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Imaging modalities in high-grade gliomas: Pseudoprogression, recurrence, or necrosis?
Journal of Clinical Neuroscience 19 (2012) 633–637
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Imaging modalities in high-grade gliomas: Pseudoprogression, recurrence, or necrosis? I. Caroline, M.A. Rosenthal ⇑ Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia Department of Medicine, University of Melbourne, Victoria, Australia
a r t i c l e
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Article history: Received 13 July 2011 Accepted 18 October 2011
Keywords: High-grade glioma Necrosis Pseudoprogression Recurrence
a b s t r a c t 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. Ó 2011 Elsevier Ltd. All rights reserved.
1. 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 ⇑ Corresponding author. Tel.: +61 3 93477508. E-mail address: [email protected] (M.A. Rosenthal). 0967-5868/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.10.003
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
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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. 2. Methods 2.1. 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.
determining the value of diagnostic methods. Studies regarding low-grade gliomas, treatment protocols, case reports, comments, letters, and articles with abstracts only were excluded. 3. 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 (Tables 2–5). 3.1. MRI A conventional Gd-MRI shows recurrent HGG as an enhancing lesion with mass effect and edema.11 Two papers reported that conventional MRI was more sensitive (66.7% and 93.5%) than specific (63.9% and 50%) in differentiating recurrent HGG from RN.12–14. Recurrent HGG have a higher rCBV compared to RN on a perfusion MRI scan.15,16 Perfusion MRI provided better specificity (90–100%) than sensitivity (50–91.7%) in differentiating recurrent HGG from RN.17–19 The increased cellular density associated with recurrent HGG leads to decreased water mobility with low ADC on diffusionweighted imaging (DWI).20 Diffusion tensor imaging (DTI) provides additional information to DWI.21 DWI and DTI have been reported to have similar accuracy (86.7% and 85.7%) in detecting recurrent disease.22,23 High Cho on MR spectroscopy suggests recurrence, while low Cho with a lipid or lactate peak indicates RN.24 MR spectroscopy was demonstrated to be more sensitive (89–100%) when performed months after radiotherapy and more specific (100%) in weeks after treatment.24–26
2.2. Inclusion and exclusion criteria 3.2. PET 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 allowed comparison of the use of previous and current imaging tools in differential diagnosis of HGG. Only articles with statistical analyses were included, as statistical measures such as sensitivity and specificity are important in
Recurrent tumors are associated with hypermetabolism that displays increased radiotracer uptake in PET scan. Chao et al. reported that 18F-FDG was 75% sensitive and 81% specific in differentiating recurrence from RN.27 Two studies compared the use of 18 F-FDG and 11carbon-methionine (11C-MET) and concluded that
Table 1 Characteristics of pseudoprogression (PP), recurrence and necrosis (RN) in patients with high-grade glioma2–10 Time after treatment Imaging
Histopathology
MRI Enhancement Perfusion (rCBV) Diffusion (ADC) Spectroscopy Cho Cho/NAA,Cho/Cr Lactate, lipid PET (18F-FDG) (11C-MET) SPECT (201Thallium) (123I-IMT) Necrotic foci Blood vessels Mitotic figures
PP 2–3 mo
Recurrence 2 mo to 5 yrs
RN 3 mo to 20 yrs
" N/A N/A
" " ;
" ; "
N/A N/A N/A
" " ;
; ; "
; N/A
" "
; ;
N/A N/A
" "
; ;
Amorphous Hyalinised
Hypercellular edges Endothelial hyperplasia +
Hypocellular edges Hyalinised, telangiectatic, angionecrotic
= less pronounced. + = more pronounced, 11C-MET = 11C-methionine, 123I-IMT = Iodine-123-alpha-methyl-tyrosine, 18F-FDG = 18fluorine-fluorodeoxyglucose, ADC = apparent diffusion coefficient, Cho = choline, Cr = creatine, mo = months, N/A = not available, NAA = N-acetylaspartate, PD = progression disease, PET = positron emission tomography, PP = pseudoprogression, rCBV = regional cerebral blood volume, RN = radionecrosis, SPECT = single photon emission CT, yrs = years.
