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Letters to the Editor
845
5. Crozier JA, Andhavarapu S, Brumble LM, Sher T. First report of Nocardia beijingensis infection in an immunocompetent host in the United States. J Clin Microbiol 2014; 52: 2730–2.
Congenital orbital primitive neuroectodermal tumour A 14-day-old female presented to the eye department with left proptosis present at birth. She was born in the 39th week of gestation via an uncomplicated vaginal delivery. On examination, she had a palpable mass over her left superior orbital margin. There was left proptosis and her eye was displaced downward and outwards, with no visible pulsation or inflammation (Fig. 1). The pupils were normal and a complete physical examination was unremarkable. Magnetic resonance imaging demonstrated an isolated left extraconal orbital mass (Fig. 2). Her chest X-ray and ultrasound of the abdomen were normal. Full blood count, biochemical studies, coagulation studies and liver function tests were normal except for a slightly raised activated partial thromboplastin time (32 s) and bilirubin (32 μmol/ L), and some normochromic irregular-shaped cells on the blood film. She underwent a biopsy of the extraconal mass with the rest of the mass being extensively debulked by suction aspiration. Histologically, the tumour had a lobulated architecture with sheets of cells divided into lobules by prominent thin-walled vascular network. The cells were small and monotonous with round to oval nuclei, fine chromatin, multiple small nucleoli and ill-defined, vacuolated, pale-staining cytoplasm. There was no necrosis. (Fig. 3a). Immunohistochemistry was strongly positive for CD99 (Fig. 3b), vimentin and S-100, but negative for CD56, NSE, cytokeratin cocktail, leucocyte common antigen, desmin and myogenin. Fluorescent in-situ hybridization (FISH) detected an EWSR1 (22q12) gene rearrangement in all 100 cells examined (Fig. 3c), which confirmed the diagnosis of orbital primitive neuroectodermal tumour (PNET). The parents were offered intensive chemotherapy for their child, followed by local therapy consisting of either complete surgical excision with clear margins of the tumour or adjunct radiotherapy if clear margins were not obtained, followed by additional chemotherapy. Given the extremely poor prognosis and significant treatment sideeffects, the parents opted for palliation therapy only, and the infant passed away 7 weeks later. Primary orbital PNET is a subset of peripheral PNET (pPNET) tumour. It is part of the Ewing sarcoma (ES) family of tumours.1 pPNET and ES are considered mani-
Figure 1. Prominent supraorbital mass on the left with obvious proptosis and incomplete lid closure. The eye appeared noninflammed, and it is displaced inferiorly and temporally. festations of the same disease spectrum, with pPNET having a higher degree of neural differentiation than ES.2 It is extremely rare and believed to affect primarily children and adolescents, with no gender predilection. To the best of our knowledge, there have been 26 reported cases of primary orbital PNET in the literature, of which 17 cases occurred in the paediatric population. There are only two congenital orbital PNET reported in the literature based on histology and immunohistochemistry.3,4 We believed our patient is the first congenital orbital PNET where the diagnosis confirmation has included cytogenetic testing besides histology and immunohistochemistry. The diagnosis of PNET can be made based on the following:
1
2
3
Conflict of interest: None. Funding sources: None. © 2015 Royal Australian and New Zealand College of Ophthalmologists
Histology: These tumours contain a high nuclear to cytoplasmic ratio. The hyperchromatic cell nucleus may contain one or more nucleoli, giving it the characteristic features of a ‘small round cell’ tumour. The cells usually contain glycogen, which can be detected by the periodic acid Schiff stain.1 Occasionally, rosette formation is observed.1 Immunohistochemistry: A profile of the tumour is obtained by recognizing the surface antigens present on the tumour cell surface. CD99, S-100 protein, glial fibrillary acidic protein, cytokeratin, epithelial membrane antigen, neurofilament, neuron-specific enolase, vimentin and synaptophysin have all been associated with PNET.2 CD99 is present in up to 95% of pPNET and ES tumour, making it a highly sensitive marker,5 although with poor specificity, as other tumours such as lymphoblastic lymphoma, rhabdomyosarcoma, synovial sarcoma also express CD99. Absence of certain gene products helps rule out other differential diagnoses.5 Cytogenetic studies: More than 85% of pPNET/ES tumour have a t(11;22) (q24:q12) translocation resulting in the fusion of EWRS1 (also known as EWS) gene on chromosome 22q12 to the FLI1 gene on chromosome 11q24. This translocation gives rise to a chimeric fusion gene known as EWS-FLI1, which expresses CD99 surface antigen.1 Another 10–15% involve a t(21;22) (q22;q12) translocation giving rise to
846
Letters to the Editor
Figure 2. Magnetic resonance images (MRI) showing a left extraconal orbital mass which immediately abutted the orbital contents, displacing the globe and intraconal compartment anteriorly and inferiorly, and extended directly into the anterior cranial fossa with attenuation of the surrounding bones and dura. It was predominantly solid with a small cystic component. Arrows indicate (a) the area of restricted diffusion on transverse view of apparent diffusion coefficient MRI; (b) isointense supraorbital mass on sagittal view of T2 weighted pre-contrast scan; and (c) contrast enhancement of the supraorbital mass on coronal view of T1 weighted post-contrast scan.
