Key rates for the grades and transformation ability of glioma: model simulations and clinical cases

Abstract

Tumor progression to higher grade is a fundamental property of cancer. The malignant advancement of the pathological features may either develop during the later stages of cancer growth (natural evolution) or it may necessitate new mutations or molecular events that alter the rates of growth, dispersion, or neovascularization (transformation). Here, we model the pathological and radiological features of grades 2-4 gliomas at the times of diagnosis and death and study grade development and the progression to higher grades. We perform a retrospective review of clinical cases based on model predictions. Simulations uncover two unusual patterns of glioma progression, which are supported by clinical cases: (1) some grades 2 and 3 gliomas lack the ability of progression to higher grades, and (2) grade 3 glioma may evolve to GBM in a few weeks. All 13 gliomas that recurred at the same grade carry either the IDH1-R132H or the ATRX mutation. All (five of five) grade 3 tumors are 1p/19q co-deleted, IDH1-R132H mutated and ATRX wt. Furthermore, three of seven grade 2 gliomas are both IDH1-R132H mutated and ATRX mutated. Simulations replicate the good prognosis of secondary GBM. The results support the hypothesis that constant rates of dispersion, proliferation, and angiogenesis prescribe either a natural evolution or the inability to progress to higher grades. Furthermore, the accrual of molecular events that change a tumor's ability to infiltrate, proliferate or neovascularize may transform the glioma either into a more aggressive tumor at the same grade or elevate its grade.

Prognostic histopathologic features of canine glial tumors

“…Multiple studies of human glial tumors indicate that these tumors often undergo malignant transformation from low-grade tumors to high-grade malignant tumors. 11,13 Malignant transformation reflects increased rates of replication, angiogenesis, and migration due to genetic mutations. In contrast, higher numbers of mitotic figures were associated with a poor outcome in biopsies ( P = .0421) as well as in whole-brain samples, suggesting that this observation is a more robust histological feature in biopsies for prediction of outcome.…”

Diagnosing growth in low-grade gliomas with and without longitudinal volume measurements: A retrospective observational study

“…The x -axis in (a–f) corresponds to the time interval from the baseline MRI. (g) The results of simulations of the mathematical model for grade 2 gliomas, showing percent of brain invaded by the tumor ( y -axis) as a function of the parameter for mitotic rate (per hour) in the presence of a low angiogenesis rate (0.1/hour), see Scribner et al [18]. (h) The curve fit of the normalized data of 14 patients with nonlinear growth using the model f(x) = a * exp( b * x ), coefficients (with 95% confidence bounds): a = 0.03751 (0.02759, 0.04743), b = 2.98 (2.69, 3.27), sum of squares due to error = 1.3701, r 2 = 0.8580. astro, astrocytoma; CAD, computer-assisted diagnosis; oligo, oligodendroglioma.…”

“…The authors have recently reported a system of partial differential equations (PDEs) that model glioma growth at the scale of MRI and pathology. The equations include the rates of replication (mitosis), brain invasion, angiogenesis, and a threshold for hypoxia; the numerical methods used to solve the system of PDEs are detailed elsewhere [18,28,29].…”

“…Some studies have reported a correlation between radiation therapy and cognitive impairment in patients with low-grade gliomas [15,16]; however, a recent European Organisation for Research and Treatment of Cancer study found no difference in global cognition in patients treated by radiotherapy versus chemotherapy [17]. At the time of growth detection, low-grade gliomas may remain at the same grade or could have transformed to higher grades [18]; they may again be treated by surgery with or without radiation therapy and chemotherapy [19,20].…”

Spatial distribution of malignant transformation in patients with low-grade glioma

“…In spite of often rather well-defined margins on MRI, tumor cells are present outside the radiologically visible tumor, making this an infiltrative disease [3,4]. At an unpredictable point of time, LGG speed of growth increases due to malignant transformation [5,6]. Malignant transformation is a key clinical event and leads to intensified treatment, increased morbidity and premature death [7][8][9].…”