Aggressive atypical teratoid/rhabdoid tumor with extensive leptomeningeal metastasis in an 8-year-old boy: a case report and narrative review

Introduction

Atypical teratoid/rhabdoid tumor (AT/RT) is a grade 4 embryonal tumor of the central nervous system (CNS) according to the World Health Organization (WHO) classification (1). AT/RT is rare and accounts for about 6% of solid pediatric high-grade CNS tumors, with an age-adjusted incidence rate of 0.83–2.15 per one million person-years (2,3). AT/RT primarily afflicts young children of <3 years old and is highly aggressive, with a propensity for early metastasis. Large-scale surveillance data suggest a distant metastatic rate of approximately 13% (4,5), most commonly from an infratentorial primary lesion (6). The prognosis of AT/RT is dismal with a median survival of 6–13 months (7-10). However, AT/RT in children above 3 years old generally follows a relatively favorable clinical course (11-13).

There are currently no treatment guidelines available for AT/RT, partly due to the rare disease occurrence and paucity of randomized trials. AT/RT with metastatic disease poses additional challenges for management as no trials have been specifically tailored to these patients. Consequently, whether to pursue an intensified treatment in metastatic AT/RT patients remains a significant dilemma facing clinicians and families. Here, we present a case of a highly aggressive AT/RT in an 8-year-old boy with extensive leptomeningeal disease at diagnosis (Figure 1). Notably, the patient received no adjuvant therapy following surgery, providing a stark observation of the disease’s natural history (Figure 1A). The subsequent precipitous clinical decline underscores the devastating progression of untreated AT/RT, followed by a discussion on current therapeutic challenges and emerging management strategies. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-897/rc).

Figure 1 Clinical timeline and CT of the head. (A) Clinical timeline. (B) Non-enhanced CT revealed a 6.2 cm × 4.9 cm × 5.5 cm heterogenous mass involving the left frontal, parietal, and insular cortex. Hyperdense calcification and a thick hypodense rim were present. (C) Non-enhanced postoperative CT suggested maximal resection of the lesion. AT/RT, atypical teratoid/rhabdoid tumor; CT, computed tomography; MRI, magnetic resonance imaging.

Case presentation

An 8-year-old boy was referred to our tertiary hospital for a four-day history of an unremitting severe headache, projectile vomiting, and lethargy. Physical examination revealed equal bilateral pupil size and reactivity, diminished strength (grade 3–4) in the right upper limb and positive Babinski sign on the right. Due to financial concerns, computed tomography (CT) of the head was performed instead of magnetic resonance imaging (MRI). Non-contrast head CT showed a 6.2 cm ´ 4.9 cm ´ 5.5 cm left frontoparietal heterogenous mass with internal calcification and a hypodense rim (Figure 1B). Whole spine MRI revealed multifocal linear and nodular enhancement of the leptomeninges of the brainstem, the cervical and lumbar spine and the cauda equina (Figure 2), suggesting extensive cerebrospinal fluid (CSF) seeding. Diagnosis of a high-grade glioma or embryonal tumor was suspected and surgical intervention was pursued. Maximal safe resection of the left frontoparietal lesion was performed, where a 6 cm ´ 6 cm ´ 5.5 cm mass with calcification and soft tissue components was resected. Microscopic examination demonstrated infiltrative growth of small and densely-populated tumor cells, characterized by prominent atypia, amidst foci of interstitial edema, hemorrhage and necrosis, suggestive of medulloblastoma or other embryonal tumors (Figure 3). A proportion of tumor cells showed trabecular arrangement and a few cells displayed the typical rhabdoid morphology. Immunohistochemical staining confirmed loss of integrase interactor 1 (INI-1) in tumor cells with variable differentiation into distinct phenotypes, indicated by positive staining for epithelial membrane antigen (EMA), synaptophysin (SYN), S100, and smooth muscle actin (SMA). The Ki-67 index was high (40%). Brahma-related gene 1 (BRG1) expression was retained. Collectively, these findings were consistent with a diagnosis of AT/RT, WHO CNS grade 4. The patient experienced right hemiplegia post-operatively and refused to feed on post-operative day 10. Head CT confirmed complete resection of the primary tumor (Figure 1C) and CSF analysis ruled out CNS infection, suggesting that the clinical deterioration was likely due to the overall tumor burden outside of the primary lesion. Despite discussion of options for radiotherapy and chemotherapy, the patient’s family decided to resort to palliative care. Consequently, the patient was discharged to home on post-operative day 13 on the family’s request. Subsequent telephonic follow-ups confirmed that no further antineoplastic treatment was administered. During the post-discharge period, the patient was maintained on enteral nutrition via a nasogastric tube. However, the clinical course was characterized by rapid and profound neurological deterioration. Within one month of discharge, the patient manifested escalating headaches and a diminishing level of consciousness, alongside progressive hemiparesis. Driven by the relentless trajectory of the malignancy, the patient ultimately succumbed to respiratory failure four months following discharge. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the minor’s legal guardian for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 2 MRI of the spinal cord. Sagittal view of contrast-enhanced T1-weighted MRI imaging revealed multifocal leptomeningeal enhancement in the cervical spinal cord (A) and cauda equina (B), suggesting disseminated disease. The abnormal signals were also appreciated on axial view of the cervical cord (C) and cauda equina (D). MRI, magnetic resonance imaging.

