Response Assessment in Neuro-Oncology Criteria for Gliomas: Practical Approach Using Conventional and Advanced Techniques

Abstract

The Response Assessment in Neuro-Oncology criteria were developed as an objective tool for radiologic assessment of treatment response in high-grade gliomas. Imaging plays a critical role in the management of the patient with glioma, from initial diagnosis to posttreatment follow-up, which can be particularly challenging for radiologists. Interpreting findings after surgery, radiation, and chemotherapy requires profound knowledge about the tumor biology, as well as the peculiar changes expected to ensue as a consequence of each treatment technique. In this article, we discuss the imaging findings associated with tumor progression, tumor response, pseudoprogression, and pseudoresponse according to the Response Assessment in Neuro-Oncology criteria for high-grade and lower-grade gliomas. We describe relevant practical issues when evaluating patients with glioma, such as the need for imaging in the first 48 hours, the radiation therapy planning and isodose curves, the significance of T2/FLAIR hyperintense lesions, the impact of the timing for the evaluation after radiation therapy, and the definition of progressive disease on the histologic specimen. We also illustrate the correlation among the findings on conventional MR imaging with advanced techniques, such as perfusion, diffusion-weighted imaging, spectroscopy, and amino acid PET. Because many of the new lesions represent a mixture of tumor cells and tissue with radiation injury, the radiologist aims to identify the predominant component of the lesion and categorize the findings according to Response Assessment in Neuro-Oncology criteria so that the patient can receive the best treatment.

Fig 1.

Examples of measurable and nonmeasurable disease, according to the RANO criteria. A, Axial contrast-enhanced T1-weighted image shows a heterogeneously enhancing lesion in the left parietal lobe (arrows), corresponding to recurrent GBM, with both perpendicular measurements of >10 mm, thus representing measurable disease. The more commonly seen examples of nonmeasurable disease are represented in the axial T2 image (B), depicting a hyperintense infiltrating lesion in the left parieto-occipital region (arrowheads) in a patient with anaplastic astrocytoma. The axial contrast-enhanced T1-weighted image (C) shows a subcortical enhancing nodule representing a recurrent GBM (arrow), in which perpendicular diameters are <10 mm. The axial contrast-enhanced T1-weighted image (D) shows residual tumor in the resection cavity of a partially resected GBM (curved arrow), which has poorly defined margins.

Fig 2.

Postoperative findings after GBM resection in the right parietal lobe (not shown) in a 55-year-old man. A, Axial contrast-enhanced T1-weighted image in the immediate postoperative period demonstrates a fluid-filled surgical cavity (arrow) without any enhancing lesions, which is defined as gross total resection. B, An axial diffusion-weighted image shows marked restricted diffusion in the margins of the cavity (arrowhead), representing cytotoxic edema related to surgical manipulation. C, Axial contrast-enhanced T1-weighted image obtained 3 months after an operation shows the development of an enhancing focus in the surgical bed (arrowhead), corresponding to development of granulation tissue in the area of previously restricted diffusion, also a typical and predictable postoperative feature, which should not be misdiagnosed as recurrent or residual tumor.

Fig 3.

Delineation of the radiation therapy target for the treatment of a gross totally resected GBM in the right temporal lobe and its relation to tumor recurrence. A, Fused planning CT and axial contrast-enhanced T1-weighted postoperative image allow visualization of the radiation dose effectively delivered in the brain parenchyma adjacent to the surgical cavity (isodose chart). The high-dose region is defined as the area inside the pink line, corresponding to the 100% isodose line (60 Gy) plus the area between the pink and green lines, corresponding to the 80% isodose line (48 Gy). B, Fused planning CT and axial contrast-enhanced T1-weighted follow-up images demonstrate that a significant portion of the new enhancing lesion was located outside the high-dose radiation field (inside the green line), which is consistent with progressive disease.

Fig 4.

