Katsuyuki Aozasa

Interleukin 6 (IL-6) has been suggested to be involved in the pathogenesis of polyclonal and monoclonal plasma cell abnormalities. To address this possibility, transgenic mice carrying the human IL-6 genomic gene fused with a human immunoglobulin heavy chain enhancer were generated. High concentrations of human IL-6 and polyclonal increase in IgG1 (120- to 400-fold) in sera of all transgenic mice were observed. A massive plasmacytosis in thymus, lymph node, and spleen and an infiltration of plasma cells in lung, liver, and kidney were observed. However, the plasma cells were not transplantable to syngeneic mice and were found not to contain chromosomal aberrations including c-myc gene rearrangements. The evidence indicates that deregulated gene expression of IL-6 can trigger polyclonal plasmacytosis but cannot induce plasmacytoma. It is suggested that additional genetic changes may be required for the generation of plasma cell neoplasia. Other interesting findings in these transgenic mice were the development of mesangio-proliferative glomerulonephritis and an increase in megakaryocytes in bone marrow.

BACKGROUND: Differential diagnosis of angiosarcoma, predominantly showing a non- or poorly vasoformative proliferation from other types of sarcomas, poorly differentiated carcinomas, and amelanotic melanoma, is often problematic. METHODS: The use of antibodies directed against Factor VIII-related antigen (FVIIIRA), Ulex europaeus lectin type 1 (UEA-1), CD31, and vascular endothelial growth factor (VEGF) in the diagnosis of angiosarcoma was examined in 98 cases of autopsy-proven angiosarcoma diagnosed during 1974-1990 in a survey of 178 Japanese hospitals. Reactivity of angiosarcoma cells for epithelial membrane antigen, cytokeratin, and melanoma cell antigen (HMB45) also was examined. RESULTS: Histologic specimens were formed exclusively by vasoformative areas in 32 cases and combined vasoformative and varying extents of non- or poorly vasoformative areas in another 66 cases. In vasoformative areas, the proliferating cells showed a diffuse positive reaction in the cytoplasm and/or cell surface for anti-FVII-IRA in 82 (84%) of 98 cases, for anti-CD31 in 78 (80%), and for UEA-1 in 69 (70%). In non- or poorly vasoformative areas, the positivity rate for FVIIIRA, CD31, and UEA-1 was 29%, 62%, and 46%, respectively. A positive reaction was found for either one of three endothelial markers in the non- or poorly vasoformative areas of 57 cases (86%). Epithelial membrane antigen and anticytokeratin antibody were positive in 4 and 11 cases, respectively, in the vasoformative areas and in 3 and 14 cases, respectively, in non- or poorly vasoformative areas with a simultaneous positive reaction for either one of three endothelial cell markers. None of the proliferating cells showed a positive reactivity for HMB45. The positivity rates of the angiosarcoma cells for each marker were different according to the primary tumor sites. The angiosarcoma cells in non- or poorly vasoformative areas showed the lowest positivity rate for anti-FVIIIRA in the heart (9%) and for anti-CD31 in the extremities (17%) and the highest positivity rate for anticytokeratin in the trunk (60%). Ulex europaeus lectin type 1 had almost the same reactivity rate (30-56%) in every organ. Angiosarcoma cells in 13 (36%) of 36 biopsy specimens and 8 (14%) of 56 autopsy specimens were positive for the anti-VEGF antibody. CONCLUSION: These findings suggest that the combined use of endothelial cell markers including FVIIIRA, UEA-1, and CD31 is useful in the diagnosis of angiosarcoma, especially in cases exclusively with a non- or poorly vasoformative pattern.

Castleman's disease is a syndrome consisting of giant lymph node hyperplasia with plasma cell infiltration, fever, anemia, hypergammaglobulinemia, and an increase in the plasma level of acute phase proteins. It has been reported that clinical abnormalities disappear after the resection of the affected lymph nodes, suggesting that products of lymph nodes may cause such clinical abnormalities. Interleukin-6 (IL-6) is a cytokine inducing B-cell differentiation to immunoglobulin-producing cells and regulating biosynthesis of acute phase proteins. This report demonstrates that the germinal centers of hyperplastic lymph nodes of patients with Castleman's disease produce large quantities of IL-6 without any significant production of other cytokines. In a patient with a solitary hyperplastic lymph node, clinical improvement and decrease in serum IL-6 were observed following surgical removal of the involved lymph node. There was a correlation between serum IL-6 level, lymph node hyperplasia, hypergammaglobulinemia, increased level of acute phase proteins, and clinical abnormalities. The findings in this report indicate that the generation of IL-6 by B cells in germinal centers of hyperplastic lymph nodes of Castleman's disease may be the key element responsible for the variety of clinical symptoms in this disease.

Transgenic mice deficient for the p53 gene were reported to frequently develop angiosarcoma (AS), suggesting that alterations in the gene are associated with tumorigenesis of AS. However, little is known about genetic changes, including p53 gene alterations, in human AS because of its rarity. We analyzed p53 mutations on paraffin-embedded specimens from 33 patients with AS by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by direct sequencing. Age of patients ranged from 18 to 91 (median 70) years, with a male to female ratio of 1.5:1. Sites of tumor were the head in 13 patients, the trunk in 4, the extremities in 4, the heart in 4, bones in 2 and others in 6. PCR-SSCP revealed aberrant mobility shifts of bands in 17 cases: 11 in exon 5, 5 in exon 7 and 4 in exon 8. Direct sequencing on these 17 cases revealed a total of 20 mutations. The frequency of p53 mutations was different by site of tumors: 7 of 13 in head, all 4 in extremities, 2 of 4 in heart and none of 4 in trunk. Our findings suggest that occurrence of p53 mutation is a major pathway for development of human AS.

Primary pancreatic lymphoma (PL) is an extremely rare disease, and large-scale studies are rarely performed even in Western countries, in which all cases of PL reported to date were of the B-cell type. Little information regarding PL is available in Japan. Nineteen cases of PL were collected through a nationwide study in Japan, and paraffin-embedded specimens were processed for staining with hematoxylin and eosin and by immunohistochemical procedures. Clinicopathological findings were reviewed and compared with those reported in Western countries. The patient population consisted of 13 men and 6 women, ranging in age from 46 to 84 (average 62) years. Abdominal pain was the most common presenting symptom. Tumors were located in the pancreatic head (12 cases), tail (4 cases) and body (2 cases), and ranged in size from 4 to 17 cm. Clinical stage was I(E) in 9 cases and II(E) in 10. Radical resection was performed in 10 cases and bypass operation in 1, followed by chemotherapy in 8. Immunophenotypically, 15 cases were B-cell and 4 were T-cell lymphomas. Seventy-three percent of B-cell tumors were diffuse large B-cell lymphomas. The 1-year actuarial survival rate for B-cell lymphomas (51.9%) was better than that of T-cell lymphomas (0%). However, in Japan the incidence of T-cell PLs was higher, and, partly as a consequence of this, prognosis was poorer than in Western countries.