Progression patterns in diffuse gliomas

Abstract

Diffuse gliomas are the most common adult-onset primary brain tumours. After diagnosis with a diffuse glioma, the patient is treated with surgery, radiotherapy and chemotherapy. Despite this extensive treatment, in most patients, the residual tumour will eventually grow on follow-up MRI. This may be the result of true progressive disease (PD) or of treatment-associated changes. Such treatment-associated changes are composed of treatment-associated tissue damage of the malignancy, but also of the surrounding healthy cells. The distinction between treatment-associated changes and PD is of great importance for further treatment policy, because management strategies differ. Whereas PD requires mostly a change in antineoplastic treatment, treatment-associated changes generally do not. The follow-up of brain tumour patients includes regular MRIs and clinical examination. In patients with treatment-associated changes, the clinical status can vary from asymptomatic to severe decline and does not discriminate between PD and treatment-associated changes. Equally, both PD and treatment-associated changes may generate contrast-enhancement, mass-effect and oedema on MRI. Therefore, it remains challenging to discern PD and treatment-associated changes reliably. Furthermore, some patients suffer from treatment-associated changes more and earlier than others, with a range in histological specimens from 0 to 100%. The reason for this heterogeneous response to treatment between tumour patients remains unknown. This PhD thesis focused on the clinical, radiological and histopathological characteristics of progression patterns. We discovered that treatment-associated changes can develop more than once in the same patient and occur more often in patients with certain clinical characteristics, such as treatment with high radiotherapy doses, a long time from radiotherapy to progression, or certain genetic tumour traits (an MGMT promoter methylation). We used conventional MRI with T1-, T2- and FLAIR-sequences, and diffusion and arterial spin labelling perfusion MRI. We have found several characteristics in patients with a new or increasing contrast-enhancing lesion that correlate with PD, such as a soap bubble enhancement, a FLAIR-signal intensity change of the surgical cavity or high vascular perfusion. On histopathological examinations of recurrent-resected diffuse gliomas, our aim was to characterise treatment-associated changes and the underlying pathophysiological processes. We discovered that survival in patients with treatment-associated changes was significantly longer than in patients with mitotically active tumor. Haemorrhage, dystrophic calcification and mitosis count were independent predictors of survival. The aim of this PhD project was to characterise and subdivide progression patterns in diffuse gliomas with a focus on the difference between treatment-associated changes and PD. These characteristics can help the clinician to interpret the individual signs, form an overall synthesis and make the best choices for the patient. Hence, our results may help to decrease the feeling of uncertainty in patients and physicians and the number of unnecessary treatments. In addition, a better diagnosis may improve the patients’ prognosis by administering the appropriate treatment more quickly. Furthermore, certain discovered elements may contribute to a deeper understanding of the pathophysiology, which is expected to lead to new diagnostic and therapeutic tools.