Figure 3. (a) High magnification (×400) histological specimen showing small malignant cells with multiple nucleoli, scanty cytoplasm and vascular network. (b) Immunostaining with CD99 was positive in malignant cells. (c) Fluorescent in-situ hybridization showing two homologous chromosomes: one normal (white arrow) with co-localization of green [3'EWSR1] and orange probes [5'EWSR1] indicating normal gene sequence, and the other homologue (yellow arrows) with separated green and orange probes indicating rearrangement of EWSR1 gene.
the EWS-ERG fusion gene.1 Other translocations and more complex gene fusions have been described in the literature but contribute to less than 5% of the pPNET/ES cases.1 These translocations can be easily identified using FISH – a cytogenetic analysis that locates specific gene sequences on the chromosomes by using complementary fluorescent tags to bind to these gene sequences. The previous two congenital cases were diagnosed purely on histology and immunohistochemistry.3,4 However, cytogenetic studies add further support for the diagnosis. Treatment usually follows closely to that for ES as PNET is extremely rare. These include combinations of surgical removal/debulking and chemotherapy with or without radiotherapy.2 One case had the tumour excised and chemoradiotherapy, but the tumour rapidly re-grew at the resection margin, and she passed away months later. The other case only had chemotherapy but died during the fourth cycle. Our patient died at week 7 without treatment despite extensive debulking of the
orbital component of the tumour at the time of biopsy. It appears that congenital orbital PNET appears more aggressive with rapid growth and fatality compared with other age groups.2 The diagnosis of pPNET can be made based on histology, immunohistochemical and cytogenetic testing. Primary orbital PNET is rare, and even more rarely presents at birth. Current treatment of orbital PNET follows closely that of ES, although there is still no general consensus, and the rarity of the disease means that evaluation of treatment modalities remains difficult. Congenital orbital PNET appears to be more aggressive compared with those occurring in other age groups, and age may be an important prognostic factor. Although we can now diagnose orbital PNET more accurately, optimal treatment remains to be determined.
Dickson Wong MBChB and Robert Weatherhead FRANZCO Eye Department, Christchurch Hospital, Christchurch, New Zealand Received 16 February 2015; accepted 23 June 2015.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Letters to the Editor
REFERENCES 1. Desai SS, Jambhekar NA. Pathology of Ewing’s sarcoma/PNET: current opinion and emerging concepts. Indian J Orthop 2010; 44: 363–8. 2. Chokthaweesak W, Annunziata CC, Alsheikh O et al. Primitive neuroectodermal tumor of the orbit in adults: a case series. Ophthal Plast Reconstr Surg 2011; 27: 173–9. 3. Bakhshi S, Meel R, Naqvi SG et al. Therapy and outcome of orbital primitive neuroectodermal tumor. Pediatr Blood Cancer 2009; 52: 544–7.
847 4. Lim TC, Tan WT, Lee YS. Congenital extraskeletal Ewing’s sarcoma of the face: a case report. Head Neck 1994; 16: 75–8. 5. Ambros IM, Ambros PF, Sterhl S, Kovar H, Gadner H, Salzer-Kuntschik M. 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 tumor from MIC2 expression and specific chromosome aberration. Cancer 1991; 67: 1886– 93.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Letters to the Editor
845
5. Crozier JA, Andhavarapu S, Brumble LM, Sher T. First report of Nocardia beijingensis infection in an immunocompetent host in the United States. J Clin Microbiol 2014; 52: 2730–2.
