Questions

EBV in the Transplant Patient — Questions

Study questions for EBV in the Transplant Patient.

Mock Exam mode

Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.

17 questions: 10 MCQ, 7 written.

High-priority (past-paper) questions only

Why C

Both 2022 systems (the World Health Organization 5th edition and the International Consensus Classification) stopped treating PTLD as its own disease and folded it into one larger family: lymphoid proliferations and lymphomas arising in the setting of immune deficiency and dysregulation. The reasoning is that the same lesions, with the same EBV biology, appear wherever immune control is lost (inherited immune defects, HIV, transplant, autoimmune disease, drugs, and the immune senescence of age), so they are classified once by shared biology.

Nothing histological is lost (the standalone four-category option describes the older scheme): the familiar categories survive, but each lesion now carries a three-part name (histology, virus, and immune setting). PTLD is not chronic active EBV infection, a reactive hyperplasia, or a Hodgkin subtype.

Why B

The functional framework splits the spectrum into quintessential, EBV-driven PTLD (reactive hyperplasia through to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) and post-transplant lymphoma (a true lymphoma that behaves as it would in an immunocompetent patient and needs lymphoma-directed treatment).

EBV-negativity is the principal warning sign for the second group: EBV-negative disease tends to arise late, be monomorphic, and behave aggressively. The other options point the opposite way: EBV-positivity, polyclonality and early onset all favour quintessential disease, and tonsillar enlargement is a feature of reactive, non-destructive lesions.

Why B

The diagnosis of PTLD is histological. It needs a tissue biopsy (preferably a generous excisional biopsy) characterised by morphology, immunophenotype (including CD20 status, which decides whether rituximab can be used), EBV-encoded RNA (EBER) in-situ hybridisation for EBV, and clonality studies.

Blood tests cannot make the diagnosis: a high or rising EBV-DNA load is only suggestive, a normal load does not fully exclude disease, and serology merely shows past exposure. Imaging localises and stages disease but does not characterise it. The blood load raises suspicion; the biopsy settles it.

Why C

Reducing immunosuppression is the foundation of treatment for every subtype, because it gives the patient back the EBV-specific T cells that immunosuppression had removed. Early, EBV-driven, low-burden disease often responds to this alone.

The other options are later rungs on the graded ladder: rituximab is added for CD20-positive disease, chemotherapy (such as rituximab with CHOP) is reserved for disease that does not respond or for true post-transplant lymphomas, and EBV-specific T cells are used in EBV-positive disease, especially after stem-cell transplant. Antivirals have no role in treating established PTLD, because the latent virus offers them nothing to act on.

Why B

In solid-organ transplant the seronegative recipient of a seropositive organ (donor positive, recipient negative) is at highest risk. Such a recipient meets EBV for the first time, a primary infection, while immunosuppressed and with no EBV-specific T cells to contain it. This is why PTLD falls disproportionately on children, who are most often EBV-naive at transplant.

The other combinations carry lower risk because the recipient already has EBV-specific memory T cells, or because a seronegative organ transmits no virus. Serostatus is one of the strongest single predictors, so the claim that it is irrelevant is wrong. (The high-risk combination reverses in stem-cell transplant, where the graft is the new immune system.)

A complete answer recognises the high-risk setting, works through diagnosis and staging, keeps the differential in mind, and sets out a graded management plan.

Recognise the setting

This is the highest-risk solid-organ scenario: an EBV-naive child (recipient negative) receiving a seropositive organ, now undergoing a primary EBV infection while immunosuppressed, in the first-year window when EBV-positive PTLD is most likely. The rising load and new lymphadenopathy should be treated as possible PTLD until proven otherwise.

Diagnosis and staging

Confirm and trend the EBV-DNA load, and take a focused history and examination. Definitive diagnosis needs tissue: an excisional lymph-node biopsy with histology, immunophenotype (including CD20), EBER staining and clonality, to place the lesion on the spectrum. Stage with cross-sectional imaging (with metabolic imaging where available), assess graft function, and add bone-marrow or central-nervous-system assessment if indicated. Supportive findings include a raised lactate dehydrogenase.

Keep the differential in mind

Fever and lymphadenopathy in a transplant child also raise infection and, where the graft is involved, rejection, and these can coexist with PTLD.

