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.

Keywords: brain connectome; epilepsy; low-grade glioma; peritumoral zone; quality of life; surgery.

Figure 1

Connectome-based supratotal resection of a left parietal LGG achieved in awake patient. Left: Preoperative axial FLAIR-weighted MRI achieved in a 54-year-old man, engineer, who experienced seizures that allowed the discovery of a left parietal DLGG. The neurological examination was normal. The tumor volume was 35 cm³. Middle: Intraoperative view after resection in awake patient. The anterior part of the left hemisphere is on the right, and its posterior part is on the left. The resection was achieved according to functional boundaries, identified using direct electrical stimulation both at the cortical level (5: naming site) and at the subcortical level as follows: Tag 48: somatosensory fibers inducing dysesthesia of the right upper limb when stimulated, and representing the anterior and deep limit of resection; Tag 49: posterior part of the arcuate fasciculus generating phonemic paraphasia when stimulated, and representing the anterolateral and deep limit of resection; Tag 50: optic tracts, eliciting visual disturbances when stimulated, and representing the inferior part of resection. Right: Postoperative axial FLAIR-weighted MRI (performed 3 months after resection) demonstrating a supratotal resection, that is, with removal of a margin all around the preoperative FLAIR abnormality. The patient resumed a normal familial, social, and professional life within 3 months after surgery. A diffuse WHO grade II oligodendroglioma (1p19q codeleted) was diagnosed, and no adjuvant treatment was administrated. The imaging is stable with 13 years of follow-up, and the patient continues to enjoy an active life, with no symptoms.