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Abstract
Paediatric sinonasal tumours comprise numerous aetiologies. Ewing’s sarcoma (ES) consists of a malignancy of neuroectodermal origin. This type of sarcoma affects mainly children and adolescents and can assume the skeletal or extra-skeletal form. Primary ES of head and neck is extremely rare, accounting for only 4%–9% of all cases. So far, as much as we know, only a few cases of sinonasal ES have been reported in literature. The authors present a case of a previous healthy 12-year-old girl who presented with a rapidly growing and expansive frontal mass and unilateral nasal obstruction. Immunohistochemical, molecular and cytogenetic analysis of the lesion showed diffuse expression of CD56 and CD99 on tumour cells and a translocation involving chromosome 22q12, confirming ES diagnosis.
- ear, nose and throat/otolaryngology
- paediatrics (drugs and medicines)
- chemotherapy
- head and neck cancer
- paediatric oncology
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- ear, nose and throat/otolaryngology
- paediatrics (drugs and medicines)
- chemotherapy
- head and neck cancer
- paediatric oncology
Background
Sinonasal neoplasms of paediatric age comprise a wide range of differential diagnoses, making their diagnosis complex, either by their unspecific and similar clinical presentations or by their rarity. Ewing’s sarcoma (ES) consists of a small round and blue cell malignancy of neuroectodermal origin. It comprises the same spectrum of other neoplastic diseases that share the same mesenchymal cellular origin and histopathological features (known as the ES family of tumours (EFT)), which also includes peripheral primitive neuroectodermal tumour and Askin tumour (small cells malignancy of thoracopulmonary region)).1 ES is an aggressive tumour that affects mainly children and adolescents. In England, EFT is responsible for 2.8% of all tumours in individuals from 15 to 19 years old. In the USA, 50% of all cases of EFT affect people aged 10–20 years. Furthermore, it seems to have a slight predilection for males (1.5 male:1 female).2 3 ES can assume skeletal or extra-skeletal forms. The first one, much more common, affects mainly the long bones of the extremities (predominantly the pelvis, axial skeleton and femur).4 The less common extra-skeletal form involves soft tissues. Primary ES of head and neck is extremely rare, accounting for only 4%–9% of all cases. Besides, sinonasal localisation is even more rare and only a few cases are reported in literature. Diagnosis is usually confirmed by cytogenetic or molecular genetic studies. Almost all cases express a translocation involving the EWSR1 gene (ES gene) on chromosome 22q12, which is a hallmark of diagnosis.5 6 Treatment guidelines consist primarily on poly-chemotherapy followed by surgery and/or radiotherapy.
Although rare, the EFT represents the second most common primary bone malignancy in childhood, after osteosarcoma.7
Here we present a rare case of a sinonasal extra-skeletal ES of a 12-years-old girl who was successfully treated with chemotherapy and radiotherapy.
Case presentation
A 12-year-old girl presented to her family doctor with a 3 months history of complaints of frontal swelling and pain, persistent bilateral nasal obstruction and recurrent frontal headaches. Topical nasal corticosteroid and a nasal saline irrigation were prescribed, with mild improvement. One month later, she presented to our emergency department with left eyelid oedema, ptosis and xerophthalmia. There were no history of nasal discharge, nasal bleeding, hyposmia or fever. She had no relevant medical or family history. On examination, a midline located frontal mass was noted (figure 1). This mass was soft, floating and tender to touch without any cutaneous inflammatory signs. She also showed a mild left eyelid oedema and ptosis with incomplete ocular opening. Anterior rhinoscopy revealed a whitish polypoid mass arising from and occupying the left middle meatus. It was soft, did not bleed easily when touched and completely obstructed left nasal cavity. No changes were found in the contralateral nasal fossa and there were no signs of ocular and visual impairment. We found no cervical masses or adenopathies.
A 12-year-old girl with a soft, floating, tender to touch and midline-located frontal mass; A mild left eyelid oedema and ptosis are also visible.