Management

Begin with reduction of immunosuppression, the foundation in a kidney recipient because the graft can, if necessary, be supported by dialysis. If the disease is CD20-positive and does not regress, add rituximab, and escalate to chemotherapy only if it fails or the histology is a true lymphoma. Manage jointly with oncology and the transplant team. Pre-emptive reduction of immunosuppression or rituximab on a rising load is also used in this high-risk group to prevent progression.

A complete answer covers the pathogenesis, the stem-cell-specific risk, EBV-DNA monitoring, and the treatment principles.

Pathogenesis

EBV infects B cells for life and, in its latent state, can switch on a growth programme that drives the B cell to proliferate. This is normally controlled by EBV-specific cytotoxic T cells. Transplant immunosuppression targets T cells, removes that surveillance, and lets EBV-driven B cells grow unchecked.

The stem-cell-specific risk

After stem-cell transplant the graft is the new immune system, so the highest-risk patient is a seropositive recipient of a seronegative or T-cell-depleted donor: the recipient carries EBV, but the new donor immunity brings no EBV-specific T cells. Most such PTLD is donor-derived, EBV-positive, and appears within the first year.

Monitoring

High-risk patients undergo EBV-DNA surveillance of the blood, most intensively in the early months. A high or rising load flags risk and can trigger pre-emptive treatment before disease declares itself, though thresholds are not standardised and a load never substitutes for a tissue diagnosis once a lesion is present.

Treatment

The principles are to reduce immunosuppression where graft-versus-host disease allows, give rituximab for CD20-positive disease (including pre-emptively on a rising load), escalate to chemotherapy for disease that does not respond, and, because the disease is EBV-positive, restore immunity with EBV-specific T cells, which are particularly effective in the stem-cell setting. Antivirals have no role against the latent virus.

A complete answer defines PTLD, sets out the older histological categories, explains the 2022 reframing, and adds the practical functional view.

Definition

Post-transplant lymphoproliferative disorder (PTLD) is an overgrowth of lymphocytes, almost always B cells, that arises after transplantation when immunosuppression weakens the T cells that normally control EBV. It is best defined as a spectrum rather than a single disease, running from a reactive, polyclonal hyperplasia, through clonal neoplasia, to frank malignant lymphoma.

The older histological categories

The previous World Health Organization scheme treated PTLD as a standalone entity with four categories: non-destructive (early) lesions, polymorphic PTLD, monomorphic PTLD (usually a diffuse large B-cell lymphoma), and classic Hodgkin lymphoma PTLD. An EBV-encoded RNA (EBER) stain is performed on every case to establish EBV status.

The 2022 change

The 2022 World Health Organization 5th edition and the International Consensus Classification both stopped treating PTLD as its own entity and placed it within a larger family: lymphoid proliferations and lymphomas arising in immune deficiency and dysregulation. The histological categories survive, but each lesion now carries a three-part name: the histological diagnosis, the driving virus (EBV or KSHV/HHV-8), and the immune setting (here, post-transplant, solid organ or bone marrow).

The functional view

In practice the spectrum is read as quintessential, EBV-driven PTLD (reactive hyperplasia to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) versus post-transplant lymphoma (a true lymphoma needing lymphoma-directed treatment), with EBV-negativity the principal warning sign of the latter.

A complete answer states the competing goals, how the spectrum sets intensity, the graded ladder, and the points commonly overlooked.

The two goals

Management balances two aims that often conflict: eradicate the PTLD and preserve the graft. Reducing immunosuppression serves the first but risks the second, and which wins depends on whether the organ can be supported by other means (a failing kidney can return to dialysis; a failing heart cannot).

Let the spectrum set the intensity

Quintessential, EBV-driven PTLD is treated with the lowest-intensity approach that works, escalating only as needed. A post-transplant lymphoma is treated from the start as the corresponding lymphoma would be in an immunocompetent patient.

The graded ladder

Reduce immunosuppression first, for every subtype. Add rituximab for CD20-positive disease. Escalate to chemotherapy (such as rituximab with CHOP, often in a response-guided sequence) for disease that does not respond or for true lymphomas. In EBV-positive disease, especially after stem-cell transplant, restore EBV-specific T cells. Localised complications may need surgery, and central-nervous-system disease is treated as a primary central nervous system lymphoma.

