An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series

Abstract

Bilateral basal ganglia germinomas are exceptionally rare intracranial germ cell tumors associated with significant diagnostic delays and irreversible neurological impairment. This study addressed this diagnostic challenge by analyzing the largest dedicated cohort of histopathologically confirmed bilateral basal ganglia germinomas (n = 8). We identified alarming diagnostic delays (median, 1.2 years) in 62.5% of cases, culminating in irreversible deficits such as paralysis and cognitive impairment. Key early clinical indicators included adolescent predominance (mean age, 12.4 years), marked male predominance (7:1), cognitive decline (87.5%), and hemiparesis or monoparesis (62.5%). Magnetic resonance imaging detected cerebral atrophy in 87.5% of patients, with 25.0% showing concomitant mass lesions and atrophy, a distinctive radiological pattern not previously emphasized in unilateral basal ganglia germinomas. Cerebrospinal fluid beta-human chorionic gonadotropin analysis demonstrated superior sensitivity to serum testing (57.1% vs 28.6%). To mitigate devastating outcomes, we propose integrated cerebrospinal fluid beta-human chorionic gonadotropin screening combined with magnetic resonance imaging, with an emphasis on atrophy detection. In patients exhibiting progressive deficits or serial radiological progression despite negative biomarker results, stereotactic biopsy should be prioritized to enable early intervention and preserve neurological function.

Introduction

Basal ganglia germinomas (BGGs) are a distinct subtype of intracranial germ cell tumors (GCTs) that typically manifest as unilateral lesions. Bilateral involvement is exceptionally rare, with only sporadic cases reported worldwide.^1–5 Due to their insidious onset, nonspecific imaging features, and low incidence, bilateral BGGs present significant diagnostic challenges, often resulting in delayed diagnosis. Although germinomas exhibit high radiosensitivity and chemosensitivity (5-year overall survival >90% with multimodal therapy), most BGGs are diagnosed at advanced stages.^6,7 Irreversible basal ganglia destruction and progressive cerebral atrophy commonly result in permanent neurological deficits, including paralysis, cognitive impairment, and dysarthria, severely compromising long-term functional outcomes. ⁸ Given these irreversible sequelae, early diagnosis is crucial for optimizing therapeutic outcomes. This study retrospectively analyzed a cohort of bilateral BGG cases to delineate their clinical and neuroimaging characteristics, aiming to identify early diagnostic indicators and facilitate timely initiation of disease-modifying interventions. To the best of our knowledge, this study represents the largest cohort of exclusively bilateral BGGs (n = 8) with integrated clinicoradiological characterization reported to date.

Materials and methods

Study design and patient selection

We retrospectively reviewed pediatric patients with bilateral BGGs who were treated at Beijing Tiantan Hospital, Capital Medical University between January 2019 and June 2024. The inclusion criteria were as follows: (a) histopathological confirmation via stereotactic biopsy and (b) neuroimaging evidence of bilateral basal ganglia involvement. The exclusion criteria were as follows: (a) coexistence of other intracranial tumors and (b) a history of radiotherapy, chemotherapy, or targeted therapy.

Data collection

Demographic characteristics (age and sex), clinical symptoms, and laboratory parameters were systematically reviewed. Serum and cerebrospinal fluid (CSF) levels of beta-human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) were measured using electrochemiluminescence immunoassays at the hospital laboratory (reference ranges: β-hCG, 0–2.6 mIU/mL; AFP, 0–7 ng/mL). Diagnostic delay was defined as a duration of ≥6 months from symptom onset to histopathological confirmation. ⁹ Neuroimaging was performed using a 3.0T magnetic resonance imaging (MRI) system (Siemens Skyra® or Philips Ingenia®), with abnormalities independently assessed by two blinded neuroradiologists.

Ethics approval and participant consent

This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (Approval Number: KY 2021-119-02). Written informed consent was obtained from the guardians of all pediatric patients prior to their inclusion in the study. We have de-identified all patient details, ensuring confidentiality and anonymity of the data collected. The reporting of this study conforms to the Case Report (CARE) guidelines. ¹⁰

Results

Eight pediatric patients with bilateral BGGs were identified, accounting for 7.1% (8/112) of all BGG cases diagnosed at our institution between January 2019 and June 2024. All cases were confirmed by histopathology. This cohort exhibited a marked male predominance (7:1), with a median age at diagnosis of 11.2 years (range, 7.2–12.8 years) (Table 1).

Table 1.

