Table of Contents
Definition / general | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Case reports | Prognosis and treatment | Microscopic (histologic) images | Flow cytometry description | Molecular / cytogenetics description | Differential diagnosis | Variant associated with fludarabine treatmentCite this page: Luca DC. Posttransplant lymphoproliferative disorders. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBposttrans.html. Accessed January 22nd, 2021.
Definition / general
- Lymphoid or plasmacytic proliferations due to immunosuppression in a recipient of a solid organ (SOR), bone marrow (BMR) or stem cell (SCR) allograft
- Comprise a spectrum ranging from EBV driven infectious mononucleosis type polyclonal proliferations to EBV positive or negative proliferations indistinguishable from a subset of B cell or less often T cell lymphomas that occur in immunocompetent individuals (WHO Classification, 2008)
Terminology
- Monomorphic (M-PTLD) and Hodgkin-like PTLD are further categorized as in immunocompetent individuals, according to the lymphoma they resemble
- Indolent B cell lymphomas (follicular, MALT) in allograft recipients are not considered PTLD and are designated as in a normal host
- Note: AIDS associated lymphoproliferative disorders are similar
Epidemiology
- Most important risk factor for EBV driven PTLD is EBV seronegativity at time of transplantation
- 95% are B cell, 5% are T cell
- Affects 5% of transplant patients (10% of children, 3% of adults), who have 50:1 relative risk for non-Hodgkin B cell lymphoma
- Adult solid organ recipients: kidney; < 1%; liver and heart; 1 - 2%; heart-lung; 2 - 6%, lung; 4 - 10%, intestine; 20% (significantly higher rates in children)
- Bone marrow and stem cell - generally low risk (~1%) but rate of up to 22% if two of these factors: unrelated / HLA mismatched related donors, donor bone marrow selective T cell depletion, use of antithymocyte globulin or anti-CD3
- Unexpectedly high risk of EBV driven PTLD (17%) is associated with unrelated umbilical cord blood transplants with a nonmyeloablative preparative regimen containing anti-thymocyte globulin
- In lung transplant patients, lung usually involved, occurs median 7 months after transplant (vs. 41 months for other organs), short survival (Mod Pathol 2002;15:647)
- PTLD-like lesions are rare after autologous bone marrow transplant (are considered iatrogenic, not posttransplant)
Sites
- Lymph nodes, GI tract, lungs, liver - common; CNS - rare; Bone marrow - uncommon; peripheral blood - rare
- Allograft involvement in solid organ recipients may cause confusion with rejection or infection; very rare in the transplanted heart
- Early lesions often present in tonsils or adenoids
- Bone marrow recipients tend to have widespread disease: lymph nodes, liver, spleen, GI tract, lungs
Pathophysiology
- Arise from germinal center or post-germinal center B cells (B-PTLD)
- EBV infection of lymphocytes (usually from host; subclinical or infectious mononucleosis) immortalizes B cells
- Extended life of EBV infected B cells increases the probability of acquiring additional molecular aberrations that confer growth advantage
- Immunosuppressed patients unable to mount the usual T cell cytotoxicity, causing plasmacytic and polyclonal lymphocytic proliferation
- Monoclonal populations may emerge and with mutations, cause malignancy
- Tumors of donor origin may be more indolent than of recipient origin (Mod Pathol 2000;13:1180)
Etiology
- Associated with intense immunosuppression (decreased T cell immune surveillance) that accompanies solid organ and bone marrow transplantation
- Majority (up to 80%) are EBV related (usually type A); infection occurs shortly after transplantation
- Prior to PTLD onset: serum EBV antibody titer and blood EBV DNA load increase, number of EBV+ cytotoxic T cells decreases
- Usually monoclonal B cell, less often polyclonal B cell or monoclonal T cell proliferations
- ~30% are EBV negative; 2/3 of T-PTLD are EBV negative
- EBV negative PTLD: increasing incidence, more common in adults, tend to occur later than EBV positive cases, more likely to be monomorphic
- Etiology of EBV negative PTLD unknown in most cases (may be due to EBV that is no longer detectable); HHV8+ PTLD including primary effusion lymphoma has been reported
- SV 40 detected in 13% of cases, restricted to malignant cells (Hum Pathol 2006;37:1130)
- Most ( > 90%) PTLD in SOR are of host origin, a minority is of donor origin (most commonly in liver and lung allograft recipients, also involving the graft)
- Most PTLD in BMR are of donor origin
- Higher risk with certain types of immunosuppressive drugs: tacrolimus, OKT3 monoclonal antibody, antithymocyte globulin
Clinical features
- Infectious mononucleosis-like, GI or systemic symptoms, organ specific dysfunction
- Highly variable, function of allograft type and morphologic category
- SOR (usually managed with cyclosporin or tacrolimus): presents during first year of transplantation
- BMR: within the first 6 months
- EBV negative and T/NK PTLD: occur 4 - 5 and 6.5 years posttransplant, respectively
Case reports
- EBV associated lymphoma of fetal origin in placental villi (Am J Surg Pathol 1999;23:595)
- Following nonmyeloablative allogeneic stem cell transplant (Am J Surg Pathol 2004;28:794)
- EBV+ T cell PTLD in a pediatric liver transplant patient (Am J Surg Pathol 2004;28:967)
Prognosis and treatment
- Stop immunosuppressive therapy; give acyclovir or interferon alpha; use chemotherapy (including single agent rituximab) for polymorphic or monomorphic disorders
- Early lesions: tend to regress with reduction in immune suppression, excellent prognosis (if no graft rejection), particularly in children
- Polymorphic (P-PTLD) and (less often) M-PTLD may also regress but rejection leading to graft loss and death may occur
- P (some) and M (more often) PTLD may not regress and require additional therapies (chemo +/- anti-CD20)
- Myelomatous lesions: usually no regression with reduced immunosuppression
- T/NK cell PTLD: aggressive (except LGL-type), some may respond to restoration of the immune system
- Plasmacytoma-like PTLD: variable outcome
- Other negative prognostic factors: EBV negativity, multiple site involvement, advanced stage, older age, late onset, high IPI, high LDH
- Mortality: BMR > SOR; adults > children
- Remission / response may occur in patients treated with EBV specific T cells
Flow cytometry description
- Often negative for CD20 and surface immunoglobulin light chain negative (Arch Pathol Lab Med 2004;128:181)
Molecular / cytogenetics description
- Determine clonality by flow cytometry in addition to genotypic studies (Am J Clin Pathol 2002;117:24)
- mTOR pathway activated in all types of PTLD
Differential diagnosis
- Classical Hodgkin lymphoma: CD15+, CD20- (usually), no history of transplantation
- EBV+ diffuse large B cell lymphoma: no history of transplantation, usually complete architectural effacement, uniformly monoclonal
- Plasma cell neoplasms: no history of transplantation, architectural effacement, EBV-
- Reactive follicular hyperplasia: no effacement of the architecture, no clonality, EBV- (usually)
- Note: for M-PTLD, differential diagnosis is same as for corresponding lymphomas in the immunocompetent host
Variant associated with fludarabine treatment
Definition / general:
- Arises in patients with CLL or splenic marginal zone lymphoma treated with fludarabine (Am J Surg Pathol 2002;26:630)
- Treatment was excision, nothing (regressed spontaneously), chemotherapy or antiviral therapy
- Tumors clonally distinct from initial B cell tumor
Micro description:
- Resembles P-PTLD, polymorphic cells with geographic necrosis and some CD20+ Reed-Sternberg-like cells