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Radiological and surgical aspects of polymorphous low-grade neuroepithelial tumor of the young (PLNTY)

Radiological and surgical aspects of polymorphous low-grade neuroepithelial tumor of the young... Background Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a low-grade epilepsy-associated tumor recently introduced in WHO 2021 classification. Since it has been recognized as an independent nosological entity, PLNTY has been mainly studied from a genetic and molecular perspective, not recognizing unique characteristic clinical and radiological features. Methods A systematic literature research has been conducted aiming to identify all relevant studies about the radiologi- cal, clinical and surgical features of PLNTY. We described a representative case of a 45-year-old man treated with awake- surgery with confirmed diagnosis of PLNTY, reporting the radiological and surgical characteristics through imaging and intra-operative video. We performed a statistical meta-analysis attempting to assess the presence of relationships between surgical and radiologic tumor characteristics and clinical outcome and type of surgery. Results A total of 16 studies were included in the systematic review. The final cohort was composed of 51 patients. Extent of resection (EOR) and outcome are not significantly associated with the different genetic profiling (p = 1), the presence of cystic intralesional component, calcification (p = 0.85), contrast-enhancing and lesion boundaries (p = 0.82). No significant correlation there is between EOR and remission or better control of epilepsy-related symptoms (p = 0.38). The contrast enhancement in the tumor is significantly associated with recurrence or poor control of epileptic symptoms (p = 0.07). Conclusions In PLNTYs, contrast enhancement seems to impact prognosis, recurrence, and seizure control much more than radiological features, genetic features and type of resection of the tumor. Abbreviations EOR Extent or resection PLNTY Polymorphous low-grade neuroepithe-BRAF B-Raf proto-oncogene lial tumor of the young FGFR Fibroblast growth receptor CNS-WHO Central Nervous Tumor-World Health FGFR2/FGFR3 Fibroblast growth factor receptors 2 and Organization 3 LEATs Low-grade epilepsy-associated tumors MAPK Mitogen-activated protein kinase PRISMA Preferred reporting items for systematic IDH Isocitrate dehydrogenase reviews and meta-analysis GTR Gross total resection MRI Magnetic resonance imaging Introduction Cho-NAA Choline/n-acetyl-aspartate Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a low-grade tumor comprised of infiltrating “oli- Daniele Armocida and Luigi Valentino Berra have contributed godendrocyte-like” cells [1] that stain with CD34 immuno- equally. positivity [2]. It frequently affects children and young adults, with a slightly female predominance [3]. PLNTY is a typical * Daniele Armocida low-grade epilepsy-associated tumor recently described and danielearmocida@yahoo.it introduced in Central Nervous Tumor-World Health Organi- A.U.O. “Policlinico Umberto I”, Neurosurgery Division, zation (CNS-WHO) 2021 classification [2 , 3]. Before the Sapienza University, Rome, Italy last updated classification, PLNTY it was considered to take Human Neurosciences Department, Via del Policlinico, 155, part of a group known as low-grade epilepsy-associated 00161 Rome, Italy Vol.:(0123456789) 1 3 Acta Neurologica Belgica tumors (LEATs), an umbrella of developmental tumors, with The first selection step was describing the clinical favorable clinical outcomes, with varying histologic appear- entity of PLNTY in pediatric and adult patients and its ances, associated with early-onset seizures, since other glial characteristics. tumors, such as pilocytic astrocytomas or oligodendroglio- In this regard, we chose to evaluate only the studies mas, usually had distinct diagnostic criterion that assists in focused on PLNTY only PLNTY-focused studies and papers further clinical management [1, 4]. Several distinguishing that described patients or series reported and described clini- factors of PLNTY may be implicated in its pathogenesis cally and radiologically. and clinical manifestation, the most suspicious of which are Given these premises, we selected papers according to the BRAF V600E gene mutant, increased CD34 expression, and following inclusion criteria: FGFR gene fusion products [5]. Radiologically, clinically and surgically still, very little Availability of full-text articles; is known about this rare tumor. The diagnostic challenge • English text only; most often involves distinguishing this tumor from an oligo- Patients with a diagnosis of PLNTY; dendroglioma, given, especially in adults, the morphologic • Reported details on imaging; and clinical overlap and the potential for misdiagnosis are Presence of neurological outcome evaluation. No specific significant [1 ]. Because of their rare etiology, only a few limitation was applied regarding the timing of neurologi- PLNTYs have been described to date. It is unclear how its cal evaluation after treatment. characteristics impact the pathogenesis and the outcome of the disease [6]. Clinically, Oligodendroglioma is associated Conversely, exclusion criteria were: with a lower rate of epilepsy and a worse clinical prognosis. At the same time, PLNTYs, tend to exhibit a benign (typi- Full-text articles in languages other than English; cal of WHO grade I) clinical course, and appear to be well • Studies reporting patients with the low-grade tumors; controlled by gross total resection (GTR). However, some No data available about the neurological outcome; reports describe cases of difficult therapeutic control or dis- • No imaging details were reported; ease recurrence [7–9]. PLNTYs, indeed, can be morphologically highly variable, Data extracted from each study were (1) authors, (2) year manifesting as well-circumscribed lesions, cystic lesions, or of publication, (3) number of patients included, (4) age, (5) infiltrative growth patterns. The constant element appears sex, (6) clinical debut and presentation on diagnosis, (7) to be the calcific component that is always present in the side involved, (8) major cerebral lobe involved, (9) imaging context of the lesion, leading it to be in differential diag- characteristics, (10) presence of contrast-enhancing in mag- nosis with oligodendroglioma [1]. In this review and meta- netic resonance imaging (MRI) studies, (11) major diameter analysis, we want to identify the clinical, radiological, and of tumor in MRI studies, (12) characteristics of radiologi- surgical features known about PLNTY, reporting a typical cal limits of the lesion (defined as “circumscribed” when case of misdiagnosis with adult oligodendroglioma from our limits are well-identifiable on MRI, in contrast on “blurred” experience, providing as much surgical information as pos- limits), (13) mutation identified on diagnostic molecular sible through the presentation of an intra-operative video. analysis, (14) surgical treatment indicating the extent or In addition, by reviewing the research on cases reported in resection (EOR), (15) clinical and neurological outcome other series, we tried to conclude that the radiological char- after treatment. acteristics and genetic alterations of PLNTY could predict We added and described a representative case from our the outcome of this new kind of epileptogenic tumor. experience reporting the radiological and surgical charac- teristics through imaging and intra-operative video. From the available data, we performed a statistical meta-analysis Methods attempting to assess the presence of significant relationships between surgical and radiologic tumor characteristics and An extensive systematic search has been conducted on Pub- clinical outcome and type of surgery. med according to the Preferred Reporting Items for System- atic Reviews and Meta-analysis (PRISMA) guidelines, to identify all potentially relevant studies about the radiologi- Case description cal, clinical, and surgical characteristics of PLNTY reported. In searching for relevant studies, the reference section of A 45-year-old right-handed man without relevant clinical included articles was analyzed. The search was performed history presented to our institution for partial seizure in left by typing the following items: “Polymorphous low-grade hand. In addition, He reported approximately two recent epi- neuroepithelial tumor of the young AND/OR PLNTY.” sodes of extreme fatigue in which he would fall asleep and 1 3 Acta Neurologica Belgica be unarousable for hours, as well as shorter duration facial given the reassuring fMRI data. Intraoperative evalua- and arm paresthesias. The patient was admitted for neurolog- tion of the tumor demonstrated a high variable lesion in ical care and underwent neuroimaging to rule out a structural consistency, aspect, and coloration (Video 1). The tumor cause for his symptoms. The patient underwent a preop- was just partially removed in a piecemeal fashion. The erative brain MRI scan included a high-field 3 Tesla volu- debulking was stopped in case of speech or motor arrest metric study with the following sequences: T2w, FLAIR, of patients. In the postoperative phase, the patient mani- isotropic volumetric T1-weighted magnetization-prepared fested hemiparesis in the left arm and recovered over the rapid acquisition gradient echo (MPRAGE) before and after next 2 weeks after