Abstract
A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations.
Keywords: chronic active Epstein-Barr virus infection, adult, cord blood stem cell transplantation
Introduction
Chronic active Epstein-Barr virus (CAEBV) infection is characterized by persistent or recurrent infectious mononucleosis-like symptoms and by the chronic proliferation of Epstein-Barr virus (EBV)-infected T/NK cells. Most cases of CAEBV are reported in childhood, and little is known about the characteristics or the treatment strategies for adult cases. Patients with CAEBV occasionally develop hemophagocytic lymphohistiocytosis and hematopoietic malignancies. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a curative treatment option. Although unrelated bone marrow is considered the first choice of stem cell source for patients who do not have an human leucocyte antigen (HLA)-identical sibling donor, the long period required for donor coordination makes it difficult for patients with aggressive disease to receive HSCT. Cord blood is an alternative stem cell source, and less time is needed for donor coordination. There have only been a few reports of adult cases of CAEBV receiving cord blood stem cell transplantation (CBT). We herein describe a case of a 41-year-old man who received CBT for the treatment of aggressive CAEBV.
Case Report
A 41-year-old man was referred to our hospital for a gingival tumor. His clinical history started in 1980 at the age of 6 years, when he developed an occasional fever and numerous recurrent, pea-sized, erythematous nodules and papules on his face and extremities, which then spread to his whole body and were exacerbated by sun exposure and insect bites. In 1987, at the age of 13, he was diagnosed by our hospital dermatology division with hydroa vacciniforme (HV) associated with lymphomatoid papulosis-like eruptions, and he was treated with prednisolone (PSL) and cyclophosphamide (1). Iwatsuki et al. have shown that EBV can be detected in the dermal tissue using in situ hybridization and a polymerase chain reaction (PCR) (2). In 1996, at 23 years of age, he was diagnosed with EBV-associated cutaneous T-cell lymphoproliferative disorder. He was also observed by other hospital teams. In March 2003, he developed a cerebellar hemorrhage of unknown etiology and underwent surgical removal of the hematoma. At that time, his EBV-DNA levels in the peripheral blood were 8.9×104 copies/106 cells.
In May 2014, at 41 years of age, he complained of abdominal pain with fever, which was found to be due to cholecystitis. Multiple pulmonary nodule shadows, hepatosplenomegaly, and a gingival mass were noted (Figure 1, 2). 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed FDG accumulation in the gingival mass, the systemic eruptions, and the gluteal muscle (Fig. 3). A pathological examination of the mass revealed the growth of atypical lymphocytes that were positive for CD3 (partial), CD4 (partial), CD30, MUM1, granzyme B, and TIA-1 and negative for CD79a, CD20, CD8, CD56, and anaplastic lymphoma kinase (ALK) on immunostaining. EBV-encoded small RNA in situ hybridization (EBER-ISH) was positive in atypical lymphocytes (Figure 4, 5). Given these findings, ALK-negative anaplastic large cell lymphoma was diagnosed.
Figure 1.
Macroscopic findings of gingival mass and gluteal skin eruptions.
Figure 2.
Computed tomography shows multiple pulmonary nodule shadows in whole lung fields.
Figure 3.
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) shows FDG accumulation in the gingival mass, the systemic eruptions, and the gluteal muscle. Multiple pulmonary nodules show poor FDG avidity on FDG-PET image.
Figure 4.
Histological study of gingival mass (original magnification, ×200): Atypical lymphocytes diffusely invade to muscular layer.
Figure 5.
Immunohistochemical studies and EBER-ISH of gingival mass: CD30+, granzyme B+, ALK–, and EBER-ISH+.
After two courses of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) therapy, the gingival mass rapidly decreased in size, and the lung nodules disappeared. However, his fever persisted, and the levels of serum hepatobiliary enzymes increased. CAEBV was diagnosed based on the findings of EBV antibody titer elevation (viral capsid (VCA)-IgG 320 titers; VCA-IgM <10 titers; EB nuclear antigen (EBNA) 40 titers; early antigen (EA)-IgG 80 titers) and positive EBV-DNA in the peripheral blood (4.7×104 copies/106 cells), in addition to the infectious mononucleosis-like symptoms. Monoclonal proliferation of EBV-infected cells was demonstrated in the peripheral blood and in the oral mass tissue via a Southern blot analysis (Fig. 6).
Figure 6.
EBV southern blot analysis (A: whole blood, B: gingival mass). M: size marker, 1: positive control, 2: negative control, 3: patient specimen. Monoclonal proliferation of EBV-infected cells was demonstrated in peripheral blood and in gingival mass tissue by Southern blot analysis.
