Dissecting Stemness in Aggressive Intracranial Meningiomas: Prognostic Role of SOX2 Expression

Abstract

Meningiomas are mostly benign tumors that, at times, can behave aggressively, displaying recurrence despite gross-total resection (GTR) and progression to overt malignancy. Such cases represent a clinical challenge, particularly because they are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription factor with a key role in stem cell maintenance and has been associated with tumorigenesis in a variety of cancers. The purpose of the present work was to dissect the role of SOX2 in predicting the aggressiveness of meningioma. We analyzed progressive/recurrent WHO grade 1–2 meningiomas and WHO grade 3 meningiomas; as controls, non-recurring WHO grade 1 and grade 2 meningioma patients were enrolled. SOX2 expression was evaluated using both immunohistochemistry (IHC) and RT-PCR. The final analysis included 87 patients. IHC was able to reliably assess SOX2 expression, as shown by the good correlation with mRNA levels (Spearman R = 0.0398, p = 0.001, AUC 0.87). SOX2 expression was an intrinsic characteristic of any single tumor and did not change following recurrence or progression. Importantly, SOX2 expression at first surgery was strongly related to meningioma clinical behavior, histological grade and risk of recurrence. Finally, survival data suggest a prognostic role of SOX2 expression in the whole series, both for overall and for recurrence-free survival (p < 0.0001 and p = 0.0001, respectively). Thus, SOX2 assessment could be of great help to clinicians in informing adjuvant treatments during follow-up.

Paths of Evolution of Progressive Anaplastic Meningiomas: A Clinical and Molecular Pathology Study

“…Interestingly, PD-L1 was poorly expressed in pre-anaplastic samples, while expression levels increased in 40% of cases at anaplastic progression. As previously reported [ 9 ], Sox2 was expressed in most cases, both in the pre-anaplastic and in the anaplastic samples. However, by comparing expression levels in paired samples, at anaplastic progression we observed an increase in Sox2 expression in 40% of cases, a decrease in 30% cases, and no variations in the remaining 30% of cases.…”

“…Mechanisms leading to progression in meningiomas are poorly understood. Accumulating literature data point to the role of molecular biology in predicting the prognosis of meningiomas across all grades [ 8 , 9 , 27 , 28 , 29 ]. Relatively few gene-level alterations, including CDKN2A/B, TERT , and NDRG2 (N-myc downstream-regulated gene family member 2), have been strongly associated with the malignant progression of meningioma [ 30 , 31 , 32 ].…”

“…We retrospectively enrolled 41 consecutive patients undergoing neurosurgery for anaplastic meningioma (WHO grade III according to WHO 2016) at the Department of Neurosurgery, A. Gemelli University Hospital, Rome, Italy, between 1999 and 2018 [ 9 ]. Baseline demographics; clinical status, according to modified Rankin scale; tumor location (classified as skull base, non-skull base, and intra-ventricular); and the number of neurosurgeries, surgical complications, extent of resection (gross total resection, GTR, i.e., Simpson 1–3, vs. subtotal resection, STR, i.e., Simpson 4–5), and adjuvant treatments were registered.…”

“…Sox2 expression was evaluated using immunohistochemistry, as already described. A sample was scored as positive where ≥25% cells showed nuclear or nuclear-cytoplasmic expression of Sox2 [ 9 ]. EGFR and PD-L1 were assessed immunohistochemically using anti-human EGFR (1:50, clone C1, UCS diagnostics, Morlupo, Italy) and anti-human PD-L1 (1:50; clone 22C3, Dako, Milan, Italy).…”

“…Recently, using the NGS platform, omics have been investigated in meningiomas [ 8 ] with interesting results, which are difficult to translate into the clinical practice. In a previous study that used immunohistochemistry and real-time RT-PCR, we showed that the expression of the stemness marker Sox2 is associated with a worse prognosis independently from the WHO meningioma grade [ 9 ]. In particular, we showed that Sox2-expressing grade 1 and 2 meningiomas are associated with an increased risk of progression to anaplastic tumors.…”