EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome.

ABSTRACT: Epstein-Barr virus (EBV)-positive (EBV+) nodal T- and natural killer (NK)-cell lymphoma is a peripheral T-cell lymphoma (EBV+ nPTCL) that presents as a primary nodal disease with T-cell phenotype and EBV-harboring tumor cells. To date, the genetic aspect of EBV+ nPTCL has not been fully investigated. In this study, whole-exome and/or whole-genome sequencing was performed on 22 cases of EBV+ nPTCL. TET2 (68%) and DNMT3A (32%) were observed to be the most frequently mutated genes whose presence was associated with poor overall survival (P = .004). The RHOA p.Gly17Val mutation was identified in 2 patients who had TET2 and/or DNMT3A mutations. In 4 patients with TET2/DNMT3A alterations, blood cell-rich tissues (the bone marrow [BM] or spleen) were available as paired normal samples. Of 4 cases, 3 had at least 1 identical TET2/DNMT3A mutation in the BM or spleen. Additionally, the whole part of the EBV genome was sequenced and structural variations (SVs) were found frequent among the EBV genomes (63%). The most frequently identified type of SV was deletion. In 1 patient, 4 pieces of human chromosome 9, including programmed death-ligand 1 gene (PD-L1) were identified to be tandemly incorporated into the EBV genome. The 3' untranslated region of PD-L1 was truncated, causing a high-level of PD-L1 protein expression. Overall, the frequent TET2 and DNMT3A mutations in EBV+ nPTCL seem to be closely associated with clonal hematopoiesis and, together with the EBV genome deletions, may contribute to the pathogenesis of this intractable lymphoma.

Comprehensive genomic analysis identifying heterogeneity in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are common in Japan. ATLL is an incurable T-cell malignancy induced by human T-cell lymphotropic virus type 1 (HTLV-1). The global genomics of ATLL can be summarized as alterations involving T-cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral-mediated T-cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV-1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL-related genes is identified in a part of HTLV-1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL-NOS is a heterogeneous disease type of T-cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL-NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.

Nodal EBV+ cytotoxic T-cell lymphoma: A literature review based on the 2017 WHO classification.

Nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL) is a primary nodal peripheral T-cell lymphoma (PTCL) characterized by a cytotoxic phenotype and EBV on the tumor cells. This disease reportedly accounts for 21% of PTCL not otherwise specified (NOS). However, few nodal EBV+ lymphomas have been documented in detail. Nodal EBV+ CTL and nasal-type NK/T-cell lymphoma (NKTL) both exhibit cytotoxic molecule expression and EBV positivity on the tumor cells; however, nodal EBV+ CTL is characterized as a systemic disease without nasopharyngeal involvement, and exhibits a CD8+/CD56- phenotype distinct from NKTL. The clinicopathological uniqueness of nodal EBV+ CTL is further supported by its T-cell origin in most reported cases. In the 2008 WHO classification, it was unclear whether nodal EBV+ CTL should be classified as PTCL or NKTL. However, based on additional data, the 2017 revision classifies nodal EBV+ CTL as PTCL. In the present review, we focus on the clinicopathological characteristics of nodal EBV+ CTL, discuss the relationship between chronic active EBV infection and nodal EBV+ lymphoma, and highlight future perspectives regarding the treatment of this disease.

High-Throughput Sequence Analysis of Peripheral T-Cell Lymphomas Indicates Subtype-Specific Viral Gene Expression Patterns and Immune Cell Microenvironments.

