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Ewing’s sarcoma of the jaws: An institutional study of four cases
International Journal of Pediatric Otorhinolaryngology Extra 13 (2016) 33–39
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j p o r l
Case Report
Ewing’s sarcoma of the jaws: An institutional study of four cases Aadithya B. Urs a,*, Priya Kumar a, Garima Rawat a, Sujata Mohanty b a b
Department of Oral & Maxillofacial Pathology, Maulana Azad Institute of Dental Sciences, BSZ Marg, New Delhi 110002, India Department of Oral & Maxillofacial Surgery, Maulana Azad Institute of Dental Sciences, BSZ Marg, New Delhi 110002, India
A R T I C L E
I N F O
Article history: Received 7 January 2016 Received in revised form 25 March 2016 Accepted 27 March 2016 Available online Keywords: Ewing’s sarcoma Jaws Multimodal therapy
A B S T R A C T
Ewing’s sarcoma (ES) is a rare malignant small round cell tumour that primarily affects the skeletal system. It accounts for less than 4–10% of all types of bone malignancies, with long bones and pelvis being involved most commonly. Clinically, ES can mimic odontogenic inflammation/abscess. Integration of clinical, radiographic, histologic and immunohistochemical information is essential for prompt diagnosis. Aggressive multimodal therapy and continuous follow up results in better prognosis of patient diagnosed with Ewing’s sarcoma. Through this paper we reiterate the importance of promptly diagnosing and treating this rare tumour entity that can help in improving the prognosis. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction
2. Materials and method
Ewing’s sarcoma (ES) is a rare malignant small round cell tumour that primarily affects the skeletal system. It accounts for less than 4–10% of all types of bone malignancies, with long bones and pelvis being the most commonly involved [1–3]. It affects mainly the adolescents and young adults and is rarely seen before the age of 4 and after the age of 30 years. Males are twice more commonly affected than females. The occurrence of this tumour in head and neck region is unusual and when it occurs in the jaw, mandible is more frequently affected than maxilla [4]. Only 10% of mandibular ES are metastatic lesions, whereas the other 90% are primary tumours [5]. Prompt diagnosis is essential for good prognosis as the lesion shows aggressive behaviour characterised by rapid growth and nonspecific clinical findings [1,2,6]. Histopathologically, ES is composed of small, poorly differentiated cells with medium sized round or oval nuclei. Combined therapy including surgery, radiotherapy and chemotherapy is the best approach for treatment of the tumour. The aim of the present study was to perform an in depth clinical, radiological and histological analysis of cases of Ewing’s sarcoma that presented to a tertiary care dental hospital over a seven year period.
Archival data of the patients diagnosed histopathologically as Ewing’s sarcoma was retrieved from the year 2007 to 2015 from the records of Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India. The clinical, radiographic and histopathological features of all the cases were analysed. Special stains and immunohistochemistry were performed to facilitate correct diagnosis.
* Corresponding author at: Aadithya B. Urs, Department of Oral & Maxillofacial Pathology, Maulana Azad Institute of Dental Sciences, BSZ Marg, New Delhi 110002, India. Tel.: +91 9582948857; fax: +91 1123217081. E-mail address: [email protected] (A.B. Urs). http://dx.doi.org/10.1016/j.pedex.2016.03.005 1871-4048/© 2016 Elsevier Ltd. All rights reserved.
3. Results Case #1 A 17-year-old male reported to the outpatient department with the chief complaint of a slowly growing swelling on left cheek since 4 months. He gave a history of trauma to the upper jaw prior to appearance of the swelling. He also complained of nasal obstruction and slight pain in relation to the swelling. On extraoral examination, there was a firm, tender, well defined, swelling approximately 6 × 6 cm in size, in the left canine space causing obliteration of the left nasolabial fold. The overlying skin was normal and adherent to the underlying swelling. Intraorally, buccal and palatal cortical plates were expanded from maxillary left central incisor to left first premolar. The maxillary left lateral incisor and canine were displaced but non tender and immobile. The overlying mucosa was non ulcerated with bluish tinge on the buccal aspect. The radiographic findings (OPG and CT scan) have been described in Table 1. An incisional biopsy was performed under local anaesthesia via the intraoral approach which was followed by uneventful healing.
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Table 1 Radiographic presentation and treatment. S. no
Orthopantomogram (OPG)
Computed tomography (CT) scan
Fine needle aspiration cytology (FNAC)
Treatment
1
Ill defined osteolytic lesion in relation to maxillary left central incisor to premolar, with non sclerotic borders displacing roots of maxillary lateral incisor and canine. NA
Diffuse ill defined homogenous density lesion involving maxillary sinus and reducing in size, crossing the midline with thinning of cortical plate of hard palate Irregular soft tissue density lesion within body and ramus of left mandible causing erosion of overlying cortices and showing periosteal new bone formation: sun ray appearance NA
NA
Radiotherapy + chemotherapy
Suggestive of small malignant round cell tumour
Surgery + chemotherapy
NA
Surgery + chemotherapy
Well-defined multilocular expansile lytic lesion from 33 to 36 with erosion of cortices, perforation of the buccal cortex and displacement of roots of premolars and molars
Suggestive of small malignant round cell tumour
Surgery + chemotherapy
2
3 4
Ill defined osteolytic lesion in the right mandibular body Well-defined multilocular radiolucency extending from 33 to 36 up to inferior border of mandible displacing roots of teeth (34, 35, 36). Thinning of the inferior border of mandible.
NA, not available.
The tissue specimen was sent for histopathological analysis. The microscopic findings along with immunohistochemistry have been elaborated in Table 2. Based on the microscopic picture and immunohistochemistry findings a final diagnosis of Ewing’s sarcoma of rhinomaxillary complex was made and the patient was referred to the Head and Neck Oncology Centre where he received radiotherapy followed by chemotherapy. The patient is on regular follow-up since 8 years and no recurrence is observed to date. Case #2 An 18-year-old male reported with an 8 month history of a painless, gradually increasing swelling in the left posterior mandible. Extraorally, bony hard swelling measuring 4 × 3 cm was present along the mandibular body on left side extending up to the angle region covered with normal overlying skin. Intraorally, swelling was bony hard, non-tender and causing expansion of the buccal cortical plate and extending from second premolar to second molar. The teeth were immobile and asymptomatic. The patient was apparently healthy with no signs of paresthesia/lymphadenopathy. Fine needle aspiration cytology (FNAC) and computed tomography (CT) scan (Fig. 1) have been elaborated in Table 1. The patient underwent incisional biopsy under local anaesthesia. The microscopic picture and immunohistochemistry results have been discussed in Table 2. Hence, a final diagnosis of Ewing’s sarcoma of the mandible was made. The patient was referred to higher centre for further treatment where surgery and chemotherapy were done. Patient is undergoing chemotherapy intermittently since 2 years.
