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 Table of Contents  
Year : 2018  |  Volume : 51  |  Issue : 2  |  Page : 76-80

Metachronous adenocarcinoma and large cell neuroendocrine carcinoma of the colon

1 Department of Surgery, Division of General Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan
2 Division of Pathology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan

Date of Submission12-Jan-2017
Date of Decision05-Apr-2017
Date of Acceptance14-Aug-2017
Date of Web Publication24-Apr-2018

Correspondence Address:
Dr. Meng-Lin Huang
Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan #81345, No. 553, Junxiao Road, Zuoying District, Kaohsiung City 813
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/fjs.fjs_2_17

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Neuroendocrine tumors are a group of heterogeneous tumors originating from peptidergic neurons and neuroendocrine cells and can occur in many organs and tissues of the body. We reported a 77-year-old woman who had undergone a left hemicolectomy for descending colon adenocarcinoma 20 years previously, postoperatively; the final disease stage was T1N0M0 (Stage I). However, neuroendocrine carcinoma (NEC) at ascending colon with liver metastasis was found in a regular colonoscopy, accidentally. There are interesting with the findings in our case where the patient had an advanced stage of NEC in the ascending colon and an early-stage adenocarcinoma in the descending at the different time. She refused any palliative therapy even though she died 8 months postoperatively. To our best knowledge, this is the first case of metachronous adenocarcinoma and large-cell NEC at the different side of the colon. We believe surmise that previous adenocarcinoma of descending colon should be included in the risk factor even if the patient stood well after the operation in the follow-up.

Keywords: Adenocarcinoma, colon, large cell, metachronous, neuroendocrine carcinoma, rectum

How to cite this article:
Lin KH, Chang NJ, Liou LR, Su MS, Tsao MJ, Huang ML. Metachronous adenocarcinoma and large cell neuroendocrine carcinoma of the colon. Formos J Surg 2018;51:76-80

How to cite this URL:
Lin KH, Chang NJ, Liou LR, Su MS, Tsao MJ, Huang ML. Metachronous adenocarcinoma and large cell neuroendocrine carcinoma of the colon. Formos J Surg [serial online] 2018 [cited 2021 Feb 27];51:76-80. Available from: https://www.e-fjs.org/text.asp?2018/51/2/76/231140

  Introduction Top

Adenocarcinoma is the most common cancer of the colon and rectum. Carcinoids are relatively rare and slow-growing neuroendocrine tumors (NETs). Neuroendocrine cells are diffusely distributed throughout the body and are found in the gastrointestinal tract, pancreas, lung, thyroid, adrenal gland, and many other organs. NETs are a group of heterogeneous tumors originating from peptidergic neurons and neuroendocrine cells. It is not usually we know a single kind of a tumor, but a large group of tumors in general. NETs can occur in many organs and tissues of the body, according to the different parts of the primary tumor, NETs can be divided into foregut (thymus, esophagus, lung, stomach, pancreas, duodenum), midgut (ileum, appendix, ascending colon), and hindgut (distal large intestine and rectum), of which gastrointestinal pancreatic NETs are the most common. Most neuroendocrine cells are located in the gastrointestinal tract. In the WHO 2010,[1] a new histological classification of NETs was established and widely accepted by physicians worldwide. The following categories are recognized: NET, neuroendocrine carcinoma (NEC), and mixed adenoneuroendocrine carcinoma. Primary colonic adenocarcinoma and NEC are very rarely known to present as metachronous tumors.

We report the first case in bibliography of metachronous adenocarcinoma and large-cell NEC at the different side of the colon, a highly aggressive and rare tumor with poor prognosis.

  Case Report Top

A 77-year-old woman was referred to our hospital for general checkup of colonoscopic and gastroscopic evaluations initially. She had undergone a left hemicolectomy for descending colon adenocarcinoma 20 years previously in the other hospital. Postoperatively, the final disease stage was T1N0M0 (Stage I) according to the tumor, node, and metastasis classification. There had been no evidence of recurrence or metastasis during 2 years of follow-up. The patient showed no signs of familial adenomatous polyposis. There was no significant medical history of inflammatory bowel disease, bleeding disorders, change in bowel habits, or significant weight loss. Family history was unremarkable.

