Formosan Journal of Surgery (2014) 47, 201e203

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CASE REPORT

Mixed endocrine-glandular carcinoma ofcecum

Tung-Jung Liang a,*, Tuan-Ying Ke b

a Division of Colon and Rectal Surgery, Department of Surgery, Cheng Ching Hospital, Taichung, Taiwanb Department of Pathology, Cheng Ching Hospital, Taichung, Taiwan

Received 13 March 2014; received in revised form 17 April 2014; accepted 13 May 2014Available online 10 August 2014

KEYWORDSadenocarcinoma;cecum;neoplasm;neuroendocrinetumor

Conflicts of interest: The authorsrelevant to this article.* Corresponding author. Division of

Department of Surgery, Cheng ChingStreet, Central District, Taichung City

E-mail address: candy56@mail2000

http://dx.doi.org/10.1016/j.fjs.2014.1682-606X/Copyright ª 2014, Taiwan

Summary Colorectal mixed endocrine-glandular neoplasms, a subtype of neuroendocrine tu-mors, are mainly diagnosed based on pathological characterization. The rarity and unusualpresentation of mixed endocrine tumors makes their prognosis relatively poor, and an optimalmanagement strategy for the tumors has yet to be devised. Here, we report a case of cecalmixed adenocarcinoma and neuroendocrine carcinoma with ileal tumor seeding, lymph nodes,and left iliac crest metastasis. After undergoing right hemicolectomy, target therapy, chemo-therapy, and radiotherapy for adenocarcinoma, the patient survived for more than 15 monthsand remains alive at the time of writing.Copyright ª 2014, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rightsreserved.

1. Introduction

Colorectal mixed endocrine-glandular neoplasms, whichare rare and heterogeneous in composition, are a type ofneuroendocrine tumor. These tumors are composed of atleast two populations and account for at least 30% of alltumor cases.1 Because the prognosis of mixed endocrine-glandular neoplasms of the colon and rectum is poor,diagnosing these tumors immediately is crucial for enabling

have no conflicts of interest

Colon and Rectal Surgery,Hospital, No. 139, Pingdeng400, Taiwan..com.tw (T.-J.Liang).

05.003Surgical Association. Published by

patients to benefit from treatment with alternative cyto-toxic chemotherapeutic agents.2

2. Case report

A 52-year-old woman with no major systemic disease wasadmitted to an emergency room because of right lowerabdominal pain for 3 days. The patient history revealedthat she experienced left iliac pain for approximately 3months and right lower abdominal pain 3 days beforeentering the emergency room. In our emergency room,epigastric tenderness was noted. Blood test results were:white blood cell count, 11.1 � 109/L; neutrophils, 82.4%; C-reactive protein, 0.37 mg/dL; glutamyl oxaloacetic trans-aminase, 26 U/L; Na, 139 meq/L; and K, 4.3 meq/L. An X-

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Figure 1 Monotonous hyperchromatic cells with adenoidnesting growth pattern (hematoxylin and eosin stain, 200�).

Figure 3 Synaptophysin (þ) for tumor cells.

202 T.-J. Liang, T.-Y. Ke

ray of the kidney, ureter, and bladder showed mildincreased bowel gas in the central abdomen. An abdominalsonogram revealed the presence of ascites and suggesteddiverticulitis or appendicitis. Abdominal computed tomog-raphy revealed an irregular eccentric mass, with di-mensions of approximately 4.3 cm � 3.2 cm, in the cecumwith ileocecal valve involvement and blurring of the sur-rounding pericolic fat plane, metastatic lymphadenopa-thies in the mesenteric cavity and intercavo-aortic spacewith the largest lymphadenopathy being approximately1.6 cm � 2.4 cm, and a suspicious osteolytic lesion in theleft iliac crest. The patient then received right hemi-colectomy, and a polypoid tumor, approximately6 cm � 5 cm in size, was detected along with nearobstruction in the cecum, several enlarged and hard lymphnodes in the mesenteric root, dilatation of the small in-testine, and tumor seeding in the terminal ileum. Pathologyrevealed a mixed adenocarcinoma and neuroendocrinetumor (Fig. 1) with terminal ileum seeding and regionallymph node metastasis (8/12), including angiolymphaticand neural/perineural invasion. The neuroendocrine tumor

Figure 2 Cytokeratin (þ) for tumor cells.

was classified as G2 grade, and the adenocarcinomatousparts were poorly differentiated. An immunohistochemicalstudy showed positive staining for the epidermal growthfactor receptor (1þ, 30%), cytokeratin (Fig. 2), synapto-physin (Fig. 3), and Ki-67 (15%). The American Joint Com-mittee on Cancer 7 staging was pT3N1M1. In addition, awhole-body bone scan performed using technetium-99mmethylene diophosphate revealed bone metastasisthrough the left anterior iliac crest to the upper aspect ofthe left acetabulum. After the operation, a full course (1course 2 weeks; 12 courses) of target therapy and chemo-therapy using bevacizumabeFOLFIRI was administered, andradiotherapy (3000 cGy/10 frs) was administered to the leftiliac crest. Thereafter, the patient was followed up at ouroutpatient department regularly and received nomedication.

