Optic Nerve Sheath Meningiomas: Solving Diagnostic Challenges with 68Ga-DOTATOC PET/CT

68Ga-DOTATOC PET could be a noninvasive, highly sensitive, and specific technique for the challenging diagnosis of optic nerve sheath meningioma (ONSM). Our objective was to report the use and results of 68Ga-DOTATOC PET in suspected ONSM. Twelve subjects who underwent 68Ga-DOTATOC PET for suspected ONSM in our department were retrospectively included. Standardised clinical and radiological data were collected. The PET examination results were classified as positive or negative, and lesion standardised uptake values (SUVmax) were recorded. 68Ga-DOTATOC PET confirmed positive uptake in six cases (SUVmax > 5), leading to ONSM diagnoses followed by radiation therapy in patients with vision loss. Six 68Ga-DOTATOC PET scans were considered negative (SUVmax < 5); these comprised one case of neurosarcoidosis, one cavernous malformation, and four uncertain diagnoses, leading to further investigation. 68Ga-DOTATOC PET was helpful in tumour volume delineation before radiation therapy, leading to a decrease in dose exposure. Noninvasive 68Ga-DOTATOC PET should be performed before treating nonhistologically proven meningiomas with radiotherapy or stereotactic radiosurgery, particularly in cases of uncertain diagnosis with MRI, which characterises most ONSM cases. PET SUVmax thresholds to distinguish meningioma from nonspecific uptake in other lesions need to be adapted to ONSM. 68Ga-DOTATOC PET improves the intraorbital lesion diagnostic approach and therefore impacts therapeutic management.


Introduction
Optic nerve sheath meningiomas (ONSMs) are benign tumours that arise from meninges around the optic nerve. The optic nerve sheath is a rare meningioma location, accounting for 1-2% of meningiomas [1], which are a frequent cause of primary optic nerve tumours [2] with variable clinical presentations and prognoses.
ONSMs most frequently occur in adults between 30 and 50 years of age and most often in females, with a sex ratio of 3:1 [2]. However, ONSMs can occur in any age group, even children. Rarely, they can be bilateral.
ONSMs' clinical presentation can vary from no symptoms to ocular motility disturbance, proptosis, exophthalmos, and progressive vision loss via compressive optic neuropathy, as specified in ophthalmologic examinations. Papilledema might also be observed. Prognosis varies and is essentially functional, depending on location, the main risk being definitive vision loss if left untreated.

Materials and Methods
All patients who underwent 68 Ga-DOTATOC PET in the Department of Nuclear Medicine, Marseille, APHM, between January 2020 and April 2022 for suspected ONSM were retrospectively included. 68 Ga-DOTATOC PET was performed using an integrated PET/CT camera (General Electric Healthcare Discovery PET/CT 710) after the intravenous injection of a 2.5 MBq/kg radiotracer. A protocol of 7 min of acquisition, 1 h postinjection, was used. Images were reconstructed on a 192 × 192 matrix using the ordered subsets expectation maximisation algorithm and were corrected for attenuation using a CT transmission scan.
Standardised clinical and radiological data were recorded. When MR images were available, PET images were fused with the MR images using alignment algorithms. Hence, images could be represented as PET/MRI fused images, even if acquired with a PET/CT camera, and secondarily fused with MRI. PET examination results were classified as positive if DOTATOC uptake was considered elevated and negative if DOTATOC uptake was considered low or null by two independent nuclear physicians. The maximum standardised uptake values of the optic lesion and pituitary gland were recorded. Initially, PET was classified as positive or negative based on visual interpretation. Subsequently, an optimal threshold, based on SUV max , to classify PET as positive or negative was chosen via discussion amongst the authors.
No biopsies were performed. All cases were discussed in multidisciplinary meetings with a neuro-oncologist, radiotherapist, neurosurgeon, and nuclear physician. Patients were followed up by physicians, and further examinations were performed when necessary (for example, spinal tap examinations and FDG PET in cases of suspected lymphoma). Follow-up visits and multidisciplinary meetings were employed to (i) validate the diagnosis of ONSM, (ii) give the case an uncertain diagnosis, or (iii) choose other diagnoses.
Preradiation therapy (RT) volume delineation was performed on all cases by the same radiation therapist. The biological target volume (BTV) was defined using 68 Ga-DOTATOC PET. The gross tumour target volume (GTV) was defined using MRI with at least T1weighted gadolinium and T2 FLAIR sequences. The clinical target volume (CTV) was defined as the GTV expanded by a 3 to 5 mm margin to consider the microscopic extension of the disease. CTV could be manually modified by the radiation oncologist according to the MRI interpretation. BTV and CTV were compared in patients who were treated in our department.
This study was approved by the institutional review board of the French College of Neurosurgery (approval code: IRB00011687; date of approval: 13 May 2022). Retrospective observations required nothing other than informed consent according to French and European regulations.

