DOTATATE PET/MR Imaging Differentiates Secondary-Progressive from de Novo World Health Organization Grade 3 Meningiomas

DISCUSSION

While meningiomas overall are the most common primary brain tumor, WHO grade 3 meningiomas are rare and thus understudied, with only around 300 cases of WHO grade 3 meningiomas diagnosed annually in the United States, limiting our understanding of the natural history as well as the optimal diagnostic and therapeutic management.¹¹ While patients with WHO grade 3 meningiomas are typically treated with maximal surgical resection and RT, clinical outcomes are poor, with recurrence rates of 50%–90% by 5 years after surgery and a 5-year overall survival rate of 20%–50%.^1⇓-3 Given their high morbidity and mortality rates, it is critical to optimize the diagnostic and therapeutic management of WHO grade 3 meningiomas.

Whether WHO grade 3 meningiomas arise de novo or from secondary progression has also proved to have important prognostic implications. Approximately one-half of all WHO grade 3 meningiomas are diagnosed de novo, while the other half arise from secondary progression of a previously diagnosed lower histologic grade. In our study, patients with secondary-progressive WHO grade 3 meningiomas had markedly decreased PFS compared with the de novo cohort, consistent with previous findings from other studies.^2,4 The exact mechanism underlying this observation is not yet clearly understood, though 1 explanation may lie in the differences in molecular pathology.

Although it is known that higher-grade meningiomas have greater rates of genetic mutations, we found that even within WHO grade 3 meningiomas, those that progressed from lower-grade tumors compared with de novo cases had a distinct molecular profile with higher rates of genetic mutations overall and in specific genes such as NF2 and CDKN2A/B, which have been known to be implicated in more aggressive disease reported in the literature.¹² Our genetic data were collected through the Oncomine Comprehensive Assay, which is a targeted next-generation sequencing assay that tests a panel of genes with known oncologic implications, but it notably did not include TERT promoter mutations. For the secondary-progressive cohort, genomic data were available from 6 patients; however, some samples were analyzed before dedifferentiation to WHO grade 3, with 1 sample being WHO grade 1 and 2 samples being WHO grade 2 at the time of molecular testing. Nevertheless, the secondary-progressive cohort still had a greater mutational burden both in number and clinical relevance compared with the de novo cohort. This finding may help to explain the more aggressive clinical course of secondary-progressive WHO grade 3 meningiomas, arguing that de novo–versus–secondary-progressive status may be an important prognostic factor for WHO grade 3 meningiomas, and they may even be considered 2 distinct clinical entities moving forward.

MR imaging, the criterion standard for meningioma surveillance, has significant limitations such as distinguishing recurrent or residual disease from postoperative findings, and there has been a marked unmet need for more targeted imaging strategies, especially in intermediate- and high-risk tumors.⁶ More recently, (⁶⁸Ga) DOTATATE PET has demonstrated high utility in meningioma evaluation, including diagnostic confirmation, surgical planning, delineation of radiation therapy target volumes, and posttreatment surveillance.⁷ Although the utility of (⁶⁸Ga) DOTATATE PET/MR has been shown in meningioma diagnosis and treatment-planning, its role has not previously been systematically investigated in patients with WHO grade 3 meningioma, in part due to limited sample sizes. This is the first study evaluating the clinical characteristics and utility of (⁶⁸Ga) DOTATATE PET/MR imaging in a cohort of patients with exclusively WHO grade 3 meningioma and comparing secondary-progressive and de novo cohorts. Just as seen previously with WHO grades 1 and 2 meningiomas, (⁶⁸Ga) DOTATATE PET is very useful in distinguishing recurrent or residual disease from postoperative findings in WHO grade 3 meningioma compared with evaluation on MR imaging alone. For instance, 1 patient with surgical resection of WHO grade 3 meningioma was thought to have achieved GTR on postsurgical MR imaging with questionable residual disease versus postoperative changes but then later was found to have had definitive residual disease and subtotal resection on (⁶⁸Ga) DOTATATE PET.

Previously, (⁶⁸Ga) DOTATATE has been routinely used in the evaluation of gastroenteropancreatic neuroendocrine tumors years before it was used in meningioma management. For gastroenteropancreatic neuroendocrine neoplasms, the sensitivity of (⁶⁸Ga) DOTATATE decreases with an increased grade of the tumor, possibly due to downregulation of SSTR2 with increasing tumor grade.¹³ A similar mechanism in meningiomas could be hypothesized; however, we found that on the contrary, (⁶⁸Ga) DOTATATE PET SUV was significantly higher in secondary-progressive WHO grade 3 tumors compared with de novo tumors, despite the secondary-progressive tumors having significantly higher rates of genetic mutations. Our findings suggest that downregulation of SSTR2 does not occur with an increase in WHO grade in meningiomas, with the possibility that the receptor may be upregulated. Thus, (⁶⁸Ga) DOTATATE remains a clinically useful approach in meningiomas regardless of WHO grade.

