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Lymphoma - Non B cell neoplasms

Post-transplantation lymphoproliferative disorders (PTLD) - General


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 7 February 2012, last major update September 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● 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
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● 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
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● 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 non-myeloablative 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 post-transplant)

Etiology
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● 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

Pathophysiology
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● 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)

Sites
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● 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

Clinical features
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● 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 post-transplant, respectively

Case reports
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● EBV associated lymphoma of fetal origin in placental villi (Am J Surg Pathol 1999;23:595)
● Following non-myeloablative 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)

Treatment and prognosis
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● 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

Micro images
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Various images

Flow cytometry
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● Often negative for CD20 and surface immunoglobulin light chain negative (Arch Pathol Lab Med 2004;128:181)

Flow cytometry images
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Various images

Genetics and molecular
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● 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 (early lesions and P-PTLD)
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● Plasma cell neoplasms: no history of transplantation, architectural effacement, EBV-
● EBV+ diffuse large B cell lymphoma: no history of transplantation, usually complete architectural effacement, uniformly monoclonal
● Classical Hodgkin lymphoma: CD15+, CD20- (usually), no history of transplantation
● 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
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● 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
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● Resembles P-PTLD, polymorphic cells with geographic necrosis and some CD20+ Reed-Sternberg-like cells

End of Lymphoma - Non B cell neoplasms > Post-transplantation lymphoproliferative disorders > Post-transplant lymphoproliferative disorders


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