the procedure. No manifestations of intravenous administration of paramagnetic contrast agent; tactile sensory alterations, stereoagnostic disturbances, or diffusion tensor sequences (DTI) with 3D tractography and visuospatial localization have been reported. functional MRI (fMRI). The procedure was performed with The patient did well postoperatively without immedi- an infrared-based Neuronavigator (Brainlab, Kick Purely ate complications. Histological diagnosis confirmed the Navigation), in a standard neurosurgical theatre, with a presence of PLNTY (grade I WHO) with ki-67 = 3% and standard operative microscope (Leica, model OH4). In the BRAF-V600E mutation. first postoperative day, as routine, the patients underwent volumetric Brain MRI scan to evaluate the EOR. Statistical methods Imaging The sample was analyzed with SPSS version 18 (SPSS An initial non-contrast head CT showed a partially calci- Inc., Chicago, Illinois, USA). A comparison between nom- fied intra-axial mass in the right temporoparietal lobe. MR inal variables was made with the chi-square test. Means imaging confirmed the presence of the lesion in the peri - of continuous variables were compared with one-way trigonal area involving the corpus callosum and internal and multivariate analysis of variance along with contrast capsule, which demonstrated a heterogeneous signal with analysis and post hoc tests. Continuous variable correla- few intralesional calcifications. Faint T1 hyperintensity was tions were investigated with Pearson bivariate correlation. seen within the tumor, while other regions demonstrated The threshold of statistical significance was considered at minimal enhancement. Focal regions of elevated relative p < 0.05. CBV were noted within the tumor on DSC perfusion imag- ing. A mild associated mass effect was seen, with efface - ment of the adjacent right lateral ventricle and expansion of an overlying right temporal lobe gyrus, DTI show just Results a minimal displacement of with fibers involving the right arcuate fasciculus. However, there was no midline shift or A total of 28 studies were found through PubMed database herniation. Preoperative imaging was completed on a 3T search and reference section screening. An automatic tool MR imaging scanner to optimize fMRI and spectroscopy. working on Microsoft Excel spreadsheets carried out a On this examination, the signal with multivoxel did not duplicate check. Out of 28 initial papers, one duplicate show significant spikes or reversal of the choline/n -acetyl- and 2 paper with another language other than English were aspartate (Cho-NAA) ratio. Initial imaging raised concern removed; thus 25 potentially articles were identified, and, for an oligodendroglioma, though location and dense central following the eligibility criteria, 20 papers were screened. calcifications were thought to be atypical. In particular, manuscripts did not fulfilling the eligibil- Preoperative language fMRI was predominantly used to ity criteria, because they were out of topic (focusing on establish the patient’s hemispheric language dominance and general low-grade tumor of low-grade CD34+, three the dislocation of the primary motor area; because the tumor papers), not focusing on clinical characteristics (genomic location and posterior corpus callosum involvement would or biological analysis, two papers), and four papers were have necessitated an awake resection with electrocortical excluded for insufficient detail of case analysis and finding stimulation mapping to prevent a postoperative motor and (four papers). A total of 16 articles were included in the coordination deficit. The patient performed fMRI language systematic review. Out of 50 patients overall included, 1 tasks in the scanner. The derived statistical maps demon- patient was successfully added to the analysis from our strated left-hemispheric language dominance (Fig. 1). institutional experience. The selection flowchart diagram The patient underwent resection of the mass via a right is reported in Fig. 2. Due to the low number of patients in temporoparietal craniotomy. The surgeons elected to the final series, patient demographics, clinical data, and approach the tumor through a corticectomy of the right tumor imaging characteristics are reported descriptively superior parietal lobule, the shortest route to the tumor in Table 1. 1 3 Acta Neurologica Belgica Fig. 1 The panel shows the MRI images obtained in our representa- ate fascicle of the right hemisphere. Spectroscopy examination shows tive case documenting the presence of the unimpaired motor area of a minimal choline peak without inversion only in the deep peri-cal- the hand in its physiological position. The DTI images document lit- losal part of the mass tle infiltration of the tumor mass with partial involvement of the arcu- Fig. 2 Selection study flowchart 1 3 Acta Neurologica Belgica 1 3 Table 1 Reported cases of PLNTY in the literature No. Authors Year Pts Age Sex Clinical pres- Side Major lobe Imaging Contrast Major Limits of Mutation Treatment Outcome entation involvement enhance- diameter lesion ment (mm) 1 Bale et al. [7] 2021 1 15 F Seizure Left Temporal Calcified, Yes 12 Circum- FGFR3- GTR Shift, recur- cystic scribed TACC3 rence 2 Bitar et al. [8] 2018 1 31 M Epilepsy Right Temporal – – Blurred BRAF V600E Lobectomy Re-surgery 3 Chen et al. 2020 3 14 F Seizure Left Temporal Calcified, No – Blurred FGFR3- GTR Under control [14] cystic TACC3 15 M Seizure Right Temporal Calcified, Yes – Blurred BRAF V600E GTR Under control cystic 16 M Seizure Right Frontal Calcified, Yes – Blurred N/A GTR Under control cystic 4 Gupta et al. 2021 5 11 M Epilepsy Right Frontal – – – – FGFR2 – – [1] 17 M Epilepsy Left Temporal – – – – FGFR2 – – 10 F Epilepsy Left Temporal – – – – FGFR2 – – 38 M Seizure Right Temporal – – – – FGFR2 – – 11 F Epilepsy Right Temporal – – – – FGFR2 – – 5 Gupta V.R. 2019 1 30 M Epilepsy Right Temporal Solid No 6 Circum- BRAF V600E Lobectomy Seizure-free et al. [2] scribed 6 Huse et al. [9] 2016 10 16 M Seizure Right Temporal Calcified No 7 Circum- BRAF V600E GTR scribed 18 F Seizure Right Temporal Calcified, Yes – Circum- BRAF V600E PR Psychosis cystic scribed 23 F Seizure Right Temporal Calcified No – Circum- BRAF V600E – – scribed 17 F Seizure Right Temporal Calcified No – Circum- FGFR3- GTR Seizure-free scribed TACC3 4 M Seizure Left Temporal Calcified No 30 Circum- FGFR2 GTR Seizure-free scribed 9 M Seizure Right Frontal Cystic Yes – Circum- KIAA1598- GTR Re-surgery scribed FGFR2 fusion 10 M Headache Right Occipital Calcified No – Circum- KIAA1598- GTR Under control scribed FGFR2 fusion 23 F Seizure Right Temporal Calcified No – Circum- – GTR Under control scribed 32 F Seizure Right Temporal Calcified No – Circum- – GTR Seizure-free scribed 24 F Visual distur- Right Occipital Calcified No – Circum- – GTR Re-surgery bances scribed Acta Neurologica Belgica 1 3 Table 1 (continued) No. Authors Year Pts Age Sex Clinical pres- Side Major lobe Imaging Contrast Major Limits of Mutation Treatment Outcome entation involvement enhance- diameter lesion ment (mm) 7 Jhonson et al. 2019 9 12 F – Left Temporal Calcified, No – Circum- KIAA1598- – – [17] cystic scribed FGFR2 fusion 12 F – Left Temporal Calcified, No – Circum- FGFR2 – – cystic scribed 26 F – Left Temporal Calcified, Yes – Circum- BRAF V600E – – cystic scribed 16 F – Right Temporal Calcified No – Circum- BRAF V600E – – scribed 25 M – Right Temporal Cystic No – Blurred BRAF V600E – – 15 F – Left Temporal Calcified, No – Circum- NTRK2 dis- – – cystic scribed ruption 5 F – Right Parietal Calcified, No – Circum- KIAA1598- – – cystic scribed FGFR2 fusion 34 M – Right Temporal Calcified, Yes – Circum- BRAF V600E – – cystic scribed 17 F – Median Third ventricle Calcified, Yes – Circum- BRAF V600E – – cystic scribed 8 Riva et al. [15] 2018 1 57 M Headache Right Frontal Cystic No 25 Blurred FGFR3- GTR Asymptomatic TACC3 9 Sumdani et al. 2019 1 19 M Seizure Right Parietal Calcified No 15 Blurred BRAF V600E GTR Under control [5] 10 Surrey et al. 2019 6 7 M Epilepsy – Temporal Cystic – – – FGFR2 GTR Under control [18] 10 F Epilepsy – Parietal – – – – FGFR2 GTR Re-surgery 14 M Epilepsy – Parietal – – – – FGFR3- GTR Seizure-free TACC3 16 M Epilepsy – Temporal – – – – BRAF V600E GTR Seizure-free 8 M Epilepsy – Temporal Cystic – – – BRAF V600E GTR Seizure-free 14 F Epilepsy – Temporal Cystic – – – BRAF V600E GTR Seizure-free 11 Tateishi et al. 2020 1 14 M Epilepsy Left Temporal Calcified, No 20 Circum- BRAF V600E GTR Seizure-free [6] cystic scribed Acta Neurologica Belgica 1 3 Table 1 (continued) No. Authors Year Pts Age Sex Clinical pres- Side Major lobe Imaging Contrast Major Limits of Mutation Treatment Outcome entation involvement enhance- diameter lesion ment (mm) 12 Fei et al. [19] 2022 8 5 M Epilepsy Right Occipital Cystic No – – N/A PR Seizure-free 25 M Seizure Right Temporal Calcified No – – BRAF V600E PR Seizure-free 21 M Epilepsy Right Temporal Calcified, Yes – – BRAF V600E GTR Seizure-free cystic 51 M Epilepsy Left Frontal Calcified Yes – – N/A GTR Seizure-free 30 F Seizure Right Frontal Calcified No – – N/A GTR Seizure-free 46 M Epilepsy Left Temporal Calcified, No – – N/A GTR Under control cystic 28 M Epilepsy Left Temporal Calcified No – – BRAF V600E GTR Seizure-free 47 M Epilepsy Right Frontal Cystic Yes – – BRAF V600E GTR Under control 14 Lelotte et al. 2019 1 33 F Seizure Right Temporal Cystic No 25 Blurred BRAF V600E GTR Under