Imaging features of the nonenhacing component of glial tumors. A 36-year-old man underwent partial resection and adjuvant radiation therapy of an extensive diffuse astrocytoma (World Health Organization, grade II) involving both parietal lobes (not shown). A, Axial FLAIR image obtained 5 years after completion of radiation therapy demonstrates extensive hyperintensity crossing the midline through the splenium of the corpus callosum (arrows), probably representing a mixture of lower-grade tumor and radiation injury. B, Axial FLAIR image obtained 8 months later depicts blurring of the gray-white matter in the left parietal lobe (arrowheads), as well as effacement of the left lateral ventricle (asterisk), which is consistent with neoplastic infiltration (progressive disease).

Fig 5.

Pseudoprogression in a 56-year-old man who underwent chemoradiation after gross total resection of a GBM in the left parietal lobe. A, Axial contrast-enhanced T1-weighted image obtained 1 week after an operation shows thin ring enhancement in the surgical bed (asterisk), which was considered to represent granulation tissue, related to the operation. The study was not obtained within the first 48 hours due to hemodynamic instability of the patient. B, Soon after completion of radiation therapy, the patient developed marked enhancement in the margins of the surgical cavity (arrow), with effacement of the adjacent sulci. In the following 3 months, he presented with progressive altered mental status and right-side hemiparesis. C, At that time, axial contrast-enhanced T1-weighted imaging showed an increase in mass effect, midline shift, with a slight increase in enhancement extension, which turned to a soap bubble appearance (arrowhead), a pattern typically associated with radiation necrosis. D, The patient improved clinically, and after 4 months, a new image depicted fading of the enhancing lesion (curved arrow) and a marked decrease in mass effect, which is the classic course of pseudoprogression.

Fig 6.

Pseudoresponse in a 36-year-old woman with a partially resected GBM in the right temporal lobe and insula. Axial contrast-enhanced T1- weighted (A) and FLAIR (B) images obtained in the immediate postoperative period show an extensive hyperintense FLAIR lesion (arrows) with multiple foci of contrast enhancement (arrowheads). C, An anti-VEGF agent was administered, and a follow-up axial contrast-enhanced T1-weighted image depicts a striking decrease of the enhancing component (arrowhead). D, However, there is also an increase of the nonenhancing infiltrative component, manifested as FLAIR hyperintensity in the right frontotemporal region and insula, with an expansive effect, blurring, and loss of the cortical-subcortical differentiation (arrows).

Fig 7.

A progressive low-grade glioma in a 33-year-old man previously diagnosed with Li-Fraumeni syndrome. Initial axial FLAIR (A) and contrast-enhanced T1-weighted (B) images showed subtle cortical-subcortical FLAIR hyperintensity in the left inferior parietal lobule, with minimal expansive effect and no postcontrast enhancement, which was presumably considered to be a low-grade glial tumor (arrowhead). Two years later, axial FLAIR (C) and contrast-enhanced T1-weighted (D) images depict a marked increase in the expansive effect, with loss of gray-white matter differentiation and heterogeneous enhancement (arrowhead). Those findings are consistent with malignant transformation of a lower-grade glioma (progressive disease).

Fig 8.

DSC perfusion in pseudoprogression and progressive disease. A, Axial contrast-enhanced T1-weighted and the corresponding rCBV map images show an enhancing lesion that developed after radiation therapy and temozolomide in a 46-year-old patient with multicentric GBM. The DSC perfusion of the enhancing lesion in the surgical bed (white ROI) shows decreased rCBV (0.5) in comparison with normal contralateral white matter (green ROI), which is consistent with predominance of radiation injury within the lesion (pseudoprogression). B, Axial contrast-enhanced T1-weighted and corresponding rCBV map images in a 60-year-old patient with a previously resected GBM show an enhancing lesion (white ROI) close to the margin of the radiation field. The DSC perfusion of the enhancing lesion in the surgical bed shows increased rCBV (2.8) in comparison with normal contralateral white matter (green ROI), indicating predominance of malignant cells within the lesion (progressive disease).

