Abstract
The Ewing’s sarcoma family of tumors is a group of cancers that commonly arises in young adults during their second decade of life. It frequently involves the trunk and long bones of the body with primary Ewing’s sarcoma of the paranasal sinuses being exceedingly rare. We describe the case of a 39 year-old female with primary Ewing’s Sarcoma originating from the ethmoid sinus with intracranial extension into the anterior cranial fossa and the orbit. The radiologic and histopathologic profiles are presented with a review of the literature. To our knowledge, this is the second reported case with the tumor involving the anterior cranial fossa, but the only case where immunochemical staining and molecular genetic analysis are available for definitive diagnosis.
1
Introduction
Ewing’s sarcoma family of tumors (ESFT) consists of a wide spectrum of small round cell neoplasms of neuroectodermal origin. It is the second most common primary bone malignancy commonly affecting adolescents and young adults. While ESFT usually arises from the trunk and long bones, Ewing’s sarcomas (ES) involving the paranasal sinuses are exceptionally rare. The literature published on this topic mainly consists of case reports. There were a total of 26 cases reported where the primary tumor originated within the paranasal sinuses or the nasal cavity. In these reports, the maxillary sinus was the most common location involved. The ethmoid sinus, on the other hand, consisted of only 11 cases. We describe the relevant clinical findings of a rare case of ES arising from the ethmoid sinus with intraorbital and anterior cranial fossa extension. The MRI, CT and histopathological findings along with a discussion of treatment options for this type of tumor are addressed. In addition, a literature review of primary ES of the paranasal sinuses is performed.
2
Case report
A previously healthy 39-year-old female presented with a one year history of anosmia, nasal obstruction, severe left fronto-parietal headaches accompanied by nausea and vomiting, and the recent development of disinhibited behaviors. She was initially evaluated by physicians at an outside institution who referred the patient to the Cleveland Clinic after a CT scan revealed a large mass eroding through the right ethmoid sinus into the orbit and through the base of the skull into the anterior cranial fossa.
Otorhinolaryngological examination via flexible endoscope revealed a fleshy vascular mass in the right nasal cavity medial to the turbinates with extension superiorly to the roof and inferiorly to the floor of the nasal cavity with significant bowing of the nasal septum to the left. Neurological examination was significant for anosmia and mild diplopia on left lateral gaze. Gross extraocular movements were intact without signs of proptosis. The rest of the neurological exam was otherwise unremarkable.
Transnasal biopsy of the tumor was performed, and microscopic examination of the specimen revealed a population of epithelioid cells with uniformly round nuclei ( Fig. 1 ). Few mitotic figures were seen under high-power field and focal necrosis was present. The tumor cells were immunohistochemically positive for CD99 ( Fig. 2 ), neuron-specific enolase, S100, CD56, AE1/3, CAM5.2, CK5/6, p63, CK20, synaptophysin, chromogranin and GFAP but were negative for CK7, smooth muscle actin, desmin and myogenin. Furthermore, interphase fluorescence in-situ hybridization (FISH) demonstrated a translocation of the EWSR1 gene (22q12). The diagnosis of ES was made based on histopathology findings, immunoprofiles and the FISH results.
MRI of the brain and spine was also obtained, which revealed a large heterogeneous enhancing mass with contiguous extracranial and intracranial components ( Fig. 3 ). The extracranial portion measured 6.5 × 4.4 × 3.9 cm and was centered within the ethmoid air cells with eccentric extension inferiorly and posteriorly into the nasal cavity and the sphenoid sinus, respectively. Invasion into the medial portion of the right orbital wall was present with mass effect on the right medial rectus muscle and narrowing of the orbital apex. Additionally, the tumor extended superiorly into the frontal sinuses bilaterally and through the cribriform plate with the intracranial component measuring 4.4 × 7.1 × 6.6 cm. The intracranial tumor had both solid and cystic components with encasement of the anterior falx and extension across the midline. There was mass effect on both frontal lobes with posterior displacement of the corpus callosum leading to distortion of the third ventricle and the hypothalamus. However, there were no signs of metastatic disease involving the spine noted on MRI. Further metastatic evaluation including Technetium-99 whole body bone scan and FDG PET/CT scan from the base of the skull to the proximal femur was negative.
