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B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T-Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia.

Hanaoka N, Murata S, Hosoi H, Shimokado A, Mushino T, Kuriyama K, Hatanaka K, Nishikawa A, Kurimoto M, Sonoki T, Muragaki Y, Nakakuma H - Hematol Rep (2015)

Bottom Line: We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia.The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma.This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology.

ABSTRACT
B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab.

No MeSH data available.


Related in: MedlinePlus

EBV-negative oligoclonal B-LPD, the clonal proliferation of T cells, and EBV following ATG therapy. (A) Histochemical staining of an abdominal lymph node (100×). Inset right below for each panel was a high magnification image (400×). H&E, staining with hematoxylin and eosin; EBER, FISH of EBV-encoded RNA. (B-D) Southern blot analysis of DNA extracted from LPD lesions. Blots were hybridized with the IGH gene probe JH (B), EBV-specific DNA probe Bam HIW (C), and TCR gene probe Jγ (D). Arrows indicate rearranged bands. In panel B, DNA was digested with the restriction enzymes Bam HI (lane 1), both Bam HI and Hind III (lane 2), and Hind III (lane 3). In panel C, DNA was digested with Bam HI: lanes 1 and 2, positive and negative controls for EBV, respectively; lane 3, LPD lesion. Lane M, DNA molecular weight markers. In panel D, DNA was digested with Hind III: lane 1, lymphocytes of a healthy control; lane 2, LPD lesion. The arrow indicates a missing 5-kb fragment (TCR rearrangement). (E) Capillary electrophoresis of PCR products from the LPD lesion exhibiting T-cell clonality when assessed by TCRγ rearrangement. (F) Immunohistochemical detection of IL-10 and IL-6 in the kidney showing the marked infiltration of B-cells.
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fig002: EBV-negative oligoclonal B-LPD, the clonal proliferation of T cells, and EBV following ATG therapy. (A) Histochemical staining of an abdominal lymph node (100×). Inset right below for each panel was a high magnification image (400×). H&E, staining with hematoxylin and eosin; EBER, FISH of EBV-encoded RNA. (B-D) Southern blot analysis of DNA extracted from LPD lesions. Blots were hybridized with the IGH gene probe JH (B), EBV-specific DNA probe Bam HIW (C), and TCR gene probe Jγ (D). Arrows indicate rearranged bands. In panel B, DNA was digested with the restriction enzymes Bam HI (lane 1), both Bam HI and Hind III (lane 2), and Hind III (lane 3). In panel C, DNA was digested with Bam HI: lanes 1 and 2, positive and negative controls for EBV, respectively; lane 3, LPD lesion. Lane M, DNA molecular weight markers. In panel D, DNA was digested with Hind III: lane 1, lymphocytes of a healthy control; lane 2, LPD lesion. The arrow indicates a missing 5-kb fragment (TCR rearrangement). (E) Capillary electrophoresis of PCR products from the LPD lesion exhibiting T-cell clonality when assessed by TCRγ rearrangement. (F) Immunohistochemical detection of IL-10 and IL-6 in the kidney showing the marked infiltration of B-cells.

Mentions: The present study gives a new insight into EBV-associated LPD through a rare AA patient undergoing ATG therapy and subsequently developing fatal LPD with autopsy analysis. Histological examinations revealed that lymphocytes densely infiltrated into the para-aortic lymph nodes (Figure 2A), liver, kidney, pancreas, and thyroid. Flow cytometry showed that most lymphocytes expressed pre-B-cell markers such as CD3-, CD7-, CD19+, CD20+, CD38+, and κ-chain+ (data not shown). Apparently, the LPD indicated EBV-associated B-LPD with EBV infection. However, of interest, the elaborate analyses showed that lymphocytes in the LPD lesions were oligoclonal when assessed by Southern blotting (Figure 2B) and the detection of two serum M-proteins (IgG and IgM). Predominant lymphocytes within the LPD lesions were also negative for EBER when limited by the presence of CD3- CD20+ B cells (inset right below for each panel in Figure 2A) and no major chromosomal abnormalities were detected (data not shown). Moreover, it did not affect the quantity of the two digested bands in Southern blotting for the IgH rearrangement (Figure 2B, lanes 2 and 3 of the patient) in spite of only a small minority of clonal EBV-positive cells. Thus, these results suggest that oligoclonally expanding EBV-negative B cells virtually occupied the LPD lesions.


