NFPMAs can cause hypopituitarism and hyperprolactinemia or even show no endocrinologic abnormalities, which is similar to SSMs [
16]. Headaches, loss of visual acuity and visual field are some other common symptoms for these patients [
7,
17]. Most intra-suprasellar adenomas are excised via the trans-sphenoidal route to our knowledge [
18]. Unlike the soft pituitary adenomas, SSMs are highly vascular, firm and adhesive to adjacent neurovascular structures [
19]. A transcranial approach is commonly considered for most SSMs, which can achieve a high rate of total resection with a low rate of postoperative cerebrospinal fluid leak, hemorrhage and nerve injury [
4,
20,
21]. SSMs are sometimes amenable to resection by trans-sphenoidal route and some authors advocated that this approach can result in comparable outcomes with trans-cranial approach in carefully and critically selected patients [
22,
23]. Generally speaking, the determination of an optimum surgical approach depends on multiple factors, such as tumor size, consistency, location, relationships with the adjacent structures and the presenting symptoms [
24]. Therefore, surgical plan could be implemented more effectively and safely if an accurate pre-operative diagnosis is available.
MRI has played an irreplaceable role in the diagnosis of sellar and suprasellar tumors for a long time and most SSMs can be differentiated from NAPMAs based on it. Sometimes SSMs can break through the diaphragma sellae and grow into the pituitary fossa, making it similar to NFPMAs extending anteriorly and superiorly on conventional morphological imaging [
7,
25]. Magnetic resonance brain functional imaging methods such as perfusion-weighted imaging (PWI) can be valuable for brain tumors by detecting the hemodynamic state. However, PWI is not always used in an efficient way. Firstly, PWI is highly user-dependent because the accurate recognition of blood vessels is challenging and the standardization is lacking in data processing methods presently. Besides, PWI is difficult to implemented in regions close to a brain–bone–air interface such as the skull base [
26‐
28]. As one of the most important molecular imaging modalities, PET should be considered as complementary tools in the evaluation of brain tumors and PET even seems to show a more significant role than such MR advanced techniques [
28,
29].
18F-FDG is the most common PET/CT tracer and the molecular mechanism has been clarified previously [
30]. However, the inherent limitation of high physiologic uptake in the normal brain tissue necessitates the search for other newer PET tracers. Although
13N-ammonia has a short half-life time, it is rapidly spreading in recent years because of its diagnostic power (perfusion-metabolism coupling tracer) and the easier interpretation for clinicians owing to the higher tumor to back-ground contrast compared to PWI and other PET tracers [
31]. On the other hand, the short half-life time has the advantage of reducing the radiation. Actually, the synthesis time for
13N-ammonia is short and the process is convenient by the cyclotron. According to previous studies of our department,
13N-ammonia has potential diagnostic value in brain tumor [
10,
11,
32,
33].
In our study, SSMs showed a higher uptake than NFPMAs on
13N-ammonia PET images. In contrast, NFPMAs showed a higher uptake than SSMs on
18F-FDG PET images. All SSMs are grade I, demonstrating lower glucose consumption than normal gray matter. The normal pituitary gland showed little uptake because of its small size and low metabolic rate on
18F-FDG PET images. On the other hand, pituitary adenomas were more metabolically active than normal pituitary gland and SSMs and the uptake was related to the size of the adenomas [
34,
35].
18F-FDG PET/CT was useful for detecting NFPMAs [
36,
37]. For
13N-ammonia, we found it had great value in the diagnosis of SSMs.
13N-ammonia is lipid soluble and has small molecular weight (16 Da) compared to Gd-DTPA (approximately 470 Da) [
38]. The blood ammonia mainly exists in two forms at physiological blood pH, that is unionized ammonia (NH
3, about 3%) and ionized species (NH
+4, about 97%). Compared with ionized form. The unionized form can pass the blood brain barrier (BBB) freely and be rapidly supplemented from the ionized form since the two forms are in equilibrium through the reaction NH
+4 ↔ NH
3 + H
+ [
39‐
41]. Actually, the initial extraction of
13N-ammonia depends on the cerebral blood flow (CBF) and capillary permeability-surface (PS) area product [
42]. As glutamine contributes to the production of adenosine triphosphate (ATP), the biosynthesis of macromolecules and the modulation of redox homeostasis, it is important for the survival of tumor cells [
43]. Tumor cells can not only obtain glutamine from plasma but also can synthesize glutamine by themselves intracellularly. GS is the only enzyme known which can convert ammonia and glutamate to glutamine in the mammalian brain tissue [
39]. Since the up-regulation of GS is widely interpreted as a reflection of active glutamine metabolism and the up-regulation has been reported in many tumors [
42,
44‐
46], the expression of GS is another factor contributing to the
13N-ammonia trapping, that is, metabolic trapping [
47‐
49]. In our study, meningiomas exhibited extremely high accumulation of
13N-ammonia against the surrounding tissue because of the absence of BBB, increased regional CBF coupled with increased PS (due to neovascularization), indicating that
13N-ammonia is an ideal tracer to identify meningiomas. Immunohistochemical staining of brain tumor biopsies indicated that the GS activity of meningiomas was strongly positive and the expression was not limited to any particular histopathological variants. Amongst the tumors the highest levels were found in the astrocytoma and oligodendroglioma and GS level was higher in meningiomas than pituitary adenomas [
39,
46]. Similarly, the normal pituitary tissue clearly showed obviously high uptake of
13N-ammonia. Previous study also demonstrated that GS activity was present in the anterior pituitary gland [
50]. Since
13N-ammonia PET/CT imaging is valuable in detecting pituitary tissue, surgeons can carefully find the pituitary tissue guided by PET so that maximize the protection of the pituitary tissue. This is another reason for the use of
13N-ammonia in the sellar region tumors [
51]. For NFPMAs, relatively poor neovascularization compared with SSMs and normal pituitary tissue was confirmed on contrast CT and MRI imaging, providing a limited amount of radiotracer for trapping. From the visual results, we found there were uptake overlap between NFPMAs and SSMs for each tracer. The combination of
18F-FDG and
13N-Ammonia PET/CT could derive a more favorable results for increasing the accuracy to the maximum.
Our study yielded significant results and proposed a new viewpoint for the prediction of SSMs. However, it was inevitable that there were several limitations. Firstly, we collected a small sample of SSMs, and the research results need further confirmation by prospective studies with larger sample capacity. In addition, 13N-ammonia has a very short half-life time (9.965 min), so a cyclotron onsite is required for clinical application. Lastly, we failed to detect the GS expression in meningioma specimens limited to the access to resources.