Figure 3 Pathologic examination. Tissue sections were prepared with a Leica BondMAX automated staining system (Leica Bio systems, Wetzlar, Germany) using antibodies purchased from Zhongshan Golden Bridge Biotechnology (Beijing, China). Hematoxylin and eosin staining revealed small and densely-populated tumor cells characterized by prominent atypia, a high nucleus-to-cytoplasm ratio, scant and faint cytoplasm, vesicular chromatin, and visible small nucleoli (A). Atypical mitotic figures (B), interstitial edema (C), geographic hemorrhage, and focal necrosis were present. The tumor cells demonstrated infiltrative growth without a discernible border from the surrounding normal brain tissue (D). On immunohistochemical staining, the tumor cells were negative for IN1-1 (E) and positive for EMA (F), SYN (G), S100 (H), and SMA (I). The Ki-67 index was high (40%+) (J). These findings were consistent with the diagnosis of AT/RT, WHO CNS grade 4. AT/RT, atypical teratoid/rhabdoid tumor; CNS, central nervous system; EMA, epithelial membrane antigen; INI-1, integrase interactor 1; SMA, smooth muscle actin; SYN, synaptophysin; WHO, World Health Organization.

Discussion

This case of a supratentorial AT/RT and widespread CSF seeding in an eight-year-old boy with an aggressive clinical course despite maximal safe resection of the primary lesion highlights several challenges in the diagnosis and management of AT/RT. Given the rare disease occurrence and lack of treatment guidelines outside of clinical trials, we attempted a narrative review as follows, summarizing the disease characteristics and advances in clinical management.

AT/RT most commonly occurs in children under 3 years old (4,14,15), and has a slight male predominance (4). A recently reported Chinese cohort of 20 AT/RT patients showed predominance of older children (8), suggesting possible ethnic variability in the patient demographics. The posterior fossa is the most common site affected (4). AT/RT rarely occurs in adults, frequently localized to the sellar/suprasellar region (16,17). Germline mutations in INI-1 (also known as SMARCB1) predispose to AT/RT formation, and account for up to one third of rhabdoid tumors (18). Through dissection of ancestry-based genetic background in pediatric patients with CNS tumors, AT/RT was found enriched among patients with African ancestry, with an odds ratio of 2.6 (19), which also points to a genetic predisposition.

The presenting symptoms of AT/RT are unspecific and largely depend on the tumor location. The most common symptoms result from increased intracranial pressure and may include headache, vomiting, lethargy, and, in younger children, macrocephaly (20). Infratentorial lesions may also present with ataxia, whereas supratentorial lesions may manifest with focal deficits, including diplopia (21). Very rarely, AT/RT may arise in the spinal cord or peripheral nerves (22). Spinal or cauda equina involvement may cause lower back pain, lower extremity pain and weakness, and gait disturbance (23). The onset of symptoms is usually in the range of a few weeks (20). The acuity of clinical presentation in our case of merely 4 days indicates particular aggressiveness of the tumor.

