Intracranial germinomas are extremely sensitive to chemotherapy and radiotherapy. Accurate diagnosis and differential diagnosis are critical to implement effective therapeutic regimens, especially in cases without noticeable elevation of the serum levels of tumor markers. We conducted the present retrospective study on a large cohort of patients with “non-secreting” germinomas, reported patients’ characteristics at baseline, performed treatment procedures, and analyzed the clinical short-term outcomes.
The present study revealed that there were no statistically significant differences in age, gender, and tumor location between germinoma with STGCs and pure germinoma groups. Besides, germinomas at pineal region mainly occurred in men, while germinomas at sellar/suprasellar region showed a higher frequency in female patients. The preference of gender in different regions might illustrate that the biological behavior of germinomas in different locations might vary because of the potential mechanisms. Patients with basal ganglia germinomas were younger than those with tumors at sellar/suprasellar and pineal regions. These results could be associated with patients’ clinical symptoms. Patients with basal ganglia germinomas are always accompanied with motor impairment, and the symptoms could be detected at the early-stage of onset. However, delay in diagnosis mainly occurs in patients with sellar/suprasellar germinomas because of the discernible presentations and the negative imaging results during the early-stage [8–10]. This is similar with our results of duration of the symptoms. Endocrinological alteration had significant longer duration, some symptoms like polyuria/polydipsia, growth retardation and menstruation disorders may persist for years before diagnosis. With the slow growth of tumors, patients with pineal lesions may have manifestations in the advanced-stage.
Intracranial germ cell tumors have a trend to disseminate throughout the neuroaxis of the ventricles and spinal subarachnoidal space [11, 12]. In the present study, intracranial dissemination was detected in 61 (26.3%) patients, and a statistically significant difference was found in distribution of primary tumor locations (P<0.001). Intracranial tumor seeding was significantly associated with bifocal and multifocal regions, whereas tumors from the basal ganglia region showed a remarkable reluctance to CSF dissemination. The higher rate of ventricular seeding in bifocal tumors was previously reported, in which 47.8% of patients with bifocal tumors presented with tumor seeding in comparison with 11.4% without bifocal tumors . Besides, 24.8% of patients who received MRI of spine had spinal seeding in the present research. The spinal seeding rate of cases with bifocal or multifocal lesions was higher than that in the other regions. The rate of spinal seeding in pathologically proved intracranial germinoma was reported to be in the range of 5-13% , which was lower than that in our study.
Whether the bifocal germinoma is a synchronous local disease or disseminated disease remains controversial. Previous studies reported that no recurrence after therapy was found in patients with bifocal tumors who only received ventricular radiotherapy without spinal irradiation, indicating that bifocal germinoma was a localized disease [15, 16]. However, other scholars demonstrated that patients with bifocal germinoma who were treated with craniospinal irradiation presented with no treatment failure, while recurrence was observed in cases who were treated without spinal irradiation, suggesting that bifocal germinoma would be a disseminated disease [17–20]. Based on the significant trend of dissemination and the results of our study, we hypothesized that bifocal tumors may result from the metastatic spread of suprasellar or pineal tumors rather than synchronous oligometastatic disease. Meanwhile, intracranial dissemination and spinal seeding are important factors influencing the therapeutic outcomes, and further aggressive treatments are therefore required [13, 21]. We suggest that neurosurgeons should pay additional attention to the imaging findings at diagnosis, especially in bifocal and multifocal diseases, to assess the patients’ status comprehensively.
In our study, we observed that the preoperative KPS scores significantly differed between the two groups, and it was found that a worse clinical status on admission could be related to hydrocephalus. In patients presented with hydrocephalus, lower KPS scores were identified in the open craniotomy group compared with those in the biopsy group (81.4±13.3 vs. 88.8±7.8, P=0.009). No significant difference in KPS scores was detected between the two groups (85.2±9.3 vs. 88.8±9.5, P=0.624). Patients who underwent open craniotomy had lower KPS scores than those who underwent biopsy and the deterioration of KPS scores at discharge was observed in 29 of 115 cases, which indicated that some patients might not benefit from the surgical resection because of the surgical trauma and the postoperative complications. SAWAMURA et al. found that radical resection of intracranial germinomas was not advantageous compared with biopsy, and they suggested that when the histological diagnosis of pure germinoma is made by craniotomy, no risk should be taken to pursue extended resection . In another research, no significant difference in 5-year event-free survival or progression-free survival was noted between patients with residual lesions and those without residual lesions . Thus, according to the lower decrease of KPS scores at discharge in the biopsy group, extended resection may not be necessary when diagnosis was confirmed by intraoperative tissue biopsy during craniotomy.
Importantly, biopsy is less traumatic than open craniotomy in patients with a shorter length of hospital stay. However, postoperative complications should not be ignored, especially postoperative hemorrhage. In our study, intracerebral hemorrhage and epidural hemorrhage after biopsy were found in 7 (6.0%) and 4 (3.4%) cases, respectively. All cases presented with a small amount of hemorrhage and required no surgical intervention except for one case. In a 14-year-old male patient, epidural hemorrhage after stereotactic biopsy was noted that accompanied with the gradually increase of the amount of hemorrhage, and the volume of hemorrhage on CT was 64*22 mm, in which the patient subsequently received craniotomy for evacuation of the hematoma. Postoperative hemorrhage is the most common complication of stereotactic biopsy, with an incidence of 4.7%-9.0%[23–26]. With the development of the stereotactic biopsy planning software merged with imaging examinations (e.g., CT and MRI), it is important for neurosurgeons to provide accurate and safe biopsies to prevent cerebral hemorrhage. Barkley et al. reported that immediate and delayed postoperative deficits and seizures were highly correlated to post-biopsy hemorrhage, and they recommended the use of postoperative CT as a screening tool to evaluate a patient’s clinical status after biopsy , which was consistent with the objectives of our research. Thus, cranial CT as a routine examination after biopsy is recommended to avoid hemorrhage-associated adverse events.
The limitations of this study should be pointed out. First, as a retrospective and observational study, selection bias and recall bias were inevitable. All of our cases were selected depending on the histological diagnosis. Second, biopsy might be not valuable for patients with intermediate serum levels of tumor markers, and such patients might alternatively receive chemoradiotherapy. Third, within half of the cases underwent stereotactic biopsy, and specimens might not fully reflect the characteristics of tumors and increase the possibility of under-diagnosis. However, multi-target biopsy may increase the accuracy of the results. Fourth, there were missing data because of unstandardized patterns of diagnosis, A considerable proportion of cases had no data of the levels of CSF tumor markers, besides, the lack of spinal MRI results and cytological examination results of CSF might negatively influence the reliability of our findings.
The treatment strategies of intracranial germ cell tumors still rely on chemoradiotherapy, the further study should combine the details of the follow-up treatment after accurate diagnosis in order to demonstrate the effect of tumor removal and point out the influences to the prognosis and recurrence.