Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus shown to cause human diseases, such as adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy/tropic spastic paraparesis (HAM/TSP). Despite extensive study for three decades, it remains elusive how HTLV-1 induces these diseases. HTLV-1 mainly infects CD4 T cells, inducing dysregulation of the host immune system. Recent studies have uncovered the mechanisms of differentiation and function of CD4 T cells at the cellular and molecular levels, extending our understanding of the pathological conditions associated with HTLV-1 infection. This review focuses on recent advances in our understanding of the interaction between HTLV-1 and the host immune system, which should provide us a clue to the mechanisms of HTLV-1 mediated pathogenesis. [J Clin Exp Hematopathol 50(1) : 1-8, 2010]

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Adult T-cell Leukemia (ATL) is an aggressive malignant disease of CD4⁺ T-cells associated with human T-cell leukemia virus type I (HTLV-I). Prognosis of ATL patients is directly correlated to the subtype of ATL. Treatment of the aggressive forms (acute and lymphoma types) of ATL remains inadequate, as most ATL patients receive conventional chemotherapy without stem cell rescue. At present, LSG15 is the standard chemotherapy for the treatment of aggressive ATL, but the efficacy of LSG15 in most patients is transient. To prolong median survival time, additional therapies for maintenance of complete response (CR) are needed after achieving CR by induction chemotherapy. Improved outcome after allogeneic stem cell transplantation (allo-SCT), despite a high incidence of graft-versus-host disease, has been reported. Thus, allogeneic bone marrow transplantation and allogeneic peripheral blood SCT may have great potential for eradication of HTLV-1 and cure of ATL. Recently, reduced-intensity conditioning stem cell transplantation was also reported to be effective for ATL. Although several issues, including selection criteria for patients and sources of stem cells remain to be resolved, allo-SCT may be considered as a treatment option for patients with aggressive ATL. To evaluate whether allo-SCT is more effective than the standard chemotherapy (LSG15) for aggressive ATL, an upfront phase II clinical trial of JCOG-LSG is now being planned. Novel innovative targeted strategies, such as antiretroviral therapy, arsenic trioxide, nuclear factor-κB inhibitors, proteasome inhibitors, histone deacetylase inhibitors, several monoclonal antibodies including anti-CC chemokine receptor 4, anti-folate, purine nucleotide phosphorylase inhibitor, mTOR (mammalian target of rapamycin) inhibitor, bendamustine, small molecule Bcl-2 inhibitors and Tax-targeted immunotherapy, should be promptly studied in order to develop curative treatments for ATL in the near future. [J Clin Exp Hematopathol 50(1) : 9-25, 2010]

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The purpose of this study is to determine the same or different clonality between bilateral or recurrent lesions, or between or among ocular adnexal lesions and systemically multifocal lesions in 10 consecutive patients with ocular adnexal lymphoma : 8 had extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) and 2 had mantle cell lymphoma, observed from 1995 to 2008 at Okayama University Hospital. A discrete DNA fragment was generated by polymerase chain reaction amplification of the immunoglobulin heavy chain gene from all samples except for two samples of bilateral orbital mantle cell lymphoma lesions and one sample of the scalp skin MALT lymphoma lesion. The size of DNA fragments were the same between bilateral orbital or conjunctival lesions of 5 patients, between original and recurrent conjunctival lesions of one patient, between the orbital lesion and the oral cavity lesion in one patient, and among bilateral orbital lesions, buccal, rectum, and stomach lesions of one patient. Sequencing of the DNA fragments showed the same sequence between bilateral or recurrent or multifocal lesions in 8 patients except for one : the bilateral orbital lesions, rectum, and stomach lesions shared the same sequence while the buccal lesion had one nucleotide difference compared to the sequence shared by the other 4 lesions. In conclusion, bilateral, recurrent, or systemically multifocal lesions of ocular adnexal lymphoma shared the clonality between or among the lesions. [J Clin Exp Hematopathol 50(1) : 27-38, 2010]

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Localized Castleman's disease (CD) has been divided two types, the classical hyaline vascular (HV) type and the rare plasma cell (PC) type. Recently, we have reported two cases of IgG4-related disorder of the retroperitoneum showing PC type of CD. To further clarify the clinicopathological findings of CD of the retroperitoneum, eight such cases have been studied. A single lesion was located in the retroperitoneum (n=3), ureter (n=2) and renal hilum (n=2). One case had bilateral ureter lesions. The HV type of CD accounts for approximately 90% of cases. However, 50% (n=4) of our cases were the PC type of CD. Three of the four lesions of HV type had lymph node lesions, whereas all four PC type of CD were soft tissue masses. These clinicopathologic findings appear quite different from previous descriptions. Immunohistochemical study demonstrated numerous IgG4⁺ plasma cells accounting for more that 50% of IgG4⁺ cells in three cases of the four PC type of CD. Moreover, serum IgG4 concentration was increased in two of the four cases of PC type of CD that were examined. The serum interleukin-6 levels were within the normal range in two cases of PC type that were examined. The present study suggests that a majority of the PC type of CD arising in the retroperitoneum appears to be an IgG4-related disorder. [J Clin Exp Hematopathol 50(1) : 39-44, 2010]

