Malignancy & PTLD

The contract between this chapter and the reader.

1. 1. Explain why immunosuppression increases cancer risk.
2. 2. Identify the cancer spectrum after transplant.
3. 3. Recognise skin cancer as the most common malignancy.
4. 4. Explain the EBV-driven mechanism of PTLD.
5. 5. Recognise and diagnose PTLD.
6. 6. Treat PTLD, starting with immunosuppression reduction.
7. 7. Manage skin cancer, including mTOR conversion.
8. 8. Apply cancer screening and prevention.
9. 9. Balance immunosuppression against cancer.

A sixty-second reading. Each bullet stands alone.

• Immunosuppression impairs immune surveillance, increasing the risk of many cancers, especially virus-associated ones.
• Skin cancer is by far the most common malignancy after transplant, and squamous cell carcinoma is aggressive.
• Post-transplant lymphoproliferative disorder is an EBV-driven proliferation of B cells.
• PTLD risk is highest in EBV-seronegative recipients of seropositive donors (primary infection), especially children.
• PTLD ranges from polyclonal hyperplasia to monomorphic lymphoma and can involve the graft, gut, and CNS.
• PTLD is diagnosed by biopsy (with EBV staining and clonality), imaging, and EBV PCR.
• The first treatment of PTLD is to reduce immunosuppression, restoring T-cell surveillance.
• Rituximab and chemotherapy are added for more aggressive PTLD.
• Skin cancer is managed by excision, sun protection, surveillance, and reducing immunosuppression.
• Conversion to an mTOR inhibitor can reduce recurrent skin cancer.
• Other virus-associated cancers include Kaposi sarcoma (HHV-8) and HPV-related cancers.
• Prevention includes vigilant screening, sun protection, HPV vaccination, EBV monitoring, and minimising cumulative immunosuppression.
• Treating cancer usually means reducing immunosuppression, balanced against rejection risk.

The medical core. An expert should agree malignancy and PTLD are fully covered here.

Why it matters at the bedside

Cancer is the long shadow of immunosuppression. The same blunting of the immune system that protects the graft also lifts the surveillance that normally catches malignant and virus-transformed cells — so transplant recipients get more cancer, of distinctive kinds, and earlier. The recurring move, opposite to almost everything else, is to treat the cancer by taking immunosuppression away.

Why cancer risk is increased

• The immune system continuously surveils for malignant and virally-transformed cells; immunosuppression impairs that surveillance, raising the risk of many cancers — most strikingly the virus-associated ones, where a normally-controlled oncogenic virus is unleashed. The risk scales with the cumulative dose and duration of immunosuppression, which is one more reason to minimise it over time.

The cancer spectrum

• The post-transplant cancer spectrum is distinctive: skin cancer is overwhelmingly the most common; post-transplant lymphoproliferative disorder is the important lymphoid malignancy; and virus-associated cancers — Kaposi sarcoma (HHV-8), HPV-related anogenital and cervical cancer, virus-associated hepatocellular carcinoma — are over-represented. Other solid cancers are modestly increased, and pre-existing recipient cancers (managed by the cancer-free interval) and rare donor-derived cancers complete the picture.

Skin cancer

• Skin cancer is the commonest malignancy by a wide margin, driven by ultraviolet exposure on a background of immunosuppression. Non-melanoma skin cancer predominates, and — unlike the general population — squamous cell carcinoma outnumbers basal cell and behaves aggressively, with real metastatic potential. Management is excision, rigorous sun protection, and regular dermatologic surveillance, with reduced immunosuppression and mTOR conversion for recurrent or multiple lesions.

PTLD: the mechanism

• Post-transplant lymphoproliferative disorder is, in most cases, EBV-driven: the Epstein-Barr virus transforms B cells, and immunosuppression removes the T-cell control that normally restrains them, allowing proliferation that ranges from a polyclonal hyperplasia to a frank monomorphic lymphoma. The highest risk is in an EBV-seronegative recipient of a seropositive donor — a primary EBV infection without prior immunity — which is why it disproportionately affects children.

