the term  neuroendocrine reflects the origin of endocrine cells from the embryonic neural crest . neuroendocrine cells are characterized by their ability to produce and secrete different peptides and neuroamines . they aggregate in classical endocrine glands ( e.g. hypothalamus and the pituitary gland ) or in the diffuse neuroendocrine system distributed throughout the body , such as the gastrointestinal tract and lungs . gastroenteropancreatic neuroendocrine neoplasms ( gep - nens ) are a heterogeneous group of neoplasms defined as malignant transformation of neuroendocrine cells in the diffuse neuroendocrine system that regulates secretion , absorption and motility of the gastrointestinal tract . the incidence of gep - nens continues to exhibit a persistent increase ; the most recent epidemiological study from the us surveillance shows that the overall incidence of gep - nens increased from 1 to 3.65 cases per 100,000 . a genetic etiology of gep - nens has been well documented in around 5 - 10% of cases as part of hereditary syndromes such as multiple endocrine neoplasia type 1 , von hippel - lindau syndrome , neurofibromatosis 1 or tuberous sclerosis syndrome . these tumors commonly present with a wide spectrum of clinical manifestations according to site of origin and biological behavior . they can present with abdominal pain , weight loss , obstructive jaundice and intestinal obstruction . moreover , the symptoms related to hormone secretion include flushing , diarrhea , wheezing , hypoglycemia , cardiovascular and peptic ulcers disease . the diagnosis is based on histological features , including tumor differentiation and grade , in addition to immunohistochemical stains for general endocrine markers , including chromogranins , synaptophysin and neuron - specific enolase . tumor markers such as chromogranin a , pancreatic polypeptide , serum neuron - specific enolase and subunit of glycoprotein hormones have been used . it is useful for staging , prognosis and follow - up , since the serum concentration correlates with the tumor mass . in the presence of symptoms or syndrome suspicious of functional nens , biochemical testing for peptide hypersecretion should be ordered , e.g. gastrin level for patients with zollinger - ellison syndrome or insulin for hypoglycemic syndromes . imaging studies are an important tool in nen workup ; abdominal ultrasound , computed tomography and magnetic resonance imaging have a high sensitivity and specificity in detecting many types of primary nens . functional imaging such as in - pentetreotide ( octreoscan ) or i - metaiodobenzylguanidine ( mibg ) plays a critical role in the diagnosis and in establishing the eligibility for therapy . combining functional imaging with computed tomography or magnetic resonance imaging is superior for staging and detection of primary tumors of undetermined location . gep - nens can be classified according to the site of embryologic origin ( foregut , midgut and hindgut ) , grade , differentiation or the hormones produced . the grade refers to the biological aggressiveness of the neoplasm which is defined by the number of mitoses per 10 high - power microscopic fields or per 2 mm ( mitotic rate ) , or as the percentage of tumor cells that immunolabel for the ki-67 antigen ( ki-67 index ) . while the differentiation refers to the extent to which the neoplastic cells resemble their non - neoplastic counterparts , in 2010 , the world health organization proposed the most widely accepted classification : ( 1 ) neuroendocrine tumor grade 1 ( g1 ) , ( 2 ) neuroendocrine tumor grade 2 ( g2 ) , ( 3 ) neuroendocrine carcinoma ( nec ) , grade 3 ( g3 ) , and ( 4 ) mixed adenoneuroendocrine carcinoma . also , nens are divided into well - differentiated and poorly differentiated ( table 1 ) . in general , gep - nens are staged according to the primary tumor ( t ) , lymph node involvement ( n ) and distant metastases ( m ) tnm system , similar to other types of carcinomas . medical therapy of inoperable or metastasized nens includes multimodality options such as long - acting somatostatin analogs , -interferon , systemic chemotherapy and ablation therapy . there is no established regimen due to heterogeneity of the studies , including various grades , sites and inconsistent response criteria . novel therapies like mammalian target of rapamycin ( mtor ) , tyrosine kinase and angiogenesis inhibitors have showing promising results in clinical trials . we herein report a case of esophageal large - cell necs and review the published literature on this rare disease . a 66-year - old saudi female housewife with a background of diabetes , hypertension and hypothyroidism was seen initially by a gastroenterologist . she was suffering from progressive difficulty in swallowing , mainly of solid food , with a feeling of food stuck in the middle of her chest for more than 6 months . she denied any painful swallowing , oral thrush , chocking attacks , food impaction or nasal regurgitation . she denied any abdominal pain , distension , rectal bleeding or change in bowel habits . she had lost about 3 kg from a baseline weight of 68 kg despite normal appetite . her history was unremarkable for esophageal disease , tuberculosis contact , neck swelling or radiation exposure . the patient underwent esophagogastroduodenoscopy ( egd ) which revealed a small esophageal nodule in an otherwise normal esophagus ( fig . 1a ) , and nodule biopsy was consistent with papilloma . despite of the prescription of a proton pump inhibitor ( esomeprazole ) , her symptoms worsen so that she was referred to our institution in december 2014 for further evaluation and endoscopic ultrasound . upon evaluation she was well , not pale or jaundiced , her weight was 64.8 kg and her body mass index was 26.6 . the abdomen was soft and non - tender , and no mass or lymph node was observed . her complete blood count showed white blood cell 16.9  10/l , hemoglobin 11.8 g / dl and platelets 306  10/l . c - reactive protein was < 3.5 mg / l and chest x - ray was normal . repeat egd and endoscopic ultrasound examination revealed an ulcerated esophageal mass 4 cm in diameter 23 - 27 cm from the incisor line ( fig . it was shown as a hypoechoic mass at the level of the third submucosal layer with no local lymph node or vascular infiltration ( fig . a computed tomography scan showed an eccentric 3.2  2.0 cm mass in the lower esophagus , inseparable from the esophageal wall . positron emission tomography / computed tomography revealed a hypermetabolic esophageal tumor with left cervical lymph node and midsacrum and right acetabulum metastasis ( fig . histopathological examination of the deep biopsies concluded that the mass was a nec of the large - cell type in view of irregular strands of large polygonal cells with an intermediate amount of pale oncophilic cytoplasm . the nuclei had occasional molding of salt and paper chromatin and visible nucleoli with extensive nuclear crushing artifact and immunohistochemical evidence of neuroendocrine differentiation . the patient was therefore staged as metastatic high - grade large - cell neuroendocrine tumor of the esophagus . chemotherapy was initiated by the oncologist and she received three cycles of cisplatin 90 mg / m in divided doses over 3 days and etoposide 100 mg / m per day on days 1 - 3 of each treatment cycle . large - cell nec of the esophagus is exceedingly rare ; few cases have been reported in the literature . the incidence of esophageal nens ranges between 0.05 and 2.4% in most of the recent studies . the literature clearly shows that nens in this anatomical location occur more frequently in males in the sixth and seventh decades of life , with a male : female ratio of 4:1 . similar to other esophageal tumors , patients usually present with vague symptoms , including constitutional symptoms , weight loss , chest pain or pressure and odynophagia . by far dysphagia is the most common presenting symptom and carcinoid symptoms are rare . from endoscopic findings , esophageal nens this is because neuroendocrine cells are mainly distributed in mucosal glands of the distal esophagus . among the categories of nens , nec is a poorly differentiated , high - grade malignant neoplasm composed of small or large cells , sometimes with organoid features resembling well - differentiated neuroendocrine tumors , diffusely expressing the general markers of neuroendocrine differentiation ( diffuse expression of synaptophysin , faint or focal staining for chromogranin a ) , with marked nuclear atypia , multifocal necrosis and a high number of mitoses ( > 20 per 10 high - power fields ) ; high grade ( g3 ) is defined according to proliferation fraction and histology ( table 1 ) . large - cell tumors all consist of cells with solid nests or acinar structures , a low nuclear / cytoplasm ratio , often abundant cytoplasm , many mitoses , focal areas of necrosis , vesicular chromatin and visible nucleoli . for practical purposes , esophageal necs can be staged according to the tnm / staging classification for esophageal carcinomas . in contrast to other gastrointestinal sites , there is no proposed tnm / staging classification for necs of the esophagus . however , proliferative activity , assessed by mitotic count or ki-67 immunostaining , was described as a significant prognostic factor in a previous study . there have been a few randomized , prospective and controlled therapeutic trials published thus far . unfortunately , in those trials several tumor entities ( e.g. tumors arising from the stomach , pancreas and colon ) were all included . moreover , there are not specific recommendations , given that doses and schedules were different in the various studies . high - grade necs of the esophagus are rare tumors exhibiting an overall aggressive behavior , and their prognosis is dismal . the majority are locally advanced or metastatic at presentation and are rarely associated with secretory hormonal syndromes . treatment regimens are extrapolated from more robust data published on pulmonary high - grade necs .
neuroendocrine carcinomas of the esophagus are very rare , and the majority are high grade ( poorly differentiated ) . 
 they occur most frequently in males in their sixth and seventh decades of life . 
 there have been no concrete data published on clinical features or on prognosis . 
 we report a case of large - cell neuroendocrine carcinoma of the esophagus in a 66-year - old saudi female with progressive dysphagia and weight loss . 
 upper endoscopy revealed an esophageal ulcerated mass .