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The patient was a 51-year-old man who had undergone living donor liver transplantation for type B cirrhosis at the age of 37 years, and had a history of immunosuppressive drug use. He had developed focal seizures starting from his right upper limb, and MRI showed a lesion in the subcortical white matter of his left parietal lobe. Sensory disturbance and paralysis progressed in his right upper and lower limbs, and his brain lesion rapidly enlarged. A brain biopsy revealed diffuse large B-cell lymphoma, and Epstein-Barr virus-encoded small RNA in situ hybridization was positive. The patient was diagnosed with primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) with no lesions in other organs. There are few reports of PCNS-PTLD cases after living donor liver transplantation in Japan. Although rare, it is nevertheless important to consider this disease in patients receiving immunosuppressive drugs after organ transplantation who develop brain lesions, regardless of which organ was transplanted.

A Japanese female patient underwent a living lung transplant at age 29 and has been on immunomodulatory drug therapy since then. At age 52, she presented with sudden hematochezia. Despite abdominal computed tomography scan, esophagogastroduodenoscopy, and colonoscopy, no definitive source of bleeding was identified. Considering the possibility of small bowel bleeding, video capsule endoscopy was performed, which revealed a suspected ulcerative lesion in the jejunum. Subsequent per-oral double-balloon endoscopy confirmed the presence of an ulcerative lesion in the jejunum. A potential pathological diagnosis of post-transplant lymphoproliferative disorder (PTLD) was considered based on endoscopic biopsy specimens from the jejunal lesion. However, before the pathologic biopsy results were available, the patient experienced small intestinal perforation, necessitating emergency partial resection. Pathologic examination revealed a dense proliferation of medium-to-large atypical lymphocytes with neutrophilic infiltration in the perforated area of the small intestinal wall. Immunostaining showed lymphoid cells positive for CD20 but negative for CD3. Epstein-Barr virus (EBV) -encoded RNA was detected by in situ hybridization, and Ki-67 staining demonstrated a higher percentage of positive cells. Consequently, an EBV-positive diffuse large B-cell lymphoma, developed as PTLD, was diagnosed. Complete remission was achieved with a reduced immunomodulatory drug dosage and rituximab therapy. She has been alive for 8 months postoperatively without recurrence. This case suggests that PTLD should be considered in assessing patients presenting with abdominal symptoms following organ transplantation.

Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPD) is a rare disease characterized by persistent or recurrent inflammation accompanied by EBV infection of T or NK cells that is not self-limiting, and it is fatal, if untreated. After receiving the first dose of the BNT162b2 mRNA COVID-19 vaccine, a 79-year-old male presented to the hospital with a 2-week history of fever. Laboratory results indicated pancytopenia, elevated liver transaminase levels, hyperferritinemia, and hypofibrinogenemia. Computed tomography revealed hepatosplenomegaly, but lymphadenopathy was not observed. A bone marrow biopsy, a random skin biopsy, and a liver biopsy revealed no malignancy, but an infectious evaluation revealed EBV viremia (5.19 Log IU/ml). Flow cytometry and RT-PCR revealed that the EBV genome was localized in NK cells, suggesting the diagnosis of EBV-NK-LPD. We administered prednisolone, intravenous immunoglobulin, and etoposide, but the EBV-DNA load failed to decrease, and he died 2 months later. Recently, case reports of COVID-19 vaccination-related hemophagocytic lymphohistiocytosis have been published. Although the mechanisms and risk factors for EBV-LPD after BNT162b2 mRNA COVID-19 vaccination remain unknown, it is important to note the possibility of reactivation of EBV after COVID-19 vaccination to initiate early and targeted therapy.

