Large B-cell lymphoma with IRF4 rearrangement of retroperitoneal lymph node in an elderly male with concomitant high-grade B-cell lymphoma without IRF4r masquerading as a gastric ulcer

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Ejas Palathingal Bava, MD; Hira Qadir, MD
Yulei Shen, MD, PhD; Juan Gomez-Gelvez, MD
Xiaolan Fang, PhD; Kedar Inamdar, MD, PhD
Wei Liu, MD, PhD; Sharmila Ghosh, MD

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4r) was recognized as a provisional entity in the revised fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues in 2017.¹ This condition is also now acknowledged as a distinct entity in the International Consensus Classification. It predominantly occurs in children and young adults. However, IRF4 rearrangements are also found in about two percent of adult-onset large B-cell lymphomas. The clinical, pathological, immunophenotypic, and cytogenetic characteristics of older patients with LBCL having concurrent IRF4 rearrangement have not been well described.^2,3 Here we present a case of an elderly male with LBCL-IRF4r of retroperitoneal lymph node as well as a concomitant large B-cell lymphoma without IRF4 rearrangement presenting as a gastric ulcer, and we discuss the molecular genetic alterations seen in this rare entity using next-generation sequencing. This case explores the complexity of molecular pathogenesis of this rare entity.

Case. A 74-year-old male with a history of smoking for more than 50 pack-years had a screening CT chest for lung cancer, which showed emphysema, right upper lobe nodules, and pleural effusion. Right thoracentesis yielded 1,250 mL bloody fluid, exudate, lymphocyte predominant, with negative cytology. Because of these findings, a right video-assisted thoracoscopic surgery, total decortication, and mediastinal lymph node biopsy and pleural biopsy were done, which showed focal lymphohistiocytic inflammation.

PET scan showed hypermetabolic adenopathy in bilateral neck with small and mildly enlarged lymph nodes, mediastinal lymphadenopathy, axillary lymphadenopathy, splenomegaly, and multiple pleural-based densities in lungs, extensive on the right side with hypermetabolism, likely relating to malignancy. Axillary lymph node biopsy showed reactive lymphoid hyperplasia, fatty replacement, and black-colored pigment-laden histiocytes and negative for histopathologic evidence of lymphoma or metastatic neoplasm. CT showed an increase in the size and number of retroperitoneal lymph nodes, as compared with a previous scan, and were suggestive of malignant neoplasm.

Needle biopsy of retroperitoneal lymph node showed high-grade B-cell lymphoma, morphologically consistent with diffuse large B-cell lymphoma (DLBCL), germinal center type (CD10+, BCL6+, and MUM1+), as shown in Fig. 1A–E. There were frequent mitoses and apoptotic bodies. MIB1 proliferation index was 90 percent. FISH was positive for IRF4 gene rearrangement (55 percent). When the IRF4 gene is intact, the 5′IRF4 (red) and 3′IRF4 (green) are close or together, so merged signal (yellow) or green and red signals very close to each other are seen. In this sample, isolated red signals were seen, indicating that the 5′IRF4 is remaining but 3′IRF4 is missing, and rearrangement was present, as shown in Fig. 1F. FISH analysis was performed for IGH (14q32) but not for IGK or IGL (because they are not routinely performed in our lab, as they are less common compared with IGH rearrangement in B-cell lymphoma). An integrated diagnosis of large B-cell lymphoma with IRF4 rearrangement was made. The tumor was negative for MYC and BCL2 rearrangement. By FISH analysis, 65 percent of cells showed two IGH probe signals and one BCL2 probe signal, suggesting loss of BCL2 (65 percent). Next-generation sequencing using a lymphoid neoplasm sequencing panel revealed tier 1/2 mutations in MYD88 p.(Met232Thr) (AF = 33.9 percent), GNA13 p.(Trp110*) (AF = 36 percent), and MEF2B p.(Tyr69His) (AF = 35.3 percent). Variants of uncertain significance mutations were seen in CARD11 p.(Lys215Gln) (AF = nine percent), MYC p.(His374Arg) (AF = 34.7 percent), and GNA13 p.(Asp155Gly) (AF = 31.7 percent).

After two weeks, the patient underwent esophagogastroduodenoscopy for abdominal pain, which showed a nonbleeding ulcer. Biopsies of the gastric ulcer showed high-grade B-cell lymphoma, with features of DLBCL, germinal center phenotype, as shown in Fig. 2A–E. The present tumor from the GI biopsy appeared to be immunophenotypically and genetically different from the previously diagnosed high-grade lymphoma diagnosed from the lymph node. Compared with the LBCL-IRF4r lymphoma, the gastric lymphoma did not express CD10 and MUM1. There were frequent mitoses and apoptotic bodies. The MIB1 proliferation index was greater than 90 percent. It was morphologically similar to the previously diagnosed lymphoma in the retroperitoneal lymph node.

