Диффузный глиома полушария, H3 G34-мутант с выраженным периваскулярным проникновением у мужчины среднего возраста: отчет о случае и обзор литературы по случаям среднего и пожилого возраста.

Abbreviations

apparent diffusion coefficient

central nervous system

diffuse hemispheric gliomas, H3 G34‐mutant

diffusion‐weighted imaging

fluorodeoxyglucose‐positron emission tomography

fluid‐attenuated inversion recovery

glioblastoma

methionine

magnetic resonance imaging

overall survival

progression‐free survival

primitive neuroectodermal tumor

T1‐weighted imaging

temozolomide

tumor treating fields

Introduction

Diffuse hemispheric gliomas, H3 G34‐mutant (DHGs) are rare non‐midline hemispheric high‐grade gliomas with glycine to arginine or valine substitutions at codon 35 of the histone gene H3F3A (H3.3) [ 1 ]. G35R (also known as G34R) accounts for about 94% of mutations, and most of the remaining cases harbor G35V (also known as G34V) mutation [ 2 , 3 ]. Extremely rare cases with G35M, G35E, and G35L mutations have also been reported [ 3 , 4 ]. DHGs mainly affect adolescents and young adults, with a median age at diagnosis of 22–23 years [ 3 , 4 ]. Molecular studies have revealed that DHGs account for approximately 14% of high‐grade gliomas in adolescents and young adults [ 5 ]. On the other hand, DHGs in middle‐aged and elderly individuals (40 years or older) are exceedingly rare, and the clinicopathological characteristics of these cases have not been elucidated.

DHGs can exhibit various histopathological features, such as glioblastoma (GBM)‐like or central nervous system (CNS) embryonal tumor‐like morphology, the latter of which was previously referred to as CNS primitive neuroectodermal tumor (PNET) [ 6 , 7 , 8 ]. Other histopathological patterns may include multinucleated giant cells, oligodendroglial appearance, epithelioid GBM‐like morphology, pleomorphic xanthoastrocytoma‐like areas, sarcoma‐like spindle cell regions, or astroblastoma‐like morphology [ 6 , 8 , 9 , 10 , 11 , 12 ]. Despite the heterogeneous histopathological appearance, DHGs consistently show characteristic immunohistochemical and genetic findings; they demonstrate Olig2 negativity, loss of ATRX expression, p53 overexpression, MGMT promoter methylation, and absence of TERT promoter mutations [ 4 , 7 , 8 , 13 ].

Here, we describe a middle‐aged case of DHG, which showed a GBM‐like morphology with extensive perivascular invasion of spindle‐shaped tumor cells. We also discuss the clinicopathological features of DHGs in middle‐aged and elderly individuals, based on a literature review. To the best of our knowledge, this is the first report to describe the characteristics of DHGs in middle‐aged and elderly cases.

Clinical Summary

A 45‐year‐old man presented with a five‐month history of memory loss and recent onset of alexia. He had no previous medical or family history. Magnetic resonance imaging (MRI) revealed a T2 and fluid‐attenuated inversion recovery (FLAIR) hyperintense, ill‐defined lesion infiltrating into the subcortical area and deep white matter of the left temporal lobe, measuring 46 × 34 × 29 mm. On T1‐weighted imaging (T1WI), the lesion appeared hypointense with focal and faint gadolinium enhancement. Diffusion‐weighted imaging (DWI) demonstrated focal diffusion restriction, suggesting high cellularity (Figure 1A–D ). There was focal peritumoral edema extending near the inferior horn of the lateral ventricle, minimal leptomeningeal contact, and no midline shift. Fluorodeoxyglucose‐positron emission tomography (FDG‐PET) revealed uptake (SUVmax: 11.4) in the middle temporal gyrus. Based on these findings, a high‐grade glioma was suspected, and an awake craniotomy was performed. Gross total resection of the enhancing lesion was achieved, and the postoperative course was uneventful. The patient received adjuvant radiotherapy with concurrent temozolomide (TMZ), followed by maintenance TMZ and Tumor Treating Fields (TTFields) therapy.

The tumor recurred 5 months after surgery. MRI revealed an enhancing lesion in the medial and posterior regions of the surgical cavity. The T2/FLAIR hyperintense area extended to the left temporal and occipital lobes, left side of the brainstem, left basal ganglia, corpus callosum, hypothalamus, and optic tract, with diffusion restriction (Figure 1E–H ). The patient underwent an additional resection followed by TMZ and TTFields therapy, resulting in a partial response. However, 12 months after the second surgery, MRI revealed multiple enhancing lesions in the bilateral periventricular walls. Despite impaired consciousness, the patient is alive 24 months after the initial surgery.

