Nongerminomatous Germ Cell Tumors Research Articles

Update on MRI in pediatric intracranial germ cell tumors-The clinical and radiological features.

Intracranial germ cell tumors (iGCTs) are uncommon brain tumors that mainly occur in children. Differing in histology, location, and gender of the patients, iGCTs are often divided into germinomas and non-germinomatous germ cell tumors (NGGCTs). Early diagnosis and timely treatment are crucial to iGCTs, the subtypes of which have substantial variations. This review summarized the clinical and radiological features of iGCTs at different sites, and reviewed the recent advances in neuroimaging of iGCTs, which can help predict tumor subtypes early and guide clinical decision-making.

Outcomes and surgical approaches for pineal region tumors in children: 30 years' experience.

Pineal region tumors account for 2.7%-11% of all CNS tumors in children. In this series, the authors present their surgical results and long-term outcomes from a pediatric pineal region tumor cohort. A total of 151 children aged 0-18 years were treated from 1991 to 2020. Tumor markers were collected in all patients; if positive, chemotherapy was performed, and if negative, biopsy was performed, preferably endoscopically. Resection was performed when there was a residual germ cell tumor (GCT) lesion after chemotherapy. The distribution based on histological type, as verified by markers, biopsy, or surgery, was germinoma (33.1%), nongerminomatous GCT (NGGCT) (27.2%), pineoblastoma (22.5%), glioma (12.6%), and embryonal tumor (atypical teratoid rhabdoid tumor) (3.3%). A total of 97 patients underwent resection, and gross-total resection (GTR) was achieved in 64%; the highest GTR rate (76.6%) was found in patients with GCTs, and the lowest (30.8%) was found in those with gliomas. The supracerebellar infratentorial approach (SCITA) was the most common, performed in 53.6% of patients, followed by the occipital transtentorial approach (OTA), performed in 24.7% of patients. Lesions were biopsied in 70 patients, and the diagnostic accuracy was 91.4. The overall survival (OS) rates at 12, 24, and 60 months as stratified by histological type were 93.7%, 93.7%, and 88% for patients with germinomas; 84.5%, 63.5%, and 40.7% for patients with pineoblastomas; 89.4%, 80.8%, and 67.2% for patients with NGGCTs; 89.4%, 78.2%, and 72.6% for patients with gliomas; and 40%, 20%, and 0% for patients with embryonal tumors, respectively (p < 0001). The OS at 60 months was significantly higher in the group with GTR (69.7%) than in the group with subtotal resection (40.8%) (p = 0.04). The 5-year progression-free survival was 77% for patients with germinomas, 72.6% for patients with gliomas, 50.8% for patients with NGGCTs, and 38.9% for patients with pineoblastomas. The efficacy of resection varies by histological type, and complete resection is associated with higher OS rates. Endoscopic biopsy is the method of choice for patients presenting with negative tumor markers and hydrocephalus. For tumors restricted to the midline and with extension to the third ventricle, a SCITA is preferred, whereas for lesions with extension toward the fourth ventricle, an OTA is preferred.

Primary Intracranial Germ Cell Tumors: A Study with an Integrated Clinicopathological Approach.

Primary intracranial germ cell tumors (ICGCTs) are rare and are histologically classified as germinomas and non-germinomatous with distinctive prognostic and therapeutic implications. ICGCTs, essentially due to the inherent difficulty of surgical access, pose different challenges and management connotations than their extracranial counterparts. This is a retrospective analysis of histologically verified ICGCTs, which was undertaken to evaluate various clinicopathological features and their implications on patient management. Eighty-eight histologically diagnosed cases (over 14 years) of ICGCT at our institute formed the study cohort and were classified into germinoma and non-germinomatous germ cell tumors (NGGCTs). Additionally, germinomas were further subdivided on the basis of 1) tumor marker (TM) levels, as germinoma with normal TM, mildly elevated TM, and markedly elevated TM and 2) radiology features, as germinomas with typical radiology and atypical radiological features. ICGCT with age ≤6 years (P = 0.049), elevated TM (P = 0.047), and NGGCT histology (P < 0.001) showed significantly worse outcomes. Furthermore, germinomas with markedly elevated TM and certain atypical radiological features showed prognosis akin to NGGCT. Analysis of our largest single cancer center Indian patient cohort of ICGCT shows that inclusion of age ≤6 years, raised TM, and certain radiological features may assist clinicians in overcoming the limitations of surgical sampling, with better prognostication of histologically diagnosed germinomas.

