Satoko Shimada

Nodal T/NK‐cell lymphoma of nasal type: a clinicopathological study of six cases

Aims:  To investigate the clinicopathological features of six unusual cases of nodal CD56+ and Epstein–Barr virus (EBV)+ T/natural killer (NK)‐cell lymphoma, a putative nodal counterpart of nasal NK/T‐cell lymphoma (nodal T/NK‐cell lymphoma of nasal type) in comparison with nasal NK/T‐cell lymphoma with secondary lymph node involvement (n = 24) and peripheral T‐cell lymphoma (PTCL) of cytotoxic molecule (CTM)+ and EBV+ type (n = 21).

Nestin expression as a new marker in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST) can be difficult to diagnose because it lacks specific immunohistochemical markers. S‐100, which is a useful marker of MPNST, has limited diagnostic utility. Recent studies suggest that nestin, which is an intermediate filament protein, is expressed in neuroectodermal stem cells. The diagnostic utility of immunostains for nestin and three other neural markers (S‐100, CD56 and protein gene product 9.5 (PGP 9.5)) were evaluated in 35 cases of MPNST and in other spindle cell tumors. All MPNST cases were strongly positive for nestin and had cytoplasmic staining. Stains for S‐100, CD56, and PGP 9.5 were positive in fewer cases (17/35, 11/35, and 29/35 cases, respectively), and had less extensive staining. Nestin was negative in 10/10 leiomyomas, and weak nestin expression was seen in 10/10 schwannomas, 3/10 neurofibromas, 2/8 synovial sarcomas, 2/10 liposarcomas, 4/7 carcinosarcomas and 3/7 malignant fibrous histiocytomas. In contrast, strong nestin positivity was seen in 10/10 rhabdomyosarcomas, 15/19 leiomyosarcomas, and 9/9 desmoplastic melanomas. Nestin is more sensitive for MPNST than other neural markers and immunostains for nestin in combination with other markers could be useful in the diagnosis of MPNST.

Evaluation of organ involvement in intravascular large B-cell lymphoma by 18F-fluorodeoxyglucose positron emission tomography.

To evaluate the role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in intravascular large B-cell lymphoma (IVLBCL), we retrospectively analyzed four consecutive IVLBCL patients receiving FDG-PET before treatment between May 2006 and November 2007. Patients were two men and two women (median age 62 years, range 54–76 years). All patients received bone marrow biopsies and random skin biopsies and two of the four patients underwent renal biopsy for diagnosis. Accuracy of FDG-PET for the detection of organ involvements was analyzed by comparing results of pathological findings. Concordant results with respect to bone marrow involvement were accurately obtained for two patients. Skin and renal involvements were undetectable by FDG-PET regardless of positive pathological findings. One patient with a false-negative FDG-PET result showed fewer lymphoma cells in the bone marrow specimen than patients with concordant FDG-PET results. These results suggest false-negative results for some types of organ involvement. Careful interpretation of the results of FDG-PET in IVLBCL is thus required.

TIA-1 expression in hairy cell leukemia

We measured T-cell intracellular antigen-1 (TIA-1) expression in neoplastic cells from patients with hairy cell leukemia. Five of nine cases were positive for cytoplasmic TIA-1, with a small, dot-like, granular expression pattern. However, neoplastic cells were granzyme B- and perforin- negative in all cases. Other positive markers were CD20 in 9/9 cases, CD19 in 9/9 cases, DBA44 in 8/9 cases, LeuM5(CD11C) in 8/9 cases, IL-2R(CD25) in 7/9 cases, CD103 in 7/9 cases, FMC7 in 6/9 cases, and tartrate- resistant acid phosphatase in 5/7 cases. We also analyzed TIA-1 expression in 94 B cell lymphomas, including 19 diffuse, large cell lymphomas, 19 mantle cell lymphomas, six follicular lymphomas, two extranodal marginal zone B-cell lymphomas, 13 nodal marginal zone B-cell lymphomas, one mediastinal large-cell lymphoma, 19 diffuse small-cell lymphomas, 14 myelomas, and one splenic lymphoma with villous lymphocytes. All cases were negative for TIA-1 expression. Based on these findings, TIA-1 expression in neoplastic cells of low-grade B-cell lymphomas may be a good diagnostic marker for hairy cell leukemia. Moreover, TIA-1 reactivity in lymphomas does not necessarily indicate a T- or NK-cell derivation.

Comparative clinicopathological study of primary CNS diffuse large B‐cell lymphoma and intravascular large B‐cell lymphoma

Primary CNS diffuse large B‐cell lymphoma (CNS DLBCL) is confined to the CNS, and constitutes a distinct entity. In the present study a series of 40 Japanese patients with CNS DLBCL who presented with neurological, but not systemic symptoms, was reviewed. Median survival was 18.7 months. CD5, CD10, Bcl‐6, MUM‐1, and Bcl‐2 were positive in 30%, 10%, 84%, 100%, and 93% of patients, respectively. All CD10‐negative patients had non‐germinal center B‐cell type. There was no significant difference in survival among the immunophenotypic subgroups. CNS DLBCL appeared to be homogenous as a group, which prompted the comparison with another distinct extranodal entity, intravascular large B‐cell lymphoma (IVLBCL) in Japanese patients. CNS DLBCL patients did not differ in age, sex, or immunophenotype, including CD5 positivity, from IVLBCL patients, but were significantly less likely to have poor prognostic parameters than IVLBCL patients: the international prognostic index score was low or low–intermediate in 86% of CNS DLBCL patients and high or high–intermediate in 98% of IVLBCL patients. Notably, despite this difference, their survival curves almost overlapped. The present study highlights the issue of clinical distinctiveness of aggressive extranodal lymphomas, the peculiar migration and localization of which should be further clarified.

