Intracranial Germ Cell Tumors Research Articles

Outcome of Children and Adolescents With Primary Intracranial Germinoma Treated With Chemotherapy and Reduced Dose-Field Irradiation: A Prospective Brazilian Experience

This prospective Brazilian single-arm trial was conducted to determine response to chemotherapy and survival after response-based radiotherapy in children with intracranial germinomas, in the setting of a multi-institutional study in a middle-income country (MIC) with significant disparity of subspecialty care. Since 2013, 58 patients with histologic and/or serum and CSF tumor marker evaluations of primary intracranial germ cell tumors were diagnosed; 43 were germinoma with HCGβ levels ≤200 mIU/mL and five between 100 and 200 mIU/mL. The treatment plan consisted of four cycles of carboplatin and etoposide followed by 18 Gy whole-ventricular field irradiation (WVFI) and primary site(s) boost up to 30 Gy; 24 Gy craniospinal was prescribed for disseminated disease. Mean age 13.2 years (range, 4.7-25.5 years); 29 were males. Diagnosis was made by tumor markers (n = 6), surgery (n = 25), or both (n = 10). Two bifocal cases with negative tumor markers were treated as germinoma. Primary tumor location was pineal (n = 18), suprasellar (n = 14), bifocal (n = 10), and basal ganglia/thalamus (n = 1). Fourteen had ventricular/spinal spread documented by imaging studies. Second-look surgery occurred in three patients after chemotherapy. Thirty-five patients achieved complete responses after chemotherapy, and eight showed residual teratoma/scar. Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 44.5 months, overall and event-free survivals were 100%. The treatment is tolerable, and WVFI dose reduction to 18 Gy preserves efficacy; we have demonstrated the feasibility of successfully conducting a prospective multicenter trial in a large MIC despite resource disparity.

Clinical significance and pitfalls of human chorionic gonadotropin-related tumor markers for intracranial germinomas.

Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in clinical use: hCGβ, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers. We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGβ, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive. The positivity rates of serum hCGβ, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGβ (p = 0.041). Both intact and total hCGs showed similar values. The median values of hCGβ, intact hCG, and total hCG before treatment were 0.1ng/mL, 4.6mIU/mL, and 4.5mIU/mL, respectively. Serum intact and total hCGs have higher detection rates than hCGβ in patients with germinoma using available commercial measurement tools.

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.

Implications of deferred diagnosis of paediatric intracranial germ cell tumours.

This study analysed the clinical features of a cohort of children with intracranial germ cell tumours (IC-GCTs). We retrospectively reviewed timelag between symptoms onset, clinic-radiological findings, diagnosis and outcomes. Symptoms at diagnosis were divided into four groups: (1) raised intracranial pressure (RICP); (2) visual impairment; (3) endocrinopathies; (4) other. Total diagnostic interval (TDI), defined as the interval between symptom onset (including retrospective recall of symptoms) and definitive diagnosis of IC-GCT, was calculated and compared to survival rates. Our cohort included 55 children with median follow-up of 78.9 months (0.5-249.9). The majority (63.6%) had germinomas and 10.9% were metastatic at diagnosis. IC-GCTs were suprasellar (41.8%), pineal (36.4%), bifocal (12.7%) or in atypical sites (9.1%). The most common presenting symptoms were related to RICP (43.6%); however, by the time of tumour diagnosis, 50.9% of patients had developed endocrine dysfunctions. All pineal GCTs manifested with RICP or visual impairment. All suprasellar GCTs presented with endocrinopathies. TDI ranged between 0.25 and 58.5 months (median 4 months). Pineal GCTs had the shortest TDI (median TDI 1 month versus 24 months in suprasellar GCTs, p<.001). TDI>6 months was observed in 47.3% of patients and was significantly associated with endocrine presenting symptoms. No statistically significant difference was found in progression-free survival and overall survival between patients with TDI>6 months and with TDI≤6 months. Approximately half of the IC-GCT patients in this cohort had TDI>6 months. These presented mostly with endocrine deficits. TDI>6 months was not associated with increased relapse or mortality rates.

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.

