
				 olfactory neuroblastoma ( onb ) is a rare malignant tumor arising from the olfactory epithelium of the nasal cavity and the paranasal sinuses .
the anatomic origin in the superior nasal cavity leads to nonspecific symptoms that make early diagnosis difficult .
direct extension of the tumor into the anterior cranial fossa , either at presentation or at disease recurrence , is common .
onb is mostly a locally aggressive tumor that can spread to lymph nodes but metastatic involvement of bone , bone marrow , and other organs was also reported .
the most commonly used staging system proposed by kadish is currently based on computer tomography and magnetic resonance imaging . in stage
a , the tumor is limited to the nasal cavity , in stage b the tumor extends to paranasal sinus , and in stage c the tumor is extending over the nasal cavity and sinus and/or metastasized distantly .
a histological grading system based on microscopic findings proposed by hyams at 1988 showed a clear correlation of survival with histological differentiation of disease .  
however most authors believe that craniofacial resection followed by rt offers the gold standard treatment in this disease . despite aggressive therapies , local , regional relapse , and distant metastasis occur frequently and often after extended periods of follow - up .
data for this case series were acquired retrospectively from the files of division of medical oncology , cerrahpasa medical faculty , istanbul university .
additional information regarding the clinical course and outcome was collected from the patients ' charts and phone calls to the patients , their relatives , and their general practitioners . in this study , we have reviewed 19 cases of olfactory neuroblastomas treated over 24-year period and analyzed the clinical features , treatment outcomes , and prognostic factors .
the data of nineteen patients of olfactory neuroblastomas treated and followed up between 1986 and 2010 at division of medical oncology , cerrahpasa medical faculty , istanbul university , were analyzed retrospectively .
patient characteristics , initial symptoms , tumor extent , histologic features , primary therapy , tumor recurrence , and treatments of recurrent disease were determined .
patients were staged according to the kadish staging system . a single pathologist with expertise in head and neck neoplasms reviewed the histological specimens .
local ethics committee 's approval and patients ' or their next of kin 's informed consent were taken before the study .
treatment response was assessed by clinical examinations and computed tomography ( ct ) or magnetic resonance imaging ( mri ) .
survival rates were calculated from diagnosis to the death of the patient using the kaplan - meier life table method .
the madian age at diagnosis was 46 ( range : 19 to 68 years ) .
tumor staging was kadish stage a in 3 , stage b in 5 , and stage c in 11 patients .
four patients had metastasis of cervical lymph nodes , two brains , one bone marrow , one bone and lung metastases , and one bone , mediastinal lymph node , and liver metastases at the time of diagnosis .
tumor localization , clinical symptoms , and presentations at the time of diagnosis are listed in table 1 .
median time from onset of first symptoms until diagnosis was 8.8 months ( range : 1.829 months ) .
the common presenting symptoms were nasal obstruction ( 53% ) , epistaxis ( 31% ) , rhinorrhea , and facial pain ( 26% ) .
patient treatments consisted of surgical resection , radiation therapy , and chemotherapy ( ctx ) ( table 3 ) .
initial treatments included surgery alone in three patients , radiotherapy ( rt ) with or without ctx in five , surgery plus postoperative rt in seven and multimodality therapy ( surgery plus postoperative ctx plus postoperative rt ) in three , and finally ctx alone in one . in 14 patients ,
four of these patients had also radical neck dissection due to cervical lymph nodes involvement .
nasal tumor resection in 2 patients , maxillectomy plus orbital exenteration in 1 , and external ethmoidectomy ( ee ) in 1 were also used as surgical treatments . of these 14 patients who underwent surgical tumor resection ,
4 were treated with surgery alone , 5 with adjuvant radiation therapy after surgery , 2 with adjuvant ctx after surgery , and the remaining 3 with radiation therapy and ctx after surgery . of the remaining 5 patients , four in advanced stage and one in early stage refused surgical treatment .
radiation therapy was administered to two of the patients , radiation therapy followed by ctx to the other two , and ctx alone to one patient .
the average radiation dose was 57.9 gy and the ctx was chosen from cisplatin - based regimens . as a part of the primary treatment modality , 12 patients underwent radiation therapy , so did the five relapsed patients .
