The clinical and imaging features of infratentorial germinomas compared with supratentorial ectopic germinomas

Abstract

Background

Intracranial germinoma is very sensitive to chemoradiotherapy, while the risk of infratentorial operation is high. The accurate diagnosis can provide the more reasonable treatment, avoiding the unnecessary therapeutic risks.

Purpose

To evaluate the clinical and imaging features of infratentorial germinomas.

Material and Methods

The clinical and imaging data of 13 infratentorial germinomas were collected and compared with 17 supratentorial germinomas in the same period. The clinical and imaging findings were retrospectively analyzed.

Results

Infratentorial germinomas were more common in female patients than supratentorial ones (53.85% vs. 11.76%, P = 0.020). The mean age of the infratentorial group (23.0 ± 10.2 years) was significantly older than that of supratentorial group (12.4 ± 3.3 years, P = 0.003). Most infratentorial germinomas (12/13, 92.31%) underwent surgical resection, while stereotactic biopsy was more common in the supratentorial group (11/17, 64.71%, P = 0.002). Infratentorial germinomas were significantly smaller than supratentorial ones (25.85 ± 8.13 mm vs. 37.18 ± 18.11 mm, P = 0.031). Cystic lesions were more common in supratentorial germinomas (12/17, 70.59%), while most infratentorial germinomas were solid lesions (10/13, 76.92%, P = 0.025). On post-contrast T1-weighted imaging, obvious enhancement was more common in infratentorial germinomas than in supratentorial ones (100% vs. 64.71%, P = 0.024).

Conclusion

In addition to the common findings with supratentorial germinomas, infratentorial lesions have some specific clinical and imaging features.

Keywords

Central nervous system ectopic germinoma infratentorial germinoma magnetic resonance imaging computed tomography

Introduction

Germinomas account for 65%–75% of all intracranial germ cell tumors. Most of them are located exclusively in the pineal or suprasellar region (1); the rest are intracranial ectopic germinomas, mostly located in the basal ganglia, accounting for 5%–10% of intracranial germinomas (2). Only 3.2% of intracranial germinomas occur at other sites. The infratentorial germinomas are rarer, mainly located in the brainstem (3). Intracranial germinomas are very sensitive to chemoradiotherapy, while the risk of infratentorial operation is high. An accurate diagnosis can provide more reasonable treatment, avoiding unnecessary therapeutic risks. In the present study, 13 infratentorial germinomas and 17 supratentorial ectopic germinomas were compared to capture the clinical and imaging features of infratentorial germinomas. To the best of our knowledge, this study is the largest series on this subject.

Material and Methods

Clinical data

From January 2015 to November 2019, 30 patients with intracranial ectopic germinoma conformed by histology were collected. Patients with previous treatment were excluded. According to the location of the lesions, they were divided into the infratentorial group (13 cases) and the supratentorial group (17 cases). Preoperative tumor markers were available in 22 patients (eight infratentorial germinomas, 14 supratentorial germinomas), such as alpha fetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG). According to the standard of our institution, AFP > 7 ng/mL or β-hCG > 5 mIU/mL were considered positive in this study. Clinical data—such as the distribution of lesions, gender, age of onset, course of disease, and tumor marker levels—were recorded and analyzed.

Imaging analysis

Before treatment, all 30 patients underwent magnetic resonance imaging (MRI) using either a GE (Milwaukee, United States) or Phillips (Eindhoven, the Netherlands) 3.0-T scanner, and underwent plain computed tomography (CT) using a Siemens CT scanner (Erlangen, Germany). Conventional sequences included T1-weighted (T1W) imaging, T2-weighted (T2W) imaging, and fluid-attenuated inversion recovery (FLAIR). Post-contrast T1W imaging after gadolinium injection (0.2 mL/kg) was obtained. The imaging indicators included: the size of lesion (the maximal diameter); the tumoral cystic solidity (cystic, solid); enhancement degree (subtle, obvious); mass effect (subtle, obvious); peritumoral edema (subtle, obvious); and obstructive hydrocephalus (subtle, obvious). The tumoral cystic solidity was relative and based on the size ratio of the maximal cystic part to the whole tumor (cystic lesion >1/2; solid lesion <1/2). The maximal diameter of peritumoral edema >5 mm was defined as the obvious edema. Meanwhile, the tumor density (CT value) and MR enhancement were both targeted at the solid parts of the lesions for assessment. Avoiding intratumoral cystic change, hemorrhage, and calcification, the density of each lesion was determined by the mean value of three different regions of interest (ROI; 20–100 mm²) on the reconstructed images with a slice thickness of 1 mm to minimize the influence of partial volume artifact. All imaging data were reviewed separately by three experienced neuroradiologists who were blind to the histological results. In case of disagreement, the consensus was reached by discussion or majority obedience.

Statistical analysis

For statistical analyses, IBM SPSS version 22.0 (SPSS, Chicago, IL, USA) was used. Descriptive statistics were performed to characterize the clinical data and imaging findings. Independent t-test (two tailed) or Mann–Whitney U test was used for the statistical comparison of continuous variables between two groups. Fisher’s exact test (two-tailed) was used to test the difference of dichotomous variables. All data are presented as n (%), median (range), or mean ± SD. P < 0.05 was defined as statistically significant.

Results

Clinical findings

The gender distribution and clinical symptoms of both groups are shown in Table 1. The clinical comparisons between the two groups are shown in Table 2. Infratentorial germinomas were more common in female patients (7/13, 53.85%), while most of supratentorial germinomas were male patients (15/17, 88.24%, P = 0.020). The mean age of the infratentorial group (23.0 ± 10.2 years) was older than that of the supratentorial group (12.4 ± 3.3 years, P = 0.003). There was no significant difference in the course of disease (P = 0.837) or tumor marker tests (P = 0.515) between the two groups. Most of the infratentorial germinomas (12/13, 92.31%) underwent surgical resection, while stereotactic biopsy was more common in the supratentorial group (11/17, 64.71%, P = 0.002) and followed by the combined chemoradiotherapy.

Table 1.

Gender distribution and symptoms of both groups.

Group	Distribution	Gender/n	Symptoms
Infratentorial	Cerebral peduncle (n = 5) +cerebellum (n = 1)	M/6	Headache, ataxia, limbs tremor
	Pons n = (3) + MO (n = 2) +MCP (n = 1) + vermis (n = 1)	F/7	Ataxia, dizziness, limbs numbness, dysphagia, hypophasis, hypotonia
Supratentorial	Basal ganglia (n = 11)	M/9, F/2	Hemiparesis, hemifacial nerve palsy, hemianopsia
	Thalamus (n = 4) + frontal lobe (n = 2)	M/6	Headache, cognitive disorders

MCP, middle cerebellar peduncle; MO, medulla oblongata.

Table 2.

Clinical and imaging findings of both groups.

	Infratentorial group	Supratentorial group	P
Clinical findings
Gender (M : F)	6:7	15:2	0.020*
Age of onset (years)	23.0 ± 10.2	12.4 ± 3.3	0.003*
Course of disease (months)	13 (1–36)	10.5 (3–26)	0.837
Tumor marker tests (positive : negative)	0:8	2:12	0.515
Clinical management (surgery : biopsy)	12:1	6:11	0.002*
Imaging findings
Size (mm)	25.85 ± 8.13	37.18 ± 10.11	0.031*
Mass effect (subtle : obvious)	7:6	13:4	0.255
Hydrocephalus (subtle : obvious)	8:5	14:3	0.242
Peritumoral edema (subtle : obvious)	10:3	13:4	1.000
Tumoral cystic solidity (solid : cystic)	10:3	5:12	0.025*
Enhancement (subtle : obvious)	0:13	6:11	0.024*
CT value (HU)	42.17 ± 4.71	41.47 ± 5.22	0.622

Values are given as n, mean ± SD, or median (range).

*Significance values.

Imaging findings

All 30 patients showed solitary lesions. No abnormal findings were found in the suprasellar or pineal regions. Similar to the supratentorial group, infratentorial lesions showed slight hyperdensity on CT (Fig. 2a), iso-hypointensity on T1W imaging, and iso-hyperintensity on T2W imaging (Figs. 1a, 1b, 2b, 2c, 3a, 3b). However, there was a significant difference in the MR enhancement degrees between the two groups (P = 0.024). All 13 infratentorial lesions showed obvious enhancement (Figs. 1c, 2d, 3c), while subtle enhancement was more common in the supratentorial group (6/11, 35.29%), especially in the basal ganglia lesions (n = 5). Infratentorial germinomas (25.85 ± 8.13 mm) were significantly smaller than supratentorial ones (37.18 ± 10.11 mm, P = 0.031). Cystic lesions were more common in supratentorial germinomas (12/17, 70.59%), while most infratentorial germinomas were solid lesions (10/13, 76.92%, P = 0.025). Mass effect, peritumoral edema, and obstructive hydrocephalus were subtle in both groups (P = 0.255, P = 1.000, P = 0.242). There was no significant difference in the mean CT value between the two groups (42.17 ± 4.71 HU vs. 41.47 ± 5.22 HU, P = 0.622). Most of the infratentorial germinomas (10/13, 76.92%) were in the brainstem, and half of them (three in the pons, two in the medulla oblongata) were located in the dorsal parts. Only the three cystic lesions in the pons, cerebral peduncle, and vermis caused obstructive hydrocephalus (Fig. 3c), and only the peritumoral edema of the cerebellar hemispheric lesion was obvious (Fig. 2a–c). The detailed imaging findings of both groups are shown in Table 2.