Case #3 A 4-year-old boy reported to the Department of Oral Pathology with a 4–5 months history of a painless, progressively enlarging swelling in the right mandible which mimicked a dental abscess. On clinical examination, a hard fixed expansile mass, approximately 3 cm in diameter was observed on the right side of the mandible. Intraoral examination revealed an expansile mass extending from deciduous canine to deciduous second molar causing expansion of the buccal cortex and obliteration of buccal vestibule (Fig. 2A). On palpation, the mass was hard in consistency and nontender. Deciduous first molar was missing and deciduous second molar had grade I mobility. The child appeared to be in good health and there was no lymphadenopathy. Orthopantomogram (OPG) has been described in Table 1. An incisional biopsy was done under general anaesthesia and the tissue was histopathologically analysed (Table 2). Based on microscopic picture and immunopositivity for CD-99, a final diagnosis of Ewing’s sarcoma was given. The patient was referred to Paediatric Oncology Centre where he underwent neo-adjuvant chemotherapy. Following chemotherapy, surgery was performed and the tissue obtained for histopathological examination was free from any tumour cells. Case #4 A 15-year-old female presented to the Department of Oral Pathology, Maulana Azad Institute of Dental Sciences with the complaint of a swelling on left side of face since 15 days. The swell-
Table 2 Histopathological presentation and immunohistochemistry. Case
Histopathological presentation
Immunohistochemistry
1
Sheets of small round cells with vesicular nuclei, hyperchromatism and mitotic figures. Sheets of round cells having large, vesicular nuclei and indiscernible cytoplasmic boundary. Few cells show hyperchromatic nuclei and mitotic figures. PAS positive diastase sensitive glycogen in the cytoplasm of the tumour cells. Numerous clusters, cords strands of small, round cells with vesicular nuclei. Connective tissue stroma is fibrovascular. PAS positive diastase sensitive intracytoplasmic glycogen in round cells. Nests, cords and sheets of dysplastic round to ovoid cells showing hyperchromatism, pleomorphism, few mitosis and vesicular nuclei. Few areas of central necrosis. Connective tissue was fibro collagenous with moderate cellularity and increased vascularity. PAS positive diastase sensitive glycogen in the cytoplasm of the cells.
CD99 +++ (membranous positivity) Negative: S-100, desmin and HMB-45 CD99 ++ (membranous positivity) Negative: S-100
2
3
4
+, intensity of positive staining.
CD99 ++ Negative:S-100, CD 45, desmin, neuron specific enolase (NSE), synaptophysin CD99 +++ Focal S-100 positivity Negative: CD 45, desmin, neuron specific enolase (NSE), synaptophysin, chromagranin, HMB 45, LCA
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Fig. 1. CT scan revealing ill defined osteolytic lesion within body and ramus of left mandible causing erosive destruction of overlying cortices and showing periosteal new bone formation giving a sun ray appearance (case #2).
Fig. 3. CT scan showing well-defined multilocular expansile lytic lesion from left canine to first molar with perforation of both the cortices and displacement of roots of premolars and molars (case #4).
ing tremendously increased in size over a period of 10 days when the patient was reviewed again causing extensive destruction. There was no associated history of trauma, pain or pus discharge. The bony hard swelling increased from an initial size of 2 × 2 cm to 4 × 4 cm and extended from the symphysis to the mid-body region and was covered with normal overlying skin. It was nodular and nontender on palpation. On intraoral examination, bony hard swelling was seen extending from canine to second premolar on left side causing expansion of the buccal cortical plate and obliterating the left buccal vestibule. Slight lingual expansion was present in the premolar region. The canine and premolars showed grade II mobility. Later on the swelling extended from the incisors to the molar region causing expansion of both the cortical plates and obliterating the buccal vestibule and was covered with erythematous mucosa. The lesion caused displacement and mobility of canine, premolars and molars (Figs 2B and 3). Orthopantomogram (OPG) and CT scan (Fig. 4) have been described in Table 1. The patient was planned for incisional biopsy under local anaesthesia and the tissue was sent for histopathological examination. Microscopic examination findings have been elaborated in Table 2. Based on H&E staining a diagnosis of small round cell tumour was made. A panel of immunomarkers were used to reach a diagnosis. The round tumour cells stained positive for CD99 (Table 2) and a final diagnosis of Ewing’s sarcoma was given. With
this diagnosis, the patient was started with neo-adjuvant chemotherapy followed by surgical excision. After surgery the patient is undergoing adjuvant chemotherapy and the healing is satisfactory without recurrence. During neo-adjuvant chemotherapy, the patient underwent 6 cycles and the chemotherapeutic agents used were cisplatin (120 mg), ifosfamide (0.3 mg) and mesnex (600 mg). 4. Discussion Ewing’s sarcoma (ES) is a rare malignant round cell tumour that was first described by James Ewing in 1921, who believed the tumour to be of endothelial origin [3,7]. Currently, the tumour is thought to have a neuroectodermal origin since it has similar reciprocal translocation as seen in peripheral neuroectodermal tumour (PNET). These tumours are considered to be the ends of a histological spectrum of “Ewing’s family of tumours” (EFT) [8]. The EFT in 85–95% of cases is characterised by oncogenic chromosomal translocations. 85% of the tumours are associated with translocation t (11;22) (q24;q12) resulting in chimeric fusion transcript EWSFLI1 formation. In the remaining 10–15% of cases, the translocation t (21;12) (22;12) is seen resulting in EWS-ERG (Etsrelated gene) fusion product. EWS gene (also known as EWSR1Ewing sarcoma breakpoint region 1) encodes a multifunctional protein involved in DNA dependent regulation of transcription. FLI1 (Friend leukaemia virus integration 1, also known as EWSR2) and
Fig. 2. (A) Intraoral photograph showing bony hard swelling from 53 to 55 expanding buccal cortical plate and causing obliteration of buccal vestibule (case #3). (B) Intraoral photograph showing destructive bony hard swelling with erythematous surface from incisors to molar region displacing teeth (case #4).
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Fig. 4. (A–C) Extraoral photographs showing exponential increase in the swelling in a short duration (10 days) (case #4). (D) Post treatment extraoral photograph (case #4).
