Overview of Classification Systems for Posttransplant Lymphoproliferative Disorders

• Frizzera et al., 1981
• Nalesnik et al., 1988
• Knowles et al., 1995
• Harris et al., 1997

Prior to 1981, lymphoid tumors in transplant patients were uniformly referred to as immunoblastic sarcomas. In that year, Frizzera and colleagues from the University of Minnesota examined tumors from a small number of renal transplant recipients. They observed several forms of lymphoproliferation which had not been previously described and applied the term "polymorphic" to emphasize the heterogeneity in size and shape of the tumor cells. Ancillary studies showed the tumors to be comprised of B lymphocytes. In the classification system of Frizzera et al., polymorphic diffuse B cell hyperplasia and polymorphic B cell lymphoma were distinguished from reactive lymphoid hyperplasia and from immunoblastic sarcoma. The authors stressed that the behavior of posttransplant lymphoproliferations could not be reliably predicted by pathologic studies alone.

In 1988, Nalesnik and colleagues reported their experience with PTLDs observed in the University of Pittsburgh transplant population. They also were unable to discern any significant difference in the clinical behavior of the two types of polymorphic lesions and combined them under the heading of polymorphic PTLDs. In contrast, lesions which resembled typical nonHodgkin's lymphomas also occurred and behaved, as a group, in a more aggressive fashion. In the classification system of Nalesnik et al., the term monomorphic PTLD was introduced to distinguish these lesions from polymorphic PTLDs. In a followup study in 1989, Locker and Nalesnik described several categories of PTLDs based on combined pathologic and molecular features. The most recalcitrant tumors had a monomorphic histology, were monoclonal, and contained rearrangements of the c-myc proto-oncogene.

In 1995, Knowles and his collaborators evaluated posttransplant lymphoproliferations in a series of heart transplant patients from Columbia-Presbyterian Medical Center. By combining morphologic appearance with molecular genetic analysis they were able to distinguish three separate categories of lesions. In the classification system of Knowles et al., the first category consisted of reactive hyperplasia of plasma cells. The second comprised the lesions of polymorphic hyperplasia and polymorphic lymphoma, both of which were monoclonal, but both of which were recognized to behave similarly. The third category was considered to represent true lymphomas and hematopoietic neoplasms which were monoclonal and could contain alterations in proto-oncogenes and/or tumor suppressor genes.

A Society for Hematopathology Workshop held in Duarte, California, in October 1995 led to discussions which expanded the spectrum of recognized posttransplant lymphoproliferations. However, the spectrum of categories continued to include reactive or early lesions, polymorphic PTLDs, and lesions which appeared to represent lymphomas or hematopoietic neoplasms. The Society for Hematopathology Workshop Classification includes additional lesions such as plasmacytomas, T cell rich B-cell lymphomas, and T cell lymphomas under the umbrella term of PTLD.

Selected References

1. Frizzera G, Hanto DW, Gajl-Peczalska KJ, Rosai J, McKenna RW, Sibley RK, Holahan KP, Lindquist LL. Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 41 4262-4279, 1981.
2. Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J. The pathology of posttransplant lymphoproliferative disroders occurring in the setting of cyclosporine A-Prednisone immunosuppression. Am J Pathol 133:173-192, 1988.
3. Locker J, Nalesnik M. Molecular genetic analysis of lymphoid tumors arising after organ transplantation. Am J Pathol 135:977-987, 1989.
4. Knowles DM, Cesarman E, Chadburn A, Frizzera G, Chen J, Rose EA, Michler RE. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplant lymphoproliferative disorders. Blood85:552-565, 1995.
5. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: Summary of Society for Hematopathology Workshop. Semin Diagn Pathol 14:8-14, 1997.

University of Pittsburgh.