Points commonly overlooked

Antivirals have no role against the latent virus. CD20 status determines whether rituximab can work. A blood EBV-DNA load guides suspicion and tracks response but does not diagnose disease. Newer approaches (agents targeting CD30, antibodies against interleukin-6, and expanding cellular therapies) may broaden the options, but availability differs widely between settings.

A complete answer explains what controls EBV, identifies the high-risk combination in each setting, and gives the single reason they differ.

What controls EBV

EBV-infected B cells are held in check by EBV-specific cytotoxic T cells. PTLD risk is highest whenever the virus is present but those specific T cells are absent.

Solid-organ transplant

The patient keeps their own immune system; the organ is what is foreign. The danger is a seronegative recipient receiving a seropositive organ (donor positive, recipient negative), who meets EBV for the first time while immunosuppressed and has no EBV-specific T cells to contain the primary infection.

Stem-cell transplant

Here the logic reverses because the graft becomes the new immune system. The danger is a seropositive recipient given a seronegative or T-cell-depleted graft (donor negative, recipient positive): the recipient already carries EBV, but the incoming donor immunity brings no EBV-specific T cells to control it. Most PTLD after stem-cell transplant is therefore donor-derived, EBV-associated, and appears within the first year.

The single reason

In both cases the high-risk patient is the one with EBV present but no matching T-cell immunity. Because the immune system comes from the recipient in solid-organ transplant but from the donor in stem-cell transplant, the serostatus that creates that mismatch flips.

A complete answer explains the spectrum, the EBV-driven imbalance that produces it, the functional grouping, and how each follows through to treatment intensity.

The spectrum

PTLD is not one disease but a continuum: a reactive, polyclonal hyperplasia at one end (resembling infectious mononucleosis, architecture preserved, no genetic hallmarks of malignancy), a clonal neoplasia in the middle, and a monoclonal malignant lymphoma at the other end. The same label therefore covers lesions of very different behaviour.

What drives progression

Progression reflects the balance between EBV-driven B-cell proliferation and T-cell control of EBV: EBV promotes proliferation, EBV-specific T cells normally restrain it, and immunosuppression removes that restraint. How far a patient progresses depends on how far EBV is driving the disease and how much T-cell control has been lost.

The functional grouping

The functional reading sorts the spectrum into quintessential, EBV-driven PTLD (hyperplasia through EBV-positive large-cell neoplasia) and post-transplant lymphoma (a true lymphoma behaving as in an immunocompetent patient). EBV status is the principal discriminator: EBV-positive disease is more often the controllable, quintessential form; EBV-negative disease raises concern for a true lymphoma.

How this guides management

Treatment intensity follows position on the spectrum. Quintessential disease is treated with the lowest-intensity approach that works, escalating only as needed: reduce immunosuppression, then add rituximab for CD20-positive disease, then chemotherapy if it does not respond. A post-transplant lymphoma is treated from the outset as the matching lymphoma would be in an immunocompetent patient. EBV-positive disease, especially after stem-cell transplant, can also be treated by restoring EBV-specific T cells. Position on the spectrum therefore determines the intensity of treatment.

Why D

Adoptive therapy with EBV-specific cytotoxic T cells restores the exact immunity that immunosuppression removed: T cells that recognise and kill EBV-infected B cells. It can only work where the tumour is EBV-positive, and it is most effective after stem-cell transplant, where the disease is almost always EBV-driven and donor-derived.

It is therefore not used for EBV-negative disease (which carries no EBV target), is not limited to Hodgkin or CD20-negative subtypes, and is not applicable to all PTLD. Off-the-shelf, third-party EBV-specific T cells are now reaching practice for relapsed or refractory EBV-positive disease, with little risk of graft-versus-host disease.

Why A

Cell-free plasma EBV-DNA is more specific for established EBV-positive disease, while whole blood (which also captures virus inside circulating cells) is more sensitive and so better for surveillance. Many centres therefore use whole blood to screen and plasma to help confirm.

Either sample is acceptable, and both are in routine use, so options C to E are wrong. The deeper point is that neither result diagnoses PTLD: the load raises or lowers suspicion, but tissue biopsy makes the diagnosis, and loads cannot be compared between laboratories because assays differ.

Why C

The depth of T-cell suppression is the central driver of PTLD, so T-cell-depleting induction (antithymocyte globulin, the historical OKT3) is strongly linked to early disease. Cumulative maintenance immunosuppression, by contrast, drives the late peak.