Malignant mesothelioma of the tunica vaginalis testis: a case with a predominant sarcomatous component.

We present a case of malignant mesothelioma (MM) of the tunica vaginalis testis. A 64‐year‐old man was referred for an operation on a right hydrocele that later proved to be a tumor during surgery. The tumor was malignant with a biphasic pattern of epithelial and sarcomatous components. The latter component was predominant. Cuboidal or columnar cells formed irregular tubular structures in the epithelial component. In contrast, spindle‐shaped or polygonal cells formed   intricate structures with   stromal  connective tissues in the sarcomatous component. Immunohistochemical staining revealed that the tumor was mesothelial in origin and positive for cytokeratin, vimentin, HBME‐1 antigen and calretinin. In general, MM occur in the pleura or peritoneum; those originating in the tunica vaginalis testis are very rare and represent less than 5% of all MM. In addition, MM in the tissues usually consist primarily of an epithelial component. According to previous reports tumors with a predominant sarcomatous component are extremely rare. In general, a sarcomatous component predicts poor prognosis and our case does, in fact, deteriorate over time. Our case suggests that despite its low incidence, MM must be considered when a case is diagnosed as hydrocele testicle.

Fatal varicella infection in a girl with systemic lupus erythematosus after oral acyclovir prophylaxis

A fatal varicella infection in a 13-year-old girl with systemic lupus erythematosus (SLE) after oral acyclovir prophylaxis is reported. The patient was receiving oral prednisolone and azathioprine as a maintenance therapy. On July 5, 2003, the patient’s older sister developed varicella. Since the patient had a negative history for varicella and varicella-zoster virus (VZV) vaccination, she received prophylactic oral acyclovir (1000 mg q.i.d., or 4000 mg/day total) for 7 days. The prophylaxis was initiated 7 days after the initial exposure. Fifty days after the onset of her sister’s varicella infection, the patient suddenly developed severe lumbago, fever, and skin rash. She was admitted to Tosei General Hospital. Numerous small vesicles were observed over her whole body, and subsequent culture of the fluid isolated from these skin vesicles revealed the presence of VZV. On the day following her admission the patient developed severe virus-associated hemophagocytic syndrome with disseminated intravenous coagulopathy. Azathioprine administration was discontinued, and she was treated with a combination therapy of intravenous acyclovir (10 mg/kg t. i.d., or 30 mg/kg/day total, for 16 days), γ-globulin (200 mg/kg/day for 2 days), immunosuppressive therapy (methylprednisolone pulse, lipo-dexamethasone, and cyclosporine), and plasma exchange. However, multiple organ failure progressed, and she suffered from systemic fungal infection owing to the long-term immunosuppressive therapy. Both candida and aspergillus were detected from her pleural effusions. She died of hepatic failure and invasive aspergillosis 34 days post-admission. Autopsy revealed systemic invasive aspergillosis (lungs, bronchus, cardiac muscles, brain, and meninges) and intrahepatic cholestasis and fibrosis with hepatocellular necrosis. Virus-infected cells were not detected in any of the tissues examined by immunohistochemical analysis using a monoclonal antibody against VZV. Before treatment, a large quantity of VZV DNA (5,200,000 copies/10peripheral blood mononuclear cells) was detected in her blood by a real-time PCR assay [6]. In accordance with the acyclovir therapy, VZV DNA decreased gradually. Fatal varicella has been observed in children treated with high doses of corticosteroids for tissue connective diseases [3]. The patient in our case received both steroids and azathioprine for the treatment of SLE, which is also a I. Hirose . H. Ymamaguchi Department of Pediatrics, Tosei General Hospital, Seto, Japan

Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells

Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development.

An autopsy case of lymphomatosis cerebri showing pathological changes of intravascular large B-cell lymphoma in visceral organs

We describe the case of a 61‐year‐old man presenting with subacute encephalopathy. The clinical manifestations included progressive dementia and pyramidal and extrapyramidal tract signs. Brain CT scan and MRI showed diffuse bilateral white matter changes in the cerebral hemispheres, basal ganglia, thalamus and brainstem. No contrast‐enhanced lesion was observed. Peripheral blood studies, CSF analysis, and brain and muscle biopsies were nonspecific and failed to reveal diagnostic evidence of any specific disease. The patient was diagnosed with and treated for a cerebral demyelinating disorder. Post mortem examination showed diffuse infiltration of lymphoma cells without mass lesions in the extensive cerebral white and gray matter with minimal intravascular patterns, particularly in the perivascular and periventricular spaces. These findings were consistent with lymphomatosis cerebri (LC). In other visceral organs such as the lungs, liver, kidneys and adrenal glands, blood vessels were plugged by numerous neoplastic cells which were morphologically and immunohistochemically similar to those observed in the CNS, consistent with intravascular malignant lymphoma (IVL). To our knowledge, this is the first autopsy report showing the coexistence of LC and IVL. This case suggests a possible link between LC and IVL.

Epstein-Barr virus–positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection–associated T/NK-cell lymphoproliferative disorder: a case report

A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection.