Glioblastoma Pseudoprogression Differential diagnosis

Glioblastoma Pseudoprogression Differential diagnosis

The suspicious lesion may represent post-treatment radiation effects (PTRE) such as pseudoprogression, radiation necrosis or Glioblastoma recurrence 1).

A study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in de novo isocitrate dehydrogenase (IDH) wild-type GBM patients. Methods: New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date). Results: Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (OR: 2.161, P = 0.026), gross total removal (GTR) of the tumor (OR: 6.571, P < 001), located in the frontal lobe (OR: 2.561, P = 0.008), non-subventricular zone (SVZ) infringement (OR: 10.937, P < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (OR: 9.737, P < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve. Conclusion: Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging 2).

Conventional structural MRI is insufficient for distinguishing pseudoprogression from true progressive disease, and advanced imaging is needed to obtain higher levels of diagnostic certainty. Perfusion MRI is the most widely used imaging technique to diagnose pseudoprogression and has high reported diagnostic accuracy. Diagnostic performance of MR spectroscopy (MRS) appears to be somewhat higher, but MRS is less suitable for the routine and universal application in brain tumor follow-up. The combination of MRS and diffusion-weighted imaging and/or perfusion MRI seems to be particularly powerful, with diagnostic accuracy reaching up to or even greater than 90%. While diagnostic performance can be high with appropriate implementation and interpretation, even a combination of techniques, however, does not provide 100% accuracy. It should also be noted that most studies to date are small, heterogeneous, and retrospective in nature. Future improvements in diagnostic accuracy can be expected with harmonization of acquisition and postprocessing, quantitative MRI and computer-aided diagnostic technology, and meticulous evaluation with clinical and pathological data 3).

The key features pseudoprogression will demonstrate include:

Magnetic resonance perfusion imaging: reduced cerebral blood volume (viable tumor will usually have increased rCBV)

Proton magnetic resonance spectroscopic imaging

low choline

ratio Cho/NAA ratio ≤1.4

increased lactate peak

increased lipid peak

the trace may also be generally flat (hypometabolic)

Apparent diffusion coefficient

tumors that respond to treatment and result in pseudoprogression will have elevated ADC values due to cell death ADC mean values ≥1300 x 10-6 mm2/s 8

Moassefi et al. reported the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice 4).

Incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression 5).

see Glioblastoma progression.


Parvez K, Parvez A, Zadeh G. The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence. Int J Mol Sci. 2014 Jul 3;15(7):11832-46. doi: 10.3390/ijms150711832. PMID: 24995696; PMCID: PMC4139817.

Li M, Ren X, Dong G, Wang J, Jiang H, Yang C, Zhao X, Zhu Q, Cui Y, Yu K, Lin S. Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features. Front Oncol. 2021 Apr 20;11:627325. doi: 10.3389/fonc.2021.627325. Erratum in: Front Oncol. 2021 May 19;11:700599. PMID: 33959496; PMCID: PMC8093388.

Thust SC, van den Bent MJ, Smits M. Pseudoprogression of brain tumors. J Magn Reson Imaging. 2018 May 7;48(3):571–89. doi: 10.1002/jmri.26171. Epub ahead of print. PMID: 29734497; PMCID: PMC6175399.

Moassefi M, Faghani S, Conte GM, Kowalchuk RO, Vahdati S, Crompton DJ, Perez-Vega C, Cabreja RAD, Vora SA, Quiñones-Hinojosa A, Parney IF, Trifiletti DM, Erickson BJ. A deep learning model for discriminating true progression from pseudoprogression in glioblastoma patients. J Neurooncol. 2022 Jul 19. doi: 10.1007/s11060-022-04080-x. Epub ahead of print. PMID: 35852738.

Lee J, Wang N, Turk S, Mohammed S, Lobo R, Kim J, Liao E, Camelo-Piragua S, Kim M, Junck L, Bapuraj J, Srinivasan A, Rao A. Discriminating pseudoprogression and true progression in diffuse infiltrating glioma using multi-parametric MRI data through deep learning. Sci Rep. 2020 Nov 23;10(1):20331. doi: 10.1038/s41598-020-77389-0. PMID: 33230285; PMCID: PMC7683728.