Fig. 1.

Axial MR scans reveal the solid tumor in the left middle cerebellar peduncle, showing isointensity on T1W imaging (a), slight hyperintensity on T2W imaging (b), and homogeneous enhancement on post-contrast T1W imaging (c). The peritumoral edema is mild and the fourth ventricle is compressed slightly. MR, magnetic resonance; T1W/T2W, T1-weighted/T2-weighted.

Fig. 2.

Axial CT scan reveals a slightly hyperdense mass in the right cerebellum with extensive hypodense peritumoral edema, and the fourth ventricle is slightly compressed (a). Axial MR scans reveal slight hypointensity on T1W imaging, isointensity on T2W imaging (b, c), and obvious enhancement on post-contrast T1W imaging (d). CT, computed tomography; MR, magnetic resonance; T1W/T2W, T1-weighted/T2-weighted.

Fig. 3.

Axial MR scans reveal the cystic lesion in the dorsal part of the pons, showing iso-hypointensity on T1W imaging (a), iso-hyperintensity on T2W imaging (b), and heterogeneous enhancement on sagittal post-contrast T1W imaging (c). The fourth ventricle is occluded, and with the supratentorial ventricular dilation. MR, magnetic resonance; T1W/T2W, T1-weighted/T2-weighted.

Postoperative histology and follow-up

Histologically, the tumor cells were large and irregularly distributed, with oval unclei, prominent nucleoli, abundant cytoplasm, and lymphocytic infiltration. Immunohistochemistry was as follows: placental alkaline phosphatase (+); β-HCG (–); AFP (–); and Ki-67 (50%–80%). In the follow-up periods (range = 10–36 months), recurrence or ependymal seeding occurred in three supratentorial cases and one infratentorial case. Sequelae such as hemiparesis, dyskinesia, and mental slowing occurred in six supratentorial cases. The ataxia (four cases), hypertrophic olivary degeneration (two cases with pontine lesion), and vegetative state (one case with medulla oblongata lesion) occurred in infratentorial group.

Discussion

The pathogenesis of intracranial ectopic germinoma is not conclusive. It may be caused by the migration obstacle or mesodermal dislocation of primordial germ cells during the embryonic development (4). Gender disparity and age of onset are helpful in reaching a correct diagnosis. Intracranial germinoma is mostly seen in children or young adults, and with a male predominance (5). In the present study, most supratentorial germinomas (15/17, 88.24%) occurred in male patients, while the male-to-female ratio of the infratentorial group was 6:7 (P = 0.020). The infratentorial lesions in seven female patients were located in the pons (n = 3), medulla oblongata (n = 2), middle cerebellar peduncle (n = 1), and vermis (n = 1). Previous studies elucidated that germinomas in the pineal region, basal ganglia, and midbrain were more common in male patients, while those in the suprasellar region, pons, and medulla oblongata showed a female predominance (5,6). Our results were consistent with these findings. Closure of anterior neuropores is later in female patients compared to male patients, which may lead to the embedded primordial germ cells reaching deeper positions in female patients (7).

In the present study, the mean age at onset of infratentorial germinomas was significantly older than that of supratentorial ones (P = 0.003). The slow tumor growth and insidious symptoms are the possible causes (8). In addition, there was no significant difference in the course of disease between the two groups (P = 0.837). Perhaps the exact course is difficult to determine clinically. The clinical symptoms of intracranial ectopic germinomas can be attributed to the locations (9,10). The infratentorial germinomas were located in the brainstem and cerebellum, showing ataxia, dizziness, dysphagia, hypophasis, hypotonia, and so on, while the supratentorial germinomas were mostly located in the basal ganglia, which could lead to hemiparesis, dyskinesia, hemianopsia, cognitive disorders, etc. Most of the intracranial germinomas are non-secretory tumors, so the tumor markers tests (β-hCG, AFP) may be within the normal ranges. This makes early diagnosis difficult (11).

