|Year : 2006 | Volume
| Issue : 1 | Page : 31-35
Ewing's sarcoma of the mandible
P Sharada, HC Girish, HS Umadevi, NS Priya
Department of Oral and Maxillofacial Pathology, V.S. Dental College, Bangalore, India
Department of Oral and Maxillofacial Pathology, V.S.Dental College & Hospital, K R Road, V.V Puram, Bangalore
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Ewing's sarcoma is a highly lethal and the sixth most common malignant neoplasm of bone and soft tissue, composed of small round cells of uncertain histogenesis. However, recent studies suggest that Ewing's Sarcoma is a neuroectodermally derived tumor with various degrees of differentiation of the primitive neural tissue. A case of Ewing's sarcoma of mandible is presented and controversial issues in the histogenesis and molecular biology of Ewing's sarcoma are focused, with emphasis on ultrastructure, immunohistochemical analysis, and prognostic indicators.
Keywords: Ewing′s sarcoma, histogenesis, round cell tumor, EWS gene.
|How to cite this article:|
Sharada P, Girish H C, Umadevi H S, Priya N S. Ewing's sarcoma of the mandible. J Oral Maxillofac Pathol 2006;10:31-5
|How to cite this URL:|
Sharada P, Girish H C, Umadevi H S, Priya N S. Ewing's sarcoma of the mandible. J Oral Maxillofac Pathol [serial online] 2006 [cited 2020 Apr 1];10:31-5. Available from: http://www.jomfp.in/text.asp?2006/10/1/31/37800
| Introduction|| |
Ewing's sarcoma was first described in 1921 by James Ewing who believed it to be a tumor of endothelial origin and described it under the term 'diffuse endothelial myeloma' . Ewing's sarcoma is a `distinctive primary malignant tumor of bone accounting for 4-15% of all primary bone tumors and 1 % of all malignant tumors in children . About two thirds of all Ewing's sarcomas appear in the lower skeleton and involvement of facial skeleton is quite rare (0.74%), with mandible being the most commonly affected bone .
| Case report|| |
A 15-year-old boy was referred with a swelling in the right side of the jaw, since 6 months. The swelling was initially small, but gradually enlarged to the present size. The medical and dental history was non-contributory.
Extra oral examination revealed facial asymmetry on the right side, extending superiorly upto ala tragus line, inferiorly upto right angle and ramus of the mandible, crossing the midline up to 2 cm [Figure - 1]. On Intraoral examination, a diffuse large swelling was seen measuring about 7cm x 6cm, extending from 34 to 48, obliterating the buccal sulcus. It was firm in consistency with mild tenderness and without paraesthesia [Figure - 2]. Teeth 35, 36, and 37 showed grade II mobility and 41-48 showed grade III mobility.
Occlusal radiograph showed floating teeth arrangement [Figure - 3]. OPG revealed an osteolytic lesion with ill-defined borders, without any significant sclerosis [Figure - 4]. Hemoglobin level was 8.2% and other routine hematological findings were within normal limits. The provisional diagnosis of sarcoma was made.
Incisional biopsy was performed under local anesthesia and subjected to histopathological examination. On microscopic examination, sections showed sheets of uniform, small, round cells arranged in diffuse pattern, with indistinct outline, scanty cytoplasm, and well-defined nuclear outline, with round to oval nucleus and inconspicuous nucleoli. Fibrovascular septa were seen between the nests of tumor cells. The round cells showed ill-defined cellular borders and well defined nuclear borders. Disperse chromatin clumping was seen. Mitotic figures were rare. A diagnosis of malignant small round cell tumor was made based on the above histopathological findings [Figure - 5],[Figure - 6],[Figure - 7],[Figure - 8]
The sections were stained with PAS (Periodic Acid Schiff) and intracytoplasmic glycogen was demonstrated [Figure - 9]
A panel of immunohistochemical markers namely CD99, CK, CD3, CD20, CHR, MPO, desmin, Tdt, and SYN were used to rule out other small round cell tumors. Tissue sections showed positive expression for CD99 (MIC2), with characteristic membranous pattern [Figure - 10].
Demonstration of intracytoplasmic glycogen by PAS and IHC staining positivity for CD99 confirmed the diagnosis of Ewing's Sarcoma of mandible.
Patient was treated with neoadjuvant chemotherapy followed by surgical excision and reconstruction.
