Relationship among hypoxia, 18F-fluoromisonidazole positron emission tomography uptake, and tumor angiogenesis in oral squamous cell carcinoma

Abstract

Objectives Hypoxia is a common feature of cancer and, thus, is a prognostic factor for many types of cancer. Clinically, the prognosis of cancer with low oxygenation level is poor, and there is strong evidence that hypoxia in the tumor microenvironment is related to tumor angiogenesis and malignant progression. 18F-fluoromisonidazole (18F-FMISO) has been used in clinical and preclinical studies to provide spatially resolved images for localizing and quantifying tissue hypoxia.18F-FMISO can detect tumor hypoxia noninvasively. Hypoxia-inducible factor (HIF-1) is a key player in the transcriptional response to low oxygen in many types of cancer. Most transcriptional responses to low oxygen (O2) are mediated by HIFs, which are highly conserved transcription factors that control the expression of various angiogenic, metabolic genes. 18F-FMISO imaging of hypoxia in head and neck cancer remains challenging. It is unclear whether 18F-FMISO positron emission tomography (PET) can identify tumor anigiogenesis and HIF-1α expression in oral squamous cell carcinoma (OSCC). We evaluated the relationship among 18F-FMISO PET uptake, HIF-1α expression, and tumor angiogenesis in OSCC. Study Design In this retrospective study, immunohistochemistry was performed for CD31 and HIF-1α on 40 OSCC specimens. Each patient was evaluated by both 18F-FMISO PET before surgery, and the tumor–muscle ratio (TMR) of 18F-FMISO PET were measured. The threshold for the hypoxic volume based on TMR was set at 1.25 (TMR ≥ 1.25: hypoxic tumor; and TMR Results 18F-FMISO uptake in the primary site of OSCC indicates a hypoxic environment with HIF-1α expression. The CD31-positive vessel area was increased in the hypoxic tumor compared with that in the nonhypoxic tumor. The tumor vessel in the hypoxic tumor was morphologically more irregular and tortuous than that in the nonhypoxic tumor. Conclusions We demonstrated a significant relationship between 18F-FMISO TMR and CD31 and HIF1α expression in OSCC. In the future, we will perform detailed research on the relationship between tumor angiogenesis and 18F-FMISO uptake.