Post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD), also known as post-transplant lymphoproliferation disorder, represents a variety of conditions ranging from lymphoid hyperplasia to malignancy, included in the WHO classification of haematolymphoid tumors under "lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation." It can be a life-threatening fulminant disorder. 

Epidemiology

PTLD develops in no more than 2% of all patients who receive transplants, somewhat higher in pediatric patients ¹⁰. It is the second most common type of malignancy in post-transplant patients with two peaks demonstrated: at 1 year post-transplant and 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%

• hematopoietic stem cell transplant: 0.6-1.2% ⁶

Risk factors

Some risk factors are recognized, 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 regimen also affects the distribution of PTLD: 

• azathioprine: more common CNS and allograft involvement 

• cyclosporine or tacrolimus: 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 tumors 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 hematopoietic stem cell transplant recipients, it usually arises from the donor cells ⁷.

Location

PTLD may be focal or diffuse and can affect almost any organ system and even the allograft. It usually manifests as extranodal disease, and 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

• central nervous system

• osseous: rare ⁸

• cutaneous ⁹

Macroscopic appearance

Macroscopically these tumors have been likened to uncooked fish flesh ¹.

Microscopic appearance

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

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 hemorrhage, more common than in sporadic 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 the disease. Options include ^6,8:

• reduction of immunosuppression

• surgical resection of localized disease

• radiotherapy

• medical agents

  • rituximab

  • alpha interferon therapy

  • antiviral therapy (limited success)

  • IL-2 infusions

Prognosis depends on the grade of the lymphoma, and cell type: the low-grade lymphoid proliferation of polyclonal B-cell origin with EBV implication has a better prognosis than other cell types of higher grade. The 5-year survival is ~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

• kidneys

  • perinephric myxoid pseudotumor of fat

• lung

  • metastases

  • infection

  • lymphoid interstitial pneumonia (LIP)

• head and neck

  • infectious mononucleosis

  • reactive nodal enlargement, e.g. from URTI