Pediatric thalamic incidentalomas: an international retrospective multicenter study

Danil A. Kozyrev Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel;

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Jehuda Soleman Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel;
Department of Neurosurgery and Pediatric Neurosurgery, University and Children’s Hospital of Basel, Switzerland;
Faculty of Medicine, University of Basel, Switzerland;

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Deki Tsering Division of Neurosurgery, Children’s National Medical Center, Washington, DC;

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Robert F. Keating Division of Neurosurgery, Children’s National Medical Center, Washington, DC;

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David S. Hersh Department of Surgery, St. Jude Children’s Research Hospital, Memphis, Tennessee;
Department of Surgery, Connecticut Children’s, Hartford, Connecticut; and
Departments of Surgery and Pediatrics, UConn School of Medicine, Farmington, Connecticut

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Frederick A. Boop Department of Surgery, St. Jude Children’s Research Hospital, Memphis, Tennessee;

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Pietro Spennato Department of Neurosurgery, Santobono-Pausilipon Children’s Hospital, Naples, Italy;

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Giuseppe Cinalli Department of Neurosurgery, Santobono-Pausilipon Children’s Hospital, Naples, Italy;

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Gianpiero Tamburrini Institute of Neurosurgery, Catholic University of the Sacred Heart, Milan, Italy;

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Ulrich-Wilhelm Thomale Pediatric Neurosurgery, Campus Virchow Klinikum, Charité Universitätsmedizin, Berlin, Germany;

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Robert J. Bollo Division of Pediatric Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah;

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Sandip Chatterjee Department of Neurosurgery, VIMS and Park Clinic, Kolkata, India;

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Harishchandra Lalgudi Srinivasan Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel;

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Shlomi Constantini Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel;

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Jonathan Roth Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel;

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OBJECTIVE

Widespread use of modern neuroimaging has led to a surge in diagnosing pediatric brain incidentalomas. Thalamic lesions have unique characteristics such as deep location, surgical complexity, and proximity to eloquent neuronal structures. Currently, the natural course of incidental thalamic lesions is unknown. Therefore, the authors present their experience in treating such lesions.

METHODS

A retrospective, international multicenter study was carried out in 8 tertiary pediatric centers from 5 countries. Patients were included if they had an incidental thalamic lesion suspected of being a tumor and were diagnosed before the age of 20 years. Treatment strategy, imaging characteristics, pathology, and the outcome of operated and unoperated cases were analyzed.

RESULTS

Overall, 58 children (23 females and 35 males) with a mean age of 10.8 ± 4.0 years were included. The two most common indications for imaging were nonspecific reasons (n = 19; e.g., research and developmental delay) and headache unrelated to small thalamic lesions (n = 14). Eleven patients (19%) underwent early surgery and 47 were followed, of whom 10 underwent surgery due to radiological changes at a mean of 11.4 ± 9.5 months after diagnosis. Of the 21 patients who underwent surgery, 9 patients underwent resection and 12 underwent biopsy. The two most frequent pathologies were pilocytic astrocytoma and WHO grade II astrocytoma (n = 6 and n = 5, respectively). Three lesions were high-grade gliomas.

CONCLUSIONS

The results of this study indicate that pediatric incidental thalamic lesions include both low- and high-grade tumors. Close and long-term radiological follow-up is warranted in patients who do not undergo immediate surgery, as tumor progression may occur.

ABBREVIATIONS

DWI = diffusion-weighted imaging; LGG = low-grade glioma; HGG = high-grade glioma; MT = malignant transformation; T1WI = T1-weighted imaging; T2WI = T2-weighted imaging.

OBJECTIVE

Widespread use of modern neuroimaging has led to a surge in diagnosing pediatric brain incidentalomas. Thalamic lesions have unique characteristics such as deep location, surgical complexity, and proximity to eloquent neuronal structures. Currently, the natural course of incidental thalamic lesions is unknown. Therefore, the authors present their experience in treating such lesions.

METHODS

A retrospective, international multicenter study was carried out in 8 tertiary pediatric centers from 5 countries. Patients were included if they had an incidental thalamic lesion suspected of being a tumor and were diagnosed before the age of 20 years. Treatment strategy, imaging characteristics, pathology, and the outcome of operated and unoperated cases were analyzed.

RESULTS

Overall, 58 children (23 females and 35 males) with a mean age of 10.8 ± 4.0 years were included. The two most common indications for imaging were nonspecific reasons (n = 19; e.g., research and developmental delay) and headache unrelated to small thalamic lesions (n = 14). Eleven patients (19%) underwent early surgery and 47 were followed, of whom 10 underwent surgery due to radiological changes at a mean of 11.4 ± 9.5 months after diagnosis. Of the 21 patients who underwent surgery, 9 patients underwent resection and 12 underwent biopsy. The two most frequent pathologies were pilocytic astrocytoma and WHO grade II astrocytoma (n = 6 and n = 5, respectively). Three lesions were high-grade gliomas.

CONCLUSIONS

The results of this study indicate that pediatric incidental thalamic lesions include both low- and high-grade tumors. Close and long-term radiological follow-up is warranted in patients who do not undergo immediate surgery, as tumor progression may occur.

In Brief

The authors sought to evaluate the natural history and pathological spectrum of incidental thalamic tumors in children from eight pediatric centers. The key finding was that thalamic incidentalomas in children included mostly low-grade lesions; however, high-grade lesions may also present as incidentalomas. Thus, radiological follow-up of lesions is mandatory, as even lesions with a typical low-grade appearance may evolve over time.

Brain incidental findings are common in the pediatric population, detected on 10% to 25% of all MRI studies.1–3 Of these incidental findings, about 0.2% represent brain neoplasms.2,3 The term “incidentaloma” refers to an asymptomatic intracranial lesion with the radiological characteristics of a space-occupying lesion that most likely represents a tumor.4,5 Incidentalomas have been diagnosed more often recently due to the widespread use of neuroimaging. They are found in all parts of the central nervous system, but there are limited data on the natural history of these lesions. Although rare, malignant transformation (MT) of even small and “benign-looking” incidental lesions has been reported.6 Currently, there is no consensus or widely accepted guideline on the management of incidental lesions. Hence, there is uncertainty regarding the optimal management strategy. Multiple factors can influence the management approach. Decisions are often influenced or even determined by the natural history, which remains unknown.7 The risk of surgery versus the potential risk of a conservative approach (e.g., tumor growth or MT) must be weighed individually. An incidental thalamic lesion often presents an even greater treatment dilemma due to its deep location, eloquent region, and the surrounding condensed functional tissue, further increasing surgical risk, even for biopsy.8 In light of these considerations, the current study of combined experience from 8 tertiary pediatric centers was designed to analyze the natural history, pathological spectrum, treatment, and outcome of thalamic incidentalomas in children.

Methods

Patient Selection

After receiving IRB approval at each center, we conducted an international retrospective, multicenter study. Patients were selected from the databases of 8 tertiary neurosurgical departments, based on personal communication among the authors (Table 1). Each center retrospectively collected data regarding children who fulfilled the inclusion criteria and were treated or followed by the pediatric neurosurgical team. There were no unified criteria that each center followed or by which they treated these children, and possibly, at some centers, the nonoperative cases were not managed by the neurosurgical team. Relevant data were collected from patient files, pathology reports, and the PACS imaging system for all patients treated between January 1, 2004, and December 31, 2018.

TABLE 1.

Participating pediatric centers

CenterNo. of PtsOp, n (%)
ImmediateDelayedTotal
Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv, Israel151 (7)2 (13)3 (20)
Children’s National Medical Center, Washington, DC, US142 (14)1 (7)3 (21)
St. Jude Children’s Research Hospital, Memphis, TN, US104 (40)2 (20)6 (60)
Santobono-Pausilipon Children’s Hospital, Naples, Italy82 (25)1 (12)3 (37)
Catholic University of the Sacred Heart, Milan, Italy501 (20)1 (20)
Campus Virchow Klinikum, Charité Universitätsmedizin, Berlin, Germany303 (100)3 (100)
University of Utah School of Medicine, Salt Lake City, UT, US22 (100)02 (100)
VIMS and Park Clinic, Kolkata, India1000 (0)
Total no.5811 (19)10 (17)21 (36)

Pts = patients.

Inclusion criteria were diagnosis of a presumed tumor that was considered unrelated to the primary imaging indication, age < 20 years at the time of the initial diagnosis, a lesion with a thalamic epicenter, and available MRI. Some patients, especially those presenting in a trauma context, also had a CT scan. A lesion was presumed to be a tumor by the treating team if it had the characteristics of a space-occupying lesion, and in the absence of any of the exclusion criteria.

Patients were excluded if they had unidentified bright objects that were not causing a mass effect, vascular lesions, lesions suspected of being inflammatory, predisposing cancer syndromes (e.g., neurofibromatosis, tuberous sclerosis, mismatch mutation repair syndrome, or Li-Fraumeni syndrome), and ventriculomegaly during presentation.

Indications for Imaging

The primary indication for imaging (presenting symptom) was considered unrelated to the thalamic lesion if its anatomical location or mass effect could not explain the presenting symptoms. This generalization was agreed on by all participating centers. An incidental tumor must have been noticed secondarily during workup for an unrelated reason that required neuroimaging, including head trauma, endocrinological changes, seizures, headaches, and others.

Headaches were considered unrelated to the lesion if a lesion was small, parenchymal, without significant mass effect, with no dural attachments, and not causing hydrocephalus. Tumors discovered during a workup for presenting seizures were also included as incidentalomas, since despite there being an entity known as “thalamic related seizures,”9,10 the conventional wisdom is that in the absence of associated hydrocephalus and secondary spread, thalamic lesions are rarely associated with seizures. Lesions not involving endocrine-related pathways (along the hypothalamic-pituitary axis) were considered unrelated to endocrinological changes. Other unrelated reasons for imaging included developmental delay, nonlocalized perception problems, and strabismus (Table 2). We assumed these symptoms to be unrelated to the lesions in the absence of any known anatomical association between the neurological symptom and lesion location.

TABLE 2.

Indications for imaging

IndicationNo. of PtsOp, n (%)
Unspecified*198 (42)
Headaches, unrelated146 (40)
Seizures, unrelated92 (22)
Workup of unrelated head/neck/spine condition71 (14)
Trauma related64 (67)
Endocrinopathy30 (0)
Total no.5821 (36)

Includes, for example, research, developmental delay, and behavioral changes.

Study Variables

We collected and analyzed data on patient demographics, imaging indications, anatomical location of the lesion, clinical symptoms, radiological characteristics of the lesion, and changes during follow-up.

Radiological characteristics included the following sequences of MRI: T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T1WI with contrast enhancement, FLAIR, and diffusion-weighted imaging (DWI). Any change from the baseline radiological character of the lesion observed on follow-up imaging was also noted. Radiological data regarding contrast enhancement were available for all patients; information about restricted diffusion on DWI was available for 55 of 58 patients. All images were reviewed by two of the authors to reach a consensus about eligibility.

For surgical cases, we analyzed the indications for surgery, time from diagnosis to surgery, need for repeat surgery, extent of resection, pathology, and additional treatment. No universal follow-up protocol was identified for patients in this series. In each case, treatment decisions were personalized based on the recommendations of the treating team and family preferences. There were no unified standardizations for treatment protocols; however, each center retrospectively categorized the indication for surgery according to the following options: tumor growth, physician recommendation, parental decision, and suspected high-grade tumor.

Anatomical Localization of Lesions

Based on the anatomical subdivision of the thalamus (location of major groups of thalamic nuclei11 and proximity to thalamic anatomical borders), we defined the lesion location within the thalamus as one of the following 5 regions: pulvinar (lesions in the posterior thalamus), medial (abutting the third ventricle), anterior, thalamopeduncular (relating to the lateral aspect, in close proximity to the internal capsule), and body (Fig. 1).

FIG. 1.
FIG. 1.

Illustration of thalamic lesion distribution by region. Numbers indicate the number of patients per region. Figure is available in color online only.

Data Collection and Statistical Analysis

Data were collected using FileMaker Pro version 16 (Claris International, Inc.). All statistical analyses were performed using IBM SPSS Statistics version 21.0 (IBM Corp.). Correlation testing was done using Pearson’s correlation test. Univariate analysis assessing possible factors influencing surgical treatment was done using Fisher’s exact test or the chi-square test for contingency analysis, and the Mann-Whitney U-test for continuous analysis. Multivariate analysis was done using logistic regression analysis of variables showing significance in the univariate analysis. Comparison between various patient groups was done using the log-rank test and presented as Kaplan-Meier curves. A p value < 0.05 was considered significant.

Results

Overall, 58 patients (23 females and 35 males) with thalamic incidentalomas were identified from the 8 centers (Table 1). The patient age at diagnosis varied from 21 months to 20 years (mean 10.8 ± SD 4.0 years). The most common indication for imaging was nonspecific, including developmental delay, research, and behavioral changes (n = 19) (Table 2). Headaches (n = 14) and seizures (n = 9) were the second and third most common indications for imaging, respectively.

The most common lesion location was pulvinar (n = 29). The medial thalamus was the second most common location (n = 17) (Fig. 1). There was no correlation found between the presenting symptoms and any specific lesion location.

The mean follow-up period was 56.5 ± 41.0 months (range 1.6–130.4 months).

Radiological Characteristics

Radiological characteristics are presented in Table 3. Almost all lesions were hyperintense on T2WI, and either hypointense or isointense on T1WI. Almost two-thirds of lesions had no contrast enhancement on MRI, and around 90% had no diffusion restriction and no cystic component. For the 21 surgically treated lesions, analysis of the correlations between pathology and other parameters revealed the following. The only homogeneous contrast-enhancing tumor with a biopsy was a high-grade glioma (HGG). Of the nonenhancing tumors, 86% were low-grade gliomas (LGGs) and 14% were HGGs (12 of 18 LGGs had no enhancement [66.7%] and 2 of 3 HGGs had no enhancement [66.7%]; p > 0.99). All heterogeneous contrast-enhancing tumors were LGG (n = 6) (p = 0.006). No significant correlation was seen between pathology and DWI (p = 0.0532) or lesion location (p = 0.198). Change in size was significantly more often in the HGG group (66.7% vs 5.6%, p = 0.018).

TABLE 3.

Radiological characteristics of thalamic incidentalomas

MRI ModalityNo. of Incidentalomas
T1WI
 Hypo26
 Hyper5
 Iso27
T2WI
 Hypo0
 Hyper56
 Iso2
T1WI + contrast
 Hetero12
 Homo6
 None43

Hetero = heterogeneous; homo = homogeneous; hyper = hyperintense; hypo = hypointense; iso = isointense.

Due to the limited number of patients in our surgical series, these correlations might create a wrong impression. For example, of 3 patients with homogeneous contrast-enhancing tumors, only 1 underwent surgery and pathology showed an HGG; 1 patient had a homogeneous enhancing lesion that was stable over 29 months and 1 patient was lost to follow-up. Of 11 patients with heterogeneous contrast-enhancing tumors, 6 underwent surgery and all the tumors proved to be LGGs, while the remaining 5 patients were stable.

Synchronous brain lesions were present in 1 patient (1.5%), displaying diffuse paraventricular signal changes without signs of hydrocephalus. This patient was initially followed; 27 months later, on lesion progression, surgery revealed a pilocytic astrocytoma.

Treatment Groups

Of the total 58 patients, 21 patients (36%) underwent 26 surgeries. Indications for surgery differed significantly between the centers (p = 0.024). At one center, parental preference was a leading indication for intervention. At another center, suspicion of a high-grade tumor was the main indication for intervention, although all final pathologies showed low-grade tumors. At a third center, physician recommendation was the leading cause for intervention. In general, across the participating centers, physician recommendations regarding early intervention were not standardized and were based on a wide variety of lesion characteristics such as size, contrast enhancement, or diffusion restriction.

The 21 initial surgeries (either immediate or delayed) included 12 biopsies, 5 gross-total resections, and 4 partial resections. Five patients underwent additional surgeries following an initial biopsy including 3 repeat biopsies and 2 resections. Both of the additional resections were done due to progression of known LGGs. Two repeat biopsies were done after a long follow-up period, due to new radiological changes of previously known tumors. The third repeat biopsy was indicated because the prior biopsy was nondiagnostic.

Immediate Surgery Group

Eleven patients (19%) underwent surgery shortly after diagnosis. Indications for intervention were either physician recommendation (n = 9, without elaboration on the exact reasoning) or a suspected HGG (n = 2; both proved to be LGGs) (Fig. 2). Five of the 11 patients had contrast enhancement, and 6 had a cystic component within the tumor. Only three patients had tumors that showed both radiological features. Of these, 1 patient had an HGG (WHO grade III astrocytoma) and underwent surgery due to physician recommendation; this tumor was homogeneously enhancing and had a cystic component.

FIG. 2.
FIG. 2.

Flowchart presenting the pathologies of the surgical and nonsurgical cases and other patient group separations. astro = astrocytoma; DNT = dysembryoplastic neuroepithelial tumor; phys = physician; pts = patients; radio = radiological; susp = suspected; II, III, IV = WHO grade II, III, IV.

Watch and Wait Group

Forty-seven patients (81%) were initially followed (Fig. 3), of whom 37 never underwent surgery. The mean time to surgery in the delayed surgery group was 11.4 ± 9.5 months. The mean follow-up for nonsurgical cases was 59.8 ± 41.6 months. No new symptoms developed during follow-up in this group. Thirty-seven unoperated lesions were stable radiologically. Three lesions showed minimal radiological changes; 1 decreased in size (Fig. 4) and 2 grew minimally.

FIG. 3.
FIG. 3.

MR images obtained in an 11-year-old girl who was asymptomatic with a left pulvinar incidentaloma (arrows). A: On routine examination, a suspected papilledema was found but was excluded on subsequent examinations. B: The patient continued to be asymptomatic, but serial imaging showed radiological progression of the lesion after 1.5 years of follow-up. C: The patient was planned for a stereotactic biopsy; however, repeat imaging just before surgery showed further lesion progression with a new enhancing component (arrowhead) and obstructive hydrocephalus. Histopathology showed a diffuse midline glioma that was WHO grade IV and H3K27M positive. Figure is available in color online only.

FIG. 4.
FIG. 4.

MR images obtained in a 13-year-old girl who experienced seizures that were subsequently fully controlled with antiepileptic medications. A: MR image showing a suspected incidentaloma of the left thalamus (arrow). B and C: The child has never undergone surgery and has been observed for 11 years with significant regression of the lesion. Figure is available in color online only.

The mean follow-up for the 37 patients with unoperated tumors (59.8 ± 41.6 months) was significantly different from that of the 10 patients who underwent delayed surgery, where marked radiological changes occurred at a mean of 9.71 ± 7.37 months after the first imaging (log-rank chi-square test = 7.38, p = 0.2) (Fig. 5).

FIG. 5.
FIG. 5.

Kaplan-Meier survival curve for developing radiological changes among the initially followed patients, in surgical (red) and nonsurgical (blue) cases. Figure is available in color online only.

Delayed Surgery Group

Ten of the 47 followed patients (21%) eventually underwent surgery at a mean of 11.4 ± 9.5 months after diagnosis. Indications for eventual surgery included tumor growth (n = 6), physician recommendation (n = 3), or parental preference (n = 1) (Fig. 2). Two of the delayed surgeries revealed HGGs. There was a slight difference in the mean time until radiological changes were found for LGGs (8.73 ± 8.88 months) versus HGGs (11.70 ± 7.37 months), but the difference was not significant (p = 0.355).

Tumor growth (p = 0.002) and new enhancement (p = 0.003; 2 of 3 patients with new enhancement underwent surgery) were the radiological parameters most associated with an eventual surgery during follow-up. Restriction of diffusion (p = 0.028) was significantly correlated with surgery; 3 patients with diffusion restriction on DWI MRI underwent surgery, 2 immediately and 1 after 1 month of follow-up. Thereby, tumor growth, new enhancement, and restriction on diffusion were associated with a proactive intervention strategy. The lesion sizes at the time of diagnosis and follow-up were not collected. Thus, we could not define a size or change-in-size threshold which correlated to the need for surgery or biopsy.

Parameters Not Associated With Surgery

The following parameters were not associated with surgical treatment at any time point: sex (p = 0.707), neurological symptoms at presentation (p = 0.985), lesion location (p = 0.169), T1WI (p = 0.409), T2WI (p = 0.53), contrast enhancement (p = 0.372), and age (p = 0.549). There was a significant association between the treating center and whether a patient underwent surgery or not (p = 0.031). On multivariate analysis, none of the tested variables listed above remained significant.

Histopathological Results and Subsequent Treatment

The pathology report confirmed a neoplastic process in all surgical cases, including 18 LGGs (6 of which were pilocytic astrocytomas) and 3 HGGs. Among the 10 tumors operated on after an initial follow-up period, 8 were low grade and 2 were high grade.

We found 1 patient with a presumed case of MT in the group that was initially observed. That child was initially monitored for almost 1.5 years with a stable lesion. After radiological progression (Fig. 3), a stereotactic biopsy was performed, showing a WHO grade IV astrocytoma. This case may present either MT or progression of a primarily high-grade tumor.

After histopathological confirmation, 6 patients received radiotherapy and 2 received chemotherapy. None of the patients received both treatment modalities. All 3 patients with HGGs received radiation therapy, 1 of whom received biological treatment also. No patients received treatment blindly without prior histopathological confirmation.

Discussion

To the best of our knowledge, this is the first study focusing on incidental pediatric thalamic tumors. The main take-home messages from this study are that incidental brain tumors may occur in any thalamic region and they include low- and high-grade tumors. Radiological characteristics did not correlate with tumor histology or with treatment approaches (surgery vs follow-up). This work is a continuation of our ongoing research in an effort to better understand the natural history and management approach of all pediatric brain incidentalomas.6,7,12–15 Thalamic incidentalomas pose a unique management dilemma. As the thalamus is deeply located, involved in many neurological circuits and functions, and surrounded by many highly functional regions, the pros and cons of surgery versus follow-up may differ from other brain regions.

Radiological Features of Incidental Lesions

Contrary to a prior publication stating that no clear radiological diagnostic criteria were identified that distinguished between presumably low- and high-grade tumors,13 our analysis of surgical cases showed some correlation between radiological features and pathology. However, the number of patients who underwent surgery is too small to deduce absolute treatment recommendations. Most lesions in our series were hypo- or isointense on T1WI, hyperintense on T2WI, and without diffusion restriction or contrast enhancement. All these features are presumed to be characteristics of low-grade brain tumors.16,17

In a previous study, we showed that incidental lesions of the infratentorial compartment that displayed contrast enhancement and restriction diffusion were more likely to require surgery at any point in time, either immediately after diagnosis or during the follow-up period.12 In the current study we were not able to find any correlation between radiological features of incidentally found thalamic lesions and their likelihood of receiving surgery. Malignant tumors that received surgery only after a period of follow-up showed obvious radiological changes (e.g., lesion growth and/or new contrast enhancement patterns) in later imaging.

Presenting Symptoms

No consensus exists within the medical literature regarding the term “incidentaloma,” as many colleagues are skeptical about the incidental nature of these lesions. In our series, 36 of 58 patients had some neurological symptoms (e.g., headaches and seizures). As discussed in other studies, small parenchymal lesions without significant mass effect, hydrocephalus, and/or dural involvement are unlikely to cause headaches.7,12,13,15 Thus, the presence of headaches in patients with such lesions would most likely be unrelated to the lesions. Similarly, small thalamic lesions are less likely to cause nonfocal neurological symptoms that are not explained anatomically.

Nine patients presented with seizures. Thalamic involvement in seizure circuits has been extensively studied. The term “centrencephalic seizures” was proposed 70 years ago by Penfield.18 From that time, discussions in the scientific literature9 about the role of the thalamus in seizure generation have been ongoing. Animal experiments regarding seizure origin suggest the cortex is responsible, but others favor the thalamic area.19,20 Although the thalamus may be involved in epileptic circuits, it is seldom the epileptogenic zone, and, thus, thalamic lesions are not presumed to cause seizures. Therefore, patients with a thalamic lesion presenting with seizures were still included in the current study.

Three patients presented with various endocrinological symptoms, including growth hormone deficiency and short stature. A recent work from our institution analyzed 17,445 MR images of 11,011 patients.14 From these patients, 524 were referred for MRI due to various endocrinological problems. In 13 of those patients (2.5%), incidental lesions with presumed neoplastic nature were diagnosed in various locations of the brain, including the thalamus. As thalamic lesions are located distant from the hypothalamic-pituitary-adrenal axis, we included them as incidentalomas.

MT of Incidental Lesions

The risk of MT of previously low-grade tumors in general, and specifically in the thalamus, is not clearly defined. Although in the pediatric population such a phenomenon has been estimated to be very rare,21 current data show an increasing number of reported cases of presumed low-grade tumors that underwent MT,6,22–24 including one presumed case (1.7%) from the present series.

Photon radiation is known to be a risk factor for MT.25 By comparison, the risk of MT following proton radiation treatment is unknown. Some preliminary data indicate that proton radiation treatment has reduced late toxicity and a lower rate of secondary tumors compared with photon radiation.26 One of the patients in the current study who was treated with proton radiation therapy after the initial biopsy eventually developed what appeared to be MT.

Molecular profiling might play a role in predicting the potential risk of MT. Pediatric low-grade brain tumors with a BRAF V600E mutation and CDKN2A deletions were shown to have a higher risk of MT.27,28 Specifically for pediatric thalamic gliomas, H3F3AK27M mutation was described as a possible risk factor for MT or histopathological grade progression.23 However, some authors have described this mutation itself as a predictor for a dismal prognosis similar to that of a diffuse intrinsic pontine glioma (regardless of histopathological grading).29 More studies are needed to have enough solid data for clinical recommendations.

Management Approach

This series represents the cumulative experience of 8 tertiary centers with different treatment approaches to incidental thalamic lesions. Currently, decision-making for thalamic incidentalomas is not standardized, with different indications and thresholds for surgery. We found that some centers favor early intervention while others are more conservative. The lack of a generally accepted treatment protocol for these patients reflects the differences between centers in management approach. Through these large multicenter studies, we have been trying to identify common factors and patterns in incidentaloma presentation and treatment. For example, in our previous work, we created a general protocol for management of pediatric posterior fossa incidentalomas based on characteristics of posterior fossa lesions.12

However, data regarding thalamic incidentalomas are limited. In a recent study from Boston Children’s Hospital, incidental lesions in the thalamus were discovered in 26 patients. None of them underwent surgical intervention,21 although 3 lesions grew during the follow-up period. Our cumulative data show that 19% of the current series (11/58) underwent surgery immediately after diagnosis, and another 17% (10/58) underwent delayed surgery due to tumor growth and/or changes in radiological characteristics. In total, over one-third of the patients in our series underwent surgery. Three patients had malignant tumors, including 2 with tumors that had undergone MT. Such a stark difference from the Boston series may represent the different treatment indications in each of the participating groups. As natural history is unknown, the same lesion can be managed differently depending on the treating center, but given the rarity of thalamic incidentalomas, the differences may simply be a function of the low numbers.

Treatment strategies for children with thalamic incidental lesions are complex and should take multiple factors into consideration. The patient’s family must be part of a comprehensive discussion regarding all aspects of the disease and various other considerations.

Lesions that show changes in radiological characteristics and/or growth should prompt early intervention. Histopathology and molecular profiles might be employed for more accurate prediction of possible MT and further management options; however, the value of early treatment on reducing the rate of MT and on the overall survival is unknown. Lesions that are stable may be followed clinically and radiologically. Many of them may never require intervention; nevertheless, they should still be followed, as MT may occur even after a prolonged period (Fig. 3). Lesions that are stable over a period of initial close observation may be followed with increasing time gaps between imaging, with intervals increasing from 3 to 6 to 12 months. Continued stability may enable increasing the time gap even more.

Limitations

This retrospective study has several limitations. The first is selection bias. In some centers, neurosurgeons follow only surgical cases, and oncologists and neurologists follow nonsurgical cases, while in other centers neurosurgeons follow both surgical and nonsurgical cases. This can partially explain the differences in the number of surgical cases added to this study from the different centers, as well as treatment patterns (conservative vs surgical). Another major limitation is the lack of rigid criteria to define a lesion, other than as “presumably a tumor.” Especially for relatively small lesions, there is no accepted radiological technique (including advanced techniques such as MR spectroscopy, PET, and radiomics) to differentiate neoplastic from nonneoplastic lesions and to determine the grade of the neoplastic lesions.6,12 Thus, potentially different centers (and even different surgeons at the same center) may include or exclude various lesions differently. However, to minimize variability, representative images of all cases were sent to the lead authors and centrally reviewed to achieve an agreement regarding the mass effect and localization.

Patients were not routinely and uniformly assessed for inflammatory processes (such as lumbar tap, full CNS MRI, and other supplementary tests). There was no uniform treatment protocol, and indications for surgery were not specified or agreed on and were determined individually based on each surgeon’s and center’s approach. Also, “physician recommendation” was not elaborated on and no additional reasoning was provided; thus, we could not fully state the surgical indication.

Another weakness of this study is the relatively short and limited follow-up. The study lacks centralized radiological reviewing, as well as quantification of lesion volume and change in volume or enhancement over time. Thus, we cannot quantify “radiological changes” or compare them between groups. The timing of imaging and follow-up periods was based on preferences of the treating teams and not on objective data. Additionally, for obvious reasons, lesions that were only followed did not have histopathological proof of a neoplastic nature and may still represent other pathologies like inflammatory changes or hamartomas. Finally, only cases without obvious correlations between the lesions and symptoms like headaches and seizures were included. However, even small and supposedly asymptomatic lesions may theoretically cause headaches, seizures, and other symptoms. Despite these limitations, this work potentially adds to our knowledge of incidentalomas in the thalamic region. The joint efforts of centers dealing with this pathology, including prospective studies, are needed to shed light on the natural history of these tumors and enable creation of evidence-based management protocols for such lesions.

Conclusions

Thalamic incidentalomas represent a diverse group of lesions, including low- and high-grade tumors. The majority of these lesions are presumed to be low grade and require radiological follow-up. MT is rare but may occur. Any changes in clinical or radiological characteristics should prompt early surgery with tissue sampling for histopathological analysis and molecular profiling.

Acknowledgments

We would like to thank Yaroslava A. Kozyreva for the drawing included in this article and Mrs. Adina Sherer for linguistic editing and valuable comments.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Roth, Kozyrev, Constantini. Acquisition of data: Roth, Kozyrev, Tsering, Keating, Hersh, Boop, Spennato, Cinalli, Tamburrini, Thomale, Bollo, Chatterjee. Analysis and interpretation of data: Roth, Kozyrev, Soleman. Drafting the article: Roth, Kozyrev, Lalgudi Srinivasan. Critically revising the article: Roth, Kozyrev, Soleman, Keating, Hersh, Boop, Spennato, Cinalli, Tamburrini, Thomale, Bollo, Chatterjee, Lalgudi Srinivasan, Constantini. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Roth. Statistical analysis: Kozyrev, Soleman. Administrative/technical/material support: Constantini. Study supervision: Roth, Kozyrev, Constantini.

References

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    • Crossref
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    Jansen PR, Dremmen M, van A, Dekkers den Berg IA, Blanken LME, Muetzel RL, et al. Incidental findings on brain imaging in the general pediatric population. N Engl J Med. 2017;377(16):15931595.

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    Li Y, Thompson WK, Reuter C, Nillo R, Jernigan T, Dale A, et al. Rates of incidental findings in brain magnetic resonance imaging in children. JAMA Neurol. 2021;78(5):578587.

    • Crossref
    • PubMed
    • Search Google Scholar
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  • 4

    Morris Z, Whiteley WN, Longstreth WT Jr, Weber F, Lee YC, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009;339:b3016.

    • Crossref
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    Perret C, Boltshauser E, Scheer I, Kellenberger CJ, Grotzer MA. Incidental findings of mass lesions on neuroimages in children. Neurosurg Focus. 2011;31(6):E20.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Soleman J, Roth J, Ram Z, Yalon M, Constantini S. Malignant transformation of a conservatively managed incidental childhood cerebral mass lesion: controversy regarding management paradigm. Childs Nerv Syst. 2017;33(12):21692175.

    • Crossref
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    Roth J, Soleman J, Paraskevopoulos D, Keating RF, Constantini S. Incidental brain tumors in children: an international neurosurgical, oncological survey. Childs Nerv Syst. 2018;34(7):13251333.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    McGirt MJ, Woodworth GF, Coon AL, Frazier JM, Amundson E, Garonzik I, et al. Independent predictors of morbidity after image-guided stereotactic brain biopsy: a risk assessment of 270 cases. J Neurosurg. 2005;102(5):897901.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Blumenfeld H. The thalamus and seizures. Arch Neurol. 2002;59(1):135137.

  • 10

    Kelemen A, Barsi P, Gyorsok Z, Sarac J, Szűcs A, Halász P. Thalamic lesion and epilepsy with generalized seizures, ESES and spike-wave paroxysms—report of three cases. Seizure. 2006;15(6):454458.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Sheridan N, Tadi P. Neuroanatomy. Thalamic Nuclei. StatPearls Publishing;2020.

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    Kozyrev DA, Constantini S, Tsering D, Keating R, Basal S, Roth J. Pediatric posterior fossa incidentalomas. Childs Nerv Syst. 2020;36(3):601609.

  • 13

    Soleman J, Kozyrev DA, Ben-Sira L, Constantini S, Roth J. Management of incidental brain tumors in children: a systematic review. Childs Nerv Syst. 2020;36(8):16071619.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Brener A, Kozyrev DA, Shiran SI, Azoulay E, Pratt LT, Precel R, et al. Incidental findings on brain magnetic resonance imaging (MRI) in pediatric endocrine patients. Endocr Pract. 2020;26(10):11051114.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Roth J, Keating RF, Myseros JS, Yaun AL, Magge SN, Constantini S. Pediatric incidental brain tumors: a growing treatment dilemma. J Neurosurg Pediatr. 2012;10(3):168174.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wright E, Amankwah EK, Winesett SP, Tuite GF, Jallo G, Carey C, et al. Incidentally found brain tumors in the pediatric population: a case series and proposed treatment algorithm. J Neurooncol. 2019;141(2):355361.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ali ZS, Lang SS, Sutton LN. Conservative management of presumed low-grade gliomas in the asymptomatic pediatric population. World Neurosurg. 2014;81(2):368373.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Penfield W. Epileptic automatism and the centrencephalic integrating system. Res Publ Assoc Res Nerv Ment Dis.1952;30:513528.

  • 19

    Prince DA, Farrell D. “Centrencephalic” spike and wave discharges following parenteral penicillin injection in the cat. Neurology. 1969;19:309310.

  • 20

    Vergnes M, Marescaux C, Micheletti G, Reis J, Depaulis A, Rumbach L, Warter JM. Spontaneous paroxysmal electroclinical patterns in rat: a model of generalized non-convulsive epilepsy. Neurosci Lett. 1982;33(1):97101.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Zaazoue MA, Manley PE, Kapur K, Ullrich NJ, Silvera VM, Goumnerova LC. Natural history and management of incidentally discovered focal brain lesions indeterminate for tumor in children. Neurosurgery. 2020;86(3):357365.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Broniscer A, Baker SJ, West AN, Fraser MM, Proko E, Kocak M, et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol. 2007;25(6):682689.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Ishibashi K, Inoue T, Fukushima H, Watanabe Y, Iwai Y, Sakamoto H, et al. Pediatric thalamic glioma with H3F3A K27M mutation, which was detected before and after malignant transformation: a case report. Childs Nerv Syst. 2016;32(12):24332438.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Winograd E, Pencovich N, Yalon M, Soffer D, Beni-Adani L, Constantini S. Malignant transformation in pediatric spinal intramedullary tumors: case-based update. Childs Nerv Syst. 2012;28(10):16791686.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Parsa CF, Givrad S. Juvenile pilocytic astrocytomas do not undergo spontaneous malignant transformation: grounds for designation as hamartomas. Br J Ophthalmol. 2008;92(1):4046.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Mizumoto M, Oshiro Y, Yamamoto T, Kohzuki H, Sakurai H. Proton beam therapy for pediatric brain tumor. Neurol Med Chir (Tokyo). 2017;57(7):343355.

  • 27

    Frazão L, do Carmo Martins M, Nunes VM, Pimentel J, Faria C, Miguéns J, et al. BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions—markers in the clinical stratification of pediatric gliomas. BMC Cancer. 2018;18(1):1259.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol. 2015;33(9):10151022.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20(1):123131.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand

Illustration from Kozyrev et al. (pp 141–149).

  • FIG. 1.

    Illustration of thalamic lesion distribution by region. Numbers indicate the number of patients per region. Figure is available in color online only.

  • FIG. 2.

    Flowchart presenting the pathologies of the surgical and nonsurgical cases and other patient group separations. astro = astrocytoma; DNT = dysembryoplastic neuroepithelial tumor; phys = physician; pts = patients; radio = radiological; susp = suspected; II, III, IV = WHO grade II, III, IV.

  • FIG. 3.

    MR images obtained in an 11-year-old girl who was asymptomatic with a left pulvinar incidentaloma (arrows). A: On routine examination, a suspected papilledema was found but was excluded on subsequent examinations. B: The patient continued to be asymptomatic, but serial imaging showed radiological progression of the lesion after 1.5 years of follow-up. C: The patient was planned for a stereotactic biopsy; however, repeat imaging just before surgery showed further lesion progression with a new enhancing component (arrowhead) and obstructive hydrocephalus. Histopathology showed a diffuse midline glioma that was WHO grade IV and H3K27M positive. Figure is available in color online only.

  • FIG. 4.

    MR images obtained in a 13-year-old girl who experienced seizures that were subsequently fully controlled with antiepileptic medications. A: MR image showing a suspected incidentaloma of the left thalamus (arrow). B and C: The child has never undergone surgery and has been observed for 11 years with significant regression of the lesion. Figure is available in color online only.

  • FIG. 5.

    Kaplan-Meier survival curve for developing radiological changes among the initially followed patients, in surgical (red) and nonsurgical (blue) cases. Figure is available in color online only.

  • 1

    Gur RE, Kaltman D, Melhem ER, Ruparel K, Prabhakaran K, Riley M, et al. Incidental findings in youths volunteering for brain MRI research. AJNR Am J Neuroradiol. 2013;34(10):20212025.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Jansen PR, Dremmen M, van A, Dekkers den Berg IA, Blanken LME, Muetzel RL, et al. Incidental findings on brain imaging in the general pediatric population. N Engl J Med. 2017;377(16):15931595.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Li Y, Thompson WK, Reuter C, Nillo R, Jernigan T, Dale A, et al. Rates of incidental findings in brain magnetic resonance imaging in children. JAMA Neurol. 2021;78(5):578587.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Morris Z, Whiteley WN, Longstreth WT Jr, Weber F, Lee YC, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009;339:b3016.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Perret C, Boltshauser E, Scheer I, Kellenberger CJ, Grotzer MA. Incidental findings of mass lesions on neuroimages in children. Neurosurg Focus. 2011;31(6):E20.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Soleman J, Roth J, Ram Z, Yalon M, Constantini S. Malignant transformation of a conservatively managed incidental childhood cerebral mass lesion: controversy regarding management paradigm. Childs Nerv Syst. 2017;33(12):21692175.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Roth J, Soleman J, Paraskevopoulos D, Keating RF, Constantini S. Incidental brain tumors in children: an international neurosurgical, oncological survey. Childs Nerv Syst. 2018;34(7):13251333.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    McGirt MJ, Woodworth GF, Coon AL, Frazier JM, Amundson E, Garonzik I, et al. Independent predictors of morbidity after image-guided stereotactic brain biopsy: a risk assessment of 270 cases. J Neurosurg. 2005;102(5):897901.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Blumenfeld H. The thalamus and seizures. Arch Neurol. 2002;59(1):135137.

  • 10

    Kelemen A, Barsi P, Gyorsok Z, Sarac J, Szűcs A, Halász P. Thalamic lesion and epilepsy with generalized seizures, ESES and spike-wave paroxysms—report of three cases. Seizure. 2006;15(6):454458.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Sheridan N, Tadi P. Neuroanatomy. Thalamic Nuclei. StatPearls Publishing;2020.

  • 12

    Kozyrev DA, Constantini S, Tsering D, Keating R, Basal S, Roth J. Pediatric posterior fossa incidentalomas. Childs Nerv Syst. 2020;36(3):601609.

  • 13

    Soleman J, Kozyrev DA, Ben-Sira L, Constantini S, Roth J. Management of incidental brain tumors in children: a systematic review. Childs Nerv Syst. 2020;36(8):16071619.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Brener A, Kozyrev DA, Shiran SI, Azoulay E, Pratt LT, Precel R, et al. Incidental findings on brain magnetic resonance imaging (MRI) in pediatric endocrine patients. Endocr Pract. 2020;26(10):11051114.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Roth J, Keating RF, Myseros JS, Yaun AL, Magge SN, Constantini S. Pediatric incidental brain tumors: a growing treatment dilemma. J Neurosurg Pediatr. 2012;10(3):168174.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wright E, Amankwah EK, Winesett SP, Tuite GF, Jallo G, Carey C, et al. Incidentally found brain tumors in the pediatric population: a case series and proposed treatment algorithm. J Neurooncol. 2019;141(2):355361.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ali ZS, Lang SS, Sutton LN. Conservative management of presumed low-grade gliomas in the asymptomatic pediatric population. World Neurosurg. 2014;81(2):368373.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Penfield W. Epileptic automatism and the centrencephalic integrating system. Res Publ Assoc Res Nerv Ment Dis.1952;30:513528.

  • 19

    Prince DA, Farrell D. “Centrencephalic” spike and wave discharges following parenteral penicillin injection in the cat. Neurology. 1969;19:309310.

  • 20

    Vergnes M, Marescaux C, Micheletti G, Reis J, Depaulis A, Rumbach L, Warter JM. Spontaneous paroxysmal electroclinical patterns in rat: a model of generalized non-convulsive epilepsy. Neurosci Lett. 1982;33(1):97101.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Zaazoue MA, Manley PE, Kapur K, Ullrich NJ, Silvera VM, Goumnerova LC. Natural history and management of incidentally discovered focal brain lesions indeterminate for tumor in children. Neurosurgery. 2020;86(3):357365.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Broniscer A, Baker SJ, West AN, Fraser MM, Proko E, Kocak M, et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol. 2007;25(6):682689.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Ishibashi K, Inoue T, Fukushima H, Watanabe Y, Iwai Y, Sakamoto H, et al. Pediatric thalamic glioma with H3F3A K27M mutation, which was detected before and after malignant transformation: a case report. Childs Nerv Syst. 2016;32(12):24332438.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Winograd E, Pencovich N, Yalon M, Soffer D, Beni-Adani L, Constantini S. Malignant transformation in pediatric spinal intramedullary tumors: case-based update. Childs Nerv Syst. 2012;28(10):16791686.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Parsa CF, Givrad S. Juvenile pilocytic astrocytomas do not undergo spontaneous malignant transformation: grounds for designation as hamartomas. Br J Ophthalmol. 2008;92(1):4046.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Mizumoto M, Oshiro Y, Yamamoto T, Kohzuki H, Sakurai H. Proton beam therapy for pediatric brain tumor. Neurol Med Chir (Tokyo). 2017;57(7):343355.

  • 27

    Frazão L, do Carmo Martins M, Nunes VM, Pimentel J, Faria C, Miguéns J, et al. BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions—markers in the clinical stratification of pediatric gliomas. BMC Cancer. 2018;18(1):1259.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol. 2015;33(9):10151022.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20(1):123131.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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