Whole-body diffusie-gewogen MRI in het maligne lymfoom: stadiëring en vroege therapieopvolging

Malignant lymphoma is the 5th most common tumor type, comprising a large group of cancers with distinct histopathological features, which translates into different treatment plans and prognosis. Two main categories can be identified, Hodgkin (HL) and non-Hodgkin lymphoma (NHL), the latter of which can be subdivided in aggressive and indolent lymphoma based on the clinical behavior. The lymphatic system is a circulatory system throughout the body consisting of lymph nodes and lymphatic vessels, which explains why disease can arise virtually anywhere in the body and typically has a systemic spreading pattern. Therefore, a whole-body imaging technique is required to capture the full disease extent (=staging). Currently, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) is the standard imaging technique not only to stage lymphoma, but also to assess treatment response during and at the end of treatment. However, FDG-PET/CT is expensive and exposes patients to a significant amount of ionizing radiation, which is an increasing area of concern due to improving survival rates, particularly in young patients requiring lifelong follow-up. Furthermore, not all lymphoma subtypes are FDG-avid, while the addition of immunotherapy to the standard chemotherapy regimens has notably decreased the technique’s specificity due to a treatment-induced confounding inflammatory response. To counteract the disadvantages of FDG-PET/CT, the purpose of this doctoral thesis was to evaluate the potential of diffusion-weighted magnetic resonance imaging (DWI/MRI) as an alternative imaging method. By probing the motion of water molecules on a microstructural level, malignancy can be detected with high sensitivity. Diffusion-restricting lesions can be appreciated on the DWI/MR images, but quantified as well by calculating the apparent diffusion coefficient (ADC), a measure which correlates inversely with cellularity. As such ADC is useful for pretreatment lesion characterization, while treatment response can be monitored by ADC changes during and after treatment. Technical advancements in the last decade have allowed clinical implementations of DWI/MRI in a whole-body protocol, making it now suitable to assess systemic diseases such as malignant lymphoma. The first chapter of this doctoral thesis consists of two pilot studies performed in patients with aggressive NHL. In the first pilot study, whole-body DWI/MRI (WB-DWI/MRI) was found to be a feasible method to stage patients. Visual analysis of the images sufficed to detect the vast majority of malignant bone and soft tissue lesions, while accurate lymph node characterization required additional quantitative analysis, consisting of ADC calculations. A second pilot study focused on the role of WB-DWI/MRI in the assessment of treatment response and its ability to predict treatment outcome. Interval ADC changes between the pretreatment scan and the scan performed 2 and 4 weeks after the start of therapy were significantly different for responding and non-responding lesions and correlated significantly with patient’s progression-free-survival (PFS). Subsequent studies are categorized in two sections: staging and early treatment response assessment. For the staging section of this doctoral thesis, a larger-scale, prospective staging study was performed including both HL and NHL patients. Diagnostic performance of CT and visual analysis of WB-MRI with and without DWI were compared with the reference standard, namely FDG-PET/CT in combination with bone marrow biopsy (BMB) results. For Ann Arbor staging, WB-MRI with DWI showed the closest to the reference standard, and its accuracy was further improved by adding ADC calculations to the visual analysis. In an additional study, the quantitative analysis consisting of conventional ADC mean calculations of lymph nodes was extended with ADC histogram analysis. This approach allowed the identification of ADC skewness - a measure of histogram asymmetry - as a more accurate and robust parameter for lymph node characterization than the commonly used mean ADC. In the following treatment response section, the potential of WB-DWI/MRI for early treatment response assessment and outcome prediction was explored in both aggressive NHL and HL. A larger-scale study in aggressive NHL patients showed that quantitative WB-DWI/MRI after only one cycle of immunochemotherapy was an accurate and independent prognostic factor of treatment outcome in comparison with interim and end-of-treatment FDG-PET/CT as well as several prognostic histopathological parameters. Taking into account the low tumor cell density in HL, lesion ADC histogram analysis was complemented with 3D (ADC) texture analysis. In contrast to interval changes of ADC histogram analysis parameters, texture analysis parameters reflecting tumor heterogeneity, namely ADC energy, ADC local homogeneity and ADC entropy, were significantly different between responding and non-responding lesions and correlated with PFS. In conclusion, this doctoral thesis demonstrated that WB-DWI/MRI may be feasible for staging malignant lymphoma and may be a valuable tool to assess and predict treatment response after only 1 cycle of (immuno)chemotherapy without the burden of ionizing radiation or contrast injection.status: publishe