The other options reduce risk or are neutral: lower drug levels and aggressive tapering lessen the net immunosuppressive burden, and calcineurin-inhibitor withdrawal is used to treat PTLD, not cause it. One agent worth remembering separately is belatacept, which is specifically associated with central-nervous-system PTLD in EBV-seronegative recipients.

Why D

EBV association falls in bands across the spectrum. The reactive and early ends are almost always EBV-positive (non-destructive and polymorphic lesions, over 95 per cent), and classic Hodgkin lymphoma PTLD and the EBV-positive mucocutaneous ulcer are usually positive too.

The monomorphic, lymphoma-like end is more mixed: large B-cell and Burkitt types are often positive, but T/NK-cell, high-grade B-cell and plasma-cell types are frequently EBV-negative (under half). The T/NK-cell lymphomas are therefore the least EBV-associated of the options, and sit at the post-transplant-lymphoma end that needs lymphoma-directed treatment.

Why E

Aciclovir and ganciclovir must be activated by a viral thymidine kinase, which is made only when EBV is replicating (the lytic cycle). The proliferating B cells of PTLD carry EBV in its latent state: the virus is not replicating and makes no thymidine kinase, so the drugs are never activated and have nothing to act on.

This is why antivirals do not treat established disease, although they show a weak signal for prevention (where some lytic replication may be targetable). The drugs are not expelled by the cells, not intrinsically resistant, and not specific to cytomegalovirus.

A complete answer states how central nervous system PTLD is treated and the reason it cannot simply follow the usual ladder.

The approach

PTLD in the central nervous system is treated on the lines of a primary central nervous system lymphoma, using regimens designed to reach the brain (high-central-nervous-system-penetrating, methotrexate-based therapy, with radiotherapy or rituximab as appropriate), alongside reduced immunosuppression.

Why it differs

Most of the chemotherapy used for systemic PTLD does not cross the blood-brain barrier in useful concentrations, so standard systemic regimens leave central nervous system disease undertreated. Central nervous system involvement is also a recognised adverse prognostic feature, which reinforces the need for a dedicated, brain-directed strategy rather than the systemic ladder alone.

High priorityMCQ
In the 2022 WHO and International Consensus classifications, how is PTLD now categorised?
- A. As a standalone entity with four categories
- B. As a form of chronic active EBV infection
- C. Within the immune deficiency and dysregulation family
- D. Among the reactive nodal hyperplasias
- E. As a subtype of classic Hodgkin lymphoma
Show answer
Correct answer: C
Why C

Both 2022 systems (the World Health Organization 5th edition and the International Consensus Classification) stopped treating PTLD as its own disease and folded it into one larger family: lymphoid proliferations and lymphomas arising in the setting of immune deficiency and dysregulation. The reasoning is that the same lesions, with the same EBV biology, appear wherever immune control is lost (inherited immune defects, HIV, transplant, autoimmune disease, drugs, and the immune senescence of age), so they are classified once by shared biology.

Nothing histological is lost (the standalone four-category option describes the older scheme): the familiar categories survive, but each lesion now carries a three-part name (histology, virus, and immune setting). PTLD is not chronic active EBV infection, a reactive hyperplasia, or a Hodgkin subtype.
High priorityMCQ
In the functional view of PTLD, which feature most suggests a post-transplant lymphoma rather than quintessential, EBV-driven PTLD?
- A. EBV-positive status
- B. EBV-negative status
- C. Polyclonal proliferation
- D. Early onset after transplant
- E. Tonsillar enlargement
Show answer
Correct answer: B
Why B

The functional framework splits the spectrum into quintessential, EBV-driven PTLD (reactive hyperplasia through to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) and post-transplant lymphoma (a true lymphoma that behaves as it would in an immunocompetent patient and needs lymphoma-directed treatment).

EBV-negativity is the principal warning sign for the second group: EBV-negative disease tends to arise late, be monomorphic, and behave aggressively. The other options point the opposite way: EBV-positivity, polyclonality and early onset all favour quintessential disease, and tonsillar enlargement is a feature of reactive, non-destructive lesions.
High priorityMCQ
What is required to diagnose established PTLD?
- A. A high blood EBV-DNA load alone
- B. Tissue biopsy with histology and EBER
- C. A rising EBV-DNA trend over time
- D. EBV serology indicating past infection
- E. Imaging showing an enlarging mass
Show answer
Correct answer: B
Why B

The diagnosis of PTLD is histological. It needs a tissue biopsy (preferably a generous excisional biopsy) characterised by morphology, immunophenotype (including CD20 status, which decides whether rituximab can be used), EBV-encoded RNA (EBER) in-situ hybridisation for EBV, and clonality studies.

