Recurrent Mandibular Ewing sarcoma in an 11-year-old boy: a rare pediatric case and review of the literature.

Introduction

Ewing sarcoma (ES) is a small round cell tumor originating from bone or soft tissue, representing the fourth most common primary bone malignancy after multiple myeloma, osteosarcoma, and chondrosarcoma [ 1 , 2 ]. This rare and aggressive tumor primarily affects the long bones (58%), pelvis (20%), and ribs (7%), with less than 3% of cases occurring in the head and neck region. Mandibular involvement accounts for only 0.7% of all sites, while the maxilla is even less commonly affected [ 3 , 4 ]. Key prognostic factors include tumor location, volume, and the presence of metastases. Disease progression leads to cortical bone destruction and soft-tissue invasion, manifesting as swelling, pain, loose teeth, toothache, mucosal ulceration, trismus, and paresthesia in the jaw and facial region [ 5 ].

ES belongs to the Ewing sarcoma family of tumors (ESFT), which also includes peripheral neuroectodermal tumor (PNET), neuroepithelioma, and Askin tumor [ 6 , 7 ] First described by James Ewing in 1920 as a diffuse endothelioma of bone, ES accounts for 4–15% of all primary bone tumors [ 8 ] and 1% of childhood malignancies [ 1 ]. In 1992, Delattre et al. identified the EWSR1/FLI1 fusion transcript in ES cells, resulting from the t(11;22) (q24;q12) translocation in most cases [ 9 – 11 ]. ES typically presents between ages 5 and 30, with a higher incidence in White populations and males [ 5 , 11 ]. Its aggressive nature and resemblance to odontogenic infections often delay diagnosis, with potentially fatal consequences. This report describes a rare case of recurrent mandibular ES in an 11.5-year-old boy treated at Imam Khomeini Hospital, emphasizing radiologic findings, multimodal therapy, and the potential role of immunotherapy in relapsed disease.

Case presentation

An 11.5-year-old Iranian boy of Middle Eastern ethnicity presented to the pediatric oncology service with a 1-month history of progressive swelling and persistent pain in the left mandibular region. The patient had no significant past medical history, no known genetic disorders, no history of previous malignancy, and no family history of cancer. He was not receiving any regular medications at presentation. The pain was described as a dull aching discomfort that progressively increased in intensity over several weeks and was exacerbated by mastication. Initially attributed to a dental abscess, he was treated with oral antibiotics without improvement. The pain subsequently became more persistent, prompting referral for further evaluation. On physical examination, a firm, non-mobile mass was palpable over the left mandibular body, measuring approximately 6 cm in greatest dimension. The lesion extended superiorly toward the alveolar ridge, inferiorly to the lower border of the mandible, posteriorly to the mandibular angle, and anteriorly to the premolar region. The overlying skin was intact without erythema, warmth, ulceration, or sinus formation. Intraoral examination revealed normal mucosa and no obvious dental pathology. There was no trismus or airway compromise. Regional lymph nodes were not enlarged, and the patient denied fever, weight loss, or systemic symptoms.

Laboratory investigations showed normal complete blood count, erythrocyte sedimentation rate, and C-reactive protein levels. Panoramic radiography demonstrated a poorly defined radiolucent lesion in the left mandibular body with cortical thinning and periosteal reaction, suggestive of an aggressive lesion. Computed tomography (CT) of the head and neck confirmed a destructive mass involving the left mandibular body, extending superiorly toward the alveolar ridge, inferiorly to the lower border of the mandible, posteriorly to the mandibular angle and ramus, and anteriorly toward the premolar region. The lesion also extended into adjacent soft tissues, demonstrating a sunburst periosteal reaction, with no evident lymphadenopathy (Fig. 1 ). Magnetic resonance imaging (MRI) further delineated the lesion as T1-isointense and T2-hyperintense with heterogeneous contrast enhancement, measuring 6.5 × 4.2 × 3.8 cm, without involvement of the mandibular canal or adjacent muscles.

Incisional biopsy under local anesthesia yielded small round blue cells with scant cytoplasm and hyperchromatic nuclei, arranged in sheets. Immunohistochemistry demonstrated strong membranous CD99 positivity and nuclear NKX2.2 expression, confirming Ewing sarcoma. Representative photomicrographs were not available; histopathologic features are described in detail in the text. Immunohistochemistry demonstrated strong membranous CD99 positivity, nuclear NKX2.2 expressions, and negativity for desmin, myogenin, synaptophysin, and leukocyte common antigen, consistent with ES. Fluorescence in situ hybridization confirmed the EWSR1 rearrangement.

