Pathogenetic roles of human herpesvirus (HHV)-6 in lymphoproliferative diseases have been of continued interest. Many molecular studies have tried to establish a pathogenic role for HHV-6 in lymphoid malignancies. However, whether HHV-6 plays a role in these pathologies remains unclear, as positive polymerase chain reaction results for HHV-6 in those studies may reflect latent infection or reactivation rather than presence of HHV-6 in neoplastic cells. A small number of studies have investigated HHV-6 antigen expression in pathologic specimens. As a result, the lack of HHV-6 antigen expression on neoplastic cells argues against any major pathogenic role of HHV-6. The role of HHV-6 in childhood acute lymphoblastic leukemia (ALL) has also been of interest but remains controversial, with 2 studies documenting higher levels of HHV-6 antibody in ALL patients, and another 2 large-scale studies finding no significant differences in HHV-6 seroprevalences between ALL patients and controls. Alternatively, HHV-6 is increasingly recognized as an important opportunistic pathogen. HHV-6 reactivation is common among recipients of allogeneic stem cell transplantation (SCT), and is linked to various clinical manifestations. In particular, HHV-6 encephalitis appears to be significant, life-threatening complication. Most HHV-6 encephalitis develops in patients receiving transplant from an unrelated donor, particularly cord blood, typically around the time of engraftment. Symptoms are characterized by short-term memory loss and seizures. Magnetic resonance imaging typically shows limbic encephalitis. Prognosis for HHV-6 encephalitis is poor, but appropriate prophylactic measures have not been established. Establishment of preventive strategies against HHV-6 encephalitis represents an important challenge for physicians involved with SCT. [J Clin Exp Hematopathol 49(2) : 57-67, 2009]

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Cladribine is approved to be used in 24-hour continuous infusion for the treatment of low-grade lymphoma by the Ministry of Health, Labor and Welfare in Japan. Pharmacokinetic studies showed that the antitumor activity of cladribine by 2-hour infusion should be comparable to that given by continuous infusion. The safety and anti-tumor activity of short infusion of cladribine was shown in hairy cell leukemia, chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma in Europe. We therefore underwent a pilot study to confirm the safety and efficacy of cladribine given by 2-hour infusion for Japanese patients with relapsed or refractory indolent B-cell lymphoma. Cladribine at a dose of 0.09 mg/kg was administered in 2-hour intravenous infusion for 5 consecutive days. The treatment was repeated at a 28-day interval for at least 2 cycles, and its efficacy and toxicity were investigated. Fourteen patients were entered into this study. Eight patients (57%) responded to cladribine, including 2 (14%) complete response (CR) and 6 (43%) partial response (PR). The median duration of response was 20+ and 21+ months for CR, and 12 months ranging from 3 to 34 months for PR, respectively. Grade 3 or 4 neutropenia and lymphocytopenia occurred in 43% and 71% of patients, respectively, but there was no febrile neutropenia or opportunistic infection associated with cladribine treatment. No other adverse events greater than grade 3 were encountered. The tumor response and degree of toxicity were comparable with those observed in cladribine treatment given by continuous infusion at a same dose. Cladribine can be administered in 2-hour infusion in an outpatient clinic and is therefore quite convenient for patients. [J Clin Exp Hematopathol 49(2) : 69-75, 2009]

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The purpose of this study is to report the role of whole-body 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography fused with computed tomography (PET/CT) after immunocytochemical and clonal diagnosis of intraocular lymphoma with vitrectomy cell blocks. Eleven patients with intraocular lymphoma were involved in this study : 6 patients presented with vitreous opacity in both eyes and 5 patients presented with unilateral involvement. The concurrent retinal lesions were present in 6 eyes of 5 patients. Brain lymphoma was diagnosed in 7 of the 11 patients : simultaneous with eye lesions in one patient, following the eye lesions in 3, and prior to the eye lesions in 3. Vitrectomy was done in 17 eyes of the 11 patients, and vitrectomy cell blocks were processed for immunocytochemical staining and clonality analysis by polymerase chain reaction amplification of the immunoglobulin heavy chain gene. The 7 most recent patients were evaluated with fluorodeoxyglucose whole-body PET/CT. Immunocytochemical staining of vitrectomy cell blocks in all patients showed large cells which were positive for CD20 and Ki-67 but negative for CD3, consistent with diffuse large B-cell lymphoma. The size and sequence of amplified fragments of the immunoglobulin heavy chain gene were different between the lesions of both eyes in one patient while they were the same in another patient. PET/CT after the diagnosis by vitrectomy revealed abnormal uptake in the cerebellum of two patients, in the eye as a recurrent lesion of one patient, and in both eyes as residual retinal lesions of one patient. In conclusion, PET/CT could be considered as a method to confirm brain lymphoma or as a reference for initiating additional therapy in the case of eye recurrence or residual lesions after vitrectomy. The clonality of lymphoma cells was variable between the lesions in both eyes. [J Clin Exp Hematopathol 49(2) : 77-87, 2009]