ERG [vets erythroblastosis virus E26 oncogene homolog (avian)] are closely related members of the erythroblast transformation specific (ETS) family of transcription factors, containing ETS type DNA binding domain. In fusion, EWS exon 7 is fused to FLI1 exon 6 (type 1) most commonly, and it may show also fusion with FLI1 exon 5 (type 2), or ERG exon 9 [8–11]. ES is an unusual disease comprising about 4–6% of all primary bone tumours. It originates in the marrow cavity and is found in the epiphyses of long and flat bones. Involvement of the head and neck region is very rare in Ewing’s sarcoma and accounts for approximately 1–4% of all the cases. When jaws are involved, mandible is more frequently affected compared to maxilla [1,2,6,12]. Although, Allam A et al. found maxilla as the most common site of presentation (9/15 cases) [6]. Out of 4 cases studied in the present study, 3 cases involved the mandible and only 1 case affected the maxilla. From the year 2000 to 2016, only 21 cases of ES involving the jaws in children (0–18 years) have been reported in the World literature (Table 3). Majority of the cases occur during first two decades of life with significant male predominance. In the current series, of the four cases, three were males and one female. Age of the patients ranged from 4 years to 18 years (average age being 13.5 years). The common presenting signs and symptoms in maxillofacial region include swelling, pain, loose teeth, paresthesia, ulceration, trismus and toothache [20]. Swelling was observed in all the cases and was associated with pain in one case. Only one case was associated with a history of trauma (case #1), whereas another was
clinically aggressive and presented with a painless swelling involving the left mandible which rapidly increased in size over 10 days causing extensive destruction and displacing all the teeth in that region (case #4). ES usually presents as a lytic, permeative, poorly defined lesion. “Onion skin” periosteal reaction may be seen but rarely in jaws [20,24]. All our cases showed an osteolytic lesion destroying the cortices. Sun ray appearance was observed in one case but onion skin appearance was not noted (Table 1). Microscopically, tumour is composed of small, round cells with minimal cytoplasm and indiscernible boundary (Fig. 5A). The cytoplasm is pale staining, ill-defined and sometimes irregularly vacuolated due to the presence of intracellular glycogen deposits. The nucleus is round to oval, hyperchromatic and vesicular, it may be indented sometimes by the glycogen droplets. The tumour cells may be arranged in various patterns like sheets, cords, strands and nests (Fig. 5B). The cells may show presence of mitotic figures (Fig. 5C). Areas of necrosis and haemorrhage may be seen in the stroma and these have been associated with poor prognosis (Fig. 5D). The amount of intracellular glycogen varies from one part of tumour to other. 75% of the cases show positivity to Periodic Acid Schiff (PAS) staining due to the presence of these intracytoplasmic glycogen granules in the round cells. These glycogen granules are diastase sensitive. Presence of PAS positive diastase sensitive glycogen may help in the diagnosis, but is not specific, as it can be observed in other small round cell tumours [3,5]. In the present series, three cases showed presence of PAS positive diastase sensitive glycogen in the cytoplasm of tumour cells hinting at the diagnosis of ES (Table 2).
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Table 3 Review of published cases of Ewing’s sarcoma from the year 2000 to 2016 in world literature [1–3,7,12–23]. Year
Authors
Age/sex
Site
Duration
2001 2003 2003 2003 2005 2005 2006 2007 2007 2008 2008 2009 2010 2010 2011 2011 2012 2013 2014 2014 2014 2015
Gorospe L et al. [3] Wexler LH et al. [13] Quesada JL et al. [14] Talesh et al. [12] Schultze-Mosgau S et al. [15] Infante-Cossio P et al. [16] Sharda et al. Varshney S et al. [17] Lopes SL et al. [18] Solomon LW et al. [19] Prasad V et al. Deshingar et al. Brazão-Silva MT et al. [1] Dadhe et al. Rao et al. [2] Pampori et al. Mukherjee A et al. [7] Krishna KBB et al. [20] Sinha DK et al. [21] Forouz Keshani et al. [22] Jairamdas Nagpal DK et al. [23] Present series (4 cases)
12/F 9/F 14/F 17/F 7/M 17/M 15/M 15/M 14/M 15/F 18/M 15/F 4/F 12/M 11/F 16/F 8/F 3.5/F 18/F 16/F 15/F 4–18/M > F
Ramus of mandible Maxilla Mandible Condyle and ramus of mandible Mandible Maxilla and zygoma Both jaws Maxilla with intraorbital extension Mandible Mandible Maxilla Zygoma Mandible Maxilla Mandibular ramus Maxilla Anterior mandible Mandible Mandible Mandible Maxilla Mandible> maxilla
1 week 1 month – 10 months 3 months 2 months 6 months 1 year 2 months 1 year 6 months 1 month 1 month 4 months 6 months 6 months 7 months 1 week 2 months – – 15 days to 8 months
Across the ES family of tumours a spectrum of histological and ultrastructural features is seen that can help distinguish between these tumours. Transmission electron microscopy of classical ES demonstrates densely packed undifferentiated tumour cells with cytoplasmic glycogen and scarce organelles. Occasionally, desmosome-like junctions are seen. There is absence of neural differentiation such as dense core neurosecretory granules, neuritic processes, and microtubules. Whereas, PNET ultrastructurally shows abundant organelles, dense core neurosecretory granules and neuritic processes [24]. ES should be differentially diagnosed from other round cell tumours like small cell osteogenic sarcoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, neuroblastoma, desmoplastic small
round cell tumour, lymphoblastic lymphoma and poorly differentiated synovial sarcoma. A panel of immune markers are needed to differentially diagnose these small round cell tumours which include vimentin, CD99, leucocyte common antigen (LCA), pancytokeratin, desmin, MYOD1/myogenin, chromogranin, and S100 protein (Table 4). The most useful, though nonspecific marker is CD99, which produces a strong diffuse membranous staining pattern in “chain-mail pattern” in up to 98% cases [20,24,25]. CD99 also known as MIC2 is a 32-kDa integral membrane glycoprotein is encoded by the MIC2 gene located in the end of the short arm of the X and Y chromosomes. CD99 has a key role in several biological processes, including cell adhesion, migration, and apoptosis; differentiation of T cells and thymocytes; diapedesis of
Fig. 5. (A) Photomicrograph showing tumour mass composed of small, round cells with minimal cytoplasm and indiscernible cytoplasmic boundary (H&E 40×). (B) Photomicrograph showing tumour cells arranged in cords and strands. (H&E 10×). (C) Photomicrograph showing the presence of mitotic figures in round cells (arrow). (H&E 100×). (D) Photomicrograph showing an area of tumour cells undergoing necrosis (encircled area). (H&E 40×). (E, F) Photomicrographs showing membranous positivity for CD99 in round cells.