Statistical Analysis
Mean values as well as ratios were calculated using Microsoft ® Excel 2023.

Results
Twelve 68 Ga-DOTATOC PET scans for suspected ONSM were analysed. All patients presented with a unilateral optic nerve lesion in MR images. Most MRI examinations showed an isointense T1-weighted lesion with peripheral enhancement. Six examinations were considered positive due to intense 68 Ga-DOTATOC uptake, and six exams were considered negative. Table 1 summarises the main clinical data on the reported cases with their 68 Ga-DOTATOC results.   Of these, two patients presented with progressive vision loss at onset, and two were older patients (74 and 82 years old) with rapid vision loss. One patient (case 6) had already  Of these, two patients presented with progressive vision loss at onset, and two were older patients (74 and 82 years old) with rapid vision loss. One patient (case 6) had already visual impairment of the treated eye. 68 Ga-DOTATOC PET was performed to confirm the diagnosis of meningioma before they underwent novel radiotherapy.
One positive case had no vision loss (case 4; Figure 3). This 41-year-old woman presented with isolated retro-ocular pain. She had been under progestin hormonal treatment (chlormadinone acetate) for more than 10 years for endometriosis. Given the long-term hormone intake and the lack of visual trouble, hormonal treatment withdrawal with close ophthalmologic follow-up was proposed.  Concerning the six positive 68 Ga-DOTATOC PET scans, the SUVmax values of the retained ONSMs ranged from 6.3 to 19.6, with a mean SUVmax = 10.8.
The SUVmax ONSM/pituitary ratios ranged from 0.4 to 1.1, with a mean ratio of 0.8. Case 5 was a 74-year-old woman first referred for right blurred vision. An ophthalmologic examination revealed disc pallor and diminished vision in the right eye. MRI showed a hyperintense T2 enlargement of the intraorbital and intracanalar right optic nerves, with peripheral enhancement shown in T1-weighted images. Neuritis, lymphoma, and ONSM were suspected. The results of the medullary MRI, spinal tap, and two 18 F-FDG whole-body and brain PET scans were negative. High-dose corticosteroid therapy had no clinical effect. 68 Ga-DOTATOC PET showed moderate-high DOTATOC uptake with an SUVmax of 6.3, but the lesion/pituitary ratio was low (0.4). The absence of any FDG uptake by the lesion combined with radioclinical stable evolution and moderate 68 Ga-DOTATOC uptake led to the diagnosis of ONSM. RT was discussed but not started for personal reasons.

