Evaluation

Serologic testing has traditionally been used to investigate EBV-related disorders. However, such testing may be unreliable in the transplant population as a result of altered antibody production by host immunosuppres-sion and passive transfer of antibody from blood products given in the peritransplant period. One of the most useful techniques to evaluate for EBV-PTLD is polymerase chain reaction (PCR) testing of peripheral blood, which may detect disease before the onset of clinical symptoms.30 High EBV viral loads in high-risk patients often predict for the development of EBV-PTLD. Aalto et al. evaluated serum samples from 12 HSCT recipients who had died from PTLD using quantitative PCR (qPCR) for EBV-DNA.31 They found that all of the PTLD patients became EBV-DNA positive with progressively rising copy numbers, and that EBV-DNA was first detectable 23 days before death, which was earlier than the onset of symptoms (which occurred 15 days before death). In their patient population, they noted that qPCR for EBV-DNA in serum was highly sensitive (100%) and specific (96%). However, Wagner et al. found that the detection of two or more levels of EBV-DNA above 4000 copies/mcg had a sensitivity of 100% for the prediction of early PTLD but a specificity of only 50%.32 Carpentier et al. evaluated the utility of EBV early-antigen (EA) serologic testing in conjunction with peripheral blood EBV-DNA viral load testing as a marker for risk of PTLD. They found that at the EBV-DNA threshold at which PTLD occurs, the positive predictive value based on the absence of high-titer EA antibody was increased to 75%; that is, patients with high EBV-DNA load but without significant EA antibody titers had a 75% risk of developing PTLD.33 Such testing would not be useful in patients with EBV-negative PTLD or those EBV-positive patients who do not shed large amounts of EBV into the peripheral blood.34

Detailed radiologic investigations including CT scans of the chest, abdomen, and pelvis are necessary to evaluate the extent of disease. Patients with GI complaints may require endoscopy with biopsy. Thoracentesis may be necessary to evaluate pleural effusions, and paracentesis to evaluate ascites. Patients with CNS signs or symptoms or abnormal head CT

Figure 62.1 PTLD: reactive plasmacytic hyperplasia-type polyclonal

scans or MRI scans may warrant a lumbar puncture with CSF evaluation. Castellano-Sanchez et al. reported the features of 12 patients with primary CNS PTLD; by neuroimaging, most patients showed multiple (3-9) intra-axial, contrast-enhancing lesions. CNS PTLDs were noted to be uniformly high-grade lymphomas and were associated with extremely short survival periods.35

Tissue biopsy confirms the diagnosis of PTLD. Excisional biopsy provides adequate tissue for evaluation of cell type, clonality, virologic studies, and architectural background (Figures 62.1 to 62.8). Cytology alone has a limited role in the diagnosis of PTLD as it does not permit subclassification. Immuno-phenotyping by flow cytometry or immunohisto-chemistry should be performed to determine the cell type (B vs T) and cell marker status, which may direct therapy (e.g., CD20 expression). While the majority of these are B-cell tumors and are associated with EBV, approximately 9% of all PTLD and as many as 27% of EBV-negative tumors may be of T-cell origin.26-28 PTLD can be confused with organ transplant rejec-

Figure 62.3 PTLD: polymorphic monoclonal

tion unless the cells are identified as B cells by B-cell markers such as CD19, CD20, CD21, or CD22. Also, PTLD may coexist with acute rejection. When the allograft itself is affected, histologic features such as plasmacytoid infiltrates, immunoblastic cells, nodular infiltrates, and serpiginous necrosis, especially in the absence of neutrophils, is suggestive of PTLD. Tumor clonality may be determined by evaluating for immunoglobulin or T-cell receptor gene rearrangements. Evaluation for viral markers should also be performed with in situ hybridization for Epstein-Barr early RNA (EBER) or immunostaining for EBV LMP.316 A formal classification system of PTLD was established by two international consensus groups (ASTS/ ASTP EBV-PTLD Task Force and the Mayo Clinic organized International Consensus Development Meeting on EBV-Induced PTLD) and published in 1999.3 They suggested that the term PTLD should be used to encompass the large spectrum of EBV lymphoproliferative processes seen after organ or stem cell transplantation.

Figure 62.2 PTLD: polymorphic polyclonal type Figure 62.4 PTLD: monomorphic

Figure 62.7 PTLD: plasmacytoma-like (monoclonal kappa)

Figure 62.5

Figure 62.7 PTLD: plasmacytoma-like (monoclonal kappa)

In addition, they recommended that posttransplant IM and plasma cell hyperplasia continue to be included under the heading of PTLD, but that they be clearly segregated as reactive hyperplasias. They also recommended that the term PTLD, when not further qualified, be used to refer to neoplastic forms of PTLD that are termed "polymorphic PTLD" (including polymorphic lymphoma and polymorphic B-cell hyperplasia, which can be a monoclonal lesion), or "lym-phomatous" PTLD (including so-called monomorphic PTLD). Harris et al. described polymorphic PTLDs as destructive lesions that produce architectural effacement of lymph nodes but that, unlike most lymphomas, show a full range of B-cell maturation from immunoblasts to plasma cells with small- and medium-sized lymphocytes and numerous cells resembling centrocytes/cleaved follicular center cells.36 In contrast, monomorphic PTLDs often have sufficient architectural and cytological atypia to be categorized

Figure 62.6 PTLD: Burkitt's type (EBVISH)

as high-grade lymphomas. Monomorphic PTLDs are characterized by infiltrates causing nodal architectural effacement with confluent sheets of transformed cells; all or most cells are large, transformed, blastic cells with prominent nucleoli and basophilic cytoplasm.36 Most monomorphic PTLDs fall into the category of diffuse large cell lymphomas. The consensus groups also stated that neoplastic forms of EBV-positive PTLD should ideally have (1) disruption of underlying architecture by a lymphoproliferative process, (2) presence of monoclonal or oligoclonal cell populations as revealed by cellular and/or viral markers, and (3) evidence of EBV infection in many of the cells. The demonstration of a lymphoid tumor containing unequivocal evidence of any two of these features was felt to be sufficient to establish the diagnosis of neo-plastic PTLD. A working diagnosis could be made in the presence of (1) or (2) alone in the proper clinical setting. In practical terms, this eliminates all inflammatory lesions in which EBV might be demonstrated, with the exceptions of plasma cell hyperplasia and IM.

Figure 62.8 PTLD: myeloma type

Figure 62.6 PTLD: Burkitt's type (EBVISH)

Figure 62.8 PTLD: myeloma type

Table 62.3

Harris formulation

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