Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system (CNS) and comprises approximately 48.6% of primary malignant brain tumors and approximately 57.7% of all gliomas (1). Recently, with a better understanding of the biological behavior of GBM, the long-held dogma that GBM does not metastasize outside the brain has been overturned. A growing number of reports have documented extracranial metastasis in GBM (2). Though highly invasive, the extracranial metastases of GBM are rare, with an incidence estimated at 0.4%-2% (3). The majority of extracranial metastases occur after craniotomy, but spontaneous metastasis has also been documented (4). Usually, extracranial metastases are not discovered until the very advanced stage of the course of GBM, and the median duration from detection of extracranial metastases to death is 1.5 months (range: 0–14 months) (2). The pathogenesis of extracranial metastasis of GBM remains unclear, and effective treatment strategies are lacking. Further case studies are therefore needed to better understand disease processes.

GBM with primitive neuronal component (GBM-PNC) is an emerging variant of GBM introduced in the new WHO classification of tumors of the CNS in 2016 and was renamed from “glioblastoma with primitive neuroectodermal tumor (PNET)-like component” (5). On histology, PNC is detected in about 0.5% of GBM cases (6). GBM-PNC is widely regarded as an aggressive malignant tumor with a high risk of metastasis and short survival (7). Most previous reports on this rare entity are case reports or case series with limited sample size, and the documentation of extracranial metastases from GBM-PNC is scarce. Consequently, the diagnosis and treatment of GBM-PNC are not yet established, and extracranial metastases from this tumor pose a formidable challenge to clinicians.

Here, we describe a case of GBM-PNC with extensive axial skeletal extracranial metastases without local recurrence, treated with three surgeries and chemoradiotherapy. The particularity of clinical manifestations and the results of histological and genetic examinations are briefly discussed.

In this report, we focused on the unusual extensive osteophilic extracranial metastases from GBM-PNC, a rare concomitance of two highly malignant CNS tumor components, glioblastoma and PNC (previously called PNET). Given its rarity, the diagnosis, treatment, and investigation of GBM-PNC are difficult. Since the awareness of this uncommon entity, around 200 cases of GBM-PNC have been reported, of which many were sporadic (6, 7, 16–18). To our knowledge, this is the first report of extensive skeletal metastases from GBM-PNC with complete information about multiple surgical interventions for both intracranial and spinal lesions. The present case adds practical information about the treatment and outcome of this challenging GBM subtype.

Studies on composite CNS tumors with malignant glial and neuronal elements can be traced back to 1973, when the nomenclature of “primitive neuroectodermal tumor” was proposed by Hart and Earle (19, 20). However, early reports adopted an unfocused concept, the “malignant glioneuronal tumors” (MGNT), with pathological features of the glial component resembling astrocytoma or other lower-grade gliomas instead of GBM in most cases (19). Varlet et al. reported 40 cases of MGNT, of which five had PNET-like foci, and only two were confirmed as GBM-PNC (21). In 2001, Wharton et al. first identified primitive neuroepithelial components in gliosarcoma, a variant of GBM, making it the first report of GBM-PNC in broad terms (22). The first case series was published in 2009 by Perry and colleagues (7). The 53 enrolled patients were defined as CNS malignant glioma with PNET components, including 47 GBM-PNCs. Highly aggressive biology, 9.1-month median survival, anaplastic hypercellular PNC, up to 40% of cerebrospinal fluid (CSF) dissemination, and possible application of platinum-based chemotherapy were reported by the authors. The latest and largest cohort was studied by Suwala et al., who reported a distinct methylation profile with frequent alterations of TP53 in 63 cases of GBM-PNC (17).

Extracranial metastases are rare, seen in only 0.4%–2% of GBMs (3, 4, 23, 24). The low incidence of extracranial metastases is associated with the short survival and intrinsic blood–brain barrier (2). Recently, a growing number of related cases and the detection of circulating GBM tumor cells have confirmed the ability of GBM to develop extracranial metastases (25, 26). Bearing in mind inconsistencies in time-frame and inclusion criteria, previous literature reviews identified 79–150 cases of extracranial or extra-CNS metastases from GBM, and the most prevalent extracranial metastases sites were bone, lung, lymph nodes, and liver (2, 25, 27–30). Extracranial metastases of GBM were also reported in pediatric patients and cases with the absence of previous neurosurgical intervention (31–33). Goodwin and colleagues reviewed 28 cases of GBM metastases to the vertebra, with a mean age at presentation of 38.4 years and an average overall survival of 26 months, of which seven patients received surgery for vertebral metastases (34). After a systematic search on Medline, Embase, and Google Scholar, we retrieved 25 cases of GBM-PNC with extracranial metastases from 14 reports ( Table 2 ) (7, 16, 17, 22, 35–44). CSF dissemination occurred in 88% (22/25) of the patients, whereas only 4 patients (16%) suffered bone metastases. The age at diagnosis and overall survival ranged from 17 to 65 years and 2 to 31 months, respectively.

