Skull and Spinal Ewing's Sarcoma in Children: An Institutional Study.

BACKGROUND: Ewing's sarcoma is a disease of children and young adults and occurs most often in bone and soft tissues. The intracranial and spinal manifestation of the disease is rare and reported incidence is 1%-6%. AIMS AND
OBJECTIVES: We conducted this study to determine the surgical outcome of children with skull and spine Ewing's sarcoma (SSES).
METHODS: This is a prospective analysis of 13 patients of SSES who reported to the Department of Neurosurgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India, between 2014 and 2016. All cases after detailed examination, magnetic resonance imaging, and computed tomography scan were subjected to surgery followed by adjuvant therapy comprising chemotherapy and radiotherapy. Outcome was analyzed at 6 months as well at latest follow-up. Neurological function, local recurrence, primary or secondary nature of the disease, distant relapse, and treatment-related complications were analyzed in this study.
RESULTS: There were eight female and five male patients with a mean age of 12 years (ranging from 4 to 8 years). Pain was the common presenting feature in all cases. Focal neurological deficits corresponding to the anatomical location was seen in six patients. These 13 cases were distributed anatomically as four cases involving the cloves, two cases with occipital bone and lobe involvement, one case of parietal bone and lobe involvement, and six cases of spinal involvement. Surgery was performed in all cases where gross total excision (Ozge C, Calikoglu M, Cinel L, Apaydin FD, Ozgür ES. Massive pleural effusion in an 18-year-old girl with Ewing sarcoma. Can Respir J 2004;11:363-5), near-total excision, and subtotal excision was achieved in these 13 cases (Steinbok P, Flodmark O, Norman MG, Chan KW, Fryer CJ. Primary Ewing's sarcoma of the base of the skull. Neurosurgery 1986;19:104-7). Subsequently all cases underwent multiagent chemoradiotherapy. Postsurgery pain subsided in 12 (92%) of patients. Ten patients maintained or improved motor function. In seven cranial cases and in six spinal cases, four cases showed improvement whereas three (23%) had deterioration of motor function.
CONCLUSIONS: Surgical outcome of SSES in short-term follow-up is good with current recommended management regimen of maximum excision followed by chemo and radiotherapy. However, metastasis is not uncommon.

INTRODUCTION

Ewing’s sarcoma (ES) is a highly malignant round cell tumor arising from the bone. James Ewing first described it in 1921 as “diffuse endothelioma of bone.” Pediatric small round blue cell tumors of the central nervous system (CNS) include several families of malignant tumors. A relatively rare malignancy, the ES, is the second most common bone tumor in the pediatric age group. Intracranial presentation of ES is rare, with a reported incidence of 1%–6% of all cases.[1] The cranial lesions commonly involve the calvarium.[23] The skull base remains an infrequent site of primary occurrence.[345]

CNS metastases, which account for 2.3%, occur for bone and soft tissue tumors. The incidence is second to kidneys and adrenal glands metastasis due to ES[3]. These statistics illustrate well the rarity of brain metastases from bone and soft tissue neoplasms in pediatric population. Metastatic lesions carry poor prognosis; the overall mean survival is estimated at 7–16 months, with the majority surviving less than 12 months. Primary ES arising from calvarial bones account for only 1%–4% of all ES.[3]

MATERIALS AND METHODS

This study was taken up with purpose to determine the surgical outcome in children with skull and spine Ewing’s sarcoma (SSES). It was a prospective study of 13 patients who reported to the Department of Neurosurgery, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India, between 2014 and 2016. All cases after detailed examination, skeletal survey, magnetic resonance imaging (MRI), and computed tomography (CT) scan were subjected to surgery followed by adjuvant therapy comprising chemotherapy and radiotherapy. Institutional protocol of chemo and radiotherapy was followed. Outcome was analyzed at 6 months and at latest available follow-up. Neurological function, local recurrence, primary or secondary nature of the disease, distant relapse, and treatment-related complications were analyzed in this study.

Surgical protocol

Surgical protocol composed of maximum safe excision of lesion along with the involved bony segment. Duroplasty was performed with neighboring pericranial tissue or fascia lata.

Institutional radiation protocol

Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy were given for 5–7 weeks.