Heterogeneity of IGF-1 Levels in Children with hCG-Induced Precocious Puberty

Sex steroid stimulates growth hormone release during puberty. However, the role of IGF-1 levels in human-chorionic-gonadotropin-induced precocious puberty remains unclear. A retrospective study reviewing thirty patients with precocious puberty due to human-chorionic-gonadotropin-secreting intracranial germ cell tumors was performed. Changes in IGF-1 levels were collected. All patients included were boys. At diagnosis, the median IGF-1 standard deviation was 0.87 (0.1, 1.87). When human-chorionic-gonadotropin normalized, the median IGF-1 standard deviation was 1.58 (-0.53, 2.55), which is slightly higher than baseline (p = 0.408). When patients completed their therapeutic plan, the median IGF-1 standard deviation was 0.10 (-1.05, 0.68), which was significantly lower than that of baseline (p = 0.004) and of human-chorionic-gonadotropin being normalized (p = 0.003). At the last visit, the mean IGF-1 standard deviation was -1.11(-1.97, 0.76), which is slightly lower than that of baseline (p = 0.109) and post-therapy levels (p = 0.575), but significantly lower than that of human-chorionic-gonadotropin being normalized. Two patients had IGF-1 levels above 2 standard deviations at diagnosis, eight at the time when human-chorionic-gonadotropin normalized, and two at the end of therapy. Only one patient had an IGF-1 level below 2 standard deviations at diagnosis and at the time when human-chorionic-gonadotropin normalized, and two patients at the end of therapy. At the last follow-up, all patients had normal IGF-1 levels. IGF-1 levels in patients with human-chorionic-gonadotropin-induced precocious puberty have heterogeneity, but IGF-1 standard deviations are mostly within the normal range. If elevated, it might decline later with a decrease in human-chorionic-gonadotropin level. IGF-1 levels seem not valuable enough to assess human-chorionic-gonadotropin-induced precocity regression.

RADT-37. THE OUTCOMES OF INTRACRANIAL GERM CELL TUMOR PATIENTS WITH CHORIOCARCINOMA COMPONENT AND/OR Β-HCG HIGHER THAN 500IU/L UNDER RADIOTHERAPY-BASED TREATMENTS

Abstract BACKGROUND In the previous studies, intracranial germ cell tumor (iGCTs) patients with pure choriocarcinoma or mixed germ cell tumors containing choriocarcinoma components showed similar dismal prognoses with median overall survival of 22 months and a one-year survival rate around 60%. However, those conclusions need update since radiotherapy, a milestone for this disease, was not applied to many patients in the published reports. Patients and METHODS Clinical data of iGCTs patients with histologically confirmed choriocarcinoma component and/or β-HCG &amp;gt; 500IU/L were collected from the archive of our institute and studied retrospectively. RESULTS Totally, 76 patients were eligible for the study. 11 patients took surgery as initial treatment, followed by chemoradiotherapy in terms of treatments. Sixty-one patients initiated their treatments with chemotherapy. Among them, twelve patients received second-look surgery due to residue disease. Subsequently, all received radiotherapy except for two early deaths. Four patients received radiotherapy initially, followed by chemotherapy. The median follow-up time was 63 months. The 5-year EFS and OS were 81.5% and 84.1%, respectively. Among patients who did not suffer from early death or progressed disease after induction chemotherapy (n = 68), multivariate analysis found chemotherapy cycles ( &amp;gt; 4 vs ≤ 4) (Hazard ratio [HR] for EFS 0.156, p = 0.021; HR for OS 0.110, p = 0.032), β-HCG level ( &amp;gt; 3000IU/L vs ≤ 3000IU/L) (HR for EFS 4.512, p = 0.052; HR for OS 6.604, p=0.028), and intertumoral hemorrhage (Yes vs No) (HR for EFS 23.177, p = 0.006; HR for OS 12.173, p = 0.081) were independent factors for survival. While radiation field (CSI vs non-CSI) was not proved to be a prognostic factor, either for EFS or OS. CONCLUSIONS iGCTs patients with choriocarcinoma component or β-HCG &amp;gt; 500IU/L showed improved survival with radiotherapy-based treatments. Patients with higher β-HCG levels and hemorrhage had a poorer prognosis. More chemotherapy cycles could bring additional survival benefits.

Intracranial germ cell tumors in pediatric and adolescent patients in China: systematic review and meta-analysis

Background: Intracranial germ cell tumors (IGCTs) are rare neoplasms occurring predominantly in pediatric and adolescent patients. They are rare in Western countries, but are more common in East Asia. We conducted this review and meta-analysis of existing evidence to evaluate the treatment condition and prognosis of IGCT in China and explore the associated problems and challenges.

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.

Dynamic analysis of immune status in patients with intracranial germ cell tumor and establishment of an immune risk prognostic model.

