Know it, to control it

Low- high grade gliomas — latest concepts

A major revision of central nervous system (CNS) tumors was made by the World Health Organization (WHO) in 2016 from their original 2007 classification. Instead of being based simply on microscopy, the revision incorporated molecular parameters into the classification of CNS tumor entities. The 2016 update contains numerous differences from the 2007 CNS WHO classification. In this new classification, the diffuse gliomas include the WHO grade II and grade III astrocytic tumors, the grade II and III oligodendrogliomas, the grade IV glioblastomas, as well as the related diffuse gliomas of childhood.

Clinical implications

The molecular basis is the presence of the mutation in isocitrate dehydrogenase, IDH1, and found in 80% of the tumors. Of the 20% that don’t have the mutation, they have the molecular alterations of glioblastoma, and a prognosis that is similar to glioblastoma, even though they’re diagnosed as grade II or III tumors.

Among the 80% that have the mutation, 30% have 1p/19q co-deletion, so they are oligodendrogliomas, and the 50% that don’t have 1p/19q co-deletion are astrocytomas. They have other molecular alterations like p53 or ATRX, and they have a different prognosis, but the oligodendroglioma group carries the best prognosis with the astrocytoma group having a worse outcome. The tumors that do not have the IDH mutation have the worst prognosis and biologically, are much more aggressive tumors. Hence, low grade tumors (LGG) may now include grade II gliomas with a potential for aggressive behavior. Genomic analysis and molecular markers are better markers for survival than histological subtype as was previously assumed. So a LGG without the IDH mutation behaves more like a glioblastoma than just a LGG.

Therefore, the management of these low-high grade gliomas has become challenging with respect to prognosis and survival. A report indicated that procarbazine, lomustine, and vincristine added to radiation therapy in low-high risk patients (grade II LGGGs) who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, significantly improved overall and progression-free survival irrespective of tumor type at 10 years compared to those treated with radiation alone, although hematological toxicities were greater in the combination therapy group. As a result, the better tolerated oral temozolomide, favored for glioblastomas, is being given as 12 cycles, safely and effectively along with radiation therapy. Currently, 3 year survival rate data available is encouraging (73.1%).

Decision making is left to the treating neuro-oncosurgeon based on individual cases as far as these diffuse LGGs are concerned. In Europe, despite the recognized value of molecular markers in the prognosis of diffuse LGGs, 40% of the clinicians participating in a survey did not consider biological markers for the therapeutic decision. 1p19q co-deletion and IDH mutation were the most frequently considered. Temozolomide was first-line chemotherapy for both unresectable and resectable diffuse LGGs and only 15% recommended irradiating in the low-grade period as the first-line treatment, while 45% irradiated patients only after malignant transformation, and 50% only in case of progressive disease after a first line of chemotherapy.

In conclusion, these fundamental issues and variations in approach of diffuse LGGs deserve more future in-depth studies.