control [3] 15 Broggi et al. [ 2021 1 50 F Epilepsy Left Temporal Calcified No 20 Circum- N/A GTR Under control scribed 16 Benson et al. 2021 1 44 F Mood disorder Left Temporal Calcified, Yes – Circum- BRAF V600E GTR Under control [16] cystic scribed 17 Our case 2022 1 45 M Seizure Right Parietal Calcified Yes 45 Blurred BRAF V600E PR Under control Acta Neurologica Belgica between lesions with calcifications in their context or cysts Population analysis (chi-square test, p = 0.85 Fig. 4A and p = 0.39 Fig. 5, respec- tively). We evaluated how the presence of lesion margins The final cohort was composed of 51 patients. The aver - age age of the patients was 22.16 years (min = 4, max = 57), defined as "blurred", i.e., tumors that are not exactly circum- scribed, may impact the outcome measure, verifying that with a slight predominance of male sex (54.9% versus 45%). The main symptom of the onset is seizure comprehensive there is no statistically significant association (chi-square test, p = 0.34, Fig. 6). of a single seizure attack (18 patients, 42.9%) and intracta- ble epilepsy (20 patients, 47.6%). Other symptoms at onset Interesting, there is a substantial difference in outcome in cases where there is graphic contrast enhancement in reported are headache (two patients, 4.8%), visual distur- bance (one patient, 2.4%), and mood disorder (one patient the context of the tumor, where there is a more significant association of recurrence or poor control of epileptogenic with depression, 2.4%). Regarding the genetic profile, the most expressed muta- symptoms (chi-square test, p = 0.07 Fig. 4B). tion is BRAF V600 (23 pts—47.9%) followed by FGFR2 alterations (9 pts—18.8%), FGFR3-TACC3 (5 pts—10.4%), Discussion KIAA1598-FGFR2 fusion (4 pts—8.33%), NTRK2 disrup- tion (1 patient—2.1%), although 6 patients do not present a PLNTY was first described in 2017 [10], and today, it is specific alteration (6 pts—12.5%). We analyzed the reported radiological features of cystic intralesional component, cal- part of the group of pediatric glial neoplasms of the benign type according to the WHO classification of 2021 [11, 12]. cification and contrast-enhancing and data available about the choice of treatment and clinical outcome. None of the The designation of PLNTYs as “polymorphous” is meant to acknowledge that, while all harbored components prompting reported cases described the features the tumor took on about the eloquent areas and white matter bundles identifi- consideration of oligodendroglioma in the differential diag- nosis, most also contained patently astrocytic or ambigu- able on tractography examinations. All the relevant details are included in Table 2. ous appearance and several manifested foci of developed perivascular pseudorosetting [3]. Analysis on EOR Since its discovery, studies published on PLNTY show that predominant importance has been given to its genetic The descriptive analysis of the literature shows how impor- and molecular peculiarities rather than to radiological and surgical features [13]. Histologically distinguishing between tant EOR is in treating PLTNY. We analyzed the main clini- cal and radiological factors that may result in gross total the LEATs subtypes can be challenging, and molecular pro- filing is now recognized as critical for accurate classification resection of the tumor. We did not identify any significant variables regarding the achievement of complete resection [1]. Indeed, the final differential diagnosis, especially with oligodendroglioma, is often made by interpreting the histol- of the tumor. In particular, we analyzed how radiologic fea- tures could impact the different types of surgical treatment ogy in light of the molecular profile [1 ]. Characteristics shared by PLNTY and oligodendroglioma selected in terms of EOR. Analyzing the presence of cys- tis, calcification, and lesion boundaries (blurred or circum- include clinical presentation and course, appearance on radi- ologic imaging, and histopathology. Our study shows that scribed), we did not find any statistically significant correla- tion (cystic and calcification related to EOR, p = 0.85, lesion the age of onset is typically within the pediatric or young adult age range for the cases of PLNTY (mean 22.16) versus boundaries (blurred or circumscribed) with EOR, p = 0.82). the peak incidence between 40 and 60 years, which is more descriptive of oligodendroglioma [5] Analysis on outcome Both neoplasms can be incidentally found, but otherwise, patients are most likely to complain of new seizures with the We further analyzed the main variables that could, accord- ing to our hypothesis, most influence patients' outcomes: epileptogenic mass [5]. The distinction of these diagnoses can be clinically significant since oligodendroglioma has we first evaluated how an EOR corresponding to a gross total resection correlated with remission or better control of more aggressive behavior than PLNTY. PLNTY is associ- ated with an indolent course, and seizure control can typi- epilepsy-related symptoms, and it turns out that there is no statistically significant difference (chi-square test p = 0.38 cally be attained with total surgical resection [8]. Examining the outcomes of the few surgically treated Fig. 3), and secondly the principal clinical variables such age, sex, clinical debut and tumor location without any sig- patients diagnosed with PLNTY shows that the outcome is not always optimal. Indeed, even though a GTR or lobec- nificant association. We compared the main radiological appearance variables tomy occurs, the patient does not have complete control of seizures and that despite a typical genetic expression, reported and found no significant difference in outcome 1 3 Acta Neurologica Belgica Table 2 Study population No. cases 51 Age Mean 22.16 Min = 4 Max = 57 Sex M: 28–54.9% p = 1 F: 23–45% Clinical debut (42 pts) Seizure: 18–42.9% Epilepsy: 20–47.6% Headache: 2–4.8% Visual disturbance: 1–2.4% Mood disorder: 1–2.4% Side (45 pts) Left: 15–33.3% p = 0.26 Right: 29–64.4% Median: 1–2.2% Major lobe involvement (51 pts) Temporal lobe: 35–68.6% Frontal lobe: 7–13.7% Occipital lobe: 3–5.9% Parietal lobe: 5–9.8% Third ventricle: 1–2% Compactness 31 pts Cystic: 17–54.8% p = 0.39 No cystis: 14–14–45.16% Calcification 42 pts Calcified: 32–76.2% p = 0.85 No calcifications: 10–23.8% Contrast enhancement 40 pts Enhancement 13–32.5% p = 0.07 No contrast enhancing 27–67.5% Definition (30 pts) Circumscribed: 23–76.7% p = 0.34 Blurred: 9–30% Major diameter (10 pts) Mean: 20 Min = 6 Max = 45 Genetic alteration (48 pts) BRAF V600 = 23–47.9% FGFR3-TACC3 = 5–10.4% FGFR2 alterations = 9–18.8% KIAA1598-FGFR2 fusion = 4–8.33% NTRK2 disruption = 1–2.1% Not specific alteration = 6–12.5% Treatment (35 pts) GTR = 30–85.7% 0.38 PR = 4–11.4% Lobectomy = 5.7% Outcome (35 pts) Re-surgery = 5–14.3% 0.78 Seizure free = 15–42.9% Under control = 13–37.1% they do not correlate with a particular outcome. Cases of PLNTY stains positively. Molecular analysis has identified recurrence or biological shift to more aggressive forms of frequent genetic abnormalities involving the B-Raf proto- glioma have also been identified [7 ]. In this study, we first oncogene (BRAF), fibroblast growth receptor (FGFR), argued that molecular expression might significantly affect and a distinct methylation pattern. PLNTY has been found the outcome. to have a different DNA methylation signature [14], like PLNTY is notable for the presence of oligodendroglioma- BRAF mutation or fibroblast growth factor receptors 2 and 3 like cellular components and CD34 immunopositivity. (FGFR2/FGFR3) translocation [11], involving the mitogen- Immunohistochemical markers such as CD34 are other valu- activated protein kinase (MAPK) pathway [2, 3], lacking able tools that can readily discriminate between PLNTY and isocitrate dehydrogenase (IDH) mutations and 1p/19q code- oligodendroglioma since the last staining negatively while letion (characteristic of Oligodendroglioma) [1]. 1 3 Acta Neurologica Belgica Fig. 3 The chi-square analysis displayed graphically in these bar A p = 0.85), while there is a mild significant association between charts shows that the presence of calcifications that is not sig- patients with and without contrast-enhancement of the lesion and the nificantly associated with the outcome of treated patients (PART outcome (PART B, p = 0.07) The clinical significance of CD34 expression and BRAF reported. Precisely as in Huse's case series, our study con- mutation was investigated in a recent publication aiming to firms that most tumors localize in the temporal lobe and study the relationship between biomolecular markers and that the most common radiological features include cystic clinical–pathological features [13]. The study found that change, focal enhancement, and calcification [15]. Benson while CD34 expression was significantly associated with a et al. [16] suggested that a well-circumscribed temporal lobe longer duration of epilepsy, BRAF mutation was associated [17] mass with central calcifications, peripheral cysts, and with multiple seizure types. It was suggested that BRAF- the heterogeneous internal signal should have raised suspi- mutant protein expression might influence neural networks, cion of a PLNTY. An oligodendroglioma may have dem- causing the abnormal discharge of various populations of onstrated many of these imaging features, but the findings neurons in different locations, which in turn