FISH studies did not identify the previously detected IRF4 gene rearrangement. It was negative for MYC gene rearrangement, but loss of MYC was present (60 percent). It was negative for IGH::BCL2 gene rearrangement. It was positive for aneuploidy of IGH and BCL2 (72.5 percent). It was positive for atypical BCL6 gene rearrangements with loss of 5′BCL6 (65 percent). The result was abnormal and indicated that about 65 percent of cells have atypical BCL6 gene rearrangements; losses of chromosomes 6, 8, 14, and 18; as well as low-level gain of IGH. The BCL6 result consisted of one or two copies of the 3′BCL6 gene with loss of both 5′BCL6 gene regions, possibly indicating involvement of one or both BCL6 genes. These results suggested a hypodiploid cell population with unbalanced BCL6 gene rearrangements. The patient underwent four cycles of R-CHOP treatment, and a subsequent PET scan revealed an overall improvement in the disease condition.

Discussion. Large B-cell lymphoma with IRF4 rearrangement is a de novo mature B-cell lymphoma with follicular and/or diffuse growth pattern. It is defined by strong expression of IRF4 (MUM1) usually due to an IG::IRF4 translocation. These are rare tumors, constituting less than one percent of large B-cell lymphomas. It typically involves the cervical lymph nodes (Waldeyer’s ring) and is less common in intestinal lymph nodes.^1,4 The immunophenotype of LBCL-IRF4r shows mature B cells that are positive for the protein encoded by the IRF4 gene (MUM1), CD10, and BCL6. Gene expression profiling demonstrates a germinal center phenotype in most of the cases.⁵

They are more common in children and young adults and are very rare in the older population. Unlike in younger individuals, where it commonly appears in the Waldeyer’s ring and clinical stages I/II, in adults it tends to present more frequently as nodal disease and in advanced clinical stages. Despite these differences, the prognosis is typically favorable. Our patient also experienced an improvement in nodal disease following chemotherapy.^6,7 They constitute six to 20 percent of pediatric mature B-cell lymphomas with a morphology of DLBCL or follicular large cell lymphoma.¹

A recent study shows that although it is rare, LBCL-IRF4r should be considered in older patients and at locations other than the head and neck.⁵ Our patient was a 74-year-old male, with retroperitoneal lymph node showing LBCL-IRF4r. A gastric ulcer discovered two weeks later showed high-grade B-cell lymphoma, with features of DLBCL but without IRF4 gene rearrangement. It is uncertain whether these were two different tumors or whether there was gastrointestinal involvement by the previously diagnosed lymphoma that had undergone clonal evolution, while losing its IRF4 rearrangement, or if these could have been two concurrent lymphomas. The result of “B-cell gene rearrangement” for clonality testing was indeterminate in both tumors, as neither a monoclonal nor a polyclonal population of B lymphocytes was identified. Hence the clonal relationship of the two tumors remained inconclusive.

Intriguingly, LBCL-IRF4r had pathogenic or likely pathogenic mutations in MYD88, MEF2B, and GNA13 genes. MYD88 is a NF-κB-pathway-related gene, and mutations of NF-κB-pathway-related genes (CARD11, CD79B, MYD88) are observed in about 35 percent of cases of LBCL-IRF4r, as seen in this patient.¹ However, MYD88 mutations are also more frequent in activated B-cell like (ABC) subtype of DLBCL.⁸ MEF2B mutation was also present in LBCL-IRF4r. MEF2B encodes a transcriptional activator and is mutated in approximately 11 percent of DLBCLs. Mutations in MEF2B led to dysregulated expression of BCL6, thereby contributing to lymphomagenesis in DLBCL.⁹ Interestingly, whole exome sequencing has identified recurrent copy number gains in MEF2B proto-oncogene in high-grade B-cell lymphoma with MYC and BCL2 with or without BCL6 rearrangements.⁸ GNA13 mutation, another genetic alteration seen in germinal-center–derived DLBCL,¹⁰ was also present in LBCL-IRF4r.

Aside from the possibility of clonal evolution involving the entire tumor, it is possible that this may have reflected intratumoral genetic heterogeneity (55 percent IRF4 re­arrangement), with the IRF4-rearrangement-negative subset having undergone clonal evolution seen in the lymphoma involving the gastric ulcer. It could also represent spatial or temporal tumoral heterogeneity, with the IRF4 rearrangement-positive portion predominating in the node and the IRF4 rearrangement-negative portion predominating in the stomach. This is an important consideration because it indicates that an IRF4-rearranged lymphoma at one site may have a synchronous or subsequent DLBCL at a different site. While the consideration of clonal and subclonal tumor evolution emphasized the established notion of intratumoral genetic heterogeneity, which can occur stochastically,¹¹ the new gastric tumor offered a rare chance to gain further insights into tumor evolution.¹²

In summary, LBCL-IRF4r is a recently recognized entity commonly seen in young age and associated with a favorable prognosis, with IRF4r having an independent beneficial prognostic influence.⁶ This case report provides a rare opportunity to gain insights into the molecular genetic alterations in LBCL-IRF4r in the elderly population. It also alerts the physician to the possibility of a lymphoma masquerading as a gastric ulcer. It helps in the understanding of the pathogenesis of evolution of lymphomas and opens avenues for therapeutic targeting.

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Drs. Palathingal Bava, Qadir, Shen, Gomez-Gelvez, Fang, Inamdar, Liu, and Ghosh are in the Department of Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, Mich.