Immunosuppression was postulated to be involved in the pathogenesis of cancer in the 1960s. Avoidance of the immune system is one of the hallmarks of cancer; if a patient is immunosuppressed this means there is one less step (or at least one easier step) for a cancer to develop.
Malignancy is the second most common cause of death in patients who are chronically immunosuppressed (after infection).
The most commonly associated malignancies with immunosuppression are haematological and carcinomas; the exact type of malignancy that develops depends on the type of immunosuppression.
Immunodeficiency can be primary or secondary.
Primary immunodeficiency includes rare genetic causes where there is a germline mutation of a particular gene important for normal function of the immune system. These are often X-linked recessive (i.e. more common in males who do not have a 'normal' X chromosome to counter the deficiency) or less commonly autosomal recessive diseases. An example is X-linked severe combined immunodeficiency (X-SCID). Patients develop opportunistic infections in infancy. Milder forms may develop malignancies early in life, often lymphomas. Lymphomas are the most commonly associated group of malignancies for patients with primary immunodeficiency.
Other types of primary immunodeficiency include ataxia-telangiectasia, arising from mutation of the ATM gene. This sensor of DNA damage is also involved in homologous recombination which is required for T cell and B cell maturation. These patients are chronically immunodeficient have suffer from increased rates of solid malignancies, especially skin, gastrointestinal and CNS malignancy.
Secondary immunodeficiency is due to:
- Iatrogenic immunosuppression following solid organ transplant
- Iatrogenic immunosuppression which occurs after haematological stem cell transplant
- Infection (usually HIV/AIDS)
HIV may be sexually transmitted and patients infected by this method are also at increased risk of infection with other STDs, of which the most important for development of malignancy is human papillomavirus (HPV). Patients with HIV are less able to clear the HPV infection, allowing further carcinogenesis to occur in the infected cells. Patients are therefore at higher risk of HPV related infection, often presenting as anal or cervical carcinoma.
Iatrogenic immunosuppression following solid organ transplant is associated with a 3-5 fold increase in malignancies. About 20% of patients will develop cancer within 10 years of their transplant. It is more common in heart/lung transplants than renal transplant due to the level of immunosuppression required. The most commonly associated malignancies are:
- Skin cancer
- Squamous cell carcinoma (50-fold risk)
- Basal cell carcinoma (10-fold risk)
- Kaposi Sarcoma (1000 fold risk)
- Melanoma (5 fold risk)
- About 8% of Merkel Cell carcinomas occur in immunodeficient patients
- Post-transplant lymphoma (80% EBV associated)
- Other solid organ cancers (eg. bladder, cervical)
Immunosuppression following haematological stem cell transplant occurs while the transplant is taking, ranging from 1-30%. Some patients have T cell depletion performed to reduce graft versus host disease but this is associated with a higher risk of lymphoma development. Most cases of lymphoma occur within 6 months of the transplant and the majority are associated with EBV infection. These cases can be rapidly progressive and cause death with widespread dissemination of disease.