I have had a long-standing interest in the interrelationship between classical Hodgkin lymphoma and other B-cell lymphomas. These observations helped provide early evidence for a B-cell origin of the Reed-Sternberg cell. In 2005 we described mediastinal gray zone lymphomas, which we proposed to be a missing link between classical Hodgkins lymphoma of the nodular sclerosis subtype and primary mediastinal large B-cell lymphoma. Our recent studies have been directed towards a better understanding mediastinal gray zone lymphoma, in comparison with classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma. We had previously validated the Illumina golden gate methylation assay for the assessment of 1505 CPG sites from over 800 genes by comparing follicular lymphoma DNA from snap frozen and paraffin-embedded tissue. We used this platform to compare tumor DNA isolated by microdissection from mediastinal gray zone lymphoma, classical Hodgkins lymphoma, and primary mediastinal large B-cell lymphoma. Principal component analysis demonstrated that mediastinal gray zone lymphoma has a distinct epigenetic profile intermediate between classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma but remarkably different from that of diffuse large B-cell lymphoma. Analysis of common hypo- and hypermethylated CPG targets confirmed the findings of the principal component analysis. Based on the epigenetic profiles we were able to establish class prediction models that could distinguish between mediastinal gray zone lymphoma, classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma with a final combined prediction of 100%. Our findings confirm the close relationship between mediastinal gray zone lymphoma and both classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma. However, important differences were observed as well, allowing a clear distinction from both parent entities. Thus, mediastinal gray zone lymphoma cannot be assigned to either classical Hodgkins lymphomas or primary mediastinal large B-cell lymphoma, validating the decision to create an intermediate category in the who classification. In additional studies we have examined the genetic aberrations of mediastinal gray zone lymphoma by fluorescent in situ hybridization. . We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M: F ratio;20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared to cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkins lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75% and 93%) and p63 (50% and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkins lymphoma and mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations. In collaborative studies, the treatment outcome of mediastinal gray zone lymphoma is being studied in an NCI clinical trial. Our laboratory has had a long standing interest in follicular lymphoma, stemming from our pivotal observations in 1974, showing a relationship between the neoplastic cells and the lymphoid follicle. In 2002 we described follicular lymphoma in situ. We have delineated criteria for the distinction of follicular lymphoma in situ from partial involvement by follicular lymphoma, and in recent studies have shown that patients with follicular lymphoma in situ are at very low risk for subsequent clinically relevant follicular lymphoma. Follicular lymphoma in situ appears to be the tissue counterpart of circulating cells in the peripheral blood carrying the BCL2/IGH translocation, which can be detected in more than 50% of healthy adults over the age of 50. We are studying the extent of genetic aberrations in follicular lymphoma in situ, as compared to follicular lymphoma fully involving or partially involving lymph nodes by performing array CGH of DNA isolated from B-cells isolated by laser capture microdissection of the full spectrum of lesions. In a Plenary article appearing in Blood in 2008, we reported histiocytic/dendritic cell (H/DC) sarcomas arising in patients with FL. We provided evidence that the H/DC sarcomas were clonally related to the underlying FL, both carrying the same IGH gene rearrangement, and the t(14:18). We provided evidence that these tumors arose through a process of transdiffentiation, mediated through repression of PAX5 and upregulation of PU.1 and CEBP beta. This study was the first demonstration of transdifferentiation in a mature human B-cell in an in vivo or in vitro setting. Coupled with our earlier descriptions of histiocytic dendritic cells neoplasms in association with acute lymphocytic leukemia of either T-cell or B-cell lineage, our studies provided evidence for extraordinary lineage plasticity among cells of the hematopoietic system. Our work has led to a number of other novel observations, with representative examples as noted. We provided new insights into the incidence and clinical behavior of blastic plasmacytoid dendritic cell neoplasms in the pediatric age group. We described a unique EBV-related lesion, mucocutaneous ulcer, which despite alarming histological features has an indolent clinical course, and we have characterized the largest series of age-related EBV driven lymphoproliferations in the Western world. We expanded our prior studies of marginal zone lymphoma in the pediatric and young adult population, and characterized the lesions genetically, comparing them with their adult counterparts. We identified a high incidence of C-MYC translocation in plasmablastic lymphoma , and provided evidence for a close relationship between plasmablastic lymphoma and plasma cell myeloma with plasmablastic features. We described IgA-producing plasma cell neoplasms of lymph nodes, and characterized their unusual clinical features, typically occurring in young patients, often associated with autoimmune disease, but with a low risk of progression to plasma cell myeloma. Finally, we identified a new disease entity, NK-cell enteropathy, which mimics NK-cell or T-cell lymphoma, but has an indolent clinical course. This study was published as a Plenary article in Blood, along with an accompanying Editorial, highlighting the significance of the study.
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