Epstein-Barr virus (EBV) has the ability to immortalize not only B cells but also T and natural killer (NK) cells. The virus may also contribute to the onset of EBV-positive lymphoproliferative disorders (EBV-LPDs) by inducing the introduction of gene mutations. It is known that B cell EBV-LPDs (B-EBV-LPDs) develop with preexisting immunodeficiency, but the onset mechanism of T cell and NK cell EBV-LPDs (T-EBV-LPDs and NK-EBV-LPDs), also known as chronic active EBV disease and associated diseases, is unclear. The diagnosis of both EBV-LPDs requires the quantitative examination of EBV-DNA in the peripheral blood. Eliminating the cause of immunodeficiency or administering rituximab is effective in treating B-EBV-LPDs, but some B-EBV-LPDs and T-EBV-LPDs/NK-EBV-LPDs are resistant to pharmacotherapy. Therefore, further research is needed to explicate the pathophysiology of EBV-LPDs and develop a drug for its treatment.

A 60-year-old woman, who had a kidney transplant 16 years ago, was admitted to our hospital owing to cognitive decline and gait disturbances. She developed ataxia, consciousness disturbances, and myoclonus, and died two years after the onset of symptoms. No specific findings were observed on MRI or in the cerebrospinal fluid and blood analyses. The patient was diagnosed with post-transplant lymphoproliferative disorder (PTLD) based on the results of the autopsy. Pathological findings revealed proliferating monoclonal B cells in the perivascular space that was confined to the central nervous system. PTLD is a serious complication of transplantation. Furthermore, PTLD of the central nervous system usually presents as nodular lesions on MRI. When neurological symptoms appear after transplantation, it is necessary to consider PTLD as a differential diagnosis even if abnormal findings cannot be pointed out on MRI.

We report a 66-year-old man with primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD). He had received a living-donor kidney transplantation at the age of 64 years. Although he had a good postoperative course by continuing to take oral immunosuppressive agents, he was admitted to our hospital for subacute cognitive impairment and urinary retention two years after the transplantation. Brain MRI revealed high-intensity lesions on FLAIR and T 2 -weighted images in the left parietal operculum, deep white matter around the anterior horn of the lateral ventricle, and the genu and splenium of the corpus callosum. A part of these lesions showed ring enhancement. The cerebrospinal fluid examination revealed lymphocytic pleocytosis, elevation of protein level, and mild hypoglycorrhachia. Blood tests showed no abnormalities except for positive serum VCA-IgG antibody of Epstein-Barr virus. A brain biopsy was performed and diagnosis of PCNS-PTLD was made. There was no evidence of systemic PTLD. We reduced the dose of immunosuppressive agents and started the initial treatment with methylprednisolone pulse therapy. The patient showed a partial response to the treatment and transferred to another hospital for subsequent chemotherapy. PTLD is an important post-transplant complication that can affect the patient's prognosis. The incidence of PTLD is increasing with the growing numbers of transplantations and older age of donors and recipients. Although CNS involvement is known to be rare, PCNS-PTLD is an important differential diagnosis when symptoms of CNS origin develop in post-transplant patients.

Post-transplant lymphoproliferative disorder (PTLD) usually develops with systemic symptoms, such as fever, generalized lymphadenopathy, and elevation in the lactate dehydrogenase level. Here, we present the case of a 65-year-old female patient with PTLD localized to the colon; the patient only had mild diarrhea without systemic symptoms. She had myelodysplastic syndrome and was treated with cord blood transplantation (CBT). She had a past medical history of sigmoid colon cancer treated with colonosectomy and adjuvant chemotherapy. After CBT, she achieved complete remission and was discharged after 60 days. Further, 79 days after CBT, she presented with abdominal pain. Computed tomography scan revealed adhesive ileus. The abdominal pain was resolved in 1 day with conservative treatment, however, mild diarrhea persisted. Therefore, we performed colonoscopy and found multiple ulcerative lesions in the upper colon. A pathological examination revealed PTLD. Furthermore, elevation of EBV-DNA in the blood was also confirmed. There was no detectable lesion on positron emission tomography-computed tomography (PET-CT) outside the colon; thus, we diagnosed PTLD localized into the colon that was successfully treated with rituximab. Our present experience suggests that it might be important to perform endoscopy and monitoring of EBV-DNA for early detection of PTLD, especially localized in the gastrointestinal tract.

