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.
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.
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.