Negative 68 Ga-DOTATOC PET
Six PET examinations were considered negative due to low 68 Ga-DOTATOC uptake (cases 7 to 12). Four diagnoses remained unknown. In the absence of worsening vision loss, no biopsy was performed in these cases. One patient was diagnosed with sarcoidosis (case 7; Figures 4 and 5). This 35-year-old man was referred for blurred vision and progressive loss of vision in the left eye. MRI showed tubular thickening of the left optic nerve in its cisternal portion extending over 2.2 cm, with isointensity on T1-weighted imaging and intense homogenous enhancement. The lesion had low 68 Ga-DOTATOC and moderate 18 F-FDG uptakes. Whole-body 18 F-FDG PET highlighted marked hypermetabolic mediastinal and infra-mediastinal lymphadenopathies. The conclusion was systemic and neurologic sarcoidosis, which was confirmed with a biopsy of the inguinal node. Infliximab and corticosteroid therapy were initiated. Of these, two patients presented with progressive vision loss at onset, and two were older patients (74 and 82 years old) with rapid vision loss. One patient (case 6) had already been treated with IMRT 6 years ago for a suspected ONSM and presented 1 year ago with visual impairment of the treated eye. 68 Ga-DOTATOC PET was performed to confirm the diagnosis of meningioma before they underwent novel radiotherapy.
One positive case had no vision loss (case 4; Figure 3). This 41-year-old woman presented with isolated retro-ocular pain. She had been under progestin hormonal treatment (chlormadinone acetate) for more than 10 years for endometriosis. Given the long-term hormone intake and the lack of visual trouble, hormonal treatment withdrawal with close ophthalmologic follow-up was proposed.
Concerning the six positive 68 Ga-DOTATOC PET scans, the SUV max values of the retained ONSMs ranged from 6.3 to 19.6, with a mean SUV max = 10.8.
The SUV max ONSM/pituitary ratios ranged from 0.4 to 1.1, with a mean ratio of 0.8. Case 5 was a 74-year-old woman first referred for right blurred vision. An ophthalmologic examination revealed disc pallor and diminished vision in the right eye. MRI showed a hyperintense T2 enlargement of the intraorbital and intracanalar right optic nerves, with peripheral enhancement shown in T1-weighted images. Neuritis, lymphoma, and ONSM were suspected. The results of the medullary MRI, spinal tap, and two 18 F-FDG whole-body and brain PET scans were negative. High-dose corticosteroid therapy had no clinical effect. 68 Ga-DOTATOC PET showed moderate-high DOTATOC uptake with an SUV max of 6.3, but the lesion/pituitary ratio was low (0.4). The absence of any FDG uptake by the lesion combined with radioclinical stable evolution and moderate 68 Ga-DOTATOC uptake led to the diagnosis of ONSM. RT was discussed but not started for personal reasons.

Negative 68 Ga-DOTATOC PET
Six PET examinations were considered negative due to low 68 Ga-DOTATOC uptake (cases 7 to 12). Four diagnoses remained unknown. In the absence of worsening vision loss, no biopsy was performed in these cases. One patient was diagnosed with sarcoidosis (case 7; Figures 4 and 5). This 35-year-old man was referred for blurred vision and progressive loss of vision in the left eye. MRI showed tubular thickening of the left optic nerve in its cisternal portion extending over 2.2 cm, with isointensity on T1-weighted imaging and intense homogenous enhancement. The lesion had low 68 Ga-DOTATOC and moderate 18 F-FDG uptakes. Whole-body 18 F-FDG PET highlighted marked hypermetabolic mediastinal and infra-mediastinal lymphadenopathies. The conclusion was systemic and neurologic sarcoidosis, which was confirmed with a biopsy of the inguinal node. Infliximab and corticosteroid therapy were initiated.  One patient was diagnosed with a probable cavernous malformation (case 12). This 67-year-old man was referred for brutal left retro-ocular pain and diplopia to the right lateral gaze one month before the examination. MRI showed a round heterogeneous lesion of the left orbit, with mixed signal intensity on T1-and T2-weighted images and no enhancement. 68 Ga-DOTATOC PET was performed to rule out the diagnosis of ONSM and showed low DOTATOC uptake in the lesion, which is consistent with the diagnosis of a cavernous malformation. A repeat MRI examination three months later revealed a decrease in lesion size, suggesting previous intratumoural haemorrhage. In the absence of visual trouble, no surgical treatment was proposed.

Added Value of 68 Ga-DOTATOC PET before RT in Two Positive Cases
In two positive ONSM cases (cases 2 and 3), the BTVs obtained from 68 Ga-DOTATOC PET and the CTVs obtained from MRI were compared. Both measures were defined by the same radiation therapist. The BTVs obtained for cases 2 and 3 were 2.5 cm 3 and 1.1 cm 3 , respectively, whereas the CTVs were 6.8 and 2.5 cm 3 , respectively (see Figure 6 for case 3). In both cases, the lesion volume was overestimated with MRI because of the difficulty of tumour delineation in the optic nerve using this technique.  One patient was diagnosed with a probable cavernous malformation (case 12). Th 67-year-old man was referred for brutal left retro-ocular pain and diplopia to the rig lateral gaze one month before the examination. MRI showed a round heterogeneous lesio of the left orbit, with mixed signal intensity on T1-and T2-weighted images and no e hancement. 68 Ga-DOTATOC PET was performed to rule out the diagnosis of ONSM an showed low DOTATOC uptake in the lesion, which is consistent with the diagnosis of cavernous malformation. A repeat MRI examination three months later revealed a d crease in lesion size, suggesting previous intratumoural haemorrhage. In the absence visual trouble, no surgical treatment was proposed.

Added Value of 68 Ga-DOTATOC PET before RT in Two Positive Cases
In two positive ONSM cases (cases 2 and 3), the BTVs obtained from 68 Ga-DOTATO PET and the CTVs obtained from MRI were compared. Both measures were defined b the same radiation therapist. The BTVs obtained for cases 2 and 3 were 2.5 cm 3 and 1 cm 3 , respectively, whereas the CTVs were 6.8 and 2.5 cm 3 , respectively (see Figure 6 f case 3). In both cases, the lesion volume was overestimated with MRI because of the diffi culty of tumour delineation in the optic nerve using this technique. One patient was diagnosed with a probable cavernous malformation (case 12). This 67year-old man was referred for brutal left retro-ocular pain and diplopia to the right lateral gaze one month before the examination. MRI showed a round heterogeneous lesion of the left orbit, with mixed signal intensity on T1-and T2-weighted images and no enhancement. 68 Ga-DOTATOC PET was performed to rule out the diagnosis of ONSM and showed low DOTATOC uptake in the lesion, which is consistent with the diagnosis of a cavernous malformation. A repeat MRI examination three months later revealed a decrease in lesion size, suggesting previous intratumoural haemorrhage. In the absence of visual trouble, no surgical treatment was proposed.

Added Value of 68 Ga-DOTATOC PET before RT in Two Positive Cases
In two positive ONSM cases (cases 2 and 3), the BTVs obtained from 68 Ga-DOTATOC PET and the CTVs obtained from MRI were compared. Both measures were defined by the same radiation therapist. The BTVs obtained for cases 2 and 3 were 2.5 cm 3 and 1.1 cm 3 , respectively, whereas the CTVs were 6.8 and 2.5 cm 3 , respectively (see Figure 6 for case 3). In both cases, the lesion volume was overestimated with MRI because of the difficulty of tumour delineation in the optic nerve using this technique.

Discussion
The optic sheath nerve is a rare location for meningiomas, which explains the scarce cases with 68 Ga-SSTR ligand PET in the literature. Meningiomas usually have high SSTR2A expression and hence high 68 Ga-DOTATOC uptake, in contrast with most tumours or inflammatory lesions that can show low, nonspecific 68 Ga-DOTATOC uptake [5].

