[⁶⁸Ga]Ga-DOTA-TATE uptake in subacute stroke following craniotomy for meningioma: a diagnostic tool for stroke?

Abstract

Gallium 68 (⁶⁸Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid labelled octreotate ([⁶⁸Ga]Ga-DOTA-TATE) positron emission tomography (PET) is an established imaging technique for identifying tumours of neuroendocrine origin and meningiomas; the radiotracer binds to somatostatin receptor type 2 (SSTR2), which is richly expressed by these malignancies. Here, we present a rare case hinting at novel ischaemic stroke detection by [⁶⁸Ga]Ga-DOTA-TATE PET scan. The scan was performed 14 days post resection of an atypical meningioma with the intention to assess the extent of residual tumour for radiosurgical treatment of the operative cavity. Surprisingly, the [⁶⁸Ga]Ga-DOTA-TATE PET-avid region corresponded to an area of perioperative subacute ischaemic stroke detected by MRI. This case corroborates the two previously reported cases of incidental detection of ischaemic stroke during routine [⁶⁸Ga]Ga-DOTA-TATE PET imaging, collectively suggesting the need for caution when interpreting the imaging findings. A possible underlying mechanism for [⁶⁸Ga]Ga-DOTA-TATE uptake in stroke is increased SSTR2 expression by macrophages recruited into infarcted tissue.

Background

Gallium 68 (⁶⁸Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid labelled octreotate ([⁶⁸Ga]Ga-DOTA-TATE) positron emission tomography (PET) is an established imaging technique for identifying tumours of neuroendocrine origin. [⁶⁸Ga]Ga-DOTA-TATE binds to somatostatin receptor type 2 (SSTR2), which is abundantly expressed on neuroendocrine tumour cells and makes the tumour detectable by PET scan.¹ Although the intention of [⁶⁸Ga]Ga-DOTA-TATE PET/CT imaging is generally for diagnosis and management of neuroendocrine tumours, meningiomas also reliably express SSTR2 and can, therefore, be identified with this imaging modality.^{2 3} As a result, [⁶⁸Ga]Ga-DOTA-TATE PET/CT imaging can also be useful in identifying residual meningioma versus postoperative inflammation following surgery and can be used for radiation therapy targeting.^{4 5}

While [⁶⁸Ga]Ga-DOTA-TATE PET/CT imaging was not intended for stroke detection, two cases of incidental subacute stroke during routine follow-up [⁶⁸Ga]Ga-DOTA-TATE PET/CT have been reported.^{6 7} Herein, we report an another case of detection of subacute stroke during a [⁶⁸Ga]Ga-DOTA-TATE PET/CT scan that was intended to assess for residual meningioma following craniotomy for tumour resection. We believe [⁶⁸Ga]Ga-DOTA-TATE PET/CT scan has shown potential diagnostic value for identifying stroke. However, the independent use of this radiological study for the diagnosis of stroke has not been proposed previously.

Case presentation

A woman in her 50s presented with severe headaches. Brain imaging demonstrated a 3.9×4.0×4.6 cm left middle cranial fossa dural-based mass consistent with a sphenoid wing meningioma (figure 1A) with mass effect and surrounding vasogenic oedema. She subsequently underwent craniotomy for resection. Surgery and recovery were uneventful, and the patient remained at her neurologic baseline. MRI obtained on postoperative day 1 demonstrated gross total resection (figure 1B), as well as an area adjacent to the cavity consistent with perioperative ischaemic stroke (figure 1C). Pathology was consistent with atypical meningioma (WHO Grade II). Given the grade, postoperative adjuvant radiotherapy was recommended to the operative cavity. Gamma knife radiosurgery was planned for 2 weeks post operation.

Figure 1.

Preoperative T1-weighted MRI with contrast (A) demonstrating the large left sphenoid wing atypical meningioma. Immediate postoperative T1-weighted MRI with contrast (B) demonstrating the resection cavity, with an area of diffusion-weighted imaging (DWI) positivity in (C) suggesting ischaemic injury. The contrasted MRI in (D) was obtained 2 weeks postoperatively, on the day of gamma knife radiosurgery to the resection cavity, with an area of enhancement corresponding to evolving subacute stroke. The [⁶⁸Ga]Ga-DOTA-TATE scan (E) was subsequently obtained to define residual meningioma for treatment, which showed uptake in the area of subacute stroke. The final contrasted MRI (F) was obtained 1 year postoperatively, which demonstrates cystic encephalomalacia in the area of previous stroke and no residual or recurrent tumour. [⁶⁸Ga]Ga-DOTA-TATE, gallium 68 (⁶⁸Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid labelled octreotate.

