worldwide , the most common histological subtypes of esophageal carcinoma are squamous cell carcinoma and adenocarcinoma ( 2 , 3 ) . in 1952 , mckeown found 2 cases with oat cell carcinoma in 9000 autopsies ( 4 ) . this disease is so rare that no standard treatment has been accepted for these aggressive tumors so far . data on its clinical course and outcome are also limited to some retrospective small reports ( 5 - 7 ) . sometimes staging is performed based on american joint committee on cancer ( ajcc ) for esophagus cancer and sometimes it is done similar to small cell lung cancer ( 8) . small cell carcinoma ( scc ) can affect all organs but the most common anatomical sites are lung , gastrointestinal tract , genitourinary system , gynecologic organs , and head and neck region ( 9 ) . reports of scc arising in the esophagus indicate retained primitive cells with potential differentiation into small cells ( 10 ) . histologically , scc is characterized by small cells with scant cytoplasm , round nuclei , and granule formation . immunohistochemistry ( ihc ) would aid the diagnosis if there was immunoreactivity for neuroendocrine markers ( 11 , 12 ) . considering the rarity of this histology in esophagus and lack of any report from iran , this study assessed clinicopathological features , and oncologic outcomes of scec cases in northeast of iran . the study data were collected from the cancer records of two referral specialized oncologic hospitals , omid and imam reza , affiliated to mashhad university of medical sciences ( mashhad , iran ) from january 2000 to december 2012 . all patients who had histologically proven diagnosis of scec by endoscopic biopsy or surgery ( except those without follow up ) entered the study . the patients characteristics , including sex , age , history of smoking , presenting symptoms , and performance status , tumor location , tumor size , clinical stage , and endoscopic upper gastrointestinal imaging findings were recorded . the preliminary evaluation included comprehensive history , physical examination , complete blood count ( cbc ) , liver function tests ( lft ) , renal function tests ( rft ) , chest x ray , abdominal and pelvic ct - scans or sonography , and in case of bone pain , radionuclide bone scan . according to the results of these evaluations , the patients whose diseases were confined to the primary site and/or regional nodes were classified as having limited disease , while the others were considered to have extensive disease ( 6 ) . all potential clinical and pathological variables were analyzed using the spss for windows version 18 ( spss , chicago , il ) . five - year overall survival rate was defined as the percentage of patients who were alive at 5 years . nonparametric variables of patients characteristics , tumor characteristics , and treatment modalities were compared by using chi - square test ; student t - test and analysis of variance ( anova ) were used for continuous variables such as patients age and radiation dose . the overall survival durations were measured from the date of diagnosis till the death from any reason or the last follow - up . kaplan - meier was used to estimate survival experience of the different groups of the prognostic factors . the log - rank test was used to compare treatment results in each variable group . all potential clinical and pathological variables were analyzed using the spss for windows version 18 ( spss , chicago , il ) . five - year overall survival rate was defined as the percentage of patients who were alive at 5 years . nonparametric variables of patients characteristics , tumor characteristics , and treatment modalities were compared by using chi - square test ; student t - test and analysis of variance ( anova ) were used for continuous variables such as patients age and radiation dose . the overall survival durations were measured from the date of diagnosis till the death from any reason or the last follow - up . kaplan - meier was used to estimate survival experience of the different groups of the prognostic factors . the log - rank test was used to compare treatment results in each variable group . out of 4163 patients with esophageal malignancies through a period of 12 years , 24 patients ( 0.5% ) were identified to have primary scec . the patients median age at the time of diagnosis was 61 years ( range 43 - 88 years).there were 15 ( 68.2% ) female and 7 ( 31.8% ) male with a male to female ratio of 0.46 . dysphagia ( 21 cases , 95% ) and weight loss ( 18 cases , 80% ) were the most prevalent presenting symptoms with a mean duration of 6 months before diagnosis . according to karnofsky score system , 12 patients ( 55% ) showed performance status of 80 - 100 . in addition , 5 patients ( 23% ) obtained the score of 70 and 5 patients ( 23% ) gained 60 . moreover , only 3 patients ( 14% ) were smoker and none of them had the history of alcohol consumption . the tumors tended to involve the lower and middle third of the esophagus and to have larger size . approximately two - thirds ( 13 ) of the patients had limited diseases , while the other 8 cases had extensive