as a part of primary treatment modality 8 patients received ctx , so did the three relapsed patients .   
fifteen patients died of tumor progression during the follow - up , of whom 9 were at an advanced stage ( stage c ) by the time of diagnosis and 6 at an early stage ( stage a / b ) .
kadish stage c patients had a significantly poorer outcome compared to the stage a / b patients ( 2-year survival rate : 71 versus 25% , resp .
histopathologically high - grade patients ( grade 3/4 ) had a significantly poorer outcome when compared to the lower grade ( grade 1/2 ) patients ( 2-year survival rate : 16 versus 50% , resp .
primary tumor extensions to orbital area had a significantly poorer outcome compared to the tumors with no extension to orbital area ( 2-year survival rate : 22 versus 60% , resp .
there was no statistically significant difference in survival rate between male and female patients ( 2-year survival rate : 40 versus 44% , resp .
patients with age < 45 years had no poorer outcome compared to patients with age > 45 years ( 2-year survival rate : 41 versus 43% ; p = .059 ) .
brain and bone marrow involvements showed poorer outcome compared to those without such involvement ( median survival rate : 9.1 versus 28.8 months , resp . ;
survival rate was not significantly different among pateints of kadish c when stratified according to initial treatment ( p = .8 ) .  
locoregional recurrence developed in 6 and distant metastasis in 6 patients . during the follow - up period , these groups exhibited distant metastasis to the brain , spinal cord , bone , bone marrow , meninges , and lungs .
as a treatment for recurrence and metastasis , reoperation of primary site plus radiation therapy in 4 patients and radiation therapy alone in 4 patients were offered .
onb is a rare malignant tumor that comprises 4,65% of malignant nasal and paranasal tumors .
some 1000 cases have been reported in the english literature since it was first introduced in 1924 .
the incidence rate is bimodal , with peaks in the second and third decades of life and in the sixth and seventh decades of life and equal among females and males . as for our study ,
the age at diagnosis was most common in the fourth decade and female - to - male ratio was equal .
the average time between the appearance of the first symptom and the diagnosis was reported as 6 months and this period was similar also in our group .
the most common symptoms at the initial diagnosis were defined as unilateral nasal obstruction and epistaxis in the literature .
this tumor may be misdiagnosed as an undifferentiated small cell carcinoma , melanoma , rhabdomyosarcoma , or other small blue cell neoplasms .
hyam proposed a grading system with grades 14 based on the presence or absence of seven different histopathological parameters .
these are growth , architecture , mitotic activity , necrosis , nuclear pleomorphism , rosette formation , and fibrillary stroma .  
. staining paterns for neuron - spesific enolase , chromogranin , synaptophysin , s-100 , and epithelial markers can be helpful .  
there is evidence that histological grade of onb influences biologic behavior , particularly because it relates to disease progression , local recurrence , and metastasis . for the well - differentiated tumors a slower disease progression and less tendency for local recurrence have been described . in our study , the 2-year survival rate of this grade i / ii - iii / iv disease was 16 versus 50% , respectively .
more aggressive treatment , such as surgery , radiation , and intensive ctx , may be useful for patients with grade iii / iv disease .
a meta - analysis showed that the median overall survival at 5 years is 45% in 390 patients .
the distribution of onb from 21 studies according to kadish staging system was 12% at stage a , 27% at stage b , and 61% at stage c. the mean 5-year survival is 75% for stage a , 68% for stage b , and 41% for stage c .
the conclusions of the university of virginia stated that kadish stage is predictive of disease - related mortality .
however , in the series of the mayo clinic it was found that kadish stage did not affect the outcome .
danish clinicopathological study found that the staging system of kadish was able to stratify into prognostically significant groups . in our study , the 5-year survival rate of these tumors was 26% and median survival time was 23 months .
the distribution of onb according to kadish staging system was 16% at stage a , 26% stage b , and 58% stage c. however , in our study , the 5-year survival rates of these stage groups were inferior compared to those reported in other studies .
the cause of this poor result was presentation of 5 patients with distant metastases ( 26% ; 2 brain , 1 bone marrow , 2 other sites ) , 4 patients ( 21% ) with cervical lymph node metastasis , 12 patients ( 63% ) with high - grade histology at the time of diagnosis , and inability to evaluate the surgical margins of the resected tumors .
