Primary primitive neuroectodermal tumor of the orbit

Primitive neuroectodermal tumor (PNET) is a small round cell malignant tumor of neuroectodermal origin. Most of the PNETs occur in the central nervous system (CNS). PNETs recognized outside of CNS are diagnosed as peripheral PNET (pPNET). This tumor which expresses MIC-2 gene (CD99) seems to be least aggressive after complete tumor resection. We describe a rare case of PNET in a young girl. A 58-year-old-man presented with painful rapidly progressive bilateral proptosis with restricted ocular movements of 15 days duration. There was history of significant weight loss in the recent past. Computed tomography scan of the head and orbit revealed bilateral multiple, well-defined, round, soft tissue masses, isointense with muscles in intraconal and extraconal space. Fine needle aspiration cytology and incision biopsy from the lesion, urine for Bence-Jones proteins and immunofixation clinched the diagnosis of multiple myeloma. Skeletal survey did not reveal any bony involvement. The diagnosis of multiple myeloma should be kept in mind in cases of bilateral proptosis. Bony involvement is not universal in cases of orbital myeloma. Early diagnosis can be established with extensive biochemical and histopathological investigations and timely treatment is life saving for these patients.

Peripheral primary primitive neuroectodermal tumor (PNET) is seen in young adults and adolescents and has no sex predilection. Primary orbital pPNET is extremely rare and only nine cases have been reported previously. [1][2][3][4][5][6][7][8][9] pPNET shows characteristic small round cell tumor with rosette or pseudo-rosette, positive immunohistochemistry (IHC) and in some cases there are ultrastructural findings of neurosecretory granules. This report presents the clinical, radiological and histopathologic features of a left orbital mass in a young girl. IHC confirmed the diagnosis of pPNET. This rare tumor of the orbit should be considered in the differential diagnosis of hypercellular small round cell tumor of the orbit.

Case Report
An eight-year-old female child was brought to our outpatient department for progressing protrusion of the left eye ball for two months. There was associated diplopia with restriction of ocular movements superiorly and laterally. There was minimal ptosis and she had ocular pain over a period of four weeks. There was no history of injury, fever, chronic cough or other systemic symptoms. Her ophthalmic examination did not reveal any additional pathology other than a localized mass in the anterior orbit. On examination, a tender, firm, fixed, non-pulsating globular mass (4 x 3 cm) with irregular surface was felt in the supero-temporal quadrant of the left orbit. Ocular examination was otherwise normal. Computed tomography (CT) scans of the orbit and brain depicted a soft tissue enhanced irregular mass located in the supero-temporal part of the left orbit without evidence of any bone defect or erosion [ Fig. 1]. Complete hemogram, including general blood picture, erythrocyte sedimentation rate and X-ray chest were normal. Human immunovirus and HBsAg screening tests were negative. Anterior orbitotomy of the left orbit was done under general anesthesia and en block excisional biopsy of the tumor was performed. Grossly, the tumor was well encapsulated and measured 3.2 x 2.6 x 1.5 cm and weighed 12 g.
The 10% neutral buffered formalin-fixed tissue fragment was white and firm. It was embedded in paraffin and sections were stained with hematoxylin-eosin. Histopathological examination of the tumor revealed round cells having eosinophilic cytoplasm and round nuclei. The cells were arranged in sheets and cords with thin sclerotic stroma. Few pseudo-rosettes which were viable tumor cells around the blood vessels were seen. There was no evidence of necrosis and hemorrhage. [ Fig. 2A] Sections were studied by IHC for neuron-specific enolase (NSE) (ab "BBS/NC/VI-HI4), leukocyte common antigen (LCA) CD45 (ab "2BII+PD 7/26"), S-100 protein (ab "S1/61/69"), Desmin (ab "D-33") and MIC-2 (ab "12E7") using avidin-biotin complex technique. These antibodies were applied synchronously with appropriate positive control slides. In our case, IHC was positive for MIC-2 gene (CD45-ve, S-100-ve, Desmin -ve, NSE-ve) [ Fig. 2 B]. On the basis of these findings, a diagnosis of primary pPNET of the orbit was made. The patient's diplopia and pain resolved one week after the surgery. Complete systemic evaluation was carried out which was normal. Patient is being followed up every three months and orbital CT scans are repeated on every visit without any sign of recurrence. Patient is under close observation of oncologist and there are no signs of recurrence for the last six months.