Blood tests cannot make the diagnosis: a high or rising EBV-DNA load is only suggestive, a normal load does not fully exclude disease, and serology merely shows past exposure. Imaging localises and stages disease but does not characterise it. The blood load raises suspicion; the biopsy settles it.
High priorityMCQ
What is the first-line treatment for most PTLD, whatever the subtype?
- A. R-CHOP chemotherapy
- B. Rituximab monotherapy
- C. Reducing immunosuppression
- D. EBV-specific T cells
- E. Antiviral therapy
Show answer
Correct answer: C
Why C

Reducing immunosuppression is the foundation of treatment for every subtype, because it gives the patient back the EBV-specific T cells that immunosuppression had removed. Early, EBV-driven, low-burden disease often responds to this alone.

The other options are later rungs on the graded ladder: rituximab is added for CD20-positive disease, chemotherapy (such as rituximab with CHOP) is reserved for disease that does not respond or for true post-transplant lymphomas, and EBV-specific T cells are used in EBV-positive disease, especially after stem-cell transplant. Antivirals have no role in treating established PTLD, because the latent virus offers them nothing to act on.
High priorityMCQ
Which solid-organ transplant recipient is at highest risk of PTLD?
- A. EBV-seropositive recipient of a seropositive organ
- B. EBV-seronegative recipient of a seropositive organ
- C. EBV-seropositive recipient of a seronegative organ
- D. EBV-seronegative recipient of a seronegative organ
- E. Risk is independent of EBV serostatus
Show answer
Correct answer: B
Why B

In solid-organ transplant the seronegative recipient of a seropositive organ (donor positive, recipient negative) is at highest risk. Such a recipient meets EBV for the first time, a primary infection, while immunosuppressed and with no EBV-specific T cells to contain it. This is why PTLD falls disproportionately on children, who are most often EBV-naive at transplant.

The other combinations carry lower risk because the recipient already has EBV-specific memory T cells, or because a seronegative organ transmits no virus. Serostatus is one of the strongest single predictors, so the claim that it is irrelevant is wrong. (The high-risk combination reverses in stem-cell transplant, where the graft is the new immune system.)
High priorityClinical scenarioA child several months after an EBV-mismatched (donor-positive, recipient-negative) kidney transplant presents with fever, cervical lymphadenopathy and a rising blood EBV-DNA load. Discuss your approach to diagnosis and management. [10]
Model answer
A complete answer recognises the high-risk setting, works through diagnosis and staging, keeps the differential in mind, and sets out a graded management plan.

Recognise the setting

This is the highest-risk solid-organ scenario: an EBV-naive child (recipient negative) receiving a seropositive organ, now undergoing a primary EBV infection while immunosuppressed, in the first-year window when EBV-positive PTLD is most likely. The rising load and new lymphadenopathy should be treated as possible PTLD until proven otherwise.

Diagnosis and staging

Confirm and trend the EBV-DNA load, and take a focused history and examination. Definitive diagnosis needs tissue: an excisional lymph-node biopsy with histology, immunophenotype (including CD20), EBER staining and clonality, to place the lesion on the spectrum. Stage with cross-sectional imaging (with metabolic imaging where available), assess graft function, and add bone-marrow or central-nervous-system assessment if indicated. Supportive findings include a raised lactate dehydrogenase.

Keep the differential in mind

Fever and lymphadenopathy in a transplant child also raise infection and, where the graft is involved, rejection, and these can coexist with PTLD.

Management

Begin with reduction of immunosuppression, the foundation in a kidney recipient because the graft can, if necessary, be supported by dialysis. If the disease is CD20-positive and does not regress, add rituximab, and escalate to chemotherapy only if it fails or the histology is a true lymphoma. Manage jointly with oncology and the transplant team. Pre-emptive reduction of immunosuppression or rituximab on a rising load is also used in this high-risk group to prevent progression.
High priorityExam-styleA patient develops PTLD after allogeneic stem-cell transplantation. Discuss the pathogenesis of EBV-driven PTLD and the principles of monitoring and treatment. [10]
Model answer
A complete answer covers the pathogenesis, the stem-cell-specific risk, EBV-DNA monitoring, and the treatment principles.

