Recurrence patterns and clinical outcomes in adult cerebellar glioblastoma

doi:10.21203/rs.3.rs-6650922/v1

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Recurrence patterns and clinical outcomes in adult cerebellar glioblastoma

https://doi.org/10.21203/rs.3.rs-6650922/v1

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Background

Cerebellar glioblastoma in adults is a rare brain tumor with poor outcomes. This study aimed to assess the clinical characteristics, genetic features, and prognosis of a series of cerebellar glioblastomas, with special attention to their recurrence patterns.

Methods

We retrospectively analyzed patients who underwent treatment between 2008 and 2023. The patient characteristics, treatment methods, genetic features, and prognoses were assessed.

Results

Among 274 cases of histological glioblastomas, eleven patients with cerebellar glioblastomas were identified. Pathological results revealed microvascular proliferation and/or necrosis in all cases. All patients underwent surgery and local radiotherapy combined with temozolomide chemotherapy. The median progression-free survival and overall survival were 15.3 months and 22.8 months, respectively. Of the eight patients who experienced recurrence, seven had distant or disseminated recurrence, and only one experienced local recurrence. None of the tumors harbored mutations in the IDH1/2, H3F3A, or TERT promoters.

Conclusions

This study implies that cerebellar glioblastoma demonstrates the clinical characteristic of a high incidence of distant or disseminated recurrence. The genetic features indicate a low incidence of common mutations in glioma, such as IDH, H3F3A, and TERT promoter regions.

glioblastoma

cerebellum

recurrence

histological

GBM

Glioblastomas represent the most frequent form of gliomas; however, their prevalence in the cerebellum is low (0.4–3.4%) [9, 22, 23]. Therefore, reports on the treatment, prognosis, and genetic information for this group of diseases are limited. Previous reports have described cerebellar glioblastomas as demonstrating a worse, better, or similar prognosis compared to supratentorial glioblastomas [1, 4, 5, 14, 17, 19, 28]. However, reports on recurrent patterns and genetic information are limited, with studies reporting this only in a small group of patients [12, 19]. This study aimed to comprehend the clinical characteristics, including recurrent patterns and genetic features, of adult patients with cerebellar glioblastoma.

Study Population

In this retrospective study, we included all adult patients (aged > 18 years) with a diagnosis of cerebellar glioblastoma based on imaging and pathological findings, treated at Hokkaido University Hospital between 2008 and 2023. Patient data, including clinical course, treatment outcome, radiological imaging findings, and pathological findings, were retrospectively analyzed by referring to their medical records. The lesions were identified using gadolinium-enhanced T1-weighted imaging. Patients with coexisting lesions in the supratentorial region or brainstem invasion at the initial presentation were excluded. Using pathological findings and genetic information, a certified neuropathologist made an integrated diagnosis based on the revised 5th edition (2021) of the WHO classification of central nervous system (CNS) tumors [18]. All manipulations were performed with the approval of our Institutional Review Boards (018–0363). The requirement for informed consent was waived, considering that this study was retrospective in nature. Progression-free survival (PFS) and overall survival (OS) were defined as the period between the date of the first surgery and either the first tumor recurrence on magnetic resonance imaging (MRI) or the patient’s death from any cause and the date of death, respectively. OS after bevacizumab (Bev) treatment was calculated from the day Bev was first administered for recurrence to the day of tumor-related death.

We extracted adult patients with histological glioblastoma of the cerebrum from our institution’s database from 2008 to 2023 and used them as a comparison group.

Genetic Analysis

DNA was extracted from frozen tumor tissues using the AllPrep DNA/RNA Mini Kit (Qiagen, Tokyo, Japan), in accordance with the manufacturer’s recommendations. Mutation hotspots at codon 132 in IDH1 and codon 172 in IDH2, the TERT promoter (C228T and C250T), and codons 27 and 34 of H3F3A were screened using Sanger sequencing, as previously described [13].