Discussion
The differential diagnosis of pPNET of the orbit includes other small blue round cell tumors which include rhabdomyosarcoma (Actin+, Vimentin+, Desmin +, S-100-ve), Ewing's sarcoma (PGP9.5+, MIC-2+), lymphoma (LCA+, CD45+/CD20+/ CD3+), neuroblastoma (PGP9.5+, MIC-2 -ve) and metastatic retinoblastoma to orbit (NSE+, GFAP+). [2][3][4] Peripheral primitive neuroectodermal tumors are rare lesions that form part of the Ewing family of tumors, which includes osseous and extraosseous Ewing's sarcoma. All are characterized by translocations involving the EWS gene at 22q12, usually the translocation t(11;22)(q24;12). [7,8] Histopathological appearances of a small, round, dark blue cell tumor with monotonous, highly cellular pattern, pseudo-rosette formation and strong membrane positivity for the MIC-2 gene product in IHC is the Indian Journal of Ophthalmology Vol. 57 No. 5 hallmark for diagnosis of pPNET. In some cases they are NSE, synaptophysin and S-100-positive. [7] Alyahya et al. [8] had reported an orbital, intraconal pPNET in a five-year-old child with microphthalmia since birth. Orbitotomy was performed and a large, polycystic, retroscleral, intraconal tumor was removed. Subsequent histological, immunohistochemical and electron-microscopic analysis of the mass was performed. The tumor showed characteristic features of pPNET with pseudo-rosettes, positive IHC for the MIC-2 gene and synaptophysin and ultrastructral finding of neurosecretory granules. Their case report was the first orbital case of pPNET to express the MIC-2 gene. [8] The MIC-2 gene is a pseudoautosomal gene located on the short arms of both X and Y chromosomes. The gene harvests glycoproteins of related molecular weight designated p30 and p32. The proteins programmed by MIC-2 gene are neuraminidase and protease sensitive. In red cells, MIC-2 gene is synchronized by the X-linked XG gene, resulting in quantitative polymorphism for level of MIC-2 gene product. [10] MIC-2,12E7 is used in different dilutions determined on formalin-fixed paraffin-embedded tissue. A study of 70 different tumors has shown that among the neoplastic tissues, only glioblastoma and ependymoma of central nervous system (CNS) as well as certain islet cell tumors of pancreas reacted positively. Since the MIC-2 gene products are most strongly expressed on cell membranes of Ewing's sarcoma and pPNET, expression of the gene products allows for the differentiation of these tumors from other round cells tumors of childhood and adolescence. [10] In this context, our case report is the second in literature where MIC-2 fraction of IHC was positive for pPNET. In spite of aggressive malignant features of pPNET, orbital variety seems to be the least aggressive since most of the reported patients are still alive. [8,10] In our case, we can better comment on the ultimate prognosis after we follow up the case for atleast two years.
The present case report highlights that differential diagnosis of hypercellular small round cell tumor of the orbit should be recognized and pPNET must be considered as possible diagnosis by the ocular pathologists. This rare tumor can be confirmed by IHC.

