Abstract
Background/Aim: Intraventricular cerebral metastases (IVCM) are a rare but clinically significant subset of brain metastases. This systematic review aimed to provide a comprehensive analysis of IVCM by synthesizing current literature on epidemiology, clinical presentation, imaging features, pathophysiology, and treatment options. Materials and Methods: A systematic literature search was conducted, identifying 11 relevant studies encompassing 11 studies encompassing 842 IVCM cases. Data regarding primary tumor origins, patient demographics, presenting symptoms, treatment modalities, and survival outcomes were analyzed. Results: IVCM cases displayed a diverse range of primary tumor origins, with the kidney (27.4%), thyroid (21.6%), lung (19.8%), colon (11.7%), melanoma (8.4%), and breast ductal carcinoma (7.9%) being common sources. Patients presented with a wide spectrum of symptoms, including headaches (42.3%), nausea (31.5%), altered mental status (25.7%), neurological deficits (18.2%), and others. Treatment approaches varied, encompassing surgical resection (41.2%), radiation therapy (32.5%), chemotherapy (15.3%), and immunotherapy (7.9%). Overall survival was generally limited, with a mean duration of approximately 10.3 months (±8.7 months). The time to recurrence after treatment exhibited considerable variability. Conclusion: IVCM represents a challenging and underexplored metastatic disease. This systematic review underscores the need for further research to enhance our understanding of IVCM’s pathophysiology and develop tailored diagnostic and treatment approaches. Such efforts are crucial to improving outcomes and the overall quality of life for patients facing this complex condition. The multidisciplinary nature of IVCM management, involving neurologists, neurosurgeons, oncologists, radiologists, and other healthcare professionals, is emphasized as essential for individualized patient care.
- Intraventricular cerebral metastases
- brain metastases
- systematic review
- treatment
- prognosis
- diagnosis
- management
- oncology
- ventricular system
- review
Brain metastases are a common and devastating complication of systemic malignancies, affecting approximately 20-40% of cancer patients during their illness (1). Traditionally, brain metastases have been associated with primary tumors originating from the lung, breast, melanoma, and gastrointestinal tract (2). However, with advancements in cancer treatment and longer survival times, the incidence of brain metastases from other primary sites, such as renal cell carcinoma and sarcomas, has been increasing. Treatment options for intraventricular cerebral metastases (IVCM) remain limited, and no universally accepted guidelines exist (3). The management of IVCM typically involves a multidisciplinary approach, including neurosurgery, radiation therapy, and systemic therapies (4, 5). However, the optimal sequence and combination of these modalities are still a subject of debate. Additionally, the therapeutic decision-making process must consider individual patient factors, such as performance status, systemic disease control, and overall prognosis. This systematic review aims to provide a thorough understanding of IVCM by summarizing the current literature on their epidemiology, clinical presentation, imaging features, pathophysiology, and focusing on treatment options. By elucidating the unique challenges associated with IVCM, we hope to facilitate the development of more effective diagnostic and therapeutic strategies, ultimately improving the outcomes and quality of life for patients with this rare and complex condition.
Materials and Methods
A systematic literature review was conducted according to the preferred reporting items for systematic reviews and meta-analyses statement (PRISMA), with no limits in terms of publication date. Recorded studies were exported to Mendeley software. Only articles in the English language were included in the study. All duplicates were removed, and a manual search was also performed to identify additional studies in the reference sections. Two reviewers (G.S. and M.P.S.) independently screened the titles, abstracts, and full manuscripts, and then the results were combined and analyzed. The following Mesh and free text terms were used: “(ventricular metastases) AND (intraventricular metastases)”, “(cerebral ventricular metastases) AND (ventricular metastases) AND (intraventricular metastases)”, “(third ventricle metastases) AND (lateral ventricle metastases) AND (fourth ventricle metastases)” (115 results).
Eligibility criteria. The articles were selected according to the following inclusion criteria:
Full article in English; Human subjects; Clinical studies (case reports, case series, and retrospective studies); Studies focusing on ventricular metastases.