PTLD: recognition and diagnosis

• PTLD presents variously: lymphadenopathy, a mass, B symptoms (fever, weight loss, sweats), or organ involvement — the graft, gastrointestinal tract, or central nervous system — often with EBV viremia. Diagnosis rests on tissue: biopsy for histology, clonality, and EBV (EBER) staining, with imaging to stage and EBV PCR to support and monitor. It must be actively considered, because its presentations are protean.

PTLD: treatment

• The first and distinctive step is to reduce immunosuppression — restoring T-cell surveillance, which alone can cause early, polyclonal PTLD to regress. Rituximab (anti-CD20) targets the B cells and is added for CD20-positive disease, and chemotherapy is used for monomorphic or aggressive lymphoma, with surgery or radiation for localised disease. The order — reduce immunosuppression first — is the through-line.

Other virus-associated cancers

• Beyond skin and PTLD, the virus-associated cancers recur as a theme: Kaposi sarcoma from HHV-8 (which often regresses on reducing immunosuppression or converting to an mTOR inhibitor), HPV-related anogenital and cervical cancers (a reason for pre-transplant HPV vaccination and cervical screening), and virus-associated liver cancer. The pattern reflects the loss of immune control over oncogenic viruses.

Screening and prevention

• Prevention and surveillance carry much of the burden: vigilant skin surveillance with sun protection (for the commonest cancer), age-appropriate cancer screening pursued more assiduously than in the general population, HPV vaccination and a cancer-free interval before transplant (the evaluation chapter), EBV PCR monitoring in high-risk recipients, and — underlying all — minimising the cumulative immunosuppression that drives the risk.

The role of mTOR inhibitors

• The mTOR inhibitors occupy a special place here: as antiproliferative agents they appear to carry a lower skin-cancer risk than calcineurin inhibitors and can cause Kaposi sarcoma to regress, so conversion to an mTOR inhibitor is a recognised strategy for recurrent skin cancer and certain virus-associated tumours — immunosuppression with, perhaps, a smaller oncologic price.

The balance

• The organising principle is the inverse of the rejection chapters: cancer is the cost of immunosuppression, so the response to cancer is generally to reduce immunosuppression — balanced, as ever, against the risk of rejection and graft loss. mTOR conversion offers one way to keep a graft suppressed while lightening the cancer burden; honest weighing of graft against patient is the rest.

Five fully-built tables.

Table A — The cancer spectrum

Table B — PTLD

Table C — Skin cancer

Table D — Screening and prevention

Table E — Treatment principles

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — Lost surveillance

Immunosuppression → impaired immune surveillance → malignant/virus-transformed cells escape → cancer → ACTION: reduce immunosuppression to treat (and minimise cumulative dose).

Chain 2 — EBV unleashed

EBV transforms B cells + loss of T-cell control → proliferation → PTLD → ACTION: reduce immunosuppression to restore surveillance; add rituximab.

Chain 3 — Primary EBV

EBV-seronegative recipient + seropositive donor → primary EBV without immunity → high PTLD risk (especially children) → ACTION: monitor EBV PCR and reduce immunosuppression if it rises.

Chain 4 — Sun and suppression

Ultraviolet exposure + immunosuppression → aggressive squamous cell carcinoma → metastatic potential → ACTION: sun protection, dermatologic surveillance, and mTOR conversion for recurrence.

Chain 5 — The antiproliferative option

mTOR inhibitors are antiproliferative → lower skin-cancer risk and Kaposi regression → immunosuppression with a smaller oncologic price → ACTION: convert to an mTOR inhibitor for recurrent skin cancer / Kaposi.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — Cancer surveillance / screening note

• Skin: surveillance done; sun protection counselled; lesions ___.
• Age-appropriate screening up to date: ___.
• EBV status and PCR monitoring (if seronegative): ___.
• HPV vaccination / cervical screening (Chapter 4): ___.
• Cumulative immunosuppression review (minimise): ___.

Template 2 — PTLD diagnosis / treatment note

• Presentation: nodes / mass / B symptoms / organ (graft, GI, CNS); EBV PCR ___.
• Biopsy: histology; clonality (poly/monomorphic); EBV/EBER ___.
• Staging imaging: ___.
• Treatment: immunosuppression reduced (first); rituximab (CD20+); chemotherapy ___.
• Response and monitoring (EBV PCR; rejection watch): ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Nine items, each anchored in this chapter. At least one per objective.