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To clarify the clinicopathological findings of B-cell lymphoma associated with Sjögren's syndrome (SJS) among Japanese Patients, 15 individuals with this disease were studied. The patients, 14 females and one male, ranged in age from 41 to 73 years with a median age of 56 years. These lymphomas arose not only in the salivary gland (n=4) but also in other mucosal extranodal sites (n=5). Histologically, six cases were marginal zone B-cell lymphoma (MZBL) of the mucosa-associated lymphoid tissue (MALT) type, three cases were diffuse large B-cell lymphoma (DLBCL) + MALT type lymphoma, two cases were nodal MZBL and one case each was small lymphocytic lymphoma, Burkitt's lymphoma, CD10⁺ DLBCL and DLBCL + nodal MZBL. Using in situ hybridization, numerous Epstein-Barr virus⁺ tumor cells were detected only in the case of Burkitt lymphoma. There were no human-herpes type 8⁺ tumor cells in any of the 15 cases. There was no API2-MALT1 fusion transcript in any of the eight cases examined. B-cell lymphoma associated with SJS also frequently affected extranodal organs in patients from Japan as well as from patients in Western countries. The majority of B-cell lymphomas in patients with SJS also appear to be low-grade MZBLs or high-grade lymphomas probably derived from MZBL both in Western countries and in Japan. [J Clin Exp Hematopathol 49(2) : 89-95, 2009]

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This study examined the relationship between external environmental factors and Epstein-Barr virus (EBV) infection in nasal natural killer (NK)/T-cell lymphomagenesis. Archival paraffin sections from 134 cases of nasopharyngeal lymphomas in the northeast of China were investigated by in situ hybridization of EBV-encoded small RNA-1 (EBER-1) and by immunohistochemistry of the status of programmed cell death (PCD). The cases examined included 74 (55.2%) cases of NK/T-cell lymphomas (NKTCL) in T-cell and NK-cell neoplasms as well as 32 (23.9%) cases of B-cell neoplasms (B-MLs) and 9 (6.7%) cases of carcinomas. These cases indicated a significant dominant occurrence of NKTCL in the nasal cavity and of B-MLs in the pharynx. Many EBV-associated NKTCLs were seen in the nasopharynx, all three cases of EBV-associated B-MLs were in the nasal cavity and all three cases of EBV-associated carcinomas were only seen in the pharynx. The low number of NKTCL cases showing little or no EBV association, together with the existence of EBER-1-free lymphoma cells in EBV-associated NKTCLs, suggested EBV-related lymphoma cell expansion during lymphomagenesis. Peculiar necrosis, frequently observed in NKTCLs, was due to accelerated PCD. This PCD was autophagic cell death as judged by labeling of Beclin-1 and LC3, which possibly occurred due to EBV infection, when apoptosis was suppressed by survivin. Very minute squamous carcinomas, observed in 10 of 23 cases of NKTCLs with residual epithelia that were survivin-positive but not EBV-associated suggested that carcinogenesis occurred before lymphomagenesis. These data suggest that external environmental oncogenic factors initiate nasopharyngeal carcinomas and lymphomas whereas EBV infection promotes them. [J Clin Exp Hematopathol 49(2) : 97-108, 2009]

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The assessment of residual tumors after treatment of malignant lymphoma (ML) is often difficult. Here we report a case of non-Hodgkin's lymphoma with a huge sacral tumor. After chemotherapy and following radiation therapy, a residual mass was detected on magnetic resonance imaging (MRI). However, a hypermetabolic lesion in the sacrum disappeared on ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) and clinically the patient was considered to achieve complete remission. Seven months after the completion of radiation therapy, a new tumor-like lesion in the sacrum developed on MRI, but hypermetabolic lesions were not detected on ¹⁸F-FDG-PET. Recurrence of lymphoma was denied by open biopsy of the lesion. ¹⁸F-FDG-PET has been of widespread use not only for staging but for post-treatment assessment of ML. Although MRI is a standard imaging tool for the assessment of bone involvement of ML, there have been few reports documenting the results of comparative studies on the usefulness of ¹⁸F-FDG-PET and MRI for the evaluation of residual mass in bone involvement of ML. The present case suggests that ¹⁸F-FDG-PET is superior to MRI not only in the evaluation of a residual mass but in the judgment of recurrence after treatment of such patients. [J Clin Exp Hematopathol 49(2) : 109-115, 2009]

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A 20-year-old man with a primary non-seminomatous mediastinal germ cell tumor (yolk sac tumor and immature teratoma) developed hemophagocytic syndrome (HPS) three months after surgical resection. Around the same time, the patient was found to have bone metastases of the germ cell tumor. No other hereditary or acquired diseases related to HPS were found. The thrombocytopenia was refractory to corticosteroid therapy but improved after chemotherapy performed for germ cell tumor progression. Only three cases of germ cell tumor associated with reactive hemophagocytosis have been previously reported. Successful treatment of the present case by chemotherapy for HPS suggests a close relationship between this rare complication and germ cell tumor. [J Clin Exp Hematopathol 49(2) : 117-120, 2009]

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We report an autopsy case of Fabry's disease with cardiac manifestations. Electron microscopic examination of rectal biopsy specimens revealed lamellar bodies and osmiophilic irregular bodies. Biochemical analysis showed low enzymatic activity of α-galactosidase A in plasma fluid. Microscopic examination on autopsy showed marked hypertrophy and vacuolation of cardiac muscle cells. Intracytoplasmic vacuolation was also found in glomerular epithelial or endothelial cells and smooth muscle cells of renal arteries, Meissner's plexus in the submucosa of small and large intestines, and smooth muscle cells of arterioles in the cerebrum. The diagnosis of Fabry's disease was made. The patient died suddenly of cardiomyopathy. [J Clin Exp Hematopathol 49(2) : 121-123, 2009]

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