A Rare Manifestation of a Presumed Non-Osteophilic Brain Neoplasm: Extensive Axial Skeletal Metastases From Glioblastoma With Primitive Neuronal Components

Abstract

BackgroundGlioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. GBM with primitive neuronal component (GBM-PNC) is an aggressive variant identified in 0.5% of GBMs. Extracranial metastasis from GBM-PNC is a rare and challenging situation.MethodsA special case of early-onset GBM with systemic bone metastasis was enrolled. Clinical data, including patient characteristics, disease course, and serial radiological images were retrieved and analyzed. Tumor tissues were obtained by surgical resections and were made into formalin-fixed paraffin-embedded sections. Histopathological examinations and genetic testing were performed for both the primary and metastatic tumor specimens.ResultsA 20-year-old man suffered from GBM with acute intratumoral hemorrhage of the left temporal lobe. He was treated by gross total resection and chemoradiotherapy following the Stupp protocol. Seven months later, he returned with a five-week history of progressive neck pain and unsteady gait. The radiographic examinations identified vertebral collapse at C4 and C6. Similar osteolytic lesions were also observed at the thoracolumbar spine, pelvic, and left femur. Anterior spondylectomy of C4 and C6 was performed. The resected vertebral bodies were infiltrated with greyish, soft, and ill-defined tumor tissue. One month later, he developed mechanical low-back pain and paraplegia caused by thoracolumbar metastases. Another spine surgery was performed, including T10 total en-bloc spondylectomy, T7-9, L2-3, and L5-S1 laminectomy. After the operation, the patient’s neurological function and spinal stability remained stable. However, he finally succumbed to the rapidly increased tumor burden and died 15 months from onset because of cachexia and multiple organ failure. In addition to typical GBM morphology, the histological examinations identified monomorphic small-round cells with positive immunohistochemical staining of synaptophysin and CD99, indicating the coexistence of PNC. The next-generation sequencing detected pathogenic mutations in TP53 and DNMT3A. Based on above findings, a confirmed diagnosis of systemic metastases from GBM-PNC (IDH-wild type, WHO grade IV) was made.ConclusionsThe present case highlights the occurrence and severity of extensive axial skeletal metastases from GBM-PNC. This rare variant of GBM requires aggressive multimodal treatment including surgery and chemoradiotherapy targeting PNC. The pathological screening of PNC is recommended in patients with early-onset GBM and intratumoral hemorrhage. Surgery for spinal metastasis is appropriate in patients with chemoradioresistance and relatively good general status, with the objectives of restoring spinal stability and relieving spinal cord compression.

Extracranial metastasis of glioblastoma with genomic analysis: a case report and review of the literature

“…Compared with GBM researches, gene data of GBM with ECM are limit. Similar to previous studies (8)(9)(10)(11), TP53 and PTEN mutations in ECM lesion were identified in the patient. Despite the role of genetic mutations in GBM with ECM is still not fully clear, ongoing research on this topic will ultimately implement a personalized or precision medicine for this deadly disease.…”

“…Great progress has recently been made in the genomic analysis of GBM tumorigenesis and recurrence. However, after a systematic search on PubMed and Google Scholar, genomic features of GBM with ECM was found in 5 reports (Table 1) (7)(8)(9)(10)(11).…”

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

“…Each detected mutation has been described previously in various tumors (c.2259G>A in myelodysplastic syndrome 15 , c.2119G>A in GB 6 , c.1502A>G and c.1661G>A in acute myeloid leukemia 16 , 17 ). DNMT3A mutations are well-known prognostic factors in acute myeloid leukemia 18 , but only sporadic occurrence has been reported in gliomas 6 , 19 – 21 . Considering previous observations showing ALT-related phenotypes in DNMT-deficient cells 22 , the cooperation of ATRX and DNMT3A mutations in telomere length maintenance can be suspected.…”

Glioblastoma: an organ-confined disease?

“…Among the few reports that have conducted genomic analyses in patients with GB and extra-CNS metastases, mutations in TP53 have been the most frequently reported (6,12,(15)(16)(17)(18)(19).…”

“…As this case and prior reports demonstrate, recurrent GB with extra-CNS metastases has very few treatment options. Exceptions to this rule are regional relapses such as those occurring in the dura and head and neck LN, or in oligometastatic bone metastases, which various reports have shown that may be subjected to local treatments achieving longer local and systemic controls (10,11,15,26). Considering that systemic therapy has not demonstrated to prolong OS in patients with recurrent GB, its management is even more complex in patients with extra-CNS metastases.…”