may contribute favored a PLNTY. Most notably, oligodendrogliomas have to the occurrence of varying seizure patterns [8]. indistinct margins. Although the BRAF V600E genetic mutant may play a Few PLNTY cases of the following reported articles yield causative role in PLNTY’s growth and may be promising insufficient knowledge of radiology to apply to the diagnos- to pursue new medical therapy for PLNTY [5], no associa- tic setting. The only specific radiological study published tions are reported with the outcome of PLNTY patients. Our by Chen et al. [2] demonstrated that PLNTY has a wide study does not suggest a relationship between the expression radiological variability, with clinical outcomes not directly of BRAF or FGFR mutations with the risk of poor seizure dependent on the type of resection (Fig. 7). PLNTY typi- control after surgery or risk of recurrence [7]. Therefore, cally appears with hyperintense or mixed density on T2 while molecular features better explain the initial behavior magnetic resonance imaging (MRI) and hypointense or and clinic of PLNTY, we further considered in our initial mixed density on T1 imaging [2, 16], usually near the brain hypothesis if the anatomical and radiological features of the surface with frequent calcifications [17]. Calcifications are tumor may have peculiarities in post-surgical outcome. frequently seen on computed tomography (CT) images [3]. The most extensive published series of PLNTYs We can confirm that variable degrees of calcification are described by Huse et  al. [10] showed infiltrative growth observed with a confirmed diagnosis in most cases. In a and oligodendroglioma-like histopathology. In general, the study by Suldany et al. [5], 33% demonstrated enhancement extent of the lesion is considered smaller than the other epi- on post-gadolinium T1-weighted MR images for PLNTY. In leptogenic tumors [14]. However, this assertion is currently contrast, while in the case of oligodendroglioma, contrast- challenging to support, because from the cases reported enhancing is evaluated as a radiological feature of the tumor in the literature, only in ten patients were tumor diameters without any prognostic impact, we found that PLNTY may 1 3 Acta Neurologica Belgica Fig. 4 Chi-square comparison analysis shows the different outcomes from the patients treated with gross total resection (GTR), lobectomy, and partial resection (p = 0.38) be correlated with poorer control of epileptic symptomatol- borderline. The infiltrated growth patterns may explain the ogy. We suppose it may also be related to the slightly more unclear boundary with normal brain tissue in radiology [19]. aggressive behavior of the tumor. To better understand the characteristics of the tumor with The calcifications seen on MRI are also apparent in the a view to suboptimal surgical resection in our representa- histopathology of both tumors, and the general cell morphol- tive case, we evaluated DTI and spectroscopy values in ogy of PLNTY mimics oligodendroglioma closely [5]. suspicion of an early malignancy form. We identified that What is reported, however, is that in most cases, PLNTY within a multi-voxel study, only in a deep peri-callosal por- presents as a well-circumscribed tumor [5, 17] that tends tion of the tumor a mild and unremarkable choline peak was to be cystic and rich in calcifications [1 ], predominantly expressed compared to NAA (Fig. 1). The DTI study, on the located in the temporal lobe [17] and associated with corti- other hand, identified white matter fiber depreciation rather cal dysplasia. than prominent infiltration, a sign that the mass effect of the While all reported cases are shown as hyperintensity lesion appears to be minimal (but present) with minor per- in T2WI and iso- or hypointensity in T1WI with slight or ilesional edema. This finding confirmed what was reported no enhancement after contrast-enhanced, in some cases, by Chen et al. [2], the describes a slight decrease of NAA PLNTY tends to prominently show an infiltrative growth and increase of Cho in H1-MRS, without restricted diffu- pattern with adjacent tissue involvement and subpial exten- sion in DWI [6], and compression rather than disruption of sion and partly exhibit sharp borderline [17, 18]. In con- the fiber tracts in DTI, which all suggest the PLNTY to be a trast, other cases tend to have a completely well-defined low-grade, less aggressive neoplasm [2, 20]. 1 3 Acta Neurologica Belgica Fig. 5 The bar chart shows that cystis is not significantly associated with treated patients' outcomes for PLTNY. Chi-square test p = 0.39 Fig. 6 The chi-square analysis displayed graphically in this bar chart shows that the undefined limits of the lesion is not significantly associated with the outcome of treated patients (p = 0.34) The significant radiological variability present in the when it is poorly calcified and poorly defined in the margins, imaging of PLTNY does not only affect the different cases such a finding may represent an additional differential diag- reported in the literature [15–20]; in fact, we argue that such nostic feature concerning oligodendroglioma, as well as a variability is present macroscopically within the same lesion further difficulty in achieving complete resection. in the same patient, which is but also evident when the sur- Further investigation will be necessary to define the geon addresses the resection of the tumor mass, especially clinical implications of the imaging observations described 1 3 Acta Neurologica Belgica Fig. 7 The figure shows the comparison between the radio- logical images of two patients with a confirmed diagnosis of PLTNY: it is show in particular the high radiological variability that can occur in CT scanning and MRI. In the first patient, a lesion without calcifications (A), with very blurred margins (B) and without cysts in context (C) is documented, while in the second case, a well-localized lesion in the temporal lobe (D) with cysts in context (E) with well-defined margins (F) is appreciated herein. In particular, it will be important to re-evaluate Author contributions DA: writing, analysis, data curation, data collec- tion, review of literature; LVB: surgical operator, conceptualization, contrast-enhancement rates in other intra-axial pediatric supervising; AF: supervising, corrections; AS: supervising. and young adult brain tumors as current pathologic criteria define those entities. Funding Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. This research received no external funding. Data availability Not applicable, at request of corresponding author Conclusions (D.A.). Declarations PLNTYs exhibit an almost invariably benign clinical course and appear well controlled by surgical resection. Conflict of interest The authors certify that they have no affiliations The prototypical PLNTY is a well-circumscribed lesion with or involvement in any organization or entity with any financial in- with macroscopic calcification and a cystic component terest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, located peripherally within the posteroinferior temporal or other equity interest; and expert testimony or patent-licensing ar- lobe of a young patient. Still, from our recent analysis, its rangements), or non-financial interest (such as personal or professional radiological and clinical variability appears to be much relationships, affiliations, knowledge or beliefs) in the subject matter wider. Surgically, excision can be burdened by profound or materials discussed in this manuscript. The authors confirm their adherence to ethical standards and have no financial disclosures that tumor variability and difficulty identifying tumor margins. would be a potential conflict of interest with this publication. The molecular driving alterations, such as BRAF V600E and FGFR translocations, do not predict the post-surgical Human and animal ethics The study was conducted in accordance with outcome. On the radiological aspect, in PLNTY, contrast the Declaration of Helsinki. enhancement seems to impact prognosis, recurrence, and Consent for publication Informed consent was obtained from all sub- seizure control much more than radiological features of jects involved in the study. the tumor. Open Access This article is licensed under a Creative Commons Attri- Supplementary Information The online version contains supplemen- bution 4.0 International License, which permits use, sharing, adapta- tary material available at https://doi. or g/10. 1007/ s13760- 023- 02231-z . tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, Acknowledgements We confirm that the manuscript has been read and provide a link to the Creative Commons licence, and indicate if changes approved by all named authors and that there are no other persons who were made. The images or other third party material in this article are satisfied the criteria for authorship but are not listed. 1 3 Acta Neurologica Belgica included in the article's Creative Commons licence, unless indicated epileptogenic neoplasm with oligodendroglioma-like components, otherwise in a credit line to the material. 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E, Saffery R, Sexton-Oates A, Blumcke I, Capper D, Karajan - org/ 10. 25259/ SNI_ 500_ 2021 nis MA, Benayed R, Chavez L, Thomas C, Serrano J, Borsu L, Ladanyi M, Rosenblum MK (2017) Polymorphous low-grade neu- Publisher's Note Springer Nature remains neutral with regard to roepithelial tumor of the young (PLNTY): an epileptogenic neo- jurisdictional claims in published maps and institutional affiliations. plasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol 133(3):417–429. https:// doi. org/ 10. 1007/ s00401- 016- 1639-9 10. Huse JT, Snuderl M, Jones DT et  al (2017) Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Neurologica Belgica Springer Journals

