Whole Body MRI for Cancer Surveillance in A-T

Ataxia Telangiectasia (A-T) is an autosomal recessive disorder characterised with cerebellar neurodegeneration, immunodeficiency, respiratory disease and cancer susceptibility (22% by age 20). A-T is a complex disorder caused by mutations in the Ataxia Telangiectasia Mutated (ATM) gene which creates highly unstable ATM protein fragments. In the classical clinical presentation of A-T there is no kinase activity due to the absence of ATM protein. One consequence of this is that cellular DNA-repair pathways are compromised which allows breaks in DNA strands leading to genomic instability and/or cell death. As a result, there is an increase sensitivity to ionizing radiation and elevated cancer risk. Children less than 16 years with classical A-T demonstrate a predisposition to the development of different types of lymphoid cancers (lymphoma and leukaemia). However non-lymphoid tumours can also occur.

The current practice at the United Kingdom Paediatric A-T clinic for cancer surveillance is to perform blood testing, including full blood account, liver function tests and measurement of circulating tumour marker Alpha-fetoprotein. Full blood account can detect an increase white cell count and abnormal white cell populations and therefore, is effective in detecting most types of leukaemia. Elevation of Alpha-Fetoprotein can be a marker of different types of tumours, for example hepatocellular carcinoma and liver metastases, however is also often elevated in people with A-T. Therefore, its use for detecting cancer in A-T is uncertain and not currently evidence-based. The lack of evidence-based guidelines regarding the optimal cancer surveillance strategy in children with A-T could delay the diagnosis and consequently the treatment plan.

Magnetic Resonance Imaging (MRI) technology has progress rapidly since its discovery, making it possible currently to perform whole-body MRI scans with relatively short acquisition times. Presently, whole-body MRI protocols that include diffusion-weighted imaging and structural (T1/Dixon) acquisitions are used for diagnosing and monitoring cancers (sarcomas, metastases and haematological tumours like myeloma). A further advantage of this technique compared to computed tomography is that does not involve radiation, which is important given the elevated radiosensitivity of people with A-T.

The value of whole-body MRI in people with cancer predisposition has been shown in Li-Fraumeni syndrome, syndrome that, like A-T, is associated with increased risk of haematological and solid tumours. Despite the successful results of using a multimodality protocol for cancer surveillance in Li-Fraumeni syndrome, it cannot be assumed that the results will be the same in people with A-T as the also have respiratory and neurological dysfunction that could influence the tolerability and image quality of the MRI scans. Also, the profile of the tumours differs between these two syndromes. To date, the value of whole-body MRI for cancer surveillance in children and young people with A-T has not been demonstrated. It is unknown whether is possible to obtain diagnostic images, and the spectrum of findings (both cancer and non-cancer) that can be detected has not been reported.

In addition to technical considerations, it is vital to understand the perspectives of people affected by A-T regarding cancer surveillance. Participation in a cancer surveillance programme could increase anxiety for both the participant and family, and it is possible that negative psychological aspects could outweigh the perceived benefits or earlier cancer detection. Compared to other screening programmes, it should be noted that these families are already having to deal with a family member with complex progressive chronic disease, and so emotional and psychological capacity to deal with added anxiety may be limited. Hence, it is important to know, before conducting a full scale trial that will inform the current lack of evidence-based guidelines, whether cancer surveillance in children and young people with A-T using whole-body MRI is feasible and desirable.