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Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. (Anja Smits)ORCID iD: 0000-0003-2803-0343
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed) Published
Abstract [en]

Purpose Oligodendrogliomas are heterogeneous tumors in terms of imaging appearance, and a deeper understanding of the histopathological tumor characteristics in correlation to imaging parameters is needed. We used PET-to-MRI-to-histology co-registration with the aim of studying intra-tumoral 11C-methionine (MET) uptake in relation to tumor perfusion and the protein expression of histological cell markers in corresponding areas.

Methods Consecutive histological sections of four tumors covering the entire en bloc-removed tumor were immunostained with antibodies against IDH1-mutated protein (tumor cells), Ki67 (proliferating cells), and CD34 (blood vessels). Software was developed for anatomical landmarks-based co-registration of subsequent histological images, which were overlaid on corresponding MET PET scans and MRI perfusion maps. Regions of interest (ROIs) on PET were selected throughout the entire tumor volume, covering hot spot areas, areas adjacent to hot spots, and tumor borders with infiltrating zone. Tumor-to-normal tissue (T/N) ratios of MET uptake and mean relative cerebral blood volume (rCBV) were measured in the ROIs and protein expression of histological cell markers was quantified in corresponding regions. Statistical correlations were calculated between MET uptake, rCBV, and quantified protein expression.

Results A total of 84 ROIs were selected in four oligodendrogliomas. A significant correlation (p < 0.05) between MET uptake and tumor cell density was demonstrated in all tumors separately. In two tumors, MET correlated with the density of proliferating cells and vessel cell density. There were no significant correlations between MET uptake and rCBV, and between rCBV and histological cell markers.

Conclusions The MET uptake in hot spots, outside hotspots, and in infiltrating tumor edges unanimously reflects tumor cell density. The correlation between MET uptake and vessel density and density of proliferating cells is less stringent in infiltrating tumor edges and is probably more susceptible to artifacts caused by larger blood vessels surrounding the tumor. Although based on a limited number of samples, this study provides histological proof for MET as an indicator of tumor cell density and for the lack of statistically significant correlations between rCBV and histological cell markers in oligodendrogliomas.

Place, publisher, year, edition, pages
2019. Vol. 46, no 3, p. 569-579
Keywords [en]
Perfusion MR, C-11-methionine PET, Proliferation, Vascularization, Co-registration
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
URN: urn:nbn:se:uu:diva-356591DOI: 10.1007/s00259-018-4107-zISI: 000457151600005PubMedID: 30109401OAI: oai:DiVA.org:uu-356591DiVA, id: diva2:1237325
Funder
Erik, Karin och Gösta Selanders FoundationAvailable from: 2018-08-14 Created: 2018-08-08 Last updated: 2019-03-14Bibliographically approved
In thesis
1. Towards new tools for clinical evaluation and visualization of tumor growth in patients with glioma
Open this publication in new window or tab >>Towards new tools for clinical evaluation and visualization of tumor growth in patients with glioma
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gliomas are derived from glial cells and are the most common type of primary brain tumors in adults. Gliomas are classified by the World Health Organization (WHO) according to their malignancy grade and histological and molecular features. Malignancy grades range from I to IV. WHO grade I tumors are benign tumors, mostly occurring in childhood. High-grade gliomas (WHO grades III and IV) are undifferentiated and fast-growing tumors, with glioblastoma being the most common and malignant form. Patients with glioblastomas have a median survival of only 15 months. Clinical outcomes vary, however, and markers are needed to assist in the decision-making process and management of these patients. PROX1 is a transcription factor critical for embryonic development, with a role in cell cycle control and progenitor cell differentiation. Apart from its role in normal central nervous system development, PROX1 has been ascribed both tumor suppressive and oncogenic roles in several human cancers. The role of PROX1 as a prognostic factor for survival in patients with glioblastomas was the focus of paper I.

Gliomas WHO grade II, also called diffuse low-grade gliomas (DLGGs), are well-differentiated tumors that occur mainly in adult life, with a peak incidence at around 30–35 years of age and a median survival of 5–10 years. DLGGs grow continuously at a rate of a few mm per year and have a strong tendency to infiltrate the white matter tracts surrounding the tumor. Eventually these tumors transform into high-grade gliomas, but, as is the case with glioblastomas, there is a large variety of clinical outcomes. For radiological diagnosis, magnetic resonance imaging (MRI) is routinely used, often in combination with advanced MRI. Positron emission tomography with amino acid tracers provides additional diagnostic accuracy. From a histological as well as imaging point of view, DLGGs are heterogeneous tumors. The heterogeneity of DLGGs, in particular the correlation between radiological and histological tumor features, was the focus of paper II & paper III.

Seizures are amongst the most common presenting symptoms of patients with gliomas. Seizure semiology in patients with brain tumors and other structural brain lesions is closely related to the anatomical location of the lesion and the involvement of functional networks. A possible dynamic interplay between the anatomical region of seizure onset and connected target areas within the network was the focus of paper IV.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1486
Keywords
PROX1, Histology, MRI, PET, Epilepsy, Co-registration
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-356846 (URN)978-91-513-0410-6 (ISBN)
Public defence
2018-11-30, Aula Gunnesalen, Sjukhusvägen 1, ingång 10, Uppsala, SE, 13:00 (English)
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Supervisors
Available from: 2018-10-09 Created: 2018-08-08 Last updated: 2018-11-27

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Roodakker, Kenney RoyAlhuseinalkhudhur, AliGeorganaki, MariaZetterling, MariaBerntsson, Shala G.Danfors, TorstenStrand, RobinEdqvist, Per-HenrikDimberg, AnnaLarsson, Elna-MarieSmits, Anja

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Roodakker, Kenney RoyAlhuseinalkhudhur, AliGeorganaki, MariaZetterling, MariaBerntsson, Shala G.Danfors, TorstenStrand, RobinEdqvist, Per-HenrikDimberg, AnnaLarsson, Elna-MarieSmits, Anja
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