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I. Caroline, M.A. Rosenthal / Journal of Clinical Neuroscience 19 (2012) 633–637 Table 2 MRI imaging modalities used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma MRI
Conventional
Perfusion
DWI DTI Spectroscopy
References
Study design
Mullins et al.12 Rachinger et al.13 Ekinci et al.14 Sugahara et al.17 Hu et al.18 Bisdas et al.19 Matsusue et al.22 Xu et al.23 Matsusue et al.22 Plotkin et al.24 Zeng et al.25 Nakajima et al.27
R R R P P R R P R P P R
No. patients
Scanning time *
Total
HGG
Path
27 45 50 20 13 34 21 35 21 25 28 18
23 44 39 12 13 15 6 31 6 19 28 14
15 32 20 6 13 – 3 23 3 – 21 14
6 months after radiotherapy 3 months after radiotherapy 24 hours after surgery 2 months after radiotherapy 24 hours after surgery 3 months follow-up 6 months follow-up 6 months after radiotherapy 6 months follow-up 6 months follow-up 6 weeks after radiotherapy 8–28 months after radiotherapy
Statistical measures (%) Sn
Sp
PPV
NPV
Accy
66.7 93.5 91 50 91.7 77.8 – 85 – 89 94.1 100
63.9 50 100 90 100 94.4 – 86.7 – 83 100 88.9
69.8 – 100 – – – – 89.5 – – – –
60.5 – 93.75 – – – – 81.3 – – – –
65.4 – – – 95.9 – 86.7 85.7 84.6 88 96.2 –
Accy = accuracy, DTI = diffusion tensor imaging, DWI = diffusion-weighted imaging, HGG = high-grade glioma, NPV = negative predictive value, P = prospective, PPV = positive predictive value, R = retrospective, Sn = sensitivity, Sp = specificity. Path = total number of patients with pathological confirmation.
*
Table 3 PET used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma PET
18
F-FDG
11
C-MET
18
F-FET
18
F-FDOPA
13
N-NH3 F-FLT
18
References
Study design
Chao et al.27 Van Laere et al.28 Van Laere et al.28 Terakawa et al.29 Tsuyuguchi et al.30 Rachinger et al.13 Pöpperl et al.31 Chen et al.32 Ledezma et al.33 Xiangsong et al.34 Chen et al.35
R R R R R R R P R P P
No of patients
Scanning Time
Statistical measures (%)
*
Total
HGG
Path
47 30 30 77 11 45 53 81 91 42 25
13 16 16 20 11 44 43 57 58 15 21
18 5 5 46 8 32 26 60 21 – 14
1–39 months after radiosurgery 1–18 years after primary diagnosis 1–18 years after primary diagnosis Mean: 36 months after radiotherapy 3–19 months after radiosurgery 3 months after radiotherapy 4–180 months after treatment – 3–24 months after surgery 1 week follow-up –
Sn
Sp
PPV
NPV
Accy
75 95 75 75 60 100 100 98 95.2 – 100
81 50 70 75 82 92.9 100 86 – 100 100
– – – 75 – – – 95 – – –
– – – 75 – – – 95 – – –
– 80 73 – 100 – – – – – –
11
C-MET = 11carbon-methionine, 13N-NH3 = 13nitrogenN-ammonia, 18F-FDG = 18fluorine-18 fluorodeoxyglucose, 18F-FDOPA = 18F-labeled amino acid 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine, 18F-FET = O-(2-[18F]fluoroethyl)-L-tyrosine, 18F-FLT = 30 -deoxy-30 -18F-fluorothymidine, Accy = accuracy, HGG = high-grade glioma, NPV = negative predictive value, P = prospective, PET = positron emission tomography, PPV = positive predictive value, R = retrospective, Sn = sensitivity, Sp = specificity. * Path = total number of patients with pathological confirmation.
