2011, Disease Discovery In a Plenary article appearing in Blood in 2008, we reported histiocytic/dendritic cell (H/DC) sarcomas arising in patients with follicular lymphoma (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. In more recent work we reported the morphologic, molecular and cytogenetic analysis of 7 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age, 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in 6 of 7 patients, and one patient had both tumors diagnosed at the same time. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. .Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in 5 of 6 cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBP beta. Our study provided evidence for transdifferentiation of CLL/SLL B-cells to tumors of dendritic and less often histiocytic lineage, and suggested that secondary genetic events may play a role in this phenomenon. The idea of malignant transformation of cells through a multistep process of accumulating genetic and molecular events is well accepted and recognized in solid tumors. These concepts have been difficult to apply in the lymphoid system where the cells naturally circulate and colonize different tissues. Our studies in recent years have focused on these early lesions, both follicular lymphoma in situ and more recently mantle cell in situ. We first described Follicular lymphoma in situ (FLIS) nearly a decade ago, but its clinical significance remains uncertain. In a study recently published in Blood, we reevaluated our original series and more recently diagnosed cases to develop criteria for the distinction of FLIS from partial involvement by follicular lymphoma (PFL). 34 cases of FLIS were identified, most often as an incidental finding in a reactive lymph node. 6/34 patients had prior or concurrent FL, and 5/34 had FLIS composite with another lymphoma. Of patients with negative staging at diagnosis and available follow-up (21 patients), only one (5%) developed FL . Fluorescence in situ hybridization for BCL2 gene rearrangement was positive in all 17 cases tested. PFL patients were more likely to develop FL. FLIS can be reliably distinguished from PFL, and has a very low rate of progression to clinically significant FL. FLIS may represent the tissue counterpart of circulating t(14;18)-positive B-cells. We also studied the clinical and pathologic characteristics, including SOX11 expression, of 23 cases initially diagnosed as mantle cell lymphoma (MCL) in situ. SOX11 was positive in 7 of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. Fourteen patients had at least one year follow-up (median 3 years, range 1-19.5). SOX11 expression was highly associated with risk of progression to mantle cell lymphoma. Like follicular lymphoma in situ, in-situ MCL lesions are usuallyan incidental finding with a very indolent behavior, and may not require therapeutic intervention. Also similar to follicular lymphoma in situ, a distinction should be made between partial involvement by MCL with a mantle zone pattern and in situ MCL. Our group has had a long standing interest in the classification of T-cell and NK-cell neoplasms. We had previously characterized primary cutaneous gamma delta T-cell lymphomas (TCLs), and showed that they had an aggressive clinical course, in contrast to most cutaneous TCLs of alpha beta T-cell derivation. The 2008 WHO classification recognizes only two forms of mature gamma delta TCL, hepatosplenic and primary cutaneous gamma delta TCL, respectively. We had previously suggested that gamma delta TCLs might also arise in other extranodal sites, but knowledge of these neoplasms is very limited, with only few reported cases.We have recently expanded our work on gamma delta TCLs (Garcia et al., 2011). Given the rarity of these tumors, this study was an international collaboration involving investigators from the U.S., Spain, France and Taiwan. One problem in characterizing gamma delta TCLs is the lack of reliable markers to detect TCR gamma or delta expression in paraffin sections. We were able to detect the TCR delta chain using a primary monoclonal antibody raised against the human TCR delta constant region (clone 5A6.E9). In a subset of cases that appeared to be TCR silent, negative for both TCR beta and TCR delta, we also employed a recently published antibody to detect the TCR gamma chain. Our data indicated that the spectrum of gamma delta derived TCL is broader than previously appreciated, with the documentation of gamma delta TCL presenting in other extranodal or more rarely nodal sites. We also noted that cases with features of type II EATL appear to be of gamma delta T-cell origin, but that there is still a subset of other intestinal T-cell lymphomas lacking features of enteropathy that have either a gamma delta or TCR silent phenotype. The recognition of a group of silent TCLs indicates that the lack of TCR beta expression cannot be used to predict a gamma delta T-cell origin. Additionally, the clinical behavior of the gamma delta TCLs and TCR silent TCLs was aggressive, with survival less than two years in most patients. Our group was also the first to describe MZLs affecting the dura. Most cases are identified in women, with a radiological presentation simulating meningioma. We noted that these tumors tend to arise at sites where meningothelial cells are concentrated, possibly indicating epitheliotropism similar to other extranodal MZL of MALT type. In a recent study we analyzed 32 dura-based MZLs identified in 27 females and 5 males ranging in age from 33-82 yrs (median 50). In a subset tested for IgG4, 6/18 primary dural MZL (including one epidural tumor) showed numerous IgG4-positive plasma cells;all six were light chain restricted and clonal by PCR in 5 of 6 tested cases. Three of 6 IgG4-positive MZL did not show any cytogenetic aberrations. Across all cases, FISH and RT-PCR identified abnormalities in 3/9 cases (trisomies 3 and 18;trisomies 3 and 1;trisomy 18) without any MALT-type specific translocations. Regardless of the treatment modality, 16 of 17 patients with follow-up are alive without evidence of disease over a period of 4-124 months (median 19.5). The expression of IgG4 in light chain-restricted clonal plasma cells of a significant subset of dural MZL, including one in an epidural location, is a novel finding and points to distinctive biology. Interestingly, this may be a feature shared by some orbital MZL, as recently reported by others, and expands our understanding of IgG4 related disease.

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Roswarski, Joseph; Roschewski, Mark; Lucas, Andrea et al. (2018) Phase I dose escalation study of the anti-CD2 monoclonal antibody, siplizumab, with DA-EPOCH-R in aggressive peripheral T-cell lymphomas. Leuk Lymphoma 59:1466-1469
Perry, Anamarija M; Bailey, Nathanael G; Bonnett, Michelle et al. (2018) Disease Progression in a Patient With Indolent T-Cell Lymphoproliferative Disease of the Gastrointestinal Tract. Int J Surg Pathol :1066896918785985
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Schmidt, Janine; Ramis-Zaldivar, Joan Enric; Nadeu, Ferran et al. (2017) Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 130:323-327
Brett, Francesca M; Flavin, Richard; Chen, Daphne et al. (2017) EBV driven natural killer cell disease of the central nervous system presenting as subacute cognitive decline. Hum Pathol (N Y) 10:64-68

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