Although head CT may be used, the imaging modality of choice is whole CNS MRI to also assess leptomeningeal disease. The primary lesion is usually well-demarcated but heterogeneous, with possible calcification, hemorrhage and peritumoral edema (12), as shown here. Presence of eccentric cysts is also characteristic for AT/RT (24). On MRI, AT/RT is heterogeneously iso-intense on T1-weighted images and hyperintense on T2-weighted images. Contrast enhancement is usually present and marked restriction on diffusion weighted imaging is characteristic. In the case of cranial nerve involvement, restricted diffusion is highly suggestive of a malignant tumor such as AT/RT (22). Leptomeningeal disease is primarily assessed with sagittal contrast-enhanced MRI (12). CSF cytology may enhance detection of tumor spread (25). Individual studies have reported metastatic disease in as many as 37% of AT/RT patients (2,26), although larger-scale surveillance data suggest a distant metastatic rate of approximately 13% (4,5). Age-stratified analysis revealed that about 80% of metastatic disease occurs in children of <3 years old (6), which is equivalent to the relative prevalence of AT/RT patients under 3 years of age. Hence, age alone may not be a predictor for metastatic disease. Presence of metastasis is a diagnostic cue given a much higher metastatic rate for embryonal tumors including medulloblastomas and AT/RT (12–15%), compared to high-grade gliomas (about 2%) (5). However, it is crucial to note that certain high-grade gliomas such as H3K27-altered diffuse midline gliomas also have a propensity for leptomeningeal spread, with a reported rate of 6% at diagnosis (27), and a 1-year cumulative rate of 24% (28). Metastasis beyond the CNS has also been reported, such as to the lungs (29,30). Thus, complete staging may also require whole-body MRI.

Although molecular diagnosis is not always indicated when histology and immunohistochemistry are clearly contributory, definitive diagnosis of AT/RT ultimately relies on molecular examination, because both radiographic and histologic features are often indistinguishable from those of other embryonal tumors such as medulloblastoma and embryonal tumor with multilayered rosettes. Histologically, a population of rhabdoid cells and variable components with primitive neuroectodermal, mesenchymal, and epithelial features are present (31). Rhabdoid cells fall along a spectrum from small cells with scant cytoplasm to large, typical rhabdoid cells with eccentrically located nuclei and extensive homogeneously eosinophilic cytoplasm. Occasionally, intracytoplasmic globular eosinophilic inclusions are present. Nuclei are round and contain vesicular chromatin and prominent eosinophilic nucleoli. Rhabdoid cells are the exclusive or predominant histopathological finding in only a minority of cases and may be very rare, as seen here, or even completely lacking in some cases. Subsequently, a portion of the tumor may mimic other pathologies including pilocytic astrocytoma on histologic examination (32). INI-1/SMARCB1 loss (or BRG1/SMARCA4 loss in <5% cases) differentiates AT/RT from embryonal tumors with multilayered rosettes (previously known as primitive neuroectodermal tumors) (1). Differential diagnoses include rare SMARCB1-deficient non-rhabdoid tumors forming cribriform strands, trabeculae, and well-defined borders, classified as cribriform neuroepithelial tumors. However, cribriform neuroepithelial tumors tend to impart a favorable prognosis (33). Recently, a case of AT/RT with retained INI-1 expression and BRG1 missense mutation was reported, suggesting the value of next-generation sequencing in AT/RT diagnosis (34). Additional examination of Brachyury expression may be helpful to differentiate from chordoma especially when the tumor is located near the clivus (35). Based on epigenetic features, AT/RT can be further subtyped into three variants, namely AT/RT-tyrosinase (TYR), sonic hedgehog (SHH), and MYC proto-oncogene (MYC) (36). AT/RT-TYR is characterized by overexpression of melanosomal markers including TYR, DCT, and MITF. AT/RT-SHH features overexpression of MYCN, GLI2, and ASCL1. AT/RT-MYC is characterized by overexpression of MYC and HOTAIR. Clinical distinctions also exist among the three subtypes. AT/RT-TYR mostly arises infratentorially, whereas AT/RT-MYC is more frequently supratentorial (36). AT/RT-TYR most commonly arises in <1-year-old patients, whereas AT/RT-MYC is more common in children >6 years old (36). Additionally, AT/RT-TYR is more likely to be non-metastatic at diagnosis, whereas AT/RT-SHH is more frequently metastatic (37). AT/RT-SHH is the largest molecular group and the most heterogeneous with regards to age, tumor location and epigenetic profiles. Based on data on 65 AT/RT-SHH patients, recent studies have proposed to further divide the AT/RT-SHH subgroup into SHH-1A, 1B and 2 subtypes, each with distinct clinical and molecular features (38), although their prognostic implication is controversial (39).

