Indian Journal of Pathology and Microbiology

: 2018  |  Volume : 61  |  Issue : 2  |  Page : 271--274

An unusual presentation of large B-cell lymphoma with interferon regulatory factor 4 gene rearrangement

Anuj Verma, Sridhar Epari, Sumeet Gujral, Tanuja Shet 
 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Correspondence Address:
Sridhar Epari
Department of Pathology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra


Rearrangements involving interferon regulatory factor 4 (IRF4) gene has been recently described in a subtype of diffuse large B-cell lymphoma (DLBCL). They occur in a typical clinical setting of a pediatric age group, predominantly with tonsillar mass, usually as a low-stage disease and with good response to chemotherapy. Histomorphologically, they show nodular/follicular architecture with diffuse strong immunopositivity for multiple myeloma oncogene 1. Here, the authors describe one such unusual case of large B-cell lymphoma with IRF4 gene rearrangement in a young child with the unusual location of inguinal region and detailed pathological (histological, immunohistochemical, and molecular) findings.

How to cite this article:
Verma A, Epari S, Gujral S, Shet T. An unusual presentation of large B-cell lymphoma with interferon regulatory factor 4 gene rearrangement.Indian J Pathol Microbiol 2018;61:271-274

How to cite this URL:
Verma A, Epari S, Gujral S, Shet T. An unusual presentation of large B-cell lymphoma with interferon regulatory factor 4 gene rearrangement. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Mar 30 ];61:271-274
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Interferon regulatory factor 4 (IRF4)/Multiple myeloma oncogene 1 (MUM1) is B-cell transcription factor expressed during later stages of B-cell maturation.[1],[2] Rearrangements of IRF4 gene in mature B- and T-lymphocytes have been described in literature, more commonly in B-cell and plasma cell neoplasms.[1],[2],[3],[4],[5],[6] t (6;14) involving IRF4 and IGH genes were first described in multiple myeloma.[3] In diffuse large B-cell lymphomas (DLBCL), it was described initially by Tamura et al., in 2001 and was further elaborated by Salaverria et al. who also described in follicular lymphoma (FL), grade 3B, particularly in pediatric variant and composite FL-DLBCL in 2011.[1],[4] Subsequently, IRF4 rearrangements have been described in few cases of low-grade B-cell lymphomas as well.[5] Rearrangement involving IRF4 have also been described in T-cell non-Hodgkin lymphomas, particularly in primary cutaneous anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.[6]

Salaverria et al. and Liu et al. described the IRF4/MUM1 rearrangement in a subset of pediatric DLBCL or pediatric FL (PFL) cases.[1],[2] Whereas, Liu et al. described that certain subset of PFL involving Waldeyer's ring and lymph nodes show histological, immunohistochemical, and molecular differences with preponderance of IRF4/MUM1 translocations in cases involving Waldeyer's ring of pediatric cases or young adults. They also found distinct histological and immunohistochemical features for these tumors with IRF4 rearrangements.[1],[2] The current updated WHO 2016 classification of lymphoid tumors identified PFL and large B-cell lymphoma (LBL) with IRF4 gene arrangements as distinct entities, as the former lacks t(14;18) seen in the adult FL and the latter due to distinct clinical, pathological, and biological profile.[7],[8] Here, we report an unusual case of high-grade B-cell lymphoma harboring IRF4 gene rearrangement in a 12-year-old boy involving inguinal region with no involvement of Waldeyer's ring.

 Case Report

A 12-year-old boy presented with a complaint of swelling in the left inguinal region for 1½ month, which was nontender and measured 3 cm × 3 cm. He was afebrile, had no other peripheral lymphadenopathy and there was no history of weight loss or increased sweating. Positron emission tomography-computed tomography (PET-CT) scan revealed only a fluorodeoxyglucose (FDG) avid left inguinal mass with a maximum standardized uptake value of 16.13. There were no other significant supradiaphragmatic and infradiaphragmatic adenopathy and no uptake was detected elsewhere (liver, spleen, and bone marrow were unremarkable). Left inguinal node biopsy showed effaced architecture by sheets of intermediate-sized lymphoid cells of blastoid morphology with predominant areas of vague nodular and focal diffuse architecture [Figure 1]. Thin rim of preserved lymph nodal architecture was seen at the periphery. The atypical lymphoid cells were immunopositive for CD20, PAX5, CD10, and MUM1/IRF4. CD3 and CD7 highlighted sparse admixed reactive T-lymphocytes, especially within the internodular areas. CD23 did not reveal any preserved follicular dendritic network. BLIMP1, BCL-2, CD1a, Tdt, c-kit, and CD34 were all negative. Weak c-myc protein labeling was seen in 20%–25% of cells. MIB1 labeling index was approximately 90%–95% [Figure 2]. Based on histology and immunohistochemical results, a diagnosis of high-grade LBL with IRF4 gene rearrangement was suspected. Fluorescent in situ hybridization (FISH) was done on formalin-fixed paraffin-embedded sections using ZytoLight SPEC IRF4, DUSP22 dual-color break-apart probe, which showed split red/green signals in 90%–95% of tumor nuclei [Figure 2]. This finding confirmed the diagnosis of LBL with IRF4 gene rearrangement. Bone marrow biopsy and aspirate were uninvolved. The patient underwent induction chemotherapy. PET-CT scan done after 1# of chemotherapy displayed complete metabolic and morphological response of the left inguinal mass. No FDG avid uptake was seen anywhere in the body.{Figure 1}{Figure 2}