Table 4 SPECT used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma SPECT
201
Tl
99m 99m
123
Tc-GHA Tc-MIBI
I-IMT
References
Study design
Tie et al.36 Gomez-Rio et al.37 Caresia et al.38 Barai et al.39 Yamamoto et al.40 Le Jeune et al.41 Plotkin et al.24
R P R P P R P
No. of patients
Scanning time
Total
HG
Path*
19 76 36 73 21 81 25
19 44 19 38 11 44 19
9 23 – – – 14 –
Statistical Measures (%)
1–204 months after radiotherapy – – 4–60 months after radiotherapy 2–120 months after radiotherapy 4–6 months follow-up 6 months follow-up
Sn
Sp
PPV
NPV
Accy
84 94 100 98 93 89 95
100 100 100 81 83 83 100
100 – – 92.7 – – –
57 – – 94.4 – – –
86 – – 93 90 87 96
123
I-IMT = 123iodine-alpha-methyl-tyrosine, 201Tl = 201thallium, 99mTc-GHA = 99mtechnetium-glucoheptonate acid, 99mTc-MIBI = 99mTc-hexakis-2-methoxyisobutylisonitrile, Accy = accuracy, HGG = high-grade glioma, NPV = negative predictive value, P = prospective, PPV = positive predictive value, R = retrospective, Sn = sensitivity, Sp = specificity, SPECT = single photon emission CT. * Path = total number of patients with pathological confirmation.
Table 5 Combination of imaging modalities used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma Modalities
18
F-FDG PET and MRI 201 Tl-SPECT and MRI 18 F-FDG PET and 11C MET PET 11
References
Gomez-Rio et al.37 Gomez-Rio et al.37 Van Laere et al.28
Study design
P P R
No of patients
Scanning time
Total
HGG
Path*
76 76 30
44 44 16
23 23 5
– – 1–18 years after primary diagnosis
Statistical measures (%) Sn
Sp
Accy
83 97 95
100 100 60
– – 83
C-MET = 11carbon-methionine, 18F-FDG = 18fluorine-fluorodeoxyglucose, 201Tl = 201thallium, Accy = accuracy, HGG = high-grade glioma, PET = positron emission tomography, Sn = sensitivity, Sp = specificity, SPECT = single photon emission tomography. * Path = total number of patients with pathological confirmation.
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both radiotracers were more sensitive (95% and 75%) than specific (50% and 70%) in detecting recurrence.28,29 11 C-MET has an advantage of not being accumulated in inflammatory necrosis, unlike 18F-FDG.26 Tsuyuguchi et al. showed that 11 C-MET was 100% accurate in detecting recurrence.30 Similarly, O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) is reported to have 100% sensitivity in distinguishing recurrence from necrosis.31 The use of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) was sensitive (95.2% and 98%) for recurrence detection.32,33 Other radiotracers such as 13nitrogen-ammonia (13N-NH3) and 30 deoxy-30 -18F-fluorothymidine (18F-FLT) provided 100% specificity in identifying recurrence.34,35 3.3. SPECT Low radiotracer uptake on a SPECT scan indicates the absence of tumor growth.36 201Thallium (201Tl) provided 100% specificity and variable sensitivity (84–100%) in differentiating RN from recurrence.36–38 The use of 99mtechnetium (99mTc)-glucoheptonic acid and 123iodine-(123I) alpha-methyl-tyrosine had similar accuracy (93% and 96%) in detecting recurrence.39 Another tracer, 99mTchexakis-2-methoxyisobutylisonitrile, is reported to provide better sensitivity (93% and 89%) than specificity (83% and 83%) for identifying recurrence.40,41 Thallium is superior to other tracers because there is no tracer uptake in a healthy brain. However, low energy photon emission and spatial resolution limit the administration dose.42 Technetium provides better tumor delineation and higher energy photon, but intense uptake in choroid plexus, temporalis and extraocular muscles may interfere with image interpretation.43
HGG attempting to distinguish between PP, RN and PD. We formally reviewed 26 articles from a 10-year period that addressed this question. Based on the results represented, MRI scan, especially conventional MRI and MR spectroscopy, were more sensitive in differentiating PD from RN. PET tracers are not cerebral specific, yet 18F-PET (18F-FDG, 18F-FET, 18F-FDOPA, and 18F-FLT) has been reported to be sensitive in the differentiation of PD and RN. However, SPECT scan, particularly 201Tl-SPECT, was more specific in the detection of tumour recurrence. There was little information available regarding the diagnosis of PP. The current imaging modality used to identify PP, beside conventional MRI, is 18F-FDG PET, the most widely available PET tracer. Further analysis is needed and comparison studies of MRI, PET and SPECT are needed. A combination of imaging, laboratory, and clinical evaluation remains the standard protocol for followup in patients with HGG. The limitations of this review include the retrospective study design, small sample size, and lack of pathological confirmation in many included studies. There were no prospective studies examining the correlation between radiological diagnosis and histopathology. A large prospective study with pathological correlates is essential.