The EPOCH therapy was then changed to Capizzi therapy (high-dose cytarabine and L-asparaginase) in conjunction with PSL 50 mg/body (3). However, despite two courses of Capizzi therapy, the patient's fever, eruptions, and elevated hepatobiliary enzymes recurred, and his EBV-DNA levels did not decrease. We therefore decided to perform CBT urgently.
The conditioning regimen consisted of fludarabine 125 mg/m2, melphalan 140 mg/m2, and whole-body irradiation at 4 Gy. Tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. The patient received cord blood from a human leukocyte antigen (HLA) 4/6 matched-unrelated donor, with a transplant cell count of 2.96×107/kg and a CD34 of 1.05×105/kg. He developed a pre-engraftment immune reaction 10 days after CBT, but this improved without additional treatment. Neutrophil engraftment was observed on Day 22. On Day 24, an analysis of the peripheral blood chimerism of the CD3-positive cells revealed complete donor type, and the EBV-DNA levels in the blood fell below the detection limit. Grade I acute GVHD (skin 1, liver 0, gut 0) improved with topical steroids, and the BK virus-associated hemorrhagic cystitis improved with hyperhydration and bladder irrigation, using a Foley catheter.
He was discharged on Day 75. The EBV-DNA remained below the detection limit, and the FDG-PET showed no signs of recurrence on Day 104. On Day 140, the EBV-DNA load in peripheral blood rose transiently to 1.2×104 copies/106 cells, but the peripheral blood chimerism of the CD3-positive cells and whole blood was complete donor type. On Day 165, skin eruptions appeared on the axilla and thigh. A histopathological examination of the skin eruptions revealed the invasion of EBER-ISH-positive T cells, and the withdrawal of tacrolimus successfully induced complete remission again (Fig. 7). One year after transplantation, there were no signs of recurrence.
Figure 7.
Clinical course. EPOCH: etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, Capizzi: high-dose cytarabine, L-asparaginase, CBT: cord blood transplantation, ALT: alanine aminotransferase, MMF: mycophenolate mofetil, TAC: tacrolimus
Discussion
CAEBV presents with various clinical manifestations, including a prolonged or intermittent fever, lymphadenopathy, hepatosplenomegaly, and eruptions (4). Malignant lymphoma develops in 16% of patients with CAEBV (5). Because of the various clinical features, CAEBV is sometimes difficult to diagnose. In our case, the patient showed a fever, anemia, splenomegaly, and HV-like eruptions that had started in childhood. It is difficult to differentiate CAEBV from systemic HV, but CAEBV with HV-like eruptions has been reported in the literature (6,7). In 2005, Okano et al. proposed guidelines for the diagnosis of CAEBV, one of which was the presence of EBV genomes in the affected tissues, including the peripheral blood (4). A diagnosis of CAEBV was made for the present case based on the prolonged and recurrent clinical symptoms and the presence of EBV-DNA in the peripheral blood. However, some patients may still not have been correctly diagnosed with CAEBV.
The prognosis of CAEBV is very poor. In the absence of effective therapy, almost all patients will die within 5-15 years from the onset due to hepatic or cardiac failure, hemophagocytic syndrome, malignant lymphoma, opportunistic infections, or intracranial/gastrointestinal bleeding (3,5,8). Allo-HSCT is considered to be the only curative treatment. Since the present patient had no matched sibling donors, we started a donor search through the Japan Marrow Donor Program. However, his liver dysfunction and fever worsened despite treatment with intensive chemotherapy. Cord blood is a useful donor source when immediate HSCT is required due to aggressive clinical symptoms.
Sawada et al. reported that the prognosis of patients with CAEBV who received CBT with reduced intensity conditioning (RIC) was comparable to that of patients who received bone marrow transplantation with RIC (9). They stated that the cord blood can function as an alternative source for bone marrow or peripheral blood stem cell transplantation. However, 13 of 15 cases (87%) in the RIC group in their study were children, and the outcome for adult patients who received CBT for CAEBV remained unclear.
In the literature, we found 8 adult (≥20 years old) cases of CAEBV treated with CBT (Table) (3,9-12). The median age was 38 years (range: 20-56), and engraftment was achieved in 7 cases. One patient (Case #2) died due to regimen-related toxicity before neutrophil engraftment. In six cases, the conditioning regimen was RIC. In five cases, the median number of pretransplant-therapy courses before HSCT was four. In four cases, the median nucleated cell count of the cord blood was 2.87×107/kg (range: 1.64-3.41×107/kg), and the median number of CD34-positive cells was 1.00×105/kg (range: 0.85-1.23×107/kg). Five of the six cases achieved complete remission.