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Constitutive activity of nuclear transcription factor κB (NF-κB) is observed in many pathological types of lymphoma that are associated with a poor clinical course. This suggests that NF-κB and pathways involving NF-κB are possible targets for successfully treating lymphoma. We examined 28 lymph nodes from 28 patients in whom follicular lymphoma was diagnosed from 1996 to 2006 at our institution, which were formalin-fixed and paraffin-embedded. The specimens were stained with an antibody that could recognize activated NF-κB and p65 to determine whether they were positive or negative for NF-κB activation. The clinical courses of the 28 patients were then correlated with the results of the NF-κB staining. The 10 men and 18 women had a mean age of 57.3 years (range, 25-87 years). By follicular lymphoma grade, 10 patients had grade 1, 16 had grade 2, and 2 had grade 3a. Ten patients died due to lymphoma. NF-κB was positive in 6 of the 28 cases. Analysis of the positive and negative staining groups while taking into account the clinical course, sex, age, grade of follicular lymphoma, prognostic index, CD10, CD23, Bcl-2, karyotype t(14;18), and survival showed that no significant differences. Six of the 28 lymph nodes (21.4%) exhibited consistent NF-κB activity. Three of the eleven cases that transformed to aggressive lymphoma were positive for activated NF-κB. Further research to clarify the significance of constitutive NF-κB activity in follicular lymphoma is therefore warranted. [J Clin Exp Hematopathol 50(1) : 45-50, 2010]

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We report a case of acute mixed-lineage leukemia, as seen in a 65 year-old female with MLL gene amplification and biallelic loss of wild type p53 gene. The diagnosis was based on the findings that her bone marrow (BM) blasts expressed cytoplasmic CD3 (cyCD3), B-lineage antigens and myeloid antigens accompanied by clonal rearrangements of IgH gene. The BM blasts consisted of small-sized peroxidase-negative blasts (97%) and large-sized peroxidase-positive blasts (3%). The BM blasts showed a complex “karyotype,” including dic(17;20) (p11;q11), -5 and add (11q23). Add (11q23) abnormality was found in sideline karyotypes as well as the stemline abnormality of dic(17;20) (p11;q11). For the p53 gene, which is located at 17p13, fluorescence in situ hybridization analysis showed the loss of one of two p53 alleles. Furthermore, polymerase chain reaction-single-strand conformation polymorphism and following nucleotide sequencing showed that the p53 gene was mutated at codon 215, leading to an amino acid substitution from Ser to Arg. For the MLL gene, southern blot analysis showed that the MLL gene locus was amplified but not rearranged at its breakpoint cluster region, which is usually rearranged in balanced translocations with many partner genes. These findings suggest that MLL gene amplification may in this case be based on the genetic instability caused by the preceding biallelic loss of the wild type p53 gene. [J Clin Exp Hematopathol 50(1) : 51-58, 2010]

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On rare occasions, secondary Epstein-Barr virus (EBV)-associated B cell lymphoma can develop in a patient with angioimmunoblastic T-cell lymphoma (AITL). We report a case of a 66-year-old Japanese woman who developed diffuse large B-cell lymphoma (DLBCL) in her small intestine after chemotherapy for AITL. She was found to have panperitonitis due to perforation of the small intestine. Partial ileectomy specimen showed DLBCL cells infiltrating into the intestinal wall. In situ hybridization for EBV-encoded RNA revealed positivity in the lymphoma cells. The lymph nodes diagnosed as AITL were negative for EBV infection and there was no coexistence of B cell neoplasms in them. We thought small bowel perforation in this case was caused by EBV-associated B cell lymphoma secondary to AITL. Our case showed a remarkable deficiency of cellular immunity after chemotherapy, which we postulate was related to the cause of occurrence of B-cell lymphoma. [J Clin Exp Hematopathol 50(1) : 59-63, 2010]

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Nasal natural killer (NK)/T cell lymphoma is an aggressive subtype of non-Hodgkin lymphomas, usually with a broad morphological spectrum, necrosis and angioinvasion, and is closely associated with Epstein-Barr virus (EBV) infection. We herein report a unique case of nasal NK/T cell lymphoma with frequent complete remission and relapse 12 years of follow up. A 9-year-old girl was diagnosed as having nasal NK/T cell lymphoma in 1995. The histological features were typical with diffuse lymphoid cell infiltration and angiocentric destruction. At the time of third relapse, however, biopsy showed infiltration of small sized lymphoid cells without necrosis and ulceration. These lymphoid cells were positive for both NK/T cell phenotype and EBV-encoded small RNAs. The tumor regressed spontaneously after biopsy and her clinical symptoms subsided. When she was admitted to the hospital in 2006 she had an extensive destructive lesion in the nasal cavity. These findings represent a rare case, in which histological findings changed in each time of relapse. [J Clin Exp Hematopathol 50(1) : 65-69, 2010]

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A 61-year-old male who worked as a frozen chicken processor was referred to us with necrotizing skin ulcers on his hands and feet. Serum IgG and IgA levels were 4,355 mg/dl and 605 mg/dl, respectively. Serum immunoelectrophoresis demonstrated M-bows for anti-IgGλ and anti-IgAκ. Bone marrow aspirate revealed approximately 31% atypical plasma cells. Cryoglobulin was identified in his serum. Cryoglobulin immunoelectrophoresis revealed monoclonal IgGλ paraproteins. The diagnosis was IgGλ type multiple myeloma and concurrent IgAκ type monoclonal gammopathy of undetermined significance with type I cryoglobulinemia. A skin biopsy taken from an involved site showed amorphous eosinophilic material occluding small vessel lumens. There was a good response after one cycle of chemotherapy consisting of vincristine, adriamycin and dexamethasone (VAD). There was a concurrent decrease in serum cryoglobulin levels ; this was associated with re-epithelialization of skin ulcers. Two years later, multiple myeloma progressed during a maintenance therapy of melphalan and prednisolone. Treatment with bortezomib following VAD resulted in a transient response. Serum IgG levels increased to 7,200 mg/dl, in contrast to a decrease in IgA levels to 7 mg/dl. The increase corresponded with the reappearance of skin ulcers. Shortly thereafter, the patient died of multiple myeloma. [J Clin Exp Hematopathol 50(1) : 71-74, 2010]

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