**3.1. CD20 positivity**

The prognostic role of CD20 expression and Epstein–Barr virus (EBV) positivity in PTLD after SOT is poorly understood. In a retrospective study, a total of 45 pediatric SOT patients (28 heart, 11 liver, and 6 kidney) were diagnosed with PTLD 45 months after SOT. Of the 40 evaluable PTLD cases (11 monomorphic, 19 polymorphic, 5 early lesions, and 5 rare subtypes), 32 (80%) had detectable EBV, and 28 (70%) were classified as CD20 (+). Patients whose PTLD expressed CD20 or EBV had shorter intervals between SOT and PTLD onset (28 vs. 64 or 77 months for CD20 and EBV, respectively) (P < 0.02). Patients with CD20 (+) tumors had higher 5-year PTLD-related EFS (83.7% vs. 28.6%, P < 0.001) and OS (95.8% vs. 56.3%, P = 0.01). EBV expression was unrelated to PTLD-related EFS or OS. CD20 expression is thus found to be associated with timing of development of PTLD and predicts survival in pediatric PTLD in SOT [11].

latency (LMP1+/EBNA 2-) with a role for innate and tolerogenic immune response in EBV + PT-DLBCL. EBV signature is the most important factor in the pathogenesis of EBV (+)

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Clinical, pathological, and molecular genetic characteristics of PTLD show that EBV-positive and EBV-negative PTLDs have distinct gene expression profiling with clustering related to EBV status than immune status. Except for decreased T-cell signaling, EBV-negative PTLDs are inseparable from EBV-negative IC-DLBCL. In contrast, an EBV viral response signature is

Systematic morphological, immunophenotypic, and genetic analysis of each PTLD case should be performed. In DLBCL type, one may apply BCL-6, CD10, and MUM-1 immunostains in order to establish the cell of origin according to the Hans algorithm [17]; but the value of this assignment is not well established in this setting. Based on EBV protein expression, the latency type of EBV infection is defined as LMP1-/EBNA2- (type I, restricted), LMP1+/EBNA2- (type II, intermediate), and LMP1+/EBNA2+ (type III, broad). The stromal infiltrate can be estimated semiquantitatively based on the ratio of tumor cells and stromal cells in the entire tissue section. In situ hybridization: EBER (EBV-encoded RNA) in situ hybridization is considered the standard for diagnosis of EBV infection and should be performed in all PTLD cases. PTLD cases are defined as EBV (+) if EBER was expressed in all tumor cells in which RNA was preserved [14].

Epstein-Barr virus-positive (EBV (+)) and EBV-negative (EBV (−)) PT-DLBCL have distinct gene expression profiles, and the transcriptomic profile of EBV (−) PT-DLBCL is similar to that of DLBCL in immunocompetent individuals (IC-DLBCL) and supports the hypothesis that EBV (−) PT-DLBCL are de novo lymphomas. EBV (+) and EBV (−) PT-DLBCL have distinct aCGH profiles and shared only one recurrent imbalance. EBV (−) PT-DLBCL, however, display at least ten aberrations recurrent in IC-DLBCL, among which characteristic gain of 3/3q and 18q and loss of 6q23/TNFAIP3 as well as 9p21/CDKN2A. The most prevalent aberration in EBV (+) PT-DLBCL is due to gain/amplification of 9p24.1 targeting PDCD1LG2/PDL2. FOXP1 oncogene and the tumor suppressor CDKNA2 implicated in EBV (−) DLBCL do not

Destructive PTLD, which has typically not correlated with other specific risk factors, has recently been shown to be associated with older recipient age and prolonged receipt of

clearly shown to segregate EBV (+) PT-DLBCL from EBV (−) PT-DLBCL [14, 16].

**4. EBV-positive PTLD vs. EBV-negative PTLD**

play a critical role in the pathogenesis of EBV (+) PT-DLBCL [14].

**5. Nondestructive vs. monomorphic PTLD**

PT-DLBCL [14].

**3.5. Genomic profiling of PTLD**

**3.6. PTLD diagnostic algorithm**
