Glioblastoma Differential Diagnosis

Glioblastoma Differential Diagnosis

Tumors are classically distinguished based on biopsy of the tumor itself, as well as a radiological interpretation using diverse MRI modalities.

As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its simple definition of presence of vascular proliferation and/or necrosis in a diffuse astrocytoma, the wide variety of cytohistomorphologic appearances overlap with many other neoplastic or non-neoplastic lesions 1).

General imaging differential considerations include:

Intracranial metastases

may look identical

both may appear multifocal

metastases usually are centered on grey-white matter junction and spare the overlying cortex rCBV in the ‘edema‘ will be reduced

Primary central nervous system lymphoma should be considered especially in patients with AIDS, as in this setting central necrosis is more common otherwise usually homogeneously enhancing

Cerebral abscess central restricted diffusion is helpful, however, if GBM is hemorrhagic then the assessment may be difficult presence of smooth and complete SWI low-intensity rim presence of dual rim sign

Anaplastic astrocytoma should not have central necrosis consider histology sampling bias

Tumefactive demyelination lesion can appear similar often has an open ring pattern of enhancement usually younger patients

Subacute cerebral infarction history is essential in suggesting the diagnosis should not have elevated choline should not have elevated rCBV

Cerebral toxoplasmosis especially in patients with AIDS

In a study, Samani et al. of the overarching goal are to demonstrate that primary glioblastomas and secondary (brain metastases) malignancies can be differentiated based on the microstructure of the peritumoral region. This is achieved by exploiting the extracellular water differences between vasogenic edema and infiltrative tissue and training a convolutional neural network (CNN) on the Diffusion Tensor Imaging (DTI)-derived free water volume fraction. They obtained 85% accuracy in discriminating extracellular water differences between local patches in the peritumoral area of 66 glioblastomas and 40 metastatic patients in a cross-validation setting. On an independent test cohort consisting of 20 glioblastomas and 10 metastases, we got 93% accuracy in discriminating metastases from glioblastomas using majority voting on patches. This level of accuracy surpasses CNNs trained on other conventional DTI-based measures such as fractional anisotropy (FA) and mean diffusivity (MD), which have been used in other studies. Additionally, the CNN captures the peritumoral heterogeneity better than conventional texture features, including Gabor filter and radiomic features. The results demonstrate that the extracellular water content of the peritumoral tissue, as captured by the free water volume fraction, is best able to characterize the differences between infiltrative and vasogenic peritumoral regions, paving the way for its use in classifying and benchmarking peritumoral tissue with varying degrees of infiltration 2).


Gokden M. If it is Not a Glioblastoma, Then What is it? A Differential Diagnostic Review. Adv Anat Pathol. 2017 Nov;24(6):379-391. doi: 10.1097/PAP.0000000000000170. PMID: 28885262.

Samani ZR, Parker D, Wolf R, Hodges W, Brem S, Verma R. Distinct tumor signatures using deep learning-based characterization of the peritumoral microenvironment in glioblastomas and brain metastases. Sci Rep. 2021 Jul 14;11(1):14469. doi: 10.1038/s41598-021-93804-6. PMID: 34262079.

Cryptococcoma Differential Diagnosis

Cryptococcoma Differential Diagnosis

see also Cryptococcoma Diagnosis.

Cryptococcal meningitis is the most common type of cryptococcosis involvement. Mass-effect lesions are uncommon: they are described as cryptococcomas and their prevalence is even lower among immunocompetent patients 1).

CNS lesions can be mistaken for neoplasms, especially in the context of an immunocompetent host 2) 3).

Primary and secondary brain tumors are usually the first hypotheses in these cases. Thorough preoperative investigation through cerebrospinal fluid sampling and detailed magnetic resonance imaging may lead to consideration of this diagnosis before the histopathologic analysis has been conducted 4)