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Table 4 Immunohistochemical analysis of various round cell tumours. Tumour
CD99
FLI-1
NSE
S-100
Ewing’s sarcoma/PNET Lymphoblastic lymphoma Neuroblastoma Desmoplastic small round cell tumour Mesenchymal chondrosarcoma Rhabdomyosarcoma
++ ++
++ + +
■
■
++ ++ ++ ■
■ ■ ■ ■
■ ++ ■
Desmin
MyoD1
CK
LCA
■ ++ ++ ++
++
++ ■ ■
Modified from Enzinger and Weiss’s Soft Tissue Tumors. +, frequently positive; ■, rarely positive.
lymphocytes to inflamed vascular endothelium; maintenance of cellular morphology; and regulation of intracellular membrane protein trafficking. Gene expression profiling studies have supported the hypothesis that CD99 affects differentiation and malignancy of round cells. Thus, CD99 plays a role as inhibitor of neuronal differentiation and blockade of basal CD99 function can be used as a new therapeutic approach for ES [26–28]. CD99 positivity is also seen in lymphoblastic lymphoma and mesenchymal chondrosarcoma. Amongst these, lymphoblastic lymphoma is composed of lymphoid cells, intermixed with round cell of varying size and cytoplasmic contents. The nuclei are round or oval with a distinct nuclear membrane. The reticulin stain is often positive and cells are LCA positive. Mesenchymal chondrosarcoma has biphasic pattern and is composed of scattered areas of cartilage, together with highly vascular mesenchymal tissue composed of undifferentiated spindle cells or round cells with cytoplasm. Blending of islands of cartilage with cellular areas is observed. This tumour shows NSE positivity [21]. Thus, ES can be differentiated from these two based on H&E and positivity for other markers. FLI 1 nuclear positivity has been reported in 71%–84% cases of ES/PNET and polyclonal antibodies to this protein have been developed. FLI 1 protein expression has been found in 94% cases with EWS-FLI1 fusions. But despite its high sensitivity FLI 1 is also frequently positive in lymphoblastic lymphomas. So, FLI-1 positivity can help in distinguishing ES from other CD99 positive round cell tumours and antibodies to FLI 1 may play a valuable adjunctive role in the diagnosis of ES/PNET [29]. In the present series, all cases showed strong membranous positivity for CD99 though the staining intensity was different due to different clones of antibody used (Fig. 5E and F). The tumour cells were negative for other markers with focal positivity for S-100 in one case (case#4) (Table 4). Multimodal therapy using a combination of chemotherapy, surgery, and radiotherapy is being used now for the treatment of ES. The patients are treated systemically with high dose chemotherapy, and locally, surgical excision is done if possible. Neoadjuvant chemotherapy is the initial treatment modality used which is followed by either surgery or radiation therapy depending on tumour response to the treatment. Before the advent of chemotherapy, the survival rate was less than 10% but it has improved to 50%. Rosen et al., 1974 proposed a combination of vincristine, actinomycin D, cyclophosphamide and doxorubicin (VACD) for treating ES. This combination had a 5-year survival rate of 60% [30]. Other chemotherapeutic agents being used are ifosfamide and etoposide (IE) [25,31]. In all our cases multimodal therapy was employed and chemotherapy was the initial treatment modality with surgery and radiotherapy as adjuvant therapies (Table 1). In our series, promising results were obtained using the above treatment modalities and follow-up duration ranged from 1 to 8 years with no recurrence or adverse outcome reported till date (Fig. 4). Prognosis in patients of Ewing’s sarcoma has markedly improved with the advent of multimodal therapy. The 5-year survival rate with the current treatment options is around 65%. The prognostic factors include presence of metastatic disease at time of
diagnosis, early tumour recurrence, anatomic site of involvement, tumour size and degree of treatment induced tumour necrosis. Out of all these, the most important adverse prognostic factor is the presence of metastatic disease at time of diagnosis. 5. Conclusion Ewing’s sarcoma is a diagnostic challenge because of many overlapping clinical, radiographic, histopathological and immunohistochemical features with malignant round cell tumours. Thus, the distinction between these tumours is important as they require management via multidisciplinary approach. Through this paper we reiterate the importance of promptly diagnosing and treating this rare tumour entity that can help in improving the prognosis. References [1] M.T. Brazão-Silva, A.V. Fernandes, P.R. Faria, S.V. Cardoso, A.M. Loyola, Ewing’s sarcoma of the mandible in a young child, Braz. Dent. J. 21 (1) (2010) 74–79. [2] B.H.S. Rao, G. Rai, S. Hassan, A. Nadaf, Ewing’s sarcoma of the mandible, Natl. J. Maxillofac. Surg. 2 (2) (2011) 184–188. [3] L. Gorospe, M.A. Fernández-Gil, P. García-Raya, A. Royo, F. López-Barea, P. García-Miguel, Ewing’s sarcoma of the mandible: radiologic features with emphasis on magnetic resonance appearance, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 91 (2001) 728–734. [4] A. Fonseca, R. Mezzalira, A. Crespo, A. Bortoleto, J. Paschoal, Ewing’s sarcoma of the head and neck, Rev. Paul. Med. 118 (6) (2000) 198–200. [5] J.P. Vaccani, V. Forte, A.L. de Jong, G. Taylor, Ewing’s sarcoma of the head and neck in children, Int. J. Pediatr. Otorhinolaryngol. 48 (3) (1999) 209–216. [6] A. Allam, G. El-Husseiny, Y. Khafaga, A. Kandil, A. Gray, A. Ezzat, et al., Ewing’s sarcoma of the head and neck: a retrospective analysis of 24 cases, Sarcoma 3 (1) (1999) 11–15. [7] A. Mukherjee, J.G. Ray, S. Bhattacharya, T. Deb, Ewing’s sarcoma of mandible: a case report and review of Indian literature, Contemp. Clin. Dent. 3 (4) (2012) 494–498. [8] S.S. Desai, N.A. Jambhekar, Pathology of Ewing’s sarcoma/PNET: current opinion and emerging concepts, Indian J. Orthop. 44 (4) (2010) 363–368. [9] J. Przybyl, K. Kozak, H. Kosela, S. Falkowski, T. Switaj, I. Lugowska, et al., Gene expression profiling of peripheral blood cells: new insights into Ewing sarcoma biology and clinical applications, Med. Oncol. 31 (8) (2014) 109. [10] S.L. Cohn, Diagnosis and classification of the small round-cell tumors of childhood, Am. J. Pathol. 155 (1) (1999) 11–15. [11] M.C. Le Deley, O. Delattre, K.L. Schaefer, S.A. Burchill, G. Koehler, P.C. Hogendoorn, et al., Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial, J. Clin. Oncol. 28 (12) (2010) 1982–1988. [12] K.T. Talesh, M.H. Motamedi, M. Jeihounian, Ewing’s sarcoma of the mandibular condyle: report of a case, J. Oral Maxillofac. Surg. 61 (10) (2003) 1216–1219. [13] L.H. Wexler, A. Kacker, J.D. Piro, J. Haddad Jr., L.G. Close, Combined modality treatment of Ewing’s sarcoma of the maxilla, Head Neck 25 (2) (2003) 168–172. [14] J.L. Quesada, J.M. Alcalde, J.M. Espinosa, R. García-Tapia, Ewings’ sarcoma of the mandible, J. Laryngol. Otol. 117 (9) (2003) 736–738. [15] S. Schultze-Mosgau, M. Thorwarth, F. Wehrhan, W. Holter, K.D. Stachel, G. Grabenbauer, et al., Ewing sarcoma of the mandible in a child: interdisciplinary treatment concepts and surgical reconstruction, J. Craniofac. Surg. 16 (6) (2005) 1140–1146. [16] P. Infante-Cossio, J.L. Gutierrez-Perez, A. Garcia-Perla, M. Noguer-Mediavilla, F. Gavilan-Carrasco, Primary Ewing’s sarcoma of the maxilla and zygoma: report of a case, J. Oral Maxillofac. Surg. 63 (10) (2005) 1539–1542. [17] S. Varshney, S.S. Bist, N. Gupta, R. Bhatia, Primary extraskeletal Ewing’s sarcoma of the maxilla with intraorbital extension, Indian J. Otolaryngol. Head Neck Surg. 59 (3) (2007) 273–276. [18] S.L. Lopes, S.M. Almeida, A.F. Costa, V.A. Zanardi, F. Cendes, Imaging findings of Ewing’s sarcoma in the mandible, J. Oral Sci. 49 (2) (2007) 167–171.
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[19] L.W. Solomon, J.L. Frustino, T.R. Loree, M.L. Brecher, R.A. Alberico, M. Sullivan, Ewing sarcoma of the mandibular condyle: multidisciplinary management optimizes outcome, Head Neck 30 (3) (2008) 405–410. [20] K.B. Krishna, V. Thomas, J. Kattoor, P. Kusumakumari, A radiological review of Ewing’s sarcoma of mandible: a case report with one year follow-up, Int. J. Clin. Pediatr. Dent. 6 (2) (2013) 109–114. [21] D.K. Sinha, N.K. Jha, S.K. Yadav, J. Yadav, R. Sinha, Ewing’s sarcoma of mandible: a very rare disease and review of Indian literature, Indian J. Surg. Oncol. 5 (1) (2014) 81–84. [22] F. Keshani, G. Jahanshahi, B.M. Attar, M. Kalantari, S.M. Razavi, Z. Hashemzade, et al., Ewing’s sarcoma in mandibular similar to dental abscess, Adv. Biomed. Res. 3 (2014) 62. [23] D.K. Jairamdas Nagpal, P.R. Prabhu, S.J. Palaskar, S. Patil, Ewing’s sarcoma of maxilla: a rare case report, J. Oral Maxillofac. Pathol. 18 (2) (2014) 251–255. [24] M. Hameed, Small round cell tumors of bone, Arch. Pathol. Lab. Med. 131 (2007) 192–204. [25] M. Bernstein, H. Kovar, M. Paulussen, R.L. Randall, A. Schuck, L.A. Teot, et al., Ewing’s sarcoma family of tumors: current management, Oncologist 11 (5) (2006) 503–519. [26] H. Kovar, M. Dworzak, S. Strehl, E. Schnell, I.M. Ambros, P.F. Ambros, Overexpression of the pseudoautosomal gene MIC2 in Ewing’s sarcoma
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[31]
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and peripheral primitive neuroectodermal tumor, Oncogene 5 (7) (1990) 1067–1070. A. Rocchi, M.C. Manara, M. Sciandra, D. Zambelli, F. Nardi, G. Nicoletti, et al., CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis, J. Clin. Invest. 120 (3) (2010) 668–680. I.M. Ambros, P.F. Ambros, S. Strehl, H. Kovar, H. Gadner, M. Salzer-Kuntschik, MIC2 is a specific marker for Ewing’s sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration, Cancer 67 (7) (1991) 1886– 1893. A.L. Folpe, C.E. Hill, D.M. Parham, P.A. O’Shea, S.W. Weiss, Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing’s sarcoma/primitive neuroectodermal tumor, Am. J. Surg. Pathol. 24 (12) (2000) 1657–1662. G. Rosen, N. Wollner, C. Tan, S.J. Wu, S.I. Hajdu, W. Cham, et al., Proceedings: disease-free survival in children with Ewing’s sarcoma treated with radiation therapy and adjuvant four-drug sequential chemotherapy, Cancer 33 (2) (1974) 384–393. S. Jain, G. Kapoor, Chemotherapy in Ewing’s sarcoma, Indian J. Orthop. 44 (4) (2010) 369–377.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j p o r l
Case Report
Ewing’s sarcoma of the jaws: An institutional study of four cases Aadithya B. Urs a,*, Priya Kumar a, Garima Rawat a, Sujata Mohanty b a b
Department of Oral & Maxillofacial Pathology, Maulana Azad Institute of Dental Sciences, BSZ Marg, New Delhi 110002, India Department of Oral & Maxillofacial Surgery, Maulana Azad Institute of Dental Sciences, BSZ Marg, New Delhi 110002, India
A R T I C L E
I N F O
Article history: Received 7 January 2016 Received in revised form 25 March 2016 Accepted 27 March 2016 Available online Keywords: Ewing’s sarcoma Jaws Multimodal therapy
A B S T R A C T
Ewing’s sarcoma (ES) is a rare malignant small round cell tumour that primarily affects the skeletal system. It accounts for less than 4–10% of all types of bone malignancies, with long bones and pelvis being involved most commonly. Clinically, ES can mimic odontogenic inflammation/abscess. Integration of clinical, radiographic, histologic and immunohistochemical information is essential for prompt diagnosis. Aggressive multimodal therapy and continuous follow up results in better prognosis of patient diagnosed with Ewing’s sarcoma. Through this paper we reiterate the importance of promptly diagnosing and treating this rare tumour entity that can help in improving the prognosis. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction
2. Materials and method
Ewing’s sarcoma (ES) is a rare malignant small round cell tumour that primarily affects the skeletal system. It accounts for less than 4–10% of all types of bone malignancies, with long bones and pelvis being the most commonly involved [1–3]. It affects mainly the adolescents and young adults and is rarely seen before the age of 4 and after the age of 30 years. Males are twice more commonly affected than females. The occurrence of this tumour in head and neck region is unusual and when it occurs in the jaw, mandible is more frequently affected than maxilla [4]. Only 10% of mandibular ES are metastatic lesions, whereas the other 90% are primary tumours [5]. Prompt diagnosis is essential for good prognosis as the lesion shows aggressive behaviour characterised by rapid growth and nonspecific clinical findings [1,2,6]. Histopathologically, ES is composed of small, poorly differentiated cells with medium sized round or oval nuclei. Combined therapy including surgery, radiotherapy and chemotherapy is the best approach for treatment of the tumour. The aim of the present study was to perform an in depth clinical, radiological and histological analysis of cases of Ewing’s sarcoma that presented to a tertiary care dental hospital over a seven year period.
Archival data of the patients diagnosed histopathologically as Ewing’s sarcoma was retrieved from the year 2007 to 2015 from the records of Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India. The clinical, radiographic and histopathological features of all the cases were analysed. Special stains and immunohistochemistry were performed to facilitate correct diagnosis.