Certain peripheral T-cell lymphomas (PTCLs) have been associated with viral infection, particularly infection with Epstein-Barr virus (EBV). However, a comprehensive virome analysis across PTCLs has not previously been reported. Here we utilized published whole-transcriptome RNA sequencing (RNA-seq) data sets from seven different PTCL studies and new RNA-seq data from our laboratory to screen for virus association, to analyze viral gene expression, and to assess B- and T-cell receptor diversity paradigms across PTCL subtypes. In addition to identifying EBV in angioimmunoblastic T-cell lymphoma (AITL) and extranodal NK/T-cell lymphoma (ENKTL), two PTCL subtypes with well-established EBV associations, we also detected EBV in several cases of anaplastic large-cell lymphoma (ALCL), and we found evidence of infection by the oncogenic viruses Kaposi's sarcoma-associated herpesvirus and human T-cell leukemia virus type 1 in isolated PTCL cases. In AITLs, EBV gene expression analysis showed expression of immediate early, early, and late lytic genes, suggesting either low-level lytic gene expression or productive infection in a subset of EBV-infected B-lymphocyte stromal cells. Deconvolution of immune cell subpopulations demonstrated a greater B-cell signal in AITLs than in other PTCL subtypes, consistent with a larger role for B-cell support in the pathogenesis of AITL. Reconstructed T-cell receptor (TCR) and B-cell receptor (BCR) repertoires demonstrated increased BCR diversity in AITLs, consistent with a possible EBV-driven polyclonal response. These findings indicate potential alternative roles for EBV in PTCLs, in addition to the canonical oncogenic mechanisms associated with EBV latent infection. Our findings also suggest the involvement of other viruses in PTCL pathogenesis and demonstrate immunological alterations associated with these cancers.IMPORTANCE In this study, we utilized next-generation sequencing data from 7 different studies of peripheral T-cell lymphoma (PTCL) patient samples to globally assess viral associations, provide insights into the contributions of EBV gene expression to the tumor phenotype, and assess the unique roles of EBV in modulating the immune cell tumor microenvironment. These studies revealed potential roles for EBV replication genes in some PTCL subtypes, the possible role of additional human tumor viruses in rare cases of PTCLs, and a role for EBV in providing a unique immune microenvironmental niche in one subtype of PTCLs. Together, these studies provide new insights into the understudied role of tumor viruses in PTCLs.

Expression and clinical significance of neuropilin-1 in Epstein-Barr virus-associated lymphomas.

BACKGROUND: The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated. METHODS: The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia. RESULTS: In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL). CONCLUSIONS: NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.

Cutaneous lesions of angioimmunoblastic T-cell lymphoma: Clinical, pathological, and immunophenotypic features.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic peripheral T-cell lymphoma with a follicular helper T-cell (TFH ) immunophenotype that frequently involves the skin. However, the histopathology of cutaneous involvement by AITL has not been fully established. METHODS: We reviewed the clinicopathological features of 19 patients seen at our institution with AITL involving the skin. Pan-T-cell and TFH marker expression was evaluated by immunohistochemistry. Epstein-Barr virus (EBV) was detected using in situ hybridization (ISH) for Epstein-Barr virus-encoded small RNA (EBER). T-cell receptor (TCR) gene rearrangement was evaluated by PCR. RESULTS: AITL affected both trunk and extremities in 15/19 cases (79%). Perivascular infiltration by small and/or medium-sized lymphocytes was seen in 18/19 (95%). Granulomatous inflammation was identified in 4/19 (21%). Aberrant loss of CD2, CD5, or CD7 was identified in 1/18 (6%), 2/18 (11%), or 7/19 (37%) cases, respectively. Seventeen of eighteen evaluable cases (95%) expressed 2 to 3 TFH markers: PD-1 in 19/19 (100%), BCL6 in 94% (17/18), and CD10 in 37% (7/19). EBV-positive cells were detected in 3/18 (17%) with varying density. Clonal TCR gene rearrangement was identified in 9/11 (82%). CONCLUSIONS: Cutaneous involvement by AITL shows relatively non-specific histopathological features. However, an immunohistochemical panel including TFH markers and EBER ISH is useful in differential diagnosis.

A case of AITL complicated by EBV-positive B cell and monoclonal plasma cell proliferation and effectively treated with lenalidomide.

