Primary Immunodeficiency And Cancer

Introduction

Primary immunodeficiencies (PIDs) are a group of over 450 rare conditions characterised by the improper functioning of the immune system. The defects that cause PIDs are typically present from birth, with affected individuals experiencing frequent, long-lasting infections that are difficult to treat. Besides their influence on infections, PIDs can also increase the risk of cancer. This is because your immune system plays a vital role in recognising and destroying abnormal cells before they lead to cancer.¹

Understanding the relationship between PIDs and cancer is essential for both patients and healthcare professionals, as it highlights the importance of early detection and management of PIDs for minimising cancer risk. Therefore, this article aims to explore the relationship between these two health conditions. 

Understanding primary immunodeficiency

Causes

PIDs are most commonly caused by genetic mutations. These mutations are inherited (passed down) within families. Different PIDs are associated with different inheritance patterns; for example, some PIDs are X-linked - meaning they are generally passed down from mother to son via the X chromosome. 

Mutations can also occur spontaneously, meaning a child can be born with a PID with no family history of the disorder. 

Types

Your immune system is a complex network made up of cells, tissues, organs, and protein components - such as antibodies, complement proteins, and adhesion molecules. With such complexity comes a wide variety of PIDs, which can affect different features of the immune system. Examples include:

• Antibody deficiencies, such as common variable immune deficiency (CVID)
• Adhesion molecule defects, such as leukocyte adhesion deficiency (LAD) 

Different PIDs vary in terms of severity, with some being life-threatening. One of these is severe combined immunodeficiency (SCID), which is a group of disorders characterised by the absence or poor functioning of white blood cells known as lymphocytes. 

Symptoms

The principal symptoms of someone with a PID are frequent or repeated infections that last longer than expected. Additionally, individuals with PIDs are more susceptible to opportunistic infections - that is, infections caused by organisms that typically do not cause disease in healthy individuals. Common infections in people with PIDs include:

• Ear infections
• Sinus infections
• Pneumonia
• Skin infections

Infants and children with PIDs may also experience delayed growth and development - known as faltering growth or failure to thrive. 

Diagnosis

If an individual shows symptoms of a PID, their doctor will likely perform a physical examination before assessing their medical history and family history for any prior incidence of a PID. 

Following initial investigations, screening and laboratory tests will be carried out to identify which PID the patient is likely to have. The most common laboratory tests used to help diagnose PIDs are those that identify:

• Antibody deficiencies
• Lymphocyte (especially T cell) defects
• Neutrophil disorders
• Complement deficiencies

Doctors may also use genetic tests to diagnose PIDs, as these tests help to identify relevant genetic mutations. 

Treatment

One of the principal aspects of managing PIDs is promptly treating infections as they arise. This involves using antibiotics, antifungals, and antivirals. Some individuals will also be prescribed these antimicrobial medications as a preventative measure (prophylactic) to reduce the frequency and severity of infections.²

Further treatment depends on the type of PID an individual is affected by. For example, those with severe antibody deficiencies may be offered immunoglobulin (antibody) replacement therapy, which is a blood-based treatment that provides the antibodies necessary for fighting infection. Other specialist treatments include:

• Bone marrow transplantation, which provides healthy stem cells that enable the production of fully functional lymphocytes
• Gene therapy - which replaces an individual’s defective gene with a functional gene, thus restoring normal immune system function

The link between primary immunodeficiency and cancer

As mentioned previously, your immune system plays a critical role in preventing the development of cancer by recognising and destroying precancerous cells.¹ Therefore, some individuals with PIDs are at an increased risk of developing cancer as a result of their impaired immune systems. In particular, certain types of PID increase an individual’s risk of developing cancer. These include:

• CVID
• Ataxia telangiectasia
• Wiskott-Aldrich syndrome
• X-linked lymphoproliferative disease

It is essential to note that having a PID doesn’t mean you will definitely get cancer; most people with PIDs remain unaffected by cancer throughout their lives.³ 

Types of cancer associated with primary immunodeficiency

PIDs do not increase the risk of developing all cancers. Evidence shows that PIDs are not associated with an increased risk of developing the most common cancers - namely breast, lung, prostate, and colorectal cancers. Instead, an association has been found between PIDs and cancers of white blood cells - including lymphomas and leukaemias - as well as some types of skin cancer.⁴

If you or someone you know has a PID, it is vital to be aware of the signs and symptoms of these PID-associated cancers. For skin cancer, the most common sign is a change in the skin, such as a new growth, a wound that doesn’t heal, or a change in a mole. For lymphomas and leukaemias, the symptoms may be more difficult to spot. Common signs of lymphoma include swollen glands, chest pain, coughing or breathlessness, and extreme tiredness. Leukaemia can cause similar signs, but there are six main symptoms to look out for:

• Fatigue
• Breathlessness
• Fever or night sweats
• Bruising or bleeding
• Bone and joint pain
• Repeated infections (however, this is also the primary symptom of PIDs, so it may be difficult to recognise this as a symptom of another issue)

Mechanisms involved in cancer development in individuals with primary immunodeficiency

One of the chief mechanisms that link PIDs with cancer development is the reduced ability of the immune system to recognise and destroy precancerous cells.¹ Besides this, there are a variety of complex mechanisms that can contribute to the development of cancer in some individuals with PIDs - including chronic inflammation. 

Chronic inflammation can occur as a result of repeated infections in individuals with PIDs.⁵ This persistent state of inflammation can promote tumour growth and development as it:

• Aids the rapid production (proliferation) and survival of cancerous cells
• Promotes the formation of new blood vessels around the growing tumour (angiogenesis)
• Promotes the spread of cancer cells to other sites in the body (metastasis)
• Disrupts specific immune responses 
• Changes in normal responses to hormones

Managing primary immunodeficiency to reduce cancer risk

Importance of early detection and treatment of primary immunodeficiency

Timely detection of PIDs is crucial for ensuring prompt medical interventions, which, in turn, reduce the chances of complications and may potentially lower the risk of cancer. Therefore, it is essential to promptly consult healthcare professionals if you notice any signs or symptoms that may indicate a PID.

If you are diagnosed with a PID, your doctor will organise a treatment plan to help manage your symptoms, boost your immune function, and reduce your risk of infection and associated complications - such as cancer. Treatment options have been discussed previously, and include preventative antimicrobials, immunoglobulin replacement therapy, and gene therapy. 

You must also attend regular medical check-ups and screenings if you are diagnosed with a PID so that your health status can be monitored and any early signs of cancer can be detected. 

Lifestyle factors

Besides medical interventions, you can also implement lifestyle changes to reduce your risk of developing cancer if you have a PID. These changes focus on supporting immune function and reducing chronic inflammation and include:

• Maintaining a healthy diet
• Ensuring good hygiene
• Minimising stress
• Engaging in frequent exercise
• Getting enough sleep and maintaining a consistent sleep schedule

Summary

PIDs are rare conditions that affect the immune system and can increase an individual’s risk of developing cancer. It is essential that we understand the link between PIDs and cancer so that any early signs of cancer development can be detected and appropriately managed in individuals with PIDs. As well as ensuring early detection and treatment, people affected by PIDs can implement lifestyle changes - such as maintaining a consistent sleep schedule and eating a healthy diet - to reduce their cancer risk.