* Corresponding author at: Aadithya B. Urs, Department of Oral & Maxillofacial Pathology, Maulana Azad Institute of Dental Sciences, BSZ Marg, New Delhi 110002, India. Tel.: +91 9582948857; fax: +91 1123217081. E-mail address: [email protected] (A.B. Urs). http://dx.doi.org/10.1016/j.pedex.2016.03.005 1871-4048/© 2016 Elsevier Ltd. All rights reserved.
3. Results Case #1 A 17-year-old male reported to the outpatient department with the chief complaint of a slowly growing swelling on left cheek since 4 months. He gave a history of trauma to the upper jaw prior to appearance of the swelling. He also complained of nasal obstruction and slight pain in relation to the swelling. On extraoral examination, there was a firm, tender, well defined, swelling approximately 6 × 6 cm in size, in the left canine space causing obliteration of the left nasolabial fold. The overlying skin was normal and adherent to the underlying swelling. Intraorally, buccal and palatal cortical plates were expanded from maxillary left central incisor to left first premolar. The maxillary left lateral incisor and canine were displaced but non tender and immobile. The overlying mucosa was non ulcerated with bluish tinge on the buccal aspect. The radiographic findings (OPG and CT scan) have been described in Table 1. An incisional biopsy was performed under local anaesthesia via the intraoral approach which was followed by uneventful healing.
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Table 1 Radiographic presentation and treatment. S. no
Orthopantomogram (OPG)
Computed tomography (CT) scan
Fine needle aspiration cytology (FNAC)
Treatment
1
Ill defined osteolytic lesion in relation to maxillary left central incisor to premolar, with non sclerotic borders displacing roots of maxillary lateral incisor and canine. NA
Diffuse ill defined homogenous density lesion involving maxillary sinus and reducing in size, crossing the midline with thinning of cortical plate of hard palate Irregular soft tissue density lesion within body and ramus of left mandible causing erosion of overlying cortices and showing periosteal new bone formation: sun ray appearance NA
NA
Radiotherapy + chemotherapy
Suggestive of small malignant round cell tumour
Surgery + chemotherapy
NA
Surgery + chemotherapy
Well-defined multilocular expansile lytic lesion from 33 to 36 with erosion of cortices, perforation of the buccal cortex and displacement of roots of premolars and molars
Suggestive of small malignant round cell tumour
Surgery + chemotherapy
2
3 4
Ill defined osteolytic lesion in the right mandibular body Well-defined multilocular radiolucency extending from 33 to 36 up to inferior border of mandible displacing roots of teeth (34, 35, 36). Thinning of the inferior border of mandible.
NA, not available.
The tissue specimen was sent for histopathological analysis. The microscopic findings along with immunohistochemistry have been elaborated in Table 2. Based on the microscopic picture and immunohistochemistry findings a final diagnosis of Ewing’s sarcoma of rhinomaxillary complex was made and the patient was referred to the Head and Neck Oncology Centre where he received radiotherapy followed by chemotherapy. The patient is on regular follow-up since 8 years and no recurrence is observed to date. Case #2 An 18-year-old male reported with an 8 month history of a painless, gradually increasing swelling in the left posterior mandible. Extraorally, bony hard swelling measuring 4 × 3 cm was present along the mandibular body on left side extending up to the angle region covered with normal overlying skin. Intraorally, swelling was bony hard, non-tender and causing expansion of the buccal cortical plate and extending from second premolar to second molar. The teeth were immobile and asymptomatic. The patient was apparently healthy with no signs of paresthesia/lymphadenopathy. Fine needle aspiration cytology (FNAC) and computed tomography (CT) scan (Fig. 1) have been elaborated in Table 1. The patient underwent incisional biopsy under local anaesthesia. The microscopic picture and immunohistochemistry results have been discussed in Table 2. Hence, a final diagnosis of Ewing’s sarcoma of the mandible was made. The patient was referred to higher centre for further treatment where surgery and chemotherapy were done. Patient is undergoing chemotherapy intermittently since 2 years.
Case #3 A 4-year-old boy reported to the Department of Oral Pathology with a 4–5 months history of a painless, progressively enlarging swelling in the right mandible which mimicked a dental abscess. On clinical examination, a hard fixed expansile mass, approximately 3 cm in diameter was observed on the right side of the mandible. Intraoral examination revealed an expansile mass extending from deciduous canine to deciduous second molar causing expansion of the buccal cortex and obliteration of buccal vestibule (Fig. 2A). On palpation, the mass was hard in consistency and nontender. Deciduous first molar was missing and deciduous second molar had grade I mobility. The child appeared to be in good health and there was no lymphadenopathy. Orthopantomogram (OPG) has been described in Table 1. An incisional biopsy was done under general anaesthesia and the tissue was histopathologically analysed (Table 2). Based on microscopic picture and immunopositivity for CD-99, a final diagnosis of Ewing’s sarcoma was given. The patient was referred to Paediatric Oncology Centre where he underwent neo-adjuvant chemotherapy. Following chemotherapy, surgery was performed and the tissue obtained for histopathological examination was free from any tumour cells. Case #4 A 15-year-old female presented to the Department of Oral Pathology, Maulana Azad Institute of Dental Sciences with the complaint of a swelling on left side of face since 15 days. The swell-
Table 2 Histopathological presentation and immunohistochemistry. Case
Histopathological presentation
Immunohistochemistry
1
Sheets of small round cells with vesicular nuclei, hyperchromatism and mitotic figures. Sheets of round cells having large, vesicular nuclei and indiscernible cytoplasmic boundary. Few cells show hyperchromatic nuclei and mitotic figures. PAS positive diastase sensitive glycogen in the cytoplasm of the tumour cells. Numerous clusters, cords strands of small, round cells with vesicular nuclei. Connective tissue stroma is fibrovascular. PAS positive diastase sensitive intracytoplasmic glycogen in round cells. Nests, cords and sheets of dysplastic round to ovoid cells showing hyperchromatism, pleomorphism, few mitosis and vesicular nuclei. Few areas of central necrosis. Connective tissue was fibro collagenous with moderate cellularity and increased vascularity. PAS positive diastase sensitive glycogen in the cytoplasm of the cells.
CD99 +++ (membranous positivity) Negative: S-100, desmin and HMB-45 CD99 ++ (membranous positivity) Negative: S-100
2
3
4
+, intensity of positive staining.
CD99 ++ Negative:S-100, CD 45, desmin, neuron specific enolase (NSE), synaptophysin CD99 +++ Focal S-100 positivity Negative: CD 45, desmin, neuron specific enolase (NSE), synaptophysin, chromagranin, HMB 45, LCA
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Fig. 1. CT scan revealing ill defined osteolytic lesion within body and ramus of left mandible causing erosive destruction of overlying cortices and showing periosteal new bone formation giving a sun ray appearance (case #2).