The aim of a study was to detect and localize fungal brain lesions caused by Cryptococcus species based on Chemical Exchange Saturation Transfer (CEST) MR imaging of endogenous trehalose, and hereby to distinguish cryptococcomas from gliomas. In phantoms, trehalose and cryptococcal cells generated a concentration-dependent CEST contrast in the 0.2 – 2 ppm chemical shift range, similar to glucose, but approximately twice as strong. In vivo single voxel MRS of a murine cryptococcoma model confirmed the presence of trehalose in cryptococcomas, but mainly for lesions that were large enough compared to the size of the MRS voxel. With CEST MRI, combining the more specific CEST signal at 0.7 ppm with the higher signal-to-noise ratio signal at 4 ppm in the CryptoCEST contrast enabled localization and distinction of cryptococcomas from the normal brain and from gliomas, even for lesions smaller than 1 mm3. Thanks to the high endogenous concentration of the fungal biomarker trehalose in cryptococcal cells, the CryptoCEST contrast allowed identification of cryptococcomas with high spatial resolution and differentiation from gliomas in mice. Furthermore, the CryptoCEST contrast was tested to follow up antifungal treatment of cryptococcomas. Translation of this non-invasive method to the clinic holds potential for improving the differential diagnosis and follow-up of cryptococcal infections in the brain 5).

The aim of a study is to highlight the importance of cryptococcosis as one of the most common fungal infections of the central nervous system, stressing the consideration of a cryptococcoma within the list of differential diagnosis of intraventricular masses in immunocompetent hosts 6).

A 54-year-old man presented with two episodes of dysarthria and left facial droop. Both episodes resolved by the time of examination. MRI of the brain revealed a right frontotemporal, heterogeneously enhancing mass with surrounding vasogenic oedema, suggestive of a high-grade primary brain neoplasm. The patient was administered preoperative 5-aminolevulinic acid hydrochloride (Gliolan), and fluorescence-guided resection of the lesion was undertaken. Cryptococcus gattii infection was diagnosed from the specimen and the patient was given appropriate antifungal treatment. This is the first reported case of Gliolan-mediated fluorescence in a fungal abscess and highlights one of the potential pitfalls in fluorescence-guided surgery 7).

Cryptococcal CNS infections in immunocompetent hosts can mimic the intraventricular form of racemose neurocysticercosis. Distinguishing between the two is essential because the medical management of the 2 conditions is distinct from each other 8).

Yeh CH, Lin SF, Chiu MC, Kuo CL, Huang HT, Shoung HM. Cerebral Cryptococcoma in an HIV-Negative Patient: Experience Learned From a Case. J Neuropsychiatry Clin Neurosci. 2014 Fall;26(4):E34-5. doi: 10.1176/appi.neuropsych.13070161. PMID: 26037882.


Paiva ALC, Aguiar GB, Lovato RM, Zanetti AVD, Panagopoulos AT, Veiga JCE. Cryptococcoma mimicking a brain tumor in an immunocompetent patient: case report of an extremely rare presentation. Sao Paulo Med J. 2018 Sep-Oct;136(5):492-496. doi: 10.1590/1516-3180.2017.0046210417. Epub 2017 Nov 6. PMID: 29116307.

Ulett KB, Cockburn JW, Jeffree R, Woods ML. Cerebral cryptococcoma mimicking glioblastoma. BMJ Case Rep. 2017 Feb 10;2017:bcr2016218824. doi: 10.1136/bcr-2016-218824. PMID: 28188169; PMCID: PMC5307282.

Carol L, Tai MS, Yusoff SM, Rose N, Rafia MH, Viswanathan S. Spinal cryptoccoma mimicking a spinal cord tumor complicated by cryptococcal meningitis in an immunocompetent patient. Neurol India. 2018 Jul-Aug;66(4):1181-1183. doi: 10.4103/0028-3886.237012. PMID: 30038119.

Kelly A, Mpanza P, Lekgwara P, Otto D. Multicentric Cryptococcomas Mimicking Neoplasia in Immunocompetent Patient. World Neurosurg. 2018 Oct;118:5-8. doi: 10.1016/j.wneu.2018.06.226. Epub 2018 Jul 6. PMID: 29981908.

Vanherp L, Govaerts K, Riva M, Poelmans J, Coosemans A, Lagrou K, Gsell W, Vande Velde G, Himmelreich U. CryptoCEST: A promising tool for spatially resolved identification of fungal brain lesions and their differentiation from brain tumors with MRI. Neuroimage Clin. 2021 Jun 24;31:102737. doi: 10.1016/j.nicl.2021.102737. Epub ahead of print. PMID: 34225021.

