Ewing’s Sarcoma of Mandible: An Impressive Case of Spontaneous Mandible Regeneration

Ewing’s sarcoma (ES) is an uncommon aggressive bone malignancy that mainly affects children and adolescents. Mandible involvement is quite rare and usually represents metastasis from another skeletal site. Combined therapy including wide surgical resection and preoperative and postoperative chemotherapy has been demonstrated as the mainstay of therapeutic approach. As improved therapeutic modalities have significantly increased survival over the last decades, functional and esthetic reconstruction of the postmandibulectomy defect is usually necessary for patient’s total rehabilitation. We report a case of ES of the mandible with special consideration to the postresection spontaneous structural and functional regeneration of the mandible. How to cite this article Chatzistefanou I, Kabesi S, Paraskevopoulos K, Koliouskas D, Antoniades K. Ewing’s Sarcoma of Mandible: An Impressive Case of Spontaneous Mandible Regeneration. Int J Clin Pediatr Dent 2016;9(3):273-277.


INTRODUCTION
Ewing's sarcoma (ES) is a poorly differentiated primary bone malignancy that mainly affects children and adolescents. [1][2][3] Since its initial description by James Ewing in 1921, 4 ES remains a neoplasm of unclear pathogenesis. More than 50% of ES cases originate in the pelvis and long bones, 2,5,6 with distant dissemination at diagnosis being the rule rather than the exception, reflecting its aggressive biological behavior. 7 Facial bones are rarely involved (1-2%) and when do so their involvement usually represents metastatic disease from a primary skeletal lesion. [8][9][10][11] The mandibular ramus is the predominant site of occurrence, with only few cases reported in the anterior mandible or maxilla. [12][13][14][15][16][17] As improved therapeutic modalities have significantly increased survival, the current maxillofacial surgeon may need to face the challenge of an extensive surgical resection followed by a demanding functional and esthetic reconstruction of the ablative defect. We report a case of an ES developed in mandibular ramus of a 2-year-old girl with special consideration to the postmandibulectomy spontaneous structural and functional bone regeneration that made any plans for secondary mandible reconstruction unnecessary.

CASE REPORT
A 2-year-old girl with a 3-month history of a painless, progressively deteriorating swelling in the right mandible was referred to the Oral and Maxillofacial Department for evaluation. A fixed, hard in consistency, irregular, nontender, expansive mass of the right mandible was observed on clinical examination. No trismus or other signs of odontogenic infection were mentioned. The panoramic radiograph revealed a mixed radiolucent and radiopaque lesion with ill-defined borders extending from tooth 84 to the mandible angle. A computed tomography scan revealed a suspicious expansive lytic mass of approximately 4.0 × 4.5 cm with cortical erosion and periosteal reaction, suggesting a potential neoplastic process (Fig. 1). Magnetic resonance imaging (MRI) was used to evaluate soft tissue involvement (Fig. 2).
An open incisional biopsy of the lesion was performed, showing a high-density infiltration of small, round, hyperchromatic cells. Immunohistochemical staining with positive and negative controls was also performed, revealing positivity for CD99, CD117, vimentin, BCL2, and epithelial membrane antigen. Antibodies to cytokeratin ΑΕ1/3, synaptophysin, desmin, alpha smooth muscle, osteonectin, neuron-specific enolase, CD45, S100, Myo-D1, and CD34 were not reactive with the specimen. Histopathological and immunohistochemical findings were compatible with ES/primitive neuroectodermal tumor (PNET).
After diagnosis, the patient was referred to the Pediatric Oncology department for further care. Total body bone-scan revealed increased uptake in the right pelvis, which was considered as the primary ES lesion based on tumor's demographics. The patient was assigned to vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) (EURO-EWING 99) Oncology Protocol, receiving six courses of induction chemotherapy with an almost complete clinical response. A segmental mandibulectomy, extending from the neck of the right mandibular condyle to the distal edge of the right lower primitive 1st molar, was subsequently performed through a submandibular approach (Fig. 3). The uninvolved periosteum was carefully preserved. The tumor was resected with adequate free margins. We decided on delayed reconstruction of the bony continuity defects. The final histopathology report demonstrated only limited tumor residuals, confirming the tumor's response to the chemotherapeutic regimen. Postoperative chemotherapy was followed in consistency with the oncology protocol.
Clinical and radiological evaluation was performed 2 years after surgery, showing no evidences of locoregional recurrence. An imprecise reparative reaction of the healthy osseous tissue, leading to an almost complete structural and functional regeneration of the resected mandible, was reported (Fig. 4), making our initial plans for secondary reconstruction unnecessary. There was no significant facial asymmetry, while the patient reported no trismus and regular diet tolerance (Fig. 5). Dental implants, with or without distraction osteogenesis or autogenous bone-grafting techniques, would be used for rehabilitation of the permanent dentition and restoration of normal occlusion. Orthognathic surgery could also be taken under consideration if it was deemed necessary.

