A spindle cell variant of diffuse large B-cell lymphoma is characterized by T-cell/myofibrohistio-rich stromal alterations: analysis of 10 cases and a review of the literature.

Spindle-shaped diffuse large B-cell lymphoma (Sp-DLBCL) has been recognized as a rare morphologic variant of DLBCL. However, the biological processes that contribute to the specific features of Sp-DLBCL remain poorly understood. In this study, a combined immunophenotypic and genetic analysis was performed in 10 Sp-DLBCL. First, we investigated several unique markers for anaplasia (CD30, ALK, CD68, and EBER-ISH), mesenchyma (SMA, desmin, and vimentin), and B-cell differentiation (CD10, BCL6, and MUM1). We also performed conventional cytogenetic and fluorescence in situ hybridization studies to look for common chromosomal break points (BCL2, BCL6, and MYC). We found that most Sp-DLBCLs were germinal center B cell-like and that none had any other specific phenotypes or any karyotypic abnormalities. Instead, T cells, CD68-positive macrophages and SMA-positive myofibroblasts were significantly increased in Sp-DLBCL when compared with conventional GCB origin DLBCL cases (n = 10) (P = 0.012, P < 0.001, and P < 0.0001, respectively). To further characterize Sp-DLBCL, we next compared the expression of fibroblast growth factor 2 (FGF2) and transforming growth factor-ß1 (TGFß1) between the two types of DLBCL. Finally, we confirmed that the number of FGF2- and TGFß1-positive stromal cells was markedly increased in Sp-DLBCL and that the difference between these and conventional GCB origin DLBCLs was significant (P < 0.0001 and P = 0.0017, respectively). Thus, T-cell/myofibrohistio-rich stromal alterations in Sp-DLBCL, especially those mediated by TGFß1 and FGF2, may play a role in the transition of lymphoma cells into those with spindle-shaped features.

Uncommon case of chronic myeloid leukemia with multiple myeloma.

We describe a 72-year-old woman who was diagnosed with asymptomatic multiple myeloma (MM) while being treated for Philadelphia (Ph)-positive chronic myeloid leukemia (CML) with imatinib mesylate (400 mg/day). The diagnosis of CML was based on the presence of the Ph chromosome and chimeric BCR-ABL messenger RNA. Three months after starting imatinib mesylate treatment, the patient achieved a complete cytogenetic response. However, bone marrow analysis at that time demonstrated plasmacytosis, and paraprotein (IgG, kappa-type) was also detected. Hypercalcemia, renal failure, anemia, and bone lesions were not observed, which suggested that asymptomatic MM had developed. The coexistence of CML and MM is an extremely uncommon event that has only been reported in 12 cases. We discuss the relationship between CML and MM.

[Successful treatment with intensive immunosuppressive therapy and mechanical ventilation for idiopathic pneumonia syndrome following allogeneic bone marrow transplantation].

A 45-year-old man with acute myelogenous leukemia (WHO classification, AML with multilineage dysplasia) received allogeneic bone marrow transplantation from an HLA-identical brother in first remission. He became febrile on day 7, and pulmonary failure and multi-organ failure developed subsequently, requiring mechanical ventilation. Chest X-ray and CT scan demonstrated diffuse interstitial shadows, suggesting the development of idiopathic pneumonia syndrome. Administration of methylprednisolone and tacrolimus was effective, but respiratory failure exacerbated along with a decrease in the dose of steroids. Lung biopsy revealed organizing pneumonia with CMV pneumonia. Methylprednisolone and mycophenolate mofetil were instituted, which led to an improvement of lung injury. Intensive immunosuppressive therapy with mechanical ventilation should be considered for the treatment of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.

[Bacillus cereus sepsis and subarachnoid hemorrhage following consolidation chemotherapy for acute myelogenous leukemia].