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma with an aggressive clinical course and poor prognosis after conventional chemotherapy, for which there is no current standard of care. We describe here an 87-year-old woman with AITL, whose clinical diagnosis was complicated by the presence of B immunoblasts positive for Epstein-Barr virus in the lymph nodes and monoclonal plasma cells in the bone marrow at initial presentation. Rebiopsy of the lymph node led to the correct diagnosis of AITL with concurrent smoldering plasma cell myeloma. She was treated with several courses of conventional chemotherapy, resulting in progressive disease, and then switched to the immunomodulatory drug lenalidomide, which used in Japan for the treatment of multiple myeloma. Lenalidomide was effective in controlling both AITL and plasma cell myeloma.

Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas.

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes.

The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.

Development of Epstein-Barr Virus-related Primary Diffuse Large B-cell Lymphoma of the Central Nervous System in a Patient with Peripheral T-cell Lymphoma, Not Otherwise Specified after Mogamulizumab Treatment.

Mogamulizumab is a defucosylated humanized anti-CC chemokine receptor type 4 (CCR4) antibody that exerts an anti-tumor immune effect against various tumors through a suppressive effect on regulatory T-cells. We herein report a patient with peripheral T-cell lymphoma who developed Epstein-Barr virus (EBV)-related primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) after mogamulizumab therapy. Our experience should alert physicians to the possibility of the development of EBV-related CNS DLBCL in patients treated for primary lymphoma and suggests that the anti-tumor immune effect of mogamulizumab is ineffective for the prophylaxis of EBV-related lymphomas.

[Clinical Significance of Peripheral blood EB Virus Detection in NK/T Cell Lymphoma Patients].

OBJECTIVE: To explore the clinical significance of peripheral blood EB virus detection in NK/T cell lymphoma patients. METHODS: The positive rate of EB virus and EBV-DNA in 85 cases of NK/T cell lymphoma was assayed; the correlation of positive rate of EB virus with clinical staging, short-term and long-term prognosis was analyzed. RESULTS: The positive rate of EB virus in NK/T cell lymphoma was high (80.00%). The EBV-DNA copy number in peripheral blood leukocytes was higher than that in peripheral plasma (P<0.05), but there was no significant difference in EBV-DNA level between peripheral leukocytes and serum (P>0.05). The I-II stages ratio of patients in EBV+ group was significantly lower than that in EBV- group. The CR rate and ORR in EBV+ group was significantly lower than those in EBV- group, the 3 year OS rate and 3 year DFR in EBV+ group also was significantly lower than those in EBV- group. CONCLUSION: The detection of periphera blood EBV may be used as an reference indicator for anxiliary diagnosis of NK/T cell lymphoma and evaluation of prognosis for patients, thus possessing a certain value for clinical application.

Clinicopathological Study of 30 Cases of Peripheral T-cell Lymphoma with Hodgkin and Reed-Sternberg-like B-cells from Japan.

The presence of Hodgkin and Reed-Sternberg (HRS)-like B-cells in peripheral T-cell lymphoma (PTCL) is rare and its clinicopathological features still remain unclear. Here, we describe 30 cases of PTCL with HRS-like B-cells from Japan. Twenty-three cases (77%) presented evidence of follicular T-helper phenotype (TFH) derivation: 12 were angioimmunoblastic T-cell lymphoma and 11 PTCL with TFH phenotype (PTCL-TFH). The remaining seven cases were diagnosed as PTCL, not otherwise specified (PTCL-NOS). Epstein-Barr virus (EBV) reactivation was detected in 25 cases (83%), but HRS-like B-cells were EBER in only 20 cases (67%). The median age at diagnosis was 77 years (range, 39-91 y), including 24 patients (80%) were older than 60 years of age. Most of the patients presented at an advanced clinical stage and were associated with higher risk according to the International Prognostic Index. The 3-year overall and progression-free survival rates were 44% and 27%, respectively. No significant clinicopathological differences were detected between PTCL-TFH, PTCL-NOS and the angioimmunoblastic cases. Cases with EBER HRS-like B-cells were associated with inferior overall and progression-free survival compared to those with EBER HRS-like B-cells, but the difference was not significant. In conclusion, HRS-like B-cells were found in a subset of T-cell lymphomas, especially in association with the TFH phenotype and EBV reactivation. These cells have a tendency to affect elderly patients and to be associated with advanced clinical stages and dismal prognosis. The EBV status of HRS-like B-cells does not seem to affect the clinicopathological features of this group of PTCLs.

