CNS Embryonal Tumor with PLAGL Amplification, a New Tumor in Children and Adolescents: Insights from a Comprehensive MRI Analysis

DISCUSSION

ET, PLAGL is a recently defined embryonal tumor primarily observed in children and adolescents and has not yet been included in the current 2021 WHO classification of CNS tumors. In this study, we present the MRI characteristics of this new tumor type for the first time and in the largest cohort so far, to raise awareness within the neuroradiology community.

We found no preferential localization with respect to the supra- or infratentorial space, though PLAGL2-amplified tumors were slightly more common in the supratentorial localization, but the low case number does not allow us to draw reliable conclusions. There were no tumors primarily located in the spinal cord. The supratentorial tumors frequently originated in the temporal and insular regions, extending into the deep gray matter, with two appearing to originate from the ventricular system. However, due to their often-substantial size, determining the primary region of origin was challenging. Among the infratentorial tumors, the brainstem was more frequently affected than the cerebellum. At the time of diagnosis, only one tumor was bifocal, indicating dissemination. The remaining tumors were not metastasized, yet only slightly more than one-half of the cases had undergone spine imaging, preventing a definitive exclusion of spinal dissemination.

In our cohort, a common MRI characteristic of both PLAGL1- and PLAGL2-amplified tumors was their often-multinodular structure, accompanied by nonsolid components representing cysts and/or necrotic areas. In some cases, the nonsolid appearance was more prominent, with only a few small nodules or non-nodular, solid components present. All tumors exhibited contrast enhancement that was intermediate to strong in most cases. The T2WI and FLAIR signals were heterogeneous, mainly iso- to mildly hyperintense, while the T1WI signal was primarily hypointense, unless there was calcification and/or hemorrhage present, which could alter the signal. Determining the frequency of hemorrhage and/or calcification was challenging, because T2* and SWI series were often not available. When these modalities were accessible, signal loss was consistently present. In most cases, though, we could not ascertain whether susceptibility were due to blood products or calcifications. ADC values in the solid parts were equal to or higher than those in normal-appearing WM in most cases and lower in a minority of cases. We were not able to identify a discernible pattern that distinguished between PLAGL1- and PLAGL2-amplified tumors. However, this issue is not surprising given the relatively low number of cases.

In our analysis, some ET, PLAGL tumors exhibited MRI characteristics seen in low-grade tumors, such as T2WI hyperintensity and little-or-no diffusion restriction. Like other embryonal tumors, including medulloblastoma, ET, PLAGL tumors are histopathologically defined by primitive, embryonal-like cells with numerous mitoses.⁴ Generally, such tumors exhibit T2WI hypointensity in at least parts of the lesion and demonstrate diffusion restriction, suggesting high cell density. However, these expected characteristics were rarely observed in our cases. Other embryonal CNS tumors, such as ATRT, ETMR, and CNS neuroblastoma-FOXR2,^6⇓⇓–9 also show high proliferation rates and can exhibit T2WI hyperintensity. However, they typically display strong diffusion restriction, which contrasts with most ET, PLAGL tumors in our cohort.

The reasons behind the relatively high T2WI signal and ADC values in these tumors remain unknown. It is well-known that DWI signals are influenced not only by cellularity and the nucleus-cytoplasm ratio, but also by myelin content,¹⁰ cell morphology, water compartments, and architectural variances in the respective anatomic region,¹¹ which are not fully captured by standard DWI. Advanced imaging techniques, such as neurite orientation dispersion and density imaging or diffusional kurtosis imaging, might be required to understand these aspects more comprehensively.^12,13 In our study, the presence of numerous necrotic regions, detectable both histologically and on MRI, could contribute to the T2WI hyperintensity and relatively high ADC values. This observation underscores the complexity and variability in imaging characteristics of ET, PLAGL, and other embryonal tumors. ADC values are traditionally regarded as a key parameter for differentiating high-grade from low-grade tumors and are particularly useful in distinguishing posterior fossa tumors in children,¹⁴ but the increasingly detailed 2021 WHO classification of CNS tumors may challenge some of the conventional imaging principles.

To date, the MRI phenotype of ET, PLAGL has not been systematically described. A recent case report of a 4-year-old girl with a PLAGL1-amplified tumor describes an exophytic pontine tumor with T2WI hypointensity, diffusion restriction, and moderate homogeneous enhancement.¹⁵ While these findings seem at odds with our results, the images provided closely match those from cases presented here; we would have characterized the tumor as T2WI isointense to cortical GM with intermediate, slightly heterogeneous enhancement, and no diffusion restriction according to our definition. However, a definitive assessment can obviously only be made with access to the full data set and highlights the need for standardized imaging criteria within the community. Additionally, a recent study by Tauziède-Espariat et al¹⁶ discussed two patients with PLAG1 fusions that showed epigenetic, radiologic, and histopathologic similarities to ET, PLAGL. In their study, while a detailed description was not provided, the images displayed similar characteristics such as T2WI iso- to hyperintensity, partially heterogeneous enhancement, signal loss on SWI, and no perifocal edema. However, on the basis of just two cases, it is challenging to conclusively group tumors with PLAG1 fusion and PLAGL1/2 amplification together. Furthermore, as observed in our study, reliably distinguishing these tumors from other, particularly embryonal, tumors remains difficult.

While patient age at diagnosis can be a helpful factor in narrowing down the differential diagnosis in other embryonal tumors, it is less clear in ET, PLAGL. For example, ATRT typically presents in children younger than 2 years of age,¹⁷ similar to PLAGL2-amplified tumors (median age, 1.9 years). Patients with PLAGL1-amplified tumors, with a median age of 7.3 years in our cohort, fall into the same age group as those with CNS neuroblastoma-FOXR2 (median age, 5–8 years) and are older than patients with CNS tumors with BCOR-ITD (median age, 4 years) or ETMR (median age, 2.5 years).¹⁸ The age of patients with PLAGL2-amplified tumors can also overlap with that of patients with BRAF V600E-mutated astrocytomas, a low-grade glioma that can have similar imaging characteristics with T2WI hyperintensity and occasional diffusion restriction.¹⁹ However, in our cohort, PLAGL1-amplified tumors could not be differentiated from PLAGL2-amplified tumors on the basis of imaging. Therefore, they must be summarized as a group with a median age of 3 years, which is similar to that of patients with ETMR. The imaging characteristics of ETMR, however, are distinct, typically characterized by T2WI hyperintensity, weak enhancement, and consistent diffusion restriction.⁸ Comparative studies on ADC values have been conducted on common pediatric posterior fossa tumors, including medulloblastoma, ependymoma, ATRT, pilocytic astrocytoma, and diffuse midline glioma,^20⇓–22 but, to our knowledge, are still lacking for rare embryonal tumors. On the basis of known comparative studies with common pediatric brain tumors, ET, PLAGL appears to have less diffusion restriction than medulloblastomas and ATRT but more than pilocytic astrocytomas and may be comparable with ependymomas.^20,22

This study has several limitations. First, the analysis was conducted retrospectively and on a relatively small number of cases, a common challenge when dealing with rare, newly described tumor entities. This feature underscores the importance of close collaboration among centers to collect sufficient cases, especially as tumor classification becomes increasingly detailed and results in inherently low case numbers. Another limitation is the variability and sometimes incompleteness of the MRI data, eg, missing SWI, T2*, or DWI, which hinders the systematic analysis. The adoption of standardized imaging protocols across centers treating patients with pediatric tumors would significantly mitigate this issue.²³ Additionally, the limited availability of advanced imaging techniques in our data set represents a considerable constraint.