The Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) is a group of highly malignant neoplasms composed of undifferentiated small round cells with significant differentiation potential into various tissue types, including neuronal, gliomatous, and mesenchymal elements (1–3). These tumors originate from primitive neuroepithelium and are considered rare, particularly in the pediatric population (4).

The clinical presentation of ES/PNET often includes localized pain, which may be accompanied by neurological compression symptoms such as weakness, sensory deficits, or autonomic dysfunction, depending on the tumor's location (5). Primary spinal ES/PNET, in particular, is exceedingly rare, with only a few cases reported in the literature, making them a challenging diagnosis for clinicians (6).

This case report presents the clinical and radiological findings, as well as the histopathological diagnosis, of an 11-year-old boy with primary spinal ES/PNET. By documenting this rare case, we aim to enhance understanding and awareness of this uncommon condition among healthcare professionals.

The informed consent was obtained from the patient's mother prior to the publication of this case report.

A 11-year-old male patient was admitted to the Department of Neurosurgery at Siping Central People's Hospital on March 27, 2022, due to unsteady gait for 5 days and progressive weakness in both lower limbs that developed over the last 10 h (Table 1). The patient had been experiencing unsteady gait for 5 days prior to admission, but his symptoms were initially ignored by his mother, and no medical treatment was sought. On the day before admission, the unsteady gait persisted without improvement, prompting his mother to urgently seek medical attention.

The Ewing sarcoma/primitive neuroectodermal tumor is rare, aggressive malignancies derived from primitive neuroepithelium, predominantly affecting adolescents. These tumors are clinically challenging due to their rapid growth, high tendency for local invasion, and early metastasis, which often result in poor outcomes, with survival rates typically limited to less than five years. In this case, the preoperative cranial MRI showed no abnormalities, excluding metastatic disease and supporting the diagnosis of a primary spinal ES/PNET.

Spinal ES/PNET can arise in various locations within the spinal canal, including the extradural space, subdural extramedullary region, intramedullary space, or outside the spinal canal at any spinal segment (8, 9). Lesions in the extradural space lack specific imaging features, making them difficult to differentiate from other spinal tumors, such as Ewing sarcoma (8). On MRI, both can appear as low, iso-, or hyperintense signals on T1-weighted imaging (T1WI), low or hyperintense signals on T2-weighted imaging (T2WI), and exhibit uneven enhancement. Hemorrhage or necrosis, which are sometimes present, may further complicate differentiation based on imaging alone. MRI remains the most effective modality for evaluating tumor extension and its relationship to surrounding structures, although definitive diagnosis relies on histopathological examination (10).

The diagnosis of spinal ES/PNET is primarily based on pathological analysis, with immunohistochemical studies playing a crucial role in distinguishing it from other conditions, such as lymphoma, eosinophilic granuloma, spinal Rosai-Dorfman disease, and vascular lipoma (8). Grossly, the tumor often appears as a purple-red or gray-white mass, with a soft or firm texture and abundant blood supply. Microscopically, spinal ES/PNET is characterized by densely packed small round or spindle-shaped primitive cells with hyperchromatic nuclei, scant cytoplasm, and occasional rosette formations (11).

This patient's immunohistochemical results revealed the following: CD99 diffuse (+), CyclinD1 (+), CD56 (+), and KI-67 index of 80% (+). Immunohistochemistry is particularly useful for distinguishing PNET subtypes. Peripheral PNETs (pPNETs) typically express CD99, while central PNETs (cPNETs) do not. Since the lesion in this patient was CD99-positive, it was consistent with a diagnosis of pPNET. Additionally, genetic studies have shown that over 90% of pPNETs exhibit the characteristic t(11;22)(q24;q12) chromosomal translocation, which is not observed in cPNETs (12, 13). While BRAF mutations are rarely seen in PNETs (approximately 3% of cases), their presence does not correlate with prognosis (8, 14).

A principal limitation of this case is the inability to perform molecular testing for the EWSR1-FLI1 gene fusion, which is the current diagnostic standard for definitive diagnosis of Ewing sarcoma (2, 3, 15). This limitation was due to constraints in our hospital's molecular pathology laboratory resources and testing capabilities at the time of diagnosis. Another limitation is the lack of an extended immunohistochemical (IHC) panel in the initial diagnostic workup, which could have further refined the differential diagnosis of small round blue cell tumors (SRBCTs) (2, 3). Specifically, immunohistochemical markers such as Desmin (a marker of rhabdomyoblastic differentiation), Myogenin (specific for skeletal muscle lineage), INI1 (loss of expression observed in rhabdoid tumors and certain SRBCTs), FLI-1 (a sensitive marker for Ewing sarcoma), and NB84 (a marker for neuroblastoma) were not assessed. This was primarily due to institutional IHC protocol limitations and sample-related considerations at the time. Consequently, the diagnosis was established based on histopathological findings, immunohistochemical staining (including strong and diffuse CD99 positivity), and clinical correlation, with particular attention to the patient's age and the anatomical location of the lesion.

