Elevated expression of N-myc downstream regulated gene 1 protein in glioblastomas reflects tumor angiogenesis and poor patient prognosis.

N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis.

Elevated expression of transforming acidic coiled-coil-containing protein 3 (TACC3) reflects aggressiveness of primary central nervous system lymphomas.

Transforming acidic coiled-coil-containing protein 3 (TACC3) plays an important role in centrosome/microtubule dynamics. Deregulation of centrosomes/microtubules causes mitotic spindle defects, leading to tumorigenesis. However, the correlation between TACC3 and primary central nervous system lymphomas (PCNSLs) is unknown. The present study investigated the association between the immunohistochemical expression of TACC3, p53, and Ki-67, and the clinical factors in 40 PCNSLs. We evaluated the staining of TACC3 based on the histoscore (H-score) that contains a semiquantitative evaluation of both the intensity of staining, and the percentage of positive cells. Expression level of each component was classified as low or high according to the median H-score value. Patients with PCNSLs were divided into groups depending on TACC3 expression levels (no expression and low expression, 18; high expression, 22). Disease-free survival and overall survival of patients with high TACC3 expression were significantly shorter (p < 0.01 and p < 0.05, respectively). These results suggest that elevated expression of TACC3 could reflects aggressiveness of primary central nervous system lymphomas.

Gliosarcoma with unusual glial components: Two case reports.

Gliosarcoma is characterized by the presence of alternating lesions of glial and mesenchymal components. Although many mesenchymal components have been reported, there are few reports on glial components. We here report two cases of gliosarcoma. Case 1 was a 42-year-old woman with right hemiparesis and motor aphasia. Magnetic resonance imaging (MRI) identified a tumor in the left frontal lobe. Pathological analysis of the tumor removal specimen revealed gliosarcoma, with a glial component resembling pleomorphic xanthoastrocytoma. Postoperatively, radiotherapy and chemotherapy were conducted, and the patient was symptom-free over 12 months after surgery. Case 2 was a 67-year-old woman with a consciousness disorder and left hemiparesis. MRI revealed a tumor in the right frontal lobe. Pathological analysis of the first tumor removal specimen identified gliosarcoma, with a glial component characterized by large tumor cells. Additionally, the Ki-67 labeling index of the glial component was greater than that of the mesenchymal component, and molecular genetic analysis disclosed a mutation in the telomerase reverse transcriptase (TERT) gene (TERT). Chemotherapy and radiotherapy were performed. Four months later, MRI revealed recurrence, and the second surgery was performed. Pathological analysis revealed giant cell glioblastoma without TERT mutation. The patient died due to tumor progression 12 months after the first surgery. It is essential to continue histopathological evaluation of glial components, and further genetic evaluation on gliosarcoma is required.

Myxoepithelioid tumour with chordoid features: a clinicopathological, immunohistochemical and genetic study of 14 cases of SMARCB1/INI1-deficient soft-tissue neoplasm.

AIMS: Complete loss of SMARCB1/INI1 in soft-tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity. METHODS AND RESULTS: We analysed 160 cases of SMARCB1/INI1-deficient soft-tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α-smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow-up; four patients developed local recurrence and/or metastases. CONCLUSION: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma-like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumours.

Correlation between histone acetylation and expression of Notch1 in human lung carcinoma and its possible role in combined small-cell lung carcinoma.

Combined small-cell lung carcinoma (cSCLC) is composed of small-cell lung carcinoma (SCLC) admixed with non-small-cell lung carcinoma (NSCLC). Evaluating the molecular differences between SCLC and NSCLC could lead to a better understanding of the pathogenesis of such neoplasms. Therefore, in this study, we investigated the correlation between histone acetylation and Notch1 expression in lung carcinoma. Using chromatin immunoprecipitation (ChIP) assay, we measured the level of acetylated histone H3 around the promoter region of Notch1 in SCLC and NSCLC cells. We then treated SCLC cells with trichostatin A (TSA) and characterized the level of histone H3 acetylation at Notch1. In addition, TSA-treated cells were injected into immune-compromised mice, for analysis of the ex vivo tumor xenograft phenotype. The level of acetylated histone H3 surrounding the Notch1 promoter was lower in lung cancer cells not expressing Notch1. Tumors originated from TSA-treated SCLC cells occasionally formed an epithelial-like glandular arrangement of cells; with Notch1 expression and decreased expression of neuroendocrine (NE) markers. Histone deacetylation around the promoter region of Notch1 inhibits Notch1 protein expression in SCLC and the restoration of Notch1 expression in SCLC leads to the concurrent appearance of epithelial-like areas within the SCLC, which could provide a possible mechanism for histogenesis of cSCLC.

