38 Two forms of acquired immunodeficiency dominated the last quarter of the 20th century and are responsible for the majority of cancers in the immunosuppressed. Both human immunodeficiency virus (HIV) and iatrogenic immunosuppression following allogenic transplantation are associated with cancers that are linked with oncogenic viruses. The first renal transplant was performed between identical twins by Joseph Murray at Boston’s Brigham Hospital in 1953. The development of azathioprine by George Hitchings and Gertrude Elion 10 years later enabled successful allogeneic transplantation and began an era of transplantation medicine dependent upon iatrogenic immunosuppression. The allogeneic organ transplant recipients who received immunosuppressant therapy were found to be prone to post-transplantation lymphoproliferative diseases (PTLDs) and other tumours. The emergence of post-transplant tumours is widely quoted as evidence to support Burnet’s immune surveillance theory that states that the immune system acts to remove abnormal clones of cells. In 1949, Frank Macfarlane Burnet described a theory of acquired immunological tolerance, proposing that lymphocytes that were able to respond to self-antigens were deleted in prenatal life. This hypothesis was confirmed experimentally by Peter Medawar who shared the Nobel Prize with Burnet in 1960. Peter Medawar also wrote several wonderful books and collections of essays and I would encourage anyone who is thinking of doing scientific research to read Advice to a Young Scientist. In the 1960s, however, in a volte face that signalled a paradigm shift, Burnet began to champion the view that a major function of the immune system is to eliminate malignant cells. This was based upon evidence that animals can be immunized against syngeneic transplantable tumours. This theory of immune surveillance led to the identification of tumour antigens and of immunotherapy strategies to treat tumours. In addition to these acquired, secondary forms of immunodeficiency, hereditary primary immunodeficiencies, although rare, also predispose to malignancy. Primary immunodeficiencies are mainly single-gene inherited disorders that present in early childhood. They include nearly 100 syndromes, three-quarters of which have been characterized genetically. One important exception is common variable immunodeficiency (CVID), a complex, polygenic disease that often manifests first in early adulthood. Classically, primary immunodeficiency disorders are classified into B-lymphocyte, T-lymphocyte, phagocytic cell and complement deficiencies. This classification is useful, as it helps us establish the clinical manifestations. For example, B-cell deficiencies usually present after the age of 6 months, when maternal antibodies are exhausted, and the most common pathogens are encapsulated bacteria (like Streptococcus and Haemophillus), fungi (such as Giardia and Cryptosporidia) and enteroviruses. In contrast, primary T-cell deficiencies usually present within the first 6 months of life, with opportunistic infections, such as Mycobacterium, Candida, Pneumocystis jiroveci and cytomegalovirus. Both B-cell and T-cell primary immunodeficiency may be associated with an increased risk of malignancy (Table 38.1). An increased risk of cancer has not been found with complement deficiencies or phagocyte abnormalities. The risk of cancer following an organ transplant varies with the organ that has been transplanted, and the type and duration of the immunosuppressive regimen used post-transplant. Physicians involved in transplantation tend to continue with immunosuppression of their patients for very long periods; however, the duration of immunosuppression required has not been established and the longer the treatment continues the more significant is the risk of malignancy developing. The greatest risk of cancer is with heart and heart–lung transplants because they require more aggressive immunosuppression, but overall more cancers occur in renal transplant recipients as many more renal transplants are performed. In addition to PTLD that is caused by the Epstein–Barr virus (EBV), the risks of Kaposi’s sarcoma (caused by Kaposi sarcoma herpesvirus (KSHV) which is also known as