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1212
Letters to the Editor
Lack of activation-induced cytidine deaminase
expression in in situ follicular neoplasia
The immunoglobulin heavy chain (IGH) genes undergo class switch recombination (CSR) and somatic hypermu- tation (SHM) to produce a diverse repertoire of high affinity antibodies. CSR and SHM occur in mature B lym- phocytes in the highly specialized microenvironment of germinal centers (GC) and depend on activation-induced cytidine deaminase (AID), an enzyme present in germinal center B cells. AID mediates deamination of cytosine (C) to uracil (U) at cytosine:guanine (C:G) base pairs to gen- erate uracil:guanine (U:G) mismatch, and double-strand DNA breaks (DSB) into switch (S) region sequences of IGH. This process introduces point mutations at a high frequency in IGHV and IGLV genes, allowing for affinity maturation of the antibody response, and replaces the heavy chain constant region of the antibody from the default IgM to IgG, IgA or IgE isotypes.1
In addition to IGH, endogenous AID affects numerous genes across the B-cell genome but at much lower levels than the immunoglobulin loci. Off target AID activity during the germinal center reaction contributes to lym- phomagenesis.2 In malignancies of mature B-cell origin, recurrent translocations often arise as a result of DSB within the IGH switch region and a partner gene. These translocations arise as a result of aberrant AID mediated CSR.2 Mutations in various oncogenes implicated in the pathogenesis of B-cell lymphomas like BCL6, PAX5, MYC and BCL2 share features similar to immunoglobulin gene mutations suggesting a role for aberrant SHM.1
Based on RNA expression data, AID appears to be selectively expressed in GC B cells and GC-derived malig- nancies.3 Follicular lymphoma (FL) originates from GC B cells and shows heterogeneity in the SHM pattern, sug- gesting the possible heterogeneous expression of AID in this entity. The reported expression of AID in FL by immunohistochemistry (IHC) varies from 25% to 100%, acknowledging that some of this variation may be due to technical and definitional differences.3,4,5 More recently, Scherer and colleagues demonstrated that AID messen- ger RNA (mRNA) and protein expression were highly correlated in FL by quantitative reverse transcriptase
polymerase chain reaction (RT-PCR) and IHC, respective- ly. However, there was great variability with 38% of cases showing less than ten IHC-positive cells/high power field (hpf).6 This translates to 1% or less of cells in a hpf of small lymphocytes. Interestingly, duodenal-type FL (DFL) lacks AID expression, which has been postulat- ed to be related to its extremely indolent clinical behav- ior.7 Immunophenotypically, DFL cells typically strongly co-express CD10 and BCL2 proteins. In situ follicular neo- plasia (ISFN) is characterized by partial or total coloniza- tion of reactive germinal centers by BCL2+/CD10+ co- expressing B cells harboring IGH-BCL2 fusions in an oth- erwise architecturally preserved lymph node. BCL2 and CD10 IHC staining is characteristically intense and is higher than that seen in systemic FL cells, much like DFL. Given all the overlapping characteristics of these entities, we explored AID expression in ISFN.
Institutional pathology archives (2002-2017) were searched for cases of ISFN and re-reviewed to confirm diagnosis. We identified 16 patients with ISFN (six male, ten female) with adequate tissue for study. The median age was 66 years (range, 50–83 years) at the time of diag- nosis. Additional clinical information was obtained by review of the medical records and was available for 13 patients. The ISFN was discovered incidentally in all the cases, during pathologic review of biopsies performed for a variety of clinical indications. Ten patients had other hematolymphoid or non-hematolymphoid neoplasms at some point in time. Two patients had a history of preced- ing FL, and one patient had concurrent FL at another anatomic site. Of the non-FL patients, none developed subsequent FL on median follow-up of 43.5 months (range, 13-97 months). 11 patients were alive at last the follow-up, one was lost to follow-up and one patient died from complications of chronic myelomonocytic leukemia and related treatment. The clinicopathologic features are summarized in the Online Supplementary Table S1.
Morphologically, the lymphoid and immune architec- ture was preserved in all ISFN cases, with a few follicles demonstrating BCL2 highly overexpressing GC B cells. Initially, six ISFN cases were subjected to immunohisto- chemical staining with AID which suggested lack of staining in ISFN cells compared to the expression in reac-
AB
Figure 1. BCL2 and AID immunohistochemistry. (A ) Intense BCL2 staining in follicle involved by in situ follicular neoplasia (ISFN) (blue arrow) and negative BCL2 staining in reactive follicle (black arrow). (B) In contrast, ISFN follicle (blue arrow) lacks activation-induced cytidine deaminase (AID) , and reactive follicle (black arrow) is positive for AID.
haematologica | 2021; 106(4)