Impact of tumor markers on diagnosis, treatment and prognosis in CNS germ cell tumors: correlations with clinical practice and histopathology

Tumor markers in CNS germ cell tumors (GCTs) include human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP), which have significant diagnostic implications, as elevation of either one leads to clinical diagnosis of non-germinomatous GCTs without histopathological confirmation, justifying intensified chemotherapy and irradiation. The current study, based on an international cohort of histopathologically verified GCTs that underwent biopsy (n = 85) or resection (n = 76), sought to better define the clinical role and prognostic significance of tumor markers from serum and CSF in this challenging patient population. We found that HCG was elevated only in cases with a germinoma or choriocarcinoma component, and there existed a clear cut-off HCG value between the two. AFP was often elevated in GCTs without a yolk sac tumor component, especially immature teratoma. HCG was elevated only in CSF in 3-of-52 cases, and AFP was elevated only in serum in 7-of-49 cases, emphasizing the potential utilization of both serum and CSF studies. Immature teratoma demonstrated unfavorable prognosis independent of tumor marker status, with 56% 5-year overall survival; however, co-existent germinoma components indicated a more favorable prognosis. Taken together, the study findings emphasize the importance for routine assessment and guarded interpretation of tumor markers in CNS GCTs.

Histogenesis of intracranial germ cell tumors: primordial germ cell vs. embryonic stem cell.

Intracranial germ cell tumor (iGCT) is a rare disorder and often occurs during childhood and adolescence. iGCTs are frequently localized in pineal region and hypothalamic-neurohypophyseal axis (HNA). In spite of well-established clinical and pathological entity, histogenesis of iGCTs remains unsettled. Current theories of histogenesis of iGCTs include germ cell theory (from primordial germ cells (PGCs) of aberrant migration) and stem cell theory (transformed embryonic stem (ES) cells). In order to comprehend the histogenesis, we revisit the origin, migration, and fate of the human PGCs, and their transformation processes to iGCT. In "germ cell theory," transformation of ectopic PGCs to iGCT is complex and involves multiple transcription factors. Germinoma is derived from ectopic PGCs and is considered a prototype of all GCTs. Non-germinomatous germ cell tumors (NGGCTs) develop from more differentiated counterparts of embryonic and extra-embryonic tissues. However, there is a distinct genomic/epigenomic landscape between germinoma and NGGCT. ES cells transformed from ectopic PGCs through molecular dysregulation or de-differentiation may become the source of iGCT. "Stem cell theory" is transformation of endogenous ES cells or primitive neural stem cell to iGCTs. It supports histological diversity of NGGCTs because of ES cell's pluripotency. However, neural stem cells are abundantly present along the subependymal zone; therefore, it does not explain why iGCTs almost exclusively occur in pineal and HNA locations. Also, the vast difference of methylation status between germinoma and NGGCT makes it difficult to theorize all iGCTs derive from the common cellular linage. Transformation of PGCs to ES cells is the most logical mechanism for histogenesis of iGCT. However, its detail remains an enigma and needs further investigations.

A 2-step prediction model for diagnosis of germinomas in the pineal region.

Germinomas are sensitive to radiation and chemotherapy, and their management distinctly differs from other kinds of pineal region tumors. The aim of this study was to construct a prediction model based on clinical features and preoperative magnetic resonance (MR) manifestations to achieve noninvasive diagnosis of germinomas in pineal region. A total of 126 patients with pineal region tumors were enrolled, including 36 germinomas, 53 nongerminomatous germ cell tumors (NGGCTs), and 37 pineal parenchymal tumors (PPTs). They were divided into a training cohort (n = 90) and a validation cohort (n = 36). Features were extracted from clinical records and conventional MR images. Multivariate analysis was performed to screen for independent predictors to differentiate germ cell tumors (GCTs) and PPTs, germinomas, and NGGCTs, respectively. From this, a 2-step nomogram model was established, with model 1 for discriminating GCTs from PPTs and model 2 for identifying germinomas in GCTs. The model was tested in a validation cohort. Both model 1 and model 2 yielded good predictive efficacy, with c-indexes of 0.967 and 0.896 for the diagnosis of GCT and germinoma, respectively. Calibration curve, decision curve, and clinical impact curve analysis further confirmed their predictive accuracy and clinical usefulness. The validation cohort achieved areas under the receiver operating curves of 0.885 and 0.926, respectively. The 2-step model in this study can noninvasively differentiate GCTs from PPTs and further identify germinomas, thus holding potential to facilitate treatment decision-making for pineal region tumors.

