Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity with a high incidence of central nervous system (CNS) involvement at diagnosis. To evaluate CNS involvement, particularly recurrence including progression on therapy and relapse of IVLBCL, we retrospectively analyzed 109 patients with IVLBCL receiving chemotherapies with or without rituximab. In 82 patients (75%) without CNS involvement at initial diagnosis, risk of CNS recurrence at 3 years was 25% with a median follow-up in survivors of 39 months (range, 2-158 months). In 27 patients (25%) with CNS involvement at initial diagnosis, risk of CNS recurrence at 1 year was 25% with a median follow-up in survivors of 18 months (range, 10-77 months). Duration from diagnosis to CNS recurrence tended to be short in patients with CNS involvement at diagnosis. No significant difference in risk of CNS recurrence was found between patients receiving chemotherapies with or without rituximab. On multivariate analysis skin involvement at initial diagnosis was identified as a predictive factor for CNS recurrence in patients without CNS involvement at diagnosis (hazard ratio, 5.27; 95% confidence interval, 1.59-17.4; P = 0.007). Survival rate after CNS recurrence at 2 years was 12% in patients without CNS involvement at diagnosis. Central nervous system recurrence is a serious complication in IVLBCL patients and optimal strategies for CNS involvement should be established to obtain further improvements to clinical outcomes in the rituximab era.

De novo CD5+ diffuse large B-cell lymphoma: results of a detailed clinicopathological review in 120 patients.

BACKGROUND: De novo CD5-positive diffuse large B-cell lymphoma (CD5(+) DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5(-)) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5(+) DLBCL. DESIGN AND METHOD: From 1984 to 2002, 120 patients with CD5(+) DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. RESULTS: Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5(+) DLBCL was more frequent than in CD5(-) DLBCL (p=0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5(+) DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5(+) DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants (p=0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. CONCLUSIONS: Our study revealed the morphological spectrum of CD5(+) DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5(+) DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

Clinical implications of idiopathic multicentric castleman disease among Japanese: a report of 28 cases.

To clarify the clinicopathologic findings of idiopathic multicentric Castleman disease among Japanese, 28 cases were studied. Two variants were delineated by the clinicopathologic findings (1) idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (n = 18) and (2) nonidiopathic plasmacytic lymphadenopathy type (n= 10). Clinicopathologically, idiopathic plasmacytic lymphadenopathy was defined by the prominent polyclonal hyperimmunoglobulinemia, normal germinal centers, and sheet-like infiltration of plasma cells in the interfollicular area of the lymph node. Histologically, the nonidiopathic plasmacytic lymphadenopathy type was characterized by hyaline-vascular germinal centers of the lymph node lesion. In comparison with idiopathic plasmacytic lymphadenopathy, patients with nonidiopathic plasmacytic lymphadenopathy showed infrequent prominent polyclonal hyperimmunoglobulinemia and frequent association with autoimmune disease. However, there was no difference in the overall 5-year survival between the 2 subtypes. Compared with idiopathic multicentric Castleman disease in Western countries, the chronic course of the disease of idiopathic multicentric Castleman disease in Japan appears to be related to negativity for human herpesvirus 8 infection.

Establishment of a stroma-dependent human acute myelomonocytic leukemia cell line, NAMO-2, with FLT3 tandem duplication.

We have established a stroma-dependent myelomonocytic cell line, NAMO-2, with FLT3 internal tandem duplication (FLT3/ITD). Leukemia cells from a patient with acute myelomonocytic leukemia were administered to form subcutaneous tumors in nude mice, which were maintained successively, although we failed to establish continuously growing cells from the original leukemia cell culture. In the cultures of cells from subcutaneous tumors, there were stroma cells that had originated from the nude mice and showed continuous growth. The leukemia cells showed continuous growth dependent on this stroma, and this cell line was named NAMO-2. Detection of FLT3/ITD by the reverse transcriptase polymerase chain reaction (PCR) and genomic PCR showed that NAMO-2 was homozygous for FLT3/ITD. Constitutive activation of FLT3 was detected by Western blotting, and the phosphorylation of Akt, MEK, and STAT5 was also observed. FLT3 kinase inhibitor AG1296 specifically inhibited cell growth. NAMO-2 provides a useful tool to analyze adherence-dependent survival signaling of leukemia with FLT3/ITD and a model for the screening of FLT3 kinase inhibitors.

[Successful salvage therapy with cladribine and rituximab for a patient with a relapsed Asian variant of intravascular large B-cell lymphoma].

