Post-transplant lymphoproliferative disorder (PTLD) is the name given to a group of B cell lymphomas occurring in immunosuppressed patients following organ transplant. It is an uncommon condition occurring in 0.2% of patients within one year of transplant, with an annual incidence of 0.04% thereafter. The risk of developing the disease is higher in children and recipients of heart transplants.
The disease is an uncontrolled proliferation of B cell lymphocytes following infection with Epstein-Barr virus. Production of an interleukin-10, an endogenous anti-T cell cytokine, has also been implicated. In immunocompetent patients, Epstein-Barr virus causes infectious mononucleosis, characterised by a proliferation of B-lymphocytes which is controlled by Suppressor T cells. However, calcineurin inhibitors (tacrolimus and cyclosporine) used as immunosuppressants in organ transplantation inhibit T cell function, and can prevent the control of the B cell proliferation. Depletion of T cells by use of anti-T cell antibodies in the prevention or treatment of transplant rejection further increases the risk of developing post-transplant lymphoproliferative disorder. Such antibodies include ATG, ALG and OKT3. Polyclonal PTLD may form tumor masses and present with symptoms due to a mass effect, e.g. symptoms of bowel obstruction. Monoclonal forms of PTLD tend to form a disseminated malignant lymphoma.
The diagnosis of PTLD may often be complicated. Initial studies are often focused on the manifesting symptoms, such as imaging localization of the mass and determination of its extent, invasiveness, and homogenicity. Ultrasonography, CT scanning, or MRI can be used, depending on the area of interest. Pickhardt et al have published an extensive series of reviews of imaging features of PTLD by body segment.26, 27, 28, 29, 30 CT scanning is preferred for abdominal and chest imaging. Either CT scanning or MRI can be performed for neuroimaging. Bone marrow biopsies are necessary to help define marrow involvement, which may rarely be the only affected tissue. These imaging and biopsy tests may also be repeated after treatment to assess the response. Concomitant serologic tests (ie, immunoglobulin [Ig] G and IgM) should be performed to determine recent EBV or CMV primary or secondary infection. The sera can also be analyzed for Epstein-Barr–viral capsid antigen (EB-VCA). Histopathologic diagnosis of biopsy tissue remains the criterion standard for making the diagnosis of PTLD. Using light microscopy, infiltrates of polymorphous or monomorphous mononuclear cells (small lymphocytes and plasma cells) are observed that disrupt the architecture of the invaded tissue, such as the lymph node. Depending on the degree of proliferation and dedifferentiation, lesions may be characterized as hyperplastic, lymphomatous, or intermediate. Abnormal cells may be positive for the B-cell markers CD19, CD20, CD21, or CD22, although not in every patient. Lymphocyte CD20 expression is of value on determining therapy choices. Determination of cell surface heavy and light chain Ig expression allows for classification as polyclonal or monoclonal. Detailed cytogenetic studies may be needed in patients with nuclear changes suggestive of frank malignancy. EBV can frequently be revealed within the abnormal cells using various methods. Epstein-Barr–encoded RNA can be detected by the Ebstein-Barr early region (EBER) immunostaining assay . The EBV latent membrane protein (LMP) can also be identified through immunostaining. Some PTLDs demonstrate Reed-Sternberg–like cells that may cause confusion with Hodgkin disease; CD15 staining is typically positive in true Hodgkin disease and negative in the HD-like condition. PTLD may occur alongside acute rejection, and the diagnoses may be difficult to separate, especially with T-cell PTLD within the allograft. According to Nalesnik, the features that favor the diagnosis of PTLD in such cases include nodular infiltrates, serpiginous necrosis, plasmacytoid and immunoblastic cells, and absence of ancillary cells such as neutrophils. In an effort to improve the likelihood of successful therapeutic interventions, many investigators have studied methods that may result in early identification of disease in patients at high risk for this disorder. Monoclonal proteins, particularly IgM-related proteins, have been reported to appear with greater frequency in serum and urine of patients with PTLD (71%) than in patients without PTLD (27%). Darenkov et al reported that CD19+ B cells could be detected in the peripheral blood of patients with PTLD but not in those without PTLD, provided no antiviral prophylaxis was used. Of greater promise are the variations of quantitative or semiquantitative polymerase chain reaction (PCR) techniques to detect EBV viral DNA from the peripheral blood lymphocytes. These techniques measure DNA in blood that can be membrane bound or free. Multiple studies have demonstrated that increased EBV viral loads can be used to differentiate between latent infection and PTLD. Rooney et al showed that levels of EBV DNA between 20,000 and 200,000 copies per microgram of peripheral blood DNA were associated with subsequent PTLD (normal
The prognosis of PTLD widely varies. Most mild cases regress, but graft rejection may occur (reported rates vary widely from 10-60%). The outlook for more severe cases is less favorable, particularly in frank malignancies or CNS PTLD. Although individual centers with high PTLD rates report good patient and graft survival rates, multicentered registry data suggest somewhat poorer graft survival outcomes. Non-EBV positive or late onset cases have a poorer prognosis.
PTLD may spontaneously regress on reduction or cessation of immunosuppressant medication, and can also be treated with addition of anti-viral therapy. In some cases it will progress to non-Hodgkin's lymphoma and may be fatal.