Pathogenesis

EBV infects B cells for life and, in its latent state, can switch on a growth programme that drives the B cell to proliferate. This is normally controlled by EBV-specific cytotoxic T cells. Transplant immunosuppression targets T cells, removes that surveillance, and lets EBV-driven B cells grow unchecked.

The stem-cell-specific risk

After stem-cell transplant the graft is the new immune system, so the highest-risk patient is a seropositive recipient of a seronegative or T-cell-depleted donor: the recipient carries EBV, but the new donor immunity brings no EBV-specific T cells. Most such PTLD is donor-derived, EBV-positive, and appears within the first year.

Monitoring

High-risk patients undergo EBV-DNA surveillance of the blood, most intensively in the early months. A high or rising load flags risk and can trigger pre-emptive treatment before disease declares itself, though thresholds are not standardised and a load never substitutes for a tissue diagnosis once a lesion is present.

Treatment

The principles are to reduce immunosuppression where graft-versus-host disease allows, give rituximab for CD20-positive disease (including pre-emptively on a rising load), escalate to chemotherapy for disease that does not respond, and, because the disease is EBV-positive, restore immunity with EBV-specific T cells, which are particularly effective in the stem-cell setting. Antivirals have no role against the latent virus.
High priorityExam-styleDefine post-transplant lymphoproliferative disorder, and outline how it is classified, including the change introduced in 2022. [8]
Model answer
A complete answer defines PTLD, sets out the older histological categories, explains the 2022 reframing, and adds the practical functional view.

Definition

Post-transplant lymphoproliferative disorder (PTLD) is an overgrowth of lymphocytes, almost always B cells, that arises after transplantation when immunosuppression weakens the T cells that normally control EBV. It is best defined as a spectrum rather than a single disease, running from a reactive, polyclonal hyperplasia, through clonal neoplasia, to frank malignant lymphoma.

The older histological categories

The previous World Health Organization scheme treated PTLD as a standalone entity with four categories: non-destructive (early) lesions, polymorphic PTLD, monomorphic PTLD (usually a diffuse large B-cell lymphoma), and classic Hodgkin lymphoma PTLD. An EBV-encoded RNA (EBER) stain is performed on every case to establish EBV status.

The 2022 change

The 2022 World Health Organization 5th edition and the International Consensus Classification both stopped treating PTLD as its own entity and placed it within a larger family: lymphoid proliferations and lymphomas arising in immune deficiency and dysregulation. The histological categories survive, but each lesion now carries a three-part name: the histological diagnosis, the driving virus (EBV or KSHV/HHV-8), and the immune setting (here, post-transplant, solid organ or bone marrow).

The functional view

In practice the spectrum is read as quintessential, EBV-driven PTLD (reactive hyperplasia to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) versus post-transplant lymphoma (a true lymphoma needing lymphoma-directed treatment), with EBV-negativity the principal warning sign of the latter.
High priorityExam-styleDiscuss the principles of managing established PTLD. [10]
Model answer
A complete answer states the competing goals, how the spectrum sets intensity, the graded ladder, and the points commonly overlooked.

The two goals

Management balances two aims that often conflict: eradicate the PTLD and preserve the graft. Reducing immunosuppression serves the first but risks the second, and which wins depends on whether the organ can be supported by other means (a failing kidney can return to dialysis; a failing heart cannot).

Let the spectrum set the intensity

Quintessential, EBV-driven PTLD is treated with the lowest-intensity approach that works, escalating only as needed. A post-transplant lymphoma is treated from the start as the corresponding lymphoma would be in an immunocompetent patient.

The graded ladder

Reduce immunosuppression first, for every subtype. Add rituximab for CD20-positive disease. Escalate to chemotherapy (such as rituximab with CHOP, often in a response-guided sequence) for disease that does not respond or for true lymphomas. In EBV-positive disease, especially after stem-cell transplant, restore EBV-specific T cells. Localised complications may need surgery, and central-nervous-system disease is treated as a primary central nervous system lymphoma.