B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T-Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia.

Hanaoka N, Murata S, Hosoi H, Shimokado A, Mushino T, Kuriyama K, Hatanaka K, Nishikawa A, Kurimoto M, Sonoki T, Muragaki Y, Nakakuma H - Hematol Rep (2015)

EBV-negative oligoclonal B-LPD, the clonal proliferation of T cells, and EBV following ATG therapy. (A) Histochemical staining of an abdominal lymph node (100×). Inset right below for each panel was a high magnification image (400×). H&E, staining with hematoxylin and eosin; EBER, FISH of EBV-encoded RNA. (B-D) Southern blot analysis of DNA extracted from LPD lesions. Blots were hybridized with the IGH gene probe JH (B), EBV-specific DNA probe Bam HIW (C), and TCR gene probe Jγ (D). Arrows indicate rearranged bands. In panel B, DNA was digested with the restriction enzymes Bam HI (lane 1), both Bam HI and Hind III (lane 2), and Hind III (lane 3). In panel C, DNA was digested with Bam HI: lanes 1 and 2, positive and negative controls for EBV, respectively; lane 3, LPD lesion. Lane M, DNA molecular weight markers. In panel D, DNA was digested with Hind III: lane 1, lymphocytes of a healthy control; lane 2, LPD lesion. The arrow indicates a missing 5-kb fragment (TCR rearrangement). (E) Capillary electrophoresis of PCR products from the LPD lesion exhibiting T-cell clonality when assessed by TCRγ rearrangement. (F) Immunohistochemical detection of IL-10 and IL-6 in the kidney showing the marked infiltration of B-cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591498&req=5

fig002: EBV-negative oligoclonal B-LPD, the clonal proliferation of T cells, and EBV following ATG therapy. (A) Histochemical staining of an abdominal lymph node (100×). Inset right below for each panel was a high magnification image (400×). H&E, staining with hematoxylin and eosin; EBER, FISH of EBV-encoded RNA. (B-D) Southern blot analysis of DNA extracted from LPD lesions. Blots were hybridized with the IGH gene probe JH (B), EBV-specific DNA probe Bam HIW (C), and TCR gene probe Jγ (D). Arrows indicate rearranged bands. In panel B, DNA was digested with the restriction enzymes Bam HI (lane 1), both Bam HI and Hind III (lane 2), and Hind III (lane 3). In panel C, DNA was digested with Bam HI: lanes 1 and 2, positive and negative controls for EBV, respectively; lane 3, LPD lesion. Lane M, DNA molecular weight markers. In panel D, DNA was digested with Hind III: lane 1, lymphocytes of a healthy control; lane 2, LPD lesion. The arrow indicates a missing 5-kb fragment (TCR rearrangement). (E) Capillary electrophoresis of PCR products from the LPD lesion exhibiting T-cell clonality when assessed by TCRγ rearrangement. (F) Immunohistochemical detection of IL-10 and IL-6 in the kidney showing the marked infiltration of B-cells.
Mentions: The present study gives a new insight into EBV-associated LPD through a rare AA patient undergoing ATG therapy and subsequently developing fatal LPD with autopsy analysis. Histological examinations revealed that lymphocytes densely infiltrated into the para-aortic lymph nodes (Figure 2A), liver, kidney, pancreas, and thyroid. Flow cytometry showed that most lymphocytes expressed pre-B-cell markers such as CD3-, CD7-, CD19+, CD20+, CD38+, and κ-chain+ (data not shown). Apparently, the LPD indicated EBV-associated B-LPD with EBV infection. However, of interest, the elaborate analyses showed that lymphocytes in the LPD lesions were oligoclonal when assessed by Southern blotting (Figure 2B) and the detection of two serum M-proteins (IgG and IgM). Predominant lymphocytes within the LPD lesions were also negative for EBER when limited by the presence of CD3- CD20+ B cells (inset right below for each panel in Figure 2A) and no major chromosomal abnormalities were detected (data not shown). Moreover, it did not affect the quantity of the two digested bands in Southern blotting for the IgH rearrangement (Figure 2B, lanes 2 and 3 of the patient) in spite of only a small minority of clonal EBV-positive cells. Thus, these results suggest that oligoclonally expanding EBV-negative B cells virtually occupied the LPD lesions.

Bottom Line: We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia.The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma.This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology.

ABSTRACT
B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab.

No MeSH data available.


Related in: MedlinePlus