PTLD (Ix and Mx) (2010)

Intro

 

Epidemiology

-       Up to 10% of solid organ transplant patients

-       2nd commonest malignancy after skin cancer in adult transplant (1st in children)

-       85% B-cell, 15% T/NK (T-cell up to 40% in Asia due to HTLV)

-       80% Associated with EBV

 

Spectrum

-       From indolent polyclonal lymphoproliferation early post-transplant to rapidly fatal aggressive lymphoma.

 

EBV

-       Gamma herpes virus

-       Causes blastic transformation and uncontrolled proliferation in B-cells

-       In healthy people, EBV controlled by CD4 and CD8 T-cells

-       In healthy people causes IM, a benign self-limiting proliferation of lymphoid cells

-       In EBV PTLD, the virus is often monoclonal indicating its involvement in the early stage of clonal expansion and therefore a driver of the disease development.

-       Most NK cell PTLD is EBV positive

 

EBV-negative PTLD

-       May represent ‘incidental’ lymphomas occurring in post-transplant patients

-       Yet may still respond to reducing immunosuppression

-       Most T-cell PTLD is EBV negative

 

Laboratory Investigation

 

 

Essential pathology Ix

-       Morphology

-       Immunophenotyping

-       EBV-encoded RNA (EBER) in situ hybridization (EBER ISH)

 

Early PTLD Lesions

-       Histology

o   PH shows plasma cells and immunoblasts

o   IM-like shows reed-sternberg-like cells

-       Immunophenotype

o   Immunobloasts CD20+, CD79a+, PAX-5+, CD30+, CD15-

-       Molecular

o   Oligoclonal or polyclonal EBV / IGH / TCR genomes

 

Polymorphic PTLD

-       Histology

o   Mixed lymphocytes and plasma cells. Necrosis, high proliferation

-       Immunophenotype

o   B cells CD20+, CD79a+, PAX-5+, EBER+

o   Plasma cells CD138+

-       Molecular

o   Clonal EBV, clonal IGH, polyclonal TCR

 

Monomorphic B-cell PTLD

-       Histology

o   DLBCL type shows immunoblastic, centroblastic, pleomorphic morphology

o   BL type shows monomorphic cells with apoptosis (‘Starry Sky’)

o   Plasmacytic sheets of mature plasma cells

-       Immunophenotype

o   DLBCL - CD20+, CD79a+, PAX-5+, EBER+, May have focal Cd30+

o   BL – CD20+, CD10+, BCL2-, 100% MIB1/Ki67

o   Plasmacytic – CD138+, CD79a+ CD20-

-       Molecular

o   Cloncal IGH and EBV. Polyclonal TCR

 

Monomorphic T-cell PTLD

-       Histology

o   Depends on the T-cell type

-       Immunophenotype

o   Variable pan-T cell markers CD3, CD5, CD2, CD7

o   Aberrant CD20 may be present

o   T/NK are CD56+, CD3-

-       Molecular

o   Cloncal TCR

 

Classical Hodgkin-like PTLD

-       Histology

o   RS cells and or Hodgkin cells

-       Immunophenotype

o   CD30+, CD15+, CD45-, CD20-, CD3-

-       Molecular variable

 

Risk Factors for PTLD

 

Difficult to calculate for any one individual

Most common post Small bowel / Heart / Lung / Heart-Lung transplants

Tacrolimus may have > increase over ciclosporin

However, potential risk of PTLD should not influence choice of immunosuppressant

 

Clinical Features

 

Non-specifc and often extra-nodal

Symptoms usually relate to interference in function of the affected organ

B symptoms may be present

Isolated BM involvement can occur

 

Organ involvement

-       Tonsils/adenoids common site of involvement, esp in children

-       <10% have lymphadenopathy

 

Pre-Transplant Management

 

Screening

-       Pre-transplant EBV serology

-       Assume seronegativity in under 1 year olds (false positives from maternal IgG)

 

T-cell Archiving

-       Not in wide use

 

Post-transplant surveillance

 

Routine surveillance of adults by EBV DNA PCR not recommended except for HSCT

Children at risk of primary EBV infection should be monitored

EBV PCR for monitoring of response to PTLD treatment is not recommended

 

Management Guideline (2010)

 

MDT Approach

-       Transplant physician + haematologist + pathologist + radiologist as core team

-       Surgeons + Radiation Oncologist + Microbiologist + Palliative Care often needed

 

Staging

-       Assess transplanted organ

-       Staging CT (no good evidence for PET at present, some PTLD is PET negative)

-       +/- BMAT +/- CSF

-       Stage by Ann Arbor system

 

Prognostic scoring

-       IPI not appropriate

-       Poor performance status, monomorphic pathology and involvement of transplanted organ considered most significant. No formal scoring system

 

Defining Low Risk disease for treatment algorithm

-       <60 y.o.

-       Low LDH

-       PS <2

 

Treatment

- Reduce immunosuppression dosing if possible

- Localised disease --> Consider local excisision and/or radiotherapy

- Low risk Multifocal disease --> Rituximab --> R-Chemo if not responding

- High risk Multifocal disease --> R-Chemotherapy

 

Re-transplantation post treatment of PTLD

-       Can be successful

-       Recurrence of PTLD on re-starting immunosuppression is not guaranteed