Human Herpesvirus 8 (HHV8)), cervical cancer (caused by human papillomavirus (HPV)) and non-melanoma skin cancers are most dramatically increased. In the case of PTLD and post-transplantation Kaposi’s sarcoma, reducing the immunosuppression may sometimes lead to regression of the tumours at an early point in their development when they are still under viral influence but this of course increases the risk of graft rejection. EBV infection generally antedates transplantation occurring in childhood or adolescence. EBV establishes lifelong latent infection in memory lymphocytes following primary infection. Immunosuppression leads to reactivation of latent EBV that drives tumourigenesis. There are stages in the development of EBV-related malignancy that reflect the degree of autonomy of the tumour from its viral master. The risk of cancers after a stem cell transplant in childhood for haematological malignancy is 9%, 20-fold greater than that expected in a non-leukaemic age-matched population. There is a similar increased risk in renal transplantation that is twofold greater than expected in an age-matched population. Studies by the World Health Organization (WHO) estimated that by December 2012, over 30 million people had died of acquired immune deficiency syndrome (AIDS) and 35.3 million people were living with the virus. The number of people newly infected with HIV worldwide is approximately 2.3 million per year and 1.6 million die due to HIV/AIDS. On the brighter side, 9.7 million people living with HIV are on combination antiretroviral therapy (cART) in middle and low income countries where the cost of these drugs is now just $140 per person per year. Along with opportunistic infections, tumours are a major feature of HIV infection. The most frequent tumours in this population are Kaposi’s sarcoma (KS), non-Hodgkin’s lymphoma and cervical cancer and these three are AIDS-defining illnesses. The management of cancer in the immunodeficient host requires careful attention to the balance between antitumour effects and the toxicity associated with treatment. Combination antiretroviral treatment has both dramatically reduced the incidence of opportunistic infections and prolonged the survival of people with HIV infection. In addition, this highly active cART has reduced the incidence of AIDS-defining malignancies and improved their prognosis. However, although the use of cART reduces the incidence of AIDS-defining cancers, a number of other malignancies occur more frequently in people living with HIV and are not falling with wider use of cART. Table 38.1 Description of primary immunodeficiency syndromes The cancers that occur with primary immunodeficiency syndromes are rare and as a consequence treatment protocols and outcome data are scarce. Most patients succumb to infections and these continue to pose a major threat to life during the treatment of associated tumours. The incidence of congenital immunodeficiency-associated tumours is sufficiently low for there to be little consensus upon their clinical management. In contrast, the incidence of both PTLD and KS has risen dramatically in recent years with the spread of the HIV pandemic and the marked increase in transplant surgery. The management of PTLD relies upon enhanced immunity against EBV by reducing immunosuppression and infusing cytotoxic T lymphocytes against EBV. In addition, antiviral agents, low-dose chemotherapy and anti-CD20 monoclonal antibodies may be useful. The introduction of cART has reduced the incidence of HIV-associated KS in established market economies where this treatment is available. Moreover, early-stage KS may be successfully treated with cART alone, leading to regression of KS (Figure 38.1). Visceral KS is usually treated with systemic liposomal anthracycline chemotherapy with concomitant cART. Other tumours that arise in immunodeficient individuals are generally treated along conventional lines, with extra attention to the risk of infectious complications of therapy. Figure 38.1 Multiple pigmented Kaposi sarcoma skin lesion in a man with HIV infection. Following combination antiretroviral therapy (cART) alone there was a marked regression of these lesions. Case Study: The purple spotted geek.