Statistical Analysis

Data were analyzed using JMP Pro (version 17.2.0; SAS Institute, Cary, NC) and GraphPad Prism (version 10.2.2; GraphPad Software, San Diego, CA). Fisher’s exact test was used to examine the link between the recurrence patterns and primary site of the tumor. The Kaplan–Meier method was used for survival analysis with 95% confidence intervals. The log-rank test was used to compare the Kaplan–Meier curves.

Patient Demographics

A total of 274 patients were histologically diagnosed with glioblastoma between 2008 and 2023. Five patients harbored an H3F3A mutation and were diagnosed with “diffuse midline glioma,” and were subsequently excluded. Four patients presented with coexisting lesions in the supratentorial region or brainstem invasion and were likewise excluded.

We identified 11 patients histologically diagnosed with cerebellar glioblastoma. All patients underwent surgical resection, with pathological findings and genetic information confirmed. A certified neuropathologist confirmed microvascular proliferation and/or necrosis in every case. Ultimately, we identified 11 patients diagnosed with “glioblastoma, IDH wildtype, CNS WHO grade 4.” During the study period, 254 patients with supratentorial glioblastoma were treated at our institution.

Clinical Characteristics of Cerebellar Glioblastoma

Table 1 summarizes the clinical and genetic features of cerebellar glioblastomas. The average age of cerebellar glioblastoma onset was 66.8 ± 9.8 years. The origin sites included the cerebellar hemispheres in six cases, vermis in one case, tonsil in one case, hemisphere to tonsil in one case, flocculus in one case, and cerebellar peduncle in one case. All patients underwent surgery and chemoradiation therapy. Seven patients underwent gross total resection, two underwent subtotal resection, and one underwent partial resection. Radiotherapy consisted of localized irradiation of 60 Gy in 30 fractions (60 Gy/30 Fr) for nine patients, hypofractionated treatment of 40 Gy/15 Fr for one patient, and discontinuation of radiotherapy at 44 Gy/22 Fr for one patient due to a skin rash (case #5). Concurrent chemotherapy included temozolomide (TMZ) for all patients, though one patient discontinued treatment due to a drug rash (case #5). Adjuvant TMZ was continued according to the Stupp regimen [27]. Five patients were administered Bev at the time of recurrence, including one who also received a TMZ re-challenge. None of the 11 patients exhibited mutations in IDH1/2, TERT promoter, or H3F3A. Case #4 has been previously reported [30].

Recurrence Pattern and Treatment Outcome of Cerebellar Glioblastoma

Eight of the 11 patients with cerebellar glioblastoma experienced recurrence during the observation period. Of these, one case (12.5%) involved local recurrence, while the remaining seven cases (87.5%) involved distant recurrence or dissemination, including spinal involvement in four cases. Contrastingly, in cases of supratentorial glioblastoma, recurrence was noted in 207 of 254 cases during the observation period. The recurrence pattern was local in 165 cases (79.7%) and distant recurrence or dissemination in 42 cases (20.3%). Distant recurrence or dissemination was significantly more common in cerebellar glioblastoma (P = 0.0001) (Fig. 1).

Figure 2 illustrates the Kaplan–Meier curves. The median PFS was 15.3 months. By the last follow-up, seven of the 11 patients had died. The median OS was 22.8 months (range: 5.8–165.9 months). The 1-, 2-, and 5-year survival rates were 80%, 45.7%, and 30.5%, respectively. In supratentorial glioblastoma, the median PFS was 8.6 months, and the median OS was 17.6 months. No significant differences were observed in PFS and OS between cerebellar and supratentorial glioblastomas (P = 0.08 and P = 0.17, respectively).

In the five cases of recurrent cerebellar glioblastoma treated with Bev, the median OS after Bev was 6.6 months (range 0.6–13.7 months). In the 104 patients with recurrent supratentorial glioblastoma, the median OS after Bev was 7.8 months. No significant difference was noted in OS after Bev treatment between the cerebellar and supratentorial glioblastomas (P = 0.39).