Santander XA, Gutiérrez-González R, Cotúa C, Tejerina E, Rodríguez GB. Intraventricular cryptococcoma mimicking a neoplastic lesion in an immunocompetent patient with hydrocephalus: A case report. Surg Neurol Int. 2019 Jun 25;10:115. doi: 10.25259/SNI-104-2019. PMID: 31528451; PMCID: PMC6744787.

Solis WG, Hansen M. Fluorescence in a cryptococcoma following administration of 5-aminolevulinic acid hydrochloride (Gliolan). BMJ Case Rep. 2017 Apr 11;2017:bcr2017219469. doi: 10.1136/bcr-2017-219469. PMID: 28400397; PMCID: PMC5534904.

Mathews M, Paré L, Hasso A. Intraventricular cryptococcal cysts masquerading as racemose neurocysticercosis. Surg Neurol. 2007 Jun;67(6):647-9. doi: 10.1016/j.surneu.2006.10.049. PMID: 17512347.

Radiation necrosis differential diagnosis

Radiation necrosis differential diagnosis

Radiation necrosis (RN) may mimic recurrent (or denovo) tumor both clinically and radiographically. Differences in prognosis and treatment make it important to distinguish between tumor and RN.

Over the years many methods have been championed to differentiate radiation necrosis from recurrent high-grade glioma. None have proven adequately reliable, and this may not even be a useful exercise. Tumor cells are frequently found on biopsy. The decision whether to reoperate is usually based on whether there is progressive mass effect (regardless of whether it is necrosis or tumor), taking into consideration the patient’s neurologic condition, projected longevity, patient desires…

It is widely accepted that the capture, enumeration and identification of circulating tumor cells (CTCs) hold significant promise for early cancer screening, diagnosis and prognosis. These cells originate from primary tumors and disseminate to distant sites via the blood 1) 2) 3)

Differentiating treatment necrosis from tumor recurrence poses a diagnostic conundrum for many clinicians in neuro-oncology. To investigate the potential role of circulating tumor cells (CTCs) detection in differentiating tumor recurrence and treatment necrosis in brain gliomas, Gao et al. retrospectively analyzed the data of 22 consecutive patients with tumor totally removed and new enhancing mass lesion(s) showed on MRI after initial radiotherapy. The 22 patients were finally classified into tumor recurrence group (n = 10) and treatment necrosis group (n = 12), according to evidence from the clinical course (n = 11) and histological confirmation (n = 11). All 22 patients received CTCs detection, and DSC-MRP and 11C-MET-PET were performed on 20 patients (90.9%) and 17 patients (77.3%) respectively. The data of the diagnosis efficacy to differentiate the two lesions by CTC detection, MPR and PET were analyzed by ROC analysis. The mean CTCs counts were significantly higher in the tumor recurrence group (6.10 ± 3.28) compared to the treatment necrosis group (1.08 ± 2.54, p < 0.001). The ROC curve showed that an optimized cell count threshold of 2 had 100% sensitivity and 91.2% specificity with AUC = 0.933 to declare tumor recurrence. The diagnostic efficacy of CTC detection was superior to rCBV of DSC-MRP and rSUVmax in MET-PET. Furthermore, they observed that CTCs detection could have a potential role in predicting tumor recurrence in one patient. The research results preliminarily showed the potential value of CTC detection in differentiating treatment necrosis from tumor recurrence in brain gliomas, and is worthy of further confirmation with large samples involved 4).

Cannot reliably differentiate some cases of RN from tumor (especially astrocytoma; RN occasionally resembles glioblastoma).

Proton magnetic resonance spectroscopic imaging was reliable in distinguishing pure tumor (elevated choline) from pure RN (low choline), but was less definitive with mixed tumor/necrosis 5).

Magnetic resonance perfusion imaging, particularly Dynamic Contrast-Enhanced (DCE), help in the differential diagnosis by tumor recurrence and radiation necrosis during the follow-up after radiosurgery.

Mean ADCs were lower with recurrence (1.18 ± 0.13 X 10–3 mm/s) vs. necrosis (1.4 ± 0.17 X 10–3 mm/s) 6) (not all cases biopsy proven).

Some reports of success with thallium 201 and technetium-99 m brain scans.

