Extraneural metastases in glioblastoma patients: two cases with YKL-40-positive glioblastomas and a meta-analysis of the literature

Abstract

Glioblastoma (GBM) are high-grade gliomas that severely impact on overall survival (OS). GBM cell motility and the breakdown of the blood-brain barrier could favor GBM cell communication with the systemic circulation. In spite of this, extracranial GBM metastases are rare. Here, we describe two YKL-40-positive GBM patients with extra-CNS (central nervous system) metastases, and we present a meta-analysis of 94 cases. The analysis concluded that extra-CNS metastases occurred 8.5 months after first GBM diagnosis and OS was 12 months; surgical GBM excision was associated at a longer interval to extra-CNS metastasis than biopsy only, and even longer if followed by radiotherapy and chemotherapy. Both our case reports were adult males who developed extra-CNS, YKL-40-positive metastases at lymph nodes, lung and subcutaneous sites, after 86 and 24 months from initial diagnosis of GBM. At first GBM local recurrence, they were treated with bevacizumab (BV), an anti-vascular endothelial growth factor antibody. They died after 4 and 1 month from the occurrence of metastases. Both cases expressed YKL-40 and lacked EGFR amplification, suggesting a mesenchymal phenotype, and maintained such profile at extra-CNS recurrence; they did not show MGMT promoter methylation, IDH1/2 mutations, or c-Met upregulation. Our two cases and the meta-analysis support the idea that prolonged survival of GBM patients increases the probability of GBM cells shedding to lymphatic and hematic system. Interestingly, the present two cases showed the features of mesenchymal profile, usually related with worst prognosis that was maintained in extracranial metastases.

Extracranial Metastasis of Glioblastoma: A Rare Case

“…This property made hematogenous metastasis really rare to occur. 6,7,8 The extracranial metastasis of glioblastoma could be related with the following factors: (1) Age during diagnosis, which Piccirilli et al 5 reported on 128 cases of glioblastoma extracranial metastases in 2008. The mean age of the patients at presentation was 40 years; while other patients with glioblastoma was 54 years.…”

“…Moreover, metaanalysis supported the hypotheses that increasing survival of patients expand the probability of glioblastoma cells spreading through hematogenous and lymphatic systems. 7 (3) Surgical treatment: most patients (96%) reported with extracranial metastases had prior cranial surgery. 8 Surgery may lead to dural damage and potentially facilitate tumor cells crossing the dura mater, which is the most important barrier.…”

Extraneural Glioblastoma Multiforme Vertebral Metastasis

“…23 Bevacizumab, an inhibitor of vascular endothelial growth factor that normalizes tumor vasculature and is approved for the treatment of GBM, has demonstrated some benefit for patients diagnosed with glioblastoma; however, its role in tumor progression and metastatic dissemination remain unclear. 4,5,43,44 …”

“…Lun et al reviewed 88 cases of extracranial GBM metastases published between 1928 and 2009 and found that the time from diagnosis of GBM to detection of extracranial metastases was 8.5 months and from time of metastasis to mortality was 1.5 months. 2,4–7 They also showed a progressive increase in time from detection of extracranial metastases to death at a rate of 0.7 months per decade (from 1949 to 2009), paralleling incremental advancements in diagnosis and treatment options for patients with glioblastoma. 1 …”

Extracranial oral cavity metastasis from glioblastoma multiforme: A case report

“…Long-term local control is difficult to achieve. Extracranial metastases are reported to occur in 0.4-0.5% of all cases (8)(9)(10)(11)(12). In 1928, Davis first reported a patient with disseminated glioblastoma (13).…”