Detection of serous precursor lesions in resected fallopian tubes from patients with benign diseases and a relatively low risk for ovarian cancer.

The frequency of ovarian cancers in Japan has increased; however, doubts have been raised concerning the mechanism by which high-grade serous adenocarcinomas (HGSCs) arise. Conventionally, HGSC is thought to originate from the ovarian surface epithelium or epithelial inclusion cyst. However, recent data indicate that HGSCs may in fact develop from precursor lesions in the fallopian tube, including epithelia with a p53 signature, serous tubal intraepithelial carcinomas (STICs), secretory cell outgrowths (SCOUTs), and tubal intraepithelial lesions in transition (TILT). Here, we determined the frequency of these fallopian tube precursors in surgically excised samples from 123 patients with benign pelvic diseases. We identified 12 cases with a p53 signature (9.7%), 26 with observable SCOUTs (21.1%), and 4 with TILT (3.2%), but no STIC cases. Although the lifetime risk for developing ovarian cancer is only around 1.4% for women without germ-line mutations, it is important to evaluate the presence of precursor lesions to understand HGSC pathogenesis better. Taken together, salpingectomy appears to be an option for women who are past their childbearing age and plan to undergo elective pelvic surgery. To our knowledge, this is the first study to investigate the presence of these specific precursors post-salpingectomy in low-risk patients.

Gliosarcomas arising from the pineal gland region: uncommon localization and rare tumors.

Gliosarcomas are a variant of glioblastomas and present a biphasic pattern, with coexisting glial and mesenchymal components. In this study, two unusual cases are presented. Case 1 is a 52-year-old woman with a headache and memory disturbance for a month. Case 2 is an 18-year-old man with a headache lasting two weeks. In both cases, an MRI revealed enhancing T1-low to iso, T2-iso to high intensity lesions in the pineal gland region. Histologically, in case 1, the tumor showed spindle cell proliferation with disorganized fascicles and cellular pleomorphism. Tumor cells variously exhibited oncocytic transformation. Immunohistochemically, most of the spindle tumor cells were positive for myoglobin and desmin. Some of the tumor cells were positive for GFAP and S-100 protein. On the other hand, all tumor cells were positive for CD133, Musashi1, and SOX-2 which are the markers of neural stem cells. In case 2, the tumor showed monotonous proliferation of short spindle cells with disorganized fascicles and cellular atypism. The morphological distinction between glial and mesenchymal components was not apparent. Immunohistochemically, most of the spindle tumor cells were positive for desmin. Glial tumor cells that were dispersed within the sarcoma as single cells were positive for GFAP. In addition, all tumor cells were positive for CD133, Musashi1 and SOX-2. Based on these microscopic appearances, and immunohistochemical findings, these cases were diagnosed as gliosarcomas arising from the pineal gland region. These results also indicated that pluripotential cancer stem cells differentiated into glial and muscle cell lines at the time of tumor growth. In a survey of previous publications on gliosarcoma arising from the pineal gland, these cases are the second and third reports found in English scientific writings.

Comparison of the accuracy of breast cytological diagnosis at seven institutions in southern Fukuoka Prefecture, Japan.

