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the current world health organization histologic classification of colorectal endocrine tumors includes well - differentiated neuroendocrine neoplasms , well - differentiated neuroendocrine carcinomas , and poorly - differentiated neuroendocrine carcinomas .
neuroendocrine carcinomas of the colon and rectum are rare , representing 0.1 - 3.9% of colorectal cancers . furthermore , large cell neuroendocrine carcinomas ( lcnecs ) of the colon are extremely rare , representing 0.25% of colorectal cancers . in the colon and the rectum ,
most concurrent tumors are those that are composed of an adenocarcinoma and a well - differentiated neuroendocrine neoplasm ( carcinoid ) or an adenoma and a carcinoid .
a combination of a colorectal lcnec and a colorectal adenocarcinoma is extremely rare , and only three cases have been reported [ 3 - 5 ] . here , we present a rare case of a colonic concurrent tumor involving a lcnec and an adenocarcinoma .
contrast - enhanced computed tomography ( ct ) scans revealed eccentric wall thickening with mucosal enhancement of the proximal ascending colon ( fig .
the levels of carcinoembryonic antigen and carbohydrate antigen 19 - 9 were within normal limits .
macroscopically , the cecal wall showed necrotic change with perforation through which fecal materials had leaked .
the main colonic lesion was located in the middle of ascending colon , causing near - complete obstruction of the lumen , and was composed of two separated masses .
one was a 7.4  5.1 cm fungating mass with ulceration in the center ( fig .
the cut surface revealed a white - gray color , solid , poorly demarcated mass with focal necrosis .
1b , arrowheads ) , and it was located about 1 cm distally apart from the ulcerative fungating mass .
in addition to the right colon specimen , 29 resected regional lymph nodes were submitted .
microscopically , the ulcerative fungating mass was separated abruptly from the normal colonic mucosa ( fig .
it involved from the mucosa to the pericolic adipose tissue and showed well - differentiated neuroendocrine morphology , such as nests , trabeculae , acini and rosettes ( fig .
a focal area of tumor cells with an individually infiltrative or an indian file - like arrangement was noted ( fig .
the majority of the tumor cells had large , vesicular nuclei with prominent eosinophilic nucleoli and variable amounts of eosinophilic cytoplasm ( fig .
there were commedo - type necrosis , apoptotic bodies and high mitotic figures ( 10/10 hpf ) .
the polypoid mass was a well - differentiated adenocarcinoma that was mainly composed of irregularly branching tubules and that had invaded the submucosa ( fig . 2e ) .
the tumor cells of the ulcerative fungating mass had perinuclear , dot - like or cytoplasmic immunoreactivity for chromogranin a ( fig .
the tumor cells of the polypoid mass had no immunoreactivity for chromogranin a ( fig .
both the tumor cells of the ulcerative fungating mass and of the polypoid mass had immunoreactivity for ck20 ( fig .
paraffin - embedded tissue samples for immunohistochemistry were provided by chonbuk national university hospital , a member of the national biobank of korea , which is supported by the ministry of health , welfare and family affairs .
though we recommended adjuvant chemotherapy with the folfox ( lecovorin , 5-fu , exolatin ) regimen after a right hemicolectomy , the patient rejected our suggestion .
they are classified into three groups : 1 ) well - differentiated neuroendocrine tumors showing benign behavior or uncertain malignant potential ( carcinoid ) , 2 ) well - differentiated neuroendocrine carcinomas , which are characterized by low - grade malignancy ( malignant carcinoid ) and 3 ) poorly differentiated , usually small cell , neuroendocrine carcinomas of high - grade malignancy .
well - differentiated neuroendocrine carcinomas are aggressive lesions and represent poorly - differentiated forms of carcinoid tumors with increased mitotic activity and absent or limited extent of necrosis .
the lcnec is a newly defined high - grade malignant tumor entity of a non - small - cell - type neuroendocrine tumor , which is well established in pulmonary neuroendocrine tumors .
a colonic lcnec is a rare malignant neoplasm composed of large cells having organoid , nesting , trabecular , rosette - like and palisading patterns that suggest neuroendocrine differentiation .
tumor cells are generally in polygonal or oval shapes and show hyperchromatic or vesicular nuclei with prominent nucleoli and slightly eosinophilic cytoplasm with ill - defined cellular boundaries .
in contrast to small - cell carcinomas , the cytoplasm is more abundant , nuclei are more vesicular , and nucleoli are prominent . among colonic neuroendocrine tumors ,
48% of the cases arise in the cecum , 16% in the ascending colon , 6% in the transverse colon , 11% in the descending colon , and 13% in the sigmoid colon .
