Extracranial metastasis of brain glioblastoma outside CNS: Pathogenesis revisited

Abstract Background The most prevalent malignant tumor of the CNS in adults is glioblastoma. Despite undergoing surgery and chemoradiotherapy, the prognosis remains unfavorable, with a median survival period ranging between 15 and 20 months. The incidence of glioblastoma metastasis outside CNS is uncommon with only 0.4%–2% reported rate, compared to other tumors that exhibit a 10% incidence rate of metastasis to the brain. On average, it takes about 11 months from the time of initial diagnosis for the tumor to spread beyond CNS. Consequently, the prognosis for metastatic glioblastoma is grim, with a 6‐month survival rate following diagnosis. Findings The rarity of extracranial metastasis is attributed to the blood–brain barrier and lack of a lymphatic drainage system, although rare cases of hematogenous spread and direct implantation have been reported. The possible mechanisms remain unclear and require further investigation. Risk factors have been widely described, including previous craniotomy or biopsies, ventricular shunting, young age, radiation therapy, prolonged survival time, and tumor recurrence. Due to the lack of understanding about extracranial metastasis of glioblastoma pathogenesis, no effective treatment exists to date. Aggressive chemotherapies are not recommended for metastatic glioblastoma as their side effects may worsen the patient prognosis. Conclusion The optimal treatment for extracranial metastasis of glioblastoma requires further investigation with a wide inclusion of patients. This review discusses the possible causes, factors, and underlying mechanisms of glioblastoma metastasis to different organs.


| INTRODUCTION
Glioblastoma is the most prevalent primary malignant central nervous system (CNS) tumor in adults. 1 The standard treatment approach involves surgical resection followed by radiotherapy and chemotherapy.However, despite these treatment regimens, the patients' outcomes remain unsatisfactory, with a median survival period ranging from 15 to 20 months. 2,3Without treatment, only about one-third of patients manage to survive for 1 year. 4The 5th edition of World Health Organization (WHO) of CNS tumors has recently changed the classification of WHO-Grade 4 astrocytoma.IDH-mutant astrocytoma is currently considered a unified tumor type and graded as WHO 2-4.

The presence of necrosis and/or microvascular proliferation (MVP)
indicates grade 4 and is referred to as astrocytoma IDH-mutant WHO-Grade 4. IDH-wildtype astrocytoma, WHO-Grade 4, is reserved for glioblastoma and typically exhibits necrosis and/or MVP proliferation. 5,6Lack of necrosis or MVP with the presence of TERTp mutation, EGFR amplification or chromosome 7 gain and/or chromosome 10 loss also indicates the diagnosis of glioblastoma. 5,6ioblastoma rarely metastasizes outside the brain, with a reported incidence of approximately 0.4%-2.0%,which is significantly lower than the 10% incidence rate of CNS metastasis from other types of tumors. 3,7][10][11][12] Extracranial metastasis predominantly occurs in adult males without any specific predilection for race or geographical location. 9Earlier studies have indicated that the average duration from the initial diagnosis to the extracranial spread of the tumor is approximately 11 months, however the time from the initial diagnosis to vertebral metastasis specifically is around 26 months. 10,11As a result, the OS rate for patients diagnosed with metastatic glioblastoma outside the CNS is about 6 months. 10,11mporal lobe is the most common primary site for glioblastoma with extracranial metastases, and the spine is the most involved extracranial location near CNS.A meta-analysis conducted by Cunha and Maldaun, 13 on 115 cases of metastatic glioblastoma revealed that the majority of cases involved metastases in single organ, with approximately 12 cases exhibiting multi-site metastases.Common metastatic sites include the lungs and pleura, and lymph nodes followed by liver, skin, scalp, parotid gland, spleen, pancreas, bowel, peritoneum, epidural space, kidney, heart, bones and soft tissue, while metastasis to the meninges or spinal cord via cerebrospinal fluid (CSF) is also frequent 8,14,15 (Table 1).Among all extracranial metastases, patients with lung metastasis showed the worst prognosis 15 (Figure 1).Strong et al. 16 systematically analyzed 92 studies, case reports, and research on bone metastasis from glioblastoma spanning the years 1959-2021.Among these cases, 63% were found to involve the vertebral column, while the remaining cases were associated with lesions within the skull, sternum, rib cage, and appendicular skeleton.Piccirilli et al., 14 have collected about 128 cases of extracranial metastases of glioblastoma.It is noteworthy that metastasis in the scalp or around the surgical site can still occur even after previous administration of local radiotherapy, suggesting that radiation around the surgical scar does not provide protection against future cutaneous or subcutaneous invasion of the tumor. 14pically, computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck is not commonly used as a screening tool for patients diagnosed with glioblastoma.Radiological imaging is recommended when the glioblastoma recurs multiple times, there is prolonged disease progression, or the patient experiences extracranial symptoms.If invasive tumor biopsy or surgery is not an option, liquid biopsy of circulating tumor cells or peripheral blood biomarkers may be considered, although imaging may be less effective than biopsy.Detection of GFAP in liquid biopsy is an obsolete historical tool due to low specificity and the much better sensitivity offered by Polymerase Chain Reaction (PCR) method looking for tumor specific DNA/RNA fragments. 17However, the sensitivity and specificity of liquid biopsy need to be improved before its clinical application. 17

