Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large b-cell lymphomas of the thyroid – A study of 21 cases

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Context: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, accounting for less than 1% of thyroid malignancies (based on cases from the archives of the institute of pathology, University Hospital of Schleswig-Holstein, Campus Luebeck). Objective: On account of recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations in a study population of 21 ptDLBCL. Design: A high-resolution array-based comparative genomic hybridization approach (aCGH) was applied to quantify genomic aberrations. We also investigated the frequency of mutations in BRAF-, NRAS- and MYD88- genes in correlation with immunohistochemical data. Results: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3 and 22q11.22, losses at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33 and 21q11.2. Aberrations affecting 6p22.2, 14q32.33 and 22q11.22 differed slightly between GCB- and non-GCB-groups, significant deviations were detected at 20q13.33 and 21q11.2. Analysis of BRAF and NRAS showed mutation frequencies of 4.8% and 9.5%. No MYD88 mutations could be detected. Fluorescence-in-situ hybridization demonstrated breakage events involving the BCL2- , BCL6- and cMYC- locus in 14.3%, 9.5% and 9.5%. Conclusions: Our study revealed ptDLBCL to be predominantly composed of the GCB-type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. aCGH showed no overlapping alterations between ptDLBCL and thyroid carcinomas. Concerning other nodal or extranodal DLBCL only one region (19p13.3, containing various tumor suppressors and oncogenes) showed infrequent overlaps. Furthermore, one of the most frequently modified genomic regions proved to be the IgH locus (showing gains in 14/21 cases of ptDLBCL) which represents an early pathogenetic mechanism in a variety of B-cell malignancies.

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