Exclusion criteria. The following criteria were excluded from the study: Articles not in English; Meta-analysis.
Data extraction. The extracted data included authors, year, study design, number of patients, sex, age, primary location, histological examination, and ventricular metastatic location.
Results
A total of 115 published studies were identified through PubMed and Google Scholar databases and additional reference list searches. After removing duplicates, 72 papers were screened. Based on the titles and abstracts, the authors then excluded 45 articles. The titles and abstracts of the articles identified during the literature search were reviewed to check if they fulfilled the following inclusion criteria: full article in English, human subjects, clinical studies (case reports, case series, and retrospective studies), and studies focusing on ventricular metastases. The articles that remained were assessed in full against exclusion criteria: articles not in English and meta-analysis. A total of seven articles were not retrieved due to the unavailability of the full text, and no article was excluded because it was not in the English language. Then, another 9 papers were excluded due to incompatibility with our inclusion criteria. Finally, a total of 11 articles were included in this systematic review (Table I) (7-17). The described flowchart is reported in Figure 1. According to our literature review, only a few case reports describing ventricular metastases have been documented. Out of a total of 1848 cases analyzed, 842 cases with intraventricular metastases were reported.
Summary of clinical data from various studies on intraventricular metastatic brain tumors, including authors, publication years, number of patients, mean age, sex distribution, presenting symptoms, duration of symptoms, primary tumor locations, histological examination findings, metastatic locations, ventricular metastatic locations, survival outcomes, time to recurrence from treatment, surgical interventions, and adjuvant therapy.
Preferred reporting items for systematic reviews and meta-analyses flow diagram reports the decision algorithm for the selection of the studies of the systematic review. N: number.
Intraventricular cerebral metastases represent a challenging and intricate aspect of oncology, necessitating a comprehensive analysis to gain insights into this complex landscape. Our exploration begins with a focus on the characteristics of the patient cohort (Table II). First, we observe that the number of patients across various studies displays substantial variation, with an average of approximately 54.7 patients and a notable standard deviation of 36.1. This variance underscores the diverse nature of data sources and sample sizes, emphasizing the need for cautious interpretation. Turning to the patients themselves, their mean age stands at around 61.4 years, with a standard deviation of 11.5 years. This reveals a significant age range within the cohort, highlighting the fact that intraventricular cerebral metastases affect individuals across different life stages. Sex distribution within this dataset showcases an interesting aspect, with roughly 41.2% being male and 58.8% female. This slight female predominance prompts further exploration into potential sex-related factors in the context of intraventricular metastases.
Summary of key parameters in the study of intraventricular metastatic brain tumors. This table presents key parameters derived from the study of intraventricular metastatic brain tumors, including the number of patients, mean age, sex distribution, common presenting symptoms, duration of symptoms, primary tumor locations, histological examination findings, metastatic locations, ventricular metastatic locations, overall survival, time to recurrence from treatment, surgical intervention rates, common treatment modalities, and the average follow-up duration. The data reflects the variability and characteristics observed in this patient population.
A crucial facet of this analysis lies in the diverse array of symptoms presented by the patients. From headaches to visual deficits, limb weakness, ataxia, cognitive disorders, vertigo, back pain, memory disturbances, nausea, vomiting, language disturbances, motor deficits, fatigue, and altered mental status, these symptoms span a broad spectrum. Such symptom heterogeneity underscores the multifaceted nature of this condition, making diagnosis and management challenging.
Moreover, the duration of these symptoms displays significant variability, rendering the establishment of a uniform trend difficult. This variability may stem from the underlying cancer type, its aggressiveness, or other individual patient factors.
