Atypical teratoid/rhabdoid tumors (ATRTs) are very rare, highly malignant embryonal neoplasms in central nervous system (CNS) (1). More than 90% cases of ATRT occur in children younger than three years old (2). In addition, ATRT contributes to 40%–50% of malignant CNS tumors in children under one year old, many of which are found disseminated (3, 4). Primitive histologic appearance with multi-lineage differentiation with loss of nuclear SMARCB1 or SMARCA4 expression is a typical histological characteristic of ATRT. Based on the genetic and epigenetic profiles, 3 distinct molecular subgroups-AT/RT-TYR, AT/RT-SHH, and AT/RT-MYC have been recently identified and the prognosis of ATRT seems to differ by 3 molecular subgroups (2, 5, 6).The ATRT-TYR subgroup is enriched in genes associated with melanogenesis and neural crest development, such as TYR and DCT, and is often linked to older children with relatively better prognosis (7). ATRT-SHH is defined by the activation of the Sonic Hedgehog (SHH) signaling pathway, with tumors frequently arising in the cerebellum or midline structures, showing intermediate clinical outcomes (8, 9). The ATRT-MYC subgroup, marked by high MYC expression and other proliferation-related genes, is predominantly found in infants and is associated with the most aggressive behavior and poor prognosis (10, 11). These molecular distinctions have significantly advanced our understanding of ATRT biology and hold potential for subgroup-specific therapeutic strategies.

The current treatment of ATRT is an aggressive multi-modal approach including maximal surgical resection with subsequent adjuvant chemotherapy and radiotherapy (12, 13). In recent years, numerous studies on ATRT were initiated and prolonged the four-year overall survival rate to nearly 50% (14). Specifically, we have noted that megachemotherapy with autoBMT has been employed in protocols such as ACNS0333 (15) and EU-RHAB (16) to improve outcomes in young children with ATRT. Additionally, intraventricular chemotherapy is mentioned as a strategy to address leptomeningeal dissemination, which is common in ATRT (17, 18). These updates provide a more comprehensive overview of current ATRT treatment strategies. However, the pathogenesis of ATRT is biological puzzling and the treatment of it remains a considerable challenge in the world. There are two oncology patient registries at present, including Surveillance, Epidemiology and End Results (SEER) registry and National Center database (NCDB). Studies have reported the epidemiology, prognosis, and survival of ATRT patients by analyzing the data in SEER and NCDB (19, 20). Yet researches based on Chinese patient population are rarely reported.

In this study, we intended to characterize clinical prognostic factors of ATRTs in Chinese patients by retrospectively analyzing ATRT cases collected in Beijing Tiantan Hospital, in the hope of providing novel reference for treatment of ATRT patients.

ATRT is a rare and aggressive brain cancer, predominantly affecting children. This tumor is recognized for its swift growth and its potential to metastasize to other regions of the central nervous system, rendering it a formidable disease that poses challenges for effective treatment (15, 24).

ATRT primarily impacts young children, typically manifesting in infants and toddlers. Research has consistently shown an elevated risk of tumor development in children under the age of 3, making it a crucial concern in pediatric healthcare (10). The median age of onset of ATRT in the study cohorts reported in European and American countries is mostly less than 2 years old (14, 15). However, the reported diagnosis ages of the ATRT cohort of Chinese patients are relatively older. A study conducted by Shen et al. (25), 10 patients with ATRT were included, 80% of whom were older than 5 years old, and 3 patients were older than 30 years old. In another study conducted by Wang et al. (26), the median age of diagnosis for 15 ATRT patients was 5.5 years, and 53.3% of the patients were older than 3 years. In our study, the median diagnosis age is 4 years old and 65% of the patients were older than 3 years. This is similar to a previously reported patient-based study in China. However, whether the age of Chinese ATRT patients is older than that of European and American patients still need further studies with wider range and larger sample. In addition, while the majority of cases examined in this study involved minors, a significant proportion of patients were over 3 years old. This indicates that precisely determining the age with the highest incidence of ATRT may have some uncertainty. Therefore, during the diagnostic process, especially when dealing with pediatric patients across all age groups, it's essential not to overlook the potential for ATRT. Notably, the survival period for ATRT patients under 3 years old is considerably shorter than for those over 3 years old. Furthermore, this study identified an age below 3 years old as an independent risk factor for ATRT prognosis, consistent with earlier research findings (27–29).