On gross examination, excisional specimen showed soft, grayish white tissue with focal necrotic and hemorrhagic areas. Microscopic examination of the excised specimen confirmed the pre-operative diagnosis of Ewing's sarcoma.
| Discussion|| |
Ewing's sarcoma, a round cell tumor, constitutes less than 3% of all cases originating in the jaws. Histogenesis of Ewing's sarcoma remains obscure and unequivocal despite the extensive histochemical, tissue culture, and ultrastructural studies. It has been postulated as originating from angioblastic, embryonic reticulum cell of basement membrane myeloid cell, and undifferentiated pluripotent stem cell .
Ewing suggested the hemangiogenic origin, due to the presence of desmosomal type structures and basement membrane like material or alkaline phosphatase activity, described in hemangiomatous neoplasms. There is no clear evidence that the vessels present are really part of the tumor and there is no definite proof of a vascular origin .
Oberling considered the embryonic reticulum cell of bone marrow as the basic tumoural element, because of presence of dark cells as maturating reticulum cells. Some authors considered the dark cells to represent degenerative changes of the principal cell .
Kadin and Bensch, based on ultrastructure of tumor cells in tissue culture advocated the myelogenous nature of tumor cells with a manner of growth and spread analogous to that of plasma cell myeloma, but has not been confirmed by others .
Jaffe suggested the origin from undifferentiated pluripotential supporting cells (stem cells) of bone marrow and believed that the direction of the limited differentiation is not towards skeletogenic elements. The presence of abundant glycogen and membrane bound alkaline phosphatase activity in the tumour cells of Ewing's sarcoma as observed in immature osteoblasts, appears to confirm the hypothesis .
At present, Ewing's sarcoma is thought to have a neuroectodermal origin, since ultrastructural and IHC features are similar to that of neuroectodermal tumour and since it shares the same reciprocal 11;22 translocation .
Ewing's sarcoma is common in the second decade of life and can affect any bone. Long bones, pelvis, and ribs are frequently involved and jaw involvement is uncommon . Pain often associated with swelling is the most common symptom. Other systemic manifestations are anemia, increased ESR, leukocytosis, fever, and increased LDH levels. Metastasis to lymph nodes is uncommon. Distant metastasis to lungs and other bones is seen .
Radiographically, onion skin periosteal reaction is characteristic in long bones, but rare in jaws because of following reasons:
- Mandible is typically a flat bone with less mass than the long bones. As a result, rapid growth of tumor in the head and neck region is more likely to violate the cortex and more lytic destruction of the bone takes place rather than permeation and large amounts of periosteal reaction.
- Cortices of bones in head and neck region are thinner, so expansion of bones is more likely in slower growing lesion than in longer bones greater mass .
Microscopically, Ewing's sarcoma is composed of sheets of uniform, small, round cells with a well-defined nuclear outline and indistinct cellular borders. Mitotic activity is usually not prominent. Perivascular bearing of neoplastic cells is commonly seen. Ewing's sarcoma can show variable histological patterns namely, diffuse, lobular, filigree, trabecular, globoid, and pseudo rosette formation .
About 75% of the cases of Ewing's sarcoma contain intracytoplasmic glycogen granules with absence of reticulin in the stroma. Glycogen can be demonstrated by PAS stain and is a helpful diagnostic feature, but is not specific, since rhabdomyosarcoma also shows positive glycogen expression.
Histological differential diagnosis for Ewing's sarcoma:
- Malignant lymphomas
- Metastatic neuroblastoma
- Small cell osteosarcoma
- Primitive Neuro Ectodermal Tumour (PNET) 
Lymphomas are primary malignant tumors of lymphoreticular tissue, common in the second decade of life and present with painless, rubbery lymph nodes. Hodgkins lymphoma is composed of Reed-Stemberg cells, along with histiocytic or lymphocytic derivatives in varying degrees of differentiation. Non-Hodgkin's lymphoma may occur in nodal or extra nodal sites. It shows two basic morphological types, follicular and diffuse. Cells show scanty cytoplasm and an irregular cleaved or indented nucleus along with coarse and condensed chromatin. Burkitt's lymphoma shows classic starry sky pattern with interspersed histiocytic cells with abundant cytoplasm in a background of lymphocytes .