The primary tumor locations provide further insights into the heterogeneity of this patient population. The most common primary sites include the kidney, thyroid, lung, colon, melanoma, breast ductal carcinoma, non-small cell lung cancer, and renal cell carcinoma. This diversity reflects the wide-range of origins of intraventricular metastases, emphasizing the need for personalized treatment approaches. Histological examination reveals prevalent cancer types, with renal cell carcinoma, breast ductal carcinoma, non-small cell lung cancer, melanoma, and colon adenocarcinoma among the commonly observed diagnoses. Understanding the histological makeup is vital for tailoring treatment strategies. When it comes to metastatic locations, affecting regions include the brain, lungs, bones, liver, lymph nodes, and skin. The ventricular regions, particularly the third ventricle, frontal horn, occipital horn, temporal horn, atrium, and fourth ventricle, are commonly involved. This highlights the need for a multidisciplinary approach to address these complex cases. Examining overall survival, the average duration stands at approximately 10.3 months, with a standard deviation of 8.7 months. This wide range underscores the complexity of prognosis, which depends on various factors, including cancer type, stage, and treatment efficacy. The time to recurrence after treatment exhibits considerable variability, indicating the multifaceted nature of disease progression. Some patients may experience more prolonged periods of remission, while others face more rapid recurrences, necessitating ongoing monitoring and adaptive treatment strategies.
In terms of treatment, approximately 41.2% of patients underwent surgery as part of their management plan. This highlights the importance of surgical intervention in select cases, where tumor resection or other procedures may alleviate symptoms or improve outcomes. Finally, the range of treatment modalities employed is broad, encompassing surgery, radiotherapy, stereotactic radiosurgery, chemotherapy, and immunotherapy. This diversity reflects the evolving landscape of cancer treatment and the pursuit of personalized approaches.
Discussion
Intraventricular brain metastases (IVCM) represent a unique and complex subset of brain metastases that infiltrate the ventricular system of the brain (6). The ventricular system comprises four interconnected cavities filled with cerebrospinal fluid (CSF), playing a pivotal role in cushioning the brain, eliminating waste products, and delivering essential nutrients. It’s within this critical space that metastatic cancer cells can gain a foothold and disrupt these vital processes.
Our comprehensive literature review, drawing from the works of authors, such as Raila et al. (1998) (7), Della Puppa et al. (2010) (8), Hayashi et al. (2011) (9), Shapira Y et al. (2014) (10), Oppido et al. (2017) (11), Kong et al. (2020) (12), Scharl et al. (2020) (13), Beach et al. (2021) (14), Hrushka et al. (2021) (15), Lowe et al. (2022) (16), and Mantziaris et al. (2022) (17), has collectively contributed to our understanding of IVCM. Their works offer valuable insights into the intricacies of this condition.
Mechanisms of intraventricular metastases. The exact mechanisms through which cancer cells infiltrate the ventricles remain elusive, but two primary routes are hypothesized. Hematogenous spread, involves cancer cells migrating from the primary tumor, entering the bloodstream, and eventually reaching the brain (10). Alternatively, direct spread can take place along CSF pathways from adjacent metastases (9).
The unique ventricular microenvironment. Once within the confines of the ventricular system, metastatic cells encounter an environment uniquely suited to their survival and proliferation. The CSF, as highlighted in the studies by Mantziaris et al. (17), provides an abundant supply of nutrients. Moreover, the relatively limited immune surveillance within the ventricles (13), may permit these cancer cells to evade the body’s immune defenses. The ventricular wall itself may serve as a physical barrier, shielding the metastatic cells from systemic treatments, such as chemotherapy and radiation (14).
Clinical presentation and diagnosis. IVCM typically manifests with a range of symptoms, primarily attributable to increased intracranial pressure or the obstruction of CSF flow (8). These symptoms encompass headaches, nausea, vomiting, and cognitive changes. Depending on the exact location and size of the metastasis, patients may also experience specific neurological deficits, such as hemiparesis or vision changes. Garrido et al. reported that the lateral ventricle is the most frequently observed localization (18).
Diagnosis of IVCM often involves imaging studies, with magnetic resonance imaging (MRI) and computed tomography (CT) scans being primary tools, as commonly employed in clinical practice (15). These imaging modalities aid in identifying the presence and precise location of the metastases (19-22). Furthermore, in cases where leptomeningeal metastasis is suspected, the analysis of CSF can provide valuable diagnostic information (12).
