Gliomatosis Cerebri: Current Understanding and Controversies

Abstract

Gliomatosis cerebri (GC) is a rare, extensively infiltrating glioma involving multiple contiguous lobes of the brain. This lethal disease affects all age groups, and the majority of patients have a poor outcome despite aggressive treatment. Despite its initial recognition in 1938, GC remains a controversial entity with little consensus in its definition, histology, or treatment. The majority of GC tumors are astrocytic, although mixed phenotypes have been identified. Treatment of GC is challenging as surgery is generally not an option due to the extensive areas of brain involved, the benefit of radiation therapy is unclear, and no chemotherapy has proven efficacy. Due to the rarity of the disease and its heterogeneity, both at histopathological and molecular levels, it is difficult to conduct clinical trials tailored for this diagnosis. This review summarizes our current knowledge, examines clinical studies focusing on the treatment of GC, highlights ongoing challenges, and discusses the recent molecular insights into adult and pediatric GC. We conclude that, although no longer recognized as a distinct pathological entity, GC represents a unique disease phenotype. Given the histologic and molecular overlap with other diffuse gliomas, the research emphasis should be on investigating its unique invasive biology.

Clinical relevance of molecular subgrouping of gliomatosis cerebri per 2016 WHO classification: a clinicopathological study of 89 cases

“…Among them, only one case of a 31‐year‐old male was confirmed via H3.3‐K27M positivity as diffuse midline glioma and was excluded from the current study. The characteristics of adult H3‐K27M mutant gliomas in association with GC are yet to be completely elucidated . Whether GC with H3‐K27M mutation may represent a rare molecular pattern of GCs or not requires further investigation.…”

“…However, the unique extremely invasive phenotype of GC is unlike those of other ordinary high-grade gliomas (14), as GC infiltrates the brain extensively, but usually preserves the local parenchymal architecture, which is completely different from the destructive and necrotic infiltrating pattern observed in high-grade gliomas (5,36). The significant neovascularization and mitotic activity that are commonly present in highgrade gliomas are not prominent features of GC (14,31). Rather, the majority of GC tends to present histologically low-grade features such as rod cell-like astrocytic tumor cells with elongated fusiform nuclei without prominent microvascular proliferation or necrosis (5,29).…”

“…Although gliomatosis cerebri (GC), a rare and extensively infiltrating glioma involving multiple contiguous lobes of the brain, has been removed as an independent tumor entity from the 2016 WHO classification, it still remains a special “GC growth pattern” that can occur in both astrocytic and oligodendroglial tumors . Till date, both the phenotype and genotype of GCs remain unexplained . As described previously, the clinical behavior of GC is similar to that of WHO grade III gliomas, and secondary progression to highly malignant tumor may occur .…”

A case of pediatric gliomatosis cerebri harboring H3F3A K27 mutation

“…In the revised WHO Classification of Tumors of the Central Nervous System (2016), GC is no longer defined as a single entity and several new entities including “diffuse midline glioma with H3 K27M‐mutant” have been introduced 1 . The term “GC,” however, is still used to describe its characteristic growth pattern 2‐4 . As previously reported, GC is neither pathologically nor genetically grouped into a single entity, but most cases share molecular abnormalities commonly found in other gliomas including hot spot mutations and methylation signatures.…”

Gliomatosis cerebri: a consensus summary report from the Second International Gliomatosis cerebri Group Meeting, June 22–23, 2017, Bethesda, USA

“…In 1993, there was initial consideration as to whether it deserved inclusion as a distinct pathological entity [9]. In 2016, GC was eliminated as a distinct pathologic entity based on overlap of discrete molecular alterations with other high-grade gliomas, and the absence of distinct molecular or histologic features compared to other malignant gliomas [5, 10–12]. However, it was noted that GC merits further study as this phenotype has characteristic and unique migration and invasiveness patterns and different treatment outcomes.…”