Is Positive Radiolabelled SSTR2A-PET True Positive?
Radiolabelled SSTR2A-PET is a noninvasive tool to identify the presence of SSTR2A. A high uptake by the lesion in PET reflects that the lesion has high SSTR2 expression that has bound the tracer, which has been confirmed in anatomopathological studies [9].
Other tumours can exhibit high SSTR2A expression, such as pituitary adenoma or neuroendocrine tumours, but are not usually found in the optic pathway sheath or orbital location. Rare cases of NET metastases in the optic pathways have been described, but the primary tumour is usually noisy, and the clinical context helps to identify it.
Hence, intraorbital tumours with high 68 Ga-DOTATOC uptake can be concluded to be meningiomas with a high predictive positive value. When we see a high uptake, we do not expect a false positive in the optic pathways. Klingenstein et al. reported 100% specificity in their study on optic pathway tumours [8]. But the challenge is to find the optimal value that would define the uptake as high and, therefore, to conclude that it is a meningioma with 100% specificity. In the literature, it seems that "high uptake" relies most often on the visual interpretation of nuclear physicians, and no value has been proposed to define high uptake in PET, especially when applied to the optic nerve. In Table 2, we summarise positive radiolabelled SSTR2A-PET cases from the present study and from the literature in which detailed data were available.
In the present case series, the SUVmax values of lesions with a obtained diagnosis of ONSM ranged from 6.3 to 19.6 (mean SUVmax = 10.8), which are close to results found in the literature (mean SUVmax = 14.3 in a series of optic pathway meningiomas, also including sphenoidal and tuberculum sellae meningiomas) [8] and slightly higher than those in another series (with a median SUVmax of 5.6) [12]. Table 2. Cases considered positive in radiolabelled SSTR2A-PET from our series and from the literature with corresponding main symptoms. Standardised maximal uptake (SUVmax) values are given. NA = not available. F = female; M = male. The term "optic nerve meningioma" was chosen instead of ONSM in the two cases from the study by Klingenstein et al. [8] in which the meningiomas were extended outside of the orbit (possible secondary ONSM).

Study
Age (

Discussion
The optic sheath nerve is a rare location for meningiomas, which explains the scarce cases with 68 Ga-SSTR ligand PET in the literature. Meningiomas usually have high SSTR2A expression and hence high 68 Ga-DOTATOC uptake, in contrast with most tumours or inflammatory lesions that can show low, nonspecific 68 Ga-DOTATOC uptake [5].

Is Positive Radiolabelled SSTR2A-PET True Positive?
Radiolabelled SSTR2A-PET is a noninvasive tool to identify the presence of SSTR2A. A high uptake by the lesion in PET reflects that the lesion has high SSTR2 expression that has bound the tracer, which has been confirmed in anatomopathological studies [9].
Other tumours can exhibit high SSTR2A expression, such as pituitary adenoma or neuroendocrine tumours, but are not usually found in the optic pathway sheath or orbital location. Rare cases of NET metastases in the optic pathways have been described, but the primary tumour is usually noisy, and the clinical context helps to identify it.
Hence, intraorbital tumours with high 68 Ga-DOTATOC uptake can be concluded to be meningiomas with a high predictive positive value. When we see a high uptake, we do not expect a false positive in the optic pathways. Klingenstein et al. reported 100% specificity in their study on optic pathway tumours [8]. But the challenge is to find the optimal value that would define the uptake as high and, therefore, to conclude that it is a meningioma with 100% specificity. In the literature, it seems that "high uptake" relies most often on the visual interpretation of nuclear physicians, and no value has been proposed to define high uptake in PET, especially when applied to the optic nerve. In Table 2, we summarise positive radiolabelled SSTR2A-PET cases from the present study and from the literature in which detailed data were available.
In the present case series, the SUV max values of lesions with a obtained diagnosis of ONSM ranged from 6.3 to 19.6 (mean SUV max = 10.8), which are close to results found in the literature (mean SUV max = 14.3 in a series of optic pathway meningiomas, also including sphenoidal and tuberculum sellae meningiomas) [8] and slightly higher than those in another series (with a median SUV max of 5.6) [12]. Table 2. Cases considered positive in radiolabelled SSTR2A-PET from our series and from the literature with corresponding main symptoms. Standardised maximal uptake (SUV max ) values are given. NA = not available. F = female; M = male. The term "optic nerve meningioma" was chosen instead of ONSM in the two cases from the study by Klingenstein et al. [8] in which the meningiomas were extended outside of the orbit (possible secondary ONSM).