| MECHANISM AND PATHOGENESIS
The possible mechanisms of extracranial metastasis of glioblastoma outside CNS likely include iatrogenic, genetic and molecular factors; however, the cause remains unclear and require further investigation.
Various risk factors for extracranial metastasis have been extensively described, including a history of craniotomy, stereotactic biopsies, ventricular shunting, young age, radiation therapy, prolonged survival time, tumor recurrence, and the presence of a sarcomatous component. 18,19milton et al. 3 suggested that metastatic glioblastoma outside CNS are commonly found in patients with prior invasive surgery or biopsy, which could create an iatrogenic access to extracranial structures.Nearly more than 90% of reported patients with extracranial metastases underwent craniotomy beforehand. 19Therefore, spreading of glial cells through blood stream during surgery seems to be most likely access. 20It is also very rare that patients treated without any surgery develop extracranial metastases. 21Noch et al. 22 examined 10 patients diagnosed with extracranial metastasis of glioblastoma between 2003 and 2007.They found that the median OS from the time of diagnosis was 19 months, and the most common location of metastasis was to the bone, although metastases were also observed in lymph nodes, dura, liver, lung, and soft tissues.
They also suggested that risk factors associated with the metastatic cases were including sarcomatous dedifferentiation, disruption of anatomic barriers during surgical resection, and gene mutations.
Glioblastoma metastasis can also occur through the migration of glial cells in the CSF via peritoneal shunt or cavity, or through direct seeding to soft tissues via craniotomy defects. 23,24The presence of a chronic wound infection and tumor resection may increase the likelihood of developing extracranial metastasis, possibly due to direct surgical seeding.Conversely, the wound revision procedure itself may enable the hematogenous pathway for metastatic spread. 23Nduom et al. and Rong et al. suggested that extracranial metastasis of glioblastoma occurs because of breakdown of the BBB. 25 Although this mechanism was not extensively studied before, Nduom et al., has described the disruption of endothelial tight junctions and astrocyte-endothelial cell interactions with the breakdown of the blood-brain barrier, which affects peritumoral edema, tumor development, and progression. 25,26e nonenhancing areas were associated with preservation of the normal astrocyte-endothelial cell relationship of the preserved BBB. 25 F I G U R E 1 The pathway of extracranial metastasis of glioblastoma to the lung as well as to other distant organs such as liver, heart, kidney, and omentum.
Cancer cells can spread to remote areas through various mechanisms, such as vascular invasion, lymphatic spread, cranial nerve perineural spread, and direct invasion. 27These mechanisms were also observed in glioblastoma.However, there is uncertainty regarding the transmission of malignant glial cells through the bloodstream to other parts of the body.This transmission is considered a hematogenous route.The intracerebral glioblastoma network is distinct and recognizable, with thick-walled neoplastic vessels composed of multiple layers of endothelial cells that form irregular interconnected glomerular structures arranged in a chaotic manner.Vascular Endothelial Growth Factor (VEGF) is the predominant growth factor in glioblastoma, with concentrations up to 50 times higher in the CNS of patients with this disease than in healthy individuals. 13Hence, unlike other systemic malignancies, glioblastoma cells rarely spread through the bloodstream, making hematogenous spread a rare occurrence. 13cently, liquid biopsy is considered as a potential test to detect circulating tumor cells DNA or RNA by analyzing circulating blood or CSF. 28However, further studies are needed to validate this method.
Liquid biopsy offers several advantages, such as distinguishing tumoral pseudoprogression, selecting targeted therapies, and monitoring the mechanisms of resistance to cytotoxicity and therapeutic targets.