Fig 9.

DCE perfusion in pseudoprogression and progressive disease. A, Axial contrast-enhanced T1-weighted image and the corresponding permeability curve show an enhancing lesion that developed after radiation therapy and temozolomide in a 46-year-old patient with multicentric GBM (same patient as presented previously). The DCE perfusion of the temporal lesion (green ROI, 4) shows slowly progressive accumulation of gadolinium in the extravascular space, as shown in the graphic (green curve, 4), which is consistent with predominance of radiation injury within the lesion (pseudoprogression). The ROIs in the vessel (purple ROI, 5) and in normal white matter (purple ROI, 6) are obtained for comparison. B, Axial contrast-enhanced T1-weighted imaging and the corresponding permeability curve show an enhancing lesion in a 65-year-old patient with a previously resected GBM, who developed an enhancing lesion in the surgical bed (green ROI, 5) after radiation therapy and temozolomide. DCE perfusion shows a fast ascension curve, which implies a highly vascular lesion (green curve, 5), indicating predominance of malignant cells within the lesion (progressive disease).

Fig 10.

Characteristic findings of progressive disease and pseudoprogression on MR spectroscopy. A, A 54-year-old man presented with a ring-enhancing lesion in the left insula (not shown) distant from the radiation field after treatment of a right frontal lobe GBM. MR imaging spectroscopy shows marked elevation of the choline/NAA ratio (2.5), indicating high cellular turnover and diminished neuronal viability, typical for a malignant tumor and indicating progressive disease. B, A previously presented case of a 56-year-old man with pseudoprogression after treatment of a GBM in the left parietal lobe (Fig 5). MR imaging spectroscopy also shows elevation of choline/NAA ratio, but only slightly lower than that in the previous case (2.2 versus 2.5), which exemplifies the findings overlap between pseudoprogression and progressive disease on spectroscopy. The lipid/lactate peak is markedly elevated in patients with pseudoprogression but is also commonly present in GBM recurrence.

Fig 11.

Typical features of pseudoprogression and progressive disease on diffusion-weighted imaging. A, Axial contrast-enhanced T1-weighted image from a previously presented case of a patient with pseudoprogression (Fig 5) after treatment of a GBM in the left parietal lobe shows an enhancing lesion with irregular margins in the surgical bed (arrows). Despite an axial DWI (B) and ADC map (C) showing a punctate focus of restricted diffusion in the lesion (arrowhead), with ADC = 0.9 × 10⁻⁶ mm²/s, most of the enhancing lesion has no corresponding restricted diffusion, exhibiting ADC levels around 1.5–1.7 × 10⁻⁶ mm²/s, which is consistent with radiation injury. D, Axial contrast enhanced T1-weighted image shows a heterogeneously enhancing lesion in the right temporal lobe (arrowhead) in a patient with a resected GBM. Axial DWI (E) and an ADC map (F) show moderately restricted diffusion, with ADC values ranging from 1.0–1.1 × 10⁻⁶ mm²/s, consistent with predominance of malignant cells within the lesion (progressive disease). The ADC measurements were obtained by drawing a circular ROI in the visually lowest ADC areas on the ADC map.

Fig 12.

DWI changes after anti-VEGF agent administration in patients with GBM. Axial DWI (A) and an ADC map (B) show markedly restricted diffusion (lowest ADC = 0.5 × 10⁻⁶ mm²/s) in the right periventricular white matter (arrowheads), soon after bevacizumab was started in a patient with recurrent GBM. C, Axial contrast-enhanced T1-weighted image shows only thin rim enhancement in the area of restricted diffusion (asterisk). Those findings most likely represent ischemic changes within the tumor and should not be confused with progressive disease. The ADC measurements were obtained by drawing a circular ROI in the visually lowest ADC areas on the ADC map.