Pathological Findings and Molecular Genetic Findings

At the initial surgery, multiple specimens were submitted for pathological examination. The largest specimen measured 45 × 25 × 15 mm, and the combined sizes of the remaining smaller fragments were 15 × 15 mm and 11 × 11 mm, respectively. Microscopically, the fragments measuring 11 × 11 mm (comprising approximately 10% of the total specimens) showed a highly cellular glioma composed of pleomorphic cells with hyperchromatic nuclei and eosinophilic cytoplasm. The tumor cells were plump or spindle‐shaped, with scattered multinucleated giant cells (Figure 2A ). The mitotic count was 1.9/mm 2 . Microvascular proliferation was observed, but necrosis was absent. The remaining tissue showed cortex and white matter with slightly increased cellularity and marked perivascular invasion of spindle‐shaped tumor cells (Figure 2B ). Perineuronal satellitosis and subarachnoid spread were also focally observed (Figure 2C ). Immunohistochemically, the tumor cells were positive for GFAP, negative for Olig2, and demonstrated loss of ATRX expression. Diffuse p53 positivity was noted in the tumor cells (Figure 3A–E ). Although p53‐positive tumor cells showed a certain degree of infiltrative growth into the brain parenchyma, the perivascular infiltration was more conspicuous than the parenchymal infiltration. MTAP expression was retained. The Ki‐67 labeling index was 22% in the hypercellular area. Molecular analysis revealed H3F3A G35R mutation and MGMT promoter methylation. No mutations were identified in IDH1 , IDH2 , H3F3A codon K28, HIST1H3B codon 28, or TERT promoter.

The recurrent tumor showed mildly to moderately increased cellularity, consisting mainly of perivascular invasion of spindle‐shaped tumor cells with an Olig2‐negative, ATRX‐negative, and p53‐positive immunophenotype (Figures 2D and 3F ). Multinucleated giant cells with p53 immunoreactivity were present in the perivascular spaces and brain parenchyma. Gemistocytes with abundant eosinophilic cytoplasm were also observed, but were negative for p53, suggesting gliosis. Mitoses were inconspicuous (0/mm 2 ), and neither necrosis nor microvascular proliferation was observed.

Discussion

We report a case of DHG in a middle‐aged adult, a rare population for this tumor entity, typically observed in children, adolescents, and young adults. The tumor exhibited characteristic histopathological and immunohistochemical features of DHG, including GBM‐like morphology, Olig2 negativity, ATRX loss, and p53 overexpression. In addition, prominent perivascular invasion was observed, which might have contributed to early tumor recurrence. This case highlights the importance of recognizing DHG in older age groups and reinforces the need for comprehensive molecular diagnostics regardless of patient age.

DHGs are one of the pediatric‐type diffuse high‐grade gliomas newly defined in the 2021 WHO classification of CNS tumors. They were first identified in pediatric high‐grade gliomas in 2012 [ 14 , 15 ]. Subsequent studies revealed that DHGs also occur in young adults [ 1 , 7 ], although their frequency in adults is much lower than in children. H3F3A G35 mutations have been detected in three of 160 cases (1.9%) of adult IDH‐wildtype astrocytomas (grade II–III according to the 2007 WHO classification) [ 16 ] and in 18 of 1117 cases (1.6%) of adult non‐midline IDH‐wildtype diffuse gliomas with grade 4 morphology [ 17 ]. In a Japanese cohort, Yoshimoto et al. reported H3 G35 mutations in four of 411 glial and glioneuronal tumors (1.0%) across all age groups [ 9 ]. Although several authors have described DHGs in adults [ 8 , 11 ], most of these cases were young adults under 40 years of age, and DHGs diagnosed in patients aged 40 or older are extremely rare. To date, including our case, a total of 31 cases diagnosed at the age of 40 or older have been reported in the literature [ 1 , 3 , 4 , 7 , 8 , 12 , 13 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Although detailed information, such as radiological findings, postoperative treatments, and outcomes, was unavailable in some cases, the clinical, radiological, and pathological findings of middle‐aged and elderly patients (40 years or older) are summarized in Table 1 . The oldest patient was 70 years old; 20 cases were in their 40s, 9 in their 50s, and 2 were over 60 years old. One case harbored a G35R mutation in the H3F3B gene instead of H3F3A , with clinicopathological, genetic, and epigenetic findings similar to DHG [ 22 ]. In DHG cohorts, patients aged 40 years or older account for only 1%–2% of cases [ 3 , 4 , 18 ]. However, this may be an underestimate, as high‐grade IDH‐wildtype gliomas in middle‐aged and elderly patients are often diagnosed without H3 G35 testing, and DHGs in this population may be misclassified as IDH‐wildtype GBMs.