In the case of cervical vertebral metastasis, tumor cells can enter the Batson plexus and spread through the CSF.Additionally, there may be a connection between the meningeal and craniocervical venous systems, which can join the internal vertebral venous plexus. 29e mechanisms responsible for osteolytic metastasis of glioblastoma may involve bidirectional interactions between brain tumor cells and bone. 30In 2015, two groundbreaking discoveries were made in the field of brain physiology and anatomy: the CNS glymphatic system and the CNS (dural) lymphatic system. 31Based on these discoveries, it is likely that brain parenchymal CSF permeates into the glymphatic system, which is then connected with the meningeal lymphatic system.The meningeal lymphatic system is responsible for draining CSF to dural lymphatic vessels.Significantly, the dural lymphatic vessels can transport CSF, CNS antigens, and immune cells to the deep cervical lymph nodes. 31Based on the "seed and soil" hypothesis, certain tumor cells have a tendency to metastasize to specific regions within an organ. 22,23This suggests that the tumor cells either require a similar microenvironment to grow or possess surface markers that specifically bind to receptors on organ-or site-specific endothelial cells.
Although the molecular variants linked to glioblastoma and its subtypes are well-documented, a significant knowledge gap exists regarding the genomic drivers that may cause glioblastoma to metastasize. 32To evaluate the molecular phenotype of the primary, recur- among pathologists, oncologists, geneticists, and other experts. 33 was previously suggested that the metastatic potential of glioblastoma might be related to TP53 gene mutations and the emergence of neoplastic subclones. 34Tumor progression may be also facilitated by the overexpression of insulin-like growth factor binding protein-1 (IGFBP2) and functional deficiencies in DNA-dependent protein kinase proteins. 35udies have shown that glioblastomas with extracranial metastasis have higher levels of matrix metalloproteinase than those without extracranial spread. 23Umphlete et al. 36 screened cases with a metastatic glioblastoma to distant sites including breast, liver, and omentum.They found some cases are associated with BRCA1 and ARID1A gene mutations.In The Cancer Genome Atlas (TCGA), glioblastoma specimens showed low occurrence rates of BRCA1 and BRCA2 missense mutations, each at 1.4%. 36Newly diagnosed glioblastoma cases have also demonstrated a rare incidence rate of 0.7% for ARID1A mutations, which may be linked to an aggressive phenotype. 36Single nucleotide variant in PIK3CA and SMARCB1, has also been identified, predominantly in omental deposits. 36ndrych et al. 37 has detected NF1, NOTCH3, AIRDA1, and MTOR genetic alteration in metastatic glioblastoma to spine.It was discovered that BRAF mutation is commonly present in the primary tumor but is absent in the metastasis, where NF1 gene mutations are instead detected.This indicates that a subset of tumor cells that lack BRAF mutation may have gained the potential to metastasize. 37 to date, there are no effective treatments for extracranial metastasis of glioblastoma.Single report has indicated that aggressive therapy is not suggested in metastatic glioblastoma because of poor prognosis. 38Further research is needed to determine the best treatment approach for extracranial metastasis of glioblastoma, with a wider range of patients included in studies.In certain cases of metastatic glioblastoma with specific gene mutations, immunotherapy may be a viable alternative to temozolomide.Recent findings suggest that PARP inhibitor therapy may be effective for tumors with ARID1A and BRCA1 defects. 39Early phase clinical trials are currently assessing the poly (ADP-ribose) polymerase (PARP inhibitor) as a radio-and chemosensitizer for glioblastoma.However, no molecular biomarkers have yet been identified for predicting response. 40

| CONCLUSION
rent, and metastatic lesions, next generation-sequencing (NGS) panel must be employed.NGS technique can be performed through different methodologies and platforms screening wide range of genetic mutations.Next-generation sequencing (NGS) technology has revolutionized molecular profiling in cancer research and clinical practices like molecular tumor boards.NGS panels allow for the simultaneous analysis of multiple genes, providing a comprehensive view of the genetic landscape of tumors.This enables identification of specific mutations, gene fusions, copy number alterations, and other genomic alterations that may be driving tumor growth and progression.It also helps identify actionable mutations and genetic alterations that can guide personalized treatment strategies.It enables the selection of targeted therapies or enrollment in clinical trials that specifically target genetic abnormalities, increasing the chances of therapeutic success.The information helps clinicians understand the complexity of the tumor and select appropriate treatment strategies that target the dominant subclones.Specific mutations or gene expression patterns may indicate a higher risk of recurrence, response to specific therapies, or overall prognosis.NGS results can be integrated into multidisciplinary molecular tumor boards, enabling collaboration
Some examples of glioblastoma cases metastasize outside CNS.