The Concept of «Peritumoral Zone» in Diffuse Low-Grade Gliomas: Oncological and Functional Implications for a Connectome-Guided Therapeutic Attitude

Abstract

Diffuse low-grade gliomas (DLGGs) are heterogeneous and poorly circumscribed neoplasms with isolated tumor cells that extend beyond the margins of the lesion depicted on MRI. Efforts to demarcate the glioma core from the surrounding healthy brain led us to define an intermediate region, the so-called peritumoral zone (PTZ). Although most studies about PTZ have been conducted on high-grade gliomas, the purpose here is to review the cellular, metabolic, and radiological characteristics of PTZ in the specific context of DLGG. A better delineation of PTZ, in which glioma cells and neural tissue strongly interact, may open new therapeutic avenues to optimize both functional and oncological results. First, a connectome-based “supratotal” surgical resection (i.e., with the removal of PTZ in addition to the tumor core) resulted in prolonged survival by limiting the risk of malignant transformation, while improving the quality of life, thanks to a better control of seizures. Second, the timing and order of (neo)adjuvant medical treatments can be modulated according to the pattern of peritumoral infiltration. Third, the development of new drugs specifically targeting the PTZ could be considered from an oncological (such as immunotherapy) and epileptological perspective. Further multimodal investigations of PTZ are needed to maximize long-term outcomes in DLGG patients.

A Personalized Longitudinal Strategy in Low-Grade Glioma Patients: Predicting Oncological and Neural Interindividual Variability and Its Changes over Years to Think One Step Ahead

“…Indeed, postoperative seizure control is more likely when EOR is ≥91% and/or residual tumor volume is ≤19 cc [ 108 ]. This also supports the suggestion of supratotal resection (with removal of the PTZ) for functional reasons (in addition to the improvement of oncological outcomes), i.e., with an optimization of QoL as a result of freedom from epilepsy [ 49 ].…”

“…This could explain the high risk of glioma relapse at the periphery of the surgical cavity, even following large resection [ 48 ]. Efforts to demarcate the glioma core from the surrounding healthy brain led to the definition of an intermediate region, the so-called peritumoral zone (PTZ) [ 49 ]. An important interindividual variability exists regarding this PTZ, as demonstrated by samples which found ITC from 10 to 20 mm around the glioma core [ 43 , 46 ], in agreement with the fact that the tumor core might be more bulky or more diffuse (see above).…”

“…In the same spirit, recent advances in PET scanning using tracers easily accessible in routine practice (such as F-DOPA) have enabled an increase in sensitivity for the detection of foci of MT within the LGG, before the onset of enhancement [ 56 ]. As mentioned, metabolic imaging could also be helpful to better investigate the PTZ [ 49 ]. This additional information could be of utmost interest for deciding the best timings of new therapies during follow-up of LGG patients.…”

“…This is particularly true following gross total resection, which was significantly associated with decreased mortality and likelihood of progression at all time points compared with subtotal resection, according to a recent meta-analysis [ 80 ]. One step forward is to achieve a “supra-complete” resection, to remove the PTZ which contains ITC exposing patients to a high risk of recurrence [ 49 , 66 ]. Long-term follow-up after supra-marginal LGG excision has shown a stronger impact on the natural course of the disease [ 27 , 48 , 81 , 82 ].…”

Repeated Awake Surgical Resection(s) for Recurrent Diffuse Low-Grade Gliomas: Why, When, and How to Reoperate?

“…In addition to the considerable structural-functional variability across patients ( 57 ), the connectome is changing over time for each patient, based on constant glioma-brain dialogue ( 59 , 60 ). This is particularly true at the level of the peritumoral zone, i.e., at the interface between the glioma core and the healthy brain, where intercommunication across tumoral cells and neural networks is maximal and where glioma relapse occurs most frequently ( 61 ). Cerebral circuits reconfiguration in reaction to the behavior of DLGG (pattern of proliferation versus migration, velocity diametric expansion) itself with constant modifications (spontaneously or consecutively to treatments) is possible, owing to the dynamics within and between networks in the framework of a meta-networking (network of networks) organization of brain processing ( 62 ).…”