Acknowledgement I would like to express my gratitude to Dr Constance Ellwood and Dr Justin Bilszta for feedback.
References 3.4. Combination of MRI, PET and SPECT 201
The use of combined Tl-SPECT and MRI was more sensitive compared to 18F-FDG PET and MRI (97% versus 83% sensitivity) for detecting recurrence.37 A combination of 18F-FDG and 11CMET PET provided better accuracy (83% accuracy) than the use of 18 F-FDG PET (80% accuracy) or 11C-MET PET (73% accuracy) alone in the assessment of recurrence.28 4. 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 been particularly noted following the introduction of the European Organisation for Research and Treatment of Cancer (EORTC) protocol that includes concurrent irradiation with chemotherapy (temozolomide). The difficulty associated with distinguishing PP and RN from recurrence is well established and the clinical implications may be profound. Many patients may be asymptomatic and yet have significant Gd-MRI changes on routine scanning. If the cause of the radiological changes is RN or PP, then no anti-cancer therapy is indicated and the prognosis may be excellent. Indeed, PP may be associated with an improved long-term outcome. In contrast, recurrent tumour requires anti-cancer therapy and augurs poorly for the patient. This retrospective review researched over 6000 articles seeking papers specifically addressing the issue of imaging diagnosis in
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Imaging modalities in high-grade gliomas: Pseudoprogression, recurrence, or necrosis? I. Caroline, M.A. Rosenthal ⇑ Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia Department of Medicine, University of Melbourne, Victoria, Australia
a r t i c l e
i n f o
Article history: Received 13 July 2011 Accepted 18 October 2011
Keywords: High-grade glioma Necrosis Pseudoprogression Recurrence
a b s t r a c t 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. Ó 2011 Elsevier Ltd. All rights reserved.
1. 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 ⇑ Corresponding author. Tel.: +61 3 93477508. E-mail address: [email protected] (M.A. Rosenthal). 0967-5868/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.10.003
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
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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. 2. Methods 2.1. 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.
determining the value of diagnostic methods. Studies regarding low-grade gliomas, treatment protocols, case reports, comments, letters, and articles with abstracts only were excluded. 3. 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 (Tables 2–5). 3.1. MRI A conventional Gd-MRI shows recurrent HGG as an enhancing lesion with mass effect and edema.11 Two papers reported that conventional MRI was more sensitive (66.7% and 93.5%) than specific (63.9% and 50%) in differentiating recurrent HGG from RN.12–14. Recurrent HGG have a higher rCBV compared to RN on a perfusion MRI scan.15,16 Perfusion MRI provided better specificity (90–100%) than sensitivity (50–91.7%) in differentiating recurrent HGG from RN.17–19 The increased cellular density associated with recurrent HGG leads to decreased water mobility with low ADC on diffusionweighted imaging (DWI).20 Diffusion tensor imaging (DTI) provides additional information to DWI.21 DWI and DTI have been reported to have similar accuracy (86.7% and 85.7%) in detecting recurrent disease.22,23 High Cho on MR spectroscopy suggests recurrence, while low Cho with a lipid or lactate peak indicates RN.24 MR spectroscopy was demonstrated to be more sensitive (89–100%) when performed months after radiotherapy and more specific (100%) in weeks after treatment.24–26