Although there is no uniform guideline, it is widely accepted that the treatment of ATRT typically involves a comprehensive approach, which includes surgical intervention aimed at maximal tumor removal, followed by a combination of radiation therapy and chemotherapy. Achieving gross tumor resection (GTR) through intensive multimodal treatment is a recognized and valuable objective, associated with improved outcomes compared to cases with significant residual disease (7). Our center follows the principle of maximum surgical resection of the tumor. However, in our study, achieving total tumor resection was not identified as an independent factor for enhancing the prognosis of ATRT patients. These further underscores the malignant and highly prone-to-spread and relapse nature of ATRT. It suggests that a simple surgical approach may not effectively enhance patient survival, emphasizing the need for a multidisciplinary and comprehensive treatment approach.

Currently, the exploration of comprehensive treatment strategies for ATRT, combining surgery with chemoradiotherapy, is actively ongoing. This includes research on treatment guided by molecular typing of ATRT, which has garnered considerable attention (10, 11). The future of ATRT treatment lies in multidisciplinary and comprehensive approaches. In our study, the patients were treated with 6-cycle of Cisplatin-EP regimen alone or during radiotherapy at the center. In addition, the center stratified patients according to thier age, and developed different radiotherapy programs for patients of different age groups. We observed that overall, patients who underwent radiation therapy exhibited significantly higher survival rates compared to those who did not. Similar results were seen in patients over 3 years old, although this wasn't the case for those under 3 years old. This discrepancy may be attributed to the limited number of patients below 3 years of age receiving radiation therapy. Notably, while chemotherapy did not independently improve outcomes for ATRT patients overall, it notably extended survival for patients under 3 years old. Importantly, all patients who received radiotherapy also received chemotherapy in this study. Although not covered in this study, high dose chemotherapy and stem cell transplant are also important treatments for ATRT patients and are becoming more widely recommended and used, especially for young children (30–32). Several studies have reported promising effects of multiple treatments, including high dose chemotherapy and auto stem cell transplantation, in prolonging survival in patients with ATRT. A study by Yamada et al. put forward that ATRT patients with localized tumors without germline SMARCB1 aberrations can be rescued with multimodal therapy, including induction therapy containing ICE followed by HDCT/autoPBSCT and intrathecal topotecan maintenance therapy without radiotherapy (33). Griffith-Linsley et al. reported one case of ATRT with prolonged survival after auto stem cell transplantation treatment, and reviewed the literature on the benefit of auto stem cell transplantation treatment in four adult ATRT patients (31). Although larger studies are still needed, high dose chemotherapy and auto stem cell transplantation have promising prospects in the treatment of ATRT. Hence, treating ATRT necessitates a comprehensive approach involving multidisciplinary collaboration and a range of professionals, building upon the foundation of surgery (34).

Limitations of this study lie in its retrospective characteristics and insufficient number of cases and further prospective studies are required to validate conclusions. In addition, as an important factor affecting patient survival (34), stage statistics was not included in this study. Furthermore, this study did not collect molecular typing data of patients. Genetic testing could provide strong support for tumor diagnosis and classification, and additional insights into the underlying molecular mechanisms (35). Recent research demonstrated that ATRT subgroups are associated with distinct genotypic, chromatin, and functional landscapes that correlate with cellular responses to various signaling and epigenetic pathway inhibitors; compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated (10, 11, 36). Future studies may further investigate anatomical, functional, and genetic characteristics of molecular subgroups during treatment and surveillance of ATRT in a prospective fashion.