esthesioneuroblastoma also called olfactory neuroblastoma is a rare malignant neuroectodermal tumor of the sinonasal tract region , first described by berger et al . in 1924 . according to the world health organization , olfactory neuroblastoma is defined as a  malignant neuroectodermal tumor , that is , assumed to originate from olfactory receptor cells present high in the nasal cavity . this justifies the most common site of the tumor being cribriform plate , middle superior nasal structures and anterior skull base . these tumors show varied morphology with uncertain histogenesis which results in two extremes , i.e. an indolent growth with more than 20-year survival or an aggressive tumor with limited survival and distant metastasis . most of the pathologists encounter difficulties in the diagnosis of these malignancies because of their complex anatomic location , non - specific symptoms , variable morphology and unfamiliarity which leads to misdiagnosis as benign tumors . a case of aggressive olfactory neuroblastoma , which recurred thrice following complete surgical excision , a 24-year - old female patient reported to the outpatient department of our hospital complaining of swelling associated with pain on the left side of the face since 1 month . initially the swelling was about peanut size , which gradually increased to present size , and was associated with pricking and localized pain . her dental history revealed surgical excision of a tumor in 2007 and subsequent recurrent lesion at the same site in 2013 which was again operated . at present , extra - oral examination revealed a solitary diffuse swelling in the left infraorbital region of the face measuring approximately 4 cm  4 cm , extending mediolaterally from the medial canthus of the eye to frontozygomatic region and superioinferiorly from the lower eyelid to 1 cm above the left corner of mouth obliterating the nasolabial fold [ figure 1 ] . intraoral examination showed deficient maxilla and the absence of teeth in relation to 1428 region [ figure 2 ] . extraoral photograph revealing infraorbital swelling on the left side of the face intraoral examination depicting deficient maxilla and the absence of teeth in relation to 1428 region computerized tomography revealed a comminuted fracture of the lateral wall of the left orbit with an asymmetric outline of the globe . the posterior wall of left orbit was also incomplete with little soft tissue masses seen protruding into its posterio - lateral aspect . part of soft tissue was seen extending toward the anterior wall of left maxillary sinus which was completely effaced . two metal plates were seen , supporting the anterior lateral wall of the left maxillary antrum as artifacts . these plates were presumed to be placed in the previous surgeries [ figure 3 ] . computerized tomography revealing comminuted fracture on lateral wall and floor of the left orbit with the tumor mass extending into the orbit on reviewing the dental history , clinical and radiological features , a provisional diagnosis of recurrent ameloblastoma of the left infraorbital region was given . the tumor was surgically excised with normal tissue margins surrounding the lesion and the excised specimen was sent for histopathological examination . microscopic examination revealed a nasociliary epithelium with adjacent tumor area composed of small round cells arranged in lobular pattern separated by fibrovascular stroma . these tumor cells are arranged in pseudorosettes and glandular patterns , and showed round to oval hyperchromatic nucleus with few presenting salt and pepper chromatin pattern . the adjacent bone tissue is infiltrated by these tumor cells along with new bone formation ( osteoid ) . the stroma is fibro - cellular and -vascular with focal areas of neurofibrillary matrix , giant cells and mitoses [ figure 4 ] . photomicrograph showing ( a ) small round cells arranged in sheets and lobules ( h&e stain , 40 ) , ( b ) rosettes in neurofibrillary matrix ( arrow ) and new bone formation ( arrowhead ) ( h&e stain , 100 ) , ( c ) homer wright rosettes ( arrow ) with central neurofibrillary matrix ( h&e stain , 400 ) , ( d ) fibro - cellular and -vascular stroma ( h&e stain , 200 ) based on clinical , radiological and histological findings , a final diagnosis of olfactory neuroblastoma was established . for the confirmation of the diagnosis , immunohistochemistry with a panel of markers was performed [ table 1 and figure 5 ] , establishing the diagnosis as olfactory neuroblastoma . with the suspicion about the former treated pathologies , past records of the patient were reevaluated and subjected to histopathological and immunohistochemical examination . histopathology revealed the characteristic features of olfactory neuroblastoma and was confirmed immunohistochemically with the marker neuron - specific enolase ( nse ) which showed strong positivity [ figure 6 ] . immunohistochemical markers performed photomicrograph showing immunohistochemical staining for ( a ) neuron - specific enolase : strongly positive ( ihc stain , 200 ) , ( b ) chromogranin : positive ( ihc stain , 100 ) , ( c ) s-100 : negative ( ihc stain , 40 ) , ( d ) proliferating cell nuclear antigen : positive ( ihc stain , 40 ) , ( e ) ki-67 : positive ( labeling index : < 10% ) ( ihc stain , 100 ) [ inset : showing two positive cells , ( ihc stain , 400 ) ] , ( f ) pancytokeratins : focally positive ( ihc stain , 200 ) , ( g ) epithelial membrane antigen : negative ( ihc stain , 100 ) , ( h ) caldesmon : negative ( ihc stain , 100 ) , ( i ) cytokeratin-7 : negative ( ihc stain , 100 ) . nse : neuron - specific enolase , pcna : proliferating cell nuclear antigen , ema : epithelial membrane antigen photomicrograph showing immunohistochemical staining of marker neuron - specific enolase ( nse ) showing strong positivity in previously treated pathologies . ( a ) section of tumor mass resected in 2007 ( ihc stain , 100 ) , ( b ) section of tumor mass resected in 2013 ( ihc stain , 100 ) although there is no much evidence regarding the origin of olfactory neuroblastoma , few studies reported the possible source of this tumor to be specialized neuroectodermal olfactory cells . even in the present