3. Discussion

Neuroendocrine cells are distributed throughout the humanbody, including organs such as the gastrointestinal tract,pancreas, lung, thyroid, and adrenal glands.3 The largestpopulation of neuroendocrine cells is located in thegastrointestinal tract.4 However, neuroendocrine tumors ofthe colon and rectum are rare. The reported incidence ofthese tumors is between 0.1% and 3.9% of all colorectalmalignancies.3

Like primary colorectal adenocarcinomas, most colo-rectal neuroendocrine tumors are distributed in the rectumand cecum.4,5 In addition, data showed that the frequencyof combined adenocarcinoma and neuroendocrine tumorsin the proximal colon is high.1 In accordance with previousreports, our patient’s combined adenocarcinoma andneuroendocrine tumor was located in the cecum. Neuro-endocrine tumors behave aggressively and are associatedwith a prognosis less favorable than that of conventionaladenocarcinomas at the same stage3; moreover, 80% of thetumors exhibit distant metastases at the time of diagnosis.6

Similar signs were observed in our patient, who exhibitedleft iliac crest metastasis and lymph node and terminalileum involvement at the time of diagnosis.

Mixed endocrine-glandular neoplasm of cecum 203

According to the 2000 World Health Organization clas-sification, gastroenteropancreatic neuroendocrine tumorsare classified as well-differentiated neuroendocrine tu-mors, well-differentiated neuroendocrine carcinomas, andpoorly-differentiated neuroendocrine carcinomas (smallcell carcinomas).7 However, in 2010, the World Health Or-ganization reclassified gastroenteropancreatic neuroendo-crine tumors into neuroendocrine tumors G1, G2, and G3(large cell type or small cell type). Among these categories,only G3 is neuroendocrine carcinoma.8

The systematic application of immunohistochemicaltechniques to the study of tumors has led to the recognitionthat neuroendocrine cells occur rather frequently inexocrine neoplasms of the gut. The spectrum of combina-tions of exocrine and neuroendocrine components is wide,ranging from adenomas or carcinomas with interspersedneuroendocrine cells at one extreme to classical neuroen-docrine tumors with a focal exocrine component at theother extreme. In addition, both exocrine and neuroendo-crine components can have different morphological fea-tures, The features of exocrine components range fromadenomas to adenocarcinomas differentiated to variousdegrees, and the features of neuroendocrine componentsrange from well-differentiated to poorly-differentiatedneuroendocrine tumors.9 Usually, the neuroendocrinecomponent is well-differentiated, and it is easily recog-nized based on its clear histological features and verified byperforming immunodetection by using specific neuroendo-crine markers, including chromogranin, synaptophysin,neuron-specific enolase, prostatic acid phosphatase, so-matostatin, 5-HT, Ki67, and CD56.1,3 However, if theneuroendocrine component is poorly differentiated, thenthe demonstration of neuroendocrine markers is requiredto confirm the diagnosis.9 Because endocrine cells are ofteninconspicuous and their quantity is not substantial, thediagnosis is made only after the tumors are stained withneuroendocrine cell markers.1 Our patient had positiveneuroendocrine markers, including synaptophysin and Ki67.

Although a wide range of combinations of neuroendo-crine and exocrine components are frequently observed inroutine practice, mixed exocrineeneuroendocrine carci-nomas, recently renamed mixed adenoneuroendocrinecarcinomas (MANECs), are rare. By definition, this type ofneoplasms contains the two components, each representingat least 30% of the lesion.9 The patient in this report rep-resented a case of mixed adenocarcinoma and neuroendo-crine tumor G2, which may also be described as a mixedadenocarcinomaeneuroendocrine tumor (MANET) or MANECcontaining a well- differentiated neuroendocrine tumorcomponent according to a previous study.9

Because of the rarity and unusual presentation of MAN-ECs and MANETs, an optimal strategy for managing thesetumors has yet to be devised. A previous study recom-mended that extrapulmonary neuroendocrine carcinomas,particularly small-cell carcinomas of the colon and rectum,be treated with cytotoxic chemotherapeutic regimenssimilar to those used for small-cell carcinoma of the lung.4

In a small-scale serial trial evaluating the treatment ofmetastatic anaplastic neuroendocrine carcinomas of thecolon and rectum, the combination of cisplatin and

etoposide was associated with a 67% response rate and amedian survival of 19 months.4 However, the efficacy of thischemotherapy regimen in treating colorectal neuroendo-crine carcinomas has yet to be validated. According to theliterature, the median survival period for patients withneuroendocrine carcinomas of the colon and rectum is5e11 months,3 and 1-year survival rates have been re-ported to be 10e15%.3 Generally, the more aggressivecomponent of MANECs must be considered before deter-mining a treatment regimen for these patients. It has beensuggested that mixed tumors containing a well-differentiated neuroendocrine component and an adeno-carcinoma component should be treated in a mannersimilar to that used to treat adenocarcinoma. MANECscontaining a poorly-differentiated neuroendocrine compo-nent must be treated as poorly-differentiated neuroendo-crine carcinomas.10 Our patient had a mixedneuroendocrine tumor (G2) and poorly differentiatedadenocarcinoma of the cecum with left iliac crest metas-tasis and lymph node and terminal ileum involvement.Therefore, she was treated as if she had colorectaladenocarcinoma with bone metastasis. After undergoingtarget therapy using bevacizumab (Avastin), chemotherapyusing FOLFIRI, and radiotherapy of the left iliac crest, shehas survived for more than 15 months.

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