Points commonly overlooked

Antivirals have no role against the latent virus. CD20 status determines whether rituximab can work. A blood EBV-DNA load guides suspicion and tracks response but does not diagnose disease. Newer approaches (agents targeting CD30, antibodies against interleukin-6, and expanding cellular therapies) may broaden the options, but availability differs widely between settings.
High priorityExam-styleWhy does the highest-risk EBV serostatus combination for PTLD reverse between solid-organ and stem-cell transplantation? [5]
Model answer
A complete answer explains what controls EBV, identifies the high-risk combination in each setting, and gives the single reason they differ.

What controls EBV

EBV-infected B cells are held in check by EBV-specific cytotoxic T cells. PTLD risk is highest whenever the virus is present but those specific T cells are absent.

Solid-organ transplant

The patient keeps their own immune system; the organ is what is foreign. The danger is a seronegative recipient receiving a seropositive organ (donor positive, recipient negative), who meets EBV for the first time while immunosuppressed and has no EBV-specific T cells to contain the primary infection.

Stem-cell transplant

Here the logic reverses because the graft becomes the new immune system. The danger is a seropositive recipient given a seronegative or T-cell-depleted graft (donor negative, recipient positive): the recipient already carries EBV, but the incoming donor immunity brings no EBV-specific T cells to control it. Most PTLD after stem-cell transplant is therefore donor-derived, EBV-associated, and appears within the first year.

The single reason

In both cases the high-risk patient is the one with EBV present but no matching T-cell immunity. Because the immune system comes from the recipient in solid-organ transplant but from the donor in stem-cell transplant, the serostatus that creates that mismatch flips.
High priorityExam-styleWhy is PTLD best understood as a spectrum rather than a single disease, and how does that understanding guide management? [10]
Model answer
A complete answer explains the spectrum, the EBV-driven imbalance that produces it, the functional grouping, and how each follows through to treatment intensity.

The spectrum

PTLD is not one disease but a continuum: a reactive, polyclonal hyperplasia at one end (resembling infectious mononucleosis, architecture preserved, no genetic hallmarks of malignancy), a clonal neoplasia in the middle, and a monoclonal malignant lymphoma at the other end. The same label therefore covers lesions of very different behaviour.

What drives progression

Progression reflects the balance between EBV-driven B-cell proliferation and T-cell control of EBV: EBV promotes proliferation, EBV-specific T cells normally restrain it, and immunosuppression removes that restraint. How far a patient progresses depends on how far EBV is driving the disease and how much T-cell control has been lost.

The functional grouping

The functional reading sorts the spectrum into quintessential, EBV-driven PTLD (hyperplasia through EBV-positive large-cell neoplasia) and post-transplant lymphoma (a true lymphoma behaving as in an immunocompetent patient). EBV status is the principal discriminator: EBV-positive disease is more often the controllable, quintessential form; EBV-negative disease raises concern for a true lymphoma.

How this guides management

Treatment intensity follows position on the spectrum. Quintessential disease is treated with the lowest-intensity approach that works, escalating only as needed: reduce immunosuppression, then add rituximab for CD20-positive disease, then chemotherapy if it does not respond. A post-transplant lymphoma is treated from the outset as the matching lymphoma would be in an immunocompetent patient. EBV-positive disease, especially after stem-cell transplant, can also be treated by restoring EBV-specific T cells. Position on the spectrum therefore determines the intensity of treatment.
MCQ
EBV-specific cytotoxic T-cell therapy is appropriate for which PTLD?
- A. EBV-negative monomorphic disease
- B. All PTLD regardless of EBV status
- C. Classic Hodgkin lymphoma PTLD only
- D. EBV-positive disease, mainly after stem-cell transplant
- E. Only CD20-negative disease
Show answer
Correct answer: D
Why D

Adoptive therapy with EBV-specific cytotoxic T cells restores the exact immunity that immunosuppression removed: T cells that recognise and kill EBV-infected B cells. It can only work where the tumour is EBV-positive, and it is most effective after stem-cell transplant, where the disease is almost always EBV-driven and donor-derived.