Methotrexate-associated lymphproliferative disorder (MTX-LPD) is a rare but critical complication developing in patients treated with methotrexate. Now that methotrexate is an anchor drug in the management of rheumatoid arthritis and become commonly used, MTX-LPD cases have increased. Many things has been unclear such as incidence, demographic characters, and risk factors. However, as the researches increased, several interesting topics has been demonstrated like associations with Epsteiin-Barr virus and with cell-mediated immunity. This report reviews newly the latest findings and future challenges on MTX-LPD.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) comprise lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases, especially rheumatoid arthritis (RA) treated with methotrexate (MTX). MTX has been increasingly administered to patients with RA, resulting in methotrexate-associated lymphoproliferative disorder (MTX-LPD) in patients. We report herein on four cases of patients with RA, who diagnosed with head and neck region. In two cases (one case MTX and another case tacrolimus) drug therapy was discontinued, when the patients were diagnosed as having OIIA-LPD in only a few local findings. These patients have followed good clinical courses for 24 months. In the other two cases, consultations were performed for cervical lymphadenopathy by the Division of Rheumatology. In one case drug therapy was discontinued and a good clinical course was followed. In case of the other patient, however, who had undergone tacrolimus therapy after MTX therapy was discontinued, she relapsed and died. In the case of patients with an autoimmune disease such as RA who are taking MTX, tacrolimus, or anti TNF-α therapy, when cervical lymphadenopathy and extranodal disease are detected, OIIA-LPD should be suspected. We should cooperate with a hematologist-oncologist, a rheumatologist, and pathologist in such a case.

We report a rare case of T cell type monomorphic post-transplant lymphoproliferative disorders (PTLD) after autologous stem cell transplantation. A 53-year-old man with multiple myeloma received autologous stem cell transplantation and achieved a very good partial response. Nine months later, he developed a high fever and consciousness disturbance, and had multiple swollen lymph nodes and a high titer of Epstein-Barr (EB) virus DNA in his peripheral blood. Neither CT nor MRI of the brain revealed any abnormalities. Cerebrospinal fluid contained no malignant cells, but the EB virus DNA titer was high. Lymph node biopsy revealed T cell type monomorphic PTLD. Soon after high-dose treatment with methotrexate and cytosine arabinoside, the high fever and consciousness disturbance subsided, and the lymph node swelling and EB virus DNA disappeared. Given the efficacy of chemotherapy in this case, we concluded that the consciousness disturbance had been induced by central nervous system involvement of monomorphic PTLD.

Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) frequently involves the gastrointestinal tract, but the endoscopic characteristics of this condition have not been discussed in detail. We report two cases of EBV-related PTLD involving rapidly forming characteristic lesions. Case 1 was a 60-year-old man with acute myeloid leukemia who underwent cord blood transplantation (CBT) after which he initially achieved complete remission (CR). He developed nausea and vomiting on day 99. Gastrointestinal endoscopy showed no tumor-like lesions in his stomach. However, a second endoscopic evaluation, which was performed 7 days after the first, revealed multiple raised lesions in his stomach, and a histopathological examination of the biopsy specimen resulted in a diagnosis of EBV-related PTLD. Case 2 was a 36-year-old man with acute myeloid leukemia who underwent CBT after achieving his second CR. He suffered nausea and pharyngalgia on day 309. Although the initial gastrointestinal endoscopic examination showed only multiple erosive or small ulcerative lesions, a second endoscopic evaluation, which was performed 10 days after the first, revealed a raised lesion with a central ulcer in the duodenum. Histopathological examination of the biopsy specimen yielded a diagnosis of EBV-related PTLD. Both patients were successfully treated by reducing the dose of immunosuppressive agents and administering rituximab.