Preoperative diagnosis of DHGs is challenging, particularly in middle‐aged and elderly patients. Radiologically, most DHGs appear as cortico‐subcortical, ill‐defined lesions [ 11 , 12 ]. They predominantly affect the parietal, temporal, and frontal lobes, and some cases show gliomatosis‐like multilobar involvement [ 7 , 9 , 11 , 13 , 21 , 25 ]. Pial invasion is frequently observed, and ependymal extension is present in approximately half of the cases [ 3 ]. On MRI, DHGs typically demonstrate iso‐ to hypointensity on T1WI and hyperintensity on T2WI and FLAIR. DWI has proven useful for diagnosis, often revealing areas of apparent diffusion coefficient (ADC) restriction that reflect high tumor cellularity [ 11 , 12 , 25 ]. Methionine (MET) PET imaging is also valuable, as all reported DHGs have demonstrated MET uptake [ 23 ]. Notably, Kibe et al. suggested that all T2/FLAIR hyperintense lesions may be tumor components rather than peritumoral edema, as the MET‐accumulated area corresponded to T2/FLAIR high lesions [ 23 ]. MRI findings in middle‐aged and elderly patients are similar to those in adolescents and young adults (Table 1 ). Among the cases with available data, all showed diffusion restriction, and all but one demonstrated mild and/or focal contrast enhancement. In this age group, GBMs are far more common than DHGs; however, certain radiological features may help differentiate DHGs. Severe peritumoral edema and necrosis, which are hallmarks of GBM, are uncommon in DHGs [ 3 , 12 , 21 , 25 ]. Gadolinium enhancement is often absent or only faint and focal in DHGs, and ring‐like enhancement as seen in GBMs is rare [ 3 , 9 , 11 , 13 , 23 , 25 ]. Additionally, DHGs more frequently invade deep white matter than GBMs [ 3 , 23 ]. In our case, the tumor exhibited only focal and faint enhancement with mild peritumoral edema, which was not characteristic of IDH‐wildtype GBM and more consistent with DHG radiological characteristics. Besides GBMs, several other conditions may mimic DHGs. Picart et al. have reported that over half of their adult DHG cases were initially misdiagnosed as low‐grade glioma, primary CNS lymphoma, or non‐neoplastic lesions, including inflammatory, infectious, vascular, and metabolic diseases, due to the absence of necrosis [ 11 ]. Therefore, careful assessment of imaging features, including contrast enhancement pattern, DWI, and PET, is essential for accurate diagnosis.

Histologically, DHGs show GBM‐like (27%–73%) or PNET‐like (27%–63%) morphology [ 3 , 7 , 8 , 11 ]. Necrosis and microvascular proliferation are less common, and some cases were previously diagnosed as anaplastic astrocytoma, WHO grade III, according to the 2016 WHO classification of CNS tumors [ 8 , 21 ]. DHGs in middle‐aged and elderly patients show similar histological features, with six cases displaying GBM‐like and four showing PNET‐like morphology (Table 1 ). In addition, five cases exhibited histologic features of anaplastic astrocytoma, and one was classified as epithelioid GBM.