Differentiation between germinoma and other pineal region tumors using diffusion-and susceptibility-weighted MRI

PurposeTo evaluate the effectiveness of diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) for differentiation between germinoma and other pineal region tumors. MethodThis retrospective study consisted of 72 patients with pathologically proven pineal region tumors between January 2010 and August 2020. Tumors were classified as germinomas (40), non-germinomatous germ cell tumors (11) (NGGCT), pineal parenchymal tumors (10) (PPT), and other types of tumors (11). Visual scale score, ADC values and SWI intratumoral susceptibility signal (ITSS) score were analyzed and compared to histopathology data. ResultsThe mean apparent diffusion coefficient (ADCmean) and minimum apparent diffusion coefficient (ADCmin) ratio of germinoma were significantly lower than NGGCT. ADCmean or ADCmin cut-off ratio of ≤ 1.48 or ≤ 1.32 allowed for discrimination between germinoma and NGGCT with sensitivity and specificity of 100 % and 63.6 %. An ADCmin cut-off ratio of ≥ 0.93 allowed for discrimination between germinoma and PPT with sensitivity and specificity of 60 % and 80.0 %. ADCmin cut-off ratio of ≤ 1.15 allowed for discrimination of germinoma from other types of tumors with sensitivity and specificity of 87.5 % and 54.5 %. ConclusionsADC ratio can differentiate germinoma from other types of pineal region tumors. Our initial results suggest that ITSS score was not significantly correlated with specific histology subtype.

PD-L1 and PD-1 expression in pediatric central nervous system germ cell tumors

Central nervous system (CNS) germ cell tumors (GCTs) represent 2–3% of all primary CNS tumors. The majority are germinomas, which are radiosensitive and have an excellent prognosis. Contrarily, CNS non-germinomatous GCTs (NGGCTs) have less favorable prognosis and require more aggressive treatment. The expression of checkpoint/immune markers in CNS GCTs, particularly NGGCTs, is unknown. We previously reported a case of a patient whose intracranial NGGCT (predominantly choriocarcinoma) responded to immune checkpoint inhibition therapy. This case led us to evaluate our archive of intracranial GCTs for expression of PD-L1 and PD-1. With IRB approval, we searched the pathology archives at our institution for CNS GCTs. Demographic, radiologic, clinical, and histologic information was extracted from the medical records. Immunohistochemistry for lymphocytic markers (CD4, CD8, CD20), PD-1, and PD-L1 was performed. PD-L1 was considered positive if greater than 1% of tumor cells were positive and PD-1 was reported as a percentage of positive inflammatory cells. Fifty cases were identified, including 28 germinomas (mean age at diagnosis: 15.5 years; 17 males, 11 females), and 22 NGGCTs (mean age at diagnosis: 12.0 years, 21 males, 1 female). Germinomas were mostly suprasellar (17/28) and NGGCTs were predominantly pineal (17/22). Twenty-two germinomas (79%) were positive for PD-L1 expression, and 13 NGGCTs (57%) were positive for PD-L1. Cases of choriocarcinoma showed the most diffuse PD-L1 expression. PD-1 expression was seen in lymphocytes among 27/28 of the germinomas and 20/23 of the NGGCTs (ranging from 1–40% of lymphocytes). As expected, larger quantities of inflammatory cells were present in cases of germinoma. We demonstrate immune activity in CNS GCTs, and our results suggest that immune checkpoint inhibitors may be efficacious in the treatment of intracranial GCTs. Among NGGCTs, cases of choriocarcinoma showed the highest expression of PD-L1 in tumor cells, suggesting that this subtype may have the greatest benefit from checkpoint blockade.

