Hematopathology staff list

Hematopathology Fellowship Information

The goal of our research is to understand the biology and pathogenesis of malignant lymphomas, which can be viewed as tumors of the immune system. We seek to define clinicopathologic entities based on morphologic, immunophenotypic, molecular, and clinical features. Delineation of disease entities is the first step towards elucidation of pathogenesis. Precise definition of disease entities also is required for comparison of data on clinical trials. Immunophenotypic analysis can also be utilized to identify potential targets for immunotoxin-directed therapies. The approach developed in the Hematopathology Section formed the basis for the Revised European-American Lymphoma (REAL) classification proposed by the International Lymphoma Study Group, and was adopted by the World Health Organization classification system.

Prior studies from our laboratory had established that lymphomatoid granulomatosis (LYG) was an Epstein Barr virus (EBV)-associated B cell lymphoproliferative disorder (LPD), with many similarities to post-transplant-associated lymphoproliferative disease. Based on a numerical predominance of T lymphocytes within the lesions, it had been suspected of being of T cell lymphoma. However, we showed an absence of clonal T cell receptor gene rearrangements. We identified it as a B cell LPD based on the frequent presence of clonal immunoglobulin gene rearrangements, as well as clonality of the EBV sequences. Patients with lymphomatoid granulomatosis frequently exhibit subtle or overt defects in cell-mediated immunity. Based on our laboratory observations, a new therapeutic protocol was initiated in collaboration with the Medicine Branch utilizing interferon alfa-2b as an immunomodulatory reagent. This treatment was demonstrated to be highly effective in inducing remissions, even in chemotherapy-resistant patients.

Recent studies in our laboratory have been directed towards an analysis of 1) the underlying immunodeficiency findings in patients with LYG; 2) the sequelae of the disease, both direct (i.e, the atypical lymphoproliferation which can progress to over lymphoma), and indirect (i.e., vasculitis, infectious complications, hemophagocytic syndrome); 3) immunologically-mediated sequelae of EBV-infection, including disregulation of cytokines and chemokines.

We also have been interested in identifying other unique clinicopathologic entities in the broad group of T cell lymphomas. We have helped to characterize hepatosplenic gamma/delta T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, cutaneous gamma-delta T-cell lymphoma, and extranodal NK/T-cell lymphoma, nasal and nasal-type.

We recently described a syndrome affecting young children of Asian and Hispanic decent associated with acute EBV infection, and leading to a fulminant T-cell lymphoproliferative disorder associated with the hemophagocytic syndrome. This report identifies another EBV-associated neoplasm with a genetically linked predisposition in Asian and Hispanic patients. This racial profile is similar to that of extranodal NK/T-cell lymphoma, nasal type, and expands the profile of EBV-associated malignancies. (Blood, 2000)

In collaboration with Dr. Stephen Straus, we have been characterizing the lymphoid lesions of patients with autoimmune lymphoproliferative syndrome (ALPS). We identified that patients with ALPS have a significantly increased risk of developing Hodgkin's lymphoma (>50 fold) and non-Hodgkin's lymphoma (>15 fold). These are predominantly germinal center derived lymphomas of diverse types. The development of lymphoma in ALPS can serve as a multifactorial model of lymphomagenesis related to: 1) defective apoptosis of B and T-cells; 2) Defective T-cell surveillance; 3) Autoimmunity; 4) B-cell stimulation related to increased IL-10 production; and 5) EBV-infection (50% of lymphomas were EBV+). (Blood, 2001)

Other aspects of our work relate to elucidating the relationship between Hodgkin's disease and non-Hodgkin's lymphomas (NHL), which is closer than once previously thought. Using immunophenotypic and molecular methods, we have explored the association of NHL and HD occurring both simultaneously and sequentially, and have investigated the pathogenetic factors responsible for histologic progression.

Recent Publications
Quintanilla-Martinez, L., Kumar, S., Fend, F., Reyes, E., Teruya-Feldstein,J., Kingma,D.W., Sorbara, L., Raffeld, L., Straus, S., Jaffe, E.S.: Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: A distinct clinicopathologic syndrome. Blood 96: 443-451, 2000

Beaty, M.W., Toro, J., Sorbara, L., Stern, J.B., Pittaluga, S., Raffeld, M., Wilson, W., Jaffe, E. S. Cutaneous Lymphomatoid Granulomatosis: Correlation of Clinical and Biological Features, Am. J. Surg. Pathol,25: 1111-1120, 2001

Jaffe, E.S., Harris, N.L., Stein, H. Vardiman, J.W. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001

Straus, S. E., Jaffe, E. S., Puck, J. M., Dale, J. K., Elkon, K.B., Rosen-Wolff, A, Peters, A.M.J., Sneller, M. C., Hallahan, C. W., Wang, J., Fischer, R. E., Jackson, C.M., Lin, A. Y., Baumler, C., Siegert, E., Marx, A., Vaishnaw, A.K. Grodzicky, T., Fleisher, T.A., and Lenardo, M. J.: The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98: 194-200, 2001.

Cong, P., Raffeld, M., Teruya-Feldstein, J., Sorbara, L., Pittaluga, S., Jaffe, E.S. "In situ localization of follicular lymphoma: description and analysis by laser capture microdissection. Blood, in press.

Collaborators
Wyndham Wilson, M.D.; Robert J. Kreitman, M.D.; Stephen E. Straus, NIAID, Thomas Waldmann, M.D., Giovanna Tosato, M.D