DHGs show a distinct immunohistochemical phenotype characterized by Olig2 negativity, ATRX loss, and p53 positivity, regardless of PNET‐like or GBM‐like morphology. Loss of Olig2 and ATRX has been reported in 100% and 82%–100% of DHGs, respectively [ 1 , 7 , 8 , 11 , 20 , 25 ]. TP53 /p53 abnormalities (immunoreactivity or mutation) have been found in 75–100% of tumors [ 1 , 4 , 7 , 8 , 11 , 12 , 20 , 25 ]. In middle‐aged and elderly cases with available data, Olig2 negativity, loss of ATRX expression (or confirmed ATRX mutation), and p53 overexpression/ TP53 mutation were observed in 100%, 88%, and 85% of cases, respectively. Although ATRX loss and p53 immunoreactivity are commonly observed in IDH‐mutant astrocytomas, these tumors usually show Olig2 positivity and, by definition, always harbor IDH1/2 mutations. Ebrahimi et al. evaluated ATRX expression in astrocytic, oligodendroglial, and ependymal tumors (grades I–IV according to the 2016 WHO classification) and reported that 7 of 23 cases (30%) with ATRX loss and IDH1/2 ‐wildtype status harbored H3F3A G35R mutations. Among the remaining 16 cases with ATRX loss, IDH1/2 and H3F3A G35 wildtype tumors, two were diffuse midline gliomas, H3 K27‐altered, one was an anaplastic pilocytic astrocytoma with a KIAA1549::BRAF fusion, and one was associated with Lynch syndrome. The other 12 cases were histologically diagnosed as GBM or anaplastic astrocytoma (IDH‐wildtype), but their integrated diagnoses were not described [ 26 ]. Based on methylation profiling, adult brain tumors with loss of ATRX expression have been classified as IDH‐mutant low‐ and high‐grade astrocytomas, diffuse midline gliomas, H3 K27‐altered, DHGs, high‐grade astrocytoma with piloid features, and, rarely, IDH‐wildtype GBM [ 19 ]. The European Association of Neuro‐Oncology (EANO) recommends molecular analysis for H3F3A G35R/V mutations in IDH‐wildtype gliomas with nuclear ATRX loss in patients younger than 50 years [ 27 ]. Trejo‐Lopez et al. also emphasized the rarity of DHGs in adults over 50 years, suggesting that H3 G35 testing is most diagnostically useful in adults aged 50 or younger [ 17 ]. However, a literature review identified 10 cases in patients aged 50 or older, one of which showed anaplastic astrocytoma morphology without necrosis or microvascular proliferation. Therefore, for accurate diagnosis and grading, molecular analysis for H3F3A should be considered in hemispheric IDH1/2 ‐wildtype diffuse gliomas with Olig2 negativity, ATRX loss, and p53 overexpression, regardless of patient age or CNS WHO grade. Although commercially available antibodies specific for the G35R and G35V mutant proteins are useful for screening, they are neither specific nor sensitive, and alternative mutation detection methods are warranted for accurate diagnosis of DHGs [ 28 ].

Perivascular invasion, defined as the growth of tumor cells along Virchow–Robin spaces surrounding blood vessels, is one of the secondary structures of Scherer, originally described in the context of glioblastoma invasion [ 29 ]. The secondary structures of Scherer also include perineuronal satellitosis and subpial spread. Scherer noted that perivascular invasion was an early manifestation of tumor spread and probably one of the initial pathways of invasion; however, it also tended to be present in highly infiltrative areas of later‐stage tumors [ 29 ]. Although perivascular invasion was not initially reported in pediatric DHGs, Puntonet et al. later reported its presence in 75% of pediatric and young adult cases, often accompanied by subpial infiltration, extensive leptomeningeal involvement, and perineuronal satellitosis [ 25 ]. Subsequent studies have also described perivascular invasion in DHGs with frequencies of 25% to 73% [ 8 , 12 ]. Puntonet et al. compared radiological and pathological findings of DHGs with perivascular infiltration and demonstrated that some cases with microscopically highly infiltrative tumors were radiologically well‐delineated with minimal peripheral T2 hyperintensity [ 25 ]. These findings suggest that DHGs with marked perivascular invasion may lead to incomplete resection, even when gross total resection appears to be achieved. In our case, gross total resection of the enhancing lesion was achieved, but the tumor had likely infiltrated into the non‐enhancing region and possibly extended beyond the T2/FLAIR hyperintense area via perivascular invasion, ultimately leading to tumor recurrence.

Cases with DHGs generally show a dismal prognosis, but the impact of patient age on outcome remains unclear. A systematic review demonstrated that age above 18 years was associated with a more favorable prognosis [ 3 ]. On the other hand, comprehensive literature reviews across all age groups have shown a median progression‐free survival (PFS) of 10.0 months and median overall survival (OS) of 14.4–17.3 months [ 2 , 30 , 31 ], whereas studies including only adult patients showed median PFS of 8.8–10 months and median OS of 12.4–14 months [ 8 , 11 ]. In our case, the tumor recurred 5 months after surgery, but the patient remained alive 24 months after the initial operation. Among patients aged 40 years or older, the median OS was 24.6 months, which was longer than that reported in other DHG populations and patients with GBM [ 32 , 33 ]. However, the number of middle‐aged and elderly cases was too small to draw definitive conclusions, and further investigation in a large cohort is needed.