Endoscopic aqueductal membrane fenestration was effective for intractable hydrocephalus after removal of a nongerminomatous germ cell tumor exhibiting growing teratoma syndrome: a case report

BackgroundPrimary central nervous system (CNS) germ cell tumors (GCTs) are rare neoplasms predominantly observed in the pediatric and young adult populations. A mixed GCT including immature teratoma exhibiting growing teratoma syndrome is presented. The pathogenesis of growing teratoma syndrome remains unclear, and its treatment strategy has not been established. GCTs are often located within the ventricles, causing hydrocephalus, which sometimes improves after removal of the tumor due to restoration of cerebrospinal fluid (CSF) flow. On the other hand, even if the flow route of CSF from the third ventricle to arachnoid granulations on the brain surface quadrigeminal cistern is restored after removal of the tumor, hydrocephalus may not improve.Case presentationA case whose intractable hydrocephalus improved after penetrating the aqueductal membrane via endoscopy is described. An 11-year-old boy was treated for pineal intracranial growing teratoma syndrome (IGTS). The tumor grew rapidly in a short period, and hydrocephalus progressed despite endoscopic third ventriculostomy (ETV). Although the obstruction was removed by radiation, chemotherapy, and total tumor resection, the hydrocephalus did not improve. Endoscopic membrane perforation was performed because a membrane-like structure was seen at the entrance of the cerebral aqueduct on magnetic resonance imaging. The hydrocephalus improved immediately after the operation, and the patient’s consciousness disturbance also improved significantly.ConclusionThe purpose of this report is to update the current knowledge and standards of management for patients with growing teratoma syndrome, as well as to drive future translational and clinical studies by recognizing the unmet needs concerning hydrocephalus.

NIMG-97. A FULLY AUTOMATED MRI-BASED DEEP-LEARNING ALGORITHM FOR CLASSIFYING GERMINOMAS AND NONGERMINOMATOUS GERM CELL TUMORS

Abstract Intra-cranial germ cell tumors (iGCTs) are classified into two pathological subtypes Germinomas (GEs) and nongerminomatous germ cell tumors (NGGCTs). Accurate preoperative determination of iGCT subtypes is essential to guide clinical decision making and prognosis assessment. This study aims to develop a deep-learning algorithm to automatically segment iGCTs and classify subtypes using preoperative T2-weighted (T2W) images. Brain MR imaging and corresponding pathologic information were retrospectively obtained from 594 subjects including 269 GEs and 325 NGGCTs from Beijing Tiantan Hospital between January 1, 2008, and October 31, 2020, and subdivided into training (n=416) and test (n=178) sets for iGCTs segmentation, and classification using 3D nnU-Net based on T2W images. An internal validation cohort (including 56 GEs and 17 NGGCTs) and two external validation cohorts (Center 1 including 13 GEs and 12 NGGCTs；Center 2 including 17 GEs and 12 NGGCTs) were prospectively designed as an independent sets for testing the iGCT-net. Dice scores were computed to assess tumor segmentation. Accuracy and area under the curve (AUC) were calculated to assess the GEs and NGGCTs classification. Additionally, sensitivity analysis of different tumor location (suprasellar, pineal and basal ganglia regions) was performed to access the classification accuracy. The iGCT-net for tumor segmentation achieved a mean dice score of 0.80 in all cohorts. For tumor classification, the iGCT-net achieved the mean accuracy of 90.96% of all cohorts, which was superior to that using demographics and morphologic features (mean = 67.50%, p&amp;lt; 0.01). For different tumor location (suprasellar region, pineal region, and basal ganglia region), the iGCT-net showed an mean accuracy of 87.94%, 89.38% and 65.74% in test set, internal validation set and external validation cohorts. A fully automatic deep learning algorithm to segment iGCT and discriminate GEs and NGGCTs with high accuracy based on only T2W images from a large dataset is successfully developed.

Split-Tendon Medial Transposition of Lateral Rectus for Pediatric Complete Oculomotor Palsy.

Split-tendon medial transposition of lateral rectus (STMTLR) for complete oculomotor palsy can correct large angles of exotropia in adults, but outcomes are variable, and complications are frequent. Only a few pediatric cases have been reported, and further insight is needed to assess the child's alignment outcomes and ability for postsurgical gain of function. The aim of our study is to report the outcomes of this surgical procedure in pediatric cases of complete oculomotor palsy. A retrospective review of outcomes was conducted on 5 consecutive patients with complete oculomotor palsy treated with STMTLR by a single surgeon (V.S.S.) between 2015 and 2021 at tertiary referral centers. Primary outcome was postoperative horizontal alignment, and secondary outcome was demonstration of gain-of-function activity in the field of action of the paretic medial rectus muscle. Five cases of pediatric complete oculomotor palsy underwent surgical treatment with STMTLR. Subjects averaged 5.3 years old (range 10 months-16 years). Two were female. Etiologies were heterogeneous, and all presented with unilateral (n = 2) or bilateral complete oculomotor palsy with exodeviations ranging from 45 to >120 prism diopters. Two subjects had bilateral disease secondary to military tuberculosis with CNS involvement. A third subject presented iatrogenically with complete bilateral third nerve palsies secondary to removal of a nongerminomatous germ cell tumor (NGGCT) of the pineal gland. The 2 remaining subjects had monocular involvement in their right eye, 1 from compressive neuropathy after a cavernoma midbrain hemorrhage, and 1 from a congenital right oculomotor palsy. All patients were observed to have stable ocular alignment for a period of at least 6 months before surgery. Unilateral STMTLR was performed in all cases except the subject with NGGCT, in which bilateral STMTLR was performed. Measurement of alignment permanence out to 1-3 years postop resulted in an average correction of 40.83 prism diopters (range 37.5-45 prism diopters) per operated eye. Four of 5 subjects regained limited but active adduction eye movements, and the 2 unilateral cases demonstrated improved convergence. None of the subjects experienced significant complications. STMTLR was a safe and effective approach for the surgical correction of complete pediatric oculomotor palsy in our case series. In addition, pediatric patients may benefit from STMTLR with immediate gain-of-function activity in the transposed lateral rectus muscle, which supports the hypothesis that children have a dynamic and adaptive neuroplasticity of visual target selection that predominates established agonist/antagonist neural signaling.

Long-term consequences of residual lesions after chemoradiotherapy in patients with germinoma at onset.

In patients with intracranial germ cell tumors, residual lesions are sometimes observed after completion of primary chemoradiotherapy. Although salvage resection of these end-of-treatment residual lesions is recommended for patients with nongerminomatous germ cell tumors, the necessity of early salvage resection for those with germinoma is not clear. The aim of this study was to investigate the frequency of residual germinoma lesions after primary chemoradiotherapy, as well as their management, long-term consequences, and prognosis. The authors retrospectively reviewed patients who were primarily treated for germinoma between 2002 and 2021. Residual lesions were evaluated with MRI with and without contrast enhancement within 2 weeks after chemoradiotherapy. The decision to perform salvage resection of residual lesions was at the discretion of the treating physicians. The change in appearance of residual lesions was assessed with serial MRI. Overall survival (OS), progression-free survival (PFS), and recurrence pattern were also investigated. Sixty-nine patients were treated with chemoradiotherapy for germinoma, with a mean follow-up period of 108 months. Residual lesions were radiologically observed in 30 patients (43.5%). Among these, 5 patients (3 with pineal lesions and 2 with basal ganglia lesions) underwent salvage resection. Pathological examination revealed teratomatous components in 3 patients, whereas no tumoral components were identified in 2 patients. One patient with a basal ganglia lesion showed worsening of hemiparesis postoperatively. The remaining 25 patients received watchful observation without surgical intervention. Chronological periodic radiological change in residual lesions was evaluated in 21 patients. One year after primary treatment, the size of the residual lesions was stable and had decreased in 10 and 11 patients, respectively. None of the lesions increased in size. The 10-year PFS and OS rates were 96.7% and 97.3% in patients without residual lesions (n = 39), and 87.1% and 100% in patients with residual lesions (n = 30), respectively. Presence of residual lesions had no significant effect on PFS or OS. All recurrences occurred at distant sites or via dissemination without progression of the primary tumor site, regardless of the presence of residual lesion. End-of-treatment residual lesions are not rare in patients with germinoma, and these residual lesions seldom show progression. Because of the potential risk of surgical complications, the indication for early salvage surgery for residual lesions should be carefully determined. Watchful observation is recommended for the majority of these cases.

Radiosurgery for Primary and Metastatic CNS Malignancies in the Pediatric Population

