Lymphoma and plasma cell neoplasms
Posttransplantation lymphoproliferative disorders (PTLD)
General

Author: Dragos Luca, M.D. (see Authors page)

Revised: 21 March 2017, last major update September 2011

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Posttransplantation lymphoproliferative disorders (PTLD)

Cite this page: Posttransplant lymphoproliferative disorders. PathologyOutlines.com website. http://pathologyoutlines.com/topic/lymphomanonBposttrans.html. Accessed May 24th, 2017.
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 anti-thymocyte 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
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
Microscopic (histologic) images

Images hosted on other servers:

   

Various images

Flow cytometry description
Flow cytometry Images

Images hosted on other servers:

Various images

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
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