Disease discovery and disease definition are critical first steps in elucidating pathogenetic mechanisms of cancer. Most insights into the molecular pathogenesis of lymphomas have followed on the heels of a precise elucidation of the disease entity based on clinical, pathological, or immunophenotypic grounds. Our work focuses on the definition of malignant lymphomas as tumors of the immune system, delineation of new disease entities, studies related to the pathophysiology of malignant lymphomas, and clinical correlations including prognosis and response to treatment. Significant new observations have been reported over the past year. We have continued our collaborations with Dr. Stephen Straus regarding the biology and clinical manifestations of ALPS, the autoimmune lymphoproliferative disorder. Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in Fas-mediated apoptosis, characterized most often by childhood onset of lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune phenomena. Children with sinus histiocytosis with massive lymphadenopathy (SHML) have a somewhat similar clinical phenotype in which prominent adenopathy also is associated with hypergammaglobulinemia, and autoimmune phenomena are reported in 10-15% of cases. We observed histopathological features of SHML in the lymph nodes of some of our ALPS patients, further suggesting an association between these two disorders. Eighteen of 44 (41%) patients with ALPS Type Ia had a histiocytic proliferation resembling SHML. The affected patients included 15 males and 3 females ranging in age from 11 months to 30 years at the time of the LN biopsy. The male predominance is of interest; SHML changes correlated with severity of disease, suggesting greater penetrance in males than females. Furthermore, because SHML shares many clinical features with ALPS, we sought evidence of ALPS in sporadic SHML. We attempted to sequence TNFRSF6 DNA from archived tissue of 14 cases of Rosai-Dorfman disease. Full sequencing of the gene was successful in 4 of the cases; no mutations were identified. Nevertheless, our observations suggest that histologic features of SHML are part of the pathologic spectrum of ALPS type Ia. It remains to be determined if some cases of apparently sporadic SHML may be associated with heritable defects in Fas-mediated apoptosis.In a study that is in press we described a new entity -- mediastinal grey zone lymphoma (MGZL) -- a category of disease that sheds light on both classical Hodgkin's lymphoma and mediastinal large B-cell lymphoma. MGZL have features transitional between cHL nodular sclerosis (-NS) and primary mediastinal large B-cell lymphoma (MLBCL). We identified twenty-one MGZL cases over a twenty year period. We also studied 6 cases of composite or synchronous lymphoma with two distinct components at the same time (cHL-NS and MLBCL) and 9 sequential cases with MLBCL and cHL-NS at different times. All patients had a large mediastinal mass. Immunohistochemical studies focused on markers known to discriminate between cHL and MLBCL, including B-cell transcription factors. VJ-PCR was performed in 8 cases to look at clonality of the immunoglobulin heavy chain gene (IgH). Two cases of sequential lymphoma showed rearrangements of the IgH gene of identical size; one in which MLBCL was the first diagnosis, and one in which MLBCL was diagnosed at relapse, indicating clonal identity for the two components of cHL and MLBCL. B-cell transcription factor expression in the grey zone cases more closely resembled MLBCL than cHL with expression of Pax5, Oct2, and BOB.1 in all but one case studied (14/15). MAL staining, a feature of MLBCL, also was found in 7/10 MGZL, and in at least one component of 6/7 evaluable composite or sequential MLBCL/cHL cases. Our study further supports a relationship between MLBCL and cHL-NS, which had been suggested by gene profiling.
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