Her colonoscopy revealed dark bloody fluid collection at whole colon, >4.0-cm diameter, large, ulcerating with easy bleeding mass of the proximal ascending colon, lying beneath the mucosa [Figure 1]. This tumor could not be classified by biopsy initially. Biopsies of the lesion showed poor-differentiated tubular adenocarcinoma. An abdominal-enhanced computed tomography (CT) revealed a 6.1 cm × 4.8 cm solid tumor with low-density area located at ascending colon wall thickening, a small liver nodule about 1.07 cm at S5, and severe metastatic enlarged confluent lymph nodes (largest one >4.5 cm) of aortocaval space, gastrohepatic ligament, mesenteric roots and mesentery of abdomen, suspect distant metastasis [Figure 2]. No free fluid was identified around the mass in the abdominal cavity. Under the tentative diagnosis of ascending colon adenocarcinoma, the right hemicolectomy was performed, with free macroscopic surgical margins. Intraoperative findings showed an outgrown tumor, measuring 7 cm × 4 cm in the ascending colon with rupture mucosa about 4 cm × 4 cm, suspect submucosa lesion without seeding to nearby soft tissues [Figure 3]. Total blood loss amount was about 200 ml. The patients' postoperative course was uneventful. The specimen included an ulcerative intramural tumor, measuring 4 cm × 3.5 cm × 2 cm, with its lower edge located 3 cm from the distal surgical margin. The overlying mucosa shows ulceration.
Figure 1: Dark bloody fluid collection at whole colon fungating tumor >4 cm in size, located at ascending colon

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Figure 2: Abdominal enhanced computed tomography scan revealing a 6.1 cm × 4.8 cm solid tumor with a low-density area

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Figure 3: Segmental resection of the ascending colon tumor. A fungating tumor, 7 cm × 4 cm, rupture mucosa 4 cm × 4 cm at ascending colon, suspect submucosa lesion

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The tumor had elastic consistency, compact form, grayish, and partially brownish color, and infiltrated the entire muscular wall. The tumor extends through the muscularis propria and subserosa and penetrates the serosa. Tumor invades pericolic soft tissue.

The microscopic examination revealed a tumor with small nests, rosettes, prominent trabecular and peripheral palisading pattern, clearing, and enlargement of the nuclei in the solid tumor nests with lymphovascular and perineural invasion [Figure 4]. There were also neoplastic emboli in lymphatics and vessels. There was absent of polyps. The large tumor cells with faintly granular cytoplasm had diffuse architecture with necrosis, ample cytoplasm, and numerous mitotic figures >10 >20 mitoses per 10 high-power field.
Figure 4: Identification of the involvement of lymphatic channel of ascending neuroendocrine tumor on serial tissue sections. (a) Identification of trabecular pattern using hematoxylin–eosin staining. Original magnification ×250. (b) Identification of palisading pattern using hematoxylin–eosin staining. Original magnification ×250

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On the immunohistochemical staining panel of neuroendocrine markers, the tumor was positive for synaptophysin A and CD56 but negative for chromogranins [Figure 5]. She denied any further palliative chemotherapy then was died at 8 months postoperatively. These reports are consistent with the findings in our case where the patient had an advanced stage of NEC in the ascending colon and an early stage adenocarcinoma in the descending colon at the different time. Fifteen of 18 resected lymph nodes were positive for metastatic tumor. According to the WHO 2010 criteria, the final stage was T3N1M1 stage IV.
Figure 5: Immunohistochemical staining revealed positive findings for (a) CD56 (+) (b) Synaptophysin (+) and (c) Chromogranin A (−) Original magnification ×250