Clinical characteristics and tumor marker profiles in pediatric patients with bilateral basal ganglia germinoma.

Case No.	Age (yrs)	Sex	Diagnostic duration	Initial symptoms	Atrophy	β-hCG (mIU/mL)		AFP (ng/mL)
						Serum	CSF	Serum	CSF
1	10	Male	3 months	Involuntary movement	Left mass effect + right hemispheric atrophy	NP	NP	NP	NP
2	12.4	Male	4 months	Left hemiparesis	Right cerebral peduncle atrophy	0.123	1.77	<0.605	<0.605
3	11.7	Male	2 years	Bilateral weakness	No atrophy	3.63↑	4.97↑	<0.605	1.6
4	7.6	Male	10 months	Right hemiparesis	Bilateral hemispheric atrophy	0.776	2.86↑	<0.605	<0.605
5	11.2	Female	2.3 years	Diabetes insipidus	Bilateral hemispheric atrophy	5.9↑	11.21↑	2.71	<0.605
6	10.8	Male	2.5 years	Left hemiparesis	Left cystic-solid lesions + right hemispheric atrophy	<0.1→<0.1	1.13→5.51↑	2.24→2.94	<0.605 →0.844
7	12.8	Male	1.9 years	Diabetes insipidus	Bilateral hemispheric atrophy	1.28	1.83	1.01	<0.605
8	7.2	Male	5 months	Right hemiparesis	Right hemispheric atrophy	<0.1	0.846	1.25	<0.605

NP: Not performed; ↑: elevated biomarker concentrations exceeding institutional reference ranges (Beijing Tiantan Hospital: β-HCG 0–2.6 mIU/mL; AFP 0–7 ng/mL); →: longitudinal biomarker profiling during disease progression (Case 6 exemplifies dynamic β-hCG and AFP fluctuations); β-HCG: beta-human chorionic gonadotropin; AFP: alpha-fetoprotein; CSF: cerebrospinal fluid.

Clinical presentation

Initial symptoms at disease onset included hemiparesis or monoparesis (62.5%, 5/8), diabetes insipidus (25.0%, 2/8), and involuntary movements (12.5%, 1/8). The median interval from symptom onset to diagnosis was 1.2 years (range, 3 months to 2.3 years). A diagnostic delay was observed in 62.5% (5/8) of the cases. Reasons for diagnostic delay were case-specific and included initial misdiagnoses as demyelinating disease (Cases 3 and 4), diabetes insipidus (Case 5), or mitochondrial encephalomyopathy (Case 1) as well as management with follow-up due to nonspecific symptoms (Case 6). Among the five patients who experienced a diagnostic delay, three progressed from initial unilateral weakness to bilateral paralysis, whereas the other two, who initially presented with diabetes insipidus, subsequently developed unilateral and bilateral paralysis, respectively. In contrast, two patients with shorter symptom durations (4 and 5 months), who did not experience a diagnostic delay, maintained unilateral weakness. The remaining patient, who initially presented with involuntary movements, developed bilateral paralysis during treatment, which persisted after completion of therapy. Comorbidities identified at diagnosis included cognitive decline (87.5%, 7/8), dysarthria (50.0%, 4/8), and seizures (12.5%, 1/8).

Neuroimaging features

All patients underwent cranial computed tomography (CT) and MRI examinations. Noncontrast CT revealed hyperdense lesions in three of the eight patients (37.5%; calcified in two patients) (Figure 1(a)), heterogeneous lesions in two patients (25.0%; no representative image shown), and a solitary cystic-solid lesion in one patient (12.5%) (Figure 3(c)); the scans for the remaining two patients (25.0%) were unremarkable. MRI confirmed bilateral basal ganglia involvement in all patients, with concomitant thalamic (n = 2) or pituitary stalk (n = 2) lesions observed in four cases (50.0%). The majority of lesions (5/8, 62.5%) showed T1 hypointensity or isointensity and T2 hyperintensity (Figures 1(b) and 2(a) and (b)), whereas two cases (25.0%) exhibited isointensity on T1- and T2-weighted sequences. Restricted diffusion was observed only in the solid component of the cystic-solid lesion (1/8). Postcontrast studies (n = 7) demonstrated heterogeneous enhancement in four cases (57.1%) (Figure 2(c)). Notably, cerebral atrophy was observed in seven patients (87.5%), presenting as bilateral (n = 3) (Figure 2(a)), unilateral (n = 2), or concurrent mass effect with atrophy (n = 2) (Figure 3(d)). Cerebral atrophy was a common finding, and representative images from three cases are presented in the main figures (Figures 1 to 3). Comprehensive neuroimaging for the remaining four patients exhibiting cerebral atrophy is provided in the Supplementary Material (Supplementary Figures 1 and 2).