OBJECTIVE: Cytological examination is inexpensive and relatively simple to carry out and deserves utilization in breast cancer screening. We investigated the status of cytological diagnosis at seven facilities in southern Fukuoka Prefecture, Japan. METHODS: We collected data on the criteria for cytological judgments and status of breast cytological diagnosis at seven different facilities in this region. RESULTS: Among 5693 individuals who underwent breast cytological examination, analyses were conducted on 1250 individuals (22.0%) in whom cytological diagnoses were confirmed by histological diagnoses. Among these patients, cytological diagnosis had an absolute sensitivity of 71.9%, a specificity of 76.0%, a false-negative value of 6.7% and a false-positive value of 0.08%. At three facilities with relatively large numbers of cases (>300), excluding a facility for specialized breast disease, similar trends of high complete sensitivity (94.3, 95.6 and 97.1%, respectively) and low absolute sensitivity (60.4, 74.8 and 57.2%, respectively) were found. No false-negative or false-positive cases were seen in individual facilities with relatively low numbers of cases (<150). CONCLUSIONS: The accuracy of cytological diagnosis at the facilities we surveyed was relatively high compared with the goals of assessment of diagnostic accuracy. However, the performance was dependent on the facility type, i.e. number of cases, staff involved and whether it was specialized or not, making the diagnosis specific for this region. We recommend that management of the accuracy of cytological diagnosis be undertaken jointly by multiple facilities to establish systems in Japan that lead to more useful diagnostic tools.

Malignant melanoma arising in a plaque-type blue nevus.

Blue nevus is a type of dermal melanocytosis and has a variety of clinicopathological characteristics. A few particular variants are generally accepted as discrete clinicopathological entities. Plaque-type blue nevus (PTBN) is one of the variants of blue nevus. PTBN presents at birth or arises in early childhood, and shows a combination of features found in common blue nevus and cellular blue nevus. In this report, we describe a malignant melanoma arising in association with a PTBN in a 65-year-old male. The tumor appeared as a well circumscribed but partially infiltrative upper-abdominal mass, and was heavily pigmented and consisted of a spindle or epithelioid highly cellular component with mitotic figures and tumor necroses. In the skin around the tumor, multiple pigmented lesions were scattered around the trunk, and these had been recognized since childhood. Histologically, skin lesions showed sparse and wide distribution of the dendritic melanocytes with dense melanin pigments and melanophages between the collagen bundles from the reticular dermis to the abdominal skeletal muscle. We also discuss the histological features and clinical course in our patient in context with previous related literature.

[From the position of a private sector hospital: ISO 15189 acquisition by a clinical laboratory, and quality management system deployment in the whole hospital].

St. Mary's Hospital Medical Inspecting Center acquired ISO 15189 authorization in December, 2007. In the process of authorization acquisition, measures were taken to improve various quality issues, and a marked effect was seen in patient services and medical safety control. Furthermore, we tried to improve ward nursing management using ISO, drew up standard operating procedures through detailed job analysis, and enabled ward operation standardization. In this paper, while describing the effect of ISO 15189 on clinical examinations, we refer to the significance of improving quality of hospital management which our clinical laboratory lead to.

Left atrial myxoma mimicking papillary fibroelastoma.

A 67-year-old woman was referred to our hospital with a diagnosis of deep vein thrombosis due to surgery for left patellar fracture. Deep vein thrombosis resolved with thrombolytic therapy. Transthoracic echocardiogram revealed a mobile left atrial tumor. Transesophageal echocardiography showed a fragile tumor with multiple fronds, implying a papillary fibroelastoma. Because this patient had a history of cerebral embolism, urgent surgery was scheduled. The excised tumor showed a sea anemone-like appearance in saline, which was similar to that of a papillary fibroelastoma. However, histological examination revealed the features of a myxoma and not papillary fibroelastoma. Herein, we illustrate a very rare case of left atrial myxoma with papillary fibroelastoma-like features in terms of both echocardiographic and gross findings.

Case of polycythemia vera with unusual organizing pneumonia mimicking the clinical features of military tuberculosis and possibly caused by the involvement of neoplastic megakaryocytes.

