Case 22 – summary

Our patient had undergone emergency liver transplant for a paracetamol overdose 9 months ago. He had been well, but on routine clinic visit was noted to be progressively more pancytopenic with deteriorating LFTs. His EBV PCR had risen rapidly and he gave (vague) history of weight loss and fever; imaging revealed stage 4B disease with nodes in the thorax, pelvis and groin and bone marrow and liver involvement. Bone marrow biopsy confirmed the presence of an EBV positive monomorphic PTLD of DLBCL subtype. Management options include reduction of immunosuppression and chemo-immunotherapy.

The important learning point of this case is that pancytopenia in transplant patients may be due to a number of different conditions, many of which are serious and require rapid investigation and diagnosis.

The differential diagnosis for cytopenias in SOT patients is briefly summarised below:

Process	Onset	Cell lineage	Other key features	Investigation	Management	Prognosis
Passenger Lymphocyte Syndrome(ABO mismatched SOT)	1-3 weeks	Red cells (recipient cells haemolysed by PLs producing Ab)		Haemolysis screen and identification of ABO abs	Transfusion support	Good
Drug Induced	variable	Ganciclovir and valgan = all; immunosuppressives = all, Septrin = all	May trigger autoimmune cytopenias through immune dysregulation	Withdraw drug and observe response; check folate; invx as per autoimmune process	Withdraw drug where possible
Thrombotic micorangiopathy	Usually in first 3 months	RBC and plts	Renal impairment	Check viruses and ADAMTS13	Withdraw immunosuppression, consider plasma exchange, treat viruses	Variable
HHV6/HHV8	variable	Leukopenia predominates		PCR	Respond to gancoclovir/foscarnet/cidofovir	Good
Parvovirus B19		Red cells		Parvovirus PCR	Supportive +/- IVIG	Good
Haemophagocytosis	Usually in first 3 months	All	Often EBV drivenHigh ferritin and triglycerides	BMA&TViral screen?PTLD	Treat any infective or PTLD trigger	Poor (app 50% survival)
PTLD	Usually first year	Pancytopenia	Nodal and extranodal disease	BM A&T, CT staging and biopsy of lesion	Withdrawal of immunosuppression; rituximab; chemotherapy	Depends on histological subtype
SOT GVHD	Usually within 1 month	Pancytopenia	Skin, liver and gut dysfunction	BM A&T, chimerism	controversial	Poor 30-100% mortality depending on organ of transplant
Immune mediated cytopenias	Variable	Can cause PRCA, ITP or AIHA		As per non transplant pt; exclude viruses		variable

Summary of PTLD

• Occurs in up to 10% of SOTs.
• 85% of cases are of B cell lineage in the western world. T lineage PTLD is more common in the far east and is HTLV driven.
• 80% are EBV driven. EBV is able to induce blastic transformation and proliferation of B cells. In healthy patients T cells control EBV infection, but once T cell function is lost proliferation may occur unchecked. It is this mechanism that explains management options in EBV driven PTLD: firstly to remove immunosupression and allow T cell regeneration (although not a viable option in T cell depleted HSCT, T cell reconstitution in SOT is rapid on withdrawal of immunosuppression), and secondly to use rituximab to control B cell proliferation.

Histological classification of PTLD

1) Early lesions

• Usually seen within a year of transplant.
• Most likely to be seen in patients who were EBV negative pre-transplant.
• Polyclonal or oligoclonal EBV DNA and IgH.
• Histology shows preservation of normal architecture and is classified as either plasmacytic hyperplasia or Infectious Mononucleosis-like, although there is significant morphological overlap.

2) Polymorphic PTLD

• More malignant histological changes with effacement of normal architecture and clonal IgH and EBV DNA. However the lymphocyte infiltrate remains polymorphic.

3) Monomorphic PTLD

• All forms of T cell PTLD are classified as monomorphic and are subcategorised as per WHO lymphoma classifications in the non-PTLD setting. This is a small proportion of monomorphic PTLD; the majority of cases are of the B cell lineage.
• The following all have morphology, cytogenetics and cell markers as seen in non-PTLD setting. It can be subcategorised into:
  • DLBCL           (most common form of monomorphic PTLD)
  • Burkitt Lymphoma
  • Plasmacytoma-like or Plasma cell myeloma

4) Classical Hodgkin Lymphoma-Like PTLD

• Histology and markers are as expected outwith the PTLD setting.
• Usually occurs later than other subtypes of PTLD.

Management of PTLD

Management options are complex, depending on:

• the transplanted organ and possibility and extent of immunosuppression withdrawal,
• Extent of PTLD
• Risk factors for PTLD:

1. Age < 40
2. High LDH
3. ECOG performace status 2-4

General principles of management include:

1. Aggressive withdrawal of immunosuppression (dictated by organ and lead by transplant team)
2. Rituximab monotherapy in low risk patients (i.e >60, normal LDH and normal ECOG
3. Anthracycline based chemotherapy plus rituximab in high risk patients, or those who don’t respond to initial interventions, or those with aggressive disease. Regimen obviously guided by subtype – DLBCL treated with RCHOP, HL with ABVD, Burkitts with RCHOP through to RCODOXM/IVAC. Care must be taken regarding the organ toxicity involved in these regimens, both of the transplanted organ, but also taking into account cumulative chemo toxicity, previous viral infections and performance status at time of development of PTLD.

REFERENCES AND RESOURCES

Hematologic Disorders after Solid Organ Transplantation                                Eileen P. Smith110.1182/asheducation-2010.1.281 ASH Education Book December 4, 2010 vol. 2010 no. 1 281-286

Parker, A., Bowles, K., Bradley, J. A., Emery, V., Featherstone, C., Gupte, G., Marcus, R., Parameshwar, J., Ramsay, A., Newstead, C. and (British Transplantation Society Lead) Writing group: On behalf of the Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society (2010), Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS Guidelines. British Journal of Haematology, 149: 675–692. doi: 10.1111/j.1365-2141.2010.08161.x

The liver graft as a trojan horse: multilineage donor derived haematopoiesis after liver transplantation. Mark et al 2013. Transplantation Proceedings 45, 3438-3441         http://t.co/aPYaLBkb0A