neuroendocrine carcinoma ( nec ) is a poor differentiated , high grade malignant neoplasm composed of tumor cells that express endocrine markers ( synaptophysin , chromogranin a ) and show marked cellurar atypia , frequent necrosis and high proliferative activity . moreover , squamous differentiation has not been observed in large cell necs until now , while the coexistence of small cell carcinomas with an associated small cell carcinoma component has been described . we report the first case in bibliography of a mixed large cell nec with squamous cell carcinoma of the rectum , a highly aggressive and rare tumor . a 50-year - old male patient was admitted to our hospital with the major complaint of mild rectal bleeding for the last 5 days . he described changes in bowel habits during the last month , but no weight loss . the serum levels of cancer antigen ( ca ) 19 - 9 , carcinoembrionic antigen ( cea ) and a - fetoprotein ( afp ) were within normal range . colonoscopy was performed , which revealed an ulcerative mass of 6  cm in length ( fig . 1 ) , with its lower margin located 8  cm from the anal verge . microscopic analysis of biopsy specimens showed morphological and immunohistochemical characteristics of poorly differentiated neuroendocrine carcinoma ( chromogranin a+ , synaptophysin a+ ) . cytokeratines c5/6 were negatives . computed tomography ( ct ) scan of the abdomen revealed pathological enlarged mesorectal lymph nodes ( fig . a low anterior resection with total mesorectal excision and lymph nodes dissection was performed , with free macroscopic surgical margins . the specimen included an ulcerative tumor 6  cm    4  cm , with its lower edge located 2  cm from the distal surgical margin . the tumor had elastic consistency , compact form , grayish and partially brownish color , and infiltrated the entire muscular wall . after microscopic examination and immunohistochemical study , the diagnosis of poorly differentiated large cell neuroendocrine carcinoma was established . it was composed of isolated large cells with scart eosinophil cytoplasm and nucleus with large prominent nucleolus , while there were areas of organoid , nesting and trabecular pattern . it was classified as g3 neuroendocrine carcinoma according to who classification 2010 of tumors of the digestive system , and pt3n1m0 according to the ajcc/2010 staging system . the immunophenotype of neuroendocrine carcinoma was : synaptophysin ( + ) , chromogrnin a ( + ) , cd56 ( + ) , ck5/6 (  ) , cd.x-2 ( + ) in few cells , ck20 ( + ) in a small percentage of cells . the immunophenotype of squamous cell carcinoma component was : synaptophysin (  ) , chromogranin a (  ) , cd56 (  ) , ck5/6 ( + ) , cdx2 ( + ) , p63 (  ) , ck20 (  ) . he refused to receive adjuvant chemotherapy despite oncologist recommendations , and died 6 months later due to liver failure as a result of multiple hepatic metastases . incidence in general population ranges from 0.24 to 1.65 per 100.000 persons . according to the who classification 2010 neoplasms of the digestive system with neuroendocrine differentiation are subdivided into neuroendocrine tumors ( nets ) , neuroendocrine carcinomas ( necs ) and mixed neuroendocrine carcinomas ( manecs ) . the term nets includes well differentiated tumors ( carcinoids ) , and their grade is either g1 ( grade 1 ) or g2 ( grade 2 ) . the term necs includes poorly differentiated , high grade , small and large cell neuroendocrine carcinomas , and their grade is always g3 ( grade 3 ) . we can use the term manec only when there are both neuroendocrine and non - neuroendocrine epithelial malignant components and each component exceeds 30% . in our case the diagnosis of manec could not be established , because the squamous cell carcinoma represented the 510% of tumors cells . a nec of the rectum is a rare tumor with an incidence of less than 0.1% of all colorectal malignancies . only 22 cases ( 0.03% of total colorectal cancers ) of small cell neuroendocrine carcinoma and 16 cases ( 0.02% ) of large cell neuroendocrine carcinoma were identified from their database of colorectal cancers that included approximately 6500 patients , in a period of 23 years . only 14 cases were located in the rectum . in a recent review of 10 years management of neuroendocrine rectal tumors , only 2/37 patients ( 5.4% ) of the total nrts had tumors that were classified as neuroendocrine carcinoma . none of these tumors was found in the rectum , with the majority of them located in the right colon ( 56% ) and the left colon ( 41% ) . in addition to