Brain Locations of LGGs
Although LGGs often were observed in eloquent areas,2 explaining the risk of their resection and, thus, the use of functional mapping methods to decrease surgical morbidity,3 to our knowledge, no specific study has attempted to evaluate whether these tumors have preferential brain locations. In the current study, we observed 1) that LGGs are situated more frequently in eloquent corticosubcortical areas compared with de novo GBMs and, more specifically 2) that LGGs are located significantly more often within the SMA and insular regions.
Although we collected a consecutive series that included more LGGs than high-grade gliomas (although the literature reports that high-grade gliomas are substantially more common than LGGs), thus suggesting a possible referral bias due to the expertise of our department in surgery for LGGs,3 the exclusion of Grade 3 gliomas may explain this ratio. Moreover, the current study data appear to be in accordance with numerous surgical series, which reported resection of LGGs specifically involving the SMA5 and the insula.6 These results also may indicate that environmental factors favoring the genesis of LGGs and GBMs differ, at least in part, complementing recent molecular biology data that also argue in favor of different intrinsic mechanisms between these two kinds of tumors.7
Several hypotheses may be considered to interpret the reason for such preferential locations of LGGs in the SMA and insular regions. First, there are some cytoarchitectonic and chemoarchitectonic similarities. Indeed, the insular cortex is divided into three belts, from anterior to posterior, on the basis of a gradual cytoarchitectonic change. These include 1) an agranular belt on the anterior one-third of the insula; 2) a transitional, dysgranular belt in layers without complete laminar differentiation; and 3) a posterior granular belt with a well defined granule cell layer that occupies the posterior one-third of the insula.8 In parallel, the precentral frontomesial structures also are divided into an agranular cortex (SMA-proper, pre-SMA, and anterior cingulum) and a dysgranular-to-granular posterior cingulum.9 Thus, the so-called “SMA region” appears to be a transitional architectonic area between the agranular primary motor cortex and the granular, “multimodal” cortex. In the same way, transmitter receptor studies using cytochrome oxidase, acetylcholinesterase, and nicotinamide adenine dinucleotide phosphate-diaphorase staining demonstrated a lightly stained region on the anteroinferior part of the insula, in which neuronal somata predominate, with an intermediate profile between that of a primary area and a high-order association area.10
Second, SMA and insula have a close functional role. Indeed, both represent a functional interface between a multimodal area (prefrontal cortex) and a primary area (sensorimotor area for both SMA and insula plus the auditory cortex for insula). More specifically, both structures play a role in planning: the SMA in planning movements11 and the insula in planning speech.12
Third, because these two areas appear to represent an architectonic and functional interface, it could be hypothesized that particular interactions may exist between neurons and glia in these regions. Indeed, it is well known that glial cells play a role 1) in neuronal migration,13 which may explain the existence of migration disorders in some cortical epilepsies,14 including the extratemporal epilepsy that often originates from the SMA15 and insula16; 2) in the regulation of synaptic transmission17; 3) in the control of synapse numbers18; and 4) in the energy metabolism of the neuron, explaining the neurovascular and metabolic decoupling in gliomas.19 Consequently, if we consider that both the SMA and the insula have partly similar, particular structural and functional profiles, some repercussions with regard to the biology of the local glial cells are likely. Thus, it might be suggested that such possible changes in the local glial properties may favor the development of LGGs in these preferential corticosubcortical locations.
Although they are speculative, these nonexhaustive hypotheses are based on strong, significant, epidemiologic results concerning the rate of LGG locations, and they seem plausible considering the literature currently available in the fields of cytochemoarchitectonics, structural-functional relations, and neuron-glia communication; however, they certainly do not represent the sole explanations. If these findings are confirmed by future studies, which need to be coupled with recent progress in the fields of molecular genetics of gliomas20 and molecular manipulation of stem cells in situ,21 then they may provide a better understanding of the genesis and natural history of LGGs (possibly concerning the patterns of growth), and may improve the management of these tumors.