In situ lymphoma imaging in a spontaneous mouse model using the Cerenkov Luminescence of F-18 and Ga-67 isotopes

Zsombor Ritter,Péter Balogh,Nikolett Hegedűs,Kunal Vyas,Hussain Alizadeh,Ákos Balázs,Tibor Kovács,Ildikó Horváth,Krisztián Szigeti,Dániel Dezső,Gabriella Taba,Domokos Máthé,Dávid Szöllősi,Erzsébet Schmidt,Katalin Zámbó,Xinkai Jia,David Tuch

doi:10.1038/s41598-021-03505-3

Abstract

Cerenkov luminescence imaging (CLI) is a promising approach to image-guided surgery and pathological sampling. It could offer additional advantages when combined to whole-body isotope tomographies. We aimed to obtain evidence of its applicability in lymphoma patho-diagnostics, thus we decided to investigate the radiodiagnostic potential of combined PET or SPECT/CLI in an experimental, novel spontaneous high-grade B-cell lymphoma mouse model (Bc.DLFL1). We monitored the lymphoma dissemination at early stage, and at clinically relevant stages such as advanced stage and terminal stage with in vivo 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) and 67Ga-citrate single photon emission computed tomography (SPECT)/MRI. In vivo imaging was combined with ex vivo high resolution CLI. The use of CLI with 18F-Fluorine (F-18) and 67Ga-Gallium isotopes in the selection of infiltrated lymph nodes for tumor staging and pathology was thus tested. At advanced stage, FDG PET/MRI plus ex vivo CLI allowed accurate detection of FDG accumulation in lymphoma-infiltrated tissues. At terminal stage we detected tumorous lymph nodes with SPECT/MRI and we could report in vivo detection of the Cerenkov light emission of 67Ga. CLI with 67Ga-citrate revealed lymphoma accumulation in distant lymph node locations, unnoticeable with only MRI. Flow cytometry and immunohistochemistry confirmed these imaging results. Our study promotes the combined use of PET and CLI in preclinical studies and clinical practice. Heterogeneous FDG distribution in lymph nodes, detected at sampling surgery, has implications for tissue pathology processing and it could direct therapy. The results with 67Ga also point to the opportunities to further apply suitable SPECT radiopharmaceuticals for CLI.

Highlights

Cerenkov luminescence imaging (CLI) is a promising approach to image-guided surgery and pathological sampling
In the case of the advanced (8 days post inoculation) stage lymphoma single photon emission computed tomography (SPECT) and CLI images with 67Ga-citrate, high background bowel activity and consequent CLI signal hampered the distinguishing of tumor signal from background CLI luminescence of 67Ga in mesenteric and abdominal scans, interpretation of images to tumorous or non-tumorous uptake was not possible
Using in vivo positron emission tomography (PET)/magnetic resonance imaging (MRI) we found that in an advanced lymphoma stage the infiltrated mesenteric lymph nodes clearly showed a significant accumulation of [18F]FDG following intravenous administration (Fig. 1a)

Summary

Introduction

Cerenkov luminescence imaging (CLI) is a promising approach to image-guided surgery and pathological sampling. New DLBCL subgroups have been created to provide more accurate classification and more accurate prognosis prediction with regards to response to therapy, based on special molecular genetic d ifferences[5,6] exploiting the possibility of detailed genomic characterization with generation s equencing[7,8]. In connection with these recent advances in lymphoma therapy, imaging-based diagnostic tools have evolved. The so identified subgroups of patients would benefit from quick and tailored immune- or intensive chemotherapy

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