RESULTS

There were eight female and five male patients with a mean age of 12 years (ranging from 4 to 18 years). Pain was the common presenting feature in all cases. Focal neurological deficits (FNDs) corresponding to the anatomical location were seen in six patients. These 13 cases were distributed anatomically as four cases involving the clivus, two cases with occipital lobe involvement, one case of parietal lobe involvement, and six cases of spinal involvement. Surgery was performed in all cases; gross total excision,[6] near-total excision,[3] and subtotal excision[3] were achieved in these 13 cases. Subsequently, all cases underwent multiagent chemoradiotherapy. Postsurgery pain subsided in 12 (92%) patients. Ten patients maintained or improved motor function. In seven cranial cases and in six spinal cases, four cases showed improvement whereas three (23%) had deterioration of motor function. During follow-up (mean 9 months), of 13 patients, 4 (31%) had disease-free interval. Five patients (38%) developed metastatic disease. Of 13 patients, 3 (23%) developed a local recurrence. One of these patients had paraplegia associated with the local recurrence. Four patients developed treatment-related complications.

Illustrative case 1

We present an illustrative case of a 10-year-old child who presented with a history of intermittent headache and vomiting and progressive restriction of movements of the right eye for 3 weeks. The child’s neurological deficits included right-sided complete IIIrd, IVth, and VIth nerve palsies and decreased sensations in the right V1 and V2 divisions of the trigeminal nerve. Radiologically there was a lesion noted, involving the sphenoid sinus and the clivus, and sphenoid sinus was destructed [Figures 1A–B and 2A–C].

Figure 1

(A) Bone windows of CT brain showing evidence of a destructive lesion involving the sphenoid sinus (B) and clivus

Figure 2

(A) Axial section of a T1 weighted, gadolinium-enhanced MRI of the brain showing a contrast enhancing lesion in the sphenoid sinus, sella, and clivus. (B) Coronal section of the T2-weighted image (WI) showing bilateral encasement of the cavernous carotid artery. (C) Sagittal section of a T1WI showing carpeting of the lesion onto the clivus

Decompression of the lesion was performed by microscopic, transnasal–transsphenoidal approach. Frozen section report of a malignant round cell tumor was obtained, and in view of infiltrative nature of the lesion, decompression was restricted to limited debulking. Histological examination showed sheets of small, round cells organized into lobules by variably hyalinized and vascular septae [Figure 3A–D].

Figure 3

(A) The histopathology section showing small round cells arranged in sheets and separated by broad bands of collagen. H&EX40. (B) The cells were small round with hyperchromatic nuclei and scant cytoplasm. H&EX100. (C) The cells were brightly positive for CD99. HRP Polymer CD99;100. (D) The EWS break apart FISH analysis showed almost 30% break apart signals

Illustrative case 2

This 11-year-old child, a previously diagnosed case of ES, presented with recurrence of the tumor and pain at the site of the swelling with no associated FNDs [Figures 4–6].

Figure 4

Picture showing swelling in the scalp in the midline involving the parietal bone with previous operative healed scar seen

Figure 6

Intraoperative picture of the case, showing highly vascular nature with a well defined capsule

CT brain plain involving the skull bone in parietal region with intracranial extension with destruction of the bone

DISCUSSION

The Ewing family of tumors, consisting of ES and its biological counterpart, the peripheral primitive neuroectoderm tumor, constitute an uncommon malignancy of childhood and adolescence with a predilection for soft tissue and bones of the trunk and extremities.[6789] ES of the cranial bones is a rare entity with only 71 cases reported so far in published literature. It has preponderance for males in the first and second decades of life, with a peak incidence between 5 and 13 years.

Extracranial metastasis from a primary ES in the cranium is exceptional, whereas cranial metastasis from extracranial ES is common.[10]

In ES, classical skull and spine involvement is due to metastasis from the primary focus of bone and soft tissue malignancy. ES is the second most frequent malignant bone tumor in children and is one of the common sarcoma metastasis to brain with a quoted incidence of 56%.[7]

The epidural space or intradural parenchyma gets involved as an extension of the overlying structure.

The peculiarity of our series is that all were of purely either skull or spine involvement but not as metastatic deposits [Figure 7].

Figure 7

Showing Extramedullary tumor involving D12 to L1 and enhancing on contrast

However, there is a second mechanism of spread reported in literature, which is said to be of hematogenous spread that leads to direct brain a spinal cord deposit and no overlying bone involvement.[1]

Anatomically in the skull, the parieto-occipital region is the most common area of involvement seen but also involves the frontal and temporal bone. Skull base predilection is negligible. In this series however, clivus, with six patients having the site for ES, was the most common region of skull involvement, which is definitely a noteworthy point to be noted in this series.