Fig. 3. CT scan showing well-defined multilocular expansile lytic lesion from left canine to first molar with perforation of both the cortices and displacement of roots of premolars and molars (case #4).
ing tremendously increased in size over a period of 10 days when the patient was reviewed again causing extensive destruction. There was no associated history of trauma, pain or pus discharge. The bony hard swelling increased from an initial size of 2 × 2 cm to 4 × 4 cm and extended from the symphysis to the mid-body region and was covered with normal overlying skin. It was nodular and nontender on palpation. On intraoral examination, bony hard swelling was seen extending from canine to second premolar on left side causing expansion of the buccal cortical plate and obliterating the left buccal vestibule. Slight lingual expansion was present in the premolar region. The canine and premolars showed grade II mobility. Later on the swelling extended from the incisors to the molar region causing expansion of both the cortical plates and obliterating the buccal vestibule and was covered with erythematous mucosa. The lesion caused displacement and mobility of canine, premolars and molars (Figs 2B and 3). Orthopantomogram (OPG) and CT scan (Fig. 4) have been described in Table 1. The patient was planned for incisional biopsy under local anaesthesia and the tissue was sent for histopathological examination. Microscopic examination findings have been elaborated in Table 2. Based on H&E staining a diagnosis of small round cell tumour was made. A panel of immunomarkers were used to reach a diagnosis. The round tumour cells stained positive for CD99 (Table 2) and a final diagnosis of Ewing’s sarcoma was given. With
this diagnosis, the patient was started with neo-adjuvant chemotherapy followed by surgical excision. After surgery the patient is undergoing adjuvant chemotherapy and the healing is satisfactory without recurrence. During neo-adjuvant chemotherapy, the patient underwent 6 cycles and the chemotherapeutic agents used were cisplatin (120 mg), ifosfamide (0.3 mg) and mesnex (600 mg). 4. Discussion Ewing’s sarcoma (ES) is a rare malignant round cell tumour that was first described by James Ewing in 1921, who believed the tumour to be of endothelial origin [3,7]. Currently, the tumour is thought to have a neuroectodermal origin since it has similar reciprocal translocation as seen in peripheral neuroectodermal tumour (PNET). These tumours are considered to be the ends of a histological spectrum of “Ewing’s family of tumours” (EFT) [8]. The EFT in 85–95% of cases is characterised by oncogenic chromosomal translocations. 85% of the tumours are associated with translocation t (11;22) (q24;q12) resulting in chimeric fusion transcript EWSFLI1 formation. In the remaining 10–15% of cases, the translocation t (21;12) (22;12) is seen resulting in EWS-ERG (Etsrelated gene) fusion product. EWS gene (also known as EWSR1Ewing sarcoma breakpoint region 1) encodes a multifunctional protein involved in DNA dependent regulation of transcription. FLI1 (Friend leukaemia virus integration 1, also known as EWSR2) and
Fig. 2. (A) Intraoral photograph showing bony hard swelling from 53 to 55 expanding buccal cortical plate and causing obliteration of buccal vestibule (case #3). (B) Intraoral photograph showing destructive bony hard swelling with erythematous surface from incisors to molar region displacing teeth (case #4).
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Fig. 4. (A–C) Extraoral photographs showing exponential increase in the swelling in a short duration (10 days) (case #4). (D) Post treatment extraoral photograph (case #4).
ERG [vets erythroblastosis virus E26 oncogene homolog (avian)] are closely related members of the erythroblast transformation specific (ETS) family of transcription factors, containing ETS type DNA binding domain. In fusion, EWS exon 7 is fused to FLI1 exon 6 (type 1) most commonly, and it may show also fusion with FLI1 exon 5 (type 2), or ERG exon 9 [8–11]. ES is an unusual disease comprising about 4–6% of all primary bone tumours. It originates in the marrow cavity and is found in the epiphyses of long and flat bones. Involvement of the head and neck region is very rare in Ewing’s sarcoma and accounts for approximately 1–4% of all the cases. When jaws are involved, mandible is more frequently affected compared to maxilla [1,2,6,12]. Although, Allam A et al. found maxilla as the most common site of presentation (9/15 cases) [6]. Out of 4 cases studied in the present study, 3 cases involved the mandible and only 1 case affected the maxilla. From the year 2000 to 2016, only 21 cases of ES involving the jaws in children (0–18 years) have been reported in the World literature (Table 3). Majority of the cases occur during first two decades of life with significant male predominance. In the current series, of the four cases, three were males and one female. Age of the patients ranged from 4 years to 18 years (average age being 13.5 years). The common presenting signs and symptoms in maxillofacial region include swelling, pain, loose teeth, paresthesia, ulceration, trismus and toothache [20]. Swelling was observed in all the cases and was associated with pain in one case. Only one case was associated with a history of trauma (case #1), whereas another was
clinically aggressive and presented with a painless swelling involving the left mandible which rapidly increased in size over 10 days causing extensive destruction and displacing all the teeth in that region (case #4). ES usually presents as a lytic, permeative, poorly defined lesion. “Onion skin” periosteal reaction may be seen but rarely in jaws [20,24]. All our cases showed an osteolytic lesion destroying the cortices. Sun ray appearance was observed in one case but onion skin appearance was not noted (Table 1). Microscopically, tumour is composed of small, round cells with minimal cytoplasm and indiscernible boundary (Fig. 5A). The cytoplasm is pale staining, ill-defined and sometimes irregularly vacuolated due to the presence of intracellular glycogen deposits. The nucleus is round to oval, hyperchromatic and vesicular, it may be indented sometimes by the glycogen droplets. The tumour cells may be arranged in various patterns like sheets, cords, strands and nests (Fig. 5B). The cells may show presence of mitotic figures (Fig. 5C). Areas of necrosis and haemorrhage may be seen in the stroma and these have been associated with poor prognosis (Fig. 5D). The amount of intracellular glycogen varies from one part of tumour to other. 75% of the cases show positivity to Periodic Acid Schiff (PAS) staining due to the presence of these intracytoplasmic glycogen granules in the round cells. These glycogen granules are diastase sensitive. Presence of PAS positive diastase sensitive glycogen may help in the diagnosis, but is not specific, as it can be observed in other small round cell tumours [3,5]. In the present series, three cases showed presence of PAS positive diastase sensitive glycogen in the cytoplasm of tumour cells hinting at the diagnosis of ES (Table 2).