IntroductionImmune status was evaluated by means of lymphocyte subset counts and immune factors in cancer. This study analyzed the peripheral blood immune index and survival outcomes in intracranial germ cell tumor (iGCT) patients.MethodsPeripheral blood lymphocyte subset counts and levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), and interferon-γ (IFN) from 133 iGCT patients were collected and retrospectively analyzed. Their clinical information was extracted from the hospital database, and prognosis was confirmed by telephone visit. Patients (n=11) underwent prospective review and their samples of peripheral blood lymphocytes were verified.ResultsA total of 113 (84.2%) patients received comprehensive treatments, including 96 standard therapy (combination of full course chemotherapy and radiology with or without surgery) and 17 comprehensive but non-standard therapy (either without full course chemotherapy or with non-standard radiotherapy) and 98 (73.7%) reached complete or partial response. T lymphocytes (CD3+), cytotoxic T cells (CD3+CD8+ or Tc), and B lymphocytes (CD19+) decreased (p=0.047, p=0.004, and p<0.001, respectively), while activated cytotoxic T lymphocytes (CD8+CD25+) and IFN increased (p<0.001 and p=0.002, respectively) after treatment. Median survival was 45.33 months, and patients with increased Tc cells and activated Tc cells as well as IFN presented encouraging outcomes (p=0.039, p=0.041, and p=0.017 respectively). Regression analysis showed that non-increased Tc cells and non-increased activated Tc cells were independent factors of poor prognosis (p=0.016, HR=3.96, 95%CI=1.288-12.20; p=0.002, HR=4.37 95%CI= 1.738-10.97). Standard chemo-radiotherapy was independently related to reduced risk of death(p=0.022, HR=0.19, 95%CI=0.044-0.79). Consistence was seen in a nomogram established through retro and prospective studies. An immune risk model indicated the activated group (with both increased activated T cells and IFN levels) had the best prognosis, the mildly activated type with elevated IFN levels had intermediate outcome, and patients with the silent immune status had the worst outcomes (Log rank test, p=0.011).ConclusionImplementation of standard comprehensive treatments led to positive responses. Dynamic monitoring of peripheral blood lymphocyte subsets can be used as an auxiliary indicator for prognosis judgment.

Precocious puberty due to intracranial germ cell tumors: a case–control study

Children with intracranial germ cell tumors may present premature sexual development via either gonadotrophin-releasing hormone (GnRH)-dependent cause or GnRH-independent cause. We conducted a single-center retrospective study on 37 precocious puberty (PP) patients with intracranial germ cell tumors and 25 age-matched prepubertal patients with elevated human chorionic gonadotropin (hCG) levels. Classification of PP was derived from hCG, gonadotropin and sex steroid levels and their changes. Five boys were assigned to GnRH-dependent group (G1). Thirty-one boys and one girl were assigned to GnRH-independent group (G2) with a median hCG of 76.75 (8.29-2747) IU/L. Seven boys and 18 girls were conducted as controls, with a median hCG of 17.12 (2.91-1062) IU/L. Patients in G1 had constant pubertal LH and testosterone levels after tumor complete response. Patients in G2 had hCG levels that decreased simultaneously with testosterone/estradiol levels, prior to tumor regression. The differences in hCG levels and the gender ratio were significant between G2 and controls (P = 0.006 and P < 0.001, separately). Among intracranial germ cell tumor patients with positive hCG, boys with significantly higher hCG levels more easily developed PP. Our results suggest that GnRH-independent PP commonly regresses together with tumor regression. In comparison, results were inconclusive in tying tumor regression to the regression of GnRH-dependent PP.

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.

High prevalence of overweight/obesity and dyslipidemia in patients with intracranial germ cell tumors

