Diagnosis of IGCT in the basal ganglia or thalamus remains a challenging task [6]. Basal ganglionic and thalamic lesions comprise heterogenous subsets of intracranial diseases including vascular and degenerative diseases, and some types of tumors [2]. They are relatively rare and have not been well characterized, thus complicating and prolonging the diagnostic process [6,16,10]. Unlike IGCTs in pineal and suprasellar regions, these heterogeneous and rare tumors are sometimes difficult to differentiate IGCT in the basal ganglia or thalamus from other diseases. In our case series, IGCTs accounted for 55% (11 of 20 patients) of all the lesions in the basal ganglia or thalamus, besides vascular lesions. We observed that germinomas comprised the highest percentage of all IGCTs at this site.
IGCTs are divided into two categories: germinomas and non-germinomatous germ cell tumors (NGGCTs). NGGCTs include choriocarcinomas, embryonal carcinomas, teratomas (mature/immature), and yolk sac tumors [11]. These tumors may be single entities or heterogenous combinations of the above-mentioned tumor types, the latter of which are known as mixed germ cell tumors [11]. Pure germinomas and the germinomatous component of mixed germ cell tumors are undeniably sensitive to chemoradiotherapy, and are thus responsive to adjuvant therapy without surgical intervention; while some NGGCT components cannot be mitigated solely by chemoradiotherapy. Therefore, surgery is usually indicated for lesions that persist after chemoradiotherapy [6,16,10]. Thus, it is essential to determine whether the tumor is a pure germinoma, the most common type of IGCT, or if it contains a germinomatous component within the bulk of a mixed germ cell tumor, although no reliable marker is currently available for the detection of the chemoradiation-sensitive element [6].
The MRI characteristics of IGCTs in the basal ganglia or thalamus include heterogenous hypo- to iso-intensities on T1-weighted MRI and iso- to hyperintensities on T2-weighted imaging [1,17]. Basal ganglionic IGCTs are predominantly located in the caput of the caudate nucleus adjacent to the anterior horn of the lateral ventricle and cause ipsilateral hemi-atrophy [17,6,16,18,19]. These tumors appear as ill-defined, slightly high densities on computed tomography [16,10]. Moreover, previous studies have reported the use of magnetic resonance spectroscopy, fluorodeoxyglucose-positron emission tomography (PET), 11C-methionine PET, and other neuroimaging modalities [1,20]. Although these methods are useful, they are not decisive [1,6]. The MRI findings of all our patients are presented in Figures 1 and 2.
Stereotactic biopsy is commonly used to confirm the histopathological diagnosis of these tumors [8]. Stereotactic biopsy is a well-established and point-accurate procedure for obtaining sample tissue from the target area [9]. Although this procedure is reportedly safe, the morbidity rate due to postoperative hemorrhage caused by injury to the perforating arteries or the highly vascular tumors is considered to be higher for tumors in the basal ganglia or thalamus compared with other regions [9,21,8]. In addition to the risk of complications, we emphasize that difficulties may occasionally be encountered in targeting the desired region due to the small lesion size and the presence of only subtle changes on T2-weighted/fluid-attenuated inversion recovery (FLAIR) imaging with faint-to-no enhancement on T1-weighted MRI, especially with IGCTs in the basal ganglia or thalamus [9,22,16,20]. In the present study, the lesions in patients GC1, GC2, and NGC 5 were hardly visible on T1-gadolinium enhanced MRI and could barely be identified as small lesions on FLAIR imaging (Figures 1, 2).
In contrast to biopsy, the measurement of the PLAP value in CSF provides a safe, simple, timely, and less invasive method to specifically detect the germinomatous component within IGCTs [13,12,14]. First, CSF examination for tumors in the basal ganglia or thalamus is not a new or additional method. In fact, CSF examination is required for differentiating among degenerative diseases such as MS, NMO, ADEM, and Behcet’s disease, by measuring factors that are specific to each [23,3-5]. Moreover, the measurement of tumor markers such as HCG, HCG-beta, and AFP is well established and routine [6,10,20]. However, these markers can detect very limited subsets of IGCTs [11]. For instance, pure germinoma, the most common type of IGCT, rarely presents with an elevation of these tumor markers. The problem lies with the lack of a reliable marker for detecting the germinomatous component. Clinicians require information regarding the presence or absence of the germinomatous component in a tumor, because pure germinoma are responsive to chemoradiation therapy and do not require surgery, and chemoradiation can be expected to shrink the volume of the germinomatous component of mixed germ cell tumors. Neo-adjuvant therapy is applicable to these two subsets of IGCT, and surgery is indicated for the residual tumors [6]. The histopathological diagnosis of the biopsy or surgical resection specimen should be taken into consideration if the result of CSF examination is inconclusive or if the lesion continues to grow despite chemoradiotherapy. For instance, the PLAP value may not be elevated in tumors with only a mature teratoma component. The shrinkage of tumor volume cannot be expected after chemoradiation for such tumors; thus, surgical resection is recommended in the majority of cases (Figure 3).