bernick et al .   reported that 0.6% of patients with colorectal cancer were affected by neuroendocrine carcinomas and 0.2% by lcnecs .
colorectal lcnecs can be confirmed by immunohistochemistry and electron microscopy as long as a microscopic neuroendocrine morphology is present .
however , the diagnoses of colorectal lcnecs are often too difficult because colorectal carcinomas frequently exhibit neuroendocrine differentiation in 20 - 50% of cases , and neuroendocrine differentiation is more frequent in midgut - derived carcinomas than in those of hindgut origin [ 6 , 7 ] . therefore , the most important issue is to distinguish colorectal lcnecs from other colorectal carcinomas with neuroendocrine differentiation . in the present case ,
a definite neuroendocrine morphology was recognized even though a focal area of vague , undifferentiated morphology existed .
we believe that the recognition of an organoid architecture is a good initial indication of the presence of a colorectal lcnec and that a subsequent immunohistochemical stain may possibly contribute to a differential diagnosis . in immunohistochemical staining ,
colorectal neruendocrine tumors are associated with secondary primary tumors , including both adenocarcinomas and other carcinoid tumors , in other sites , particularly in the gi tract .
the overall incidence of secondary primary tumors ranges from 3% to 15% [ 8 , 9 ] .
a combination of a colorectal lcnec and a colorectal adenocarcinoma has only been reported in three cases ( table 1 ) [ 3 - 5 ] .
two of them involved a mixed tumor of either composite or collision type whereas the other involved a synchronous tumor as in the present case .
the precise pathogenesis of secondary primary tumors in patients with established neuroendocrine tumors remains unclear .
one proposed hypotheses is the field effect , stimulated growth of neuroendocrine tumor cells and secondary primary tumor cells caused by common carcinogens .
another proposed hypothesis is the stem cell theory , which relates the potency of various differentiations to several tumor types .
however , these hypotheses seem unlikely because a significant percentage of second primary malignancies occur in the genitourinary tract or even at more distant sites .
the other proposed hypothesis is a common genetic alteration that predisposes an individual to the development of neuroendocrine tumors and second primary tumors . in addition , kato et al .  
reported a ck20 positive lcnec of the colon and suggested a possible link between a colorectal neuroendocrine carcinoma and adenocarcinoma .
this report is consistent with the immunohistochemical findings in our case , where the patient had an advanced stage of lcnec and a simultaneous early - stage adenocarcinoma in the ascending colon .
however , more work is required to clarify the pathogenesis of a concurrent colorectal lcnec and adenocarcinoma .
although tumor size and microinvasion are major prognostic features in other gi neuroendocrine tumors , these features tend to be less useful in assessing the prognosis of colonic neuroendocrine tumors because most of these lesions exceed 2 cm in size and involve the muscularis propria at the time of presentation .
less than 2 cm in size metastasize whereas 74% of those more than 2 cm in size metastasize to the lymph nodes , liver , mesentery , peritoneum , pancreas , ureters , ovaries , and omentum .
therefore , colonic neuroendocrine tumors can be treated by local excision if they are found when they are small ; however , larger tumors should be treated aggressively with a standard colonic resection and lymph node dissection .
mitotic rate , overall tumor grade , and histologic pattern all influence the survival for patients with colonic neuroendocrine tumors .
colorectal lcnecs should be taken as a distinct histopathologic entity because they have a significantly worse prognosis than conventional adenocarcinomas .
this paper presented a rare example of two separated colonic tumors in a unique combination , namely , a concurrent lcnec and adenocarcinoma of the ascending colon .
large cell neuroendocrine carcinomas of the colon are rare and represent only a small percentage of all colonic endocrine tumors . here , we report a case of a colonic large cell neuroendocrine carcinomas concurrent with a colonic adenocarcinoma . a 70-year - old man presented with acute abdominal pain . 
 a spiral computed tomography scan of the abdomen revealed eccentric wall thickening on the ascending colon . 
 an explorative laparotomy and a right hemicolectomy were performed . 
 grossly , two separated masses were observed in the proximal ascending colon . 
 one was a 7.4  5.1 cm ulcerative fungating lesion , and the other was a 2.8  1.9 cm polypoid lesion . 
 microscopically , the ulcerative fungating lesion showed a well - differentiated neuroendocrine morphology with necrosis and increased mitosis . 
 most of the tumor cells had large , vesicular nuclei with eosinophilic nucleoli , variable amounts of eosinophilic cytoplasm , and immunoreactivity for chromogranin a and synaptophysin . 
 the polypoid lesion was a well - differentiated adenocarcinoma that had invaded the submucosa . 
 we diagnosed these lesions as a concurrent large cell neuroendocrine carcinoma and an adenocarcinoma of the ascending colon .