Table.
Characteristics of Adult Patients with CAEBV Receiving CBT Reported in the Literature.
| Case | Age | Sex | Disease type | Pretreatment | Conditioning | GVHD | HLA | HLA | Infused cells | Engraftment | GVHD | Outcome | Reference | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| (courses) | prophylaxis | disparity | antibody | TNC (×107/kg) | CD34+ (×105/kg) | acute | chronic | ||||||||
| 1 | 47 | F | CAEBV | NA | Flu/CY/ATG/TBI6Gy | TAC/sMTX | 4/6 | NA | NA | NA | + | - | - | Alive/CR | 3 |
| 2 | 23 | F | CAEBV | 5 | ATG/Flu/Mel/mPSL/VP16 | TAC/sMTX | 5/6 | negative | 3.41 | 0.96 | + | NA | NA | NA | 9 |
| 3 | 38 | M | CAEBV | 2 | ATG/Flu/Mel/mPSL/VP16 | TAC/sMTX | 4/6 | negative | 1.64 | 1.23 | + | NA | NA | NA | 9 |
| 4 | 20 | F | HMV+CAEBV+PTCL | NA | NA | NA | NA | NA | NA | NA | + | NA | NA | Alive /CR | 10 |
| 5 | 52 | F | CAEBV+ENKL | NA | NA | NA | NA | NA | NA | NA | - | NA | NA | Died/TRM | 10 |
| 6 | 56 | F | CAEBV | 12 | Flu/Bu/TBI4Gy | TAC | 4/6 | NA | 2.78 | NA | + | II | + | Alive /CR | 11 |
| 7 | 36 | F | CAEBV | 0 | Flu/Mel/TBI4Gy | TAC/sMTX | N/C | NA | NA | 0.85 | + | NA | + | NA/CR | 12 |
| 8 | 41 | M | CAEBV+ALCL | 4 | Flu/Mel/TBI4Gy | TAC/MMF | 4/6 | positive | 2.96 | 1.05 | + | I | - | Alive /CR | our case |
NA: not available; HMV: hypersensitivity to mosquito bite; CAEBV: chronic active Epstein-Barr virus infection; PTCL: peripheral T-cell lymphoma; ENKL: extranodal NK/T cell lymphoma; SHV: severe hydroa vacciniforme; ALCL: anaplastic large cell lymphoma; ATG: antithymocyte globulin; Flu: fludarabine; Mel: melphalan; mPSL: methylprednisolone; VP16: etoposide; Bu: busulfan; TBI: total body irradiation; CY: cyclophosphamide; TAC: tacrolimus; sMTX: short-term methotrexate; MMF: mycophenolate mofetil; TNC: total nucleated cells; GVHD: graft-versus-host disease; CR: complete remission; TRM: treatment-related mortality
However, there may be major issues with regard to CBT in adults, one of which being the conditioning regimen. Kawa et al. reported an excellent outcome in patients who received RIC. In a retrospective analysis of 29 CAEBV cases, they compared the outcomes of allo-HSCT with the myeloablative conditioning (MAC) and RIC regimens (3). The 3-year event-free survival rate was 54.4%±15.0% for the MAC group and 85.0%±8.0% for the RIC group. The 3-year overall survival rate was 54.5%±15.0% for the MAC group and 95.0%±4.9% for the RIC group (p=0.016). They reported that allo-HSCT after RIC is a promising approach in the treatment of CAEBV. This may also apply to adult cases.
In the present case, the EBV-DNA load in the peripheral blood dropped below the detection limit on Day 24 but rose transiently to 1.2×104 copies/106 cells at the time of recurrence with skin eruptions. The patient sustained a low copy number of EBV genomes in the peripheral blood, without recurrence of a fever, liver damage, or gingival lymphoma. In a case reported by Watanabe et al., the patient developed a persistent EBV infection in donor T cells and sustained a low copy number of EBV genomes in T cells without clinical symptoms for 60 months after unrelated bone marrow transplantation (13). In the present case, we detected no infected cells in the peripheral blood, but the complete donor chimerism of the peripheral blood suggested a phenomenon similar to that observed in the previous report.
In conclusion, the encouraging outcome in the present case suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations. Further studies will be required to evaluate the efficacy of CBT.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Dr. Sakuhei Fujiwara for his invaluable suggestions.
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