**4. Evidence-Based Medicine of PET/CT in Intracranial Solitary Fibrous Tumor/Hemangiopericytoma**

In the last decade, PET/CT emerged as a non-invasive, whole-body diagnostic tool with an important role in diagnosis, staging, detecting possible disease relapses and distant metastases, differentiating between scar and viable tissues, and in the follow-up of patients affected by SFT. To the best of our knowledge, this is the first literature review that focuses on the role of PET/CT in intracranial SFTs. This topic could reveal to be great interest in identifying the best accurate PET radiopharmaceutical to diagnose and follow up this rare tumor. Indeed, despite its benign nature, SFT has a malignant behavior, with a characteristic high rate of locoregional relapse and of distant metastases due to its hypervascularity.

To date, most of the authors referred to 18F-FDG as the main PET radiotracer used in this oncological field to assess glucose metabolism activity, usually increased in neoplastic cells. 18F-FDG is intracellularly trapped after GLUT-transporter uptake and hexokinase phosphorylation in glucose-6-phosphate. The hypercellularity of SFT lesions may support its application in these cases. However, the intense physiological uptake of the brain makes adequate 18F-FDG PET imaging of intracranial tumors a challenge [21]. In some cases of SFT/HPC, 18F-FDG PET may be helpful to differentiate necrotic from viable tumors, with both hypoenhancing on CT but with different metabolic activities on PET, significantly influencing the treatment decision [28]. Generally, FDG uptake in SFT/HPC cells is decreased compared with the surrounding tissue, while intense 18F-FDG hypermetabolism may suggest the presence of a more malignant variety of SFT, with a significant impact on prognosis [22]. The relatively low SUVmax values in 18F-FDG PET studies could help to differentiate SFT from other malignancies. In addition, a differential diagnosis with respect to other tumors may be facilitated by a dual-tracer technique to compare different image patterns developed by two PET radiotracers. For example, low glucose metabolism in contrast to high 11C-Methionine uptake may help to differentiate HPC from meningioma [29].

The high probability of developing metastases linked to the malignant behavior of this mesenchymal tumor makes 18F-FDG PET/CT a potential ideal tool to ensure adequate whole-body examination and to correctly guide therapeutic decision making with a tailored approach [8].

In Wu et al.'s case report, 18F-FDG PET/CT was performed to restage a 25-yearold man affected by a malignant SFT of the right occipital lobe primarily treated with multiple craniotomies and postoperative conformal RT. PET/CT showed both intracranial disease recurrence and, above all, massive bilateral pulmonary lesions and multiple bone metastases [14].

Cheung et al. confirmed the fundamental role of 18F-FDG PET/CT in identifying distant metastases from SFT/HPC describing a case of a 67-year-old woman treated with the resection of a paravertebral soft-tissue mass with histological diagnosis of HPC. After eight years, MRI detected three histologically proven SFT/HPC lesions of the right posterior occipital calvarium, while 18F-FDG PET/CT showed multiple hypermetabolic lesions involving lymph nodes and bone from the calvarium to the sacrum [15].

Furthermore, the literature reports a case of 41-year-old man surgically treated for a cerebellar HPC. After twenty-two years, the patient experienced multiple renal and pulmonary metastases, pathologically proven to be HPC, and a local intracranial recurrence, all of them surgically treated. Two years later, abdominal CT revealed a pancreatic tumor, confirmed with whole-body 18F-FDG PET/CT with intense radiopharmaceutical uptake. This lesion was surgically removed and histopathological examination confirmed the diagnosis of HPC, with similar pathological findings to those of the original cerebellum HPC [16].

However, in some cases, 18F-FDG PET/CT may not prove to be adequately reliable in accurately detecting all SFT/HPC lesions, since low–moderate glucose metabolism in both primary and metastatic lesions can be observed. Recently, Liu Xiao et al. reported a case of a 40-year-old patient affected by intracranial STF/HPC with a left renal metastatic lesion showing only mild 18F-FDG uptake and homogeneous contrast enhancement after contrast-medium administration [17].

Similarly, Hayenga and his colleagues reported a case of a 34-year-old woman affected by HPC of the right cerebellopontine angle (CPA) who underwent surgical treatment combined with postoperative RT. After 3 years of disease-free interval, 18F-FDG PET/CT was performed showing low FDG avidity both in intracranial and extracranial recurrences of the spinal canal [18]. Consistent with these reports, Yasen and colleagues reported negative FDG uptake in the presence of HPC recurrence and metastasis. Namely, a woman with bilateral-frontal-cerebral-convex and parafalx HPC was surgically treated and underwent 18F-FDG PET/CT six years later, demonstrating high-density lesions on CT images without FDG uptake and low-density solid lesions without FDG uptake in the frontal lobe parafalx and in the right posterior and left outer lobes of the liver, respectively. The histological examination of calvarium and hepatic lesions showed homogeneous features of HPC tumor [19]. These are examples of SFT/HPC lesions with low glucose metabolism, almost similar to background FDG activity, suggesting that 18F-FDG PET/CT should not be the only diagnostic tool to be used in this set of patients, especially for the detection of craniospinal-axis SFT/HPC [18].