Recurrent translocations involving IG genes are a distinctive feature of B-cell lymphomas. Systematic FISH screening of all lymphoma cases with IGH translocations in the study by Salaverria et al., lead to the identification of IRF4-IGH translocation in some of DLBCL, which showed distinct clinicopathological features. Subsequently, the current 2016 WHO update provisionally identified these LBL with IRF4 rearrangements (LBL-IRF4) as a separate entity.[8]

LBL-IRF4 lymphomas typically present as a mass in Waldeyer's ring in pediatric age group and young adults. Approximately 8% of DLBCL of Waldeyer's ring shows IRF4 gene rearrangement.[1],[2],[9] Fifty percent of PFL of tonsil expressing MUM1 show the IRF4 gene rearrangement.[2] Other rare sites reported are abdominal lymph nodes and bowel.[1] The case under discussion, however, is of inguinal lymph node involvement with sparring of Waldeyer's ring and other lymph nodes, which is an unusual lymph nodal location for LBL-IRF4. LBL-IRF4 commonly presents as low-stage disease and the present case is also of Stage 1A.[1],[2],[9] Histologically, LBL-IRF4 can show nodules or expansile follicles and diffuse areas in varying proportion, thus has overlapping histology with PFL. However, unlike the PFL, in LBL-IRF4, the nodules are composed of centroblastic or intermediate-sized lymphoid cells of blastoid morphology with a thin rim of mantle zone at the periphery.[2] The present case also showed nodular and diffuse areas composed of cells of blastoid morphology. LBL-IRF4 tumors are immunohistochemically positive for CD20 and MUM1. During normal B-lymphoid cell maturation, IRF4 expression suppresses BCL-6 expression and activates BLIMP1. However, in these tumors, the IRF4 gene rearrangement causes coexpression of MUM1 and BCL-6 coupled with lack of expression of BLIMP1.[1],[2] Thus, BCL-6 is almost always immunopositive (94%–100%) in LBL-IRF4 tumors, while BCL-2 and CD10 immunopositivity is seen in only approximately 65% of cases. MIB1 labeling index may be variable but is often high.[1],[2] The case under discussion showed similar immunophenotype except for BCL-2, which is negative. MUM1 positivity is a helpful feature in differentiating PFL involving tonsil and PFL of the lymph nodes being positive in almost all cases of PFL of Waldeyer's ring and rarely in nodal PFL.[2] Overall, these tumors resemble DLBCL, FL or DLBCL arising in a FL. Immunohistochemically, these tumors are classified as of germinal center type (GCB) by Hans algorithm in approximately 60% of cases. While the gene expression profiling studies on these tumors show a signature pattern different to both GCB type and activated B-cell (ABC) type but is closer to GCB profile pattern.[1] Fusion of IRF4 with IGH is seen in 85% of cases. IGK and IGL are rare fusion partners while fusion partners in some cases are yet to be identified.[1] Concurrent other rearrangements involving BCL-6 and CMYC genes and none involving BCL-2 gene has been described in these lymphomas.[1] However, the present case is limited by the lack of evaluation for gene expression and translocation partner gene.

The typical histomorphological features of admixed areas of nodular and diffuse architecture with typical immunohistochemical coexpression of germinal center markers (CD10 and/or BCL-6) and MUM1, in a pediatric patient does raise the suspicion and should confirm by IRF4 translocation analysis. Based on these features, an algorithm can be created to select the cases for confirmatory translocation evaluation; however, this may not be prudent to suggest based on the single case experience. Thus, the authors feel that knowledge from larger series or the pooled reported data can be used in the future to create a practical routine diagnostic algorithm [Figure 3]. This case report is an attempt to create a pool in the literature, as this case is relatively a newer described entity and lacks many larger series.{Figure 3}

However, as of now, it is important to identify these rearrangements since prognosis of these tumors has been reported to be better than other DLBCL. These tumors are indolent and a suggestion of post excision watch and wait strategy has also been advised in cases with single-site disease.[2] Nevertheless, these tumors respond well to chemotherapy with RCHOP and radiotherapy.[1] The present case was treated with chemotherapy and showed a complete metabolic and morphological response further reinforcing good biology of these tumors. However, a RCHOP refractory case of LBL-IRF4 was reported, which also showed to harbor CDKN2A/2B deletion.[9],[10] In view of inadequate experience with these tumors, optimal treatment protocol of these tumors is yet to be defined. In conclusion, this is an unusual case of LBL-IRF4 with inguinal lymph nodal presentation with a distinctive histology of nodular and diffuse architecture in combination and typical immunoprofile of diffuse MUM1, CD10, and BCL-6 expression along with immunonegativity for BLIMP1 and IRF4 gene rearrangement.

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Conflicts of interest

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