The site of CSF aspiration in each case is shown in Table 1. In the present study, 5 CSF samples were taken from the ventricles in conjunction with treatment of existing hydrocephalus, while the others were aspirated via lumbar punctures. In our experience, considering the results from all PLAP assays, all patients with IGCT, and all brain regions, the PLAP values of samples taken by lumbar aspiration tend to be higher than those taken from ventricles, though we cannot show a significant difference at this point. Therefore, even if CSF samples are obtained from ventricles, we may recommend lumbar aspiration, if possible, after resolving a hydrocephalic state in cases of IGCT accompanied by hydrocephalus. Our data demonstrated that the sensitivity and specificity of PLAP measurements were both 100%. The main objective of this study was to demonstrate the usefulness of measuring the value of PLAP in the CSF in cases of neoplasm at the basal ganglia or thalamic lesions; in these situations the lesion is isolated from the ventricular system and thus has no access to the CSF. The aforementioned results prove that the use of PLAP in CSF is feasible for differentiating the germinomatous component even in tumors in the basal ganglia or thalamus. Moreover, elevations of PLAP levels provide good evidence of a germinomatous element of some kind even if the lesion is barely visible on MRI. We admit that these results should be carefully discussed following the accumulation of evidence in the future studies. Nevertheless, we expect that the specificity and sensitivity of future PLAP measurements will be high based on the data obtained from our case series.
Furthermore, by determining PLAP levels serially, we can monitor the course of treatment in cases of IGCT and make a better-informed decision about subsequent treatment. In case GC5, for instance, the patient underwent lumbar puncture 9 times during the treatment. The initial CSF examination revealed high PLAP value (6070 pg/mL), which decreased to the level of 500 pg/mL after one course of chemotherapy. However, even though repeated chemotherapy treatments were administered, the value of PLAP showed no sign of decreasing, therefore, we selected radiation therapy as the next choice of treatment. Fortunately, the value of PLAP decreased to 19.0 pg/mL at the middle of radiation therapy and finally turned out negative after radiation therapy. It is true that it is expected for the tumor to shrink more in cases of IGCT with high PLAP value, though, the correlation between the tumor volume and PLAP value is still unknown.
Furthermore, the symptoms associated with lesions in the basal ganglia or thalamus are sometimes atypical and dissimilar compared to those associated with IGCTs in the pineal and suprasellar regions [22,18]. Diplopia, diabetes insipidus, etc., are the major symptoms of IGCTs of these regions, whereas psychological disorders, personality changes, involuntary movements, and sensory disturbances are occasionally observed in cases of IGCTs in the basal ganglia or thalamus [22,7,18-20]. This disparity prevents clinicians from recognizing the existence of tumors in the basal ganglia or thalamus in some cases, thereby delaying medical consultation or referral to the appropriate department for treating IGCTs in these anatomical regions [22]. The possible reasons for this include the complexity and invasiveness of the biopsy procedure required to differentiate IGCTs from other diseases. As already mentioned, it is sometimes difficult to approach the target for biopsy within a vaguely located tumor barely detected on MRI [22]. In contrast, the measurement of PLAP can be performed at any time or place, even in the outpatient department, and can facilitate an accurate diagnosis. Moreover, only a few days are required to obtain the PLAP value, whereas at least 1-2 weeks are required to obtain the histopathological diagnosis after biopsy. Therefore, PLAP measurement permits the early initiation of adjuvant therapy [7].
In addition to the complexity and difficulty in locating the target tissue for histological diagnosis for IGCTs in the basal ganglia or thalamus, how to decide on the optimal field for radiation therapy is still being debated owing to the inconspicuous and vague findings on MRI [24,2]. Generally, whole-brain irradiation or craniospinal irradiation is performed for basal ganglionic IGCTs [24,16,2,10]. Extended focal irradiation can be a treatment option, but there is an attendant risk with irradiating an insufficient area, because some IGCTs in the basal ganglia or thalamus can barely be identified on neuroimaging. In our case series, cerebrospinal irradiation was performed in 2 patients, whole-brain irradiation in 2, and whole-ventricle irradiation in 1, all with IGCTs in the basal ganglia, while whole-brain irradiation and whole-ventricle irradiation were performed in 1 and 4 patients, respectively, with IGCTs in the thalamus. The clinical information on radiation therapy was unavailable for one patient (patient GC6) owing to their transfer to another hospital. All patients with IGCT underwent cisplatin-based systemic chemotherapy. During our experience with treating IGCTs based on the PLAP value in a clinical setting, 1 patient succumbed to the primary disease and the others were recurrence-free during 85.2 months of follow-up.
A limitation of this study is the small number of patients included. In addition, the non-IGCT group in our case series included mainly glioma cases, followed by degenerative diseases and did not include other types of neoplasms such as metastatic brain tumor, lymphoma, and so on. Thus, further research is required to devise more optimal and adequate treatment strategies for cases of IGCTs in the basal ganglia or thalamus with collection of evidence from a greater number of relevant cases.