Congenital orbital primitive neuroectodermal tumour A 14-day-old female presented to the eye department with left proptosis present at birth. She was born in the 39th week of gestation via an uncomplicated vaginal delivery. On examination, she had a palpable mass over her left superior orbital margin. There was left proptosis and her eye was displaced downward and outwards, with no visible pulsation or inflammation (Fig. 1). The pupils were normal and a complete physical examination was unremarkable. Magnetic resonance imaging demonstrated an isolated left extraconal orbital mass (Fig. 2). Her chest X-ray and ultrasound of the abdomen were normal. Full blood count, biochemical studies, coagulation studies and liver function tests were normal except for a slightly raised activated partial thromboplastin time (32 s) and bilirubin (32 μmol/ L), and some normochromic irregular-shaped cells on the blood film. She underwent a biopsy of the extraconal mass with the rest of the mass being extensively debulked by suction aspiration. Histologically, the tumour had a lobulated architecture with sheets of cells divided into lobules by prominent thin-walled vascular network. The cells were small and monotonous with round to oval nuclei, fine chromatin, multiple small nucleoli and ill-defined, vacuolated, pale-staining cytoplasm. There was no necrosis. (Fig. 3a). Immunohistochemistry was strongly positive for CD99 (Fig. 3b), vimentin and S-100, but negative for CD56, NSE, cytokeratin cocktail, leucocyte common antigen, desmin and myogenin. Fluorescent in-situ hybridization (FISH) detected an EWSR1 (22q12) gene rearrangement in all 100 cells examined (Fig. 3c), which confirmed the diagnosis of orbital primitive neuroectodermal tumour (PNET). The parents were offered intensive chemotherapy for their child, followed by local therapy consisting of either complete surgical excision with clear margins of the tumour or adjunct radiotherapy if clear margins were not obtained, followed by additional chemotherapy. Given the extremely poor prognosis and significant treatment sideeffects, the parents opted for palliation therapy only, and the infant passed away 7 weeks later. Primary orbital PNET is a subset of peripheral PNET (pPNET) tumour. It is part of the Ewing sarcoma (ES) family of tumours.1 pPNET and ES are considered mani-
Figure 1. Prominent supraorbital mass on the left with obvious proptosis and incomplete lid closure. The eye appeared noninflammed, and it is displaced inferiorly and temporally. festations of the same disease spectrum, with pPNET having a higher degree of neural differentiation than ES.2 It is extremely rare and believed to affect primarily children and adolescents, with no gender predilection. To the best of our knowledge, there have been 26 reported cases of primary orbital PNET in the literature, of which 17 cases occurred in the paediatric population. There are only two congenital orbital PNET reported in the literature based on histology and immunohistochemistry.3,4 We believed our patient is the first congenital orbital PNET where the diagnosis confirmation has included cytogenetic testing besides histology and immunohistochemistry. The diagnosis of PNET can be made based on the following:
1
2
3
Conflict of interest: None. Funding sources: None. © 2015 Royal Australian and New Zealand College of Ophthalmologists
Histology: These tumours contain a high nuclear to cytoplasmic ratio. The hyperchromatic cell nucleus may contain one or more nucleoli, giving it the characteristic features of a ‘small round cell’ tumour. The cells usually contain glycogen, which can be detected by the periodic acid Schiff stain.1 Occasionally, rosette formation is observed.1 Immunohistochemistry: A profile of the tumour is obtained by recognizing the surface antigens present on the tumour cell surface. CD99, S-100 protein, glial fibrillary acidic protein, cytokeratin, epithelial membrane antigen, neurofilament, neuron-specific enolase, vimentin and synaptophysin have all been associated with PNET.2 CD99 is present in up to 95% of pPNET and ES tumour, making it a highly sensitive marker,5 although with poor specificity, as other tumours such as lymphoblastic lymphoma, rhabdomyosarcoma, synovial sarcoma also express CD99. Absence of certain gene products helps rule out other differential diagnoses.5 Cytogenetic studies: More than 85% of pPNET/ES tumour have a t(11;22) (q24:q12) translocation resulting in the fusion of EWRS1 (also known as EWS) gene on chromosome 22q12 to the FLI1 gene on chromosome 11q24. This translocation gives rise to a chimeric fusion gene known as EWS-FLI1, which expresses CD99 surface antigen.1 Another 10–15% involve a t(21;22) (q22;q12) translocation giving rise to
846
Letters to the Editor
Figure 2. Magnetic resonance images (MRI) showing a left extraconal orbital mass which immediately abutted the orbital contents, displacing the globe and intraconal compartment anteriorly and inferiorly, and extended directly into the anterior cranial fossa with attenuation of the surrounding bones and dura. It was predominantly solid with a small cystic component. Arrows indicate (a) the area of restricted diffusion on transverse view of apparent diffusion coefficient MRI; (b) isointense supraorbital mass on sagittal view of T2 weighted pre-contrast scan; and (c) contrast enhancement of the supraorbital mass on coronal view of T1 weighted post-contrast scan.
