Large B-cell lymphoma with IRF4 rearrangement

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a new provisional entity in the WHO Classi ﬁ cation of Tumours of Haemato-poietic Neoplasms (revised 4th edition, 2017). It shows diffuse or follicular in ﬁ ltrates of medium to large neoplastic B cells with an aberrant germinal centre phenotype with IRF4 positivity on immunohistochemistry and IRF4 gene rearrangements found on ﬂ uorescence in situ hybridization (FISH). Here, we report a case of LBCL-IRF4 in a 30 year old female with asymmetrical tonsils. Microscopy showed partial in ﬁ l-tration by a diffuse, vaguely nodular proliferation of medium-to-large, highly proliferative B-cells and a background of follicular hyperplasia. The lesional cells were positive on immunohistochemistry for CD79, CD20, BCL2, BCL6 and IRF4, weak patchy positive for CD10 and had a high proliferative index. An IRF4 rearrangement was found on analysis by FISH. We have also included the pathological features of LBCL-IRF4 cases diagnosed in the Leeds Haematological Malignancy Diagnostic Service from 2017 to 2021.

A 30-year-old female presented with tonsillitis and was found to have asymmetrical tonsils on examination. She underwent tonsillectomy and the original Histological examination report was highly suspicious for non-Hodgkin's lymphoma. The case was referred to the Haematological Malignancy Diagnostic Service (HMDS) in Leeds for review. Microscopic examination demonstrated partial infiltration by a diffuse, partly vaguely nodular neoplasm of medium-to-large, highly proliferative B-cells with no underlying FDC mesh-works. The background was follicular hyperplasia. By immunohistochemistry, the tumour cells expressed an abnormal germinal centre (GC) B-cell phenotype with positivity for CD20 and BCL2 with combination of weak patchy CD10, BCL6 and IRF4 expression. The lesional cells had a Ki67 index of 80% ( Figure 1). Tumour cells were negative on immunohistochemistry for CD23, CD30, CD5, CyclinD1 and LMP-1. Fluorescence in situ hybridization (FISH) was carried out and demonstrated an IRF4 gene rearrangement. These results allowed for the diagnosis of the provisional entity of large B-cell lymphoma with IRF4 gene rearrangement.

Discussion
Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed lymphoma globally. Whilst most of these cases are designated DLBCL not otherwise specified (DLBCL-NOS), around a fifth of cases can be categorized into one of 13 specific DLBCL variants. Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) constitutes a novel provisional entity included in the classification of lymphoid tissue recently proposed by the WHO in its fourth revised edition. 1 LBCL-IRF4 is a rare type of large B-cell lymphomas and accounts for 0.05% of cases. Literature reports it to be more common in children and young adults, with a median age of onset of 12 years. 2,3 The disease has a predilection for the lymph nodes of the head and neck region and Waldeyer ring, although extra-nodal cases have been reported. 4,5 Microscopically, there is an infiltrate of medium to large neoplastic cells with relatively open chromatin and small basophilic nuclei. The most common pattern of infiltration is diffuse, but a follicular pattern is also recognized. 1 A starry-sky pattern is usually not seen.
The neoplastic cells are positive by immunohistochemistry for mature B-cell markers CD20, CD79a and PAX5. There is usually strong, diffuse expression of BCL6 and IRF4 (MUM1). Two-thirds are positive for CD10 and BCL2. The proliferation index is high and neoplastic follicles do not show polarization. 1 The key cytogenetic feature is an IRF4 gene rearrangement detected by FISH. The gene lies close to the telomere on the short arm of chromosome 6, and occasionally the rearrangement is not detected by current methods and in these cases, an IGH gene rearrangement can usually be found. 1,3 There should not be any MYC or BCL2 gene rearrangements. 1,3 Contrary to findings in the literature, local experience has shown that adult cases are relatively common, with a median age of onset of 48 years (range 6e78 years old), with a slight female predominance (Table 1). Our local case series demonstrates a predilection for the lymph nodes, tonsillar tissues and ileum. Microscopically, these appear as a large B-cell lymphoma with an abnormal germinal centre phenotype and a high proliferation rate. All local cases were positive by immunohistochemistry for mature B cell markers CD20 and CD79 and showed an aberrant germinal centre phenotype with all cases showing positivity for BCL6, CD10 and IRF4. Of these cases, one showed weak staining for BCL6, two showed weak staining for CD10 and one showed weak staining for IRF4. All cases showed an IRF4 gene rearrangement on FISH and no MYC gene rearrangements were found. A differential diagnosis would include paediatric-type follicular lymphoma (PTFL), particularly in a younger patient with a follicular morphology. The follicles in PTFL show serpiginous morphology with a starry sky appearance and the neoplastic cells are usually negative for BCL2 and IRF4, with no IRF4 gene rearrangement on FISH. 6 It is important to distinguish LBCL-IRF4 from PTFL as they are treated differently: LBCL-IRF4 has a favourable outcome after treatment (combination of immunochemotherapy with or without radiation), whereas PTFL tends to have a good prognosis with local management alone. In older patients, follicular lymphoma is a differential in cases with a predominantly follicular pattern. In others with a diffusely infiltrative pattern of high-grade neoplastic B cells with BCL2, BCL6 and CD10 staining, DLBCL and high-grade B-cell lymphoma (HGBCL) should be excluded. The neoplastic cells of HGBCL are more blastoid in appearance with more prominent nucleoli. 7 The combination of CD10, BCL6 and IRF4 staining should trigger FISH analysis for an IRF4 gene rearrangement.

Conclusion
Here, we reported a case of large B-cell lymphoma with an IRF4 gene rearrangement in the tonsil of a 30 year old woman, with an accompanying case series. LBCL-IRF4 is a rare specific variant of large B-cell lymphomas and is an important differential to consider in cases of DLBCL or FL with aberrant germinal centre phenotypes. This rare entity, with a specific clinical presentation, is defined by the presence of a rearrangement of the IRF4 gene.A  3. IRF4 rearrangement is characteristic of: A. large B-cell lymphoma with IRF4 gene rearrangement B. Burkitt lymphoma C. Double hit lymphoma

Correct answer (A)
SHORT CASE