Thyroid Lymphomas Express Similar Immunoglobulin VH Genes.
Nidhi Aggarwal, Tiffany J Whitney, Jeffrey A Kant, Steven H Swerdlow, David W Bahler. University of Pittsburgh Medical Center, PA; University of Utah, Salt Lake City
Background: Thyroid extranodal marginal zone B-cell lymphomas of MALT type (MALT lymphomas) appear to develop from reactive infiltrates associated with Hashimoto's thyroiditis but have not been as well studied as other MALT lymphomas. Whether the more common thyroid diffuse large B-cell lymphomas (DLBCL) typically represent transformation of previously undetected MALT lymphomas is also unknown. Thyroid lymphoma immunoglobulin heavy chain variable (VH) genes were analyzed to evaluate whether DLBCL and MALT lymphomas show features suggestive of relatedness and/or growth stimulation by common antigens.
Design: 21 thyroid lymphomas were identified that had available frozen tissue or stored DNA. Diagnoses were established by morphologic analysis and immunohistochemical staining. Rearranged lymphoma VH genes were PCR-amplified from isolated DNA and the resultant products directly sequenced.
Results: Monoclonal rearranged VH genes were identified in 7 of 21 (33%) cases. Two (2/7) cases were MALT lymphomas with prominent plasmacytic differentiation, five (5/7) were DLBCL with 4/5 having a germinal center (GC) phenotype. A single functional rearranged VH gene (no stop codons) was identified in 6/7 cases; 2 functional VH genes were detected in 1 case. VH1 family gene segments were utilized in 3 cases, VH3 segments in 1, and VH4 segments in 4. Although different VH1 segments were used, 2/4 VH4 cases used the V4-34 segment, with the closely related V4-30-2 and V4-30-4 segments in 1 case each. Interestingly, V4-34 and V4-30 segments were used by both MALT and DLBCL cases. All but one of the VH gene segments were mutated (>2% difference from consensus germline sequence) with 4/5 DLBCL (all GC types) being heavily mutated (<80% homologous). 4/8 VH genes used the JH6 segment and had long CDR3 sequences (average 20 amino acids).
Conclusions: The thyroid lymphoma VH genes analyzed show similar features with over-representation of VH4 family and JH6 segments and under-representation of segments from the largest VH3 family. This suggests direct antigen stimulation is playing a role in thyroid lymphomagenesis .The use of similar VH4genes by both MALT and DLBCL further suggests the pathogenesis of these two different types of thyroid lymphoma may be related. The relatively low sequencing yield (33% of analyzed cases) likely reflects primer mismatch due to high mutation levels in most thyroid DLBCL VH genes.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 176, Monday Morning