The patient was ultimately treated with combined radiotherapy and chemotherapy. A total radiation dose of 55.8 Gy was given in 31 fractions over the course of 41 days, and a chemotherapy protocol that consisted of Vincristine, Doxorubicin and Cyclophosphamide alternating with Etoposide and Ifosfamide every 2 weeks was given for a total of 14 cycles over the course of 9 months. The patient did experience some treatment related toxicities including anemia requiring multiple transfusions, recurrent neutropenic fevers, syncope and chronic diarrhea. Thirty-two months after the diagnosis and initiation of treatment, the patient recovered well without primary, regional or distant recurrence on multiple repeated imaging ( Fig. 4 ) and endoscopic exam.
2
Case report
A previously healthy 39-year-old female presented with a one year history of anosmia, nasal obstruction, severe left fronto-parietal headaches accompanied by nausea and vomiting, and the recent development of disinhibited behaviors. She was initially evaluated by physicians at an outside institution who referred the patient to the Cleveland Clinic after a CT scan revealed a large mass eroding through the right ethmoid sinus into the orbit and through the base of the skull into the anterior cranial fossa.
Otorhinolaryngological examination via flexible endoscope revealed a fleshy vascular mass in the right nasal cavity medial to the turbinates with extension superiorly to the roof and inferiorly to the floor of the nasal cavity with significant bowing of the nasal septum to the left. Neurological examination was significant for anosmia and mild diplopia on left lateral gaze. Gross extraocular movements were intact without signs of proptosis. The rest of the neurological exam was otherwise unremarkable.
Transnasal biopsy of the tumor was performed, and microscopic examination of the specimen revealed a population of epithelioid cells with uniformly round nuclei ( Fig. 1 ). Few mitotic figures were seen under high-power field and focal necrosis was present. The tumor cells were immunohistochemically positive for CD99 ( Fig. 2 ), neuron-specific enolase, S100, CD56, AE1/3, CAM5.2, CK5/6, p63, CK20, synaptophysin, chromogranin and GFAP but were negative for CK7, smooth muscle actin, desmin and myogenin. Furthermore, interphase fluorescence in-situ hybridization (FISH) demonstrated a translocation of the EWSR1 gene (22q12). The diagnosis of ES was made based on histopathology findings, immunoprofiles and the FISH results.
MRI of the brain and spine was also obtained, which revealed a large heterogeneous enhancing mass with contiguous extracranial and intracranial components ( Fig. 3 ). The extracranial portion measured 6.5 × 4.4 × 3.9 cm and was centered within the ethmoid air cells with eccentric extension inferiorly and posteriorly into the nasal cavity and the sphenoid sinus, respectively. Invasion into the medial portion of the right orbital wall was present with mass effect on the right medial rectus muscle and narrowing of the orbital apex. Additionally, the tumor extended superiorly into the frontal sinuses bilaterally and through the cribriform plate with the intracranial component measuring 4.4 × 7.1 × 6.6 cm. The intracranial tumor had both solid and cystic components with encasement of the anterior falx and extension across the midline. There was mass effect on both frontal lobes with posterior displacement of the corpus callosum leading to distortion of the third ventricle and the hypothalamus. However, there were no signs of metastatic disease involving the spine noted on MRI. Further metastatic evaluation including Technetium-99 whole body bone scan and FDG PET/CT scan from the base of the skull to the proximal femur was negative.