Dysembryoplastic neuroepithelial tumor differential diagnosis

Dysembryoplastic neuroepithelial tumor differential diagnosis

The differential diagnosis of DNET includes oligodendrogliomas, low-grade gliomas, gangliogliomas and pleomorphic xanthoastrocytomas (PXA). Clinical features, imaging findings, and histologic findings are key in making the diagnosis

Low-grade epilepsy-associated neuroepithelial tumors (LEATs) create a diagnostic challenge in daily practice and intraoperative pathological consultation (IC) in particular.

Specific DNT is a homogeneous group of tumours sharing characteristics of pediatric low-grade gliomas: a quiet genome with a recurrent genomic alteration in the RASMAPKsignalling pathway, a distinct DNA methylation profile, a good prognosis but showing progression in some cases. The “non-specific/diffuse DNTs” subgroup encompasses various recently described histo-molecular entities, such as PLNTY and Diffuse astrocytoma MYB or MYBL1 altered 1).

Intraoperative squash smear cytology are extremely useful for accurate diagnosis; however, the knowledge of cytopathologic features of LEATs is based on individual case reports. Kurtulan et al. discuss the 3 most common and well-established entities of LEATs: ganglioglioma (GG), dysembryoplastic neuroepithelial tumor (DNT), and papillary glioneuronal tumor (PGNT).

Thirty patients who underwent surgery for GG, DNT, and PGNT between 2001 and 2021 were collected. Squash smears prepared during intraoperative consultation were reviewed by 1 cytopathologist and an experienced neuropathologist.

Among the 30 tumors, 16 (53.3%) were GG, 11 (36.6%) DNT, and 3 (10%) PGNT. Cytomorphologically, all of the 3 tumor types share 2 common features such as dual cell population and vasculocentric pattern. GG smears were characteristically composed of dysplastic ganglion cells and piloid-like astrocytes on a complex architectural background of thin- to thick-walled vessels. DNT, on the other hand, showed oligodendroglial-like cells in a myxoid thin fibrillary background associated with a delicate capillary network. Common cytological features of PGNT were hyperchromatic cells with narrow cytoplasm surrounding hyalinized vessels forming a pseudopapillary pattern and bland cells with neuroendocrine nuclei dispersed in a neuropil background.

A higher diagnostic accuracy can be obtained when squash smears are applied with frozen sections. However, it is important to integrate clinical and radiologic features of the patient as well as to know the cytopathologic features of the LEAT spectrum in the context of differential diagnosis to prevent misinterpretation in the IC 2).

A 29-year-old male from Bolivia, who lived in Spain, presented seizures and a multicystic brain lesion, initially suspected to be a dysembryoplastic neuroepithelial tumor (DNET). He underwent gross total resection of the mixed solid/cystic lesion. Pathology revealed gliosis, multiple interconnected cystic cavities with fibrous walls, inflammatory cell infiltration and no necrotizing granulomatous reaction. Inside the cavities, a parasitic form was identified as the larva of the cestode Spirometra mansoni. At 1-year follow-up, the patient had no deficits and was seizure free. Clinicians should be alerted to the possible existence of this rare entity in Europe, especially in patients from endemic areas with a possible infection history as well as “wandering lesions” on the MRI 3).

14-year-old woman admitted due to a right temporal lobe tumor.

She was transferred from other Hospital after finding a right temporal lesion on MRI in the context of seizures.

Unprovoked focal seizure. Paroxysmal episodes of blank stare, unresponsiveness, Orofacial Dyskinesia, Guttural sounds, and hypersalivation lasting approximately 30 seconds. Transient global amnesia. He refers to a similar episode a month ago.

Cranial magnetic resonance imaging without and with intravenous contrast (8ml gadovist) was performed with the usual protocol: sagittal T1 TSE, axial T2 TSE, coronal T2 TSE, axial T2 FLAIR, axial T2 EG and axial diffusion.

