Review
Imaging modalities in high-grade gliomas: Pseudoprogression, recurrence, or necrosis?

https://doi.org/10.1016/j.jocn.2011.10.003Get rights and content

Abstract

High grade gliomas (HGG) frequently recur regardless of treatment. Radiological detection of progressive disease (PD) is challenging due to the possibility of therapy-related MRI changes including: pseudoprogression (PP) and radiation necrosis (RN). Both may mimic PD. We undertook a literature review to examine existing data regarding imaging modalities and their ability to distinguish between PP, RN and PD. The review revealed 26 articles comparing the value of imaging modalities used to differentiate PP, RN and PD. Overall, conventional MRI and 18fluorine-fluorodeoxyglucose positron emission tomography (18F-FDG PET) were more sensitive, while thallium single photon emission CT (SPECT) was more specific in differentiating PD from PP and RN. However, further prospective studies comparing the clinical utility of MRI, PET, and SPECT are needed to establish the most reliable diagnostic tool for the differentiation of PP, RN and PD in HGG.

Introduction

The treatment of high grade glioma (HGG) consists of surgery, radiotherapy, and chemotherapy. In patients with glioblastoma multiforme (GBM, Grade 4) younger than 70 years of age and of good performance status, the standard of care is debulking surgery, followed by concurrent irradiation and temozolomide chemotherapy, followed by six months of temozolomide chemotherapy.1 For patients with Grade 3 tumours (anaplastic astrocytoma [AA], anaplastic oligodendroglioma [AO] and mixed AA/AO), the standard treatment is debulking surgery followed by radiotherapy. Temozolomide chemotherapy is withheld until disease recurrence.1

Despite appropriate treatment at initial diagnosis, HGG frequently recurs and the median overall survival in patients with GBM is only 14 months.1 Recurrence of disease may be manifested by features of raised intracranial pressure, seizures or focal neurological symptoms and signs. However, recurrence may also be detected on routine serial imaging without symptoms. In this group of patients in particular, the detection of recurrent tumors by serial MRI may be challenging because treatment-related changes may mimic HGG recurrence.2 These include two well-recognised entities: pseudoprogression (PP) and radiation necrosis (RN).

PP is a subacute treatment reaction associated with inflammation, edema, and increased abnormal vessel permeability.2 It is believed that PP is due to cytotoxic effects of chemotherapy and radiation.3 PP usually occurs within two to three months of treatment and, in particular, appears more frequent following concurrent chemotherapy and radiotherapy. PP lesions may decrease in size or stabilise without intervention.4 Up to 20% of patients have been observed to develop PP.5 Patients may remain asymptomatic or develop symptoms consistent with raised intracranial pressure, including headache, nausea, drowsiness, confusion and seizures.6 Focal neurological deficits are less common. In patients with PP, gadolinium contrast-MRI (Gd-MRI) scanning shows an enhancing lesion, whereas a 18fluorine-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan shows reduced glucose uptake.7 Histopathological examination includes amorphous necrotic tissue and hyalinised vessels.8

RN is a chronic radiotherapy-associated reaction resulting in disruption of the blood–brain barrier, edema and mass effect.9 It may occur anytime after treatment with irradiation commencing within months of therapy or even many years after treatment. Patients may be asymptomatic or symptomatic with symptoms of raised intracranial pressure or progressive focal neurological deficits.10 Gd-MRI scanning shows RN as an enhancing lesion. Perfusion and diffusion MRI shows low regional cerebral blood volume (rCBV) and high apparent diffusion coefficient (ADC). Magnetic resonance (MR) spectroscopy shows low choline (Cho) with a high lactate or lipid peak. Low tracer uptake on single photon emission CT (SPECT) and PET scans indicates RN.9 Histopathological features include necrotic foci with hypocellular edges and hyalinized vessels.8

Recurrent or progressive HGG may occur any time after initial diagnosis and treatment. Most patients develop recurrence within two years of treatment but a significant minority will recur many years after therapy.9 Patients may be asymptomatic, exhibit features of raised intracranial pressure or develop focal neurologic deficits. A Gd-MRI scan generally shows recurrent HGG as an enhancing lesion. Perfusion and diffusion MRI scans show high rCBV and low ADC. High Cho, low N-acetyl aspartate (NAA), and increased lactate on MR spectroscopy, as well as high tracer uptake on PET and SPECT scans suggests PD.9 Histopathological analysis demonstrates typical features of HGG including: necrotic foci with hypercellular edges, endothelial hyperplasia, and mitotic figures.8

Some clinical features may assist in distinguishing the three entities. First, chronologically, PP generally appears earlier in the post-irradiation period than RN. Second, PP also tends to be reversible without intervention, while RN may become irreversible or progressive. However, regardless of the timeline, all three clinical entities (PP, RN and PD) may appear indistinguishable as enhancing lesions on MRI (Table 1). In contrast, PET imaging shows that increased tracer uptake is more likely to represent PD while decreased uptake suggests PP or RN.

This review aims to compare imaging modalities to determine the most valuable diagnostic tool for the differentiation of PP, RN and PD in patients with HGG.

Section snippets

Search strategy

A literature search of PubMed, Medline, Scopus, and EBSCO was conducted. The Search terms used were “glioma AND (necrosis OR recurrence)” and “glioma pseudoprogression”. References provided in relevant articles were also examined. A review of bibliographies and abstracts was conducted in all articles, and relevant studies were reviewed in full.

Inclusion and exclusion criteria

Studies were included if they were published between 2000 and 2010, written in English, and involved human adult subjects. A search from 2000 to 2010

Results

Of 6455 articles retrieved, 26 fulfilled the inclusion and exclusion criteria. These articles comprised four main groups of imaging modalities used to differentiate recurrence and necrosis: MRI, PET, SPECT, and combinations of these (Table 2, Table 3, Table 4, Table 5).

Discussion

HGG are treated with combinations of surgery, radiotherapy and chemotherapy. Despite multimodality therapy, most patients eventually develop recurrent disease. Recognition of recurrence is important as it may lead to other interventions including repeat surgery, chemotherapy or other strategies. The diagnosis of recurrence may be confounded by the presence of either PP or RN.

While RN has been recognised for decades, PP has only been established as a clinical entity in the last few years. PP has

Acknowledgement

I would like to express my gratitude to Dr Constance Ellwood and Dr Justin Bilszta for feedback.

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