In this study, we demonstrate positive 68Ga-DOTATATE uptake in 92% of NFMA (34/37). This positivity rate is higher than the two thirds of patients as reported earlier with 111In-DTPA-octreotide planar scintigraphy or SPECT (Fusco et al. 2012; Borson-Chazot et al. 1997). One likely explanation for this discrepancy is the superior sensitivity, higher spatial resolution and better partial volume recovery of PET (Bai et al. 2013). The limited resolution of planar scintigraphy/SPECT makes differentiation of 111In-DTPA-octreotide uptake in the adenoma from physiological uptake in the adjacent pituitary gland difficult. Most studies have therefore compared the uptake in the sellar region of patients to that of subjects without a pituitary disease, using either a visual grading system or a background-corrected uptake index to interpret results (Fusco et al. 2012). With this method, only adenomas with increased uptake as compared with the pituitary gland are considered positive. While in some cases this may lead to false positives if physiological pituitary uptake is higher than usual, a greater risk exists for false negatives when adenoma uptake is comparable to the applied limit. Additionally, in case of heterogeneous SSTR expression within an NFA, the low resolution can induce underestimation of the activity due to the partial volume effect (Borson-Chazot et al. 1997; Bai et al. 2013).
The two- to threefold higher spatial resolution of PET/CT in combination with more accurate attenuation correction makes it the preferred functional imaging modality for smaller lesions such as pituitary adenomas. Furthermore, uptake quantification with SUVs allows for a more objective evaluation. Of note, physiological uptake in the normal pituitary is also evident with 68Ga-DOTATATE PET, which hinders a straightforward assessment of the sellar region (Aalbersberg et al. 2019; Shastry et al. 2010). In the present study, we used co-registration with high-resolution MRI to optimise localisation of radiopharmaceutical uptake in the macroadenoma versus pituitary tissue. Still, maintaining a clear margin between the adenoma and pituitary is necessary to avoid activity spillover and overestimation of adenoma uptake. We therefore decided to place a circular ROI within the adenoma instead of manual delineation of the adenoma boundaries.
Partial volume effects play a role in the underestimation of radiotracer uptake in lesions smaller than two to three times the PET system’s spatial resolution (full width at half maximum) (Bettinardi et al. 2014). In our series, however, adenoma size was at least 12 mm, and consequently, the partial volume effect in our study is negligible. This may explain why we did not observe a significant correlation between adenoma size and SUVmean. It is therefore also unlikely that the PET-negative cases are false negatives due to the partial volume effect.
It is important to note that 68Ga-DOTATATE, as compared with 111In-DTPA-octreotide, has about 100 times higher affinity for SSTR2, decreased affinity for SSTR3 and similar affinity for SSTR5 (Reubi et al. 2000). In this light, the high positivity rate in our study was unexpected based on the notion that SSTR3 is the most abundantly expressed subtype in NFA (Even-Zohar and Greenman 2018; Colao et al. 2008). However, over the years, in vitro studies examining the SSTR expression in NFA specimens have produced conflicting results, pointing to either SSTR2 (Ramírez et al. 2012), SSTR3 (Gabalec et al. 2015) or SSTR5 (Fusco et al. 2012) as the dominant subtype. Possible explanations for these inconsistencies include differences in the method (detection of mRNA expression or protein, antibody specificity, membranous or cytoplasmic staining), patient selection (only gonadotropin-expressing or histopathologically diverse NFA) and the inherent heterogeneous distribution of various SSTR subtypes in NFA tissue samples. In the largest sample studied thus far, SSTR1–3 mRNA was expressed in 100% and SSTR5 mRNA in 60% of 198 specimens, using quantitative real-time RT-PCR (Gabalec et al. 2015). Nonetheless, mRNA levels do not always equal protein expression or the presence of functional receptors. This could explain the discrepancies between in vitro and in vivo results, as correctly translated, folded and transported SSTR proteins are required for ligand binding and in vivo detection.
The major advantage of 68Ga-DOTATATE PET is that it reliably visualises SSTR expression in vivo. Furthermore, assessment of 68Ga-DOTATATE uptake in NFMA may help to predict clinical response to SSTR2 preferential SSA (Colao et al. 2008).