Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations

Abstract

A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well-to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/ TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.

Diagnostic value of STMN1, LMO2, HGAL, AID expression and 1p36 chromosomal abnormalities in primary cutaneous B cell lymphomas

“…Our results are similar to those of Pham-Ledard et al and Streubel et al who observed, respectively, BCL2 breaks in 8.5% (seven of 47) and BCL6 breaks in 7% (two of 27) of cases in their series of PCFL. 22,28 We confirmed, as supposed previously, 12 that the del 1p36 described in a subset of NFL 11,19 is involved in the pathogenesis of this cutaneous lymphoma.…”

“…Interestingly, CFL frequently expressed CD23 (13 of 32, 40.6% cases of CFL versus one of 15, 6.7% cases of CMZL). This is not surprising, as CD23 expression is variable in NFL, observed preferentially in diffuse NFL or those harbouring the del 1p36, whereas CD23 is generally negative in mucosa‐associated lymphoid tissue (MALT) lymphoma and NMZL . In their series of PCFL, Goodlad et al .…”

“…NFL with BCL6 gene rearrangement display a marked follicular growth pattern, usually show a monocytoid component and are frequently CD10‐ and BCL2‐negative . In adults, NFL with the del 1p36 preferentially involve the inguinal region, show a diffuse growth pattern, usually express CD23 and are associated with a low clinical stage . Nevertheless, PCFL without cytogenetic aberration tend to achieve CR more frequently than those with cytogenetic aberration (93.7% versus 71.4%).…”

“…9 In adults, NFL with the del 1p36 preferentially involve the inguinal region, show a diffuse growth pattern, usually express CD23 and are associated with a low clinical stage. 11,19 Nevertheless, PCFL without cytogenetic aberration tend to achieve CR more frequently than those with cytogenetic aberration (93.7% versus 71.4%). Patients in the group of PCFL with cytogenetic alterations showing PR and/or no response after first-line treatment had either the BCL6 break or the del 1p36.…”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…85 These latter 2 genetic alterations are also both occasionally seen in typical FL albeit at lower frequencies. 86 …”