Because of the identical histological components, supratentorial and infratentorial germinomas can share similar imaging features, to some extent. This is useful when detecting rare infratentorial germinomas. In this group, the solid components of infratentorial lesions also showed slight hyperdensity on CT, isointensity on T1W and T2W imaging, and with obvious enhancement. This might be explained by the high cellularity, high nucleocytoplasmic ratio, and low water content of the tumor cells (12). Similar to basal ganglia germinomas, peritumoral edemas and mass effect of infratentorial lesions are also subtle.

Compared with supratentorial ectopic germinomas, infratentorial germinomas had some specific features. The supratentorial ectopic germinomas, especially basal ganglia germinomas, tend to become large and cystic. The large growth space is one of the reasons for this (13). Intratumoral cysts can occur in about 40% of intracranial germinomas and in 83%–90% of basal ganglia germinomas (14). However, most of the infratentorial germinomas (10/13, 76.92%) in this group were small, solid, and enhanced homogeneously. The Ki-67 labeling index of both groups were elevated, suggesting the similar proliferative potential of the infratentorial lesions. However, the narrow space of posterior fossa may limit the growth and cystic change of the lesions. There was a significant difference in enhancement degrees between the two groups. This may be related to the basal ganglia germinomas at different stages in supratentorial group. Basal ganglia germinomas at the early stage could be also small and homogeneous, but without intense enhancement (15). This is different from the infratentorial germinomas. Although the infratentorial lesions were small and solid, the enhancement was obvious. In addition, the infratentorial lesions were adjacent to the fourth ventricle and aqueduct, but the obstructive hydrocephalus was not common. The small lesions, mild mass effect, or slow tumor growth might result in the compensation of cerebrospinal fluid circulation. Only the cystic lesions in the infratentorial group caused the obstructive hydrocephalus. Cystic changes may indicate rapid enlargement of the tumor (16), which may cause the obstructive hydrocephalus in a shorter time. The germinomas in the pons (n = 3) and medulla oblongata (n = 2) were located in the dorsal part and protruded into the fourth ventricle, which was consistent with the previous reports (17). Whether it is a specific sign needs further study. To date, germinomas located in the middle cerebellar peduncle and cerebellar hemisphere may be the first reported. Compared with other infratentorial lesions, the peritumoral edema of the cerebellar hemispheric lesion is obvious. It is possible that the cerebellar hemispheric structure is relatively loose and prone to edema infiltration.

The therapeutic regimen of infratentorial germinomas is still controversial. With the development of microsurgical techniques, some studies have advocated for the surgical resection of intracranial germinoma (18). In the present study, most intracranial germinomas (12/13, 92.31%) underwent surgical resection. The unclear diagnosis before surgery is another reason. Considering the important physiological functions of infratentorial structures, the operative risks still limited the outcomes. In the follow-up periods, hypertrophic olivary degeneration and vegetative state occurred in the infratentorial group. Because of the invasive growth of germinomas, combined chemoradiotherapy is the preferred choice of treatment (19).

Infratentorial germinoma can be confused with dorsal exophytic glioma of the brainstem, medulloblastoma, choroid plexus papilloma, and ependymoma. Dorsal exophytic glioma of the brainstem originates from the subependymal glial tissue of the fourth ventricle and grows into the fourth ventricle, with little enhancement (20). Medulloblastoma originates from the cerebellar vermis, and the fourth ventricle is compressed and moved forward (21). Infratentorial choroid plexus papilloma is contained within the fourth ventricle, and with the remarkable enhancement and hydrocephalus (22). Infratentorial ependymoma arises from the floor of the fourth ventricle, filling the ventricle and extending into the foramina (23).

In conclusion, the mean age at onset of infratentorial germinomas is older than that of supratentorial germinomas, and with a slight female predominance. In addition to the common imaging characteristics with the supratentorial germinomas, the infratentorial lesions are small, solid, and with homogeneous enhancement. Germinomas in the brainstem are often located in the dorsal part, but the obstructive hydrocephalus is uncommon. Ectopic germinomas should be considered, when encountering female adolescents or young adults with infratentorial lesions. Because of the low incidence of infratentorial germinoma, its clinical and imaging features require further study with a larger sample size.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Wei Li

Chao Ran

Jun Ma

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