Polycythemia vera (PV) is a clonal myeloproliferative neoplasm (MPN) of hematopoietic stem cells. Although the management of MPN patients generally focuses on the prevention of thromboembolic events caused by hypercoagulability, it is true that the patients with hematological malignancy often suffer from pulmonary diseases with atypical radiological patterns. We present here a 56-year-old woman with PV harboring a JAK2(V617F) mutation that had a diffuse reticulonodular pattern on chest radiography and was initially suspected of having military tuberculosis. Pathological assessment of a video-assisted thoracoscopic surgery lung biopsy revealed that the lesions were in fact organizing pneumonia (OP). Interestingly, pulmonary extramedullary hematopoiesis with a diffuse plugging of the alveolar blood capillaries by numerous atypical megakaryocytes was also observed around the granulation components. The histological findings of our case of unusual OP suggest that local activated neoplastic megakaryocytes and platelets played an important role in the development of spreading fibrotic lesions. JAK2 mutation or the preleukemic phase of MPN may accelerate the activation of megakaryocytes and result in the proliferative process of fibrosis.

Nuclear expression of MDM2 in hibernoma: a potential diagnostic pitfall.

Hibernoma is a rare benign adipocytic tumor composed of a proliferation of brown and white fat cells varying in their proportions. The tumor may also contain fat cells resembling lipoblasts, which makes it difficult to distinguish it from atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDLS). Although nuclear expressions of murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) are widely used as immunohistochemical surrogate markers for ALT/WDLS, the utility of these proteins in distinguishing between hibernoma and ALT/WDLS still remains to be elucidated. We evaluated immunohistochemical expressions of MDM2 and CDK4 in 10 hibernomas expressing uncoupling protein-1 (UCP-1), a mitochondrial protein transporter consistently expressed in brown fat cells, and lacking MDM2 gene amplification, which was analyzed by fluorescence in situ hybridization (FISH). In contrast to the data previously obtained, nuclear expression of MDM2 was observed in 100% (10/10 cases) of the hibernomas irrespective of the proportion of brown fat cells, whereas no cases were positive for CDK4. The tumors also showed almost concurrent expression of p53 (in 9/10 cases) and ubiquitin-specific-processing protease 7 (USP7) (in 10/10 cases), which deubiquitinates and stabilizes MDM2, potentially resulting in its nuclear expression without MDM2 gene amplification. MDM2 expression may thus be a diagnostic pitfall for hibernoma particularly in differentiating it from ALT/WDLS.

Granulocyte-colony stimulating factor-producing malignant phyllodes tumor of the breast: a rare case.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF)-producing tumors can cause leukocytosis despite an absence of infection. G-CSF-producing tumors have been reported in various organs such as the lung, esophagus, and stomach but rarely in the breast. We report a case of G-CSF-producing malignant phyllodes tumor of the breast. CASE PRESENTATION: An 84-year-old woman visited our hospital complaining of a lump in her left breast without fever and pain. Laboratory tests revealed elevated white blood cell (WBC) count and G-CSF levels. A malignant tumor of the breast was diagnosed by core needle biopsy. We performed a total mastectomy and sentinel lymph node biopsy. The tumor was identified as a G-CSF-producing malignant phyllodes tumor. Within 7 days after surgery, the patient's WBC count and G-CSF level had decreased to normal levels. She is alive without recurrence 13 months after surgery. CONCLUSIONS: We encountered a rare case of G-CSF-producing malignant phyllodes tumor of the breast. PET-CT revealed diffuse accumulation of FDG in the bone. Phyllodes tumors need to be differentiated from bone metastasis, lymphoma, and leukemia. We must be careful to not mistake this type of tumor for bone marrow metastasis.

Primary central nervous system lymphomas associated with chronic inflammation: diagnostic pitfalls of central nervous system lymphomas.