Radiological and surgical aspects of polymorphous low-grade neuroepithelial tumor of the young (PLNTY)

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Abstract

Background Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a low-grade epilepsy-associated tumor recently introduced in WHO 2021 classification. Since it has been recognized as an independent nosological entity, PLNTY has been mainly studied from a genetic and molecular perspective, not recognizing unique characteristic clinical and radiological features. Methods A systematic literature research has been conducted aiming to identify all relevant studies about the radiologi- cal, clinical and surgical features of PLNTY. We described a representative case of a 45-year-old man treated with awake- surgery with confirmed diagnosis of PLNTY, reporting the radiological and surgical characteristics through imaging and intra-operative video. We performed a statistical meta-analysis attempting to assess the presence of relationships between surgical and radiologic tumor characteristics and clinical outcome and type of surgery. Results A total of 16 studies were included in the systematic review. The final cohort was composed of 51 patients. Extent of resection (EOR) and outcome are not significantly associated with the different genetic profiling (p = 1), the presence of cystic intralesional component, calcification (p = 0.85), contrast-enhancing and lesion boundaries (p = 0.82). No significant correlation there is between EOR and remission or better control of epilepsy-related symptoms (p = 0.38). The contrast enhancement in the tumor is significantly associated with recurrence or poor control of epileptic symptoms (p = 0.07). Conclusions In PLNTYs, contrast enhancement seems to impact prognosis, recurrence, and seizure control much more than radiological features, genetic features and type of resection of the tumor. Abbreviations EOR Extent or resection PLNTY Polymorphous low-grade neuroepithe-BRAF B-Raf proto-oncogene lial tumor of the young FGFR Fibroblast growth receptor CNS-WHO Central Nervous Tumor-World Health FGFR2/FGFR3 Fibroblast growth factor receptors 2 and Organization 3 LEATs Low-grade epilepsy-associated tumors MAPK Mitogen-activated protein kinase PRISMA Preferred reporting items for systematic IDH Isocitrate dehydrogenase reviews and meta-analysis GTR Gross total resection MRI Magnetic resonance imaging Introduction Cho-NAA Choline/n-acetyl-aspartate Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a low-grade tumor comprised of infiltrating “oli- Daniele Armocida and Luigi Valentino Berra have contributed godendrocyte-like” cells [1] that stain with CD34 immuno- equally. positivity [2]. It frequently affects children and young adults, with a slightly female predominance [3]. PLNTY is a typical * Daniele Armocida low-grade epilepsy-associated tumor recently described and danielearmocida@yahoo.it introduced in Central Nervous Tumor-World Health Organi- A.U.O. “Policlinico Umberto I”, Neurosurgery Division, zation (CNS-WHO) 2021 classification [2 , 3]. Before the Sapienza University, Rome, Italy last updated classification, PLNTY it was considered to take Human Neurosciences Department, Via del Policlinico, 155, part of a group known as low-grade epilepsy-associated 00161 Rome, Italy Vol.:(0123456789) 1 3 Acta Neurologica Belgica tumors (LEATs), an umbrella of developmental tumors, with The first selection step was describing the clinical favorable clinical outcomes, with varying histologic appear- entity of PLNTY in pediatric and adult patients and its ances, associated with early-onset seizures, since other glial characteristics. tumors, such as pilocytic astrocytomas or oligodendroglio- In this regard, we chose to evaluate only the studies mas, usually had distinct diagnostic criterion that assists in focused on PLNTY only PLNTY-focused studies and papers further clinical management [1, 4]. Several distinguishing that described patients or series reported and described clini- factors of PLNTY may be implicated in its pathogenesis cally and radiologically. and clinical manifestation, the most suspicious of which are Given these premises, we selected papers according to the BRAF V600E gene mutant, increased CD34 expression, and following inclusion criteria: FGFR gene fusion products [5]. Radiologically, clinically and surgically still, very little Availability of full-text articles; is known about this rare tumor. The diagnostic challenge • English text only; most often involves distinguishing this tumor from an oligo- Patients with a diagnosis of PLNTY; dendroglioma, given, especially in adults, the morphologic • Reported details on imaging; and clinical overlap and the potential for misdiagnosis are Presence of neurological outcome evaluation. No specific significant [1 ]. Because of their rare etiology, only a few limitation was applied regarding the timing of neurologi- PLNTYs have been described to date. It is unclear how its cal evaluation after treatment. characteristics impact the pathogenesis and the outcome of the disease [6]. Clinically, Oligodendroglioma is associated Conversely, exclusion criteria were: with a lower rate of epilepsy and a worse clinical prognosis. At the same time, PLNTYs, tend to exhibit a benign (typi- Full-text articles in languages other than English; cal of WHO grade I) clinical course, and appear to be well • Studies reporting patients with the low-grade tumors; controlled by gross total resection (GTR). However, some No data available about the neurological outcome; reports describe cases of difficult therapeutic control or dis- • No imaging details were reported; ease recurrence [7–9]. PLNTYs, indeed, can be morphologically highly variable, Data extracted from each study were (1) authors, (2) year manifesting as well-circumscribed lesions, cystic lesions, or of publication, (3) number of patients included, (4) age, (5) infiltrative growth patterns. The constant element appears sex, (6) clinical debut and presentation on diagnosis, (7) to be the calcific component that is always present in the side involved, (8) major cerebral lobe involved, (9) imaging context of the lesion, leading it to be in differential diag- characteristics, (10) presence of contrast-enhancing in mag- nosis with oligodendroglioma [1]. In this review and meta- netic resonance imaging (MRI) studies, (11) major diameter analysis, we want to identify the clinical, radiological, and of tumor in MRI studies, (12) characteristics of radiologi- surgical features known about PLNTY, reporting a typical cal limits of the lesion (defined as “circumscribed” when case of misdiagnosis with adult oligodendroglioma from our limits are well-identifiable on MRI, in contrast on “blurred” experience, providing as much surgical information as pos- limits), (13) mutation identified on diagnostic molecular sible through the presentation of an intra-operative video. analysis, (14) surgical treatment indicating the extent or In addition, by reviewing the research on cases reported in resection (EOR), (15) clinical and neurological outcome other series, we tried to conclude that the radiological char- after treatment. acteristics and genetic alterations of PLNTY could predict We added and described a representative case from our the outcome of this new kind of epileptogenic tumor. experience reporting the radiological and surgical charac- teristics through imaging and intra-operative video. From the available data, we performed a statistical meta-analysis Methods attempting to assess the presence of significant relationships between surgical and radiologic tumor characteristics and An extensive systematic search has been conducted on Pub- clinical outcome and type of surgery. med according to the Preferred Reporting Items for System- atic Reviews and Meta-analysis (PRISMA) guidelines, to identify all potentially relevant studies about the radiologi- Case description cal, clinical, and surgical characteristics of PLNTY reported. In searching for relevant studies, the reference section of A 45-year-old right-handed man without relevant clinical included articles was analyzed. The search was performed history presented to our institution for partial seizure in left by typing the following items: “Polymorphous low-grade hand. In addition, He reported approximately two recent epi- neuroepithelial tumor of the young AND/OR PLNTY.” sodes of extreme fatigue in which he would fall asleep and 1 3 Acta Neurologica Belgica be unarousable for hours, as well as shorter duration facial given the reassuring fMRI data. Intraoperative evalua- and arm paresthesias. The patient was admitted for neurolog- tion of the tumor demonstrated a high variable lesion in ical care and underwent neuroimaging to rule out a structural consistency, aspect, and coloration (Video 1). The tumor cause for his symptoms. The patient underwent a preop- was just partially removed in a piecemeal fashion. The erative brain MRI scan included a high-field 3 Tesla volu- debulking was stopped in case of speech or motor arrest metric study with the following sequences: T2w, FLAIR, of patients. In the postoperative phase, the patient mani- isotropic volumetric T1-weighted magnetization-prepared fested hemiparesis in the left arm and recovered over the rapid acquisition gradient echo (MPRAGE) before and after next 2 weeks after the procedure. No manifestations of intravenous administration of paramagnetic contrast agent; tactile sensory alterations, stereoagnostic disturbances, or diffusion tensor sequences (DTI) with 3D tractography and visuospatial localization have been reported. functional MRI (fMRI). The procedure was performed with The patient did well postoperatively without immedi- an infrared-based Neuronavigator (Brainlab, Kick Purely ate complications. Histological diagnosis confirmed the Navigation), in a standard neurosurgical theatre, with a presence of PLNTY (grade I WHO) with ki-67 = 3% and standard operative microscope (Leica, model OH4). In the BRAF-V600E mutation. first postoperative day, as routine, the patients underwent volumetric Brain MRI scan to evaluate the EOR. Statistical methods Imaging The sample was analyzed with SPSS version 18 (SPSS An initial non-contrast head CT showed a partially calci- Inc., Chicago, Illinois, USA). A comparison between nom- fied intra-axial mass in the right temporoparietal lobe. MR inal variables was made with the chi-square test. Means imaging confirmed the presence of the lesion in the peri - of continuous variables were compared with one-way trigonal area involving the corpus callosum and internal and multivariate analysis of variance along with contrast capsule, which demonstrated a heterogeneous signal with analysis and post hoc tests. Continuous variable correla- few intralesional calcifications. Faint T1 hyperintensity was tions were investigated with Pearson bivariate correlation. seen within the tumor, while other regions demonstrated The threshold of statistical significance was considered at minimal enhancement. Focal regions of elevated relative p < 0.05. CBV were noted within the tumor on DSC perfusion imag- ing. A mild associated mass effect was seen, with efface - ment of the adjacent right lateral ventricle and expansion of an overlying right temporal lobe gyrus, DTI show just Results a minimal displacement of with fibers involving the right arcuate fasciculus. However, there was no midline shift or A total of 28 studies were found through PubMed database herniation. Preoperative imaging was completed on a 3T search and reference section screening. An automatic tool MR imaging scanner to optimize fMRI and spectroscopy. working on Microsoft Excel spreadsheets carried out a On this examination, the signal with multivoxel did not duplicate check. Out of 28 initial papers, one duplicate show significant spikes or reversal of the choline/n -acetyl- and 2 paper with another language other than English were aspartate (Cho-NAA) ratio. Initial imaging raised concern removed; thus 25 potentially articles were identified, and, for an oligodendroglioma, though location and dense central following the eligibility criteria, 20 papers were screened. calcifications were thought to be atypical. In particular, manuscripts did not fulfilling the eligibil- Preoperative language fMRI was predominantly used to ity criteria, because they were out of topic (focusing on establish the patient’s hemispheric language dominance and general low-grade tumor of low-grade CD34+, three the dislocation of the primary motor area; because the tumor papers), not focusing on clinical characteristics (genomic location and posterior corpus callosum involvement would or biological analysis, two papers), and four papers were have necessitated an awake resection with electrocortical excluded for insufficient detail of case analysis and finding stimulation mapping to prevent a postoperative motor and (four papers). A total of 16 articles were included in the coordination deficit. The patient performed fMRI language systematic review. Out of 50 patients overall included, 1 tasks in the scanner. The derived statistical maps demon- patient was successfully added to the analysis from our strated left-hemispheric language dominance (Fig. 1). institutional experience. The selection flowchart diagram The patient underwent resection of the mass via a right is reported in Fig. 2. Due to the low number of patients in temporoparietal craniotomy. The surgeons elected to the final series, patient demographics, clinical data, and approach the tumor through a corticectomy of the right tumor imaging characteristics are reported descriptively superior parietal lobule, the shortest route to the tumor in Table 1. 1 3 Acta Neurologica Belgica Fig. 1 The panel shows the MRI images obtained in our representa- ate fascicle of the right hemisphere. Spectroscopy examination shows tive case documenting the presence of the unimpaired motor area of a minimal choline peak without inversion only in the deep peri-cal- the hand in its physiological position. The DTI images document lit- losal part of the mass tle infiltration of the tumor mass with partial involvement of the arcu- Fig. 2 Selection study flowchart 1 3 Acta Neurologica Belgica 1 3 Table 1 Reported cases of PLNTY in the literature No. Authors Year Pts Age Sex Clinical pres- Side Major lobe Imaging Contrast Major Limits of Mutation Treatment Outcome entation involvement enhance- diameter lesion ment (mm) 1 Bale et al. [7] 2021 1 15 F Seizure Left Temporal Calcified, Yes 12 Circum- FGFR3- GTR Shift, recur- cystic scribed TACC3 rence 2 Bitar et al. [8] 2018 1 31 M Epilepsy Right Temporal – – Blurred BRAF V600E Lobectomy Re-surgery 3 Chen et al. 2020 3 14 F Seizure Left Temporal Calcified, No – Blurred FGFR3- GTR Under control [14] cystic TACC3 15 M Seizure Right Temporal Calcified, Yes – Blurred BRAF V600E GTR Under control cystic 16 M Seizure Right Frontal Calcified, Yes – Blurred N/A GTR Under control cystic 4 Gupta et al. 2021 5 11 M Epilepsy Right Frontal – – – – FGFR2 – – [1] 17 M Epilepsy Left Temporal – – – – FGFR2 – – 10 F Epilepsy Left Temporal – – – – FGFR2 – – 38 M Seizure Right Temporal – – – – FGFR2 – – 11 F Epilepsy Right Temporal – – – – FGFR2 – – 5 Gupta V.R. 2019 1 30 M Epilepsy Right Temporal Solid No 6 Circum- BRAF V600E Lobectomy Seizure-free et al. [2] scribed 6 Huse et al. [9] 2016 10 16 M Seizure Right Temporal Calcified No 7 Circum- BRAF V600E GTR scribed 18 F Seizure Right Temporal Calcified, Yes – Circum- BRAF V600E PR Psychosis cystic scribed 23 F Seizure Right Temporal Calcified No – Circum- BRAF V600E – – scribed 17 F Seizure Right Temporal Calcified No – Circum- FGFR3- GTR Seizure-free scribed TACC3 4 M Seizure Left Temporal Calcified No 30 Circum- FGFR2 GTR Seizure-free scribed 9 M Seizure Right Frontal Cystic Yes – Circum- KIAA1598- GTR Re-surgery scribed FGFR2 fusion 10 M Headache Right Occipital Calcified No – Circum- KIAA1598- GTR Under control scribed FGFR2 fusion 23 F Seizure Right Temporal Calcified No – Circum- – GTR Under control scribed 32 F Seizure Right Temporal Calcified No – Circum- – GTR Seizure-free scribed 24 F Visual distur- Right Occipital Calcified No – Circum- – GTR Re-surgery bances scribed Acta Neurologica Belgica 1 3 Table 1 (continued) No. Authors Year Pts Age Sex Clinical pres- Side Major lobe Imaging Contrast Major Limits of Mutation Treatment Outcome entation involvement enhance- diameter lesion ment (mm) 7 Jhonson et al. 2019 9 12 F – Left Temporal Calcified, No – Circum- KIAA1598- – – [17] cystic scribed FGFR2 fusion 12 F – Left Temporal Calcified, No – Circum- FGFR2 – – cystic scribed 26 F – Left Temporal Calcified, Yes – Circum- BRAF V600E – – cystic scribed 16 F – Right Temporal Calcified No – Circum- BRAF V600E – – scribed 25 M – Right Temporal Cystic No – Blurred BRAF V600E – – 15 F – Left Temporal Calcified, No – Circum- NTRK2 dis- – – cystic scribed ruption 5 F – Right Parietal Calcified, No – Circum- KIAA1598- – – cystic scribed FGFR2 fusion 34 M – Right Temporal Calcified, Yes – Circum- BRAF V600E – – cystic scribed 17 F – Median Third ventricle Calcified, Yes – Circum- BRAF V600E – – cystic scribed 8 Riva et al. [15] 2018 1 57 M Headache Right Frontal Cystic No 25 Blurred FGFR3- GTR Asymptomatic TACC3 9 Sumdani et al. 2019 1 19 M Seizure Right Parietal Calcified No 15 Blurred BRAF V600E GTR Under control [5] 10 Surrey et al. 2019 6 7 M Epilepsy – Temporal Cystic – – – FGFR2 GTR Under control [18] 10 F Epilepsy – Parietal – – – – FGFR2 GTR Re-surgery 14 M Epilepsy – Parietal – – – – FGFR3- GTR Seizure-free TACC3 16 M Epilepsy – Temporal – – – – BRAF V600E GTR Seizure-free 8 M Epilepsy – Temporal Cystic – – – BRAF V600E GTR Seizure-free 14 F Epilepsy – Temporal Cystic – – – BRAF V600E GTR Seizure-free 11 Tateishi et al. 2020 1 14 M Epilepsy Left Temporal Calcified, No 20 Circum- BRAF V600E GTR Seizure-free [6] cystic scribed Acta Neurologica Belgica 1 3 Table 1 (continued) No. Authors Year Pts Age Sex Clinical pres- Side Major lobe Imaging Contrast Major Limits of Mutation Treatment Outcome entation involvement enhance- diameter lesion ment (mm) 12 Fei et al. [19] 2022 8 5 M Epilepsy Right Occipital Cystic No – – N/A PR Seizure-free 25 M Seizure Right Temporal Calcified No – – BRAF V600E PR Seizure-free 21 M Epilepsy Right Temporal Calcified, Yes – – BRAF V600E GTR Seizure-free cystic 51 M Epilepsy Left Frontal Calcified Yes – – N/A GTR Seizure-free 30 F Seizure Right Frontal Calcified No – – N/A GTR Seizure-free 46 M Epilepsy Left Temporal