The Asian variant of intravascular large B-cell lymphoma (AIVL) is a rare aggressive lymphoma characterized by various clinical symptoms, hemophagocytic syndrome and predominant growth within vessels. We present a 73-year-old man with relapsed AIVL who had been treated with six courses of CHOP regimen. A half year later, he presented with high fever, sweat, dementia and hepatosplenomegaly without lymphadenopathy. A bone marrow biopsy showed prominent hemophagocytosis and immunological staining disclosed an augmented intrasinusal pattern of atypical large lymphocytes characteristic of the CD20+ and CD5+ phenotypes. As salvage therapy, CND-R (rituximab, cladribine, mitoxantrone, dexamethasone) was performed, and the clinical symptoms immediately and dramatically improved. Subsequently, CND-R therapy was repeated every 4 weeks. No serious adverse events were observed with the exception of grade 4 neutropenia and grade 3 thrombocytopenia. After completion of the fifth course, a bone marrow biopsy pathologically confirmed complete remission, leading to termination of this therapy. The patient has remained in remission for more than 15 months. CND-R therapy, which is effective for indolent lymphoma, may be one of the candidates in salvage therapy for relapsed AIVL.

Follicular colonization of nodal marginal-zone B-cell lymphoma resembling follicular lymphoma: report of 6 cases.

The formation of neoplastic B-cell follicles is accepted as a diagnostic criterion of follicular lymphoma. However, extranodal marginal-zone B-cell lymphomas (MZBLs) of mucosa-associated lymphoid tissue (MALT) type also sometimes contain numerous lymphoid follicles and may even have a predominantly follicular growth pattern. However, morphologic, immunohistochemical, and genotypic findings suggest that lymphoid follicles in extranodal MZBLs are neoplastic follicles formed as the result of colonization of previously reactive follicles by tumor cells (centrocyte-like cells). We present here 6 cases of nodal MZBL demonstrating a follicular growth pattern. Immunohistochemical study demonstrated that the tumor cells were CD10-, CD20+, CD79a+,CD138-, Bcl-2+, Bcl-6- and IRF4+. Residual nonneoplastic follicular center cells were CD10+, CD20+, CD79a+, Bcl-2-, and Bcl-6+. CD21/CD23 immunostain demonstrated a disrupted follicular dendritic cell pattern characteristic of follicular colonization in extranodal MZBL of MALT type. Taken in conjunction with the morphologic findings, nodal MZBL may also show a follicular growth pattern similar to extranodal MZBL of MALT type. The marginal-zone nature is most recognizable on immunohistochemistry, although the histologic appearance alone may cause some diagnostic problems. It is important for pathologists to consider this type of lesion in diagnostic practice.

Asian variant of CD5+ intravascular large B-cell lymphoma with splenic infarction.

A 57-year-old man was admitted with fever and epigastralgia, and presented with splenomegaly and pancytopenia. A CT scan revealed splenic infarctions. There were no lymphadenopathies, skin lesions, or neurological abnormalities. A splenectomy was performed. Bone marrow involvement with hemophagocytosis was noted. The diagnosis of Asian variant of intravascular diffuse large B-cell lymphoma was based on intravascular and sinusoidal distribution of large CD5+ B cells. The patient died of the disease 11 months after onset. To our knowledge, this is the first report of AIVL that presented with splenic infarction. This distinct lymphoma should be included in the differential diagnosis of splenic infarction.

[Clinicopathologic features of intravascular large B-cell lymphoma in Japan: review of the special reference to the Asian variant].

The Asian variant of intravascular large B-cell lymphoma (IVL) is characterized by hemophagocytic syndrome, i.e. the clinical features include pancytopenia, hepatosplenomegaly, and rarely mass formation. It usually lacks any neurological abnormality or skin lesions, which are typical features of classical IVL. Sixty-seven cases of IVL reported in Japan since 1990 were classified into two groups, and their clinicopathologic features were compared. Forty-five cases of IVL that met the clinical and laboratory criteria for the Asian variant were classified into Group A (average: 66 yr; male: 62%), and 22 cases that did not meet the criteria were classified into Group C (average: 65 yr; male: 73%). Hemophagocytosis was described only in Group A. The positivity rates for bone marrow invasion, fever, hyperbilirubinemia and elevated levels of LDH and CRP were significantly (p = 0.0037, p < 0.0001, p = 0.0428, p = 0.0108 and p = 0.0008, respectively) higher in Group A than in Group C. On the other hand, the positivity rates for neurological abnormality and skin lesions were significantly (p < 0.0001 and p = 0.0011, respectively) higher in Group C than in Group A. Our reassessment of the reported cases of IVL in Japan identified two major categories of IVL: the classical form and the Asian variant.