The young age at onset, hemorrhagic cystic morphology, restricted diffusion on diffusion-weighted imaging, and the Ki-67 labeling index >40% in the present case indicate co-existence of PNET-like component, which necessitate further histological screening for PNC in supposed typical GBM (7, 44–47). Grossly, the tissues of primary and metastatic lesions were all very fragile and loose, and thus prone to any accidental pinching or squashing during the surgical resection and/or specimen processing. Consequently, the micromorphology might be altered. This may be partly responsible for the more atypical geometric distribution and less clear interfaces between GBM and PNC areas in this case, compared with the well-demarcated nodular PNC within a GBM background in previous reports (7, 18, 44). An elevated proportion of PNC in metastatic lesions was observed, which suggests the invasiveness of PNC (7, 48, 49). The PNC in this case showed characteristics of both central (originating from brain parenchyma and absence of EWSR1 rearrangement) and peripheral (CD99⁺) PNET (50, 51). Peripheral PNET belongs to the Ewing sarcoma family of tumors that are common in bone and soft tissue (52). Therefore, the significant predilection of metastases for osseous tissue in this patient may be attributed to the existence of PNC.

The incidence of TP53 mutation is higher in GBM-PNC than in typical GBM (73%–80% vs. 25%–30%) (17, 53). Inactivation of p53 is linked to increased cell proliferation, neoplastic invasion, and a more stem-like phenotype (54). Therefore, the mutant TP53 identified in this case may account for the aggressiveness and extensive extracranial metastases. Our patient’s stop-gain mutation in DNMT3A was previously reported in an overgrowth syndrome with intellectual disability, but he did not exhibit the phenotype described by the authors (55). DNMT3A encodes DNA methyltransferase, and is frequently mutated in acute myeloid leukemia (56). This gene can also influence the prognosis of GBM by methylation of microRNAs (57). Because GBM-PNC has a unique DNA methylation profile, certain DNMT3A mutations may negatively affect the prognosis of GBM-PNC at the epigenome level, but further mechanism study is needed (14, 17).

The treatment dilemma of GBM-PNC lies in the co-occurrence of two histological components that have distinct clinicopathological features, responses to drugs, and prognoses. Hence, the therapeutic rationale for GBM-PNC is to combine the standard treatment for GBM with adequate coverage for PNC, to lower the risk of recurrence and extracranial metastases (6). Maximal resection of the intracranial lesion followed by radiotherapy is essential. The Stupp protocol (applied in the present case) and/or craniospinal irradiation with adjuvant TMZ can be selected according to the histological predominance of GBM or PNC (58, 59). If the adverse effects are tolerated, concomitant platinum−based chemotherapy for PNC should also be implemented (7, 41, 42, 46, 60, 61). In hypermutated GBM-PNCs, checkpoint blockade immunotherapy can be considered (40). In dealing with spinal metastasis, early detection can lead to a better prognosis. Therefore, in addition to brain MRI, surveillance MRI of the total spine is recommended, and a further PET/CT under the condition of positive findings on MRI, given the high risk of CSF dissemination in GBM-PNC (36, 62). A comprehensive evaluation based on the neurologic, oncologic, mechanical instability, and systemic disease (NOMS) decision framework is indispensable (63). Notably, the oncologic part refers to the predicted response to available therapies. More aggressive open surgical strategies, including corpectomy and en-bloc resection, are judicious in cases with severe spinal instability, high-grade metastatic epidural spinal cord compression, and a relatively good general status (64). Enhanced collaborations between radiation oncologists and spine surgeons are crucial for optimizing stereotactic spine radiotherapy, minimizing radiation-related wound complications, and avoiding excessive surgery (65).

The primary limitation of the present study is the limited significance and low level of evidence, which are intrinsic properties of a single case. Secondly, the genetic tests of the tissue samples from the three operations used inconsistent platforms and methods, which made it unfeasible to analyze the evolution of molecular profiles from primary to metastatic lesions. Another weakness was the lack of treatment targeting PNC in this patient. Future studies on multimodality treatment with long−term follow-up are imperative to optimize the therapeutic algorithm for GBM-PNC (6).

In conclusion, the present case study and review of the literature summarizes the clinical, histological, and genetic features of GBM-PNC and highlights the occurrence and severity of extensive extracranial metastases. This rare variant of GBM requires aggressive multimodal treatment, including surgery, standard chemoradiotherapy for typical GBM, and the early introduction of craniospinal irradiation and platinum−based chemotherapy for PNET-like components. Given the lack of clear diagnostic work-flow, the vigilance for PNC in supposed typical GBM should be kept in mind, and the pathological screening of PNC is recommended in patients with early onset and intratumoral hemorrhage to avoid diagnosis delay and facilitate timely treatment. Spine surgery for axial skeletal metastasis from GBM-PNC is appropriate in patients with chemoradioresistance and relatively good general status, with the objectives of restoring spinal stability and relieving spinal cord compression.

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Institutional Review Board, Beijing, Tiantan Hospital, Capital Medical University, Beijing, China (number KY2014-025-02). The patient’s parents provided their written informed consent to participate in this study on behalf of the patient.

Conception and design: TR and BL. Administrative support: BL and WL. Provision of study materials or patients: BL, WZ, XQ, and WL. Collection and assembly of data: TR, WC, DZ, BW, and ZK. Data analysis and interpretation: TR, WZ, and BL. Manuscript writing and/or revising: All authors. All authors contributed to the article and approved the submitted version.

The corresponding author (BL) has received funding from the National Natural Science Foundation of China (grant numbers 81772370 and 81972084), National Key Research and Development Program of China (grant number 2018YFF0301103), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (grant number XMLX201803). The other authors certify that neither they, nor any member of their immediate families, have other funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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