9 岁男孩后颅窝肿瘤：具有 ETMR 样特征并伴 MIR17HG 扩增的胚胎性肿瘤A 9-year-old boy with a posterior fossa tumor (Embryonal tumor with ETMR-like features and MIR17HG amplification)

Scope: PMC open-access full text (CC BY-NC-ND 4.0) — virtual slide box, case presentation, findings, final diagnosis, discussion and Figures 1–2 with captions. Author contributions, conflict of interest and ethics statements and references are not included (bracketed numbers refer to the original reference list).

BOX 1 Virtual glass slide. Access at https://isn‐slidearchive.org/?&col=ISN&fol=Archive&file=ID‐6893255.svs; https://neuro2.pathology.pitt.edu/isn/brainpathology/underyourmicroscope?&col=ISN&fol=Archive&file=ID‐6893255‐2.svs.

CASE PRESENTATION

A 9‐year‐old boy presented with a 3‐week history of worsening dizziness and nausea and a 1‐week history of left‐sided neck pain and stiffness. Magnetic resonance imaging revealed a heterogeneous solid mass in the posterior fossa (26 × 20 × 33 mm), involving the fourth ventricle, left foramen of Luschka, and cerebellar vermis with mild heterogenous contrast enhancement (Figure 1). Gross total resection was obtained, followed by multimodal therapy, according to AIEOP protocols for high‐risk CNS embryonal tumors. Disease progression occurred 2 months later; the patient died at 9 months post‐diagnosis.

FINDINGS

At histological examination, the neoplasm was heterogeneous with: (i) densely cellular perivascular aggregates of primitive undifferentiated cells alternating with fibrillary neuropil‐like areas, a pattern commonly seen in embryonal tumor with multilayered rosettes (ETMR) (Figure 2A); (ii) limited areas containing a cystic structure and tubules lined by pseudostratified neoplastic neuroepithelium, showing mitoses through the entire thickness, resembling the primordial neural tube (medulloepithelioma pattern) (Figure 2B); and (iii) heterologous rhabdomyoblastic and chondroid areas (Figure 2C,D). The tumor showed focal expression of OLIG2, synaptophysin, LIN28, and SALL4 in the ETANTR and medulloepithelioma areas; GFAP was negative; desmin, myogenin, and MYOD1 were expressed in the rhabdomyoblastic areas and S100 in chondroid components (Figure 2E,F); H3K27me3 expression was lost throughout. Based on these findings, the preliminary diagnosis was embryonal tumor with features of embryonal tumor with multilayered rosettes (ETMR) and mesenchymal heterologous differentiation. PCR analysis detected no variants in DICER1 RNase IIIb hotspot regions. Methylation profiling classified the tumor as ETMR, non‐C19MC‐altered (novel) (score 0.99, v12.8), without amplification of the microRNA cluster on chromosome 19q13.42 (C19MC). Chromosomal microarray revealed 1.7‐Mb (13q31.3; MIR17HG/miR‐17‐92/part of GPC5 gene) and 1.5‐Mb (13q33.3q34; MYO16, IRS2, part of TNFSF13B gene) amplifications (Figure 2G). RNA‐seq identified novel IRS2::GPC5 and GPC5::MIR17HG fusions in the same region; together these findings suggest a complex 13q rearrangement. Additionally, mosaic alterations included gain of 1q, 2, and 7, and partial loss of 4p (Figure 2G). No pathogenic/likely pathogenic variants were identified (TruSight™ Oncology 500) (Box 1).

FINAL DIAGNOSIS

Embryonal tumor with ETMR‐like features and MIR17HG amplification (CNS WHO Grade 4).

DISCUSSION

The case presented exhibits several hallmark features of ETMR, including perivascular aggregates of primitive undifferentiated cells alternating with fibrillary neuropil‐like areas, focal medulloepithelioma‐like morphology, focal LIN28 expression, and alignment with the ETMR methylation profile. Additionally, the CNA profile was typical, with gains of chromosome 2, 1q, and 7, among the most common CNAs identified in ETMR [1]. The aggressive clinical course, characterized by poor response to multimodal therapy, was also consistent with ETMR. However, other features were unusual for this entity, deviating from the classical ETMR spectrum. First, the patient's age exceeded the range typically observed (0–4 years). In the largest series of molecularly proven ETMR, only 7/159 (4.4%) cases occurred in patients ≥5 years [1]. Second, the phenotype showed mesenchymal heterologous areas, rarely seen in typical ETMR. This finding raises the differential diagnosis with other pediatric entities such as teratomas with malignant mesenchymal/neuroectodermal components, medulloblastomas, or atypical teratoid/rhabdoid tumors (ATRT). LIN28 immunopositivity supports the diagnosis of ETMR but is not specific and may rarely occur in other tumors, including ATRT. In such cases, retained INI1 and BRG1 expression excludes ATRT. Interestingly, rhabdomyoblastic and chondroid areas have been reported in one infantile DICER‐driven ETMR [2]. Together with SALL4 expression and H3K27me3 loss, this suggested a possible DICER1‐related pathogenesis. However, molecular analysis did not confirm this hypothesis.

A third peculiar feature was amplification of the 13q31.3 region containing the miR‐17‐92 cluster (MIR17HG) and part of the GPC5 gene. To our knowledge, MIR17HG amplification has been reported in two ETMR lacking C19MC amplification and DICER1 mutation, and in one C19MC‐positive ETMR, all occurring in infants [1]. In our case, MIR17HG was also fused with Glypican‐5 (GPC5), likely placing the oncogenic miR‐17–92 cluster under GPC5 regulation. This resembles what is observed in C19MC‐positive ETMR, where C19MC amplification is supposed to be preceded by translocation with Tweety Family Member 1 (TTYH1) or rarer partner genes [1]. Interestingly, amplification of the 13q31‐32, encompassing MIR17HG and GPC5, has been reported in different histotypes, including rhabdomyosarcoma, mainly PAX3‐rearranged alveolar rhabdomyosarcoma [3]. In vitro and in vivo studies on rhabdomyosarcomas and uterine carcinosarcomas suggest a role for GPC5 in promoting sarcomatous differentiation. It may be speculated that the alterations of the 13q31.3, together with amplification of MYO16, mapping to the adjacent 13q33.3–q34 region, account for the mesenchymal heterologous areas by activating aberrant developmental programs. A detailed description of the histological features of previously reported MIR17HG‐amplified cases was not provided, preventing comparison with our case.

This case adds to the limited literature on embryonal tumors with MIR17HG amplification. Although some features are atypical for ETMR (age at onset, heterologous components), the overall findings support a close biological relationship to this entity, broadening its clinicopathological spectrum.