At present, determining meningioma grade is not possible on the basis of neuroimaging alone. Our findings suggest the possibility of noninvasively differentiating secondary-progressive from de novo WHO grade 3 meningiomas using (⁶⁸Ga) DOTATATE PET/MR imaging, which has high clinical relevance, given the known difference in prognosis between the 2 groups previously shown by other authors and confirmed in our study.

Additionally, this work raises important questions regarding the role of SSTR2 in meningioma biology. SSTR2 downstream signaling is implicated in a diverse range of physiologic processes such as the secretion of insulin and glucagon, thyroid-stimulating hormone and growth, and neuronal excitability.^14,-,16 However, the role of SSTR2 in meningioma biology and the correlation between SSTR2 expression and clinical outcomes remain to be determined prospectively. In immunohistochemical studies, no correlation between SSTR2 expression and tumor grade was found; however, there was a positive correlation with higher microvessel density.^17,18 Clinically, higher SSTR2 expression was correlated with a higher risk of recurrence after surgical resection.^18,19 Notably, higher SSTR2 expression was correlated with improved PFS following somatostatin-receptor (SSTR)-targeted radionuclide therapy, which may be due to higher binding of the SSTR-targeted theragnostic agent and thus higher treatment effectiveness.^18,19

Taken together, it is still unclear whether SSTR2 expression is related to tumor grade or prognosis. Our data suggest that secondary-progressive WHO grade 3 meningiomas have an elevated (⁶⁸Ga) DOTATATE SUV compared with de novo disease, suggesting a link between elevated SSTR2 expression and worsened clinical outcomes, though formal immunohistochemical studies have yet to be performed. Notably, in a study encompassing all WHO grade meningiomas, a higher DOTATATE PET SUV was associated with a higher tumor growth rate,²⁰ which is concordant with our WHO grade 3–specific findings, with higher SUVs reflecting worsened PFS. However, in our study, we were unable to directly correlate tumor SUV and PFS due to the small sample size. In another study, there was a strong correlation between tumor vascularity and SSTR2 expression in WHO grades 2 and 3 but not grade 1 meningiomas, suggesting that SSTR2 may play a role in tumor vascularity in higher-grade tumors.²¹

SSTR2 expression in meningiomas has also emerged as a potential therapeutic target. SSTR2-directed peptide receptor radionuclide therapy with β-emitters 90 yttrium (⁹⁰Y) and 177 lutetium (¹⁷⁷Lu) has shown promise in the treatment of unresectable or refractory meningiomas.^22,23 Other systemic treatment options have emerged such as dacarbazine and adriamycin, hydroxyurea, temozolomide, and irinotecan, but their efficacy has not yet been shown in clinical trials.²⁴ While rare, SSTR2-negative meningioma has been reported in the literature and is an important additional indication of a lack of direct correlation between SSTR2 expression and WHO grade.²⁵ SSTR2-targeted therapeutic effort may be beneficial in WHO grade 3 meningiomas, possibly more so in the secondary-progressive cohort, which may be expressing higher levels of SSTR2.

One significant limitation of this study is the determination of de novo disease, because it is possible that tumors arose from lower-grade meningiomas but were only first diagnosed with pathology once the tumor had already progressed to WHO grade 3 disease. Although this limitation may be an unavoidable confounder in the original categorization of WHO grade 3 meningiomas as either being de novo or secondary-progressive, our data suggest that regardless of de novo–versus–secondary-progressive status, those with a higher SUV, on average, had shortened PFS following surgical resection. This finding suggests that in WHO grade 3 meningiomas, SUV alone could be predictive of worse prognosis and thus guide clinical decision-making. Another limitation to our study is the small sample size; however, due to the low incidence of the disease, this has been the case in all other published studies and remains a bottleneck in our effort to fully understand the natural history and optimal management of WHO grade 3 meningiomas. Nevertheless, our study remains the first to investigate a cohort of WHO grade 3 meningiomas with (⁶⁸Ga) DOTATATE PET/MR imaging and thus has the potential to increase our understanding of this rare entity, thereby improving clinical outcomes.