A 64-year-old man with acute myelogenous leukemia (FAB classification, M7) in remission received consolidation chemotherapy with mitoxantrone/cytosine arabinoside. WBC counts decreased to 0/microl on day 14, and fever (39.3 degrees C) and epigastralgia developed on day 15. Cefozopran was instituted for febrile neutropenia; however, on day 16, he was found to be in cardiac arrest. CT scan on day 16 revealed subarachnoid hemorrhage. Gram-positive rods were isolated from blood cultures on day 15, and were later identified as B.cereus. He recovered transiently, but eventually died on day 19. Postmortem examination demonstrated many colonies of B. cereus in the cerebrum, cerebellum, lung, and liver. Hepatocyte necrosis was also observed in the liver. Bacterial aneurysms or septic emboli were not identified in the arachnoid vessels, but necrosis of cerebral vessels was prominent, which was considered to be the cause of subarachnoid hemorrhage. Fatal subarachnoid hemorrhage has been reported to be associated with B. cereus sepsis, which developed at nadir following chemotherapy for leukemia patients. Because of the aggressive clinical course of B. cereus sepsis, including the risk for subarachnoid hemorrhage, early treatment with effective antibiotics for B. cereus sepsis would be important in the management of leukemia patients after chemotherapy.

Leukemic transformation of Langerhans cell sarcoma.

A 57-year-old man became aware of left supraclavicular lymph node swelling, which was subsequently diagnosed as Langerhans cell sarcoma, based on a positive immunophenotype for CD1a, S-100 protein, and langerin, and histologically bizarre pleomorphism. The tumor became leukemic 3 months later. Despite intensive chemotherapy, he died of disease progression 7 months after the initial diagnosis. Tumor cells in the leukemic phase expressed CD5, CD7, CD13, CD33, CD34, CD68, and CD123. These findings suggested leukemic transformation from Langerhans cell sarcoma. Leukemic transformation may be a clinical manifestation of advanced Langerhans cell sarcoma, and should be differentiated from acute myelogenous leukemia.

Clinico-pathological characteristics of p63 expression in B-cell lymphoma.

A member of the family of p53-related genes, p63 plays a role in regulating epithelial proliferation and differentiation programs, but the pathological and clinical meaning of p63 in B-cell lymphoma has not been elucidated. We investigated the expression pattern of p63 in B-cell malignancies, and evaluated the correlation between the expression of p63 and other germinal center markers. Ninety-eight B-cell lymphomas (28 FCL, 5 MCL, and 65 DLBCL) were analyzed by immunohistochemical examination for p63, bcl-6, CD10 and MUM-1 proteins, and for rearrangement of bcl-2/IgH. Expression of p63 was observed in the nuclei of tumor cells obtained from 15 of 28 (54%) FCL, 22 of 65 (34%) DLBCL, but none of 5 MCL. In DLBCL, the expression of p63 and bcl-6 showed a significant correlation (P < 0.02), but no correlation was observed between p63 and expression of CD10, MUM-1, or bcl-2/IgH rearrangement. RT-PCR revealed that TAp63alpha-type transcripts, a possible negative regulator of transcriptional activation of p21 promoter, were major transcripts in B-cell lymphoma tissues. As for prognostic significance, only patients in the p63 positive group of FCL died, and in the non-germinal center group, the p63 positive cases appeared to have inferior overall survival than other groups in DLBCL. Our preliminary results suggested that p63 expression is a disadvantageous factor for prognosis in this subgroup of B-cell lymphomas.

[Fatal opportunistic infection following disappearance of antibodies by immunosuppressive therapy in a patient with acquired factor VIII inhibitor].

An 83-year-old man without history of the hemorrhagic diathesis was admitted to our hospital with a 4-months history of purpura and subcutaneous hematoma. He had an extraordinarily prolonged activated partial thromboplastin time, and his factor VIII (F VIII) activity level was 0.2%. A study revealed the existence of an IgG type anti-F VIII inhibitor at a titer of 1004 Bethesda units/ml. He received recombinant factor VIIa and immunosuppressive therapy with cyclophosphamide, prednisolone and cyclosporin, but despite this the titer of F VIII inhibitor remained high. Although the inhibitor disappeared after methylprednisolone mini-pulse therapy, the patient died of opportunistic infections with cytomegalovirus and pneumocystis carinii. The majority of patients with acquired F VIII inhibitor belong to the elderly population, and the standard therapeutic strategy to eliminate the acquired F VIII inhibitor has not been established. Those patients with high titers of F VIII inhibitor require particularly long term immunosuppressive therapy. Therefore, it is important to bear in mind treatment-related opportunistic infections in a case with a high titer of acquired F VIII inhibitor.