Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches

Table 1 Epstein-Barr virus-positive vs Epstein-Barr virus-negative post-transplant lymphoproliferative disorders[25]

	EBV-positive PTLD	EBV-negative PTLD
Molecular-genomic studies	Fewer genomic abnormalities	Share many genomic/ transcriptmic features with diffuse large B-cell lymphoma in IC patients
Origin	Mostly B-cell proliferative lesions	Mostly T-cell proliferative lesions
Gene-expression	“Non-germinal” center B-cell	“Germinal center B-cell type”[4]
Prevalence	More common (first peak)	Less common (second peak)
Risk of PTLD	Less risk compared to seronegative TR	Seronegative SOT pediatric TR are more vulnerable to develop PTLD with increased estimated risk of 10-75[16,17]
SOT vs HSCT	Almost all cases of HSCT (100%) are EBV positive	In SOT, both EBV positive and negative are present
Clinical consequences of EBV status	Less clear	Less clear
Prognosis/response to therapy in adults.	Not prognostic/predictive of response to therapy[21,23]
Common criteria	A considerable proportion of both EBV+ve and -ve PTLD respond to RI as a sole intervention[24]
Future studies	Whole-exome/genome wide sequencing and studies of role of EBV-associated microRNAs, may further define PTLD pathogenesis with more precise molecular-genomic classification of both EBV+ve and EBV-ve PTLD

RI: Reduction of immunosuppression; IC: Immunocompetent; PTLD: Post-transplant lymphoproliferative disorders; EBV: Epstein-Barr virus; HSCT: Haplo-identical allogeneic hematopoietic stem-cell transplant; KTR: Kidney transplant recipients; TR: Transplant recipients; SOT: Solid organ transplantation.

Table 2 Early vs late onset post-transplant lymphoproliferative disorders in adults[4]

	Early PTLD	Late onset PTLD
General characteristics	EBV positivity	Frequent EBV negative tumors
	Graft involvement	Less often graft involvement[3]
	Less often: Extranodal disease	Extra-nodal disease: Common
	Nondestructive PTLD1: Present early	High incidence of late onset Hodgkin’s lymphoma after allogeneic HSCT
	Less often: Monomorphic subtype[3]	Specific tumorigenic events: C-myc translocations
	Origin: higher % of donor-derived PTLD especially in 1st post-tx year)	Elevated LDH level
Risk factors	Same	Same
Response to therapy	Same	Same
Patient survival (at 1- and 5- yr)	65% and 46%, (In adult heart/lung tx)[1,45]	53% and 41% (In adult heart/lung tx)[1,45]
Future therapy	Proteasome inhibition (bortezomib) may be useful after allogeneic HSCT[3]
Role of immun-osuppression	Induction therapy has a role	Cumulative immunosuppression is crucial
Prevalence	Majority of PTLD cases	Less prevalent

¹Non-destructive post-transplant lymphoproliferative disorders includes plasmacytic hyperplasia post-transplant (according to the Classification of PTLD by the WHO). Tx: Transplantation; PTLD: Post-transplant lymphoproliferative disorders; EBV: Epstein-Barr virus; HSCT: Haplo-identical allogeneic hematopoietic stem-cell transplant; LDH: Lactate dehydrogenase.

Table 3 Early vs late onset post-transplant lymphoproliferative disorders in pediatrics[46]

	Early PTLD	Late PTLD
General criteria	Diffuse large B-cell or other B-cell lymphoma	Burkitt’s lymphoma and Hodgkin’s disease are late events[47]
	Atypical presentation (graft dysfunction, abdominal pain, frequent extra-nodal involvement in > 80% of TR)[46]	Frequent EBV negative tumors. Specific tumorigenic events e.g., C-myc translocations are restricted to late PTLDs
Time to PTLD	Shortest for lung, heart/lung TR. Early PTLD is quite frequent in liver TR (Late PTLD beyond 5 yr is rare, immunosuppression can be tapered/hold due to tolerance)	Longest for the heart TR and at risk for late PTLD even > 10 yr after trans-plantation
Patient survival	No significant difference in most published studies[20,47-49]
Distinct criteria	B-cell origin, almost exclusively EBV+ve, reflecting reduced immunosurv-eillance as major pathogenetic factor	Resembles tumors with distinct pathogenetic alterations and nodal appearance[46]
Role of immunos-uppression	Induction therapy has a role. More likely to develop graft rejection and switch to Tac before PTLD diagnosis	Cumulative immunosuppression is crucial

Tx: Transplantation; TR: Transplant recipient; PTLD: Post-transplant lymphoproliferative disorders; EBV: Epstein-Barr virus; HSCT: Haplo-identical allogeneic hematopoietic stem-cell transplant; LDH: Lactate dehydrogenase.