Figure 1.

Imaging features of Case 1. (a) Axial noncontrast CT showing heterogeneous hyperdensities with calcifications in the bilateral basal ganglia (arrows). Mildly prominent sulci and fissures are noted over the right cerebral convexity. (b) Axial T2-weighted MRI showing irregular hyperintense foci within the bilateral basal ganglia (arrowheads) and (c) axial gadolinium-enhanced T1-weighted MRI showing no significant enhancement. CT: computed tomography; MRI: magnetic resonance imaging.

Figure 2.

Imaging features of Case 5. (a) Axial T1-weighted MRI showing bilateral cerebral hemisphere atrophy with sulcal and fissural widening. (b) Axial T2-weighted MRI showing heterogeneous hypointense foci in the basal ganglia (arrowheads) and (c) axial gadolinium-enhanced T1-weighted MRI showing heterogeneous patchy enhancement within the bilateral basal ganglia (curved arrow). MRI: magnetic resonance imaging.

Figure 3.

Neuroimaging progression in bilateral BGG in Case 6. (a to b) 2021 (1 year post-onset): arrows indicate right cerebral peduncle atrophy on CT (a) and T2-weighted MRI (b). (c to d) 2022 (1.5-year follow-up): curved arrows mark a new left basal ganglia cystic-solid mass on CT (c) and MRI (d). Arrowheads denote ill-defined right basal ganglia hyperdense foci (c) and corresponding hyperintense foci (d). BGG: basal ganglia germinoma; CT: computed tomography; MRI: magnetic resonance imaging.

Tumor marker profiles

Serum and CSF levels of AFP and β-hCG were assessed in seven patients. Serum and CSF AFP levels were within the normal range in all cases (Table 1). However, CSF β-hCG levels were elevated in four cases (57.1%; Cases 3 to 6), whereas serum β-hCG levels were elevated in two cases (Cases 3 and 5). Notably, Cases 3 and 5 exhibited higher β-hCG levels in CSF than in serum.

Treatment and clinical outcomes

All patients received four cycles of combination chemotherapy with carboplatin and etoposide every 4 weeks, followed by radiation therapy. No surgical resection was performed in any case. At a median follow-up of 45 months (range, 14–79 months), all eight patients were alive and clinically stable, with no evidence of disease recurrence. However, neurological deficits, including motor dysfunction, cognitive impairment, and dysarthria, persisted without significant improvement.

Representative case

Case 6 exemplified the diagnostic challenges of bilateral BGGs. A previously healthy 10-year-old boy initially presented with mild left hemiparesis in 2020. The initial cranial MRI revealed no abnormalities, and no intervention was undertaken. The symptoms progressed insidiously over the subsequent year, with the emergence of new-onset dysarthria and sialorrhea, prompting evaluation at our institution in 2021. Neuroimaging at that time revealed isolated right cerebral peduncle atrophy (Figure 3(a) and (b)), whereas serum and CSF levels of AFP and β-hCG remained within normal limits. Brain biopsy was recommended but deferred due to parental refusal. Given the atypical neuroimaging features and negative tumor biomarkers, the patient was enrolled in a structured surveillance program. During surveillance, the patient experienced progressive neurological deterioration. By 2022 (1.5 years following symptom onset), he re-presented with bilateral limb weakness and cognitive decline. Repeat neuroimaging revealed the following: (a) a new cystic-solid mass in the left basal ganglia with mass effect (Figure 3(c)); (b) T2 hyperintensity in the right basal ganglia (Figure 3(d)); and (c) progressive right peduncle-to-hemispheric atrophy (Figure 3(d)). Concurrently, CSF β-hCG levels were elevated (5.51 mIU/mL), whereas serum levels remained normal. Stereotactic biopsy ultimately confirmed germinoma, establishing the diagnosis after a 1.5-year delay. The patient received four cycles of polychemotherapy followed by radiotherapy; however, neurological deficits persisted without significant improvement. This paradigmatic case underscores the diagnostic challenge wherein initial unremarkable imaging and negative biomarkers contribute to delay in definitive diagnosis.