<h3>Purpose/Objective(s)</h3> Safety and efficacy of stereotactic radiosurgery (SRS) are not well described for pediatric patients. This study presents disease control and toxicity outcomes after SRS for malignant CNS lesions in pediatric patients. <h3>Materials/Methods</h3> Retrospective chart review was performed for 31 pediatric patients treated at a single institution with a non-invasive stereotactic radiosurgery instrument for primary or metastatic CNS malignancies between 2000-2020. Analyses were performed with descriptive statistics, Kaplan-Meier, and proportional hazards modeling. <h3>Results</h3> Twenty-five patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the early adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4 at the time of diagnosis. Brain metastases were from non-germinomatous germ cell tumors (n=3), papillary thyroid cancer (n=1), and neuroblastoma (n=1). 71% of patients had prior involved-field external beam radiation to the brain (median dose 59.4 Gy in 33 fractions). Median age at SRS was 14 years (range 4-21). SRS was predominantly performed in a single fraction (median dose 17 Gy, range 15-20) to a total of 42 targets among 29 patients, with a median total gross target volume (GTV) of 1.3 cc. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger brain metastases (GTVs 8.5 cc & 23.2 cc). Median follow up after SRS was 44 months (interquartile range 20-72). The 3-year actuarial rates of local control, intracranial progression-free survival, and overall survival after SRS were 77.6%, 33.3%, and 74.6%, respectively. 9 patients (29%) had no evidence of intracranial disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at a median of 13 months after SRS. 16 patients (52%) developed distant brain recurrence without local failure at a median of 9 months after SRS. Among primary CNS tumors, there was no significant association of histology, grade, or dose with disease control outcomes on univariate analysis. All patients with subsequent CNS recurrence after SRS underwent salvage therapy, including additional radiosurgery (36%), systemic therapy (23%), resection (9%), or combined modality treatment (32%). In total, 4 patients developed CTCAE grade 2-3 toxicity from SRS, all of which were related to radiation treatment effect and occurred within 1 year of SRS. 2 patients received steroids alone, and 2 underwent invasive procedures (1 shunt revision, 1 resection of nonviable tumor). <h3>Conclusion</h3> SRS for malignant CNS lesions in the pediatric population provides effective local control and is generally well-tolerated. Although there remains a substantial risk of distant CNS failures, all patients were able to receive additional salvage therapy after SRS.

Photon vs. Proton Whole Ventricular Radiotherapy for Non-Germinomatous Germ Cell Tumors

<h3>Purpose/Objective(s)</h3> The hypothesis is that dose to normal CNS structures is lower for children treated with proton therapy, as compared to photon therapy for children receiving whole ventricular radiotherapy (WVRT) for non-germinomatous germ cell tumors (NGGCT). We present data from patients enrolled in stratum 1 of the Children's Oncology Group study ACNS1123. <h3>Materials/Methods</h3> Dosimetric data for NGGCT patients on ACNS1123 who received 30.6 Gy WVRT were compared in a post-hoc analysis. Target segmentation was standardized using a contouring atlas as per the study protocol. The PTV was created by creating a 3-5mm geometric expansion from the CTV. Doses to cranial organs-at-risk (OARs) were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were compared included mean dose and dose to 40% of the OAR volume (D40). A subgroup analysis of patients treated with 3 mm PTV margins was performed. Dosimetric comparisons between proton and photons plans were conducted using two-sided Wilcoxon's rank sum test for continuous variables. <h3>Results</h3> Fifty-eight patients had WVRT dosimetry available and were included; 13 (22%) received proton treatment and 45 (78%) received photon treatment. Median age was 10 years old (range 0-21). Mean and D40 doses to the supratentorial brain, cerebellum (see Table), and bilateral temporal, parietal and frontal lobes were statistically significantly lower amongst proton-treated patients compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3 mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. <h3>Conclusion</h3> Children treated with proton therapy for WVRT had lower doses to normal brain structures when compared to those treated with photon therapy. Future work will help elucidate whether this dosimetric advantage of proton therapy translates to a reduction in toxicities for these patients.

A Case of Non-Germinomatous Germ Cell Tumors of the Frontal Lobe Arising From the Lateral Ventricle With a Synchronous Pineal Lesion

Non-germinomatous germ cell tumours (NGGCT) are rare intracranial tumours that account for 1% to 3% of cases. They are usually seen in the pineal and suprasellar regions. NGGCT of the frontal lobe arising from the lateral ventricle with a synchronous pineal lesion is uncommon. We present a case of NGGCT with multifocal lesions in the pineal gland, frontal lobe, and pons treated with chemotherapy followed by craniospinal irradiation (CSI).

Feasibility of treating pediatric intracranial germ cell tumors in a middle-income country: The Jordanian experience.