Calcified, No – – N/A GTR Under control cystic 28 M Epilepsy Left Temporal Calcified No – – BRAF V600E GTR Seizure-free 47 M Epilepsy Right Frontal Cystic Yes – – BRAF V600E GTR Under control 14 Lelotte et al. 2019 1 33 F Seizure Right Temporal Cystic No 25 Blurred BRAF V600E GTR Under control [3] 15 Broggi et al. [ 2021 1 50 F Epilepsy Left Temporal Calcified No 20 Circum- N/A GTR Under control scribed 16 Benson et al. 2021 1 44 F Mood disorder Left Temporal Calcified, Yes – Circum- BRAF V600E GTR Under control [16] cystic scribed 17 Our case 2022 1 45 M Seizure Right Parietal Calcified Yes 45 Blurred BRAF V600E PR Under control Acta Neurologica Belgica between lesions with calcifications in their context or cysts Population analysis (chi-square test, p = 0.85 Fig. 4A and p = 0.39 Fig. 5, respec- tively). We evaluated how the presence of lesion margins The final cohort was composed of 51 patients. The aver - age age of the patients was 22.16 years (min = 4, max = 57), defined as "blurred", i.e., tumors that are not exactly circum- scribed, may impact the outcome measure, verifying that with a slight predominance of male sex (54.9% versus 45%). The main symptom of the onset is seizure comprehensive there is no statistically significant association (chi-square test, p = 0.34, Fig. 6). of a single seizure attack (18 patients, 42.9%) and intracta- ble epilepsy (20 patients, 47.6%). Other symptoms at onset Interesting, there is a substantial difference in outcome in cases where there is graphic contrast enhancement in reported are headache (two patients, 4.8%), visual distur- bance (one patient, 2.4%), and mood disorder (one patient the context of the tumor, where there is a more significant association of recurrence or poor control of epileptogenic with depression, 2.4%). Regarding the genetic profile, the most expressed muta- symptoms (chi-square test, p = 0.07 Fig. 4B). tion is BRAF V600 (23 pts—47.9%) followed by FGFR2 alterations (9 pts—18.8%), FGFR3-TACC3 (5 pts—10.4%), Discussion KIAA1598-FGFR2 fusion (4 pts—8.33%), NTRK2 disrup- tion (1 patient—2.1%), although 6 patients do not present a PLNTY was first described in 2017 [10], and today, it is specific alteration (6 pts—12.5%). We analyzed the reported radiological features of cystic intralesional component, cal- part of the group of pediatric glial neoplasms of the benign type according to the WHO classification of 2021 [11, 12]. cification and contrast-enhancing and data available about the choice of treatment and clinical outcome. None of the The designation of PLNTYs as “polymorphous” is meant to acknowledge that, while all harbored components prompting reported cases described the features the tumor took on about the eloquent areas and white matter bundles identifi- consideration of oligodendroglioma in the differential diag- nosis, most also contained patently astrocytic or ambigu- able on tractography examinations. All the relevant details are included in Table 2. ous appearance and several manifested foci of developed perivascular pseudorosetting [3]. Analysis on EOR Since its discovery, studies published on PLNTY show that predominant importance has been given to its genetic The descriptive analysis of the literature shows how impor- and molecular peculiarities rather than to radiological and surgical features [13]. Histologically distinguishing between tant EOR is in treating PLTNY. We analyzed the main clini- cal and radiological factors that may result in gross total the LEATs subtypes can be challenging, and molecular pro- filing is now recognized as critical for accurate classification resection of the tumor. We did not identify any significant variables regarding the achievement of complete resection [1]. Indeed, the final differential diagnosis, especially with oligodendroglioma, is often made by interpreting the histol- of the tumor. In particular, we analyzed how radiologic fea- tures could impact the different types of surgical treatment ogy in light of the molecular profile [1 ]. Characteristics shared by PLNTY and oligodendroglioma selected in terms of EOR. Analyzing the presence of cys- tis, calcification, and lesion boundaries (blurred or circum- include clinical presentation and course, appearance on radi- ologic imaging, and histopathology. Our study shows that scribed), we did not find any statistically significant correla- tion (cystic and calcification related to EOR, p = 0.85, lesion the age of onset is typically within the pediatric or young adult age range for the cases of PLNTY (mean 22.16) versus boundaries (blurred or circumscribed) with EOR, p = 0.82). the peak incidence between 40 and 60 years, which is more descriptive of oligodendroglioma [5] Analysis on outcome Both neoplasms can be incidentally found, but otherwise, patients are most likely to complain of new seizures with the We further analyzed the main variables that could, accord- ing to our hypothesis, most influence patients' outcomes: epileptogenic mass [5]. The distinction of these diagnoses can be clinically significant since oligodendroglioma has we first evaluated how an EOR corresponding to a gross total resection correlated with remission or better control of more aggressive behavior than PLNTY. PLNTY is associ- ated with an indolent course, and seizure control can typi- epilepsy-related symptoms, and it turns out that there is no statistically significant difference (chi-square test p = 0.38 cally be attained with total surgical resection [8]. Examining the outcomes of the few surgically treated Fig. 3), and secondly the principal clinical variables such age, sex, clinical debut and tumor location without any sig- patients diagnosed with PLNTY shows that the outcome is not always optimal. Indeed, even though a GTR or lobec- nificant association. We compared the main radiological appearance variables tomy occurs, the patient does not have complete control of seizures and that despite a typical genetic expression, reported and found no significant difference in outcome 1 3 Acta Neurologica Belgica Table 2 Study population No. cases 51 Age Mean 22.16 Min = 4 Max = 57 Sex M: 28–54.9% p = 1 F: 23–45% Clinical debut (42 pts) Seizure: 18–42.9% Epilepsy: 20–47.6% Headache: 2–4.8% Visual disturbance: 1–2.4% Mood disorder: 1–2.4% Side (45 pts) Left: 15–33.3% p = 0.26 Right: 29–64.4% Median: 1–2.2% Major lobe involvement (51 pts) Temporal lobe: 35–68.6% Frontal lobe: 7–13.7% Occipital lobe: 3–5.9% Parietal lobe: 5–9.8% Third ventricle: 1–2% Compactness 31 pts Cystic: 17–54.8% p = 0.39 No cystis: 14–14–45.16% Calcification 42 pts Calcified: 32–76.2% p = 0.85 No calcifications: 10–23.8% Contrast enhancement 40 pts Enhancement 13–32.5% p = 0.07 No contrast enhancing 27–67.5% Definition (30 pts) Circumscribed: 23–76.7% p = 0.34 Blurred: 9–30% Major diameter (10 pts) Mean: 20 Min = 6 Max = 45 Genetic alteration (48 pts) BRAF V600 = 23–47.9% FGFR3-TACC3 = 5–10.4% FGFR2 alterations = 9–18.8% KIAA1598-FGFR2 fusion = 4–8.33% NTRK2 disruption = 1–2.1% Not specific alteration = 6–12.5% Treatment (35 pts) GTR = 30–85.7% 0.38 PR = 4–11.4% Lobectomy = 5.7% Outcome (35 pts) Re-surgery = 5–14.3% 0.78 Seizure free = 15–42.9% Under control = 13–37.1% they do not correlate with a particular outcome. Cases of PLNTY stains positively. Molecular analysis has identified recurrence or biological shift to more aggressive forms of frequent genetic abnormalities involving the B-Raf proto- glioma have also been identified [7 ]. In this study, we first oncogene (BRAF), fibroblast growth receptor (FGFR), argued that molecular expression might significantly affect and a distinct methylation pattern. PLNTY has been found the outcome. to have a different DNA methylation signature [14], like PLNTY is notable for the presence of oligodendroglioma- BRAF mutation or fibroblast growth factor receptors 2 and 3 like cellular components and CD34 immunopositivity. (FGFR2/FGFR3) translocation [11], involving the mitogen- Immunohistochemical markers such as CD34 are other valu- activated protein kinase (MAPK) pathway [2, 3], lacking able tools that can readily discriminate between PLNTY and isocitrate dehydrogenase (IDH) mutations and 1p/19q code- oligodendroglioma since the last staining negatively while letion (characteristic of Oligodendroglioma) [1]. 