Discussion

Germinomas of the basal ganglia represent a diagnostically challenging subset of intracranial GCTs. ¹¹ Although more than 80% of germinomas arise in the pineal or suprasellar regions, basal ganglia involvement is rare (5%–10%), and bilateral presentation is exceptionally rare.^5,12 Supporting existing epidemiological data, our series reaffirms the characteristic male predominance and a median diagnostic age of 11.2 years, further solidifying the demographic signature of this disease. ¹³

Clinically, BGGs typically exhibit an insidious onset, with hemiparesis or monoparesis as the most frequent initial symptom.^14,15 Progressive disease often leads to cognitive decline, dysarthria, and personality changes, occasionally accompanied with endocrine dysfunction.^16,17 In our cohort, 75% of the cases presented with hemiparesis or monoparesis. The high prevalence of cognitive decline is noteworthy, significantly exceeding the rates reported in unilateral cases. ¹⁸ This discrepancy reflects chronic axonal degeneration within prefrontal–basal ganglia circuits due to delayed intervention. ¹⁹

Compared with pineal or suprasellar germinomas, BGGs exhibit a longer diagnostic delay, which has been corroborated by previous studies. Sonoda et al. reported a median interval from initial neuroimaging to diagnosis of 9.9 months in BGGs, which is markedly longer than that observed in pineal (4.1 months) or suprasellar (4.4 months) germinomas. ⁸ Similarly, Ozelame et al. reported a mean symptom-to-diagnosis duration of 17 months in pediatric patients with BGGs. ²⁰ Consistent with these findings, Zhang et al. observed that 58.8% of BGG cases experienced a diagnostic delay exceeding 6 months, often associated with cognitive disturbances. Importantly, they identified that prolonged diagnostic intervals were significantly correlated with poorer survival outcomes. ¹⁷ Our data further support this trend, showing that 62.5% of patients experienced a diagnostic delay, with a median latency of 1.2 years. Critically, such delays result in irreversible neurological deterioration, as demonstrated by three cases in our cohort that progressed from unilateral weakness to bilateral deficits during the prolonged diagnostic process. Notably, existing evidence suggests that even complete tumor eradication often fails to restore preexisting neurologic deficits, underscoring the imperative to initiate treatment before tumor invasion of the internal capsule.^9,17

Placental alkaline phosphatase (PLAP) in CSF is considered a sensitive and specific biomarker for germinoma, with evidence indicating that its elevation in CSF may precede that of β-hCG. ²¹ Unfortunately, PLAP testing was not performed in this cohort because of its unavailability at our institution during the study period. Serum and CSF AFP and β-hCG levels serve as primary tumor biomarkers for the diagnosis of intracranial GCTs. Serial monitoring of these markers informs treatment response and recurrence detection. ²² Although pure germinomas typically exhibit normal AFP/β-hCG profiles, the presence of syncytiotrophoblastic giant cells may result in modest CSF β-hCG elevations (3–50 mIU/mL). ²³ Consistent with this, all patients in our cohort had normal serum and CSF AFP levels. CSF β-hCG was elevated in four cases, two of which demonstrated concurrent serum β-hCG elevation; however, serum concentrations remained lower than those in CSF. These findings confirm the superior sensitivity of CSF β-hCG for detecting germinomas, supporting its crucial role in diagnostic workflows. ²²

BGGs typically present slight hyperdensity on CT and mild T2 hyperintensity on MRI, often accompanied with minor cystic changes. Calcifications can be observed on CT. Hypointensity on T2-weighted imaging and Wallerian degeneration of the corticospinal tract, manifesting as ipsilateral cerebral peduncle or hemispheric atrophy, have been emphasized as reliable signs of BGG. ²⁴ Compared with nongerminomatous GCTs, germinomas more frequently demonstrate inhomogeneous enhancement and cystic changes. ²⁵ Radiologically, the 87.5% cerebral atrophy rate observed in our bilateral cohort is markedly higher than the 33%–75% previously reported for unilateral BGGs.^20,26 This pronounced atrophy, predominantly reflecting Wallerian degeneration, serves as a key differential feature between BGGs and inflammatory or aggressive malignancies, which typically follow shorter clinical courses. ²⁷ In particular, two cases exhibited concurrent ipsilateral mass effect and contralateral atrophy, a “mass–atrophy coexistence” pattern that encapsulates the dual pathology of active tumor proliferation and chronic degenerative changes.