To evaluate the prevalence of overweight/obesity and dyslipidemia in patients with intracranial germ cell tumor (iGCT), and to explore the risk factors of it. iGCT patients visiting Peking Union Medical College Hospital between Jan 2008 to Oct 2020 were included. The prevalence of overweight/obesity and dyslipidemia was calculated. Mixed-effects models were used to evaluate the relationship between BMI z-scores, concentration of lipid profiles and potential risk factors. One hundred and six patients were included. The median follow-up time was 27 (IQR 5-59) months. The number of patients diagnosed with overweight/obesity and dyslipidemia were 49 (46.2%) and 86 (81.1%) during visits. Higher BMI z-scores were associated with treatment (mean difference (MD) 0.51, 95%CI 0.31-0.72), surgical biopsies (MD 0.71, 95%CI 0.16-1.25), adrenal insufficiency (MD 0.37, 95%CI 0.07-0.68), hypothyroidism (MD 0.35, 95%CI 0.06-0.63), glucocorticoid supplementation (MD 0.64, 95%CI 0.40-0.87), and thyroxine supplementation (MD 0.48, 95%CI 0.24-0.72). Hypothalamus involvement was associated with increased TC (MD 0.52, 95%CI 0.06-0.98), TG (MD 0.36, 95%CI 0.01-0.72), LDL-C (MD 0.60, 95%CI 0.20-0.98), and decreased HDL-C (MD - 0.23, 95%CI - 0.44 to -0.02). Higher TC (MD 0.53, 95%CI 0.26-0.80) and LDL-C (MD 0.39, 95%CI 0.17-0.62) were observed in patients after treatment. Glucocorticoid supplementation was associated with increased TC (MD 0.70, 95%CI 0.38-1.03), LDL-C (MD 0.51, 95%CI 0.24-0.78), and HDL-C (MD 0.25, 95%CI 0.09-0.40), while sex hormone supplementation was associated with decreased TC (MD - 0.74, 95%CI - 1.2 to -0.29) and TG (MD -0.47, 95%CI - 0.86 to -0.08). Overweight/obesity and dyslipidemia were high prevalent in iGCT patients and should be screened during follow-ups.

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.

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.

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10−4, Spearman’s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

An international study evaluating the epidemiology of intracranial germ cell tumors in the native versus immigrant Japanese populations: the need for an international registry.

Pediatric intra-cranial germ cell tumors (iGCTs) occur at an incidence of 0.6-1.2 cases/million/year in Western countries. The incidence is reported up to 5 times higher in Japan. It is unknown whether this increased incidence is due to genetic predisposition or environment. The incidence of iGCTs in children ages 0-19years was evaluated from December 1st, 1996-December 1st, 2016 in stable Japanese immigrant populations living abroad and compared to current native Japanese registry data. The incidence of medullobblastoma was used as a control to account for assumptions in the data. Sites were identified based on historical and population data of known large scale emigration from Japan during a period of industrialization from 1868-1912 which resulted in large, stable Japanese immigrant populations abroad. These three representative sites included Lima, Peru, San Paolo, Brazil, and Vancouver, Canada. Data was collected from registry and hospital-based resources within each region. A review of the Brain Tumor Registry of Japan from 1984-2004 revealed an incidence of 2.5 cases/million/year, lower than previously reported, and a lower incidence of medulloblastoma at 1.2 cases/million/year. Data from Vancouver, Canada, Lima, Peru, and San Paolo, Brazil included a total population of 731,174 Japanese persons. The ratio of all medulloblastoma to iGCT cases in Japan was identified as 1:2 while the ratio was 2:1, 6.5:1, and 5:1, respectively, in the other three locations. The data suggests increased incidence in native Japan may not translate to higher incidence in immigrant Japanese populations abroad and a clear genetic component was not found in our data set. A more precise and comprehensive study is needed to determine the cause of this difference in incidence. This study also emphasizes the importance of national and state registries and is a call to collaborate on state and country level epidemiology studies.

Endocrine manifestations of paediatric intracranial germ cell tumours: from diagnosis to long-term follow-up.

We examined endocrine manifestations in a cohort of paediatric patients with IC-GCTs at diagnosis and during follow-up, integrating clinical, radiological, histopathological and laboratory data. Diabetes insipidus (DI), growth hormone deficiency (GHD), hypothyroidism, adrenal insufficiency, precocious puberty (PP)/hypogonadism were diagnosed clinically and biochemically. The prevalence of endocrine manifestations was compared to survival rates. Our population included 55 children (37 males, 18 females) diagnosed with IC-GCT with a median follow-up of 78.9 months from diagnosis (range 0.5-249.9). At tumour diagnosis, 50.9% patients displayed endocrinopathies: among them, 85.7% were affected by DI, 57.1% central adrenal insufficiency, 50% central hypothyroidism, 28.5% GHD, 10.7% hypogonadotrophic hypogonadism, 10.7% PP. These patients presented predominantly with suprasellar germinoma. If not diagnosed previously, endocrine disorders arose 15.15 months (1.3-404.2) after end of treatment (EOT) in 16.4% patients. At least one endocrinopathy was identified in 67.3% of subjects at last follow-up visit, especially GHD and adrenal insufficiency. DI, hypothyroidism, and adrenal insufficiency occurred earlier than other abnormalities and frequently preceded tumour diagnosis. Subjects with and without endocrine manifestations who survived beyond 12 months after EOT did not show significant difference in overall survival and progression-free survival (p = 0.28 and p = 0.88, respectively). Endocrinopathies were common presenting symptoms in our population. If present at diagnosis, they often persisted hence after. The spectrum of endocrinopathies expanded during follow-up up to 33.7 years after EOT. Although they did not seem to affect survival rate in our cohort, close lifelong surveillance is mandatory to provide the best care for these patients.