Treatment course

The chronological sequence of diagnostic evaluations, treatment interventions, disease recurrences, and follow-up assessments is summarized in Table 1 .

Following histopathological confirmation of Ewing sarcoma, the patient was started on neoadjuvant chemotherapy according to the Euro-EWING99 protocol. Treatment consisted of alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) with ifosfamide and etoposide (IE). Vincristine was administered at 1.5 mg/m2 (maximum 2 mg), cyclophosphamide at 1200 mg/m2 for 1 day, and doxorubicin at 37.5 mg/m2/day for 2 consecutive days. The IE cycles included ifosfamide 1,800 mg/m2/day and etoposide 100 mg/m2/day for 5 days.

After approximately 3 months of treatment (following six cycles of chemotherapy), restaging CT demonstrated a partial response, with reduction of the mandibular mass to approximately 5 × 3.5 cm. Residual involvement of the mandibular angle and ramus remained evident, accompanied by persistent periosteal reaction and adjacent soft-tissue extension. A subsequent CT examination performed approximately 3 months later showed further reduction of the mandibular lesion to 33 × 26 mm. An additional 18 × 18 mm lesion was noted in the posterolateral wall of the right sphenoid sinus.

Despite completion of 12 cycles of frontline chemotherapy, the patient developed recurrent mandibular swelling approximately 6 months after the initial diagnosis. Restaging PET–CT demonstrated persistent metabolic activity within a 3.8 × 2.5 cm lesion involving the left mandibular body and angle, without evidence of distant metastatic disease. The scan also identified a 1.5-cm metabolically inactive lesion in the right sphenoid sinus and a 3.5-cm lytic lesion in the distal right tibia consistent with a non-ossifying fibroma (Fig. 1 ).

Given the evidence of recurrent disease, salvage treatment was initiated with nivolumab (3 mg/kg every 2 weeks) in combination with temozolomide (150 mg/m2 on days 1–5) and irinotecan (50 mg/m2 on days 1–5), repeated every 21 days. Following four cycles of this regimen, repeat PET–CT demonstrated a favorable metabolic response. The mandibular lesion had decreased to approximately 3 × 2 cm and no longer exhibited FDG uptake, indicating metabolic remission despite residual structural abnormality. The sphenoid sinus and tibial lesions remained stable (Fig. 2 ).

The patient subsequently received three cycles of ICE chemotherapy consisting of ifosfamide (1800 mg/m2/day, days 1–5), carboplatin (400 mg/m2, day 2), and etoposide (100 mg/m2/day, days 1–5). Concurrent external-beam radiotherapy was administered to a total dose of 50.4 Gy in 28 fractions. Approximately 4 months later, the patient again presented with progressive facial swelling. CT imaging of the face and paranasal sinuses revealed a recurrent lytic lesion associated with cortical destruction and periosteal reaction involving the left mandible, consistent with local disease recurrence (Fig. 3 ). Subsequent MRI demonstrated a heterogeneous mass measuring 42 × 50 × 70 mm with extension into the pterygoid and masseter muscles. Repeat biopsy confirmed recurrent Ewing sarcoma, showing persistent CD99 and NKX2.2 positivity and negative desmin staining.

Additional salvage therapy consisting of vincristine (1.5 mg/m2 on day 1), irinotecan (50 mg/m2/day on days 1–5), and temozolomide (100 mg/m2/day on days 1–5) was administered for four cycles, and follow-up MRI performed approximately 6 months later demonstrated marked treatment response, characterized by thin peripheral enhancement and absence of diffusion restriction, findings suggestive of near-complete remission. However, after missing a scheduled chemotherapy session, the patient returned with rapid enlargement of the mandibular mass. MRI at that time demonstrated a destructive lesion measuring 76 × 62 × 47 mm involving the mandibular body and ramus, with extension into the pterygomaxillary fossa and oral cavity (Fig. 4 ).

Given the extent of recurrent disease, definitive surgical management was undertaken in August 2025. The patient underwent left hemimandibulectomy with immediate fibular free-flap reconstruction (Fig. 5 ). Histopathological examination of the resected specimen demonstrated residual viable Ewing sarcoma; however, all surgical margins were free of tumor.

Postoperative PET–CT performed 1 month after surgery showed complete metabolic remission with no evidence of FDG-avid disease. At the most recent follow-up, approximately 6 months after surgery, the patient remained clinically well and free of disease recurrence. Functional recovery was satisfactory, and no major treatment-related complications were observed. The patient continues to undergo regular surveillance with clinical examinations and serial imaging studies.