diseases . among those with extensive diseases , liver , lung , and lymph node ( ln ) were the most metastatic sites . furthermore , ulcerative tumors were the most prevalent endoscopic feature of the tumor and were reported in 10 patients . however , 7 cases had polypoid lesions and 5 had no specified lesions . in upper gastrointestinal ( gi ) series , 12 patients had only mucosal irregularity , while stenosis and filling defect were reported in 8 and 2 patients , respectively . thehistological diagnosis of the patients was primarily based on hematoxylin and eosin - stained examination . all the patients tumors had small round cells with hyperchromatic nuclei and scant cytoplasm with characteristic pattern of crush artifact in 5 patients . immunohistochemical ( ihc ) examination to confirm scec was required only for 6 patients ( 27% ) . abbreviations : ck : cytokeratin ; lca : leucocyte antigen ; nse : neuron specific enolase ; np : not performed . in this study , 21 patients received various treatment modalities and the remaining one did not have enough chance to receive any treatment . twenty patients received chemotherapy either alone ( 6 cases , 27% ) or in combination with radiotherapy ( 14 cases , 64% ) . crt was given concurrently in 9 patients ( 41% ) and sequentially in 5 ones ( 23% ) . in addition , 7 patients ( 32% ) underwent surgery , 1 received neoadjuvant crt , and 2 received neoadjuvant chemotherapy . the combination regimen of cisplatin and etoposide was given to a group of 14 patients ( 63% ) . the other 6 patients ( 27% ) , on the other hand , received a combined regimen of cisplatin and fluorouracil ( 5-fu ) . the median survival of the 22 patients was 11 months ( 95% ci , 5.25 - 16.75 ) ( figure 1 ) . in addition , 1 , 3 , and 5-year overall survival rates were 27% , 14% , and 4% , respectively . in fact , one of our patients who did not receive any treatment survived for 1 month and 2 patients with long - term survival had received concurrent crt without surgery . ( 3 - 6 , 12 ) . in other studies , as in ours , brain metastasis was not common . in this study , 2 patients developed second primary malignancy . one of them presented with headache , nausea , vomiting , and occipital mass in mri 6 years after the diagnosis of scec . the other patient was a 61-year - old woman who presented with axillary lymphadenopathy due to invasive ductal carcinoma of breast . she underwent mastectomy , adjuvant chemotherapy , and radiotherapy and was well at the last follow up . she underwent mastectomy , adjuvant chemotherapy , and radiotherapy and was well at the last follow up . the results of the present study revealed no association between the overall survival rate and age (  61 years versus > 61years , median survival 13 months versus 7 months , p = 0.824 ) , sex ( female versus male , median survival 13 months versus 7 months , p = 0.385 ) , performance status (  70 versus < 70 , median survival 14 months versus 4 , p = 0.074 ) , tumor stage ( limited versus extensive , median survival 13 months versus 8 months , p = 0.198 ) , size ( < 4 cm versus  4 cm , median survival 14 months versus 7 months , p = 0.251 ) , radiation dose (  40 gy versus < 40 gy , median survival 14 months versus 8 months , p = 0.759 ) , location ( upper versus middle versus lower , median survival 2 months versus 14 months versus 11 months , p = 0.924 ) , and treatment modality ( surgical versus nonsurgical , median survival 13 months versus 5 months , p = 0.243 ) . out of 4163 patients with esophageal malignancies through a period of 12 years , 24 patients ( 0.5% ) were identified to have primary scec . the patients median age at the time of diagnosis was 61 years ( range 43 - 88 years).there were 15 ( 68.2% ) female and 7 ( 31.8% ) male with a male to female ratio of 0.46 . dysphagia ( 21 cases , 95% ) and weight loss ( 18 cases , 80% ) were the most prevalent presenting symptoms with a mean duration of 6 months before diagnosis . according to karnofsky score system , 12 patients ( 55% ) showed performance status of 80 - 100 . in addition , 5 patients ( 23% ) obtained the score of 70 and 5 patients ( 23% ) gained 60 . moreover , only 3 patients ( 14% ) were smoker and none of them had the history of alcohol consumption . the tumors tended to involve the lower and middle third of the esophagus and to have larger size . approximately two - thirds ( 13 ) of the patients had limited diseases , while the other 8 cases had extensive diseases . among those with extensive diseases , liver , lung , and lymph node ( ln ) were the most metastatic sites . furthermore , ulcerative tumors were the most prevalent endoscopic feature of the tumor and were reported in 10 patients . however , 7 cases had polypoid lesions and 5 had no specified lesions . in upper gastrointestinal ( gi ) series , 12 patients had only mucosal irregularity , while stenosis and filling defect were reported in 8 and 2 patients , respectively .   