2.2. Inclusion and exclusion criteria 3.2. PET 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 allowed comparison of the use of previous and current imaging tools in differential diagnosis of HGG. Only articles with statistical analyses were included, as statistical measures such as sensitivity and specificity are important in
Recurrent tumors are associated with hypermetabolism that displays increased radiotracer uptake in PET scan. Chao et al. reported that 18F-FDG was 75% sensitive and 81% specific in differentiating recurrence from RN.27 Two studies compared the use of 18 F-FDG and 11carbon-methionine (11C-MET) and concluded that
Table 1 Characteristics of pseudoprogression (PP), recurrence and necrosis (RN) in patients with high-grade glioma2–10 Time after treatment Imaging
Histopathology
MRI Enhancement Perfusion (rCBV) Diffusion (ADC) Spectroscopy Cho Cho/NAA,Cho/Cr Lactate, lipid PET (18F-FDG) (11C-MET) SPECT (201Thallium) (123I-IMT) Necrotic foci Blood vessels Mitotic figures
PP 2–3 mo
Recurrence 2 mo to 5 yrs
RN 3 mo to 20 yrs
" N/A N/A
" " ;
" ; "
N/A N/A N/A
" " ;
; ; "
; N/A
" "
; ;
N/A N/A
" "
; ;
Amorphous Hyalinised
Hypercellular edges Endothelial hyperplasia +
Hypocellular edges Hyalinised, telangiectatic, angionecrotic
= less pronounced. + = more pronounced, 11C-MET = 11C-methionine, 123I-IMT = Iodine-123-alpha-methyl-tyrosine, 18F-FDG = 18fluorine-fluorodeoxyglucose, ADC = apparent diffusion coefficient, Cho = choline, Cr = creatine, mo = months, N/A = not available, NAA = N-acetylaspartate, PD = progression disease, PET = positron emission tomography, PP = pseudoprogression, rCBV = regional cerebral blood volume, RN = radionecrosis, SPECT = single photon emission CT, yrs = years.
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I. Caroline, M.A. Rosenthal / Journal of Clinical Neuroscience 19 (2012) 633–637 Table 2 MRI imaging modalities used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma MRI
Conventional
Perfusion
DWI DTI Spectroscopy
References
Study design
Mullins et al.12 Rachinger et al.13 Ekinci et al.14 Sugahara et al.17 Hu et al.18 Bisdas et al.19 Matsusue et al.22 Xu et al.23 Matsusue et al.22 Plotkin et al.24 Zeng et al.25 Nakajima et al.27
R R R P P R R P R P P R
No. patients
Scanning time *
Total
HGG
Path
27 45 50 20 13 34 21 35 21 25 28 18
23 44 39 12 13 15 6 31 6 19 28 14
15 32 20 6 13 – 3 23 3 – 21 14
6 months after radiotherapy 3 months after radiotherapy 24 hours after surgery 2 months after radiotherapy 24 hours after surgery 3 months follow-up 6 months follow-up 6 months after radiotherapy 6 months follow-up 6 months follow-up 6 weeks after radiotherapy 8–28 months after radiotherapy
Statistical measures (%) Sn
Sp
PPV
NPV
Accy
66.7 93.5 91 50 91.7 77.8 – 85 – 89 94.1 100
63.9 50 100 90 100 94.4 – 86.7 – 83 100 88.9
69.8 – 100 – – – – 89.5 – – – –
60.5 – 93.75 – – – – 81.3 – – – –
65.4 – – – 95.9 – 86.7 85.7 84.6 88 96.2 –
Accy = accuracy, DTI = diffusion tensor imaging, DWI = diffusion-weighted imaging, HGG = high-grade glioma, NPV = negative predictive value, P = prospective, PPV = positive predictive value, R = retrospective, Sn = sensitivity, Sp = specificity. Path = total number of patients with pathological confirmation.