In recent years, the features of lymphomas associated with chronic inflammation, referred to as diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation (DLBCL-CI), have been elucidated. DLBCL-CI is an aggressive lymphoma occurring in the context of long-standing chronic inflammation and showing an association with Epstein-Barr virus. Fibrin-associated diffuse large B-cell lymphoma (F-DLBCL) was suggested as a new and unusual form of DLBCL-CI in the most recent version of the World Health Organization classification. From the perspective of genetics, DLBCL-CI was associated with frequent TP53 mutation, MYC amplification and complex karyotypes, but cases of F-DLBCL behaved indolently and showed a relatively lower genetic complexity. In the central nervous system (CNS), several examples of DLBCL-CI and F-DLBCL have been reported. As with DLBCL-CI outside the CNS, DLBCL-CI in the CNS is an aggressive lymphoma. However, the clinical outcome of F-DLBCL in the CNS is good. Immunohistochemistry for p53 and c-Myc in DLBCL-CI and F-DLBCL in the CNS showed similar findings of those outside the CNS. However, one aggressive case showed transitional genetics and morphology between F-DLBCL and DLBCL-CI. These findings suggest that some cases of F-DLBCL in the CNS might have the potential to progress to DLBCL-CI.

Pathomorphologic study of undifferentiated carcinoma in seven cases: relationship between tumor and pancreatic duct epithelium.

BACKGROUND/PURPOSE: By the time undifferentiated carcinoma is detected, it has formed a large mass, and it is reportedly difficult to pathologically observe its relationship with the pancreatic duct. In this study, we examined the pancreatic ducts of seven patients of surgical samples, and pathomorphologically investigated the relationship between the adenocarcinomatous and sarcomatous components and the pattern of tumor extension. In addition, we evaluated the usefulness of pancreatic juice cytology by comparison with the findings of the main pancreatic duct (MPD). METHODS: Seven primary undifferentiated carcinomas of the pancreas (from three male and four female patients with a mean age of 59 years) were analyzed. Histopathological evaluation was based on the WHO diagnostic criteria. Pancreatic juice cytology was performed and evaluated in two patients. RESULTS: All the undifferentiated carcinomas contained adenocarcinomatous and sarcomatous components, and two had a distinct glandular structure. However, we could not pathomorphologically confirm the continuity of the adenomatous with the sarcomatous components in any of the patients. Three undifferentiated carcinomas contained osteoclast-like giant cells. Pathological observation of the tumor and MPD was possible in three of the seven undifferentiated carcinomas. PanIN-3 was observed in the MPD of three patients, suggesting extension into the MPD. In one of these three, the tumor presented intraductal growth in the MPD, and preoperative pancreatic juice cytology revealed atypical cells with osteoclast-like giant cells. In the remaining two, the tumor extraductally compressed the MPD upward. CONCLUSIONS: Undifferentiated carcinoma showed two patterns of cancer extension: (1) invasion and expansive growth during the sarcomatous transformation of adenocarcinoma, and (2) intraductal extension. In addition, some undifferentiated carcinomas showed extension in the MPD. Of note, postoperative pancreatic juice cytology may be useful for the diagnosis.

[Case of overwhelming postsplenectomy infection (OPSI) with chronic hepatitis type C during peginterferon/ribavirin combination therapy].

A 61-year-old woman with a past history of splenectomy was admitted to our hospital because of high fever and loss of consciousness during interferon therapy for the treatment of chronic hepatitis type C. She died of multiple organ failure, and disseminated intravascular coagulation shortly after admission. The results of blood culture and the autopsy revealed sepsis due to streptcoccus pneumonia. The neutropenia and immunosuppression by interferon therapy induced overwhelming postsplenectomy infection (OPSI), a potentially rapidly fatal septicemia. When we perform treatment with immunosuppression such as interferon therapy or anticancer drug therapy to splenectomised patients, it is necessary to carry out pnemococcus vaccination. Splenectomy is performed for patients with thrombocytopenia of chronic hepatitis type C before interferon therapy. To avoid OPSI, partial splenic arterial embolization was discussed.

Combination Treatment of Artificial Dermis and Basic Fibroblast Growth Factor for Skin Defects: A Histopathological Examination.