Study
Age (

True Negative Radiolabelled SSTR2A-PET
Low tracer uptake can be found in many tumours or inflammatory lesions, as illustrated in Table 3. Table 3 summarises cases from our experience and from the literature in which low uptake was observed in radiolabelled SSTR2A-PET of non-meningioma optic nerve lesions (see true negative). In addition, some gliomas have been found to express SSTR2A and can have a low nonspecific 68 Ga-DOTA uptake that is not necessarily correlated with SSTR2A expression (tumour SUV max = 2.25 ± 1.33 in a study consisting of 19 gliomas) [13].
A threshold of 2.3 SUV max has been suggested by some authors [9] to discriminate between meningioma tumoural and nontumoural tissue. In that study, this SUV max delineated meningiomas in PET before RT but did not seem able to differentiate meningiomas from other lesions or distinguish certain types of meningiomas, such as ONSM. In the same study by Rachinger and colleagues, 9/82 lesions with SUV max > 2.3 were identified as not being meningiomas with a specificity of 73.5% [9]. In our study and in the literature, true negatives in PET have SUV max values ranging from 1.7 to 3.6 (see Table 3). Hence, in the presence of low radiotracer uptake in PET, an optic nerve lesion should not be concluded to be a meningioma.

False Negative 68 Ga-DOTATOC PET
Rachinger et al. [9] observed that 8/81 (approximately 10%) of meningiomas had an SUV max of <2.3. In a series of 8 patients with ten suspected ONSMs, Graef et al. reported one histologically confirmed PET-negative ONSM with an SUV max of 1.7 [12]. However, in their series, they considered PET-positive optic lesions to be those with SUV max values ranging from 2.6 to 7.8, while we would have considered a lesion with an SUV max of 2.6 in PET to be negative. In Graef et al.'s study [12], in a series of 10 suspected ONSM cases, only 3 cases were histologically proven, including the case with an SUV max of 1.7. It was not detailed which other cases benefited from a biopsy. Klingenstein et al. [8] reported two cases of probable ONSM considered negative in PET but with no histological confirmation. A positive diagnosis of ONSM was made from radio-clinical typical findings (see Table 3).
Therefore, if a lesion has low 68 Ga-DOTATOC uptake, the probability of a negative 68 Ga-DOTATOC meningioma is low but cannot be completely excluded. A small percentage of meningiomas do not, or weakly, express SSTR2A. Special attention should be paid to small lesions. They may cause false negatives because of the partial volume effect due to the limited spatial resolution of PET. The spatial resolution depends on several parameters, such as the background-to-lesion ratio, PET camera characteristics, and PET acquisition parameters. Graef et al. [12] reported a 4 mm ONSM with a nearly absent PET 68 Ga-DOTATOC signal.
Additionally, rare, isolated cases of negative immunohistochemical SSTR2A meningioma have been reported [14], with subsequently low-level avidity in 68 Ga-SSTR2A radiolabelled PET. Table 4 summarises the literature results on SSTR2A expression in meningioma using polymerase chain reaction (PCR) and immunohistochemical staining (IHC). SSTR2A negative expression was close to 0% in most studies using PCR and varied from 8 to 73% using IHC. SSTR2A expression was demonstrated to be stronger in the skull base and meningothelial meningiomas, which correspond to the most frequent subtype and location of ONSM [15,16]. Based on the present study and earlier studies, an SUV max of ≥5 could be an appropriate and specific threshold to confirm the diagnosis of ONSM with high specificity and avoid biopsy (Figure 7). The use of the SUV max lesion/pituitary ratio may be helpful to improve the 68 Ga-DOTATOC power of discrimination between meningiomas and other lesions. Nevertheless, the role of the lesion/pituitary ratio still needs to be specified.

