Robot-assisted surgery allows accurate and safe interventions, often reducing postoperative risks and shortening burdensome recovery periods. In neurosurgery, robotics expanded the depth of stereotactic and functional neurosurgery, integrating the team as a tool of utmost importance.
Biopsy procedures have been a constant part of the neurosurgical armamentarium, constantly evolving in the last decades. Even more so in the subtle field of brainstem lesions that historically were considered mostly inoperable and related to significant morbidity. In the era of microsurgical techniques, these lesions remain challenging, requiring a precise approach through safe entry zones, in meticulously selected cases .
Robot-assisted biopsies can increase the potential of targeting eloquent deep-seated locations with lowered risk of complications and high diagnostic yield. Optimal trajectory planning takes into consideration lesion location, traversing grey and white matter, vessels but also vascular structures (pia layer, ependymal cells, choroid plexus) and ventricle avoidance[21-23].
Routes to the brainstem
Brainstem lesions have always generated debates from operability to adequate management. In a quest to minimize morbidity safe passageways have been methodically described from the microsurgical point of view, encompassing multiple supra and infratentorial approaches [20, 24-26]. Two stereotactic safe routes to the brainstem have proven their versatility to reach intrinsic brainstem lesions and deserve special consideration: the transcerebellar and the transfrontal routes.
The most frequently used is the transcerebellar approach, automatically linked in our opinion to the more frequent localization of lesions in or extending towards the pontine region. This approach implies an entry point on the surface of the cerebellar hemispheres, navigating the height and width of the middle cerebellar peduncle to reach mainly pontine lesions but also low-hanging mesencephalic or higher bulbar lesions. In our study, this approach was used in 59.2% of cases.
The transcerebellar approach has been described using a stereotactic frame[8, 10, 27, 28] or frameless[13, 15], with favorable results concerning complications, varying from 0% (in small cohorts) to 19.2% for transitory morbidity. Main advantages are related to shorter trajectories, passing through the middle cerebellar peduncle, thus lowering the theoretical risk of hemorrhage. In our study 16.4% of patients (10/66 cases) benefitting from a transcerebellar approach presented a biopsy-related complication, most common transitory balance impairment or motor status worsening. One noteworthy technical advantage of using a stereotactic robot regards the easiness of patient positioning, independent to frame adaptations described for brainstem lesions.
This versatile approach is complemented by the transfrontal approach, especially for mesencephalic or rostral pontine lesions. The transfrontal route is planned frequently from a precoronal entry point, navigating between the lateral ventricle, head of the caudate, basal ganglia, and internal capsule (Figure 2B and 2C). Despite longer trajectories, the transfrontal approach remains a viable option, with a low rate of complications (in our study, most often diplopia or motor status worsening)[21, 29].
Our study shows no statistical difference in biopsy-related morbidity between the transfrontal and transcerebellar trajectories (p=0.45). In their meta-analysis, Kickingereder et al. report that the weighted average proportion calculated by random-effects was 7.8% (95% CI: 5.6%-10.2%) for overall morbidity, 1.7% (95% CI: 0.9%-2.7%) for permanent morbidity, and 0.9% (95% CI: 0.5%-1.4%) for mortality. In an updated meta-analysis for pediatric brainstem tumors, Hamisch et al. report similar results: 6.7% (95% CI 4.2–9.6%) for overall morbidity, 0.6% (95% CI 0.2%– 1.4%) for permanent morbidity, and 0.6% (95% CI 0.2%– 1.3%) for mortality. Both studies showed no significant differences between the transcerebellar and transfrontal routes to the brainstem.
Impact in molecular diagnosis evolution
In our retrospective study, histopathological diagnosis was achieved in 95.8% of cases, similar to available data. A second biopsy was necessary in 6 patients. Kickingereder et al. reported on 1480 cases of frame-based or frameless stereotactic brainstem biopsies, comprising 38 studies, with a final diagnosis achieved in 96.2%. Interestingly, the authors underlined the need for highly specialized centers to increase diagnostic success, with a significant correlation between diagnostic rates and the number of biopsies performed annually in each center (p=0.011). Additionally, Hamisch et al. reported in their meta-analysis on 18 studies a diagnostic rate of 96.1% in a total of 735 pediatric brainstem biopsies.
Our center’s philosophy is to biopsy all brainstem tumors before discussing appropriate adjuvant treatment. In the era of integrated molecular analysis stereotactic brainstem biopsies could assist in early initiation of targeted therapies, especially in the diffuse intrinsic pontine glioma (DIPG) subgroup with the analysis of histone mutations (e.g., H3.3 K27M). This has marked an important change in the treatment paradigm of brainstem lesions, from the initial concept of MRI exclusive diagnosis towards precise molecular diagnosis[34-36] and current targeted treatment[37, 38].
Noteworthy, our study did not allow statistical analysis based on molecular diagnosis, covering a long period prior to the integration of molecular biology data.
Differential diagnosis for brainstem tumors
In our study we report 68 cases of diffuse glioma, representing 70.8% of the total number of successful biopsies. Brainstem metastasis was confirmed in 8 patients (8.3%) while lymphoma was reported in 7 patients (7.3%). Noteworthy, 9 patients presented with a rare histopathologic diagnosis (Table 2), illustrating the difficulty of radiologic diagnosis solely on cerebral MRI, thus warranting a stereotactic biopsy even in non-tumoral pathologies.
As reported by several studies, a step-wise MRI-based approach could help differentiate between several etiologies, especially tumor-like mimics: infectious and inflammatory lesions, vascular lesions or even uncommon cysts[39-41]. While morphology details can be quickly helpful in some pathologies, differential diagnosis of immune-mediated and inflammatory lesions of the brainstem can remain as elusive as ever. Law et al. proposed integrating essential clinical, biological and radiological data into the differential diagnosis, reviewing a remarkable large spectrum of these disorders based on cerebral MRI findings. Routine cranio-spinal morphology MRI sequences could be coupled with more advanced modalities: PET-CT, MRI spectroscopy and MRI/CT perfusion scans[39, 40, 42].
We acknowledge several limitations in our study. Firstly, it is a retrospective series with data acquisition limited by the 17 years period encompassed in our analysis. Secondly, while it is a monocentric study, patients were referred from other neurosurgical centers and thus were sometimes lost early at follow-up. This was nonetheless not the main focus in our analysis, permitting the inclusion of all consecutive patients for final analysis. Thirdly, histopathology results were limited by the absence of systematic genetic testing prior to the 2016 WHO Classification, limiting our insight into a developing and promising avenue for clinical research.