the survival rate of node positive patients is 29% compared with 64% of node negative patients .
distant metastases have been described in the pancreas , the liver , mediastinum , bone marrow , lungs , leptomeninges , skin , and breasts [ 11 , 12 ] .
cervical nodal metastases can develop in 17 to 33% of patients and distant metastases in 10 to 40% of patients over the course of disease
metastatic disease at presentation occurs in 10 to 50% of patients , depending on the study [ 6 , 13 , 14 ] .
we found the local recurrence rate to be 31.5% and distant metastasis 31.5% after initial surgery . during the follow - up periods these groups exhibited distant metastases to the brain , spinal cord , bone , bone marrow , meninges , and lungs .
patients who had brain and bone marrow metastases had poorer prognosis than others having metastatic deposits of other sites .
involvement of the orbit is a serious prognostic factor , but when the orbital periosteum is affected without penetration into the orbital structures themselves , the eye may be preserved by resection and grafting of the periosteum without an adverse effect on survival as compared with orbital clearance .
irrespective to the most sophisticated imaging , involvement of the dura and orbital periosteum can accurately be determined only at surgery . in our study ,
this group 's ( 8 patients ) survival rate is poorer than those with no involvement of the orbita ( p = .042 ) .
the institute of laryngology and otology , university college london , published a study of 42 patients treated over 23 years .
overall and disease - free survival rates were 77 and 61% at 5 years , and 53 and 42% at 10 years , respectively .
late recurrences were seen . based on this experience , combined therapy with craniofacial resection and radiation therapy is recommended by this group . in a retrospective study of 47 patients treated at multiple centers in germany from 1979 to 2001 ,
the 5-year overall survival and event - free survival rate were 64% and 50% , respectively .
patients who received multimodality therapy had a significantly better event - free survival rate compared with those who did not receive multimodality therapy ( 74 versus 41% ) .
the authors recommend a combination therapy including ctx , surgery , and postoperative radiation therapy for kadish stage c patients . in our study ,
initial treatment included surgery alone in three patients , rt with or without ctx in five , surgery plus postoperative rt in seven , and multimodality therapy ( surgery plus postoperative ctx plus postoperative rt ) in three , only ctx in one patient .
however , in our study choice of treatment modality did not show a statistically significant difference in survival rate .
the reasons for that might be including low number of patients in the study , being 5 distant site metastasis , 4 cervical lymph node metastasis at the time of diagnosis , only one orbital exentration ( although there were 8 orbital involvement ) , and 12 patients exhibiting high grade histology and inability to evaluate surgical margins in resected tumors . in conclusion , advanced tumor stage ,
the initial histopathologic grade of iii / iv , and involvement of orbita , brain , or bone marrow metastasis were the statistically significant poor prognostic factors , whereas age , sex , and treatment modality were not prognostic factors .
 
 objective . 
 the aim of this study was to evaluate clinicopathological findings and the efficacy of the treatment modalities used in patients with olfactory neuroblastomas . study design . 
 retrospective record review . setting . 
 istanbul university , cerrahpasa medical faculty , medical oncology outpatient clinic . 
 subjects and methods . 
 there were 3 stage a tumors , 5 stage b and 11 stage c according to the kadish staging system . 
 there were 5 grade i / ii and 12 grade 
 iii / iv according to the hyams ' histopathologic system . 
 involvement to orbita was detected in eight patients at the time of diagnosis . 
 results . 
 the median follow - up period was 23.7   months . 
 the 5-year survival rate for the whole group was 26% . 
 the stage a / b groups exhibited a better survival rate than the c group with 2-year survival rates being   25 versus 71% respectively ( p = .008 ) . 
 the grade i / ii groups exhibited a better survival rate than the grade iii / iv groups with 2-year survival rates being 50 versus 16% respectively ( p = .001 ) . 
 the group who had orbital involvement exhibited a poor survival rate than the group of patients who had no involvement of the orbital . 
 conclusion . in our study , 
 tumor stage , histopathologic grading , involvement of the orbita , brain and bone marow metastases were the statistically significant prognostic factors . 
1. lntroduction
2. Patients and Methods
3. Statistical Analysis
4. Results
5. Discussion