*
Table 3 PET used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma PET
18
F-FDG
11
C-MET
18
F-FET
18
F-FDOPA
13
N-NH3 F-FLT
18
References
Study design
Chao et al.27 Van Laere et al.28 Van Laere et al.28 Terakawa et al.29 Tsuyuguchi et al.30 Rachinger et al.13 Pöpperl et al.31 Chen et al.32 Ledezma et al.33 Xiangsong et al.34 Chen et al.35
R R R R R R R P R P P
No of patients
Scanning Time
Statistical measures (%)
*
Total
HGG
Path
47 30 30 77 11 45 53 81 91 42 25
13 16 16 20 11 44 43 57 58 15 21
18 5 5 46 8 32 26 60 21 – 14
1–39 months after radiosurgery 1–18 years after primary diagnosis 1–18 years after primary diagnosis Mean: 36 months after radiotherapy 3–19 months after radiosurgery 3 months after radiotherapy 4–180 months after treatment – 3–24 months after surgery 1 week follow-up –
Sn
Sp
PPV
NPV
Accy
75 95 75 75 60 100 100 98 95.2 – 100
81 50 70 75 82 92.9 100 86 – 100 100
– – – 75 – – – 95 – – –
– – – 75 – – – 95 – – –
– 80 73 – 100 – – – – – –
11
C-MET = 11carbon-methionine, 13N-NH3 = 13nitrogenN-ammonia, 18F-FDG = 18fluorine-18 fluorodeoxyglucose, 18F-FDOPA = 18F-labeled amino acid 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine, 18F-FET = O-(2-[18F]fluoroethyl)-L-tyrosine, 18F-FLT = 30 -deoxy-30 -18F-fluorothymidine, Accy = accuracy, HGG = high-grade glioma, NPV = negative predictive value, P = prospective, PET = positron emission tomography, PPV = positive predictive value, R = retrospective, Sn = sensitivity, Sp = specificity. * Path = total number of patients with pathological confirmation.
Table 4 SPECT used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma SPECT
201
Tl
99m 99m
123
Tc-GHA Tc-MIBI
I-IMT
References
Study design
Tie et al.36 Gomez-Rio et al.37 Caresia et al.38 Barai et al.39 Yamamoto et al.40 Le Jeune et al.41 Plotkin et al.24
R P R P P R P
No. of patients
Scanning time
Total
HG
Path*
19 76 36 73 21 81 25
19 44 19 38 11 44 19
9 23 – – – 14 –
Statistical Measures (%)
1–204 months after radiotherapy – – 4–60 months after radiotherapy 2–120 months after radiotherapy 4–6 months follow-up 6 months follow-up
Sn
Sp
PPV
NPV
Accy
84 94 100 98 93 89 95
100 100 100 81 83 83 100
100 – – 92.7 – – –
57 – – 94.4 – – –
86 – – 93 90 87 96
123
I-IMT = 123iodine-alpha-methyl-tyrosine, 201Tl = 201thallium, 99mTc-GHA = 99mtechnetium-glucoheptonate acid, 99mTc-MIBI = 99mTc-hexakis-2-methoxyisobutylisonitrile, Accy = accuracy, HGG = high-grade glioma, NPV = negative predictive value, P = prospective, PPV = positive predictive value, R = retrospective, Sn = sensitivity, Sp = specificity, SPECT = single photon emission CT. * Path = total number of patients with pathological confirmation.
Table 5 Combination of imaging modalities used to differentiate tumor recurrence and radiation necrosis in patients with high-grade glioma Modalities
18
F-FDG PET and MRI 201 Tl-SPECT and MRI 18 F-FDG PET and 11C MET PET 11
References
Gomez-Rio et al.37 Gomez-Rio et al.37 Van Laere et al.28
Study design
P P R
No of patients
Scanning time
Total
HGG
Path*
76 76 30
44 44 16
23 23 5
– – 1–18 years after primary diagnosis
Statistical measures (%) Sn
Sp
Accy
83 97 95
100 100 60
– – 83
C-MET = 11carbon-methionine, 18F-FDG = 18fluorine-fluorodeoxyglucose, 201Tl = 201thallium, Accy = accuracy, HGG = high-grade glioma, PET = positron emission tomography, Sn = sensitivity, Sp = specificity, SPECT = single photon emission tomography. * Path = total number of patients with pathological confirmation.