Archana Malik, Subina Narang, Uma Handa 1 , Sunandan Sood
A 58-year-old-man presented with painful rapidly progressive bilateral proptosis with restricted ocular movements of 15 days duration. There was history of significant weight loss in the recent past. Computed tomography scan of the head and orbit revealed bilateral multiple, well-defined, round, soft tissue masses, isointense with muscles in intraconal and extraconal space. Fine needle aspiration cytology and incision biopsy from the lesion, urine for Bence-Jones proteins and immunofixation clinched the diagnosis of multiple myeloma. Skeletal survey did not reveal any bony involvement.
The diagnosis of multiple myeloma should be kept in mind in cases of bilateral proptosis. Bony involvement is not universal in cases of orbital myeloma. Early diagnosis can be established with extensive biochemical and histopathological investigations and timely treatment is life saving for these patients. Multiple myeloma is a subgroup of plasma cell dyscrasias in which there is neoplastic proliferation of plasma cells or their precursors. Unilateral proptosis is a well-recognized but somewhat rare presentation of multiple myeloma in ophthalmic practice. [1,2] Bilateral proptosis with multiple soft tissue masses is an extremely rare presentation of multiple myeloma. [3] We report a case of multiple myeloma that presented with bilateral proptosis due to multiple orbital soft tissue lesions without any bony involvement.

Case Report
A 58-year-old-man presented with painful rapidly progressive bilateral proptosis with restricted ocular movements of 15 days duration. There was history of about 10-kg weight loss amounting to 15% of his body weight over a period of the past one month. Ophthalmic examination revealed visual acuity of 20/30 in both eyes. His right eyeball was pushed inferiorly and laterally and left eye showed axial proptosis [ Fig. 1]. Hertel's exophthalmometry reading was 24 mm in the right eye (RE) and 21 mm in the left eye (LE) with intercanthal distance of 110 mm. RE was shifted inferiorly by 5 mm and laterally by 2 mm as measured with plastic scale. There was increased retrobulbar resistance. In the RE, maximal restriction of ocular movements was noted in levoelevation and adduction with mild restriction in other gazes. There was mild restriction of movements in all gazes in the LE. On deep palpation a smooth, round, firm, nontender mass (approximately 2.5 cm x 2 cm) could be palpated in the superior orbit of the RE. The posterior extent of the mass could not be reached and it was free from the overlying skin.
No mass lesion could be palpated in the LE. The proptosis was non-compressible and did not have any postural variation. Anterior segment biomicroscopy and pupillary reactions were normal in both eyes except for higher intraocular pressure in the RE of 24 mm of Hg on Goldman applanation tonometry. The intraocular pressure was 12 mm of Hg in the LE. Fundus examination revealed few scattered hemorrhages and cottonwool spots in both eyes. Computed tomography (CT) scan of the head and orbit revealed bilateral multiple, well-defined, round, soft tissue masses, isointense with muscles in the intraconal and extraconal space [ Fig. 2]. Three days after his initial presentation to us, the patient noticed development of subcutaneous nodules on his left thigh and abdomen.
The differential diagnosis of secondaries from an unknown primary, blood cell-related tumor including lymphoma or plasma cell dyscrasias was kept. Hemogram and coagulation profile showed hemoglobin of 7.8 g/dl (Normal: 14-16 g/ dl) though his blood counts and coagulation profile was normal. To look for an unknown primary from the lung, prostate, gastrointestinal tract; endoscopy, colonoscopy, stool examination and prostate examination was done. Examination of the gastrointestinal tract (GIT) and prostate was unremarkable. CT abdomen revealed paravertebral soft tissue mass and contrast enhanced CT (CECT) chest revealed a soft tissue mass in the parahilar region.
Fine needle aspiration cytology (FNAC) followed by incision biopsy of the orbital mass and FNAC from the left thigh nodule showed cellular sheets of mature and immature plasma cells, many binucleate and multinucleate forms were seen, suggestive of plasmacytoma [ Fig. 3]. Keeping in the mind diagnosis of multiple myeloma Bence-Jones protein testing, bone marrow examination, skeletal survey and immunofixation was done. The urine was positive for Bence-Jones protein. Serum and urine electrophoresis showed a sharp M-band in the gamma region. Immunofixation confirmed the diagnosis of IgG multiple myeloma. Skeletal survey, however, did not reveal any