An Epstein-Barr virus susceptible immature T-cell line, WILL4, established from a patient with T-lymphoblastic lymphoma bearing CD21 and a clonal EBV genome.

We managed a patient with an Epstein-Barr virus-associated T-cell lymphoblastic lymphoma. Mediastinal tumor cells at initial admission were positive for CD4, CD8, and TdT. Interestingly, a lymph node at necropsy was compatible for a CD4-positive peripheral T-cell lymphoma without CD8 and TdT expression, suggesting a different phenotype from the mediastinal tumor. Tumor cells in pleural effusion continued to proliferate in in vitro and were designated as WILL4. WILL4 cells were positive for CD3, CD4, CD8, CD21, T-cell receptor (TcR) αß, and TdT, indicating a similar phenotype to thymocytes. Southern blot analyses showed that the pleural tumor and WILL4 cells shared a TcR gene rearrangement, and that both contained a clonal EBV genome in an episomal form. RT-PCR showed that EBNA1 and LMP1 were expressed in the fresh tumor and WILL4 cells. Southern blot analyses revealed that WILL4 cells were susceptible to EBV infection in vitro using B95-8 supernatant. Anti-CD21 antibody inhibited in vitro infection of EBV, suggesting that CD21 plays a role in EBV infection into WILL4 cells. In vitro infection of EBV did not affect latent gene expression in WILL4 cells. WILL4 is a useful tool for analyzing the roles of EBV in onocogenesis in immature T-lymphoid malignancies.

EBV-associated Peripheral T-Cell Lymphoma of Gastrointestinal Tract Presented With Widespread Chronic Inflammation: A Case Report.

We report a case of Epstein-Barr virus (EBV)-associated T-cell lymphoma of gastrointestinal (GI) tract from a 70-year-old white woman who initially presented with a widespread GI inflammation and gastric obstruction. Initial biopsies of the GI tract showed severe chronic inflammation in the esophagus, stomach, and the small intestine. Celiac disease and inflammatory bowel disease were ruled out. The patient was treated with partial gastrectomy. Histology showed gastric wall thickening with EBV-positive, mixed lymphocytic and plasma cell infiltration in the mucosa, and thickening and fibrosis of the submucosa. She developed EBV-associated T-cell lymphoma of the GI tract one and a half years later and expired due to multiorgan failure. The T-cell lymphoma diffusely infiltrated the GI wall without forming a mass lesion. The lymphoma expressed EBV and cytotoxic molecules but lacked common features of extranodal natural killer/T-cell lymphoma nasal type, such as angioinvasion/angiodestruction, necrosis, or CD56 expression. Immunoglobulin heavy chain (IGH) gene and T-cell receptor-γ gene rearrangements and EBV-positive cells were detected at the early stage of the disease. While IGH clones were transient, T-cell clones and EBV-positive cells progressively increased over the disease course. We conclude that this case is best classified as EBV-associated peripheral T-cell lymphoma of GI tract. Age-related immune senescence may have contributed to the uncontrolled GI inflammation and subsequent transformation to T-cell lymphoma.

Frequency and clinical correlates of elevated plasma Epstein-Barr virus DNA at diagnosis in peripheral T-cell lymphomas.