Complex treatment landscape. The treatment of IVCM is a complex and challenging endeavor. Surgical removal of metastases is considered in select cases (13). However, the proximity of these lesions to critical brain structures and the risk of disrupting CSF flow can render surgery a risky option. Radiation therapy, including whole-brain radiation or stereotactic radiosurgery (SRS) is employed, but the potential shielding effect of the ventricular wall may limit its efficacy (10). Mantziaris et al. (23) investigated the effectiveness and safety of SRS in treating intraventricular metastases (IVMs). The treatment showed good local control of IVMs (with rates of 91.4% and 86.1% at 12 and 24 months, respectively). However, 61% of patients exhibited distant intracranial disease progression and 6.9% of patients succumbed due to intracranial disease progression. Systemic therapies, such as chemotherapy and targeted treatments are also viable options (16). Yet, their effectiveness can be constrained by the blood-brain barrier and the ventricular microenvironment (24-26).
Prognosis and emerging research. The prognosis for patients with IVCM tends to be grimmer compared to those with other types of brain metastases. This can be attributed to multiple factors, including the inherent challenges in treatment, the typically advanced stage of disease that IVCM represents, and the critical functions of the brain regions involved (11). Median survival after diagnosis tends to be short, usually measured in the span of a few months.
In the realm of research, immunotherapies have emerged as a promising avenue, as explored in the ongoing work of Mantziaris et al. (17). These therapies aim to stimulate the body’s immune system to recognize and eliminate cancer cells. Recent studies have highlighted the significant roles of astrocytes and microglia in promoting cerebral metastases growth and interacting with the innate and adaptive immune systems. A specific target of these glial cells could enhance antitumor immunity in patients treated with immunotherapies (27). Some immunotherapies have demonstrated effectiveness in treating specific cancer types, and their potential utility in IVCM is being actively explored. However, a significant challenge lies in the relatively immune-privileged status of the brain, which restricts the immune system’s access and activity compared to other body regions.
Additionally, ongoing research endeavors aim to develop more advanced diagnostic techniques. While MRI and CT scans are currently employed (16), they may not always detect small metastases or distinguish metastases from other brain lesions (28). Researchers are investigating the use of advanced imaging methods and biomarkers to enhance the accuracy and timeliness of IVCM diagnosis. Furthermore, researchers are delving into a deeper understanding of the pathophysiology of IVCM, seeking insights into how and why cancer cells reach the ventricles and thrive within this distinctive environment (29-33). These investigations hold the potential to unveil novel prevention and treatment strategies, as envisaged by ongoing research efforts, including those by Mantziaris et al. (17).
Conclusion
In conclusion, while IVCM represents a significant challenge for clinicians and researchers, ongoing research efforts offer hope for improved understanding, diagnosis, and treatment of this complex disease in the future. It emphasizes the need for a multidisciplinary approach to patient care, involving neurologists, neurosurgeons, oncologists, radiologists, and other healthcare professionals, to create individualized care plans for each patient, and to continue to advance our knowledge and treatment options for this challenging condition.
Footnotes
Authors’ Contributions
Conceptualization, G.S. and M.P.S.; methodology, G.S., M.P.S. and R.C.; software, G.S., M.P.; validation, G.S., D.G.I., G.F.N., G.E.U. and R.M.; formal analysis, G.S., M.P.S., R.C. and M.P.; investigation, G.S. and M.P.S.; resources, R.C., M.P.S. and M.P.; data curation, G.S.; writing – original draft preparation, G.S., M.P.S., R.C. and M.P.; writing – review and editing, G.S., R.C.; visualization, R.C., R.M., G.S.; supervision, G.E.U., G.S., R.M.; project administration, G.S. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received November 29, 2023.
- Revision received December 16, 2023.
- Accepted December 18, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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