case , there was an evidence of olfactory epithelium extending along the tumor mass . other specific sites of origin for this tumor include jacobson 's vomeronasal organ , sphenopalatine ganglion , ectodermal olfactory placode , ganglion of loci ( nervus terminalis ) and autonomic ganglia of the nasal mucosa . most commonly reported in all age groups with a bimodal peak in second and sixth decade with no gender predilection . in the present case , the female patient first developed tumor at an age of 16 with recurrences noticed at 22 and 24 years . tumors in advanced stages usually present orbital symptoms such as proptosis and excessive lacrimation , which were also noticed in the current case report . computed tomography ( ct ) the ct features of olfactory neuroblastoma are nonspecific and so can not be differentiated from other tumors such as undifferentiated lymphoma , rhabdomyosarcoma , squamous cell carcinoma , extramedullary plasmacytoma and amelanotic melanoma . the aggressive nature of this tumor is determined by kadish staging system , which is based on the clinical spread of the tumor [ table 2 ] . moritaet al . modified kadish staging system by incorporating group d for tumors with regional ( cervical lymph node ) or distant metastases . an extensive research of previous cases of olfactory neuroblastomas revealed their presence in kadish stage c. the present case was also categorized under stage c as the tumor mass was shown to be extending into the orbit . however , kadish system could not give a definite comparison between the prognosis of surgically operable and inoperable tumors because tumors in the neck , orbit , intracranial portion and distant metastasis were all included in the same stage . hence , histopathological grading is also mandatory to predict the treatment outcome and survival rate of this tumor . kadish clinical staging system histopathologically , hyams grading system is used to differentiate low - grade ( grade 1 and 2 ) from high - grade tumors ( grade 3 and 4 ) . grading is based on few defining features of olfactory neuroblastoma such as lobular architecture , rosettes , neurofibrillary matrix , pleomorphism , mitoses , necrosis and presence of calcifications [ table 3 ] . two types of rosettes are seen , of which pseudorosettes ( homer wright rosettes ) are the more common . they are characterized by a delicate neurofibrillary and edematous stroma that forms the center of a palisaded arrangement of tumor cells . true rosettes ( flexner  wintersteiner rosettes ) have a tight ,  gland - like  annular arrangement . in the present case , most of the tumor cells are arranged in pseudorosette pattern in a fibro - cellular and vascular connective tissue stroma representing a stromal reaction to the proliferating tumor islands . hyams histopathological grading system histopathological evaluation of our case revealed the tumor in hyams grade 2 , which is considered as a low - grade tumor . however , according to kadish system , our case can be categorized as high - grade malignancy . despite its shortcomings , the other classification systems for olfactory neuroblastoma are according to biller et al . , and dulguerov and calcaterra . , among all classification systems , only kadish system revealed a statistically significant discrimination among stages for relapse - free survival . the differential diagnosis included primary intraosseous carcinoma , ameloblastic carcinoma and salivary gland carcinoma . to differentiate whether it was derived from the salivary gland epithelium , a panel of immunohistochemical markers such as epithelial membrane antigen ( ema ) , cytokeratin-7 ( ck-7 ) and caldesmon was used which showed a negative staining pattern . hence , the salivary gland tumors were ruled out . as histopathology showed nasociliary epithelium which shows olfactory neural cells , markers specific for neuroectodermal cells , such as nse and chromogranin , were used which showed a strong positive reaction with nse and weak positivity with chromogranin . to determine the proliferation rate , immunohistochemical staining with ki 67 and proliferating cell nuclear antigen ( pcna ) was done , which showed the labeling index of ki 67 to be < 10% and strong positivity with pcna . other markers include synaptophysin , neurofilament protein , class iii beta - tubulin , microtubule - associated protein , chromogranin , glial fibrillary acidic protein and leu-7 . the present case showed focal positivity for cks which signifies that there are focal areas of epithelial differentiation which is a common feature of olfactory neuroblastoma . caldesmon is a marker for neoplastic myoepithelial cells and ck-7 is usually positive for salivary gland neoplasms . s-100 positivity is mostly seen in the periphery , which represents the schwann cells or sustentacular cells usually present along the periphery of neoplastic lobules . in our case , s-100 staining was negative which is a common feature seen in high - grade tumors . ki-67 positivity showed < 10% labeling index , which implies that the tumor is well differentiated and associated with long - term survival , whereas poorly differentiated ( hyams grade 3 and 4 ) are associated with a high proliferation index . a combined treatment of surgery and radiation therapy ( rt ) resulted in a better recurrence -free rate ( 60100% ) compared with surgery alone ( 1456% ) . lund et al . considered the above combination as the gold standard treatment . in the present case , as the tumor was extended into the orbit ( kadish stage c ) and as the tumor recurred thrice , aggressive surgical excision with adjuvant radiotherapy is the mainstay of treatment . elkon included the presence of metastasis and local extension of the tumor ( e.g. ethmoidal , nasopharynx , orbital ) as negative prognostic factors . a proper diagnosis should be made through clinical , radiographic and histopathological findings and the tumor should be staged and graded before proceeding to surgery . aggressive surgical resection and rt is the mainstay of treatment and patients must be followed up carefully as local or regional recurrences are most commonly associated . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .