POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
Solid-organ and allogeneic hematopoietic cell transplantation have revolutionized our ability to treat disease. Immunosuppression may have negative consequences, however, such as an earlier onset and an increased frequency of malignant tumors of the skin, cervix, and colon. A new entity, a group of disorders collectively known as post-transplant lymphoproliferative disorders (PTLDs), has emerged. The group contains primarily of B-cell–mediated lymphoid and/or plasmacytic cell proliferations that have the potential for malignant transformation to lymphoma. They are the most common causes of malignancy, following solid- organ transplantation. Conversely, PTLDs account for only a minority of cancers following hematopoietic cell transplantation. The risk is highest in the first year and then drops significantly. PTLDs remain a significant cause of early graft failure and death, however.
Genetic,
immunologic, morphologic, and clinical factors are used to identify three types
of PTLDs: (1) plasmacytic hyperplasia and infectious mononucleosis-like PTLD,
(2) polymorphic PTLD, and (3) monomorphic PTLD (Table 1). Epstein-Barr virus
has been implicated in most malignant diseases; this fact high- lights the risk
of T-cell immunosuppression.
Mononucleosis
caused by Epstein-Barr virus is normally characterized by a polyclonal B-cell
proliferation, which is held in check by T-cell suppressor cells. By
down-regulating antigenic expression, some B cells will evade T-cell
suppression and lay dormant throughout life, until a period of immunocompromise
or immune-suppression develops.
In
patients who have undergone solid-organ transplant, recipient T cells are
inhibited by calcineurin inhibitors, promoting dormant B-cell proliferation. In
allogeneic hematopoietic cell transplant recipients, the T cells are inhibited
by administration of antithymocyte globulin and other cytotoxic agents.
Interestingly, most allogeneic hematopoietic cell transplant PTLDs are derived
from donors positive for Epstein-Barr virus. Dormant cells from such donors are
held in check by donor T cells until the time of transplant. Following
transplantation, these T cells are inhibited, allowing B-cell expansion.
Plasmacytic
hyperplasia and infectious mononucleosis-like PTLD can occur early in the
course after transplant. A viral prodrome similar to that of infectious
mononucleosis, including fatigue, fever, and weight loss, is common with all
these phenotypes. No atypical architectural distortions are demonstrated on
histologic studies. Symptoms may resolve with time as immunosuppression is
slowly reduced and the recipient recovers from the initial transplantation.
Polymorphic
PTLDs do not meet all the criteria for malignant lymphoma but do demonstrate
malignant transformation. They commonly present with complications of a focal
mass effect, such as bowel obstruction, lymphadenopathy, or focal lesions.
Monomorphic
PTLD generally presents as a dis-seminated malignant lymphoma of which the
majority are non-Hodgkin lymphomas of B-cell origin. Clinical presentations are
similar for disease with indolent or aggressive symptoms.
In
solid-organ transplant patients, a PTLD arising from the donor is generally
focused within the allograft tissue. This presents a great risk for allograft dysfunction
and/or loss. However, when the PTLD arises from host tissue cells, a number of
different organs, including distal sites such as the skin, liver, lung, or
central nervous system, are typically involved.
Ninety
percent to 95% of recipients are positive for Epstein-Barr virus, accounting
for most cases of PTLD. Up to 30% of patients are negative for the virus. These
patients represent genetically and immunologically distinct tumors that are
poorly understood. Therefore, thoughtful evaluation of the donor/recipient
Epstein-Barr virus status is important. Vigilant assessment of symptoms and
laboratory abnormalities, such as hypercalcemia, hyperuricemia, or elevated
lactate dehydrogenase levels; unexplained decreases in cell counts (in anemia,
thrombocytopenia, leukopenia); and monoclonal serum and urinary protein levels,
may help detect PTLDs earlier. Radiologic studies, including positron emission
tomography scanning, MRI, or ultrasound studies, are useful to help guide
tissue biopsy whenever possible to confirm or refute an underlying disorder.
Treatment
should initially consider reduction of T-cell immunosuppression while
minimizing the risk of allograft loss. Patients
with polymorphic PTLD or monomorphic PTLD that tests positive for CD20 cells
will benefit from receipt of a monoclonal antibody against B cells such as
rituximab, which has good mechanistic utility in halting progression. Mono-
morphic PTLD otherwise is best treated with CHOP (cyclophosphamide,
doxorubicin, vincristine, prednisone). A novel therapy, termed adoptive
immunotherapy, infuses Epstein-Barr virus–specific cytotoxic T lymphocytes
into the donor to treat PTLD associated with the virus. Antiviral therapies such
as ganciclovir are typically used for cytomegalovirus prophylaxis but
demonstrate activity against Epstein-Barr virus, with the unfortunate risk of
bone marrow suppression. Focal lesions are successfully treated with
chemotherapy and radiation therapy.
In general, the degree of T-cell immunosuppression, the recipient’s age and ethnic background and the aggregate time that has passed since transplant will also affect the risk for development of PTLDs. Thoughtful posttransplant clinical and la oratory surveillance is critical to diagnosing PTLDs.