Immunodeficiency-related cancers
Hereditary or primary immunodeficiency
Acquired or secondary immunodeficiency
Tumours in allograft recipients
Tumours in HIV patients
Syndrome
Inheritance and incidence
Genetic defect
Immunological defect
Clinical manifestations
Cancer risk
B-cell/antibody deficiency
X-linked (Bruton’s) agammaglobulinemia (XLA)
X-linked recessive (1 in 200,000 male live births)
Defect of Btk Bruton’s (B-cell progenitor tyrosine kinase) intracellular signalling path involved in pre-B-cell development. Less often, the mutation is of the mu heavy chain gene
There are virtually no immunoglobulins present in the serum and the number of residual B lymphocytes in blood is very low
Recurrent pyogenic bacterial infections starting aged 6 months after maternal IgG is exhausted. Chronic sinusitis and bronchiectasis may follow
Small increased risk of lymphoma
Common variable immunodeficiency (CVID)
Polygenic, most common primary immunodeficiency (1 in 30,000)
Characterized by variably decreased concentrations of all immunoglobulin classes
Recurrent bacterial infections of the respiratory tract. These disorders are also associated with autoimmune diseases (e.g. Crohn’s)
Increased risk of lymphomas and gastrointestinal cancers
Selective IgA deficiency
(1 in 700 live births)
Mapped to chromosome 6p21
No secreted IgA but surface IgA present on B-cells
Common mild onset in childhood. Sinusitis and recurrent lung infections
No increased risk
Hyper IgM syndrome (HIM)
X-linked (CD40 ligand = CD154; <1 in 1,000,000 male live births), autosomal recessive (CD40 or activation-induced deaminase)
Three defects causing lack of isotype class switching from IgM to IgG, IgA and IgE
Excess IgM production but no IgG, IgA or IgE
Prone to opportunistic infections particularly Pneumocystis carinii and Cryptosporidium parvum. The latter may progress to sclerosing cholangitis and cirrhosis
Liver cancer in X-linked HIM
Hyper IgE syndrome (HIE)
Autosomal dominant
Gene not identified yet. Mapped to chromosome 4q
Elevated IgE, defective neutrophil chemotaxis, impaired lymphocyte response to Candida antigen
Recurrent bacterial skin and lung infections, chronic mucocutaneous candidiasis, craniofacial abnormalities, scoliosis and bone fractures
No increased risk
X-linked lymphoproliferative syndrome (XLPS; Duncan’s syndrome)
X-linked signalling lymphocyte-activating molecule (SLAM)-associated protein (SAP) (<1 in 1,000,000 male live births)
SLAM activates cytotoxic T-cells and this action is regulated by SAP
Overproduction of polyclonal CD8 + cytotoxic T-cells in response to EBV infection
EBV-induced T-cell proliferation causes severe organ damage, and hypogammaglobulinaemia
Increased risk of EBV-associated lymphomas
T-cell deficiency
DiGeorge syndrome (thymic aplasia)
Most have deletions of 22q11; 1 in 3500 live births
The third and fourth branchial pouches fail to form properly
Moderate to severe lack of T-cells
Tetany and cardiac malformations just after birth. Lack of T-cells may lead to fungal, viral or other infection in infancy. Increased risk of autoimmune diseases (e.g. thyroiditis)
No increased risk
Severe combined immunodeficiency (SCID) syndromes
Nine genetic (8 autosomal recessive, 1 X-linked) defects of T-cell maturation; 1 in 30,000 live births
Genetic defects affect purine metabolism (e.g. adenosine deaminase), VDJ recombination (e.g. recombinase activating genes) and lymphocyte signalling (e.g. common γ chain of interleukin receptors)
A variety of profound deficiencies of both T-cell and B-cell function
Failure to thrive and repeated infections caused by opportunistic infections by 6 months old. Protracted diarrhoea and death by 2 years in the absence of treatment
None known
DNA-repair defects (see Chapter 2)
Ataxia telangiectasia (AT; Louis–Bar syndrome)
Autosomal recessive ataxia-telangiectasia mutated (ATM), a protein kinase that reacts to DNA damage and affects the accumulation of p53 (1 in 60,000 live births)
Chromosomal instability due to defective DNA repair may interfere with immunoglobulin and T-cell receptor gene rearrangement
Most have IgA deficiency. Other hypoimmunoglobulinaemia and T-cell function deficits occur
Progressive cerebellar ataxia, skin telangiectasia. Most die in third decade of respiratory infections or tumours
Increased risk of acute leukaemias and lymphomas
Nijmegen breakage syndrome
Autosomal recessive
Chromosomal instability due to defective DNA repair may interfere with immunoglobulin and T-cell receptor gene rearrangement
Lymphopenia
As for AT but in addition have progressive microcephaly (bird-like face)
Increased risk of acute leukaemias and lymphomas
Other
Wiskott–Aldrich syndrome
X-linked recessive
Defective gene for WASP (Wiskott–Aldrich syndrome protein) involved in cytoskeleton reorganization following activation of platelets and T-cells
Low IgM and raised IgE levels
Thrombocytopenia, eczema and increased autoimmune diseases (including vasculitis). Usually die by age 10 years
Increased risk of EBV-associated lymphomas
Tumours in primary immunodeficiency
Management of immunodeficiency-associated malignancies
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