Primary thyroid B-cell lymphoma: molecular insights into its clonal evolution and relapse

Abstract

Primary thyroid lymphomas comprise largely extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) and diffuse large B-cell lymphoma (DLBCL), followed by follicular lymphoma (FL). They commonly develop from a background of Hashimoto's thyroiditis (HT), where dysregulated immune responses trigger autoreactive infiltrates and drive clonal B-cell evolution. To understand how these lymphomas and their relapse evolve, we investigated 10 cases by mutation profiling, including five with metachronous lymphomas [primary lymphoma (EMZL = 4, DLBCL = 1) with local relapse (EMZL = 3, DLBCL = 2)], one composite EMZL and Epstein-Barr virus (EBV)-positive DLBCL, and four lymphomas (EMZL = 3, FL = 1) with prior or subsequent biopsy showing HT. In four cases with metachronous lymphomas, both common and distinct variants were seen in the paired lesions, indicating their divergent evolution from clonally related lymphoma precursor (CLP) cells. In the remaining case with metachronous lymphomas, the relapsed lesion was progressed from the initial lymphoma. In the case with composite lymphoma, the EBV-positive DLBCL was transformed from EMZL. Finally, in the four cases with paired lymphoma and HT biopsies, two showed shared mutations between the paired lesions, indicating involvement and divergent evolution from CLP cells. Thyroid lymphoma relapse may frequently develop via divergent evolution from a CLP cell, which is likely premalignant. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: Hashimoto's thyroiditis; clonal evolution; lymphoma relapse; mutation profile; thyroid lymphoma.

Figure 1

Summary of primary thyroid lymphoma and clinical follow‐up data. CR, complete remission; CT, chemotherapy; DLBCL, diffuse large B‐cell lymphoma; EMZL, extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue; FL, follicular lymphoma; HT, Hashimoto's thyroiditis; PR, partial remission; R, radiation therapy; S, surgical resection; WW, watch and wait.

Figure 2

Variants in metachronous thyroid lymphomas or composite lymphomas. The number of shared and distinct clonal variants in paired lesions and their predicted evolutionary trajectory in each case are indicated. The total number of all clonal variants (including pathogenic, benign, synonymous variants, and those in UTR regions) is given, but only representative pathogenic mutations are shown in detail. CLP, predicted clonally related lymphoma precursor cells; DLBCL, diffuse large B‐cell lymphoma; EMZL, extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue; FL, follicular lymphoma; trans+ve: translocation positive; VAF, variant allele frequency, for variants shared by paired lesions and so thought to occur in the CLP cells; the two VAF values in brackets correspond to the paired lesions in sequence.

Figure 3

Variants in thyroid lymphomas and their paired HT lesion. The number of shared and distinct clonal mutations in paired lesions and their predicted evolutionary trajectory are indicated. The total number of all clonal variants (including pathogenic, benign, synonymous variants, and those in UTR regions) is given, but only representative pathogenic mutations are shown in detail. CLP, clonally related lymphoma precursor cells; EMZL, extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue; FL, follicular lymphoma; HT, Hashimoto's thyroiditis; trans+ve, translocation positive; VAF, variant allele frequency, for variants shared by paired lesions, and so thought to occur in CLP cells; the two VAF values in brackets correspond to the paired lesions in sequence.