Another issue that deserves consideration and that may limit 18F-FDG PET/CT performance is the FDG heterogenous uptake between primitive SFT/HPC and metastatic lesions. In this regard, Grunig and colleagues reported a case of a 46-year-old patient with high FDG uptake in primary-dura HPC and liver metastases, but moderate radiopharmaceutical uptake in a leg-muscle tissue lesion [20].

In relation to these 18F-FDG PET/CT limitations, current literature debates which is the most accurate PET radiopharmaceutical to adequately study this rare benign, but with malignant behavior, tumor with possible histological or biological heterogeneity.

Some authors highlighted that SFT/HPC shows different spectral patterns on MR spectroscopy, with dominant Choline expression [30,31]. This feature suggested the potential usefulness of radiolabeled Choline as an ideal PET radiopharmaceutical in SFT/HPC detection [21,32,33]. Choline is a precursor of the biosynthesis of cell-membrane phospholipids, which is increased in the most malignant tumors, including SFTs. In fact, once intracellular uptake is performed by specific transporters, Choline is phosphorylated by choline-kinase in phosphorylcholine and incorporated into the cell membrane [34–36]. Considering the anatomical proximity with brain parenchyma, a further advantage of 18F-FCH PET/CT is the very low brain uptake with a favorable tumor-to-background ratio with a better image contrast. The low physiological distribution of Choline in normal white and grey matter may help to distinguish different brain tumors with increased uptake from benign lesions and radiation necrosis with the lowest uptake [36]. In the case report by Sardaro et al., 18F-Fluorocholine (18F-FCH) PET/CT showed superior performance compared with 18F-FDG PET/CT in a 69-year-old patient with two local recurrences of malignant orbital SFT, playing a crucial role in differentiating between small recurrences/pathological lesions and scar tissue in brain parenchyma (Figure 1) [7]. The favorable Choline tumorto-background ratio [37] allows better and well-defined visualization of the lesion with intracranial localization to be obtained [38].

Similarly, Jehanno et al. reported a case of a 50-year-old male with a previous history of surgically treated intracranial HPC who experienced a local recurrence eighteen months later. After partial resection, the authors performed both preoperative 18F-FDG PET/CT and 18F-FCH PET/CT for the treatment planning of residual disease located along the optic nerve. 18F-FDG PET/CT did not show any significant uptake. Conversely, 18F-FCH PET/CT precisely detected an intense radiopharmaceutical uptake of residual disease in the retro-orbital region, more properly guiding the following RT [21].

**Figure 1.** A 69-year-old male patient with a second loco-regional recurrence of left supraorbital solitary fibrous tumor. (**A**) A brain MRI scan revealed on axial MRI T2c+ a rounded lesion on the lateral side of the left orbit, strongly suspected of disease relapse (red arrow). (**B**) Two weeks later, 18F-FDG PET/CT showed no radiopharmaceutical uptake in the left supraorbital region (red arrow). (**C**) Conversely, after seven days, 18F-FCH PET/CT showed intense uptake in the aforementioned lesion (red arrow; SUVmax 6.8).

Some authors reported SFT lesions immunohistochemically and histologically characterized by a high expression of somatostatin receptor (SSRs), especially subtype 2, well studied with somatostatin-receptor molecular imaging methods. Lavacchi and colleagues reported a case of an intracranial SFT/HPC with distant metastasis studied with 111In Pentetreotide, a gamma-emitter radiolabeled somatostatin analogue, able to target the highly expressed SSRs in anecdotal SFT lesions, with potential theragnostic implication. In Lavacchi et al.'s case, high radiopharmaceutical uptake was observed both in primitive and distant metastases. Namely, a 64-year-old female affected by cranial-posterior-fossa SFT was restaged 18 years after surgical treatment due to an 111In Pentetreotide scan having detected multiple intracranial recurrences and hepatic, renal, and pulmonary metastases with avid tracer uptake [22]. Similarly, high SSR expression in intracranial and extracranial lesions was detected with a 111In-Pentreotide scan in a 54-year-old woman with intracranial HPC of the right optic nerve sheath and bone distant metastases. In the same patient, low FDG uptake in the aforementioned sites confirmed the unreliability of 18F-FDG PET/CT in some cases [23]. Furthermore, 68Ga -Dodecane tetra-acetic acid tyrosine-3-octreotate ( 68Ga-DOTATATE) is a PET radiopharmaceutical usually used for neuroendocrine-tumor imaging and now increasingly considered as an adjunctive imaging tracer for multiple solid neoplasms, including mesenchymal tumors [39]. Similarly to 111In-Pentetreotide, 68Ga-DOTATATE is a positron-emitter radiolabeled somatostatin analogue able to reveal a high concentration of surface SSRs, with the advantages of superior spatial resolution and accuracy, faster acquisition and lower radiation exposure [24]. In particular, Hung et al. found negligible FDG uptake but intense 68Ga-DOTATATE avidity of pulmonary metastases in a 68-year-old woman affected by primitive intracranial HPC [24].