at the end of in our study , thehistological diagnosis of the patients was primarily based on hematoxylin and eosin - stained examination . all the patients tumors had small round cells with hyperchromatic nuclei and scant cytoplasm with characteristic pattern of crush artifact in 5 patients . immunohistochemical ( ihc ) examination to confirm scec was required only for 6 patients ( 27% ) . abbreviations : ck : cytokeratin ; lca : leucocyte antigen ; nse : neuron specific enolase ; np : not performed . in this study , 21 patients received various treatment modalities and the remaining one did not have enough chance to receive any treatment . twenty patients received chemotherapy either alone ( 6 cases , 27% ) or in combination with radiotherapy ( 14 cases , 64% ) . crt was given concurrently in 9 patients ( 41% ) and sequentially in 5 ones ( 23% ) . in addition , 7 patients ( 32% ) underwent surgery , 1 received neoadjuvant crt , and 2 received neoadjuvant chemotherapy . the combination regimen of cisplatin and etoposide was given to a group of 14 patients ( 63% ) . the other 6 patients ( 27% ) , on the other hand , received a combined regimen of cisplatin and fluorouracil ( 5-fu ) . the median survival of the 22 patients was 11 months ( 95% ci , 5.25 - 16.75 ) ( figure 1 ) . in addition , 1 , 3 , and 5-year overall survival rates were 27% , 14% , and 4% , respectively . in fact , one of our patients who did not receive any treatment survived for 1 month and 2 patients with long - term survival had received concurrent crt without surgery . ( 3 - 6 , 12 ) . in other studies , as in ours , brain metastasis was not common . in this study , 2 patients developed second primary malignancy . one of them presented with headache , nausea , vomiting , and occipital mass in mri 6 years after the diagnosis of scec . the other patient was a 61-year - old woman who presented with axillary lymphadenopathy due to invasive ductal carcinoma of breast . she underwent mastectomy , adjuvant chemotherapy , and radiotherapy and was well at the last follow up . she underwent mastectomy , adjuvant chemotherapy , and radiotherapy and was well at the last follow up . the results of the present study revealed no association between the overall survival rate and age (  61 years versus > 61years , median survival 13 months versus 7 months , p = 0.824 ) , sex ( female versus male , median survival 13 months versus 7 months , p = 0.385 ) , performance status (  70 versus < 70 , median survival 14 months versus 4 , p = 0.074 ) , tumor stage ( limited versus extensive , median survival 13 months versus 8 months , p = 0.198 ) , size ( < 4 cm versus  4 cm , median survival 14 months versus 7 months , p = 0.251 ) , radiation dose (  40 gy versus < 40 gy , median survival 14 months versus 8 months , p = 0.759 ) , location ( upper versus middle versus lower , median survival 2 months versus 14 months versus 11 months , p = 0.924 ) , and treatment modality ( surgical versus nonsurgical , median survival 13 months versus 5 months , p = 0.243 ) . in this study , we reviewed and analyzed the clinicopathological features and oncologic outcome of 22 cases with scec . according to our study results , scec tends to present at a locally advanced stage , with a high frequency of distant failure and has a poor outcome . in the literature , primary scec is an uncommon disease constituting less than 1% of esophageal malignancies ( 14 ) . the prognosis is generally poor and most patients have metastasis at the time of diagnosis ( 13 ) . almost similarly , we found that at least 0.5% of our esophageal cancer patients had scec . similar to the other histological subtypes of esophagus cancer , scec has been reported predominantly in males with a male to female ratio of 1.5:3 ( 3 , 14 , 15 ) . however , almost in concordance with the more common occurrence of squamous cell carcinoma among the women in our local area ( 16 ) , our study showed that women were more vulnerable to this subtype of esophagus cancer with a 2:1 female predominance ratio . gender dominancy is also another matter of debate in this disease ( 13 , 14 ) . in addition , the patients median age at the time of diagnosis was 61 years , which is almost concordant with other studies reporting the disease occurrence between the sixth and eighth decade of life ( 14 , 15 ) . although it is not well defined yet , history of smoking and alcohol consumption seem to be related to scec ( 3 , 14 ) . in this study , only 2 patients were smokers in our study . in general , most scecs are located in middle and lower parts of esophagus ; however , this factor has no prognostic value ( 6 , 17 ) . we found no studies indicating a higher ratio of tumor in the upper part of the esophagus . due to the small number of cases and lack of randomized clinical trials , several reports have used a variety of combination therapies , including surgery , chemotherapy , and radiotherapy ( 18 - 20 ) . in a review of literature found that the type of treatment was one of the most important prognostic factors ( 19 ) . some researchers have suggested surgery to be an important part of the treatment ; nevertheless , these conclusions have been drawn from small retrospective series ( 3 , 21 , 22 ) . most researchers believe that scec should be