In the present manuscript as well as on the basis of previous experience in our institution [19], we used, for the first time, F-18 positron emission tomography (PET) for evaluating small tumor remnants after microsurgical resection or recurrence after radiosurgery (case 1). Several studies have shown a benefit of using FET-PET, as it appears to be superior to fluorodeoxyglucose (FDG)-PET for evaluating and biopsying non-contrast-enhancing brain tumors, specifically WHO grades II and III neoplasms [20].
Potential role of FDG-PET in the management of atypical CNs
Typically, FDG-PET studies in CNs show lower metabolic rate of glucose compared with the gray matter [21]. To our knowledge the only case of CN with atypical histological features, high MIB-1, and unusually intense FDG uptake was reported by Ohtani et al. [22]. The STR with adjuvant conventional RT administering total dose of 50 Gy was performed. Interestingly, shortly after completion of RT, an intense FDG uptake in residual tumor disappeared and FDG-PET was proposed as a potential follow-up examination in atypical CNs [22]. Similarly, in illustrative case 2 of aCN, the suspect discrete hyperactivity on FDG-PET was observed after the surgery, and intense glucose uptake confirmed local recurrence and out-of-field recurrence 4.5 and 9 years later. The comparison of two FDG-PETs (Fig. 2) acquired for the planning of first and second GKS showed a significant metabolic activity decrease within the PIV of first GK.
Importantly, only a few studies containing small patient populations report direct comparisons between FET and FDG-PET for the qualitative and quantitative characterization of brain lesions in humans [19]. A recent meta-analysis suggested a strong advantage of FET-PET over FDG-PET for diagnosis of brain tumors and gliomas [19].
Other imaging methods showing the high tumor proliferative activity
Not only FDG-PET, but also cerebral metabolic rate of glucose (rCMRGI) and minimum apparent diffusion coefficient (ADCmin), were proposed as markers of high proliferative activity. Mineura et al. reported that values of rCMRGl (2.68–6.26 mg per 100 ml per minute) were significantly lower compared with the contralateral gray matter (P < 0.02). In contrast to benign course of CNs exhibiting the cold foci, the only one with rCMRGI equivalent to the gray matter presented regrowth 4 months after the STR [21]. Sakamoto et al. estimated that the aCNs (MIB-1 LI > 2%) could be differentiated with 100% sensitivity (95% CI 47.8–100%) and 100% specificity (39–100%) if the threshold value of ADCmin is set at 0.55 × 10–3 mm2 per second (P < 0.0001) [23].
Importance of MIB-1 LI value
Commonly reported MIB-1 cutoff value to be able to differentiate between typical and atypical CNs is 2% [4, 15, 16]. The difference in aggressive CNs, depending on MIB-1 grade, could be also seen by our illustrative cases. In case 1, MIB-1 did not exceed 3%, even focally. Even if STR was performed, progression appeared extremely late; for example, after 7 years. On the contrary, in case 2, MIB-1 LI was 5–7%. Even if this less voluminous tumor was resected almost completely (> 99%), recurrence and out-of-field recurrence were revealed much earlier, at 4.5 and 9 years later, respectively.
The association of MIB-1 LI > 2% with shorter recurrence-free interval was well documented [15, 21, 24]. Rades et al. suggested the 3% MIB-1 to be a breakpoint, as reported local failure was 12% in MIB-1 LI ≤ 3% group, as compared to 48% in MIB-1 > 3% group [18]. Similarly, Kaur et al. reported the 4-year RR 0% in MIB-1 < 4% group compared with 100% in MIB-1 > 4% group. Moreover, the management by the STR alone leads to 0% recurrence rates in patients with MIB-1 < 4% compared with 100% recurrence rates in patients with MIB-1 > 4% [25].
Following STR, MIB-1 value should guide the next steps within the therapeutic approach. If MIB-1 is low, rather conservative management with close observation should be advocated, avoiding the potential risk (although extremely rare) of adverse radiation events (AREs) after GKS or RT. If the MIB-1 is high, adjuvant GKS should be considered owing to its steep gradient and the possibility of attaining functional preservation [26]. The importance of adjuvant RT following STR of atypical CNs has already been documented in 1997 by Schild et al. and later in 2007 by Leenstra et al. [6, 27]. The major advantage of adjuvant GKS versus RT is more conformal and selective dose distribution for the first, while performing only one treatment session [28], with possibly less AREs. Retrospectively, the upfront and immediately postoperative adjuvant GKS in case 2 might potentially have avoided the second, out-of-field CN recurrence.
Gamma Knife surgery in typical versus atypical CNs
GKS is considered a valuable therapeutic option [29] in case of residual or recurrent CNs [7,8,9,10]. Satisfactory results of GKS in CNs were documented by several recent series (for example, Yamanaka et al. [8], Genc et al. [11], Pan et al. [30], Karlssonet al. [12]). The study cohort included 22–42 patients and median follow-up period ranged from 24 months to 75 months. Median marginal doses ranging from 12 Gy to 16 Gy were prescribed to median tumor volumes from 4.9 ml to 12.6 ml [8, 11, 12, 30]. The 5- and 10-year control rates ranged from 91% to 94%, and from 81% to 91.6%, respectively [8, 11, 12]. Two permanent complications, one intratumoral hemorrhage and one radiation effect, were described by Yamanaka et al. [8]. Moreover, Karlsson et al. suggest a close imaging monitoring, because 45% of patients developed a partial enlargement of ventricular system [12].