A 27-year-old woman with acute lymphocytic leukemia, who underwent allogeneic hematopoietic stem cell transplantation, complained of nausea and blurred vision 288 days after the transplantation. Intracranial tumors were identified on brain MRI. She received whole brain radiation after open biopsy, but she died. The tumors had characteristics of diffuse large B cell lymphoma, and she was finally diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. This disease is rare and has a poor outcome. Therefore, accumulation of cases and establishment of treatments for this condition are urgently needed.

The post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous disease entity of lymphoid and plasmacytic proliferations that can occur after solid organ and bone marrow/stem cell transplantation. PTLD sometimes involves the central nervous system (CNS), but primary occurrence in central nervous system (PCNS-PTLD) is rare. The Epstein-Barr virus (EBV) plays a causative role, and up to 90% of the tumors are associated with this virus. Diagnosing PCNS-PTLD is often challenging based solely on computed tomography, magnetic resonance imaging, and physical findings; therefore, direct biopsy of the lesion is usually necessary to make a definitive diagnosis. The optimal therapy for PCNS-PTLD remains unknown. Dose reduction or discontinuation of immunosuppressive agents is effective for approximately half of PTLD patients, but not for most patients with PCNS-PTLD. It has been noted that CNS involvement is a poor prognostic factor, but early diagnosis and initiation of chemotherapy or radiotherapy seem critical for maximizing the likelihood of a favorable outcome.

A man in his 70s underwent chemoradiotherapy for squamous cell carcinoma of the esophagus in 2009. A follow-up gastroendoscopy performed 3 years later revealed a reddish depressed lesion in the greater curvature of the middle stomach body. On the basis of histological and immunohistochemical findings and clinical features, including endoscopic findings, a diagnosis of lymphomatoid gastropathy was made. Follow-up studies revealed a decrease in the size of the lesion and the development of chronic gastritis. Although lymphomatoid gastropathy is rare, recognition of this disease is important because misdiagnosis as lymphoma may lead to unnecessary radical therapeutic procedures.

We report our experience with a case of iatrogenic immunodeficiency-associated lymphoproliferative disease in a patient who had been treated with methotrexate (MTX) for rheumatoid arthritis for 9 consecutive years, which showed natural remission after discontinuation of the MTX therapy. The patient was a 64-year-old woman who was admitted emergently to our hospital with hematemesis and melena. She presented with multiple gastric ulcers and bilateral tonsillitis with a central ulcer. Biopsy of these lesions raised the suspicion of diffuse large B-cell lymphoma. Positron emission tomography (PET)- computed tomography( CT) showed increased fluorodeoxyglucose( FDG) accumulation in the pharynx, cervical lymph nodes, liver, spleen, stomach, distal part of the ileum, and para-aortic lymph nodes, with a maximum standard uptake value of 26.85. Blood test showed elevated lactate dehydrogenase( LDH)( 321 U/L) and interleukin( IL)-2R( 3,531 U/mL) levels. After discontinuation of MTX, the sore throat subsided, and the tonsillitis, lymph node enlargement, and ulcers were resolved. The levels of LDH and IL-2R returned to within the normal range. The patient could be categorized into a regressive disease group with relatively favorable prognosis among patients with MTX-induced lymphoproliferative disease. However, she should continue to be followed up regularly because there remains a possibility that lymphoproliferative disease may relapse after the discontinuation of MTX.

