Multi-institutional analysis of central nervous system germ cell tumors in patients with Down syndrome

Purpose: Primary germ cell tumors (GCTs) are the most common central nervous sys-tem(CNS)neoplasminpatientswithDownsyndrome(DS).However,astandardofcare has not been established due to paucity of data. Methods: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. Results: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location ( n = 13; 31.7%), followed by posterior fossa ( n = 7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-relatedsepsis,onefrompostsurgerycardiopulmonaryfailure,onefrom pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. Conclusion: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae. or progression; four patients experienced local relapse after CR (one germinoma, one teratoma, two NGGCTs), and five patients experienced disease progression despite therapy. Of the fourpatientswhoexperiencedlocalrelapse,salvageregimensincluded platinum-based chemotherapy ( n = 3), repeat surgery ( n = 2), and RT ( n = 1). Three patients who experienced disease relapse were successfully salvaged and had no evidence of disease (NED) at last follow-up, whereas one died from treatment-related pneumonia. Four patients who had progressive disease died, while one remained alive with residual tumor at last follow-up.


INTRODUCTION
Central nervous system (CNS) germ cell tumors (GCTs) make up <4% of primary pediatric brain tumors, with incidence rates increasing among males, individuals <20 years old, and Eastern Asian populations. 1

CNS
GCTs can be broadly classified as germinomas, non-germinomatous GCTs (NGGCTs), or teratomas. 1 Based on histological components, NGGCTs can be classified into embryonal carcinomas, yolk sac tumors (YSTs), choriocarcinomas, GCTs with mixed components (mixed GCTs), or germinoma with syncytiotrophoblastic giant cells (STGCs). 1 Teratomas may be divided into mature teratomas, immature teratomas or teratomas with malignant transformation. 1 Down syndrome (DS) has classically been associated with higher rates of blood cancers such as acute myeloid leukemia (AML). 2 The incidence of solid tumors in patients with DS is rare, yet GCTs have been found to make up a disproportionate number of intracranial tumors as compared to the general population. 3 Though associations between CNS GCTs and DS have been reported, the small number of cases is limiting; the most recent literature review reported just 21 patients with CNS GCTs and DS, with almost all studies arising from Japan or China. 4 This paucity of cases, particularly of those from Northern America, has limited our understanding of this patient population.
The standard of care for CNS GCTs includes a combination of surgery, platinum-based chemotherapy, and radiotherapy (RT), with specific treatments varying by tumor subtype and individual institution. 1 In patients with DS, treatment is complicated by their increased risk of developing acute and long-term treatment-related adverse effects. Patients with DS are at an increased risk of RTrelated cognitive impairments and cerebrovascular disease given their baseline cognitive impairments, decreased cerebral volume, and predisposition to degenerative neurologic disease. 5,6 Moreover, it is well documented that patients with DS are highly susceptible to toxicities related to standard chemotherapy drugs used in AML; these include treatment-related infection, mucositis from methotrexate therapy, anthracycline-induced cardiomyopathy, and even fatal neurotoxicity. 5,7 Due to the complexity of care and rarity of cases, a standard treatment approach that promotes both optimal survival and minimization of treatment-related adverse effects in patients with CNS GCTs and DS has not been established. Here, we describe a multinational and multiinstitutional retrospective analysis of patients diagnosed with DS and CNS GCTs, in addition to a review of the literature.

Study design and participants
A comprehensive literature search was performed using PubMed/ MEDLINE and Google Scholar. Major academic institutions across the United States, Brazil, and Australia were systematically contacted and provided with a de-identified data collection form. Each participating center received approval from their local institutional review board.

Data
The following data were collected: sex, age at diagnosis, present-

Statistical analysis
All data were summarized with standard descriptive statistics. Overall survival (OS) and corresponding 95% confidence intervals (CI) were calculated and presented using the Kaplan-Meier method. Comparison of survival curves was performed using log-rank (Mantel-Cox) tests. p-Values <.05 were considered statistically significant. Statistical analyses were calculated and graphics designed using Prism 9 software (GraphPad, La Jolla, CA, USA).

Patient characteristics
Demographics are summarized in Table 1 and clinical information in

Treatment-related adverse events
Treatment-related adverse events are summarized in Table 4

Outcomes
Time to follow-up was available for 32 patients (mean 3.   Figure 1B). There was no significant difference in 3-year OS based on treatment (p = .87).

DISCUSSION
In 1998, Satge et al. reported that GCTs make up nearly a third of intracranial tumors in patients with DS, whereas they account for <4% in the general pediatric population. 3 Though a mechanism for this interaction is unestablished, DS is known to predispose to the development of gonadal GCTs through various mechanisms. 3 Few patients with DS and CNS GCTs have since been reported. 4 This study includes the largest reported cohort of patients with DS and CNS GCTs and provides insight into the characteristics, management, and outcomes of this population.
Genetic and environmental differences influence the occurrence of CNS GCTs, as evidenced by differences in incidence by geographical location. GCTs account for <5% of all childhood CNS tumors in the United States, Germany, and Canada. [33][34][35] In contrast, GCTs account for 2.1%-9.4% in Japan and the Far East. 36 Consistent with prior studies, CNS GCTs were also seen most frequently in male patients. 34 Male sex has been strongly associated with pineal involvement, whereas suprasellar involvement has been associated with female sex. 39,40 In our study, pineal localization showed a slight male predominance (5/9; 56%), whereas sellar/suprasellar involvement showed a female predominance ( Comparable to prior studies, patients in our cohort displayed symptoms for an average of 6.9 months prior to diagnosis. 42 In a retro-  6 Given that the majority of patients in the present study died from treatment-related toxicity rather than disease progression, a reduced-intensity treatment regimen may be recommended for this population.
Our study has multiple limitations: despite being the largest cohort of patients with DS and CNS GCTs, the small number of patients limits our conclusions regarding treatment approach. Moreover, our reliance on multiple institutions limits the consistency of pathology or radiology reports, as well as tumor marker levels. The inconsistency of data reporting by previously published studies also limits the thoroughness of our retrospective cohort.

CONCLUSIONS
Patients with DS treated for CNS GCTs are at an increased risk of treatment-related death, particularly from treatment-related infection. Based on our experience, we suggest that a different therapeutic approach may be considered for this patient population in which treatment intensity is reduced. To evaluate the long-term effects of RT and chemotherapy in these patients, longer follow-up is needed. An expanded multi-institutional analysis is warranted, as well as subgroupspecific analysis for DS patients within prospective clinical trials of CNS GCTs.

CONFLICT OF INTEREST
The authors do not have any conflicts of interest to disclose. No funding was used to support this work. The authors have no financial interests to disclose.

AUTHOR CONTRIBUTIONS
All authors contributed to the study conception and design. Material preparation, data collection, and data analysis were performed by Micah K. Harris and Mohamed S. Abdelbaki. The first draft of the manuscript was written by Micah K. Harris, and all authors commented on previous versions of the manuscript. All authors read and approved the final version of the manuscript.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.