Illustrative Case

Case #7

A 66-year-old male presented with a 1-week history of right-sided ataxia. MRI showed a mass with an enhanced wall in the right cerebellar hemisphere (Fig. 3A). Glioblastoma was suspected, and surgical resection via an occipital transtentorial approach was performed. Postoperative MRI showed successful tumor removal (Fig. 3B). Histopathological assessments revealed anaplastic cells with irregularly shaped nuclei and microvascular proliferation without necrosis (Fig. 3C). Immunostaining was negative for IDH1-R132H, and the patient was diagnosed with glioblastoma. Postoperative management consisted of conventional radiotherapy at 60 Gy/30 Fr along with TMZ. Twelve courses of adjuvant TMZ (150–200 mg/m², days 1–5, every four weeks) were administered. Five months later, the patient developed a walking disorder and right-sided hemiparesis. MRI showed an enhanced mass within the left corona radiata, with distant recurrence (Fig. 3D). After irradiation with 60 Gy/30 Fr and TMZ re-challenge, distant recurrent lesions disappeared. After six months, a recurrent lesion was observed in the cerebellar vermis (Fig. 3E), and Bev was administered. However, the patient succumbed to the disease 36.5 months following the initial treatment. Additional genetic analysis confirmed the presence of wildtype IDH, the TERT promoter, and H3F3A.

Case #8

A 68-year-old female presented with a 1-month history of nausea. MRI showed a round mass with an enhanced wall in the left cerebellar hemisphere (Fig. 4A). Glioblastoma was suspected, and surgical resection was conducted (Fig. 4B). The postoperative course was uneventful. Postoperative MRI showed successful tumor removal. Histopathological assessment revealed anaplastic cells with irregularly shaped proliferating nuclei, microvascular proliferation, and necrosis (Fig. 4C). Immunostaining was negative for IDH1-R132H, and the patient was diagnosed with glioblastoma. Postoperative management consisted of conventional radiotherapy at 60 Gy/30 Fr along with TMZ. Adjuvant TMZ (150–200 mg/m², days 1–5, every four weeks) was administered. On the fifth course, the patient experienced back pain and disseminated recurrence in the brain and spine (Fig. 4D, E). Subsequently, Bev was introduced; however, the patient succumbed to the disease 11.4 months following the initial treatment. Additional genetic analysis confirmed the presence of wildtype IDH, the TERT promoter, and H3F3A.

Case #9

A 71-year-old male underwent imaging for a 3-month history of dizziness. MRI showed a round mass with a heterogeneously enhanced wall at the right cerebellopontine angle (CPA) near the jugular foramen (Fig. 5A, B). The patient did not visit the hospital as scheduled. After one year, the dizziness worsened. The patient underwent another checkup and MRI, which revealed an enlarged cerebellopontine mass (Fig. 5C). The patient underwent surgery under general anesthesia. The tumor was excised from the CPA. The tumor was contiguous with the cerebellum and brainstem at the rostral aspect of the lateral recess. Surgical views suggested that the tumor originated from the cerebellar flocculus. The postoperative course was uneventful. Dizziness was relieved postoperatively. Postoperative MRI showed successful tumor removal. Histopathological assessment revealed a highly cellular tumor with an elevated nuclear-to-cytoplasmic ratio and microvascular proliferation; however, necrosis was not observed (Fig. 5D, E). Immunohistochemical staining of the tumor cells showed a 50% proliferation rate, as determined by the Ki-67 labeling index. Genetic analysis confirmed the absence of hotspot mutations in the H3F3A, IDH1/2, and TERT promoter regions. The integrated diagnoses were glioblastoma, IDH wildtype, and CNS WHO grade 4 according to the WHO 2021 classification. Postoperative management consisted of conventional radiotherapy (60 Gy/30 Fr) along with TMZ. Adjuvant TMZ was administered (150 mg/m², days 1–5, every four weeks). MRI findings four months postoperatively showed the absence of tumor recurrence.