A 43-year-old male renal transplant recipient, who received a living related renal transplant 7 years ago and had been maintained with tacrolimus, mycophenolate mofetil (MMF), and prednisolone, was admitted to our hospital complaining of headache and nausea. MRI showed a large mass in the right hemisphere with ring-enhancement indicating brain abscess, tumor or lymphoma. Open biopsy was performed and pathological examination demonstrated diffuse proliferation of polymorphic cells, positive for CD20, bcl-2, EBER, and LMP-1. Based on these findings, primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) was diagnosed. MMF was discontinued and tacrolimus was tapered. After 2 weeks, MRI showed regression of the tumor size and after 9 months, the tumor had disappeared. Though many reports have shown the severity of PCNS-PTLD, and recommend aggressive treatments such as chemotherapy and/or radiotherapy, our case shows that reduction of immunosuppressant alone with close observation could be a choice of treatment.

A 65-year-old man presented with complaints of general malaise and severe disturbance of consciousness since 2 months prior to admission. MRI of the head showed high intensity area in FLAIR image in the left basel ganglia, the medial side of the left temporal lobe and both sides of the frontal lobe and brainstem. The contrasting effect was insignificant. Laboratory investigations showed positive results of EBV antibody titer and elevated EBV-DNA in the spinal fluid. We suspected encephalitis due to Epstein-Barr virus and the patient was treated with acyclovir and high dosage of steroids. However, the patient's consciousness gradually deteriorated and he died on day 146 of admission. Autopsy revealed proliferation of large atypical cells with clear and irregular nuclei in the brain tissue. Immunohistochemistry expressed positive EBER-ISH. This case was finally diagnosed as the central nervous system involvement by age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder.

A 64-year-old man was diagnosed as having acute myeloid leukemia. We performed sequential treatment with chemotherapy and reduced-intensity stem cell transplantation from an unrelated donor while the patient was in partial remission. After engraftment, he developed acute graft-versus-host disease of the gut on day 42 and steroid therapy was started. Despite transient aggravation of diarrhea, his symptoms slowly improved and the dose of steroid was tapered. On day 159, he complained of acute left lower abdominal pain. A CT scan showed perforation of the digestive tract and ileectomy was performed. At surgery, multiple ulcers of the intestine were found and one of the ulcers was perforated. Pathologically, transmural and diffuse proliferation of atypical cells in the ulcer were confirmed. Since these cells were positive for CD20 and Epstein-Barr-virus (EBV) encoded RNA, we made a diagnosis of EBV-associated post-transplant lymphoproliferative disorder (PTLD). Reduction in the dose of immunosuppressive agents and rituximab led to complete remission of PTLD. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare, and the development of gastrointestinal perforation after allo-HSCT is very rare.

We report here a rare case of EBV-related post-transplantation lymphoproliferative disorder (PTLD) localized to the skin. The patient was a 64-year-old man diagnosed with angioimmunoblastic T cell lymphoma (AITL). He underwent cord blood transplantation with a reduced intensity conditioning regimen during partial remission after chemotherapy. On day 70 after transplantation, subcutaneous tumors developed near the left scapula and in the left upper arm. Pathological examination of the skin tumor revealed that this tumor was composed of diffuse large centroblast-like cells, the majority of which were CD20 positive, CD 79a positive, CD30 positive and Epstein-Barr virus (EBV) latency-associated RNA (EBER) positive, and EBV-DNA was also detected in tumor cells. At that time, real-time polymerase chain reaction documented no evidence of the EBV genome in his blood. Chimerism analysis revealed that the tumor cells were derived from donor cells, which led to the diagnosis of EBV-related PTLD. For treatment, in addition to decreasing the dose of tacrolimus, we administered rituximab and local irradiation to skin lesions, which led to disappearance of the tumors followed by continued complete remission.

A 54-year-old woman was diagnosed as having polycystic kidney in 1990. Renal transplantation was performed in 1995. She received immunosuppressive therapy postoperatively. Skin lesion was recognized on the left leg in April 2002 and skin biopsy demonstrated diffuse large B cell lymphoma in March 2006. EBV-LMP, EBNA-2 and EBER were positive and she was diagnosed as having EBV-related posttransplant lymphoproliferative disease (PTLD). Radiation therapy and rituximab therapy were administered. The skin ulcer worsened and she was referred to our hospital. We reduced the dose of immunosuppressive drug and performed debridement of the ulcer, which responded well to treatment. PTLD presenting with skin involvement rarely manifests as lesions, and such lesions develop slowly, when they occur. PTLD presenting with skin involvement after transplantation must be treated.