DISCUSSION
A rapidly extensive mass of the mandible in a young-age patient is the most dominant and invariable manifestation

IJCPD
of an ES involving the facial bones. 18 Pain, sensory dysfunctions, loosening teeth, or remitted fever may also be observed in some cases, increasing the suspicion of a malignant process. 9,19-21 Radiographically, ES could mimic a variety of pathological entities involving the jaws, and thus, it is aptly characterized as the "great imitator of bone pathology" by many authors. 22 An ill-defined, motheaten lytic lesion with or without cortical erosion and bone expansion is the most characteristic radiographic feature, 3,13,23-25 while the commonly seen long bone periosteal "onion skin" reaction is rarely encountered in jaw lesions. [14][15][16][17]26,27 Computed tomography scans and MRI have been well demonstrated as the most accurate approach for evaluating the extent of the bone destruction and the soft tissue involvement respectively. 3,7,24 Microscopically, ES is characterized by poorly differentiated, small, round, blue cells. 2,3,28,29 As ES has similar clinical, radiological, and histopathological features to various other malignancies of childhood, 8,10,30-32 immunohistochemical analysis is crucial for the final diagnosis. Recent genetic studies demonstrated that ES shares a common chromosomal translocation (t:11;22) (q;24:12) with PNETs in more than 90% of cases. 14,18,27,[33][34][35] The identification of this genetic abnormality, using antibodies to CD99 (Mic-2), is highly sensitive and specific for EW/PNET tumors. [36][37][38][39][40] Positive staining to vimentin, CD117, BCL2, EMA, FLI1, S-100, glycogen, or pancytokeratin could further support the diagnosis. 7,12,14,24,29,41 Although the overall prognosis is generally poor due to the tumor's aggressiveness and the high incidence of early hematogenous dissemination, 2,7,42 recent multidisciplinary therapeutic protocols and improved chemotherapeutic regimens have significantly improved the 5-year survival from less than 15% to more than 75%. 2,13,43,44 Combined therapy including wide surgical resection and preoperative and postoperative chemotherapy has been demonstrated as the mainstay of therapeutic approach. 28,45,46 Radiotherapy is generally avoided as it may induce secondary cancer formation or interfere with facial growth. [47][48][49] Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and actinomycin-D are the most widely used anticancer agents for definitive chemotherapy. 50,51 Demanding function and esthetic reconstruction efforts are usually required for maintaining an acceptable quality of life.
However, this is not the first time that an extensive spontaneous renaissance of a postresection mandible defect has been reported. [52][53][54][55][56][57] In contrast with other tissues, bone heals by regeneration rather than scar formation. Patient's age 54,56,58 and preservation of periosteum 53,54,56,59 have been described as the main factors that favorably influence this process.
Most cases of spontaneous mandible regeneration, reported in the literature, are in children and young individuals. [52][53][54][55]57 Ihan Hren and Miljavec, 60 studying the spontaneous healing in 33 patients with large mandible defects, demonstrated that bone-healing capacity was significantly higher (p = 0.006) in patients younger than 20 years. The fact that the cellular activity associated with sequential bone absorption and regeneration is higher in young patients, in conjunction with the presence of abundant mesenchymal cells that can differentiate into osteogenic cells, offers a satisfactory theoretical background for this statement. 54,56,58 Periosteum is a well-recognized source of osteoprogenitor cells, and thus, its preservation is crucial in the attempt to maximize the spontaneous regeneration potential. 53,54,56 Other factors including anatomical location of the defect, 60 genetic behavior, 52 and infection 55 have also been suggested as potential influential factors on mechanism of bone regeneration, but without adequate scientific documentation.  The mandible is the last facial bone that reaches skeletal maturity (14-16 years of age in females and 16-18 years of age in males), and thus, surgical management of jaw pathologic lesions affecting childhood or early adolescence may restrict the mandibular growth, leading to malocclusion and facial asymmetry. [61][62][63] It is widely accepted that there are three main growth sites of the mandible. The mandibular condyle is responsible for its vertical growth through endochondral bone formation. Length is gained through constant remodeling of the ramus in response to muscle forces. New bone is deposited at the alveolar process to support teeth development and eruption. 61,64 Preserving the condylar growth center, as in our case, could, however, minimize the potential of asymmetry or deformity.

CONCLUSION
The ES/PNET is a highly aggressive malignancy of childhood that rarely affects the bones of the maxillofacial region. As it is characterized by undefined clinical, radiological, and histopathological presentation, the immunohistochemical identification of specific chromosomal translocations is the basis of final diagnosis. Current multidisciplinary oncology therapeutic protocols have significantly improved patients' survival rates, while maintaining high standards of quality of life.