Only a limited number of reports on cerebellar glioblastoma exist, owing to its rarity. Recently, multiple reports on prognostic data have emerged [1, 4–6, 12, 14, 17, 19, 28, 31]. However, several unknown aspects of its clinical and genetic characteristics still remain. In this retrospective study, we analyzed cases of cerebellar glioblastoma in accordance with the WHO 2021 criteria [18]. We found several important aspects of cerebellar glioblastoma.

First, recurrent cerebellar glioblastoma is characterized by a high rate of distant metastasis and meningeal dissemination, which differs from that of supratentorial glioblastoma. Generally, most recurrent patterns have been reported as local recurrences (79.3–80%), with distant recurrences being limited (10.3–20%) in glioblastomas [7, 20]. In our series of cerebellar glioblastomas, seven of the eight cases (87.5%) that recurred were distant or disseminated recurrences, and four of these cases involved the spinal region. Few reports exist on the recurrence patterns of cerebellar glioblastomas. Akimoto et al. reported disseminated recurrence in two cerebellar glioblastoma cases [2]. Additionally, Picart et al. reported that more than half of recurrence cases in cerebellar glioblastoma were distant or meningeal recurrences [19]. We believe that this difference in relapse patterns is of great clinical importance. Glioblastoma has an extremely high recurrence rate; therefore, it is essential to consider factors beyond local recurrence during follow-up. The high incidence of distant and disseminated recurrences may be associated with the anatomical location. Medulloblastoma, which shares the same CNS WHO grade 4 as glioblastoma and occurs in the posterior fossa, demonstrates a high rate (58–78%) of distant recurrence [10, 11]. Additionally, leptomeningeal relapse has been reported to often occur (33–50%) in metastatic brain tumors in the posterior fossa [3, 25, 29]. As malignant tumors in the posterior fossa often recur distantly or spread, cerebellar glioblastomas likely demonstrate similar tendencies.

Second, differences exist in genetic features. In glioblastomas, TERT promoter mutations have been reported to occur in approximately 80% of cases. [8, 15] In the present study, the TERT promoter was wildtype in all cases. Only a few reports exist on the genetics of cerebellar glioblastoma. One prior study reported that TERT promoter mutations occur in only one of four cases of cerebellar glioblastoma, IDH-wildtype. [12] Another reported this alteration in two of 19 cases of cerebellar glioblastoma [6]. Reinhardt et al. reported that TERT promoter mutations were observed in 31% (9/29) of cerebellar glioblastomas, in contrast to 77% (98/127) of supratentorial glioblastomas [21]. They used DNA methylation profiles to clarify the differences between cerebellar and supratentorial glioblastoma. IDH wildtype glioblastoma can be classified into seven DNA methylation subgroups. Among these, “glioblastoma IDH wildtype midline (GBM MID)” exhibits a low TERT promoter mutation rate (8%), whereas “glioblastoma IDH wildtype subclass mesenchymal (GBM MES)”, “glioblastoma IDH wildtype subclass RTK Ⅰ (GBM RTK Ⅰ)” and “glioblastoma IDH wildtype subclass RTK Ⅱ (GBM RTK Ⅱ)” show higher TERT promoter mutation rates (78%, 77%, and 83%, respectively) [26]. Cerebellar glioblastomas are characterized by a higher prevalence of GBM MID and a lower frequency of GBM MES and GBM RTK II [21]. This distribution likely accounts for the lower incidence of TERT promoter mutations in cerebellar glioblastoma. These findings suggest that glioblastomas arising in the cerebellum and supratentorial regions exhibit distinct genetic profiles.