Modern proton therapy represents a significant advancement in the treatment of spinal ES/PNET. This highly precise modality minimizes radiation exposure to surrounding normal tissues while delivering high doses to the tumor, resulting in improved tumor control and better quality of life for patients. Proton therapy has shown particular promise in the treatment of pediatric malignancies, head and neck cancers, chordomas, and cervical cancers (16). International case reports have described patients with dorsal ES/PNET who, despite local recurrence, remained disease-free for up to 10 years after receiving extensive radiotherapy.

In this case, the patient's clinical course points out the aggressive nature of spinal ES/PNET. Postoperatively, the patient initially showed improvement and was started on chemotherapy. However, the tumor recurred, as evidenced by imaging findings of intramedullary metastasis and later complications, including hypostatic pneumonia, respiratory failure, and eventual death. These outcomes highlight the challenges associated with managing spinal ES/PNET in adolescents.

ES/PNET has been reported in the literature in a number of previous cases (17, 18). The standard treatment for ES/PNET combines systemic and local therapies, including multiagent chemotherapy, surgical resection, and radiotherapy, to control the primary tumor and address potential metastases (19, 20). Despite improvements in conventional therapy, survival outcomes for spinal ES/PNET remain poor. Recent studies and case reports have investigated novel approaches such as targeted agents against EWSR1-FLI1, the PI3K-Akt-mTOR pathway, and CD99, as well as immunotherapies including checkpoint inhibitors and CAR T-cell therapy, which have shown early promise in refractory or relapsed cases (21–24). Prognosis is shaped by several factors consistently reported in both series and case reports. Metastasis at presentation is the most significant adverse predictor, with gross total resection linked to better local control and survival than subtotal resection or biopsy alone (19). Younger patients generally have more favorable outcomes than adults (25, 26), and while the EWSR1-FLI1 fusion is diagnostic, additional genetic alterations may offer further prognostic stratification (21, 27, 28).

This case presents several novel aspects compared to previously reported cases of spinal ES/PNET. First, the absence of cranial abnormalities on preoperative imaging excluded metastatic disease and supported the diagnosis of a primary spinal ES/PNET, which is relatively rare. Additionally, the lesion's unique “dumbbell” shape with extension into the left intervertebral foramen and its progression to intramedullary metastasis postoperatively highlight the aggressive and atypical behavior of this tumor. These findings are less commonly reported and emphasize the challenges in diagnosing and managing spinal ES/PNET with such presentations. Another notable difference is the development of multiple complications postoperatively, including bacteremia, compression fracture, and hypostatic pneumonia, which ultimately contributed to the patient's poor outcome. These complications emphasize the need for comprehensive perioperative care and close monitoring in patients with spinal ES/PNET. Clinically, this case highlights the importance of early diagnosis and the limitations of current treatment modalities, including surgery, chemotherapy, and radiotherapy, in achieving long-term control of this aggressive tumor. It also reveals the potential role of advanced imaging techniques and novel therapies, such as proton therapy or gene therapy, in improving outcomes for patients with spinal ES/PNET. Overall, this case adds valuable insights into the clinical presentation, diagnostic challenges, and management strategies for spinal ES/PNET, particularly in pediatric and adolescent populations.

Spinal ES/PNET typically present as extradural masses with CT findings of medium-density soft tissue and MRI findings of low T1WI and iso- or hypointense T2WI signals, often with cystic changes (29). The final diagnosis, however, is based on histopathological and immunohistochemical findings. In adolescents presenting with a single extradural spinal mass accompanied by extraspinal components, irregular CT density, or MRI signal with significant uneven enhancement, ES/PNET should be included in the differential diagnosis (30, 31).

Despite advances in multimodal treatment, including surgery, radiation therapy, and chemotherapy, the prognosis for spinal ES/PNET remains poor, with short survival times (32). Molecular targeted therapy may hold promise as a future treatment option, potentially offering more effective management of this aggressive disease (19).