The patient presented with mosquito hypersensitivity at the age of five. Thereafter, she had recurrent cervical lymphadenopathy with fever, which resolved spontaneously in a couple of weeks. When she was 14 years old, systemic lymphadenopathy with fever developed. Biopsy of cervical lymph node revealed the diagnosis of Hodgkin lymphoma. She received chemotherapy of COPP/ABVD and modified EPOCH for two years. However, febrile lymphadenopathy resumed after chemotherapy. Then, she was diagnosed as chronic active EBV infection from the persistent presence of increased EBV-DNA (104
copies/mL) in the peripheral blood and high titer of anti-EB virus antibody. Analysis of lymphocyte subsets revealed that EBV infected both αβ
T and γδ
T cells and they were expanded clonally ().
Figure 1 Infection status of EBV was monoclonal. DNA from the patient's peripheral blood mononuclear cells was digested by EcoRI, and southern blot hybridization was performed with EBV BamHI W probe. An arrow points at the monoclonal bands. Asterisk shows the (more ...)
She was referred to our hospital at the age of 20. She received peripheral blood stem cell transplantation (PBSCT) from HLA-one-locus-mismatched mother at the age of 21. Conditioning regimen included fludarabine (25
× 5), melphalan (70
× 2), and antithymoglobulin (Lymphoglobuline; 10
mg/kg × 2). GVHD prophylaxis was tacrolimus with short-term MTX. Engraftment was on the 9th day, and grade III GVHD (skin: stage 3, liver: stage 2) occurred on the 14th day, for which prednisolone and mycophenolate mofetil (MMF) were started. GVHD was intractable and grade II GVHD (skin) persisted. On the 198th day, she was discharged for follow-up of chronic GVHD on medication of tacrolimus (0.1
mg/kg/day), prednisolone (0.5
mg/kg/day), and MMF (50
mg/kg/day). EBV-DNA in the peripheral blood was turned negative on the 10th day. On the 40th day, it became transiently positive but was consistently negative after the 52nd day.
On the 227th day, she was transferred to our hospital because of convulsion. MRI revealed a mass with diameter of 20
mm in the left frontal lobe (). EBV, CMV, VZV, and HHV-1, 2, 6, 7, 8 were all negative in both of the peripheral blood and spinal fluid by PCR method. Considering the EBV-associated lymphoma or toxoplasmosis, immunosuppressive drugs were reduced and antitoxoplasma drug (pyrimethamine + sulfadiazine) was started. Stage 2 skin GVHD developed, and left temporal mass was gradually regressed. However, MRI on the 280th day disclosed another mass in the right paraventricular area (). EBV-DNA was detected in the spinal fluid on the 373rd day, although still negative in the peripheral blood. The mass was progressively enlarged in spite of stopping tacrolimus and MMF. She and her family were reluctant to further intensive therapy including radiotherapy. She died from brain stem herniation on the 417th day after PBSCT.
Brain MRI of the patient. Initial frontal tumor that was surrounded by T2 high edematous area disappeared completely on the 294th day, but right paraventricular tumor grew progressively.
Autopsy revealed EBV-positive diffuse large cell lymphoma positive for CD20 and CD79a (). Analysis of IgH and EBV terminal repeat presented monoclonal proliferation and STR (short tandem repeat) analysis showed the recipient origin (). In the left hemisphere, ghost cells were aggregated where the first mass was detected. Ghost cells were positive for CD20 and LMP-1 (latent-membrane-protein-1) and considered to be apoptotic lymphoma cells. There was no evidence of toxoplasmosis histologically.
Histology of the brain tumor. Infiltrating cells in the brain tumor were CD79a+, CD3−, and LMP-1+. Arrow indicates the right paraventricular tumor.
STR (short tandem repeat) analysis of the lymphoma cells.