The patient was ultimately treated with combined radiotherapy and chemotherapy. A total radiation dose of 55.8 Gy was given in 31 fractions over the course of 41 days, and a chemotherapy protocol that consisted of Vincristine, Doxorubicin and Cyclophosphamide alternating with Etoposide and Ifosfamide every 2 weeks was given for a total of 14 cycles over the course of 9 months. The patient did experience some treatment related toxicities including anemia requiring multiple transfusions, recurrent neutropenic fevers, syncope and chronic diarrhea. Thirty-two months after the diagnosis and initiation of treatment, the patient recovered well without primary, regional or distant recurrence on multiple repeated imaging ( Fig. 4 ) and endoscopic exam.
3
Discussion
ESFT represents a group of small round blue cell neoplasms of neuroectodermal origin under varying degrees of neuronal differentiation with ES of the bone being the least differentiated form . Other tumors of this family include extraskeletal or soft tissue ES, peripheral primitive neuroectodermal tumors of bone (pPNET) and Askin’s (thoracopulmonary) tumors . On the genetic level, ES is characterized by translocation of the EWS gene located on 22q12, and fusion with the ETS family of genes including FLI1, ERG, ETV1 and others. Most frequently, the EWS gene is fused with the FLI1 gene located on 11q24 resulting in a t(22;11) translocation leading to a EWS–FLI1 fusion gene seen in 85% of the cases of ES . The fusion genes are detectable using either FISH or reverse transcriptase polymerase chain reaction. Furthermore, the expression of cell surface glycoproteins CD99/MIC2 by the tumor cells is present in virtually all cases of ES and pPNET, and is readily detectable by monoclonal antibody O13 (anti-CD99 antibody) with a sensitivity of 100% for ES (though specificity is lower), making it an important diagnostic marker for ES and pPNET . Therefore, the definitive diagnosis of ES should be based on a combination of histological findings, molecular genetic evaluation for EWS gene translocations, and positive CD99 immunochemical staining.
Clinically, ES is the second most common primary malignancy of bone in children under the age of 20 , and most frequently arises in the trunk and diaphysis of long bones with pelvis, ribs, femur and humerus being the predominant sites . ES of the head and neck region is unusual and consists of approximately 4% of cases, with primary ES originating from the paranasal sinuses being exceedingly rare . A review of the world literature examining ES of paranasal sinuses and nasal cavity revealed a total of 26 reported cases ( Table 1 ). Of these cases, the age at the time of diagnosis ranged from 9 to 44 years old, with most patients being under the age of 20 . The majority of primary ES of paranasal sinuses develop from the maxillary sinus . Out of the 26 cases, there were a total of 11 cases where the primary location of tumor involved the ethmoid sinus . In most instances, the tumor had local extension to the maxillary sinus, frontal sinus, nasal septum, nasal cavity, orbit, base of skull or a combination of the above. There was only one case where the tumor was isolated to the sphenoid sinus , and three cases where tumors were limited within the nasal cavity . Interestingly, these nasal cavity tumors were later determined to be extraskeletal ES without any bony involvement. There were also a total of 8 cases where the tumor extended into the orbits (4 cases from the ethmoid sinus, 2 cases from the maxillary sinus and 2 cases from both) and a total of 5 cases with intracranial/skull base involvement (1 case from the maxillary sinus, 3 cases from the ethmoid sinus, 1 case from both). Comparatively, patients with ethmoid sinus ES seemed to have a higher propensity for local extension of the tumor into the orbit and the cranium. This is likely due to the limited sinus space of the ethmoid sinus resulting in the direct invasion of the tumor into the surround structures either through the thin bony lamina papyracea into the orbit, or through the skull base into the cranium. On the other hand, maxillary sinus has a larger sinus space and much thicker infraorbital bone making these expansions less likely. When intracranial extension occurred, the most common area of involvement was the middle cranial fossa. To our knowledge, there was only one other report of ES extending into the anterior cranial fossa by Howard et al. in 1985. However, at the time, the diagnosis was made solely based on histopathological and electron microscopy findings without other immunochemical staining or molecular genetics evaluation.