Surgical intervention is usually indicated in AT/RT for both diagnostic and therapeutic purposes. Historically, the extent of surgical resection was found significantly associated with survival (2). Interestingly, one recent meta-analysis suggested that neither gross total or partial resection confers a survival advantage (40), possibly due to a confounding effect caused by improved overall survival (OS) with recently-introduced multimodal therapy as well as effect modification stratified by patient characteristics such as age (41). Indeed, surgery alone has been found to be associated with a shorter OS, with a median of around 2.5–5.9 months, than surgery combined with radiotherapy and/or chemotherapy (15,29). Regardless, the general consensus still suggests gross total resection when feasible to prolong patient survival (42,43). In the context of metastatic disease, the role of maximal safe resection is less defined, with a meta-analysis showing no survival impact by the extent of surgical resection (6).

The use and extent of radiotherapy in pediatric AT/RT patients depend on patient’s age and presence of metastatic disease. Although radiotherapy can significantly improve patient survival (8,44), various studies have also reported disease response in surgery and chemotherapy-treated patients without the use of irradiation, especially among younger patient populations (45,46). Challenges facing radiotherapy in younger patients of <3 years old include the potentially adverse neurodevelopmental consequences, secondary malignancies, and requirement for repeated sedation during the treatment course (25,47). In these patients, conformal radiotherapy has been shown generally tolerable and beneficial to improving patient survival (41), although deaths due to CNS necrosis may occur in the context of concurrent intensified chemotherapy (26). Proton (versus photon) therapy is the preferred modality for volumetric accuracy (12). Conversely, non-metastatic AT/RT patients above 3 years old are recommended to receive focal radiotherapy as early as possible, e.g., after surgery (12). When metastatic disease is present, craniospinal irradiation is recommended in AT/RT patients of >3 years old, followed by a boost to the primary site and persistent metastatic lesions (12). In patients younger than 3 years old with metastatic disease, early adjuvant local radiotherapy may improve survival (48), but the risk-weighted benefits of craniospinal irradiation remain controversial.

Chemotherapy is essential to survival improvement in AT/RT patients (15). Although successful treatment has been reported with metronomic chemotherapy (49), standard-dose conventional chemotherapy is generally insufficient to delay disease progression and intensive high-dose regimens with autologous stem cell rescue are preferred to prolong survival (2,50,51). Intrathecal chemotherapy (e.g., with etoposide and cytarabine) may also significantly improve the prognosis in pediatric AT/RT patients, with a reported increase in the 2-year OS by more than 3-fold (52). Intensified treatment with the Medical University of Vienna atypical teratoid/rhabdoid tumor (MUV-ATRT) protocol, incorporating doxorubicin, high-dose methotrexate and intrathecal chemotherapy for induction, followed by high-dose chemotherapy and focal radiotherapy, resulted in a 100% 5-year OS in 9 consecutive patients whose age ranged from 9 months to 17 years (53). Notably, 4 of those patients had metastatic disease at diagnosis. The toxicity profile included myelosuppression as expected but also significant ototoxicity, requiring hearing support in some cases. A prospective trial utilizing high-dose chemotherapy and focal radiotherapy among 65 patients reported a 4-year OS of 43%, but 4 treatment-related deaths occurred (26). When metastasis is present, intrathecal and high-dose chemotherapy are independently associated with improved survival, with the latter demonstrating a much more substantial effect (6). According to the SJYC07 experience, the benefit of high-dose chemotherapy over conventional chemotherapy combined with RT appears to be risk-dependent, with comparable outcomes observed in selected non-disseminated or lower-risk patients, but not uniformly across high-risk or disseminated cohorts (37).

