Post-Transplant Malignancy
The use of
immunosuppressive therapy has led to a significant reduction in rejection, and
a consequent improvement in graft and patient survival. Thus, many transplant
recipients will be exposed to immunosuppressants for years or even decades. One
of the major complications of prolonged immunosuppression is an increased risk
of malignancy, particularly those driven by oncoviruses such as human papilloma
virus (HPV) and Epstein-Barr virus (EBV). In addition, immunosuppressive drugs
inhibit immune tumour surveillance, potentiate the effects of other carcinogens
such as ultraviolet (UV) light, and some agents directly promote tumour
formation or progression (for example ciclosporin stimulates vascular
endothelial growth factor [VEGF]-A-associated tumour vascularisation and
increases TGF-β production).
Incidence of malignancy
Overall, the frequency of malignancy is at least twofold higher in
transplant recipients compared with the normal population. Skin malignancies
are 15–200 times more common (depending on sun exposure). The incidence of
solid organ malignancies is also increased; roughly speaking, a transplant
recipient’s risk of developing a malignancy is similar to a normal individual
10–20 years older than them.
Risk factors
1. Exposure to UV light –
patients with high exposure to UV light (e.g. those in sunny climates such as
in Australia) have a 100- to 200-fold increased risk of non-melanotic skin
cancers, compared with a 20
times increased risk in those in less sun-exposed environments such as the UK.
2. Previous exposure to
immunosuppressants as treatments for primary disease,
e.g. cyclophosphamide treatment for vasculitis or lupus nephritis increases the
risk of bladder cancer and of lympho-proliferative diseases.
3. Long-term uraemia –
patients with end-stage renal failure (ESRF) on dialysis have an increased risk
of malignancy, perhaps due to an accumulation of carcinogenic toxins.
4. Chronic viral infection –
both hepatitis B and hepatitis C infection increase the risk of hepatocellular
carcinoma.
Types of cancer
Post-transplant lymphoproliferative disease (PTLD) PTLD
is the most common type of cancer observed in paediatric transplant recipients,
and the second most common in adults, occurring in 2% of adult kidney and liver
transplant recipients. Patients exposed to heavy immunosuppression,
particularly lymphocyte-depleting agents such as ATG, are at increased risk of
PTLD. Most PTLD is driven by EBV; primary EBV infection in immunocompetent
individuals results in infectious mononucleosis. The virus subsequently
establishes latency in B lymphocytes. When primary infection occurs in a
transplant recipient receiving immunosuppression, e.g. an EBV-naive recipient
receiving a transplant from an EBV-positive donor, the individual may develop
a more severe mononucleosis-like illness and in some cases an aggressive
lymphoma. Children are more likely to be EBV-naive, hence the increased
incidence of PTLD in this population. Fifty per cent of cases of PTLD are
diagnosed within the first two years post-transplant. Presenting features
include local effects (e.g. fitting in cerebral PTLD, abdominal pain if
gastrointestinal involvement, local swelling secondary to lymphadenopathy, and
transplant dysfunction if there is graft infiltration). Systemic symptoms
include fever, night sweats, and weight loss. The diagnosis is confirmed by
tissue biopsy, which allows its classification into three categories.
1 Diffuse B cell hyperplasia:
EBV-positive, normal lymphoid architecture.
2 Polymorphic PTLD: usually
EBV-positive, polymorphic atypical lymphocytes disrupting lymphoid
architechture.
3 Monomorphic PTLD: often EBV-negative;
high-grade malignant B or T cell lymphoma.
Treatment is dependent on type/severity of disease and includes:
· Reduction
in immunosuppression to allow the patient to mount an immune response to EBV.
· Rituximab,
a chimeric anti-CD20 monoclonal antibody which causes depletion of
CD20-positive cells. CD20 is expressed by most B cells, thus rituximab is
effective in B cell lymphomas.
· Systemic
chemotherapy is reserved for patients with monomor-phic PTLD.
· Radiotherapy.
· Surgery.
Skin cancers
Non-melanoma skin cancers are the most commonly observed
post-transplant malignancy in adults. The main risk factors are UV exposure,
fair skin, HPV and prolonged duration of immunosuppression. Thus, 50–75% of
Caucasian transplant recipients will be affected by skin malignancies 20 years
post-transplant. Given the importance of
sun exposure, transplant recipients are advised to apply high factor sun
blocking cream and to wear protective clothing (e.g. hat, long-sleeved shirt)
when in the sun.
Both squamous cell carcinomas (SCC) and basal cell carcinomas
(BCC) are observed post-transplant, with SCCs three times more common than BCCs
(in contrast to skin cancers in the normal population, where BCCs predominate).
SCCs also commonly develop on the lip (60-fold more common than normal
population), anus (10-fold) and perineum, all in part driven by HPV.
The good thing about skin cancers is that screening is relatively
easy, and most transplant centres routinely perform regular skin surveillance
in long-term transplant recipients and encourage patients to perform their own
screening.
Treatment of skin malignancies is by local excision and topical
cytotoxic agents (e.g. 5-fluorouracil). The use of sirolimus rather than
calcineurin inhibitors as maintenance immunosuppression seems to lower the risk
of skin cancer, therefore a switch to sirolimus following diagnosis may be
beneficial.
Malignant melanomas are also more common in transplant recipients,
although the increased risk is much less than for SCCs and BCCs (threefold more
common than normal population).
Transplant recipients are also at increased risk of Kaposi’s
sarcoma (KS), for which human herpes virus (HHV)-8 is the principal
aetiological agent. Sirolimus may be useful in reducing VEGFA-mediated
stimulation of this endothelial-derived malignancy.
Transplant-specific solid organ cancers
Kidney transplant recipients have an eightfold increased risk of
kidney cancer, and a threefold increased risk of multiple myeloma. Liver
transplant recipients have a tenfold increased incidence of oral cancer and
higher risk of oesophageal cancer, possibly reflecting lifestyle risks
associated with alcohol ingestion, such as cigarette smoking. Treatment is as
for the general population, as well as
a reduction in immunosuppression where possible.
