Page 298 - 2021_04-Haematologica-web

Letters to the Editor
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Figure 3. RNAscope, in situ hybridization for AID in in situ follicular neoplasia (results in punctate staining). (A-B) Follicle involved by in situ follicular neoplasia (ISFN) - strongly positive for BCL2 messenger RNA (mRNA) (A) and negative for activation-induced cytidine deaminase (AID) mRNA (B). The few AID positive cells are residual benign germinal center cells which are larger than the small cleaved ISFN cells. Insets are from exactly the same field on serial section. (C-D) Follicular lymphoma- positive for both BCL2 (C) and AID mRNA (D).
below the technical limits of our assays. Indeed, it has been shown that levels of AID in non-isotype switched FL cells correlate with IGHV mutations and aberrant SHM in BCL6.6 Interestingly, circulating follicular lym- phoma-like and ISFN cells, by virtue of the “allelic para- dox” phenomenon, are IgM-expressing and show much lower levels of genomic alterations compared to overt FL, consistent with the theory of very low or near absent AID activity at this “early lesion” stage.9
The AID expression results in our study are similar to the findings described by Katsuyoshi et al. in duodenal- type FL.7 All 17 studied cases of duodenal-type FL lacked expression of AID. Interestingly, a clonal relationship has been proven in a recent case report of ISFN and duode- nal-type FL in the same patient.12 Our study further demonstrates commonalities between these two entities and reinforce the hypothesis that these two entities might represent different tissue manifestations of a single precursor lesion.12 Despite the lack of AID expression, duodenal-type FL B cells have been shown to be at the memory B-cell stage with somatic and ongoing muta- tions, which later was suggested to be a consequence of BACH2 expression in tumor cells.7,13 This may be worth exploring given copy number gains of the BACH2 locus in ISFN cells.9 Interestingly, there is emerging evidence of ongoing IGH SHM in ISFN as recently shown by Kosmidis et al.14 Ongoing SHM in ISFN despite the absence of AID expression is not without precedent in typical FL. Ongoing mutations and intraclonal hetero-
geneity was detected in AID-negative FL samples, albeit at significantly lower levels than AID-positive cases.4 The regulation of AID expression is complex, involving tran- scription, posttranscription, and posttranslational mecha- nisms.15 This provides for many avenues to explore the mechanism behind ongoing mutations, mechanism for downregulated AID, and the global genetic profile of ISFN that will enhance our understanding of this entity.
Tanu Goyal, Sarah L. Ondrejka , Juraj Bodo, Lisa Durkin and Eric D. Hsi
Cleveland Clinic Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH, USA
Correspondence: ERIC D. HSI - hsie@ccf.org
doi:10.3324/haematol.2020.249342
Disclosures: EDS has received the following support, unrelated to the submitted work: research sponsorship from Abbvie, Eli LIlly as well as honoraria from Jazz, Seattle Genetics and Miltenyi; all other authors have no conflicats of interest to disclose.
Contributions: EDH, TG, SLO prepared the manuscript, JB and LD performed the laboratory work, EDH coordinated reseach.
References
1. GuX,ShivarovV,StroutMP.Theroleofactivation-inducedcytidine deaminase in lymphomagenesis. Curr Opin Hematol. 2012; 19(4):292-298.
2. YamaneA,ReschW,KuoN,etal.Deep-sequencingidentificationof the genomic targets of the cytidine deaminase AID and its cofactor
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