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  Discussion Top

Colorectal high-grade NEC was first described in 1962, but published data have been limited to small retrospective series.[2],[3] Retrospective study of NET of the large intestine (colorectal and appendiceal NET) was performed among institutions allied with the Japanese Society for Cancer of the Colon and Rectum (JSCCR), and 760 NETs from 2001 to 2011 were reassessed using the WHO 2010 criteria to elucidate the clinicopathological features of NET in the large intestine.[4] NETs are generally synaptophysin-positive cells and may also have scattered serotonin and somatostatin-positive cells and will have metastases at the time of diagnosis possibly because of the later presentation due to the absence of early symptoms. Tumors are graded into three levels based on tumor cell proliferation – G1: mitotic count <2 per 10 high-power fields (HPF) and/or Ki67 ≤2%; G2: mitotic count 2–20 per 10 HPF and/or Ki67 3%–20%; G3: mitotic count >20 per 10 HPF and/or Ki67 >20%. Neuroendocrine malignancies with Ki-67 and/or mitotic index values over these limits are classified as poorly differentiated or high-grade NECs.[5] Although both groups of malignancies stain for neuroendocrine markers such as chromogranin, synaptophysin NETs, and NECs have widely different treatment approaches that reflect their disparate clinical behaviors.[6] These tumors are morphologically and biologically similar to bronchogenic small cell carcinoma.[5] At present, the pathological diagnosis is still the gold diagnosis.[7] However, there is still a small number of randomized trials in this field, so all evidence must be considered weaker compared to other more common cancers.[7]

NECs of the colon and rectum are uncommon, comprising <1% of colon and rectal cancers.[2] The clinical presentation is not specific for NEC and may be dominated by the advanced stage at diagnosis. The most common presenting symptom was rectal bleeding and pain. These symptoms could be seen in any type of colorectal cancer. NEC at diagnosis, 36% of patients had metastatic disease.[3] Liver was the most common metastatic organ involved. These tumors are poorly differentiated and are characterized by early dissemination and rapid clinical deterioration.

The clinicopathological features of NET were variable among the rectum, colon, and appendix, and histological variability among them clearly emerged using the NET classification.[4] The extent of the tumor, its metastases, histological grade, and secretory profile should be determined as far as possible before planning treatment.[7] At the time of diagnosis, the majority of tumors have metastasized to the lymph nodes, liver, lung, or other sites. Correct diagnosis is important because it will affect treatment and may better predict the clinical course.[2]

Pathologically, these tumors are poorly differentiated carcinomas with distinctive cytoarchitectural features and are often immunoreactive for markers of neuroendocrine differentiation. Colorectal NETs are classified as either low-grade carcinoid tumors or high-grade NECs.[5] High-grade NET in the colon and rectum most commonly occur as a component of poorly differentiated adenocarcinomas; more than 50% of the tumor should show neuroendocrine differentiation to be call NEC.[2] Within the large bowel, the most frequent site is the rectum, followed by the cecum and sigmoid.[2] Classification of NETs is based on size, functionality, site, and invasion.[8] Functioning tumors are those associated with clinical manifestations of hormone production or secretion of measurable amounts of active hormone; immunohistochemical demonstration of hormone production is not equivalent to clinically apparent functionality.[8]

All colonic NETs are considered potentially malignant; none are classified as benign or low-malignant potential NETs.[8] The prognosis for high-grade NEC s is poor, as most patients have metastatic disease at the time of diagnosis.[2] Most are large, bulky, high grade, highly invasive tumors that are metastatic at presentation.[8] The tumor is composed of sheets and nests of round to fusiform cells with minimal amounts of cytoplasm, granular nuclear chromatin, and inconspicuous nucleoli.[3] Abundant necrosis, either confluent or punctuate within nests of tumor cells, is present in high-grade tumors.[9] Colorectal NET may contain adenocarcinoma components or foci of squamous differentiation as well.[2],[5],[9]