The diagnostic challenges posed by BGGs were clearly illustrated in Case 6. This patient’s clinical trajectory, beginning with subtle hemiparesis with unremarkable imaging, progressing to unilateral atrophy with negative biomarkers, and eventually culminating in bilateral involvement with CSF β-hCG elevation, encapsulates the characteristic diagnostic difficulties. Most critically, the persistence of neurological deficits despite therapy underscores the irreversible neurological toll of delayed intervention. ²⁸ Based on these findings, we advocate a heightened clinical vigilance in adolescent males presenting with insidious-onset hemiparesis. We propose the following diagnostic protocol: (a) serial MRI with specific attention to early atrophy detection; (b) concurrent serum and CSF β-hCG and AFP testing even when the initial results are negative; and (c) prompt stereotactic biopsy when radiological progression contradicts biomarker profiles.

The initial clinical presentations in this case series were highly variable, necessitating a systematic approach to differential diagnosis based on core symptomatic features and neuroimaging findings. Among adolescents presenting with hemiparesis or bilateral limb weakness in conjunction with bilateral basal ganglia lesions (Cases 2, 3, 4, 6, and 8), the primary diagnostic considerations included metabolic disorders such as mitochondrial encephalomyopathy and Wilson’s disease, infectious or inflammatory conditions such as autoimmune encephalitis and post-viral basal ganglia necrosis, toxic exposures including carbon monoxide poisoning, and hereditary neurodegenerative diseases such as pantothenate kinase-associated neurodegeneration. In cases where central diabetes insipidus was the predominant feature (Cases 5 and 7), the diagnostic evaluation prioritized the exclusion of tumors affecting the hypothalamic–pituitary axis, notably craniopharyngioma and pituitary tumors, as well as infiltrative inflammatory processes such as Langerhans cell histiocytosis while also distinguishing nephrogenic diabetes insipidus. Among patients presenting with involuntary movements alongside basal ganglia abnormalities (Case 1), the differential diagnosis encompassed genetic metabolic disorders such as Wilson’s disease and Huntington’s disease, immune-mediated syndromes including Sydenham’s chorea, toxic etiologies, and vascular pathologies. Ultimately, all cases were confirmed as germinoma, underscoring the tumor’s heterogeneous clinical spectrum and the importance of its inclusion in the differential diagnosis of adolescents with complex neurological syndromes.

This study has several limitations. The small cohort of eight patients, although reflective of the rarity of bilateral basal ganglia germinomas, may limit the generalizability of the findings. Furthermore, as a single-center retrospective analysis, the results may be influenced by selection bias. Finally, the median follow-up period of 45 months is relatively short for evaluating long-term outcomes such as delayed disease recurrence or late treatment-related sequelae.

Conclusion

Bilateral BGGs predominantly affect adolescent males, presenting with progressive hemiparesis or monoparesis and cognitive decline. An integrated screening approach combining CSF β-hCG analysis and MRI focusing on early atrophy detection is essential. For cases with serial biomarker negativity but progressive radiological abnormalities (≥2 consecutive MRIs demonstrating structural evolution), stereotactic biopsy should be prioritized to facilitate early intervention and preserve neurological function.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251390080 - Supplemental material for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series

Supplemental material, sj-pdf-1-imr-10.1177_03000605251390080 for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series by Yanqing Dong, Zhizheng Zhuo, Chunmei Yao, Yajie Wang, Bo Li, Xiaoguang Qiu and Yaxian Deng in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605251390080 - Supplemental material for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series

Supplemental material, sj-pdf-2-imr-10.1177_03000605251390080 for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series by Yanqing Dong, Zhizheng Zhuo, Chunmei Yao, Yajie Wang, Bo Li, Xiaoguang Qiu and Yaxian Deng in Journal of International Medical Research

Supplemental Material

sj-pdf-3-imr-10.1177_03000605251390080 - Supplemental material for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series

Supplemental material, sj-pdf-3-imr-10.1177_03000605251390080 for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series by Yanqing Dong, Zhizheng Zhuo, Chunmei Yao, Yajie Wang, Bo Li, Xiaoguang Qiu and Yaxian Deng in Journal of International Medical Research

Supplemental Material

sj-pdf-4-imr-10.1177_03000605251390080 - Supplemental material for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series

Supplemental material, sj-pdf-4-imr-10.1177_03000605251390080 for An integrated cerebrospinal fluid beta-human chorionic gonadotropin and atrophy-targeted magnetic resonance imaging strategy to reduce diagnostic delays in bilateral basal ganglia germinomas: A case series by Yanqing Dong, Zhizheng Zhuo, Chunmei Yao, Yajie Wang, Bo Li, Xiaoguang Qiu and Yaxian Deng in Journal of International Medical Research