Clinical findings and outcomes

Postoperative PET–CT at 1 month showed no FDG-avid disease, indicating complete metabolic remission. At 6-month follow-up, the patient remains disease-free, with good functional recovery and no major complications from therapy. He is on surveillance with quarterly imaging and clinical evaluations and is currently undergoing his second postoperative chemotherapy session.

Discussion

Mandibular ES is exceedingly rare, comprising < 1% of ES cases, and poses diagnostic challenges due to its mimicry of benign odontogenic conditions [ 3 , 4 ]. Early symptoms such as swelling and pain are often misattributed to infections, delaying biopsy and imaging, as seen in this case and reported in literature, where cases were initially treated as dental abscesses leading to tooth extractions [ 15 ]. Radiologic features, including destructive lesions with periosteal reaction on CT and heterogeneous enhancement on MRI, are critical for suspicion [ 12 ]. PET–CT is invaluable for staging and response assessment, guiding therapy in relapsed disease [ 13 ]. In this case, serial imaging (CT, MRI, and PET–CT) tracked progression, response, and recurrence, highlighting the importance of multimodal imaging.

Standard treatment for localized ES involves neoadjuvant chemotherapy (VDC/IE), local control (surgery/radiotherapy), and maintenance chemotherapy, yielding 5-year survival rates of 60–70% [ 14 ]. Relapse, occurring in 20–30% of cases, portends poor prognosis (5-year survival < 30%), necessitating salvage regimens [ 16 ]. The patient had a partial metabolic response to nivolumab-based chemoimmunotherapy, but this should not be considered the only or the ultimate factor determining remission. In the current case, nivolumab combined with temozolomide and irinotecan decreased metabolic activity and may have led to temporary disease control, enabling subsequent local treatment. Complete metabolic remission, however, was only achieved after definitive surgical resection with left hemimandibulectomy and reconstruction with a free fibular flap. Hence, surgery was the main local control modality in this case. However, immunotherapy should be considered as a potentially useful salvage treatment but not a replacement for established multimodality treatment. Nivolumab, a PD-1 inhibitor, has shown promise in refractory sarcomas by enhancing T-cell antitumor activity, though pediatric data are limited [ 17 , 18 ]. Combined with temozolomide/irinotecan, it may synergize to overcome resistance, as evidenced by metabolic improvement here. Subsequent ICE and radiotherapy facilitated surgical resection, achieving remission. Similar to reports by Guven et al. nivolumab with paclitaxel aided salvage in relapsed ES [ 19 ].

The patient had multiple recurrences with increasing mandibular disease, but definitive hemimandibulectomy was not performed earlier in the course of treatment. Several considerations led to this decision. Considering the patient’s young age, the clinical team’s priority was to pursue organ-preserving approaches to maintain mandibular function, aesthetics and overall quality of life. Furthermore, data in support of early radical surgery in relapsed mandibular Ewing sarcoma at the time of first recurrence is limited, and the standard approach favors attempting salvage systemic therapy prior to extensive resection. Therefore, we used nivolumab-based chemoimmunotherapy together with temozolomide and irinotecan as a bridging salvage strategy to decrease tumor burden and potentially enable a more controlled surgical intervention. Finally, when systemic therapy and radiotherapy failed to control the progressive local disease, hemimandibulectomy with fibular free-flap reconstruction was performed as definitive local treatment. Although theoretically earlier surgery could have changed the course of the disease, it would have created considerable functional and cosmetic difficulties, and the multidisciplinary team considered the timing chosen to be a compromise between disease control and preservation of mandibular function.

The present case shares overlapping diagnostic features and a more complex therapeutic course, when compared to previously published cases of Ewing sarcoma of the mandible. The first presentation in our patient was similar to the case reported by Gosau et al. who described an initial presentation simulating an odontogenic infection leading to an initial trial of antibiotic therapy before biopsy confirmed Ewing sarcoma [ 15 ]. This delay in diagnosis has also been emphasized in reviews of oral and mandibular Ewing sarcoma, where pain, swelling, tooth-related symptoms and inflammatory appearing mandibular lesions are common early manifestations [ 3 , 4 ]. However, unlike many previously reported cases of jaw that achieved durable remission after induction chemotherapy combined with surgery and/or radiotherapy, our patient developed early local recurrence despite standard VDC/IE-based chemotherapy. The series reported by Owosho and colleagues included six patients with primary Ewing sarcoma of the jaw, five of whom had mandibular involvement, treated with multiagent induction chemotherapy followed by surgical resection; all were alive and disease-free at a median follow-up of 6.5 years without local recurrence [ 4 ]. By contrast, the present patient was treated with multiple salvage regimens, radiotherapy and hemimandibulectomy with fibular free-flap reconstruction, due to recurrent local progression.