[DAD, new intensive chemotherapy for patients with myeloma: a preliminary report].

A new intensive chemotherapy regimen, DAD, composed of doxorubicin, melphalan and dexamethasone, was given to 17 patients with multiple myeloma. The end point of this regimen was to obtain a deep posttreatment nadir in the M-protein levels so as to increase the chance of plateau attainment which would be associated with prolonged survival in each patient. It was noteworthy that all the 17 evaluable patients achieved a partial response. Nine of the 17 (52.9%) attained a plateau. Ten of the 17 patients (58.8%) obtained a deep posttreatment nadir in their M-protein levels (IgG < 2,000 mg/dl, IgA < 1,000 mg/dl, BJP = 0 g/dl/day), and six of them reached a plateau phase, which was not significantly more frequent than those who did not obtain a deep posttreatment nadir in their M-protein levels (three of seven reached plateau phase). The median survival of the 17 patients (37.6 months) was significantly prolonged compared with that of patients treated with our previous chemotherapy regimens, VMCP (22.5 months) and MMPP (23.5 months), and was comparable to that of MMCP (29.5 months).

Characteristics of CD5-positive splenic marginal zone lymphoma with leukemic manifestation ; clinical, flow cytometry, and histopathological findings of 11 cases.

Splenic marginal zone lymphoma (SP-MZL) is a rare low-grade B-cell neoplasm that often shows leukemic manifestation. Less than 20% of cases of SP-MZL express CD5. We analyzed 11 cases of CD5-positive SP-MZL with leukemic manifestation. The clinical characteristics of these cases did not differ from those of CD5-negative SP-MZL. Flow cytometry revealed positive results as follows : CD3, 0/9 ; CD5, 11/11 ; CD10, 0/11 ; CD11c, 4/10, CD13, 5/11 ; CD19, 11/11 ; CD20, 10/11 ; CD21, 4/4 ; CD22, 7/7 ; CD23, 5/10 ; CD25, 8/11 ; FMC7, 5/7 ; κ type 6/9, and λ type 2/9. All 3 cases with monoclonal γ-globulinemia expressed CD13. Resected spleen exhibited a proliferation of neoplastic cells in white pulp in all 8 splenectomy patients and a marginal pattern was detected in 5 patients. Only 2 cases showed involvement of red pulp. Immunohistochemistry showed that the lymphoma cells were positive for CD5, CD20, and BCL-2 and negative for CD3, CD10, cyclin D1, BCL-6, and MUM-1 in all 11 cases. These results suggest that CD5-positive SP-MZL differs from B-cell chronic lymphocytic leukemia, that CD13 expression is found in about half of CD5-positive SP-MZL cases, and that CD5-positive SP-MZL may be related to memory B-cell neoplasm or plasma cell differentiation.

Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan.

PURPOSE: To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL). PATIENTS AND METHODS: We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients. RESULTS: The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy. CONCLUSION: Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.

Clinical implications of nodal marginal zone B-cell lymphoma among Japanese: study of 65 cases.

To clarify the clinical presentation and outcome of nodal marginal zone B-cell lymphoma (NMZBL), 65 Japanese patients with this disease were studied and compared with the published literature from western countries. The clinical findings of our 65 cases were similar to those of their cases in some aspects: (1) 58% of the patients were > 60 years old (median age, 64 years); (2) there was a slight female predominance; (3) 90% of the patients exhibited asymptomatic lymphadenopathy in the head and neck area; (4) only a minority of patients had B symptoms (6%) and poor performance status (8%); and (5) only 5% of patients were positive for M-protein. However, the 65 patients in this series exhibited relatively longer 5-year overall survival (85%) and failure-free survival (60%) than the NMZBL series published in western literature, suggesting that NMZBL should be classified as indolent lymphoma. Moreover, based on the histological findings, we further classified four histological subtypes as follows: (1) splenic type (n = 7); (2) floral type (n = 9); (3) mucosa-associated lymphoid tissue (MALT) type (n = 29); and (4) diffuse large B-cell lymphoma (DLBCL) + MALT type (n = 20). DLBCL + MALT type exhibited significantly poorer 5-year overall survival than the splenic variant. The recognition of DLBCL + MALT type appears important. No API2-MALT1 fusion transcript was detected in any of the 14 cases examined.

Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL characterized by preferential intravascular growth of malignant lymphocytes, aggressive behavior, and an often fatal course. IVLBCL usually affects elderly patients with poor performance status, elevated lactic dehydrogenase serum levels, anemia, and B symptoms. It displays some differences in clinical presentation among diverse geographical areas, mostly between patients diagnosed in Western countries and Japan. In addition, data from the literature suggest that pathologic diagnostic criteria as well as clinical features of this disease may be broader than described in current classification scheme(s). Under the sponsorship of the International Extranodal Lymphoma Study Group, clinicians and pathologists with interest in IVLBCL, coming from Western and Eastern countries, joined to reach a consensus on defining features as well as to focus on the most urgent unresolved issues in IVLBCL. To this end, a representative group of IVLBCL patients coming from both the aforementioned geographical areas were collectively analyzed. Additional features of IVLBCL were proposed both under clinical and pathologic stand points. At the meeting, it emerged that IVLBCL may have additional histopathologic/cytologic definition criteria with respect to those currently recommended, some clinical features are not randomly distributed worldwide, recent therapeutic approaches, such as anti-CD20-containing regimens, may improve outcome, and kidney, spleen, and liver involvement may show peculiar histopathologic features. Finally, a provisional practical diagnostic approach to hemophagocytosis-associated patients and a proposal for the most useful criteria in the settings of differential diagnosis are included.

Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5.

Intravascular large B-cell lymphoma (IVLBCL) is pathologically distinct with a broad clinical spectrum and immunophenotypic heterogeneity. A series of 96 patients with IVLBCL (median age, 67 years; range, 41-85 years; 50 men) was reviewed. Anemia/thrombocytopenia (84%), hepatosplenomegaly (77%), B symptoms (76%), bone marrow involvement (75%), and hemophagocytosis (61%) were frequently observed. The International Prognostic Index score was high or high-intermediate in 92%. For 62 patients receiving anthracycline-based chemotherapies, median survival was 13 months. CD5, CD10, Bcl-6, MUM1, and Bcl-2 were positive in 38%, 13%, 26%, 95%, and 91% of tumors, respectively. All 59 CD10- IVLBCL cases examined were nongerminal center B-cell type because they lacked the Bcl-6+MUM1- immunophenotype. CD5 positivity was associated with a higher prevalence of marrow/blood involvement and thrombocytopenia and a lower frequency of neurologic abnormalities among patients with CD10-IVLBCL. Compared with 97 cases of de novo CD5+CD10-diffuse LBCL, 31 cases of CD5+CD10-IVLBCL exhibited higher frequencies of poor prognostic parameters, except age. Multivariate analysis in IVLBCL revealed that a lack of anthracycline-based chemotherapies (P<.001, hazard ratio [HR]: 9.256), age older than 60 years (P=.012, HR: 2.459), and thrombocytopenia less than 100x10(9)/L (P=.012, HR: 2.427) were independently unfavorable prognostic factors; CD5 positivity was not. Beyond immunophenotypic diversity, IVLBCL constitutes a unique group with aggressive behavior.

De novo CD5+ diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients.

De novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBCL) is known to have phenotypically and genotypically different characteristics than CD5- DLBCL and mantle cell lymphoma (MCL). To further characterize CD5+ DLBCL, 109 patients with CD5+ DLBCL were reviewed, and the results were compared with those of 384 CD5- DLBCL and 128 cyclin D1+ MCL patients. Patients with CD5+ DLBCL showed a higher age distribution (median, 66 years; P =.0083) and a female predominance (male-female ratio, 49:60, P =.011) compared with those with CD5- DLBCL. CD5+ DLBCL was more closely associated with many aggressive clinical features or parameters than CD5- DLBCL: 69% older than 60 years (P =.039), 34% with performance status greater than 1 (P =.0016), 69% with serum lactate dehydrogenase level higher than normal (P <.0001), 62% with stage III/IV disease at diagnosis (P =.0023), 35% with more than one extranodal site (P =.023), and 40% with B symptoms (P =.0031). The overall International Prognostic Index score was thus significantly higher for the patients with CD5+ DLBCL than for those with CD5- DLBCL (P =.00005). The most frequent site of extranodal involvement was bone marrow (28%), a higher frequency than that for CD5- DLBCL (P <.0001) but lower than that for cyclin D1+ MCL (P =.0015). Histopathologically, CD5+ DLBCL showed centroblastic morphology except for 3 patients with immunoblastic disease, and interfollicular growth pattern (7%) and intravascular or intrasinusoidal infiltration (19%) were observed. Immunophenotypically, CD5+ DLBCL was characterized by a CD5+CD10-CD19+CD20+CD21-CD23- cyclin D1- phenotype and a predominance of surface IgMkappa. Of particular interest is that CD5+ DLBCL was characterized by a survival curve significantly inferior to that for patients with CD5- DLBCL (P =.0026). These findings suggest that CD5+ DLBCL may constitute a unique subgroup of DLBCL.