Pediatric intracranial germ cell tumors (iGCT) are rare, with limited data available from Arabic countries. We retrospectively reviewed the medical charts of children <18years diagnosed with iGCT at King Hussein Cancer Center/Jordan (January 2003 to December 2020) for clinical characteristics, treatment, and morbidities. Sixteen patients had germinoma; median age was 6.9years and median symptoms duration 8months. Nine tumors were suprasellar, five pineal, and two bifocal. Four were metastatic. Eight patients had slightly elevated beta subunit human chorionic gonadotropin and 11 patients had resection/biopsy. Fifteen patients received chemotherapy; mostly carboplatin (450mg/m2 )/etoposide, which had low toxicity. All patients received radiotherapy (different doses and fields). At median follow-up of 7.7years, one tumor recurred (progression-free survival: 91%±8%). Twelve patients who continued follow-up had stable visual and endocrine deficits to their initial presentation. Five finished or are finishing diploma and seven had poor school performance (four left school). Six patients were diagnosed with nongerminomatous germ cell tumor; median symptom duration was 1month. Three tumors were pineal, two suprasellar, and one at quadrigeminal plate. Three were metastatic. Five tested patients had high tumor markers and four had resection/biopsy. All patients received chemotherapy, and then five received craniospinal radiation. Two patients are alive, two died with tumor progression, one died in remission with electrolyte imbalance, and one developed leukemia and died with septic shock. We achieved excellent survival in treating germinoma using a feasible protocol for low middle-income countries. However, patients encountered significant morbidities exacerbated by delayed diagnosis and unnecessary surgical interventions despite abnormal tumor markers. Raising awareness on iGCT symptomatology and diagnosis may help limit these morbidities.

Pathogenesis of central nervous system germ cell tumors.

Intracranial germ cell tumors (IGCTs) are clinically rare. They are more common in children and adolescents and the incidence in Asia is higher than in Western countries. Histologically, IGCTs are divided into germinoma and non-germinomatous germ cell tumor (NGGCT). Germinoma is sensitive to radiotherapy and chemotherapy and therefore, patients with germinoma have a good prognosis. However, NGGCTs, especially those with malignant components, are not sensitive to radiotherapy and chemoradiotherapy, leading to a poor prognosis. The pathogenesis of IGCTs is not fully understood. By summarizing previous literature, we found that the occurrence of IGCTs may be related to the following factors: chromosomal instability, MAPK and/or PI3K pathway changes, and DNA hypomethylation in pure germ cell tumors.

Biomarkers for risk-based treatment modifications for CNS germ cell tumors: Updates on biological underpinnings, clinical trials, and future directions.

CNS germ cell tumors (GCTs) preferentially occur in pediatric and adolescent patients. GCTs are located predominantly in the neurohypophysis and the pineal gland. Histopathologically, GCTs are broadly classified into germinomas and non-germinomatous GCTs (NGGCTs). In general, germinoma responds well to chemotherapy and radiation therapy, with a 10-year overall survival (OS) rate of approximately 90%. In contrast, NGGCTs have a less favorable prognosis, with a five-year OS of approximately 70%. Germinomas are typically treated with platinum-based chemotherapy and whole-ventricular radiation therapy, while mature teratomas can be surgically cured. Other NGGCTs require intensive chemotherapy with radiation therapy, including whole brain or craniospinal irradiation, depending on the dissemination status and protocols. Long-term treatment-related sequelae, including secondary neoplasms and cerebrovascular events, have been well recognized. These late effects have a tremendous impact in later life, especially since patients are mostly affected in childhood or young adults. Intending to minimize the treatment burden on patients, the identification of biomarkers for treatment stratification and evaluation of treatment response is of critical importance. Recently, tumor cell content in germinomas has been shown to be closely related to prognosis, suggesting that cases with low tumor cell content may be safely treated with a less intensive regimen. Among the copy number alterations, the 12p gain is the most prominent and has been shown to be a negative prognostic factor in NGGCTs. MicroRNA clusters (mir-371-373) were also revealed to be a hallmark of GCTs, demonstrating the potential for the application of liquid biopsy in the diagnosis and detection of recurrence. Recurrent mutations have been detected in the MAPK or PI3K pathways, most typically in KIT and MTOR and low genome-wide methylation has been demonstrated in germinoma; this most likely reflects the cell-of-origin primordial germ cells for this tumor type. These alterations can also be leveraged for liquid biopsies of cell-free DNA and may potentially be targeted for treatment in the future. Advancements in basic research will be translated into clinical practice and can directly impact patient management. Additional understanding of the biology and pathogenesis of GCTs will lead to the development of better-stratified clinical trials, ultimately resulting in improved treatment outcomes and a reduction in long-term treatment-related adverse effects.

KRAS Mutation in Pediatric Intracranial Germ Cell Tumors.