Investigations
The patient underwent head and neck CT and MRI that showed an expansive lesion in the left frontal sinus that extended to frontal epicranial soft tissues and ipsilateral ethmoidal cells with marked bony erosion of anterior and posterior walls of frontal sinus and superior and medial walls of left orbit. The lesion also extended into the intraorbital and intracranial compartments, causing deformation of the left subfrontal cerebral parenchyma and discrete left eye proptosis. There was no involvement of the optic nerve (figures 2 and 3). After imaging studies, she was submitted to endonasal endoscopic biopsy under general anaesthesia. Intraoperatively, we found a large whitish polypoid mass completely occupying the left middle meatus. We performed a left uncinectomy and a maxillary antrostomy with aspiration of a large amount of very thick mucous. Then, we opened suprabullar cells with aspiration of brown glue from the frontal recess. A laboratorial study (with complete blood count, hepatic and renal function tests, urinalysis, C-reactive protein and sedimentation rate blood levels and immunological study) and optical coherence tomography were normal. Microbiological analysis of left maxillary sinus showed no bacterial growth. Histological analysis showed the presence of fragments of malignant small, round and blue cells with four mitotic figures per 10 consecutive high-power fields and extensive necrotic areas. An immunohistochemical study revealed diffuse expression of CD56 and CD99 in tumour cells, without a positive expression of chromogranin, synaptophysin, pancytokeratin, CD45, CD20, CD3, terminal deoxynucleotidyl transferase, desmin and myogenin. Cytogenetics showed the presence of a translocation in locus 22q12.1-q12.2, leading to definitive diagnosis of ES.
CT: (A) presence of an expansive lesion centred on the left frontal sinus, causing moulding and bone erosion of anterior and posterior walls; this lesion seems to have a small component projected at the anterior floor base, through the rupture of the internal cortex. (B) Extension of the lesion to the left anterior ethmoid and to the roof of the left orbit, in an extra-conal location, leading to bone erosion of superior and medial walls and slight ocular proptosis. (C) Tridimensional reconstruction.
MRI: (A–C) expansive lesion centred on the left frontal sinus, which causes bone erosion and erodes the superior and medial orbit walls, with apparent intraorbital extension, causing moulding of the left superior rectus muscle and discrete left eye proptosis. The left optic nerve presents normal morphology and signal emission. Extension of the lesion to the left anterior ethmoid. Inflammatory opacification of left maxillary sinuses. (C,D) An extra-axial intracranial extension is associated, causing deformation of the left subfrontal cerebral parenchyma without causing evident parenchymal oedema. This lesion is characterised by presenting a hypo-signal in T1, heterogeneous signal in T2 and homogenous contrast. No images suggestive of empyema or infectious collections are identified. No other changes in the brain parenchyma are visible. Cerebrospinal fluid circulation pathways show adequate configuration for the age group, with no signs of hydrocephalus or space conflict in the foramen magnum.
Treatment
After histologic diagnosis of ES, the patient was immediately referred to a national paediatric oncology centre (Instituto Português de Oncologia). Due to the inoperable nature of the lesion, the adolescent was proposed for neoadjuvant chemotherapy followed by radical radiotherapy. As recommended by European Ewing tumour Working Initiative of National Groups (Euro-E.W.I.N.G.) protocol, she started neoadjuvant multi-agent chemotherapy with vincristine, ifosfamide, doxorubicin and etoposide (VIDE). At the time of the second cycle, she developed febrile neutropenia complicated with frontal left periorbital cellulitis, which was conservatively treated. At the end of sixth cycle, she maintained some radiologic signs suggestive of persistent viable tumour mass for which it was decided to treat with radiotherapy, concomitant with chemotherapy with vincristine, actinomycin and ifosfamide (VAI). Since it would be a quite mutilating surgery, with a high risk of complications, non-surgical therapy was preferred (which was a shared decision between the patient, her relatives and all the professionals involved).
Five months later, immediately after conclusion of radiotherapy and eight cycles of VAI chemotherapy, imagiologic follow-up with magnetic resonance imaging (MRI) and positron emission tomography (PET) showed no signs of tumorous persistence (figures 4–6).
Frontal and lateral views, 8 months after cessation of treatment. The patient is performing magnetic resonance imaging monthly, without evidence of local, regional or metastatic active disease so far.
Radiologic follow-up with magnetic resonance imaging (post-treatment).
Radiologic follow-up with positron emission tomography (post-treatment).
Outcome and follow-up
At the time of writing this article, 17 months after diagnosis and 8 months after cessation of treatment, there is no evidence of local, regional or metastatic disease (figures 4–6).
Discussion
Paediatric sinonasal neoplams comprise a wide range of differential diagnoses, making their diagnosis complex, either by their unspecific and similar clinical presentations or by their rarity. Although rare, the EFT represents the second most common primary bone malignancy in childhood, after osteosarcoma.7 This case exemplifies the difficulty in clinical suspicion of these entities, especially by general practitioners.
For unknown reasons, this group of tumours follows an ethnic distribution and tends to affect more caucasians comparatively to black and asian people. It is reported that interethnic differences for the EWSR1 gene can explain geographical and ethnic differences in ES incidence.8 9 So far, EFT has not been associated with any familial or congenital syndrome and it seems that a minority of cases can be associated with an inherited cancer predisposition. There are no specific environmental exposures that have been linked to EFT but treatment of a primary cancer during childhood, specially with radiation therapy, seems to increase the risk of ES.10 11 Note that our patient did not present any personal or familial history of cancer or congenital syndrome.