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both radiotracers were more sensitive (95% and 75%) than specific (50% and 70%) in detecting recurrence.28,29 11 C-MET has an advantage of not being accumulated in inflammatory necrosis, unlike 18F-FDG.26 Tsuyuguchi et al. showed that 11 C-MET was 100% accurate in detecting recurrence.30 Similarly, O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) is reported to have 100% sensitivity in distinguishing recurrence from necrosis.31 The use of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) was sensitive (95.2% and 98%) for recurrence detection.32,33 Other radiotracers such as 13nitrogen-ammonia (13N-NH3) and 30 deoxy-30 -18F-fluorothymidine (18F-FLT) provided 100% specificity in identifying recurrence.34,35 3.3. SPECT Low radiotracer uptake on a SPECT scan indicates the absence of tumor growth.36 201Thallium (201Tl) provided 100% specificity and variable sensitivity (84–100%) in differentiating RN from recurrence.36–38 The use of 99mtechnetium (99mTc)-glucoheptonic acid and 123iodine-(123I) alpha-methyl-tyrosine had similar accuracy (93% and 96%) in detecting recurrence.39 Another tracer, 99mTchexakis-2-methoxyisobutylisonitrile, is reported to provide better sensitivity (93% and 89%) than specificity (83% and 83%) for identifying recurrence.40,41 Thallium is superior to other tracers because there is no tracer uptake in a healthy brain. However, low energy photon emission and spatial resolution limit the administration dose.42 Technetium provides better tumor delineation and higher energy photon, but intense uptake in choroid plexus, temporalis and extraocular muscles may interfere with image interpretation.43
HGG attempting to distinguish between PP, RN and PD. We formally reviewed 26 articles from a 10-year period that addressed this question. Based on the results represented, MRI scan, especially conventional MRI and MR spectroscopy, were more sensitive in differentiating PD from RN. PET tracers are not cerebral specific, yet 18F-PET (18F-FDG, 18F-FET, 18F-FDOPA, and 18F-FLT) has been reported to be sensitive in the differentiation of PD and RN. However, SPECT scan, particularly 201Tl-SPECT, was more specific in the detection of tumour recurrence. There was little information available regarding the diagnosis of PP. The current imaging modality used to identify PP, beside conventional MRI, is 18F-FDG PET, the most widely available PET tracer. Further analysis is needed and comparison studies of MRI, PET and SPECT are needed. A combination of imaging, laboratory, and clinical evaluation remains the standard protocol for followup in patients with HGG. The limitations of this review include the retrospective study design, small sample size, and lack of pathological confirmation in many included studies. There were no prospective studies examining the correlation between radiological diagnosis and histopathology. A large prospective study with pathological correlates is essential.
Acknowledgement I would like to express my gratitude to Dr Constance Ellwood and Dr Justin Bilszta for feedback.
References 3.4. Combination of MRI, PET and SPECT 201
The use of combined Tl-SPECT and MRI was more sensitive compared to 18F-FDG PET and MRI (97% versus 83% sensitivity) for detecting recurrence.37 A combination of 18F-FDG and 11CMET PET provided better accuracy (83% accuracy) than the use of 18 F-FDG PET (80% accuracy) or 11C-MET PET (73% accuracy) alone in the assessment of recurrence.28 4. 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 been particularly noted following the introduction of the European Organisation for Research and Treatment of Cancer (EORTC) protocol that includes concurrent irradiation with chemotherapy (temozolomide). The difficulty associated with distinguishing PP and RN from recurrence is well established and the clinical implications may be profound. Many patients may be asymptomatic and yet have significant Gd-MRI changes on routine scanning. If the cause of the radiological changes is RN or PP, then no anti-cancer therapy is indicated and the prognosis may be excellent. Indeed, PP may be associated with an improved long-term outcome. In contrast, recurrent tumour requires anti-cancer therapy and augurs poorly for the patient. This retrospective review researched over 6000 articles seeking papers specifically addressing the issue of imaging diagnosis in
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