Neuroblastoma, being the third most common malignant tumor in children, shows sheets of small cells arranged in short trabeculae or irregular groups. In neuroblastoma, greater degree of nuclear irregularity and hyperchromatism is seen, when compared to Ewing's sarcoma and shows Homer-Wright pseudo-rosette formation. Neutrophil, ganglionic differentiation, and calcification are features of neuroblastoma. Increased levels of catecholamine and their metabolites (VMA, HVA) in urine are observed .
Rhabdomyosarcoma exhibits loosely arranged round or pleomorphic cells with hyperchromatic nuclei and eosinophilic cytoplasm. Presence of racket shaped and tadpole shaped cells are characteristic features. PTAH stain demonstrates cross-striations. Small cell osteosarcoma shows the presence of osteoid in the microscopic sections .
Now it is considered that ES and PNET are closely related if not identical tumors. [Table - 1]
Ultrastructure: Cells show inconspicuous cell processes, without basal lamina, and with infrequent small thickenings of apposed membranes. Filaments are absent and microtubules are inconspicuous. Neurosecretory granules are absent and occasionally indented with dispersed chromatin .
Immunohistochemical analysis: Ewing's sarcoma shows positive expression for MIC2. MIC2 gene is a pseudoautosomal gene, located on short arms of the sex chromosomes, first identified by Levy et al. The product of MIC 2 gene is a glycoprotein (also designated as CD99/ P30/32) with a molecular mass of approximately 30,000 Daltons located on cell surface. In the hematopoitietic system the MIC2 gene product appears to be involved in cell adhesion processes like the rosette phenomenon. Another arena for the use of immunohistochemistry in Ewing's sarcoma is the documentation of p-glycoprotein. It is the gene product of the MDR1 gene and is believed to function as a drug efflux pump, causing chemotherapy resistance by excluding the therapeutic agent decreasing its concentration in the target cell .
Molecular biology: A specific chromosomal abnormality (reciprocal translocation between the chromosome t(11:22) (q 24:12) has been identified in 8590% of cases. Chromosomal translocation and functional fusion of the EWS gene is seen in any of the several structurally related transcription factor genes. At the molecular genetic level, the chromosome 22 q 12 breakpoints are clustered within a single gene designated EWS and the chromosome 11 q 24 breakpoints are within a gene called FL 1 (Friend leukemia virus integration site 1). The fusion of EWS-FL1 creates a new protein with unique function. These genetic changes are now considered a specific diagnostic feature of these tumors, and the fusion genes are believed to play an important role in ES/PNET development and biology .
Other Recurrent Chromosome Abnormalities
- t (11:22) (g24:g12) EWS-FLII translocation in Ewing's sarcoma.
- t (21:22) EWS-ERG translocation in Ewing's sarcoma.
- t (17:22) (g12:g12) EWS-E1AF translocation in Ewing's sarcoma.
- t (7:22) (p22:g12) EWS-ETV1 translocation in Ewing's sarcoma.
- del (lp36) in Ewing's sarcoma.
- 1 q Gain in Ewing's sarcoma.
- der (16) t (1:16) in Ewing's sarcoma.
- Trisomy 8 Ewing's sarcoma.
- Trisomy 12 Ewing's sarcoma (13).
Treatment of Ewing's sarcoma has undergone significant change. The utilization of integrated therapies including chemotherapy, radiation therapy, and surgery has led to an impressive improvement in prognosis.
Poor prognostic factors are patients below 10 years of age, pelvic lesions, presence of metastasis, presence of systemic symptoms, large tumor volume (>200m1), high mitotic rate, filigree pattern in histopathological sections, and poor response to chemotherapy . Ewing's sarcoma of the mandible has got better prognosis than long bones since facial sites are diagnosed earlier .
Kinsella el al have reported disease free survival rates of 52%, 37%, 35% & 33% at 2, 5, 10, and 15 years respectively . According to the recent report, 2 year disease free survival rate is 79% and 5 year actuarial survival rate is 60%.
| Acknoledgment|| |
We are thankful to Dr. Kumaraswamy, Professor and HOD, Dept. of Oral and Maxillofacial Surgery, V .S. Dental College and Dr. Mubeen, Professor and HOD, Dept. of Oral Medicine, Govt. Dental College, Bangalore, for their kind co-operation and support.
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10]
[Table - 1]