MYC expression and translocation analyses in low-grade and transformed follicular lymphoma.

Aims Low-grade follicular lymphoma ( FL) (grade 1/2, FL1/2) has an annual risk of transformation of ≈3%, which is associated with aberrations in CDKN2A/ B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL ( tFL) might predict a MYC breakpoint. Methods and results We quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2- tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks ( MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization ( FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin ( IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non- IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/ MYC+ double-hit, one was BCL2+/ BCL6+/ MYC+ triple-hit, and one was MYC+ single-hit. All three IG- MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non- IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R− tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed ≥90% MYC expression), suggesting alternative mechanisms of MYC activation. Conclusions we show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in ≈40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG- MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non- IG- MYC and MYC-negative cases. [ABSTRACT FROM AUTHOR]

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