treated in the same way as small cell lung cancers ( 4 , 22 , 23 ) . in a study which was conducted by lu on 15 patients with superficial scec who all underwent operation , the mean survival was 23 months and only 1 patient was alive at the time of report . the longer survival rated reported by lu might be due to the fact that all patients had superficial diseases ( 23 ) . compared to esophageal superficial squamous cell carcinoma with the same stage , prognosis of scec was dismal ( 24 ) . in superficial esophageal squamous cell carcinoma , 5-year survival rate can be more than 80% , while it was 6.7% in lu et al . nonetheless , it may be a better idea not to deprive any patient from adjuvant treatments . on the other hand , it is noteworthy that the patient with prolonged survival ( 108 months ) had not been treated by chemotherapy or radiotherapy after the operation ( 23 ) . in our study , 7 patients underwent surgery with no improvement in the outcome compare to those who did not undergo resection . based on the probable similarities with small cell lung carcinoma nakajima et al . ( 7 ) reported 18 patients with scec and found no significant difference between the extensive and limited disease patients regarding survival . survival in the patients with limited and extensive diseases was 17.3 and 13.9 months , respectively ( p = 0.57 ) . in that study , most of the patients had lower or middle part esophageal lesions . in addition , 10 patients were treated by both chemotherapy ( cisplatin based ) and radiotherapy and only 2 patients were alive after 54.2 and 76.2 months followup , respectively . among the other patients who were treated by chemotherapy alone , 1 patient had 58.8 months survival , but developed liver metastasis . in that study , the main cause of death was metastasis and only 2 cases developed local recurrence ( 6 ) . in our patients , all disease mortality was due to metastasis . moreover , the longest survivals in our patients were related to two patients who received concurrent crt . although it is generally believed that scec is a catastrophe for the patients , the results are controversial . various studies have shown diverse ranges of survival in a small group of patients ( 5 ) . in chin et al . study , 20% of the patients were alive for more than 40 months even after the local recurrence ( 5 ) . reported 25 patients from memorial center , out of them 3 patients were alive for more than 3 years . interestingly , one of the patients had local recurrence and was alive for 5.5 years ( 25 ) . kuo et al . also reported a 65-year - old man with 221 months survival . he was undergone operation followed by 2 cycles of etoposide and cisplatinchemotherapy ( 3 ) . although scecs are usually treated in the same way as small cell lung carcinoma , brain metastasis is not so prevalent in esophageal cases ( 3 , 7 ) . in other studies , as in ours , brain metastasis was not common . regarding the strength of the study and to the best of our knowledge , this is the first report of scec from iran . however , it must be noted that the small number of patients in this study imposed a limitation in statistical analysis as well as finding any association between the clinicopathological features and oncologic outcomes . ihc confirmation in less than one - third of cases was another limitation of the study . in conclusion
background : small cell esophageal carcinoma ( scec ) is a highly aggressive and rare neoplasm.objectives:this study aimed to report the characteristics , prognostic factors , and treatment outcomes of 22 patients with scec.patients and methods : this brief report was carried out by reviewing the medical records of 22 patients with newly histologically proven scec that were treated between 2000 and 2010 at 2 tertiary academic hospitals . 
 all the potential prognostic variables , including the patients characteristics , tumor features , and treatment modalities were analyzed to establish their influence on the patients survival rates.results:this study was conducted on 7 males and 15 females with a median age of 61 years . 
 dysphagia and weight loss were the most prevalent symptoms . according to the results , 14 patients ( 64% ) had limited diseases and 8 cases ( 36% ) had extensive diseases . in those with extensive diseases , liver , lung , and lymph nodes ( lns ) were the most metastatic sites . 
 besides , most tumors were located in lower ( 50% ) and middle ( 32% ) part of the esophagus . 
 most patients ( 91% ) were treated with sequential ( 55% ) or concurrent ( 36% ) chemoradiation ( crt ) . 
 surgical resection was also performed for 7 patients . 
 chemotherapy regimen consisted of cisplatin and etoposide in 14 patients ( 64% ) . 
 the median follow up time was 12 months . 
 the 1 , 3 , and 5-year overall survival rates were 27% , 14% , and 4% , respectively . yet 
 , no prognostic factors were found because of the small sample size of the study.conclusions:primary scec is a rare and highly aggressive tumor . however , prognosis is poor and long - term survival is exceptional . 
 crt could be an appropriate alternative to operation .