Figure 3. (a) High magnification (×400) histological specimen showing small malignant cells with multiple nucleoli, scanty cytoplasm and vascular network. (b) Immunostaining with CD99 was positive in malignant cells. (c) Fluorescent in-situ hybridization showing two homologous chromosomes: one normal (white arrow) with co-localization of green [3'EWSR1] and orange probes [5'EWSR1] indicating normal gene sequence, and the other homologue (yellow arrows) with separated green and orange probes indicating rearrangement of EWSR1 gene.
the EWS-ERG fusion gene.1 Other translocations and more complex gene fusions have been described in the literature but contribute to less than 5% of the pPNET/ES cases.1 These translocations can be easily identified using FISH – a cytogenetic analysis that locates specific gene sequences on the chromosomes by using complementary fluorescent tags to bind to these gene sequences. The previous two congenital cases were diagnosed purely on histology and immunohistochemistry.3,4 However, cytogenetic studies add further support for the diagnosis. Treatment usually follows closely to that for ES as PNET is extremely rare. These include combinations of surgical removal/debulking and chemotherapy with or without radiotherapy.2 One case had the tumour excised and chemoradiotherapy, but the tumour rapidly re-grew at the resection margin, and she passed away months later. The other case only had chemotherapy but died during the fourth cycle. Our patient died at week 7 without treatment despite extensive debulking of the
orbital component of the tumour at the time of biopsy. It appears that congenital orbital PNET appears more aggressive with rapid growth and fatality compared with other age groups.2 The diagnosis of pPNET can be made based on histology, immunohistochemical and cytogenetic testing. Primary orbital PNET is rare, and even more rarely presents at birth. Current treatment of orbital PNET follows closely that of ES, although there is still no general consensus, and the rarity of the disease means that evaluation of treatment modalities remains difficult. Congenital orbital PNET appears to be more aggressive compared with those occurring in other age groups, and age may be an important prognostic factor. Although we can now diagnose orbital PNET more accurately, optimal treatment remains to be determined.
Dickson Wong MBChB and Robert Weatherhead FRANZCO Eye Department, Christchurch Hospital, Christchurch, New Zealand Received 16 February 2015; accepted 23 June 2015.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Letters to the Editor
REFERENCES 1. Desai SS, Jambhekar NA. Pathology of Ewing’s sarcoma/PNET: current opinion and emerging concepts. Indian J Orthop 2010; 44: 363–8. 2. Chokthaweesak W, Annunziata CC, Alsheikh O et al. Primitive neuroectodermal tumor of the orbit in adults: a case series. Ophthal Plast Reconstr Surg 2011; 27: 173–9. 3. Bakhshi S, Meel R, Naqvi SG et al. Therapy and outcome of orbital primitive neuroectodermal tumor. Pediatr Blood Cancer 2009; 52: 544–7.
847 4. Lim TC, Tan WT, Lee YS. Congenital extraskeletal Ewing’s sarcoma of the face: a case report. Head Neck 1994; 16: 75–8. 5. Ambros IM, Ambros PF, Sterhl S, Kovar H, Gadner H, Salzer-Kuntschik M. 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 tumor from MIC2 expression and specific chromosome aberration. Cancer 1991; 67: 1886– 93.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