A 48-year-old woman was referred to our hospital because of fever and general fatigue. Peripheral blood analysis showed a hemoglobin level of 82 g/l, a white blood cell count of 1.95 x 10(9)/l and a platelet count of 80 x 10(9)/l. There were 9% CD5-positive B-cells in peripheral blood and 35% CD10-positive B-cells in bone marrow. The patient had a high serum soluble interleukin-2 receptor (SIL-2R) level of 5,185 U/ml and splenomegaly. Lymphoproliferative disease was suspected, however monoclonal rearranged band of immunoglobulin heavy chain was not detected. She also showed hyperthyroidism, Graves' disease and then treatment with thiamazole started. However, the treatment was stopped because of agranulocytosis and she received subtotal thyroidectomy. After treatment for hyperthyroidism, serum SIL-2R level decreased to 504 U/ml and pancytopenia gradually improved. Fifteen months postoperatively, the percentage of CD5-positive B-cells in peripheral blood and CD10-positive B-cells in bone marrow decreased to 8% and 2%, respectively. This clinical course suggests that polyclonal B-cell proliferation was caused by hyperthyroidism.

We experienced 3 cases of viral infections after lung transplantation. Case 1: Fifty-two-year-old male with pulmonary emphysema underwent left single lung transplantation from a cadaveric donor. Three months after transplantation he presented Epstein-Barr virus (EBV) viremia, resulting in multiple lymphadenopathy. Biopsy showed post-transplant lymphproliferative disorder, and he was treated successfully with rituximab. He is well without recurrence around 1 and a half years after treatment. Case 2: Thitry-eight-year-old male with pulmonary emphysema underwent double lung transplantation from a cadaveric donor. Four months after transplantation he showed multiple nodules in both lungs. Percutaneous biopsy showed post-transplant lymphproliferative disorder, and he was treated successfully with rituximab. He is well without recurrence more than 2 years after treatment. Case 3 : Twenty-four-year-old woman with lymphangioleiomyomatosis underwent living-related bilateral lobar lung transplantation. Three months after lung transplantation she presented cytomegalovirus viremia. Since it proved to be ganciclovir-resistant cytomegalovirus infection, she was treated with foscarnet successfully. She is well without recurrence about 2 and a half years after treatment.

A 71-year-old man, who had been receiving methotrexate (MTX) and prednisolone for the treatment of rheumatoid arthritis, was admitted to our hospital in August of 2004 with rectal hemorrhage. Histological examination of an ulcerative lesion of the rectum revealed diffuse large B-cell lymphoma (DLBCL). Chemotherapy with the CHOP regimen with dose reduction following cessation of MTX was initiated. However, the patient experienced septic shock secondary to febrile neutropenia and was then followed up without chemotherapy. The DLBCL rectal lesion regressed spontaneously thereafter and had resolved completely without treatment 2 years after the initial presentation, suggesting that the withdrawal of MTX led to regression of the DLBCL. The DLBCL in our patient is compatible with MTX-associated lymphoproliferative disorders. Immunoglobulin gene rearrangement and Epstein-Barr virus (EBV) infection found in tumor cells indicated that the EBV was involved in the monoclonal proliferation of B-cells in this patient whose immune function was suppressed by MTX therapy.

A 31-year-old man underwent kidney transplantation in 1996, and had been on immunosuppressants. In 2005, he presented with discomfort on swallowing. Swelling of the left tonsil and a mediastinal mass were observed. A biopsy of the left tonsil showed a monotonous proliferation of atypical lymphocytes suggesting post-transplant lymphoproliferative disorder (PTLD). The reduction of immunosuppressants did not result in any clinical improvements, and he developed bilateral cervical lymphadenopathy. A biopsy of the cervical lymph node also showed monotonous proliferation of TdT, CD3, CD5, CD7, CD10, and CD34-positive immature cells. T-cell receptor rearrangement, but not EBER, was detected. Based on these findings, monomorphic T-cell PTLD was diagnosed. He was treated with four different chemotherapeutic regimens without any clinical improvements, and the PTLD became leukemic. Chemotherapy consisting of L-asparaginase, vincristine, and dexamethasone (LVD) was then given, which resulted in massive tumor lysis. However, after two courses of LVD, complete remission was achieved. T-cell PTLD is a rare disorder, characterized by its refractoriness to chemotherapy as opposed to B-cell PTLD. Our experience suggests that L-asparaginase-based chemotherapy may improve the prognosis of T-cell PTLD.

A 65-year-old male had a two-month history of fever and fatigue. He had been receiving low dose MTX administration for about 2 years for rheumatoid arthritis. The blood chemistry findings showed elevated liver function including lactic dehydrogenase (LDH) levels. The quantified serum EBV-DNA level was 200 copies/105 peripheral blood mononuclear cells. Computed tomographic scan demonstrated splenomegaly and intraperitoneal mass lesions. One of the masses was biopsied. Some tumor cells showed a large Hodgkin cell-like appearance. These were CD3e-, CD20 +, CD30 +, CD15-, LMP1 +, EBNA2-, EBER-ISH + without imbalance of the kappa/lambda ratio. A diagnosis of MTX-associated B-lymphoproliferative disorder was made. Although the patient's fever subsided and the serum LDH levels were normalized after withdrawal of the MTX, the masses showed almost no change. Therefore, we administered rituximab weekly for a total of four doses, resulting in normalization of the serum EBV-DNA load and serum CD4/CD8 ratio. The masses persisted, however, so we carried out eight courses of R-CHOP therapy, which induced complete response without any episode of serious infection.

A 24-year-old Japanese male was admitted to our hospital because of lymphadenopathy in his left neck. He had a nine-year history of chronic renal failure, and had received an ABO-mismatched renal allograft and splenectomy in August 2000 after one year of hemodialysis treatment. After renal transplantation, he was treated with FK506, methylprednisolone (mPSL), and mycophenolate mofetil (MMF) as an immunosuppressants for his graft maintenance. On admission, April 2001, he underwent lymphadenectomy, and the immunohistochemical studies revealed that the tumor cells expressed EBV-LMP and EBNA-2 antigens with the histology of diffuse large B-cell lymphoma. Our diagnosis was an Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), and we reduced the dose of immunosuppressive agents and treated the patient with rituximab. In this case, there may have been two principal risk factors associated with PTLD: first, the patient was treated with higher levels of immunosuppressive agents because of the ABO-mismatched transplantation, and second, he was an EBV-seronegative recipient at the time of pretransplantation.

We report a case of Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) after allogeneic bone marrow transplantation (allo-BMT) from a partially mismatched related donor for acute lymphocytic leukemia, which was treated successfully by donor lymphocyte infusion (DLI). A 54-year-old woman in first complete remission from acute lymphocytic leukemia received an unmanipulated bone marrow transplant from an HLA-A 1-locus-mismatched sibling donor after preconditioning with cyclophosphamide and total body irradiation. Prophylaxis against graft-versus-host disease (GVHD) was done with tacrolimus and short-term methotrexate. Skin GVHD (grade I) occurred on day 36, but this subsided spontaneously without treatment. On day 61, rapidly progressive cervical lymphadenopathy with fever developed. Lymph node biopsy revealed lymphoid cell proliferation, which was positive for LCA, L26 and LMP-1. A diagnosis of EBV-LPD was made. After withdrawal of the tacrolimus, DLI (1 x 10(6) CD3 cells/kg) resulted in remission. This case suggests that even in the absence of risk factors such as severe GVHD, intensive immunosuppressive therapy and ATG administration, allo-BMT from an HLA 1-locus-mismatched related donor can be complicated by EBV-LPD, and that reduction of immunosuppressive therapy and DLI can be an effective treatment for it.