PET (positron emission tomography) scan: because positron emitting isotopes have short half–lives, PET scanning requires a nearby cyclotron to generate the radiopharmaceuticals at great expense. Utilizing [18F]-fluorodeoxyglucose (FDG), regional glucose metabolism is imaged and is generally increased with recurrent tumor, and is decreased with RN. Specificity for distinguishing RN from tumor recurrence is >90 %, but sensitivity may be too low to make it reliable 7) Amino acid tracers such as [11C]methionine and [18F]tyrosine are taken up by most brain tumors 8), especially gliomas, and may also be used to help differentiate tumor from necrosis. Accuracy may be increased by fusing PET scan with MRI 9).

SPECT (single positron emission computed tomography): “poor man’s PET scan.” Uses radio- labeled amphetamine. Uptake depends on presence of intact neurons and the condition of cerebral blood vessels (including blood brain barrier). Decreased radionuclide uptake indicates necrosis, whereas tumor recurrence has no decreased uptake.

For delayed radiation injury, image analysis has considerably advanced, but neuropathological findings are still required to establish diagnosis. A patient who had received radiation therapy for pineal germinoma at age 14 developed neurological and psychiatric abnormalities after 15 years as a late delayed radiation injury. Autopsy at age 59 revealed diffuse changes in the white matter consisting in order of severity of myelin pallor, demyelination, and necrosis which were characterized by a lack of glial reaction. The cerebral cortex was relatively well preserved. As delayed radiation injuries, hyalinous changes in the vascular wall, angiomatous lesions and, fresh and old petechial hemorrhages were found. Moreover, vascular changes associated with arteriosclerosis were also present. Furthermore, a focal glial nodule was detected which was considered to be a new radiation-induced neoplasia. These findings suggest that late delayed radiation injury may slowly develop over 30 years and may involve damage to neuroglial stem cell compensation. It is also evident that arteriosclerotic changes and newly induced neoplasia may develop in delayed radiation injury cases 10).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogressionpseudoresponse, or radionecrosis.

Radiation necrosis (RN), or its imaging equivalent, treatment-related imaging changes (TRIC), is an inflammatory reaction to high-dose radiation in the brain.

Patients who receive immunotherapy (IT) alone may have an increased rate of RN/treatment-related imaging changes (TRIC) compared with those who receive chemotherapy (CT) or targeted therapy (TT) alone after stereotactic radiosurgery, whereas receiving any CT may in fact be protective against RN/TRIC. As the use of immunotherapies increases, the rate of RN/TRIC may be expected to increase compared with rates in the chemotherapy era 11).


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Pantel K., Speicher M.R. The biology of circulating tumor cells. Oncogene. 2016;35:1216–1224. doi: 10.1038/onc.2015.192.

Woo D., Yu M. Circulating tumor cells as “liquid biopsies” to understand cancer metastasis. Transl. Res. 2018;201:128–135. doi: 10.1016/j.trsl.2018.07.003

Gao F, Zhao W, Li M, Ren X, Jiang H, Cui Y, Lin S. Role of circulating tumor cell detection in differentiating tumor recurrence from treatment necrosis of brain gliomas. Biosci Trends. 2021 Apr 29. doi: 10.5582/bst.2021.01017. Epub ahead of print. PMID: 33952802.

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Hein PA, Eskey CJ, Dunn JF, Hug EB. Di usion- weighted imaging in the follow-up of treated high- grade gliomas: tumor recurrence versus radiation injury. AJNR Am J Neuroradiol. 2004; 25:201–209

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Ericson K, Lilja A, Bergstrom M, et al. Positron emis- sion tomography with ([11C]methyl)-L-methionine, [11C]D-glucose, and [68Ga]EDTA in supratentorial tumors. J Comput Assist Tomogr. 1985; 9:683–689

Thiel A, Pietrzyk U, Sturm V, et al. Enhanced Accuracy in Differential Diagnosis of Radiation Necrosis by Positron Emission Tomography-Magnetic Resonance Imaging Coregistration: Technical Case Report. Neurosurgery. 2000; 46:232–234

Tanikawa S, Kato Y, Tanino M, Terasaka S, Kurokawa Y, Arai N, Nagashima K, Tanaka S. Autopsy report of a late delayed radiation injury after a period of 45 years. Neuropathology. 2019 Jan 4. doi: 10.1111/neup.12528. [Epub ahead of print] PubMed PMID: 30609132.

Colaco RJ, Martin P, Kluger HM, Yu JB, Chiang VL. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg. 2015 Nov 6:1-7. [Epub ahead of print] PubMed PMID: 26544782.
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