On the day of planned treatment, a T1-weighted MRI sequence with contrast was obtained for radiosurgical targeting. A large volume of enhancement was noted surrounding the operative cavity, which was concerning for rapid tumour recurrence, as well as enhancement in the area of known ischaemia in the perisylvian inferior frontal lobe (figure 1D). To delineate evolving infarct from recurrent tumour, as both subacute stroke and recurrent tumour can appear identical on a T1-weighted sequence, a [⁶⁸Ga]Ga-DOTA-TATE PET was performed for radiosurgical targeting. The imaging study revealed high [⁶⁸Ga]Ga-DOTA-TATE uptake in the margin along the sphenoid wing consistent with recurrent tumour. There was also elevated uptake in the superior aspect of the surgical margin at the area of evolving perioperative subacute stroke (figure 1E). The recurrent tumour was treated with gamma knife radiosurgery, and the area of stroke evolved radiographically as expected following an ischaemic event (figure 1F).

Outcome and follow-up

The patient did well following surgery and gamma knife radiosurgery to the operative cavity and recurrent disease. She had an uneventful recovery and has remained at her neurologic baseline, never experiencing a clinical deficit related to the area of perioperative ischaemic injury. At 2 year followup, she had no radiographic evidence of residual or recurrent disease.

Discussion

We report the detection of subacute ischaemic stroke by [⁶⁸Ga]Ga-DOTA-TATE PET scan, corroborating two previous case reports of a similar observation. Vallée et al identified a cerebral lesion in a 76-year-old patient with a pancreatic neuroendocrine tumour patient during a follow-up [⁶⁸Ga]Ga-DOTA-TATE PET/CT imaging.⁷ The lesion corresponded to the location of an ischaemic stroke that the patient had suffered a month prior. Dundar et al also reported [⁶⁸Ga]Ga-DOTA-TATE uptake in a 14-year-old 6 days following surgical intervention for a carotid sheath paraganglioma, which was complicated by early postoperative right middle cerebral artery thrombosis.⁶ The authors reported that the regions of increased uptake corresponded to areas of subacute ischaemia as seen on the patient’s subsequent MRI scans. These two cases, in conjunction with ours, demonstrate the incidental identification of subacute ischaemic stroke in oncologic patients using [⁶⁸Ga]Ga-DOTA-TATE PET; this suggests stroke pathophysiology involves upregulation of the SSTR2 receptor, overlapping with the oncologic diagnoses for which [⁶⁸Ga]Ga-DOTA-TATE PET imaging is commonly used.

The mechanisms behind increased [⁶⁸Ga]Ga-DOTA-TATE uptake by ischaemic stroke have not been fully characterised. However, existing evidence suggests that activated macrophages represent a prominent cellular component in the subacute phase of ischaemic stroke. Ischaemia triggers a pathobiological inflammatory reaction that leads to an upregulation of macrophages, both resident microglia and circulation-recruited monocytes, in infarcted tissue.⁸ Additional evidence reveals that monocyte-derived macrophages express SSTR2 mRNA and receptors,⁹ which [⁶⁸Ga]Ga-DOTA-TATE most strongly binds to among the SSTR receptor subtypes. This finding, in addition to the validation of the modality as a marker of atherosclerotic inflammation in the coronary vessels,¹⁰ supports the hypothesis that SSTR2-expressing macrophages that are recruited following brain injury are responsible, at least in part, for the observed [⁶⁸Ga]Ga-DOTA-TATE uptake. Further investigation is necessary to validate this hypothesis.

In conclusion, this is the third report, to the best of our knowledge, of stroke detection during routine [⁶⁸Ga]Ga-DOTA-TATE PET. The independent clinical utility of [⁶⁸Ga]Ga-DOTA-TATE PET in the diagnosis of ischaemic stroke is currently unclear and such diagnostic use has not been tested nor validated; there is currently no role for its use in this application in consideration of the rigorous guidelines applied to the evaluation of medical diagnostic tests.¹¹ However, multiple pathologies that can be PET avid in this imaging modality reinforce the need to carefully consider the circumstances in which SSTR2 can be upregulated. This is especially important as [⁶⁸Ga]Ga-DOTA-TATE PET is becoming more frequently used in neuroendocrine tumour management and detection of metastasis, in diagnosis and measurement of tumour growth in meningioma, and as a marker of atherosclerotic inflammation.^{1 4 10} Moreover, these reported findings suggest that [⁶⁸Ga]Ga-DOTA-TATE PET may provide insight into the cellular pathophysiology of ischaemic stroke and may be a topic for future research.

Learning points.

• While gallium 68 (⁶⁸Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid labelled octreotate ([⁶⁸Ga]Ga-DOTA-TATE) positron emission tomography (PET) imaging technique is primarily used for detecting neuroendocrine tumours, it is increasingly being used at our institution and other medical centres for the diagnosis and management of meningiomas. Knowledge of the clinical entities that can demonstrate [⁶⁸Ga]Ga-DOTA-TATE uptake is critical to the interpretation and utilisation of this imaging modality.

• [⁶⁸Ga]Ga-DOTA-TATE PET/CT scan may have a diagnostic value for detecting strokes; currently, this radiological study needs further research for testing and validation for this application.

• While the underlying mechanism of somatostatin receptor type 2 expression in ischaemic stroke has not been fully elucidated, existing evidence implicates macrophages as critical mediators. Further investigation is necessary to validate this and to identify other potential mechanisms underlying radiotracer uptake by ischaemic stroke in [⁶⁸Ga]Ga-DOTA-TATE PET.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).