UNLABELLED: This study examined a combination of artificial dermis and basic fibroblast growth factor (bFGF) to treat skin defects in clinical cases, and it histopathologically examined the effects on the conditions of recipient beds. MATERIALS AND METHODS: The subjects were 11 patients with skin defects from burn ulcers or traumatic ulcers. In each subject, debridement was performed and subsequently artificial dermis was applied to the defect. The bFGF was used on 1 side (combination therapy) of the artificial dermis and not used on the other side (artificial dermis monotherapy). A histopathological examination was performed on the granulation tissue collected from the recipient bed. The authors also measured skin hardness 6 months after the skin graft. RESULTS: Histologically, the combination therapy site had more extensive capillary angiogenesis than the monotherapy site. The combination therapy site also had capillary walls consisting of thick, large endothelial cells; fibroblast proliferation and activation; and more severe infiltration of inflammatory cells. Skin hardness after the graft was also much softer in the combination therapy. CONCLUSION: The results suggest the usefulness of this combination therapy in the preparation of skin graft beds to improve skin hardness after skin grafts in clinical cases.

A novel marker for Purkinje cells, KIAA0864 protein. An analysis based on a monoclonal antibody HFB-16 in developing human cerebellum.

In the search for immunohistochemical markers of the developing human brain, a monoclonal antibody, HFB-16, was raised against homogenates from the cerebrum of a 15-gestational-week-old (GW) human fetus and screened on paraffin-embedded human embryonic brain specimens. This antibody was particularly useful as a marker for Purkinje cells in the developing human cerebellum. Positive immunoreactivities with HFB-16 first appeared in the Purkinje cell layer at 17 GW. From 20 to 24 GW, positive immunoreactivities were found above the lamina dissecans. After 25 GW, dendrites of Purkinje cells were found with the HFB-16 antibody, and the nerve fibers of the Purkinje cells became positive after 35 GW. Neurons in the dentate nucleus and external and internal granular layers reacted negatively to this antibody. After 1 year, when the external granular layer faded out, the dendrites of the Purkinje cells reached the pial surface of the cerebellum, and nerve fibers began to develop in the white matter. This antibody was also useful for characterization of components in heterotopic neurons found in various anomaly syndromes such as trisomy 13. Expressional cloning indicated the antigen against HFB-16 to be human KIAA0864 protein, which is supposed to be an alternative splicing product of p116Rip, whose function has not yet been elucidated. The antigenicity of the KIAA0864 protein was confirmed using human cDNA of the KIAA0864 protein, a protein expression vector, and an HFB-16 antibody.

Splenic large B-cell lymphoma in patients with hepatitis C virus infection.

Hepatitis virus infection, especially type C (hepatitis C virus [HCV]), has been suggested to be one of the important pathogenetic factors for low- and high-grade B-cell lymphoma, including splenic marginal zone lymphoma (SMZL), in southern Europe. Here, we analyzed the incidences of HCV and hepatitis B virus (HBV) infections, and the clinicopathologic features in 29 cases of splenic diffuse large B-cell lymphoma (DLBCL), 10 SMZL, 3 splenic mantle cell lymphoma, 1 hairy cell leukemia, 13 B-chronic lymphocytic leukemia, and 12 hepatosplenic T-cell and natural killer cell lymphoma. Fifteen (51.7%) splenic DLBCL cases were HCV antibody-positive, and another 6 (20.7%) had the HBsAg. The incidence of each was significantly (P < .01) higher than those of HCV (9.3%) and HBV (1.9%) infections in 54 node-based DLBCL cases. Four examined HCV-positive DLBCL cases showed no type II cryoglobulinemia. HCV RNA was detected in fresh tumor tissues from 6 of 7 examined DLBCL cases, and HBV DNA was present in another 2, as evaluated by real-time polymerase chain reaction. Immunohistologically, tumor cells in 5 of 7 examined DLBCL cases showed intracytoplasmic reactions for HCV NS3 and E2 proteins and the viral receptor CD81. Of 6 cases, 2 showed an intranuclear reaction for the HBV surface protein. By Southern blot analysis, no rearrangement of the Bcl2 gene was detected in the tumor tissue of 7 HCV-positive DLBCL cases. For the other types of malignant lymphoma, 1 case each of SMZL (10%) and hepatosplenic T-cell and natural killer cell lymphoma (8.3%) showed HCV infection. In conclusion, persistent human hepatitis virus infections, especially HCV, may play an important role in the tumorigenesis of splenic DLBCL in Japan.