In addition to FDG and choline, the literature reports the use of other PET radiotracers for the identification of this uncommon neoplasm. In some cases, HPC/SFTs may show high 68Ga-Prostate-Specific Membrane Antigen (68Ga-PSMA) avidity [40]. PSMA is a type II integral transmembrane glycoprotein, known as folate-hydrolase 1 or glutamatecarboxypeptidase II, with neuropeptidase activity. It was found to be surprisingly overexpressed in the neovasculature endothelium of some brain tumors, such as gliomas with significant angiogenic activity, whereas low PSMA expression can be found in tumor cells or healthy brain. Low PSMA uptake in the normal brain parenchyma and its high tumorto-background ratio allows an accurate localization of intracranial lesions with PSMA overexpression to be performed, which seems not to be related to the type of brain malignancy. The literature reports higher PSMA-uptake in high-grade gliomas and metastatic brain tumors than in central-nervous-system lymphoma and radiation necrosis, while there are no data about the differential diagnosis with SFT/HPC because of the rarity of this tumor [25,36,41]. Patro and colleagues described intense 68Ga-PSMA avidity in all hepatic and bones metastases in a 53-year-old woman with primitive right-posterior-cranial-fossa HPC, in contrast with the low glucose metabolism of these lesions, probably due to PSMA overexpression in tumor neovasculature [25].

Interestingly, Zhang et al. showed an intense 68Ga-Fibroblast-activation-protein inhibitor (68Ga-FAPI) (compared with low 18F-FDG uptake) in a 23-year-old female patient with SFT/HPC of the right frontal lobe. Fibroblast activation protein (FAP) is strongly overexpressed in the stroma of human cancers, including SFTs, and its quinoline-based FAP inhibitor can be internalized after binding to the FAP enzymatic domain. This suggests the potential role of this new PET radiotracer with a specific target for FAP, which can be overexpressed in this mesenchymal tumor [26,42]. The Acetate property of being a fatty acid precursor and thus an indirect biomarker of fatty acid synthesis can be exploited. In fact, ACT is converted to Acetyl Co-A, which is incorporated into cholesterol and fatty acids. Jong et al. reported a single case of dual-tracer 11C-acetate (11C-ACT) and 18F-FDG PET /CT in a 47-year-old male patient with intracranial HPC, showing significantly higher 11C-ACT uptake of bone metastases than FDG uptake, probably due to the over-expression of fatty acid synthase in this kind of tumors [27,43].

#### **5. Conclusions**

PET/CT could play a fundamental role in diagnosis, staging, post-treatment evaluation (surgery, radiotherapy, chemotherapy), disease relapses and distant metastases detection, and follow-up of patients affected by intracranial SFT, a benign but inherently aggressive tumor.

However, the literature still debates which type of PET radiopharmaceutical could guarantee the best accuracy for correctly and promptly guiding the management of this set of patients.

18F-FDG PET/CT shows an extremely heterogeneous behavior, with modest or low radiopharmaceutical uptake in most cases of single- or dual-tracer studies, variable sensitivity and low reliability.

Compared with 18F-FDG PET/CT, 18F-FCH PET/CT appears to be superior in detecting intracranial SFTs thanks to the histological and biological features of SFT and a favorable tumor-to-background ratio.

Other radiopharmaceuticals labeled with Gallium 68 also demonstrate a promising role in SFT-relapse or distant-metastases detection.

The current literature shows that 18F-FDG is the most widely used radiopharmaceutical in this set of patients. However, although fully aware that numerous studies are needed to identify which radiotracer to use based on the biological and histological characteristics of this rare tumor, our limited experience unquestionably reveals the superiority of 18F-FCH PET/CT, compared with 18F- FDG PET/CT, for the study of patients with intracranial SFT. 18F-FCH PET/CT can play a significant role in providing information for both local recurrence and distant metastases.

Therefore, for all the aforementioned reasons, it would be desirable to include PET/CT as a diagnostic, sensitive, non-invasive method in the guidelines for the management of SFT.

**Author Contributions:** Conceptualization, P.M.; methodology, P.M. and A.G.N.; validation, A.S.; formal analysis, A.R.P. and L.B.; investigation, P.M. and D.R.; data curation, A.R.P. and L.B.; writing original draft preparation, D.R. and A.G.N.; writing—review and editing, A.S. and P.M.; supervision, G.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research study received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Informed consent was obtained from the subject included in the analysis.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
