Imaging Biomarkers in Lymphoma
Imaging has a crucial role in Lymphoma management nowadays. The main applications are based on the evaluation of disease extension in staging and in treatment response evaluation. Recently, thanks to the technology development of PET-CT and CT scanners, it has shown also a high utility in the evaluation of extra-nodular involvement, the early relapse and the transformation from indolent Lymphoma to an aggressive phenotype .
Evidence sets PET-CT and standard CT+contrast as the main imaging modalities for staging and treatment response evaluation. The most suitable modality will depend mainly on the aggressiveness and the FDG avidity of the lesion. Therefore, either for Hodgkin’s Lymphoma (HL), aggressive subtypes of non-Hodgkin’s Lymphoma (NHL) or for extra-nodal involvement evaluation in PET-CT will be the way to go for an appropriate staging. However, in cases of non-FDG avidity, mainly in indolent lymphomas (T-cell lymphoma and subtypes of NHL like Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma, Lymphoplasmacytic Lymphoma), contrast enhanced CT is the main modality. Regarding response evaluation, a similar distribution of lymphoma subtypes per modalities is arrange, with the difference in the Follicular Lymphoma (FL), where PET-CT is the most suitable technique for those FL with a high tumoral burden, whereas low tumoral burden FL should be studied by CT with contrast when studying response. Up to now, Magnetic Resonance Imaging (MRI) has still not shown enough evidence in the management of lymphoma patiens beyond Primary Brain Lymphoma. PET-MR has a promising future in Lymphoma evaluation, specially in the current need for low dose follow-up studies that could be done with this modality.
Due to heterogeneities in FDG metabolic uptake in different Lymphoma subtypes, Deauville criteria were established to grade the avidity in comparison with mediastinum and liver. However, conventional PET-CT has limitations in the staging of nodular alterations, with the exception of FL, where PET-CT helps to increase the stage of Lymphoma by detecting additional disease in up to 29% of cases. Regarding response evaluation, PET-CT has been recently considered as the gold standard at end of treatment in FL. This is one of the main conclusions from GALLIUM study.
Despite the previous comments, we understand that the staging and response evaluation in PET-CT in patients under new treatments based on targeted therapies or immunotherapy can not be only based on SUVmax evaluations. New imaging biomarkers have been developed in order to evaluate complex clinical scenarios like indolent Lymphoma or reactive inflammatory changes at the end of treatment in patients that have responded to therapy.
In the following table, specific Imaging Biomarkers for different biological objectives are provided:
|Tumoral burden||PET-CT||Metabolic Tumor Volume (MTV)|
|Tumoral burden + Metabolic activity||PET-CT||Total Tumor Glycolysis (TTG)|
|Change in metabolic activity||PET-CT||Voxelwise Delta-SUV (ΔSUV)|
|Heterogeneity||CT & PET-CT||Textures|
The first technical step of Imaging Biomarkers development workflow after an appropriate definition of the idea is the Images Acquisition. In PET-CT, European Association of Nuclear Medicine (EANM) guidelines should be followed, and centres should be ideally certified by EARL program.
Metabolic Tumor Volume (MTV)
The first Imaging Biomarker to be calculated is MTV. It is defined by consensus as those lesion voxels with a significant FDG uptake, that is >41% of SUVmax although different thresholds can be evaluated in practice. The typical units are cm^3. The analysis is performed semi-automatically by thresholding and manual correction.
Several studies have analyzed MTV values in different types of lymphoma, in the following table from Schöder H. J Clin Onc 2016, a nice summary can be appreciated:
The different thresholds used for MTV can be also appreciated (although 41% SUVmax is the one in the majority of them). Also, the wide range of MTV obtained show us the high heterogeneity of the disease and raises also the concern about treatment dose. Should we modulate the treatment given to patient by the MTV? or, on another way, does a patient with 600cm^3 of MTV have to receive the same treatment dose than a patient with 3000cm^3 ? Important research needs still to be done in this field.
Regarding MTV and Follicular Lymphoma, few studies have been performed. The most important one was a retrospective analysis from Meignan et al, where they calculated a MTV of 510cm^3 for 2-year Progression Free Survival (PFS). However, some controversy has arose mainly due to the fact that the inherent error in SUV measurements due to examination variability introduces a final MTV error in measurements around 20%, so the threshold should not be a single value, but a given range of MTV values that consider that error.
Total Tumor Glycolysis (TTG)
The TTG measurements is better applied for specific lesions rather than all lesion burden. Therefore, if we focus on specific lesions, the TTG combines information on the FDG avidity and the MTV of the lesion by the following equation:
TTG = MTV x SUVmean
The structural and anatomic information contained in the CT examination within the PET-CT acquisition can be used for spatial registration of scans of the same patient corresponding to different timepoints (e.g. registration of end-of-treatment CT on baseline CT). The idea behind this is to create a parametric map of the longitudinal SUV changes in the patient, and for that the deformation field resulting from spatial registration is applied to the end-of-treatment PET in order to convert it to the baseline geometry. After this process, the follow-up examination can be superimposed to the baseline and therefore even substracted to calculate the SUV difference between timepoints.
The image regions can be also evaluated quantitatively by means of texture analysis. Texture analysis allows for the extraction of quantitative descriptors from voxel intensities relationships within an image or region. They are organised in first order (if directly extracted from histogram) or second order (if an additional step is required for their calculation). Texture analysis and specially heterogeneity biomarkers like the entropy and kurtosis have shown promising results in many different cancerous lesions, specially as a prognostic biomarker.
In lymphoma, a recent manuscript from Ganeshan B. et al. has shown excellent results in providing complimentary information to the interim PET as a prognostic biomarker.
However, texture analysis techniques can also be applied to other type of images such as the PET component, being able to determine the metabolic heterogeneity (MH) of the lesions. In this regard, lesions with different regional FDG avidity are having a worse prognosis than lesions with a homogeneous FDG uptake.
As you have discovered in this post, there are still many Quantitative Imaging Biomarkers that can be extracted from conventional FDG PET-CT examinations, and which are showing important relationship with lymphoma progression, according to recent investigations. In QUIBIM we are a committed team dedicated to the implementation of these techniques in clinical practice, research and clinical trials. If you want to collaborate with us in this field do not hesitate to contact us and potentially upload a case through our QUIBIM Precision® platform. It will be the best way to start working together in this emerging field.