Epstein-Barr virus (EBV)-encoded RNAs (EBER) in tumor tissue and cell-free plasma EBV-DNA (pEBVd) are detected in EBV-associated lymphomas. Studies have suggested that EBER+ peripheral T-cell lymphomas (PTCL) have worse prognosis but the role of EBV in these neoplasms remains unclear. pEBVd is quantitative and more easily amenable to standardization than EBER, but frequency of pEBVd detection, clinical impact and agreement with EBER status in PTCL are unknown. We retrospectively assessed frequency of detectable pre-treatment pEBVd, presence of EBER in tumor tissue, and outcomes in 61 of 135 EBV-assessable PTCL patients. Fifteen of 61 patients (24.5%, 95% CI: 14-37%) were pre-treatment pEBVd+, with no significant differences in baseline characteristics or treatment between pEBVd+ and pEBVd- patients. EBER-ISH was performed on 10 pEBVd+ and 35 pEBVd- tumors. All 10 pEBVd+ patients were EBER+, but 9 pEBVd- patients were also EBER+. With median follow up of 24 months (range 1-96), overall survival (OS) was shorter in pEBVd+ compared to pEBVd- patients (13 vs. 72 months; p = 0.04). In our retrospective study, pre-treatment pEBVd was elevated in 25% of PTCL patients, was highly specific for EBER+ tumors, and was associated with shorter survival. pEBVd should be further explored as a prognostic variable and tumor biomarker in PTCL.

Clinical features and treatment outcome of Epstein-Barr virus-positive nodal T-cell lymphoma.

The classification of mature NK-/T-cell lymphoma mainly originating from the T-cell lineage with predominantly nodal involvement and Epstein-Barr virus (EBV) positivity in a majority of tumor cells is unresolved. We analyzed the clinical features and treatment outcomes of such patients. Five patients with EBV-positive nodal T-cell lymphoma were surveyed during follow-up period. The median age was 53 years (range 33-88 years), and all patients showed nodal involvement. The patients mostly presented advanced clinical features, such as stage III or IV disease, elevated lactate dehydrogenase, and hemophagocytosis. Four patients received cyclophosphamide-containing chemotherapy at the time of diagnosis. However, three patients (75 %) showed disease progression during the early cycles of initial treatment. The median overall survival was 1.5 months (95 % CI 0.0-3.4 months). Patients with EBV-positive nodal T-cell lymphoma mainly show lymph node involvement, but also show aggressive clinical features and poor treatment outcomes, such as aggressive NK-cell leukemia. Therefore, we should consider EBV-positive nodal T-cell lymphoma to be a unique disease entity distinct from peripheral T-cell lymphoma not otherwise specified.

[Discordant lymphoma of duodenal EBV-positive peripheral T-cell lymphoma not otherwise specified and ileal diffuse large B-cell lymphoma].

A 79-year-old woman was admitted with a 5-kg weight loss and anorexia. Computed tomography showed diffuse lymphadenopathy, and thickening of the duodenal and ileal walls. The patient then underwent biopsy of these sites. Pathological examination revealed duodenal Epstein-Barr virus (EBV)-positive peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) and EBV-negative ileal diffuse large B-cell lymphoma (DLBCL) to be present simultaneously. Combination chemotherapy including rituximab produced a reduction of the duodenal EBV-positive PTCL-NOS lesion, but had no effect on the EBV-negative ileal DLBCL lesion. Thereafter, new lymphadenopathy, high fever, and lactate dehydrogenase (LD) elevation developed, complicated by pneumonia. The patient died due to rapid deterioration of the lymphoma and pneumonia on day 108 after initiation of treatment. EBV-positive PTCL-NOS is reportedly rare and the prognosis is poor. Moreover, EBV-negative ileal DLBCL was diagnosed simultaneously. This case is considered to have had an extremely rare discordant lymphoma, although the exact etiology of its development remains unknown. We speculate that age-related disorders of the immune system and HCV infection may have been associated with the pathogenic mechanism of lymphomagenesis in this case.