Five molecular pillars with documented evidence of overlap between HT and thyroid MALT lymphoma were identified: (1) ectopic germinal center formation with progressive B-cell clonal restriction; (2) BAFF/BLyS-driven NF-κB survival signaling; (3) BCL-2-mediated apoptosis resistance indistinguishable by immunohistochemistry between advanced HT and early MALT lymphoma; (4) sustained AID-dependent mutagenesis; and (5) TNFAIP3/A20 dysregulation in 11\u0026ndash;20% of HT-associated primary thyroid lymphomas. A three-step molecular continuum from antigen-dependent oligoclonal expansion to constitutive NF-κB activation is proposed.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe available molecular and histological evidence supports biological continuity between HT and thyroid MALT lymphoma. This synthesis identifies testable hypotheses for future prospective studies and highlights molecular targets whose pharmacological modulation merits investigation in properly designed clinical trials. These findings do not constitute clinical recommendations, but provide a mechanistically grounded framework for translational research.\u003c/p\u003e","manuscriptTitle":"Molecular Convergence Between Hashimoto's Thyroiditis and Thyroid MALT Lymphoma: A Scoping Review of Shared Lymphomagenic Mechanisms and Pre-Neoplastic Potential","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 09:14:26","doi":"10.21203/rs.3.rs-9534061/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab6e42e9-7d0a-4b1a-b6b5-00f76d505028","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67034100,"name":"Endocrinology \u0026 Metabolism"},{"id":67034101,"name":"Immunology"}],"tags":[],"updatedAt":"2026-04-28T09:14:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 09:14:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9534061","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9534061","identity":"rs-9534061","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}