A Prospective Investigation of Tumor Hypoxia Imaging with 68Ga-Nitroimidazole PET/CT in Patients with Carcinoma of the Cervix Uteri and Comparison with 18F-FDG PET/CT: Correlation with Immunohistochemistry

Abstract

Hypoxia in cervical cancer has been associated with a poor prognosis. Over the years ⁶⁸Ga labelled nitroimidazoles have been studied and have shown improved kinetics. We present our initial experience of hypoxia Positron Emission Tomography (PET) imaging in cervical cancer with ⁶⁸Ga-Nitroimidazole derivative and the correlation with ¹⁸F-FDG PET/CT and immunohistochemistry. Twenty women with cervical cancer underwent both ¹⁸F-FDG and ⁶⁸Ga-Nitroimidazole PET/CT imaging. Dual-point imaging was performed for ⁶⁸Ga-Nitroimidazole PET. Immunohistochemical analysis was performed with hypoxia inducible factor-1α (HIF-1α). We documented SUVmax, SUVmean of the primary lesions as well as tumor to muscle ratio (TMR), tumor to blood (TBR), metabolic tumor volume (MTV) and hypoxic tumor volume (HTV). There was no significant difference in the uptake of ⁶⁸Ga-Nitroimidazole between early and delayed imaging. Twelve patients had uptake on ⁶⁸Ga-Nitroimidazole PET. Ten patients demonstrated varying intensities of HIF-1α expression and six of these also had uptake on ⁶⁸Ga-Nitroimidazole PET. We found a strong negative correlation between HTV and immunohistochemical staining (r = -0.660; p = 0.019). There was no correlation between uptake on PET imaging and immunohistochemical analysis with HIF-1α. Two-thirds of the patients demonstrated hypoxia on ⁶⁸Ga-Nitroimidazole PET imaging.

Keywords: 18F-FDG; 68Ga-Nitroimidazole; HIF-1α; cervical cancer; hypoxia; immunohistochemistry.

Figure 1

The mean SUVmax, SUVmean, tumor to muscle ratio (TMR) and tumor to blood ratio (TBR) for ¹⁸F-FDG and ⁶⁸Ga-Nitroimidazole at 30 and 60 min. * PET: Positron Emission Tomography

Figure 2

A 36-year-old female patient with FIGO stage II, squamous cell carcinoma of the cervix. (A). ¹⁸F-FDG PET transaxial image through the pelvis demonstrating uptake in the primary tumor (red arrow) with minimal uptake in the urinary bladder (blue arrow) (B). ⁶⁸Ga-Nitroimidazole PET transaxial image through the same plane exhibiting spatially incongruent uptake with inhomogeneous uptake in parts of the tumor (red arrow) and intense activity in the urinary bladder (blue arrow). (C) is the corresponding CT only image in the same plane with target organs marked with arrows. The fractional hypoxic volume was 36%.

Figure 3

The immunohistochemical staining of HIF-1α expression in the endocervical biopsy specimen of the patient in Figure 2. Well differentiated squamous cell carcinoma ×20 magnification. The tumor areas with well differentiated cells (yellow arrow) with brown staining, demonstrate HIF-1α expression, while the areas with other cell types (orange arrow) demonstrate little to no HIF-1α expression.

Figure 4

Scatterplot showing the relationship between the hypoxia score (data shown in the X-axis) and SUVmean of the primary tumor derived from the delayed ⁶⁸Ga-Nitroimidazole PET images.