Posttransplant lymphoproliferative disorders

Lymphoma & related disorders

Posttransplant lymphoproliferative disorders (PTLD)

Topic Completed: 1 September 2011

Minor changes: 29 December 2020

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PubMed Search: Posttransplantation lymphoproliferative disorders (PTLD)

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Cite this page: Luca DC. Posttransplant lymphoproliferative disorders. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBposttrans.html. Accessed May 6th, 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

Microscopic (histologic) images

Images hosted on other servers:

Various images

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