Several factors other than patient age have been reported to be associated with prognosis. Favorable prognostic indicators include MGMT promoter methylation [ 3 , 7 ], a well‐delineated tumor margins on MRI [ 34 ], and gross total resection [ 3 , 35 ]. In contrast, the presence of the H3F3A G35V mutation (compared to G35R) [ 30 ], PDGFRA amplification [ 30 ], and midline invasion [ 35 ] has been reported to be associated with significantly worse prognosis. Although the secondary structures of Scherer may contribute to recurrence time or patterns, their prognostic impact remains unclear and warrants further investigation in large cohorts.

Currently, due to the rarity of this tumor, there is no established chemotherapeutic regimen for DHGs in either pediatric or adult patients [ 36 ]. In adult cases, radiation therapy with concomitant and adjuvant TMZ, similar to the standard treatment for GBM, is commonly administered [ 37 ]. Approximately 75% of DHG cases exhibit MGMT promoter methylation [ 3 , 7 ], suggesting the effectiveness of alkylating agent chemotherapy. Our patient had MGMT promoter methylation and underwent postoperative radiotherapy with concomitant TMZ, followed by maintenance TMZ and TTFields therapy. TTFields therapy is a locoregional, non‐invasive anticancer modality that uses a portable device applied to the scalp and is approved for newly diagnosed GBM (in combination with maintenance TMZ) and recurrent GBM. The Commission Guidelines of the German Society for Neurology recommend TTFields therapy concomitant with TMZ maintenance therapy for patients with DHGs as well as IDH‐wildtype GBMs [ 38 ]. Although the efficacy of TTFields in DHGs has not been fully described, Kibe et al. reported a case of DHG treated with TMZ, bevacizumab, and TTFields for recurrent tumor. The patient achieved a partial response but died 13 months after surgery [ 23 ]. While current therapies have improved local tumor control, DHGs remain difficult to treat effectively, and it is critical to explore novel therapeutic strategies for this distinct tumor entity.

DHGs exhibit recurrent and potentially targetable genetic alterations, including activating mutations and amplifications in PDGFRA , as well as various alterations affecting the CDK4/6‐cyclin D‐p16 INK4a ‐Rb cell cycle pathway [ 3 , 12 , 39 ]. PDGFRA activating mutations have been reported in 50% of DHGs, with a higher frequency at recurrence than at initial diagnosis (81% vs. 44%) [ 20 ]. Chen et al. described that PDGFRA activations are potent oncogenic drivers in recurrent tumors of DHGs and suggested that PDGFRA and the downstream MAPK pathway may be actionable targets [ 20 ]. McNicholas et al. demonstrated that cells derived from an H3.3–G35R–mutant glioma model carrying the PDGFRA ‐C235Y mutation were not sensitive to the PDGFRA inhibitor avapritinib but were highly sensitive to the FGFR inhibitor infigratinib [ 40 ]. CDK4/6 amplifications and CDKN2A/B deletions have also been identified in 6% and 21% of DHGs, respectively, indicating that targeted therapy with CDK4/6 inhibitors may be effective in these tumors [ 4 ]. Liu et al. further demonstrated the potential benefit of the CDK4/6 inhibitor ribociclib in DHGs, regardless of CDK4/6 amplification status [ 41 ]. To evaluate the efficacy of molecular targeted therapies, accurate diagnosis of DHGs is essential.

In conclusion, we described a middle‐aged case of DHG with prominent perivascular infiltration. Perivascular invasion is a common finding in DHGs, indicating the need for appropriate surgical strategies and postoperative management. We also demonstrated that the clinicopathological characteristics of DHGs in middle‐aged and elderly patients are similar to those in adolescents and young adults, though overall survival may be longer in older individuals. Although rare, DHGs can occur in patients aged 40 years or older. Therefore, IDH‐wildtype diffuse high‐grade gliomas with concomitant Olig2 negativity, ATRX loss, and p53 positivity should raise suspicion for DHG, regardless of the patient's age.

Disclosure

The authors have nothing to report.

Ethics Statement

The study was approved by the Institutional Review Boards of the Asahikawa Medical University Hospital (No. 21040) and the Osaka National Hospital (No. 713).

Consent

Written informed consent was obtained from the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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