The authors experienced granular lymphocyte-proliferative disorder (GLPD) with increased lymphocyte and CD4 cell counts after HIV treatment with a protease inhibitor indinavir in a 51-year-old male AIDS patient. GLPD proved to be the chronic type, but we could not differentiate whether it was the T-cell type or the NK-cell type. EB virus was found to be activated and its chronic activity was suggested. We should note in this case that EB virus was involved in the GLPD onset and that GLPD followed the treatment with a protease inhibitor.

A 56-year-old female was admitted on November 1995 to our hospital because of the abnormal shadow on her chest X-ray. Although the chest X ray film revealed diffuse reticulonodular shadows in the bilateral lung fields and right hilar lymphadenopathy, she had not any complaints. Furthermore, mediastinal lymphadenopathy and polyclonal hypergammaglobulinemia were noted. For a further examination, transcutaneous thoracoscopic lung biopsy was performed on August 1996. The lung specimens showed a interstitial infiltration of small lymphocytes exclusively around bronchioles. And the diagnosis of lymphocytic interstitial pneumonia (LIP) was made. She had been suffered from bronchial asthma for 27 years. This is the first report of LIP accompanied with bronchial asthma. Its relationship between LIP and bronchial asthma remains unclear. In the 2 years of follow-up, she remained asymptomatic with unchanged chest radiogram. And her pulmonary function was preserved for the 2 years. But lymphocytic interstitial pneumonia may induce malignant lymphoproliferative disease potentially, we should carefully follow up.

We report two cases of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) after allogenic bone marrow transplantation which were conditioned with regimens including antithymocyte globulin (ATG). The first case was a 31 year-old man which severe aplastic anemia who was transplanted from HLA-matched unrelated donor conditioned with total lymphoid irradiation (TLI)/ cyclophosphamide/ATG and prophylactic administration of ganciclovir Grade I acute GVHD improved in response to cyclosporine (CsA). LPD as a polyclonal epipharyngeal mass developed at day +53 and spontaneously regressed along with the withdrawal of CsA. Second case was a 11 year-old boy with acute myelomonocytic leukemia (FAB:M4E). He was transplanted from HLA B locus mismatched mother conditioned with total body irradiation (TBI)/busulfan/L-PAM/ATG. He showed grade IV acute GVHD, which was controlled by steroids and FK-506. LPD as a monoclonal intestinal lymphoma was diagnosed at day +82, and he was unsuccessfully treated with ganciclovir, acyclovir, chemotherapy and transfusions of EBV-specific cytotoxic lymphocytes in addition to discontinuation of immunosuppressants, and died at day +18 due to sepsis and multiple cerebral infarction. Early detection and introduction of appropriate treatment for post bone marrow transplantation LPD is necessary.

To clarify the characteristics of chronic active EB virus infection (CAEBV) in Japan, and to investigate the relation between granular lymphocytes proliferative disorder (GLPD) and EB virus, we conducted a survey through a questionnaire conducted throughout Japan. Among 17 registered patients with CAEBV, 9 developed various types of lymphoproliferative disorders (LPDs), and 6 patients died of LPD. Among 72 cases of GLPD, 43 were CD3-positive and 27 were CD3-negative. EB viral DNA was detected in the peripheral mononuclear cells in 6 of 7 CD3-negative and 1 of 4 CD3-positive cases. These data suggest that EB virus-associated LPDs frequently derive from patients with CAEBV. However, some GLPD patients without CAEBV, especially for CD3-negative GLPD, are associated with EB virus infection. Therefore detection of EB viral DNA is very important to understand the pathogenesis of GLPD.