What Is the Place for Radiolabelled SSTR2A-PET in ONSM?
In ONSM, as with a complex skull base location, given the surgical biopsy risk and morbidity, histological proof of meningioma is not systematically required to treat a patient with radiotherapy or stereotactic radiosurgery. Typical MRI could be considered sufficient for choosing the treatment but probably leads to the misdiagnosis and mistreatment of some cases, increasing the risk of treatment failure. In ONSM, 68 Ga-DOTATOC PET positivity could reinforce the diagnosis of meningioma before RT.
Furthermore, 68 Ga-DOTATOC PET might help define the target volume for RT when tumour delineation is difficult using solely MRI or CT, as already suggested in the literature [9,12]. Therefore, 68 Ga-DOTATOC PET could impact the management of intraorbital tumours by reinforcing the radiotherapy indications in cases of positivity or avoiding radiotherapy in cases of diagnostic uncertainty. The authors of this paper suggest using 68 Ga-DOTATOC PET before treating with radiotherapy or stereotactic radiosurgery for nonhistologically proven meningioma, particularly in cases of uncertain diagnosis with MRI, as is true for most ONSMs (Figure 7). In the case of long-term progestin intake, hormonal substitution discontinuation with close monitoring should be preferred over RT [28].
Negative 68 Ga-DOTATOC PET leads to the suspicion of a rare meningioma with negative or low SSTR2A expression and a differential diagnostic process. RT should, at first, be avoided. Complementary explorations for lymphoma, inflammatory diseases, and glioma should be preferred. Therefore, in cases of uncertain diagnosis with visual stabilisation and lack of tumour progression, observation with iterative explorations should be started. In contrast, in cases of visual impairment or tumour progression, biopsy should be considered: the decision between lesion biopsy and RT should be discussed in a multidisciplinary manner.
Volume delineation is a central issue in radiation oncology. It can sometimes be challenging when tumour delineation is not obvious in morphological examinations such as MRI and CT. 68 Ga-DOTATOC PET has been proposed as a useful tool to help radiation therapists define a target volume using PET, named BTV [9,12]. Tumours that have a high lesion-to-background ratio in PET, such as meningiomas, are particularly good candidates for the use of BTV. As opposed to BTV, the gross tumour target volume (GTV) and the clinical target volume (CTV) are defined using MRI or CT. An uncertain GTV delineation

What Is the Place for Radiolabelled SSTR2A-PET in ONSM?
In ONSM, as with a complex skull base location, given the surgical biopsy risk and morbidity, histological proof of meningioma is not systematically required to treat a patient with radiotherapy or stereotactic radiosurgery. Typical MRI could be considered sufficient for choosing the treatment but probably leads to the misdiagnosis and mistreatment of some cases, increasing the risk of treatment failure. In ONSM, 68 Ga-DOTATOC PET positivity could reinforce the diagnosis of meningioma before RT.
Furthermore, 68 Ga-DOTATOC PET might help define the target volume for RT when tumour delineation is difficult using solely MRI or CT, as already suggested in the literature [9,12]. Therefore, 68 Ga-DOTATOC PET could impact the management of intraorbital tumours by reinforcing the radiotherapy indications in cases of positivity or avoiding radiotherapy in cases of diagnostic uncertainty. The authors of this paper suggest using 68 Ga-DOTATOC PET before treating with radiotherapy or stereotactic radiosurgery for nonhistologically proven meningioma, particularly in cases of uncertain diagnosis with MRI, as is true for most ONSMs (Figure 7). In the case of long-term progestin intake, hormonal substitution discontinuation with close monitoring should be preferred over RT [28].
Negative 68 Ga-DOTATOC PET leads to the suspicion of a rare meningioma with negative or low SSTR2A expression and a differential diagnostic process. RT should, at first, be avoided. Complementary explorations for lymphoma, inflammatory diseases, and glioma should be preferred. Therefore, in cases of uncertain diagnosis with visual stabilisation and lack of tumour progression, observation with iterative explorations should be started. In contrast, in cases of visual impairment or tumour progression, biopsy should be considered: the decision between lesion biopsy and RT should be discussed in a multidisciplinary manner.
Volume delineation is a central issue in radiation oncology. It can sometimes be challenging when tumour delineation is not obvious in morphological examinations such as MRI and CT. 68 Ga-DOTATOC PET has been proposed as a useful tool to help radiation therapists define a target volume using PET, named BTV [9,12]. Tumours that have a high lesion-to-background ratio in PET, such as meningiomas, are particularly good candidates for the use of BTV. As opposed to BTV, the gross tumour target volume (GTV) and the clinical target volume (CTV) are defined using MRI or CT. An uncertain GTV delineation requires manually adapting the CTV to ensure that all the tumoural tissue is englobed within the targeted volume, including the doubtful tissue observed in MRI. Defining the BTV using 68 Ga-DOTATOC PET is a much less uncertain measure and includes the whole disease extent without a margin, as with the CTV.
In the present study, 68 Ga-DOTATOC PET was helpful in improving tumour volume delineation before RT, leading to a decreased applied radiation dose, which is in accordance with previous studies [12,29]. In a series of 10 ONSM patients, Graef et al. [12] found that PET/MRI enabled the avoidance of uncertainty and the inclusion of additional safety margins for radiation planning in 7/10 lesions. Stade et al. [29] concluded that 68 Ga-DOTATOC PET helped spare normal tissue from radiation therapy in 10 skull base meningiomas, especially by reducing the dose to organs at risk.