Tumors in the Ewing’s family of sarcomas are made of primitive cells, which are cells that have not yet been decided what type of cell they are. They look blue to a pathologist because of the staining that is used when identifying the cancer, so the cells are referred to as “small round blue cells.” The Ewing’s family of sarcomas includes the following:

ES of the bone

Extraosseus ES, also referred to as extraskeletal ES (tumor growing outside of the bone)

Primitive neuroectodermal tumor

Peripheral neuroepithelioma

Askin’s tumor (ES of the chest wall)

Atypical ES

The histopathological examination showed round-to-oval cells arranged in lobules, separated by a thin vascular channel, having vesicular nuclei, with indistinct nucleoli. Mitotic figures were seen with focal areas of necrosis. Few bony trabeculae were seen embedded in the tumor island. Fat globules seen were positive for periodic acid Schiff staining.

Clinically localized pain is the hallmark of such tumors in kids. This is attributed to the involvement of free nerve endings at the site of tumor. With parenchymal involvement, however, focal neurological defect becomes evident corresponding to the anatomical localization. In this series, 13% of skull cases has FND in addition to pain all of which correlated to the location of tumor. In the six spinal cases, 16% has FND. However, progression of FND was seen in 23% of cases postsurgery and chemo and radiotherapy.

Radiologically, the X-ray shows a lytic lesion with mottling and erosion.

Though a classical onion-peel appearance is described, it is hardly seen. CT scan has a bone destruction appearance and osteomyelitis-like picture.

MRI shows typically a tumor, and parenchyma is usually seen separated and pushed from it in case of the laters involvement. Bone scan should always be performed in a suspected case of SSES. Whole-body positron-emission tomography (PET) scan reveals a focus in extracranial bone or soft tissue [Figure 8]. T1 sequence is hypointense and T2 is hyperintense. Contrast PET lesion appears circumscribed and as ↑ uptake. PET, however, is not performed routinely.

Figure 8

Bone scan images prior to starting adjuvant therapy demonstrating increased uptake in the skull base corresponding to the residual tumor. Note the absence of increased uptake in any other area

Surgery remains the best treatment modality for such tumor. Classically the dictum of maximally safe resection is followed if it is not amenable to complete excision. A study from the national cancer database by Miller et al.[11] showed that surgery at one resulted in the best overall survival for patients with ES of bone. However, due to involvement of eloquent structures, this may not be possible always in SSES where adjuvant therapy needs to be given.

Chemotherapy regimen followed in SSES is the standard combination of vincristine, cyclophosphamide, doxorubicin alternating with ifosfamide, and etoposide. In SSES, because there is a rapid increase leading to serious symptoms of raised intracranial hypertension and FND, preoperative chemotherapy to shrink the size of ES is not advisable as in the case of extracalvarial bony ES.[8]

However postsurgical chemo is always advised. We followed our regimen of vincristine, cyclophosphamide, doxorubicin alternating with ifosfamide, and etoposide [Table 1].

Table 1

Institutional chemotherapy protocol used at our institute

Agent	Regimen A	Regimen B	Regimen C
Vincristine	40	16	48
Doxorubicin	375	375	450
Cyclophosphamide	21600	9600	17600
Ifosfamide	0	90000	140000
Etoposide	0	5000	5000

This is the recommended regimen with 5-year survival rate of 70%.[12]

Radiotherapy with an institutional protocol as mentioned earlier has been given in all our 13 cases. The current literature survey for radiotherapy in ES suggests proton beam therapy. It has an advantage for high precision therapy, especially in sensitive structures such as brain and spinal cord.[13]

In this study, all were primary ES affecting CNS. Evaluation also did not reveal any other site of focus in the skeletal system.

Multimodal approaches, including surgery, radiotherapy, and intensive multiagent chemotherapy, have remarkably improved survival in patients with localized ES. By contrast, the prognosis of patients with disseminated ES remains poor.

CONCLUSION

All the cases studied in our study are primary ES affecting CNS. Surgical outcome of ES in short-term follow-up is good with current recommended management regime of maximum excision followed by chemo and radiotherapy. However, metastasis is not uncommon.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.