A signal alteration centered on the anterior pole of the right temporal lobe of approx. 2.2×2.7×1.7cm (TxAPxCC) associates diffuse cortical thickening and the presence of a heterogeneous lesion with a solid and microcystic component that is hypointense in the T1 sequences and hyperintense in the T2 sequences, it also presents a hyperintensity of the peritumoral signal and an increase in diffusion in DWI sequences without presenting signal drop in the ADC. The perfusion sequences did not show an increase in cerebral perfusion at this level with ADC: 1.3. This lesion presents a heterogeneous contrast uptake, drawing attention to the presence of a solid pole adjacent to the dura that presents intense enhancement, but does not present dural enhancement. These findings may be related to a dysembryogenic neuroepithelial tumor (DNET) or to a Ganglioglioma as the main differential diagnoses. No microbleeds were seen in the gradient echo T2 sequence or calcifications. The rest of the cerebral, cerebellar and brainstem parenchyma show no morphological or signal alterations. Middle line centered. Free basal and perimesencephalic cisterns. Centered ventricular system with preserved ventricular size. The main arterial and intracranial venous vessels show a caliber and signal void within normality. Unoccupied paranasal sinuses and mastoid cells. Slight descent of the cerebellar tonsils not significant (2 mm).

Diagnostic impression:

Heterogeneous lesion centered on the anterior temporal pole of the right temporal lobe with a solid / cystic component and enhancement after contrast administration, with tumor characteristics suggesting a Dysembryoplastic neuroepithelial tumor (DNET) or a ganglioglioma as the main differential diagnoses.


Pagès M, Debily MA, Fina F, Jones DTW, Saffroy R, Castel D, Blauwblomme T, Métais A, Bourgeois M, Lechapt-Zalcman E, Tauziède-Espariat A, Andreiuolo F, Chrétien F, Grill J, Boddaert N, Figarella-Branger D, Beroukhim R, Varlet P. The genomic landscape of dysembryoplastic neuroepithelial tumours and a comprehensive analysis of recurrent cases. Neuropathol Appl Neurobiol. 2022 Jul 14:e12834. doi: 10.1111/nan.12834. Epub ahead of print. PMID: 35836307.

Kurtulan O, Bilginer B, Soylemezoglu F. Challenges in the Intraoperative Consultation of Low-Grade Epilepsy-Associated Neuroepithelial Tumors by Cytomorphology in Squash Preparations. Acta Cytol. 2022 Jan 11:1-7. doi: 10.1159/000521249. Epub ahead of print. PMID: 35016169.

Lo Presti A, Aguirre DT, De Andrés P, Daoud L, Fortes J, Muñiz J. Cerebral sparganosis: case report and review of the European cases. Acta Neurochir (Wien). 2015 Sep;157(8):1339-43. doi: 10.1007/s00701-015-2466-9. Epub 2015 Jun 18. PubMed PMID: 26085111.

Positional Plagiocephaly Differential Diagnosis

Positional Plagiocephaly Differential Diagnosis

General practitioners (GPs) have an important role in assessment, diagnosis and referral for paediatric skull deformities. GPs are well placed to clinically differentiate between deformational plagiocephaly and craniosynostosis and provide timely referrals to optimise patient outcomes 1).

The child with unilateral lambdoid synostosis has a thick ridge over the fused suture, with compensatory contralateral parietal and frontal bossing 2). There is an ipsilateral occipitomastoid bulge, with a posteroinferior displacement of the ipsilateral ear. These characteristics are opposite to the findings in the children with deformational plagiocephaly. In the view from above, the shape of the head will be trapezoid in lambdoid synostosis and parallelogram in deformational plagiocephaly. A 3D CT will confirm the diagnosis. Torticollis is most commonly associated with deformational plagiocephaly. Chiari malformation can be present with lambdoid synostosis.


Lun KK, Aggarwala S, Gardner D, Hunt J, Jacobson E, Reddy R, Gianoutsos M, Rtshiladze M. Assessment of paediatric head shape and management of craniosynostosis. Aust J Gen Pract. 2022 Jan-Feb;51(1-2):51-58. doi: 10.31128/AJGP-09-20-5638. PMID: 35098275.

Huang MH, Gruss JS, Clarren SK, Mouradian WE, Cunningham ML, Roberts TS, Loeser JD, Cornell CJ. The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding. Plast Reconstr Surg. 1996 Oct;98(5):765-74; discussion 775-6. doi: 10.1097/00006534-199610000-00001. PMID: 8823012.
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