Effective targeted therapy is still lacking in AT/RT, although various strategies are under investigation. For instance, recent studies have identified the SWI/SNF complex as the key regulator of transcriptional networks sustaining survival of the MYC subtype AT/RT cells, and therapeutic inhibition of activator protein 1 (AP-1) or TEA domain (TEAD) can abrogate the networks and reduce tumor cell viability (54). High-throughput screening has revealed that AT/RT cell lines are sensitive to colchicine at nanomolar concentrations (55). In addition, AT/RT-SHH cell lines are sensitive to BCL2 and HSP90 inhibitors, whereas a subset of AT/RT-MYC cell lines are sensitive to kinesin spindle protein (KSP) inhibitors and the eIF4E inhibitor briciclib (56). Other pre-clinical studies have also revealed SIRT1/2 (57,58), RRM2 (59), CDK4/6 (60), ERBB2 (61), proteasome inhibition (62), and restoring SMARCB1 (63) as potential therapeutic targets for AT/RT. Moreover, oncolytic measles virus has been shown effective in prolonging survival in murine AT/RT models (64). Intra-tumoral delivery of oncolytic measles virus in pediatric patients has also been shown safe and effective in eliciting regional anti-viral responses (65). Additionally, INI-1 or BRG1 may confer an oncogenic dependency on enhancer of zeste homolog 2 (EZH2) in AT/RT, and disruption of EZH2 suppresses AT/RT cell growth and sensitizes them to radiation (66). Early phase trials have also demonstrated tolerability of EZH2 inhibitors and potential disease stabilization effect in AT/RT patients (67), although cautious electrolyte management is recommended (68). Lastly, studies have found AT/RT specific expression of claudin-6 (CLDN6), which could be leveraged for antigen-targeted antibody-drug conjugates for optimal therapeutic delivery (69). In progressive or recurrent AT/RT patients, a phase II trial found Aurora kinase A inhibitor alisertib as a single agent was well-tolerated, with 8 out of 30 patients reaching stable disease by 12 weeks (70).

The prognosis of AT/RT patients remains poor despite aggressive treatment. The median time from diagnosis to disease progression is 5.4 months (71). Timely and correct diagnosis is associated with 66.7% OS at 5 years, whereas misdiagnosis results in only 15.0% (2). Older age has long been associated with improved prognosis (8,15), with a 2-year OS of 89% in >3 years old versus 17% in <3 years old (72), although availability of more aggressive treatment such as craniospinal irradiation in older patients may have confounded the results. Metastatic disease is generally recognized as a negative prognostic factor for OS in prospective and large-scale retrospective studies (3,4,37). However, the impact of metastatic disease on OS may diminish with the use of high-intensity multimodal therapy (26). Ultimately, when tolerable, intensive treatment with gross total resection, followed by adjuvant radiotherapy and intensified chemotherapy is recommended to achieve optimal prognostic outcomes, with a 5-year OS of up to 88.2% (42,73). Such recommendation may hold true in metastatic AT/RT based on meta-analysis of these patient populations (6). However, prospective studies in these patients are unfortunately lacking.

Conclusions

Collectively, our case highlights the aggressive nature and dissemination potential of AT/RT even in an older child. Therefore, a high index of suspicion for leptomeningeal dissemination should be maintained. Once leptomeningeal metastasis is present, the natural course of the disease is fulminant and the prognosis is dismal in the absence of timely therapeutic intervention. In our case, who declined adjuvant therapy, survival was limited to only four months after surgery. Whereas maximal surgical resection, craniospinal irradiation and intensified chemotherapy are generally recommended in non-metastatic disease, the benefits of such aggressive treatment in patients with metastasis are largely undefined, especially accounting for potentially lethal adverse effects associated with the treatment. Adding to the complexity is the heterogeneous nature of AT/RT, that it is difficult to accurately predict the natural history of the disease based on molecular signatures, patient demographics, and clinical features. In addition, psychosocial factors, including family decision-making processes and treatment preferences, may critically influence therapeutic choices and clinical outcomes, as illustrated in the present case. As AT/RT is ultimately very rare, multicenter collaboration and clinical trials are urgently needed to help guide optimal therapeutic strategies in AT/RT patients who present with extensive leptomeningeal spread.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-897/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-897/prf

Funding: This work was supported by the Beijing Municipal Administration of Hospitals Incubating Program (No. PX2025044), the Beijing Research Ward Excellence Program (No. BRWEP2024W102090104), the BCH Young Investigator Program (No. 3-1-014-01-37), and the Transformation Incubation Fund for Scientific and Technological Achievements of Beijing Children’s Hospital, Capital Medical University (No. ZHFY3-1-015-06).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-897/coif). X.Y. reports that he received funding for this work from the Beijing Municipal Administration of Hospitals Incubating Program (No. PX2025044), the Beijing Research Ward Excellence Program (No. BRWEP2024W102090104), the BCH Young Investigator Program (No. 3-1-014-01-37), and the Transformation Incubation Fund for Scientific and Technological Achievements of Beijing Children’s Hospital, Capital Medical University (No. ZHFY3-1-015-06). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the minor’s legal guardian for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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