Post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD), also referred as post-transplant lymphoproliferation disorder, represents a variety of conditions ranging from lymphoid hyperplasia to malignancy, included in the WHO classification of tumours of haematopoietic and lymphoid tissues. It can be a life-threatening fulminant disorder and affects ~10% of solid organ transplant recipients. 

Epidemiology

PTLD develops in no more than 2% of all patients who receive transplants, somewhat higher in paediatric patients ¹⁰. It is the second most common type of malignancy in post-transplant patients with two peaks demonstrated - firstly at one-year post-transplant and secondly, at 4-5 years post-transplant ¹³. The incidence varies according to the type of transplant ^3,4,10:

• small bowel: high ⁵
• pancreas: 12%
• heart and lung: 3-9%
• liver: 1-2%
• cardiac: 1-2% ¹⁰
• renal: 1-2%
• haematopoietic stem cell transplant: 0.6-1.2% ⁶

Risk factors

Some risk factors are recognised, including ¹¹: 

• Epstein-Barr virus seronegativity at the time of transplantation (which may explain why the incidence of PTLD is higher in children)

• concomitant cytomegalovirus infection
• allograft type

The immunosuppressive regime also affects the distribution of PTLD: 

• azathioprine: more common CNS and allograft involvement 
• cyclosporinciclosporin or FK-506: gastrointestinal tract and lymph nodes

Clinical presentation

Clinical presentation is variable, both in symptomatology and severity, ranging from flu-like symptoms with fever and malaise to fulminant systemic disease ³. It of course also varies with the location of the PTLD (see below).

The time between transplant and development of PTLD is also variable, ranging from 1 month to 7 years ^4,9, with most occurring within a year ⁹. As a general rule, patients who present late (>1 year) have more aggressive tumours with poorer prognosis ⁶. 

Pathology

Most PTLD specimens demonstrate a polyclonal B-cell Epstein-Barr virus (EBV) positive cell population ³. Monoclonal B-cell and T-cell small bowel lymphomas do occur in patients with organ transplants but are less frequent.

When PTLD develops in haematopoietic stem cell transplant recipients, it is usuallyusually arises from the donor cells ⁷.

Macroscopic appearance

Macroscopically these tumours have been likened to uncooked fish flesh¹.

Histology

These tumours range from low-grade/benign lymphoid hyperplasia to high-grade malignant non-Hodgkin lymphoma.

Location

PTLD may be focal or diffuse and can affect almost any organ system and even the allograft. It usually manifests as an extranodal disease, and it can occur in a variety of locations, including ^8,9:

• abdominal
  • liver: most common
  • small bowel ¹
  • colon and stomach less common ⁹
• chest
  • lung ⁴
• head and neck
• primary central nervous system PTLD
• osseous: rare ⁸
• cutaneous ⁹

Radiographic features

The range of appearances is large due to the number of possible sites. In general extranodal involvement is 3-4 times more common than nodal involvement, and resembles primary lymphoma of those organs ⁹:

• solid organs (liver, spleen, kidney)
  • nodules
    • hypoechoic
    • low density on CT
  • diffuse infiltration
• bowel
  • circumferential wall thickening
  • aneurysmal dilatation
  • ulceration/perforation
  • bowel obstruction uncommon
• lung/pleura
  • nodules
    • usually homogeneous
    • may centrally cavitate
  • diffuse infiltration
• brain
  • similar to lymphoma in the setting of HIV infection
  • necrosis and haemorrhage more common than in run-of-the-mill primary CNS lymphoma
• nodes
  • non-specific nodal enlargement, similar to other lymphomas
  • most commonly affecting mediastinum (either lymphadenopathy or anterior mediastinal mass) or retroperitoneum (either as lymphadenopathy or mass) ¹³

Treatment and prognosis

Treatment is variable and depends on the location and extent of disease. Options include ^6,8:

• reduction of immunosuppression
• surgical resection of localised disease
• radiotherapy
• medical agents
  • alpha interferon therapy
  • antiviral therapy (limited success)
  • IL-2 infusions
  • rituximab

Prognosis depends on the grade of the lymphoma, and cell type: the low-grade lymphoid proliferation of polyclonal B-cell origin with EBV implication have a better prognosis than other cell types of higher grade. Five-year survival is ~ 35~35% ⁷.

Disease regression in response to a reduction in immunosuppression is a unique diagnostic feature of PTLD and distinguishes this condition from other malignant diseases. Patients should be closely monitored for allograft rejection. 

Differential diagnosis

The differential diagnosis would depend on the location of PTLD and is therefore broad:

• small bowel
  • inflammatory bowel disease, especially Crohn disease
  • acute rejection
• lung
  • metastases
  • infection
  • lymphoid interstitial pneumonia (LIP)
• head and neck
  • infectious mononucleosis
  • reactive nodal enlargement, e.g. from URTI