College of American Pathologists Hematology and Clinical Microscopy Resource
Post-transplant lymphoproliferative disorder
(PTLD) is an expansion of one or more clones of lymphoid cells that occur
in the setting of induced immunosuppression for either solid organ or
bone marrow transplant (BMT). While the etiology is not entirely understood,
most cases are thought to arise as an exaggerated immune response to a
primary Epstein-Barr virus (EBV) infection or reactivation. EBV infection
is primarily controlled by T-cell immune surveillance and these cells
are the primary target of immunosuppression typical of transplant regimens.
As such, most cases of PTLD involve an expansion of B-cell clones. Still
to be explained is the uncommon occurrence of T-cell forms of PTLD and
EBV-negative PTLD which account for about 20% of cases.
The frequency, sites of involvement and onset of PTLD
are all related to the type of graft and immunosuppressive regimen employed.
PTLD affects 1-5% of patients with solid organ transplants with variation
among the different types of allograft. BMT recipients are generally considered
low risk for PTLD (~1%); however, HLA-mismatched transplants, T-cell depleted
bone marrow grafts and immunosuppression for graft-versus-host disease
(GVHD) can have rates as high as 20%. Patients may present with either
nodal or extranodal involvement, while blood involvement is uncommon.
Nodal and GI involvement are typical of cyclosporine or tacrolimus-based
regimens, while azathioprine-based regimens typically have a clinical
picture dominated by extranodal disease including CNS involvement.
In addition, PTLD affects the allograft in 25% of cases,
thereby complicating evaluation of graft rejection. The majority of cases
of PTLD in BMT patients occur in the first 5 months after transplant.
The presentation in solid organ cases is more delayed, with a mean interval
to PTLD of 15 months for those treated with cyclosporine A and 48 months
in those treated with azathioprine. The median interval to EBV-negative
PTLD is much greater (4-5 years) than that of EBV-positive PTLD (6-10
The pathologic features of PTLD are quite variable,
as expected with the proposed mechanism of an exaggerated immune response
to EBV. In early lesions, one may see only plasmacytic hyperplasia or
an infectious mononucleosis-type reaction within lymph nodes. More advanced
is the polymorphic form of PTLD, which is characterized by some degree
of effacement in lymph node architecture. Finally, monomorphic PTLD and
Hodgkin lymphoma-like PTLD shows lymphoid proliferations that mimic typical
non-Hodgkin lymphoma or Hodgkin lymphoma respectively.
Studies to determine clonality, including immunophenotyping
and molecular analysis of antigen receptors, demonstrate polyclonal proliferations
in the early PTLD lesions, while monoclonal proliferations characterize
the polymorphic and monomorphic variants. Interestingly, oncogene mutations
are typically observed in the monomorphic but not the polymorphic forms.
Of clinical relevance, decreasing immunosuppression leads to resolution
in most cases of early PTLD (plasmacytic hyperplasia and infectious mononucleosis-like
PTLD) and some cases of polymorphic PTLD, while the monomorphic variants
generally require treatment with chemotherapy.
Brunning RD ME, Harris NL, Flandrin G, Vardiman J,
Bennett J, Head D. Acute myeloid leukaemia: Introduction. In: Jaffe ES
HN, Stein H, Vardiman JW, eds. World Health Organization Classification
of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid
Tissues. 1st Ed. Lyon, France: IARC Press; 2001:75-107.
Le Beau M. Role of cytogenetics in the diagnosis and
classification of hematopoietic neoplasms. In: Knowles D, ed. Neoplastic
Hematopathology. 2nd Ed. Philadelphia, Pa.: Lippincott Williams &
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NewsPath® Editor: Megan J.
DiFurio, MD, FCAP
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