The recurrence of such a case has clinical significance, as early relapse of Ewing sarcoma is often associated with a poor prognosis, especially if the recurrence is within 2 years of diagnosis [ 16 ]. The response with nivolumab in combination with temozolomide and irinotecan in this setting is interesting. Temozolomide–irinotecan has demonstrated clinically meaningful activity in relapsed Ewing sarcoma, with disease-control rates reported to be approximately 71% in mixed adult and pediatric cohorts. However, the use of immune-checkpoint inhibition in Ewing sarcoma is still limited and mostly based on early phase studies and single case reports. Guven et al. reported a case of a patient with multiply relapsed Ewing sarcoma who responded well and durably to nivolumab with paclitaxel for 12 months after cessation of therapy [ 19 ]. Our case differs from the report in terms of tumor location and combination regimen, as nivolumab was combined with temozolomide and irinotecan instead of paclitaxel, but both cases suggest that chemoimmunotherapy may provide significant disease control in selected patients with heavily pretreated or recurrent Ewing sarcoma. Despite this response, our patient later developed local progression. This highlights that metabolic response to salvage chemoimmunotherapy may not necessarily correlate with durable local control without definitive surgical management.

Interest in the treatment of relapsed and refractory Ewing sarcoma has been renewed with the advent of new developments in immunotherapy, although clinical evidence is limited. Recent reviews note that immune-checkpoint inhibitors, including PD-1/PD-L1 blockade, have shown variable activity across sarcoma subtypes, and Ewing sarcoma in particular is an immunologically “cold” tumor with modest response rates to single-agent immunotherapy [ 20 , 21 ]. However, emerging data suggest that combination approaches using checkpoint inhibitors with chemotherapy, targeted agents, radiotherapy or cellular therapies may enhance antitumor immune responses and improve disease control in selected patients. Recent studies have suggested a potential role for nivolumab-based approaches in advanced bone sarcomas and have identified immunotherapy as an active area of investigation for recurrent Ewing sarcoma. Although conclusive evidence is still lacking, the partial metabolic response observed in our patient is consistent with emerging data suggesting that chemoimmunotherapy can lead to temporary disease stabilization and allow for subsequent local treatment in heavily pretreated patients [ 22 – 24 ]. Future prospective studies are needed to define the optimal role of checkpoint inhibitors in pediatric Ewing sarcoma and to identify predictive biomarkers of response.

Conclusion

This report underscores the need for heightened suspicion in persistent mandibular swellings in children, early multidisciplinary intervention, and exploration of immunotherapy in relapsed ES. Maxillofacial ES may have better prognosis than axial tumors due to earlier detection [ 3 ]. Future studies should evaluate nivolumab's role in pediatric protocols to improve outcomes in this rare entity.

Acknowledgements

The authors sincerely thank the staff of the Department of Pediatric Oncology, Imam Khomeini Hospital, Tehran University of Medical Sciences, for their dedicated care of the patient and assistance with data collection.

Abbreviations

Ewing sarcoma

Ewing sarcoma family of tumors

Ifosfamide, carboplatin, etoposide

Peripheral neuroectodermal tumor

Positron emission tomography–computed tomography

Vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide

Author contributions

SMKN: data curation, methodology, and writing—review and editing. MSH: funding acquisition. TJ: methodology, supervision, and writing—original draft. All authors read and approved the final manuscript.

Funding

This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

The data supporting the findings of this study (including de-identified clinical information and imaging) are available from the corresponding author (Tahereh Jangjoo) upon reasonable request. The raw data are not publicly available due to patient privacy and ethical restrictions.

Declarations

Ethics approval and consent to participate

This study was performed in accordance with the ethical standards of the Declaration of Helsinki and was approved by the Ethics Committee of Tehran University of Medical Sciences/Imam Khomeini Hospital (IR.TUMS.IKHC.REC.1404.2783). Written informed consent was obtained from the patient’s legal guardian for participation in this case report.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interest

The authors declare that they have no competing interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

The data supporting the findings of this study (including de-identified clinical information and imaging) are available from the corresponding author (Tahereh Jangjoo) upon reasonable request. The raw data are not publicly available due to patient privacy and ethical restrictions.