1 3 Acta Neurologica Belgica Fig. 3 The chi-square analysis displayed graphically in these bar A p = 0.85), while there is a mild significant association between charts shows that the presence of calcifications that is not sig- patients with and without contrast-enhancement of the lesion and the nificantly associated with the outcome of treated patients (PART outcome (PART B, p = 0.07) The clinical significance of CD34 expression and BRAF reported. Precisely as in Huse's case series, our study con- mutation was investigated in a recent publication aiming to firms that most tumors localize in the temporal lobe and study the relationship between biomolecular markers and that the most common radiological features include cystic clinical–pathological features [13]. The study found that change, focal enhancement, and calcification [15]. Benson while CD34 expression was significantly associated with a et al. [16] suggested that a well-circumscribed temporal lobe longer duration of epilepsy, BRAF mutation was associated [17] mass with central calcifications, peripheral cysts, and with multiple seizure types. It was suggested that BRAF- the heterogeneous internal signal should have raised suspi- mutant protein expression might influence neural networks, cion of a PLNTY. An oligodendroglioma may have dem- causing the abnormal discharge of various populations of onstrated many of these imaging features, but the findings neurons in different locations, which in turn may contribute favored a PLNTY. Most notably, oligodendrogliomas have to the occurrence of varying seizure patterns [8]. indistinct margins. Although the BRAF V600E genetic mutant may play a Few PLNTY cases of the following reported articles yield causative role in PLNTY’s growth and may be promising insufficient knowledge of radiology to apply to the diagnos- to pursue new medical therapy for PLNTY [5], no associa- tic setting. The only specific radiological study published tions are reported with the outcome of PLNTY patients. Our by Chen et al. [2] demonstrated that PLNTY has a wide study does not suggest a relationship between the expression radiological variability, with clinical outcomes not directly of BRAF or FGFR mutations with the risk of poor seizure dependent on the type of resection (Fig. 7). PLNTY typi- control after surgery or risk of recurrence [7]. Therefore, cally appears with hyperintense or mixed density on T2 while molecular features better explain the initial behavior magnetic resonance imaging (MRI) and hypointense or and clinic of PLNTY, we further considered in our initial mixed density on T1 imaging [2, 16], usually near the brain hypothesis if the anatomical and radiological features of the surface with frequent calcifications [17]. Calcifications are tumor may have peculiarities in post-surgical outcome. frequently seen on computed tomography (CT) images [3]. The most extensive published series of PLNTYs We can confirm that variable degrees of calcification are described by Huse et  al. [10] showed infiltrative growth observed with a confirmed diagnosis in most cases. In a and oligodendroglioma-like histopathology. In general, the study by Suldany et al. [5], 33% demonstrated enhancement extent of the lesion is considered smaller than the other epi- on post-gadolinium T1-weighted MR images for PLNTY. In leptogenic tumors [14]. However, this assertion is currently contrast, while in the case of oligodendroglioma, contrast- challenging to support, because from the cases reported enhancing is evaluated as a radiological feature of the tumor in the literature, only in ten patients were tumor diameters without any prognostic impact, we found that PLNTY may 1 3 Acta Neurologica Belgica Fig. 4 Chi-square comparison analysis shows the different outcomes from the patients treated with gross total resection (GTR), lobectomy, and partial resection (p = 0.38) be correlated with poorer control of epileptic symptomatol- borderline. The infiltrated growth patterns may explain the ogy. We suppose it may also be related to the slightly more unclear boundary with normal brain tissue in radiology [19]. aggressive behavior of the tumor. To better understand the characteristics of the tumor with The calcifications seen on MRI are also apparent in the a view to suboptimal surgical resection in our representa- histopathology of both tumors, and the general cell morphol- tive case, we evaluated DTI and spectroscopy values in ogy of PLNTY mimics oligodendroglioma closely [5]. suspicion of an early malignancy form. We identified that What is reported, however, is that in most cases, PLNTY within a multi-voxel study, only in a deep peri-callosal por- presents as a well-circumscribed tumor [5, 17] that tends tion of the tumor a mild and unremarkable choline peak was to be cystic and rich in calcifications [1 ], predominantly expressed compared to NAA (Fig. 1). The DTI study, on the located in the temporal lobe [17] and associated with corti- other hand, identified white matter fiber depreciation rather cal dysplasia. than prominent infiltration, a sign that the mass effect of the While all reported cases are shown as hyperintensity lesion appears to be minimal (but present) with minor per- in T2WI and iso- or hypointensity in T1WI with slight or ilesional edema. This finding confirmed what was reported no enhancement after contrast-enhanced, in some cases, by Chen et al. [2], the describes a slight decrease of NAA PLNTY tends to prominently show an infiltrative growth and increase of Cho in H1-MRS, without restricted diffu- pattern with adjacent tissue involvement and subpial exten- sion in DWI [6], and compression rather than disruption of sion and partly exhibit sharp borderline [17, 18]. In con- the fiber tracts in DTI, which all suggest the PLNTY to be a trast, other cases tend to have a completely well-defined low-grade, less aggressive neoplasm [2, 20]. 1 3 Acta Neurologica Belgica Fig. 5 The bar chart shows that cystis is not significantly associated with treated patients' outcomes for PLTNY. Chi-square test p = 0.39 Fig. 6 The chi-square analysis displayed graphically in this bar chart shows that the undefined limits of the lesion is not significantly associated with the outcome of treated patients (p = 0.34) The significant radiological variability present in the when it is poorly calcified and poorly defined in the margins, imaging of PLTNY does not only affect the different cases such a finding may represent an additional differential diag- reported in the literature [15–20]; in fact, we argue that such nostic feature concerning oligodendroglioma, as well as a variability is present macroscopically within the same lesion further difficulty in achieving complete resection. in the same patient, which is but also evident when the sur- Further investigation will be necessary to define the geon addresses the resection of the tumor mass, especially clinical implications of the imaging observations described 1 3 Acta Neurologica Belgica Fig. 7 The figure shows the comparison between the radio- logical images of two patients with a confirmed diagnosis of PLTNY: it is show in particular the high radiological variability that can occur in CT scanning and MRI. In the first patient, a lesion without calcifications (A), with very blurred margins (B) and without cysts in context (C) is documented, while in the second case, a well-localized lesion in the temporal lobe (D) with cysts in context (E) with well-defined margins (F) is appreciated herein. In particular, it will be important to re-evaluate Author contributions DA: writing, analysis, data curation, data collec- tion, review of literature; LVB: surgical operator, conceptualization, contrast-enhancement rates in other intra-axial pediatric supervising; AF: supervising, corrections; AS: supervising. and young adult brain tumors as current pathologic criteria define those entities. Funding Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. This research received no external funding. Data availability Not applicable, at request of corresponding author Conclusions (D.A.). Declarations PLNTYs exhibit an almost invariably benign clinical course and appear well controlled by surgical resection. Conflict of interest The authors certify that they have no affiliations The prototypical PLNTY is a well-circumscribed lesion with or involvement in any organization or entity with any financial in- with macroscopic calcification and a cystic component terest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, located peripherally within the posteroinferior temporal or other equity interest; and expert testimony or patent-licensing ar- lobe of a young patient. Still, from our recent analysis, its rangements), or non-financial interest (such as personal or professional radiological and clinical variability appears to be much relationships, affiliations, knowledge or beliefs) in the subject matter wider. Surgically, excision can be burdened by profound or materials discussed in this manuscript. The authors confirm their adherence to ethical standards and have no financial disclosures that tumor variability and difficulty identifying tumor margins. would be a potential conflict of interest with this publication. The molecular driving alterations, such as BRAF V600E and FGFR translocations, do not predict the post-surgical Human and animal ethics The study was conducted in accordance with outcome. On the radiological aspect, in PLNTY, contrast the Declaration of Helsinki. enhancement seems to impact prognosis, recurrence, and Consent for publication Informed consent was obtained from all sub- seizure control much more than radiological features of jects involved in the study. the tumor. Open Access This article is licensed under a Creative Commons Attri- Supplementary Information The online version contains supplemen- bution 4.0 International License, which permits use, sharing, adapta- tary material available at https://doi. or g/10. 1007/ s13760- 023- 02231-z . tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, Acknowledgements We confirm that the manuscript has been read and provide a link to the Creative Commons licence, and indicate if changes approved by all named authors and that there are no other persons who were made. The images or other third party material in this article are satisfied the criteria for authorship but are not listed. 1 3 Acta Neurologica Belgica included in the article's Creative Commons licence, unless indicated epileptogenic neoplasm with oligodendroglioma-like components, otherwise in a credit line to the material. 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