**9. Other rare subtypes of PTLD**

Although the majority of monomorphic PTLDs fall into the category of diffuse large B-cell lymphoma, other types of lymphoma may also occur. These include plasma cell myeloma, classical Hodgkin lymphoma, or HL-like PTLD, EBV+ MALT lymphoma as well as various T-cell lymphomas with or without EBV infection.

#### **9.1. Burkitt PTLD**

A variety of lymphomas can develop as PTLD, although some types appear infrequently and remain poorly understood. PTLD-Burkitt lymphomas behave aggressively and require intensive chemotherapeutic intervention. These display the typical histological features of Burkitt lymphoma but are markedly positive for EBV. While BL-PTLD is a rare entity, it is a discrete form of PTLD with a high EBV expression and should be treated as a high-grade lymphoma. BL-PTLD historically represents a small, but significant, proportion of PTLD cases. BL-PTLD represents 15% of PTLD patients for pediatric heart, lung, and heart-lung transplants from 1982 to 2009, with a 1.1% overall incidence among pediatric transplant heart-lung recipients, 14% of our pediatric renal PTLD patients, 1.6% among kidney recipients, and 0.71% pediatric liver-transplant recipients, as reported in a single institution study. BL-PTLD is a more aggressive type of PTLD and does not respond to a trial of decreased immunosuppression like P-PTLD and some M-PTLDs. BL-PTLD does require cessation of conventional immunosuppression during treatment with multiagent lymphoma-specific chemotherapy. Bone marrow involvement remains a poor prognostic factor, despite the use of lymphoma-specific chemotherapy in these cases [20–24].

occur 8 months to 13 years following transplant. The large cells of HL-PTLD are pleomorphic B cells that react strongly for CD20 and/or CD79a and express CD30 but are usually negative for CD15 and have few mitoses. They are positive for EBV early RNA (EBER) using an EBER-1 probe, as are some of the background small lymphocytes. HD-PTLD is managed by withdrawal of immunosuppression and variably treated with rituximab to chemotherapy [27]. HL-PTLD and HD appear to be two related but immunophenotypically and biologically distinct forms of lymphoproliferation in posttransplant patients and may require different protocols for their management [27, 28]. Overall survival at 2 and 5 years was 86% with 81% of patients surviving event-free. Rituximab monotherapy has not been shown to lead to longterm remission, but treatment with classical HL chemotherapy is effective and tolerable. New treatment modalities such as CD30-targeted or EBV-specific agents may diminish toxicity.

Clinical and Pathological Review of Post Transplant Lymphoproliferative Disorders

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Within the PT-DLBCL series, EBV (+) cases were different from EBV (−) cases. The fact that all EBV (+) PT-DLBCL cases are of activated B-cell (ABC) origin whereas 45% EBV (−) PT-DLBCL cases were of GCB origin might contribute to the observed difference in survival. Overall, EBV (−) PT-DLBCL was similar to DLBCL arising in immunocompetent individuals regarding median age at diagnosis (63 versus 65 years). The amount of stromal infiltration was significantly higher in IC-DLBCL than PT-DLBCL (12/13 and 12/33 cases contained ≥15% stroma, respectively, P = 0.0012). Geographical necrosis was almost exclusively observed in EBV (+) PT-DLBCL (46%), compared to EBV (−) PT-DLBCL (11%). In contrast, there was no obvious difference in the absolute amount of stromal infiltration between both groups. IDO1 was variably expressed in the tumor and/or stromal cells of 7/22 EBV(+) PT-DLBCL. The Epstein–Barr virus broad latency profile (LMP1+/EBNA2+) was most frequently expressed in PT-DLBCL (n = 13/22; 59%) and associated with a more elaborate inflammatory response than intermedi-

Prevention of PTLD involves limiting the duration and degree of immunosuppression while still maintaining the adequacy of the donor graft. Achieving a balance of reduction in immunosuppression and preventing graft rejection or graft-versus-host disease can be challenging. Antiviral prophylaxis may also play a role in preventing PTLD, though data are scarce, particularly in SOT recipients. The use of antivirals such as acyclovir, valganciclovir, and ganciclovir is common for HSV, CMV, and EBV prophylaxis, though utilization varies according to

Many transplant centers will preemptively reduce immunosuppression and/or administer the anti-CD20 agent rituximab when EBV reactivation (i.e., ≥1000 EBV genome equivalents

**10. DLBCL vs. PTLD**

ate latency (LMP1+/EBNA2−).

**11. Therapy and prevention of PTLD**

institutional guidelines and protocols.

per mL) has occurred in the posttransplant setting.

BL after organ transplantation is often found in extra-nodal sites; it involves the central nervous system more frequently than it does in immunocompetent patients. In 70% of BL occurring after organ transplantation, genes or gene products related to EBV can be demonstrated within the tumor cells. The EBV status of the tumor is of important prognostic significance: EBV-positive BL occurring in organ transplant patients usually responds well to reduction or cessation of immunosuppressive therapy; in some cases permanent complete remissions can be achieved even without chemotherapy. In contrast, patients with EBV-negative BL have a very poor prognosis and rarely respond even to aggressive chemotherapy protocols [23].