This family of tumours also share some unique specific chromosomal translocations, which supports a common cellular origin. Virtually all cases of ES express genetic translocations that mostly involves chromosome 22q12, particularly within the EWSR1 gene. This gene encodes the EWS protein, an RNA-binding protein that is believed to mediate the interaction with RNA or single-stranded DNA. By fluorescence in situ hybridisation technology, it has been proved that a specific chromosomal translocation between chromosomes 11 and 22, t(11;22)(q24;q12), occurs in 85%–90% of cases of ES, which results in fusion of EWSR1 with the FLI1 gene.6 When this translocation is not present, it is reported that there are analogous translocations that results in fusion of the EWSR1 gene to other genes of the ETS family. Some of these translocations are quite sensitive and specific tumour diagnostic markers of the EFT. Today it is believed that p53 or p16 mutations may also have a prognostic value.12 Our case showed translocation in locus 22q12.1-q12.2, confirming diagnosis.
Presenting symptoms depend on location and size of the lesion. A painful and rapid growth mass is the classic presentation. Ten to twenty percent of cases present with constitutional symptoms and fever is usually a sign of advanced disease. Pathologic bone fractures can happen in 10%–15% of children at presentation.13 14 Howarth et al reported a case of a 9-year-old boy who presented with nasal fracture and subsequent lateral nasal wall hematoma that revealed an underlying ES.15 Metastatic disease occurs at presentation in less than 25% and primary head and neck localisation is associated with less rate of metastasis (12.5%).16
Extra-skeletal variant of ES affects soft tissues and is responsible for about 25% of all cases of ES. Comparatively to skeletal disease, extra-osseous is much more uncommon, affects older children and has a predilection for females.2 17–19 Primary head and neck ES is extremely rare and comprises only 4%–7% of all cases of ES. In this anatomic region, jaw and skull bones are the most involved structures. Head and neck ES usually presents in patients younger than 30 years of age, with a peak incidence between 10 and 15 years old.15 20 So far, as much as we know, only a few case reports of sinonasal ES have been reported in literature. Furthermore, there have been only 2 cases of ES arising from the middle turbinate.21 22
With modern multidisciplinary treatment, a 5-year survival rate has increased significantly in the last decades. Among patients presenting with nonmetastatic disease, long-term survival can reach 70%–80%. In those patients presenting with metastases long-term survival decreases to 37%. Euro-E.W.I.N.G. currently recommends alternate cycles of VIDE complemented with local control which can include surgical excision and/or radiotherapy. In localised disease, complete excision associated with negative margins leads to better outcomes.23 24 Our patient successfully completed six cycles of neoadjuvant multi-agent chemotherapy with VIDE and VAI regimens followed by radiotherapy. After conclusion of radiotherapy and eight cycles of VAI chemotherapy, an imagiologic follow-up with MRI and PET showed no signs of tumorous persistence.
Extra-skeletal variant, age inferior to 10 years old, a small T, location in a leg or arm or good response to chemotherapy are factors associated with better prognosis.25 26
In the face of rapidly progressive masses of atypical location, we highlight the importance of a high level of clinic suspicion. Biopsy and detailed histological analysis of the lesion can make the difference in a rare and high-mortality pathology.
Learning points
Ewing’s sarcoma (ES) consists of a small round and blue cell malignancy of neuroectodermal origin that affects mainly children and adolescents.
Primary head and neck localisation is extremely rare, accounting for only 4%–9% of all cases. ES of the sinonasal tract is even rarer. In the face of rapidly progressive masses of atypical location, we highlight the importance of a high level of clinic suspicion.
Detailed histological analysis of the lesion can make the difference between a rare and high-mortality pathology and a multidisciplinary approach, and the evaluation of radiotherapy and surgery comorbidities and complications are of extreme importance, particularly in paediatric patients.
Acknowledgments
Dr Joana Guimarães, consultant at Instituto Português de Oncologia, Porto, Portugal.
References
Footnotes
Contributors IEC planned and conceived of the presented idea. IEC, AFL and ASM participated in planning and design of this study. BR encouraged IEC to investigate Ewing’s sarcoma in paediatric age and supervised the findings of this work. Acquisition of data was made by IEC and ASM. The analysis and interpretation of data was responsibility of IEC and AFL. IEC wrote the manuscript with support from AFL, ASM and BR. All authors discussed the results and contributed to the final version of manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.