this , only 9% had an ulcerating lesion , as in our case . women with diabetes and positive family history for cancer have an increased incidence of gastric nets . this is attributed to the increased genetic susceptibility for nets development in women as compared to men . this is based on the presence of transitional tumor cells that revealed common immunoreactivity for ca 19 - 9 , keratin 19 , cluster of differentiation protein 117 and epithelial cell adhesion molecule . neuroendocrine tumors may be found incidentally at colonoscopy ( 40% ) , or patients may present with rectal bleeding , changes in bowel habits , tenesmus , discomfort and weight loss . lesions < 2  cm with a low grade and intact muscularis propria can mostly be removed by local resection . rectal tumors > 2  cm , t3 or t4 stage , g3 or rectal tumors with locoregional lymph node involvement should be treated similarly to adenocarcinoma . for rectal nets > 2  cm , anterior resection with total mesorectal excision or abdominoperineal exstirpation should be performed . the longest 6-month survival is 58% and the longest 1-year survival is 46% in the bernick 's study . this is due to the high rate of lymph node metastases , that exceeds 60% in all studies , and the high rate of distant metastases at diagnosis that exceeds 39% and reaches 73% in the gaffey 's study . in our case , the patient had lymph nodes metastases without distant metastases at the time of diagnosis . nevertheless , the carcinoma showed a highly aggressive behavior and the patient died 6 months later . we have to underline that the nec in our case had ki-67 label index 80% , thus explaining its aggressive behavior and that the patient had a large sized nec mixed with a squamous carcinoma component . there are not sufficient data in bibliography about survival and ideal adjuvant therapy after resection of mixed squamous large cell nec of the rectum . according to the nanets consensus guidelines , the combination of etoposide and cisplatin is the first line therapy for extrapulmonary necs , without specific reference in mixed squamous necs . various other chemotherapeutic regimens have been used in a small number of patients with necs with good results . a case of effective use of chemoradiotherapy for the treatment of large cell nec of the rectum has been published . low anterior resection and total mesorectal excision with free surgical margins in the presence of lymph nodes metastasis is not a sufficient treatment for rectal neuroendocrine carcinoma . more studies with larger number of patients with mixed rectal necs should be done in order to determine the ideal treatment of these rare and aggressive tumors . written informed consent was obtained from the patient for publication of this case report and accompanying images . a copy of the written consent is available for review by the editor - in - chief of this journal on request . spiros drakopoulos is the consultant of the unit and provided overall supervision , direction and suggestions for the case report .
introductionmixed large cell neuroendocrine neoplasms of the rectum are rare and aggressive neoplasms . 
 survival is poor due to the high rate of lymph node metastases and distant metastases at the time of diagnosis.presentation of casewe report a case of a 50-year - old male patient with a mixed large cell neuroendocrine carcinoma with squamous cell carcinoma of the rectum located 8  cm from the anal verge , treated with low anterior resection and total mesorectal excision with free surgical margins . 
 there were lymph nodes metastases but no distant metastases at the time of diagnosis . 
 the patient refused to receive adjuvant chemotherapy and died 6 months later due to liver failure as a result of multiple hepatic metastases.discussionthere are not known predisposing factors for the development of neuroendocrine rectal carcinoma . 
 a neuroendocrine carcinoma of the rectum is a rare tumor with an incidence of less than 0.1% of all colorectal malignancies . 
 the median survival ranges from 5 to 10.4 months in several studies and there are not sufficient data in bibliography about ideal adjuvant therapy after resection of mixed squamous large cell neuroendocrine carcinoma of the rectum.conclusionlow anterior resection and total mesorectal excision with free surgical margins in the presence of lymph nodes metastasis is not a sufficient treatment for rectal neuroendocrine carcinoma . 
 more studies should be done in order to determine the ideal adjuvant treatment of these rare and aggressive tumors .