GCT-13. KRAS MUTATION IN PEDIATRIC INTRACRANIAL GERM CELL TUMORS

BACKGROUND: Intracranial germ cell tumors (IGCTs) are rare, highly curable neoplasms. KRAS is a gene in the KIT/RAS signaling pathway, and KRAS mutations were reported in patients diagnosed with IGCTs. OBJECTIVES: To describe clinicopathologic, molecular features of KRAS mutation and treatment outcome of children diagnosed with IGCTs. METHODS: A retrospective review in patients diagnosed with IGCTs at Department of Pediatrics, King Chulalongkorn Memorial Hospital from 2007 to 2019. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue for the molecular study. Identifies mutations in codon 12,13 and 61 of the KRAS gene was performed by using the real-time PCR technique of the Cobas® test and pyrosequencing method. RESULTS: Eighteen patients were diagnosed with IGCTs (11 males and seven females). Age ranged from 5 to 14 years (median 10.5 years). The diagnosis was germinoma and non-germinomatous IGCTs in 9 patients each. Elevated markers were revealed in approximately 25% of patients. Four patients (2 patients with germinoma and 2 with non-germinomatous IGCTs) had leptomeningeal involvement. All patients underwent tumor biopsy and received neoadjuvant chemotherapy. Radiotherapy was given in 16 patients and craniospinal radiation (CSI) was given only in leptomeningeal metastasis. With the median follow-up of 26 months, overall survival is 88.9% in germinomas and 37% in non-germinomatous IGCTs. Mutation of the KRAS gene was detected by pyrosequencing technique in one patient. The mutation located at codon 61, frequency 38.3% units, nucleotide substitution CAA > CTA and amino acid substitution was Q61L. The patient who carries mutant gene was diagnosed germinomatous germinoma with CSF metastasis and eventually died from treatment-related toxicity. CONCLUSIONS: Our study revealed treatment outcomes of IGCTs in Thai children. We describe KRAS codon 61 mutation in metastasis germinoma patients with poor outcome, support KRAS codon 61 mutation (Q61L) may have a clinical correlation in IGCTs.

GCT-21. Long-term outcome and follow up of intracranial germ cell tumors: Reduced-dose radiotherapy and intensified chemotherapy improves clinical outcome and quality of life for long-term survivors

BACKGROUND: Intracranial germ cell tumors (iGCT) are heterogeneous tumors with several histopathology. Chemoradiotherapy is effective and required for treatment against them, but optimal treatment intensity should be selected from the viewpoint of both improvement of clinical outcome and avoidance of late complications. We introduced a protocol with reduced-dose radiotherapy and intensified chemotherapy for iGCT. OBJECTIVE: We retrospectively analysed the clinical outcome, especially for non-germinomatous germ cell tumors and long-term clinical outcome of late complications, enrollment and employment, as indicators of quality of life (QOL). MATERIALS AND METHODS: Thirty-eight children and young adults (28 men and 10 women) with iGCTs treated in our institution from 1997 to 2013 were enrolled in this study. They consisted of 26 germinomas including HCG-producing cases and 12 non-germinomatous GCTs (NGGCT). Local irradiation was selected for all patients, and the dose of irradiation was 23.4-54 Gy. The whole-brain irradiation was made in patients who had intracranial dissemination, but any prophylactic irradiation to the whole brain and spinal cord was not performed. For NGGCT, high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) were introduced. Second-look surgeries were performed for cases with residual tumors after induction chemotherapies. RESULTS: In germinoma group and NGGCT group, 10-year progression-free survival was 86% and 84%, 10-year overall survival was 93% and 91%, respectively. About late complications, endocrinological replacement (39%), cerebrovascular disease such as cavernous hemangioma and arterial stenosis (18%), secondary neoplasm (2.6%) were observed. Regarding QOL, enrollment and return to school rate was 92% and employment and the return rate was 89%, which were influenced by hemipararesis associated with basal ganglia lesion, intractable epilepsy and whole-brain irradiation. CONCLUSION: Reduced-dose radiotherapy and intensified chemotherapy for iGCT, especially NGGCT, improved the clinical outcome and QOL of long-term survivors, suppressing late complications. Further comprehensive follow-up and analysis are needed.