It is therefore not used for EBV-negative disease (which carries no EBV target), is not limited to Hodgkin or CD20-negative subtypes, and is not applicable to all PTLD. Off-the-shelf, third-party EBV-specific T cells are now reaching practice for relapsed or refractory EBV-positive disease, with little risk of graft-versus-host disease.
MCQ
When monitoring EBV-DNA after transplant, how do plasma and whole-blood testing differ?
- A. Plasma is more specific; whole blood more sensitive
- B. Plasma is more sensitive; whole blood more specific
- C. Both perform identically
- D. Plasma cannot detect EBV-DNA
- E. Whole blood is no longer used
Show answer
Correct answer: A
Why A

Cell-free plasma EBV-DNA is more specific for established EBV-positive disease, while whole blood (which also captures virus inside circulating cells) is more sensitive and so better for surveillance. Many centres therefore use whole blood to screen and plasma to help confirm.

Either sample is acceptable, and both are in routine use, so options C to E are wrong. The deeper point is that neither result diagnoses PTLD: the load raises or lowers suspicion, but tissue biopsy makes the diagnosis, and loads cannot be compared between laboratories because assays differ.
MCQ
Which immunosuppression-related factor is most associated with early-onset PTLD?
- A. Aggressive early steroid tapering
- B. Low maintenance drug levels
- C. T-cell-depleting induction therapy
- D. Calcineurin inhibitor withdrawal
- E. mTOR inhibitor maintenance
Show answer
Correct answer: C
Why C

The depth of T-cell suppression is the central driver of PTLD, so T-cell-depleting induction (antithymocyte globulin, the historical OKT3) is strongly linked to early disease. Cumulative maintenance immunosuppression, by contrast, drives the late peak.

The other options reduce risk or are neutral: lower drug levels and aggressive tapering lessen the net immunosuppressive burden, and calcineurin-inhibitor withdrawal is used to treat PTLD, not cause it. One agent worth remembering separately is belatacept, which is specifically associated with central-nervous-system PTLD in EBV-seronegative recipients.
MCQ
Which PTLD histology is least likely to be EBV-positive?
- A. Non-destructive (hyperplasia) lesions
- B. Polymorphic PTLD
- C. Classic Hodgkin lymphoma PTLD
- D. Monomorphic T/NK-cell lymphoma
- E. EBV-positive mucocutaneous ulcer
Show answer
Correct answer: D
Why D

EBV association falls in bands across the spectrum. The reactive and early ends are almost always EBV-positive (non-destructive and polymorphic lesions, over 95 per cent), and classic Hodgkin lymphoma PTLD and the EBV-positive mucocutaneous ulcer are usually positive too.

The monomorphic, lymphoma-like end is more mixed: large B-cell and Burkitt types are often positive, but T/NK-cell, high-grade B-cell and plasma-cell types are frequently EBV-negative (under half). The T/NK-cell lymphomas are therefore the least EBV-associated of the options, and sit at the post-transplant-lymphoma end that needs lymphoma-directed treatment.
MCQ
Why do aciclovir and ganciclovir not treat established PTLD?
- A. The drugs cannot penetrate involved lymph nodes
- B. The tumour cells actively expel the drugs
- C. The virus is intrinsically resistant to both
- D. The drugs act only against cytomegalovirus
- E. Latent virus expresses no thymidine kinase
Show answer
Correct answer: E
Why E

Aciclovir and ganciclovir must be activated by a viral thymidine kinase, which is made only when EBV is replicating (the lytic cycle). The proliferating B cells of PTLD carry EBV in its latent state: the virus is not replicating and makes no thymidine kinase, so the drugs are never activated and have nothing to act on.

This is why antivirals do not treat established disease, although they show a weak signal for prevention (where some lytic replication may be targetable). The drugs are not expelled by the cells, not intrinsically resistant, and not specific to cytomegalovirus.
Exam-styleHow is central nervous system PTLD managed, and why does it need a different approach? [5]
Model answer
A complete answer states how central nervous system PTLD is treated and the reason it cannot simply follow the usual ladder.

The approach

PTLD in the central nervous system is treated on the lines of a primary central nervous system lymphoma, using regimens designed to reach the brain (high-central-nervous-system-penetrating, methotrexate-based therapy, with radiotherapy or rituximab as appropriate), alongside reduced immunosuppression.

Why it differs

Most of the chemotherapy used for systemic PTLD does not cross the blood-brain barrier in useful concentrations, so standard systemic regimens leave central nervous system disease undertreated. Central nervous system involvement is also a recognised adverse prognostic feature, which reinforces the need for a dedicated, brain-directed strategy rather than the systemic ladder alone.