Histopathologic Validation of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in Squamous Cell Carcinoma of the Oral Cavity

Abstract

Accelerated tumor cell repopulation is an important mechanism adversely affecting therapeutic outcome in head and neck cancer. The noninvasive assessment of the proliferative state of a tumor by PET may provide a selection tool for customized treatment. 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) is a PET tracer that is phosphorylated by thymidine kinase 1 (TK-1) and, as such, reflects cellular proliferation. Before the use of 18 F-FLT PET for tumor characterization is accepted and introduced into clinical studies, validation against tumor histology is mandatory. The aim of this study was to validate 18 F-FLT PET in squamous cell carcinomas of the oral cavity using immunohistochemical staining for the proliferation marker iododeoxyuridine and for TK-1. Methods: Seventeen patients with primary squamous cell carcinomas of the oral cavity underwent an 18 F-FLT PET/CT scan before surgery, and iododeoxyuridine was administered 20 min before tumor resection. 18 F-FLT PET/CT scans were segmented, and PET/CT volumes and PET signal intensities were calculated (mean standardized uptake value [SUV mean ] and maximum standardized uptake value [SUV max ]). Multiple paraffin-embedded tumor sections were immunohistochemically stained for iododeoxyuridine and TK-1. For iododeoxyuridine, labeling indices and optical densities were calculated and correlated with SUV mean and SUV max . TK-1 staining was visually and semiquantitatively assessed. Results: All primary tumors were identified with 18 F-FLT PET but with a large range in tracer uptake (mean SUV max , 5.9; range, 2.2-15.2). Also, there was a large variability in iododeoxyuridine labeling indices (mean, 0.09; range, 0.01-0.29) and optical densities (mean, 28.2; range, 12.6-37.8). The iododeoxyuridine optical densities correlated significantly with SUV mean and SUV max , but the labeling indices did not. In most tumors, TK-1 staining of varying intensity was present but correlated with neither iododeoxyuridine binding nor 18 F-FLT uptake. Conclusion: The current study demonstrated only a weak correlation between 18 F-FLT uptake and iododeoxyuridine staining intensity in oral cavity tumors. This weak correlation may be explained by differences in biomarker characteristics, resolution, and quantification methods.

Tumor 3′-Deoxy-3′-18F-Fluorothymidine (18F-FLT) Uptake by PET Correlates with Thymidine Kinase 1 Expression: Static and Kinetic Analysis of 18F-FLT PET Studies in Lung Tumors

“…p53 function may be compromised in as many as 50% of all human cancers, thus raising the possibility that 18 F-FLT uptake may be more closely associated with tumor DNA repair than with tumor proliferation. In a recent study of 17 human oral squamous cell carcinomas, no relationship could be found between the expression of the TK1 protein and either proliferation indices or 18 F-FLT maxSUV (17).…”

“…18 F-FLT accumulates in proportion to overall tumor proliferation in resected human lung lesions (15) and several other human tumor types (16). Far less evidence is available concerning ex vivo TK1 protein expression in human tumors excised after 18 F-FLT PET (17). To our knowledge, the present study is the first to examine the relationship between the catalytic activity of the TK1 enzyme of human solid tumors ex vivo and their in vivo 18 F-FLT uptake during PET.…”

αB-crystallin stimulates VEGF secretion and tumor cell migration and correlates with enhanced distant metastasis in head and neck squamous cell carcinoma

“…Oral cavity tumor sections [18] were incubated with 100-fold diluted polyclonal rabbit αB-crystallin antiserum [19] and subsequently stained with diaminobenzidine (DAB) according to a standard protocol. Sections of the 38 available biopsies (5 μm) were mounted on poly-L-lysine coated slides, fixed for 10 minutes in acetone at 4°C and rehydrated in PBS.…”

Non-18F-FDG PET/CT in the management of patients affected by HNC

“…As the fraction of radiopharmaceutical incorporated into the DNA does not exceed 1% [65], this tracer provides an indirect measure of proliferation. However, the correlation between FLT uptake and tumour proliferation is controversial: although a report showed no significant correlation between the FLT SUV max and Ki-67 index [66] or iododeoxyuridine staining intensity in oral cavity tumours [67], another preclinical study showed good agreement between the Ki-67 index and bromodeoxyuridine and FLT semiquantitative parameters [68]. [70,71].…”