Intracranial germ cell tumors (IGCTs) are rare, highly curable neoplasms. KRAS is a gene in the KIT/RAS signaling pathway, and KRAS mutations have been reported in patients diagnosed with IGCTs. To describe the clinicopathologic and molecular features of KRAS mutation and the treatment outcome of children diagnosed with IGCTs. Patients diagnosed with IGCTs at the Department of Pediatrics, King Chulalongkorn Memorial Hospital from 2007 to 2016 were retrospectively reviewed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and used for molecular study. Mutations in codons 12, 13, and 61 of the KRAS gene were detected using the cobas® KRAS mutation test and pyrosequencing. Eighteen patients were diagnosed with IGCTs (11 males and 7 females): nine with germinomas and nine with non-germinomatous GCTs (NGGCTs). The age range of the patients was 5-14 years (median 10.5 years). Elevated markers were revealed in approximately 25% of the patients. Four patients (two with germinomas and two with NGGCTs) had leptomeningeal involvement. All patients underwent tumor biopsy and received neoadjuvant chemotherapy. Radiotherapy was administered in 16 patients, and craniospinal radiation was administered only in patients with leptomeningeal metastasis. With a median follow-up of 26 months, overall survival was 88.9% in the patients with germinomas and 37% in the patients with NGGCTs. Mutation of the KRAS gene was detected using pyrosequencing in one patient. The mutation located at codon 61, with frequency 38.3% units, nucleotide substitution CAA > CTA, and amino acid substitution, was Q61L. The patient carrying the mutant gene was diagnosed with germinoma with cerebrospinal fluid metastasis and eventually died from treatment-related toxicity. Our study revealed the treatment outcomes of IGCTs in Thai children. The metastatic germinoma patient with KRAS codon 61 mutation had a poor outcome, supporting that Q61L has a clinical correlation with IGCTs.

Diagnosis and Treatment of Pineal Region Tumors in Adults: A EURACAN Overview.

Simple SummaryPineal region tumors are rare intracranial tumors. A deeper knowledge of these tumors’ molecular mechanisms has been gained in recent years, which has led to a new classification and new potential systemic treatments. Surgery remains the mainstay of treatment, while radiotherapy and systemic therapy depend on histological, molecular, and clinical characteristics. This paper highlights recent developments in the diagnosis and treatment of these tumors.Pineal region tumors are rare intracranial tumors, accounting for less than 1% of all adult intracranial tumor lesions. These lesions represent a histologically heterogeneous group of tumors. Among these tumors, pineal parenchymal tumors and germ cell tumors (GCT) represent the most frequent types of lesions. According to the new WHO 2021 classification, pineal parenchymal tumors include five distinct histotypes: pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), pinealoblastoma (PB), and desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant; GCTs include germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed GCTs. Neuroradiological assessment has a pivotal role in the diagnostic work-up, surgical planning, and follow-up of patients with pineal masses. Surgery can represent the mainstay of treatment, ranging from biopsy to gross total resection, yet pineal region tumors associated with obstructive hydrocephalus may be surgically managed via ventricular internal shunt or endoscopic third ventriculostomy. Radiotherapy remains an essential component of the multidisciplinary treatment approach for most pineal region tumors; however, treatment volumes depend on the histological subtypes, grading, extent of disease, and the combination with chemotherapy. For localized germinoma, the current standard of care is chemotherapy followed by reduced-dose whole ventricular irradiation plus a boost to the primary tumor. For pinealoblastoma patients, postoperative radiation has been associated with higher overall survival. For the other pineal tumors, the role of radiotherapy remains poorly studied and it is usually reserved for aggressive (grade 3) or recurrent tumors. The use of systemic treatments mainly depends on histology and prognostic factors such as residual disease and metastases. For pinealoblastoma patients, chemotherapy protocols are based on various alkylating or platinum-based agents, vincristine, etoposide, cyclophosphamide and are used in association with radiotherapy. About GCTs, their chemosensitivity is well known and is based on cisplatin or carboplatin and may include etoposide, cyclophosphamide, or ifosfamide prior to irradiation. Similar regimens containing platinum derivatives are also used for non-germinomatous GCTs with very encouraging results. However, due to a greater understanding of the biology of the disease’s various molecular subtypes, new agents based on targeted therapy are expected in the future. On behalf of the EURACAN domain 10 group, we reviewed the most important and recent developments in histopathological characteristics, neuro-radiological assessments, and treatments for pineal region tumors.