Third, the prognosis of cerebellar glioblastomas is similar to that of supratentorial glioblastomas. Several previous reports exist on cerebellar glioblastoma [1, 4–6, 12, 14, 17, 19, 28, 31]. Among these, cerebellar glioblastoma prognosis has been reported to be poor, good, or similar to that of supratentorial glioblastoma [1, 4–6, 14, 17, 19, 28]. However, most reports include a mixture of different subgroups, such as those diagnosed solely based on pathological results without IDH status or those containing H3K27M mutations. IDH and H3K27M mutations are factors associated with survival prognosis [24, 32]. This report is based exclusively on the WHO 2021 diagnostic criteria for cerebellar glioblastoma. Compared to supratentorial glioblastoma at the same time, OS and PFS were similar. Contrastingly, the median OS following Bev therapy was 6.6 months, although distant metastasis and meningeal dissemination are common recurrence forms. No significant difference was observed compared to supratentorial glioblastoma. The only report on the treatment outcomes of Bev for recurrent cerebellar glioblastoma is a case report. Linsenmann et al. reported achieving 12 months of control by administering Bev and radiation therapy for spinal metastases of cerebellar glioblastoma [16]. Based on these findings, Bev’s effectiveness for distant and disseminated recurrence of cerebellar glioblastoma may be similar to that of supratentorial glioblastoma.

At our facility, we treat cerebellar glioblastoma in the same manner as supratentorial glioblastoma. We conducted surgical resection followed by adjuvant treatment consisting of TMZ radiochemotherapy as per the Stupp regimen [27]. Based on the treatment findings, treatment according to supratentorial glioblastoma can be considered reasonable at present. Nevertheless, given the various recurrence patterns, we propose that a follow-up MRI should encompass an examination of the spine and spinal cord in addition to the brain.

Limitations

This retrospective analysis has some limitations, including a small sample size and a single-center design. Additionally, a search for EGFR amplification and alterations in chromosome 7 and 10 copy numbers has not been possible, and DNA methylation analysis was not performed. Larger cohorts are required to elucidate the clinical and genetic features of cerebellar glioblastomas. Furthermore, a possibility of selection bias exists in defining the cohort by tumor type, which can be confirmed by pathological and genetic information obtained via surgical resection. Thus, the study likely did not include patients with poor prognosis who were not eligible for surgery. Thus, prospective trials are necessary to demonstrate the implications of these findings.

Here, we report the clinical and genetic features of cerebellar glioblastoma. Although several cases of distant and disseminated recurrence were observed, the prognosis was similar to that of supratentorial glioblastoma. TERT promoter mutations were not noted in any case, suggesting variations in genetic characteristics. Further assessment and a better understanding of the clinical and genetic features of this disease are necessary to establish more effective treatments.

Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

Conflicts of interest: The authors declare no conflicts of interest.

Availability of data and material: The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Code availability: Not applicable.

Ethical standards: All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent to participate: Since the study was retrospective, the requirement for informed consent was waived.

Consent for publication: The authors declare their consent for publication.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions:

Conception and design: S.O., S.Y.

Acquisition of data: S.O., S.Y., Y.I., G.M. Z.T., O.H., E.T., S.T.

Analysis and interpretation of data: S.O., Y.I, Z.T., O.H., E.T., S.T., S.T.

Drafting the article: S.O.

Critically revising the article: S.Y., Y.I., H.M., Z.T., H.O., K.N.

Approved the final version of the manuscript on behalf of all authors: S.Y

Statistical analysis: S.O.

Administrative/technical/material support: Y.I., H.M., Z.T., H.O., E.T., S.T., T.M., K.N., H.A., S.T.

Study supervision: M.F.

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Table 1 is available in the Supplementary Files section.

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Recurrence patterns and clinical outcomes in adult cerebellar glioblastoma

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Study Population

Genetic Analysis

Statistical Analysis

Results

Patient Demographics

Clinical Characteristics of Cerebellar Glioblastoma

Recurrence Pattern and Treatment Outcome of Cerebellar Glioblastoma

Illustrative Case

Case #7

Case #8

Case #9

Discussion

Limitations

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

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