Lymphatic and blood vessel invasion were independent predictive factors of lymph node metastasis and risk of lymph node metastasis in rectal NET was confirmed even in lesions <10 mm.[4] Large bowel NEC has a very poor prognosis.[10] Carcinoid tumors generally exhibit a more indolent behavior and do not response to cisplatin-based chemotherapy, whereas high-grade NECs behave aggressive but often do response transiently to cisplatin-based chemotherapy.[2] It is increasing in survival rate when the patient was diagnosed accurately at an early stage and underwent adequate curative surgical intervention. Standard resection with locoregional lymphadenectomy is appropriate.[2] Surgery should be considered in those with liver metastases and potentially resectable disease.[7] The JSCCR and Japan NET Society recommend local resection only for tumors <10 mm and without muscular invasion or vascular invasion.[4] In 2016, Kojima et al.[4] reported that NET in the large intestine showed a tumor site-dependent variety of histological and clinicopathological features and expressed lymph node metastases even in tumors smaller than 10 mm, demonstrating that indications for surgical resection should be reexamined, especially in small NET with vascular invasion.

The prognosis for NETs is poor because most patients have metastatic disease at the time of diagnosis. It is still controversial worldwide for the effective and accurate treatment process of the NEC. At present, no standard oncological treatment strategy has been defined for colorectal NEC. Surgery with or without adjuvant treatment is the preferred therapy for localized disease, while primary chemotherapy with or without radiotherapy is used for stage IV patients.

To our best knowledge, this is the first case of metachronous adenocarcinoma and large-cell NEC at different side of the colon. We reviewed the recent literature that previous colon neoplasm is not yet taken into account the risk factor in the studies. We surmise that previous adenocarcinoma of descending colon should be included in the risk factor even if the patient stood well after the operation in the follow-up.

  Conclusion Top

Metachronous adenocarcinoma and large-cell NEC of the colon are an extremely rare malignancy and poor prognosis. There is no definitive recommendation for the management of this malignancy condition. We believe that more research is needed in the future to identify predictive and therapeutic modalities for this neoplasm.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given herr consent for her images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. WHO classification of tumours of the digestive system 2010 No. Ed. 4. p.417.  Back to cited text no. 1
Bernick PE, Klimstra DS, Shia J, Minsky B, Saltz L, Shi W, et al. Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum 2004;47:163-9.  Back to cited text no. 2
Aytac E, Ozdemir Y, Ozuner G. Long term outcomes of neuroendocrine carcinomas (high-grade neuroendocrine tumors) of the colon, rectum, and anal canal. J Visc Surg 2014;151:3-7.  Back to cited text no. 3
Kojima M, Ikeda K, Saito N, Sakuyama N, Koushi K, Kawano S, et al. Neuroendocrine tumors of the large intestine: Clinicopathological features and predictive factors of lymph node metastasis. Front Oncol 2016;6:173.  Back to cited text no. 4
Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: A review of nomenclature, grading, and staging systems. Pancreas 2010;39:707-12.  Back to cited text no. 5
Kulke MH, Shah MH, Benson AB rd, Bergsland E, Berlin JD, Blaszkowsky LS, et al. Neuroendocrine tumors, version 1.2015. J Natl Compr Canc Netw 2015;13:78-108.  Back to cited text no. 6
Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012;61:6-32.  Back to cited text no. 7
Washington MK, Tang LH, Berlin J, Branton PA, Burgart LJ, Carter DK, et al. Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the colon and rectum. Arch Pathol Lab Med 2010;134:176-80.  Back to cited text no. 8
Vortmeyer AO, Lubensky IA, Merino MJ, Wang CY, Pham T, Furth EE, et al. Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst 1997;89:1448-53.  Back to cited text no. 9
Anthony LB, Strosberg JR, Klimstra DS, Maples WJ, O'Dorisio TM, Warner RR, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): Well-differentiated nets of the distal colon and rectum. Pancreas 2010;39:767-74.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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