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Table 3 Review of published cases of Ewing’s sarcoma from the year 2000 to 2016 in world literature [1–3,7,12–23]. Year
Authors
Age/sex
Site
Duration
2001 2003 2003 2003 2005 2005 2006 2007 2007 2008 2008 2009 2010 2010 2011 2011 2012 2013 2014 2014 2014 2015
Gorospe L et al. [3] Wexler LH et al. [13] Quesada JL et al. [14] Talesh et al. [12] Schultze-Mosgau S et al. [15] Infante-Cossio P et al. [16] Sharda et al. Varshney S et al. [17] Lopes SL et al. [18] Solomon LW et al. [19] Prasad V et al. Deshingar et al. Brazão-Silva MT et al. [1] Dadhe et al. Rao et al. [2] Pampori et al. Mukherjee A et al. [7] Krishna KBB et al. [20] Sinha DK et al. [21] Forouz Keshani et al. [22] Jairamdas Nagpal DK et al. [23] Present series (4 cases)
12/F 9/F 14/F 17/F 7/M 17/M 15/M 15/M 14/M 15/F 18/M 15/F 4/F 12/M 11/F 16/F 8/F 3.5/F 18/F 16/F 15/F 4–18/M > F
Ramus of mandible Maxilla Mandible Condyle and ramus of mandible Mandible Maxilla and zygoma Both jaws Maxilla with intraorbital extension Mandible Mandible Maxilla Zygoma Mandible Maxilla Mandibular ramus Maxilla Anterior mandible Mandible Mandible Mandible Maxilla Mandible> maxilla
1 week 1 month – 10 months 3 months 2 months 6 months 1 year 2 months 1 year 6 months 1 month 1 month 4 months 6 months 6 months 7 months 1 week 2 months – – 15 days to 8 months
Across the ES family of tumours a spectrum of histological and ultrastructural features is seen that can help distinguish between these tumours. Transmission electron microscopy of classical ES demonstrates densely packed undifferentiated tumour cells with cytoplasmic glycogen and scarce organelles. Occasionally, desmosome-like junctions are seen. There is absence of neural differentiation such as dense core neurosecretory granules, neuritic processes, and microtubules. Whereas, PNET ultrastructurally shows abundant organelles, dense core neurosecretory granules and neuritic processes [24]. ES should be differentially diagnosed from other round cell tumours like small cell osteogenic sarcoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, neuroblastoma, desmoplastic small
round cell tumour, lymphoblastic lymphoma and poorly differentiated synovial sarcoma. A panel of immune markers are needed to differentially diagnose these small round cell tumours which include vimentin, CD99, leucocyte common antigen (LCA), pancytokeratin, desmin, MYOD1/myogenin, chromogranin, and S100 protein (Table 4). The most useful, though nonspecific marker is CD99, which produces a strong diffuse membranous staining pattern in “chain-mail pattern” in up to 98% cases [20,24,25]. CD99 also known as MIC2 is a 32-kDa integral membrane glycoprotein is encoded by the MIC2 gene located in the end of the short arm of the X and Y chromosomes. CD99 has a key role in several biological processes, including cell adhesion, migration, and apoptosis; differentiation of T cells and thymocytes; diapedesis of
Fig. 5. (A) Photomicrograph showing tumour mass composed of small, round cells with minimal cytoplasm and indiscernible cytoplasmic boundary (H&E 40×). (B) Photomicrograph showing tumour cells arranged in cords and strands. (H&E 10×). (C) Photomicrograph showing the presence of mitotic figures in round cells (arrow). (H&E 100×). (D) Photomicrograph showing an area of tumour cells undergoing necrosis (encircled area). (H&E 40×). (E, F) Photomicrographs showing membranous positivity for CD99 in round cells.
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Table 4 Immunohistochemical analysis of various round cell tumours. Tumour
CD99
FLI-1
NSE
S-100
Ewing’s sarcoma/PNET Lymphoblastic lymphoma Neuroblastoma Desmoplastic small round cell tumour Mesenchymal chondrosarcoma Rhabdomyosarcoma
++ ++
++ + +
■
■
++ ++ ++ ■
■ ■ ■ ■
■ ++ ■
Desmin
MyoD1
CK
LCA
■ ++ ++ ++
++
++ ■ ■
Modified from Enzinger and Weiss’s Soft Tissue Tumors. +, frequently positive; ■, rarely positive.
lymphocytes to inflamed vascular endothelium; maintenance of cellular morphology; and regulation of intracellular membrane protein trafficking. Gene expression profiling studies have supported the hypothesis that CD99 affects differentiation and malignancy of round cells. Thus, CD99 plays a role as inhibitor of neuronal differentiation and blockade of basal CD99 function can be used as a new therapeutic approach for ES [26–28]. CD99 positivity is also seen in lymphoblastic lymphoma and mesenchymal chondrosarcoma. Amongst these, lymphoblastic lymphoma is composed of lymphoid cells, intermixed with round cell of varying size and cytoplasmic contents. The nuclei are round or oval with a distinct nuclear membrane. The reticulin stain is often positive and cells are LCA positive. Mesenchymal chondrosarcoma has biphasic pattern and is composed of scattered areas of cartilage, together with highly vascular mesenchymal tissue composed of undifferentiated spindle cells or round cells with cytoplasm. Blending of islands of cartilage with cellular areas is observed. This tumour shows NSE positivity [21]. Thus, ES can be differentiated from these two based on H&E and positivity for other markers. FLI 1 nuclear positivity has been reported in 71%–84% cases of ES/PNET and polyclonal antibodies to this protein have been developed. FLI 1 protein expression has been found in 94% cases with EWS-FLI1 fusions. But despite its high sensitivity FLI 1 is also frequently positive in lymphoblastic lymphomas. So, FLI-1 positivity can help in distinguishing ES from other CD99 positive round cell tumours and antibodies to FLI 1 may play a valuable adjunctive role in the diagnosis of ES/PNET [29]. In the present series, all cases showed strong membranous positivity for CD99 though the staining intensity was different due to different clones of antibody used (Fig. 5E and F). The tumour cells were negative for other markers with focal positivity for S-100 in one case (case#4) (Table 4). Multimodal therapy using a combination of chemotherapy, surgery, and radiotherapy is being used now for the treatment of ES. The patients are treated systemically with high dose chemotherapy, and locally, surgical excision is done if possible. Neoadjuvant chemotherapy is the initial treatment modality used which is followed by either surgery or radiation therapy depending on tumour response to the treatment. Before the advent of chemotherapy, the survival rate was less than 10% but it has improved to 50%. Rosen et al., 1974 proposed a combination of vincristine, actinomycin D, cyclophosphamide and doxorubicin (VACD) for treating ES. This combination had a 5-year survival rate of 60% [30]. Other chemotherapeutic agents being used are ifosfamide and etoposide (IE) [25,31]. In all our cases multimodal therapy was employed and chemotherapy was the initial treatment modality with surgery and radiotherapy as adjuvant therapies (Table 1). In our series, promising results were obtained using the above treatment modalities and follow-up duration ranged from 1 to 8 years with no recurrence or adverse outcome reported till date (Fig. 4). Prognosis in patients of Ewing’s sarcoma has markedly improved with the advent of multimodal therapy. The 5-year survival rate with the current treatment options is around 65%. The prognostic factors include presence of metastatic disease at time of
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