Limitations
Even though this study is, to our knowledge, the largest study on 68 Ga-DOTATOC PET for suspected ONSM, only 12 cases were reported in this monocentric study. It was limited by the rarity of ONSM (comprising 1% of all meningiomas) and by the lack of histological confirmation, as in most ONSM studies.
Another limitation is that apart from biopsy, there is a lack of a clear gold-standard method for ONSM diagnosis.
In the present study, high DOTATOC uptake led to a positive diagnosis of ONSM. This could be interpreted as a limitation and could indicate the presence of false positives. However, diagnoses were made in concordance with clinical and MRI data after multidisciplinary discussion and with a compatible follow-up. DOTATOC PET is a molecular technique that detects SSTR2A. Since other tumours that highly express SSTR2A are not found in the optic nerve, if the optic lesion presented a high SSTR2A level in PET, the PET was considered positive.
Concerning negative examinations, two diagnoses of tumours other than meningiomas were made (sarcoidosis and cavernous malformation), while four diagnoses remained unknown. These four diagnoses could have been false negatives (ONSMs with low SSTR2).
Larger series and new tools for meningioma diagnosis are required to specify the desirability of 68 Ga-DOTATOC PET for this indication, particularly for 68 Ga-DOTATOC PET-negative lesions.

Conclusions
As illustrated in this study, 68 Ga-DOTATOC PET is a noninvasive, powerful, and still underused tool in the diagnostic workup of intraorbital tumours, especially ONSMs.
ONSMs are frequent primary optic nerve tumours, but their diagnosis is challenging due to nonspecific clinical or MRI findings and a lack of histology on this specific location. Meningiomas usually have high SSTR2A expression and, hence, high 68 Ga-DOTATOC uptake in contrast with other tumours or inflammatory lesions that can show low, nonspecific 68 Ga-DOTATOC uptake. Previously reported SUV max cut-offs to differentiate meningioma from non-meningioma are probably not adapted to ONSM and do not seem specific enough. Based on the present series, an SUV max threshold of 5 seems most relevant for the diagnosis of ONSM.
The role of the lesion/pituitary SUV max ratio should be specified. In this case series, 68 Ga-DOTATOC PET improved the intraorbital lesion diagnostic approach and therefore impacted therapeutic management, identifying 6 ONSMs out of 12 intraorbital lesions. Negative 68 Ga-DOTATOC PET should lead to an uncertain diagnosis of meningioma and the possibility of differential diagnosis requiring complementary investigations and possible biopsy. Moreover, 68 Ga-DOTATOC PET may be helpful in tumour volume delineation during radiation therapy planning. Informed Consent Statement: Retrospective observations required nothing other than informed consent according to French and European regulations. Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The authors have full access to the data, and the data may be available on request.

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