Correlation of Neuroendocrine Differentiation with Neuroendocrine Cell Hyperplasia and Vascular Endothelial Growth Factor in Colorectal Adenocarcinoma

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Khesar Hussein Khalil
Bashar Al-Hassawi
Jasim Abdo


Neuroendocrine differentiation has been mentioned in many cancers of non-neuroendocrinal organs, involving the gastrointestinal tract. In contrast, the correlation of focally diffused neuroendocrine differentiation in colorectal adenocarcinoma with neuroendocrine cell hyperplasia has not been somewhat reported. The objective of this research is to study the relationship between neuroendocrine cell hyperplasia and neuroendocrine differentiation in colorectal adenocarcinoma and to find the correlation of neuroendocrine differentiation and VEGF expression with clinicopathological parameters of colorectal adenocarcinoma. Methods employed in the current study were including eighty-one patients with colorectal cancer. Formalin fixed paraffin embedded blocks were sectioned and stained with immunohistochemical markers; Chromogranin A and VEGF; and processed automatically according to protocols supplied by the antibody manufacturer. Results show that neuroendocrine cell hyperplasia in the mucosa nearby tumor comprised (42%) and it was associated with neuroendocrine differentiation. Neuroendocrine differentiation and vascular endothelial growth factor were positive in 48.1% and 63% respectively. Neuroendocrine differentiation did not show a relation with clinicopathological parameters with the exception of tumor that metastasizes to other tissues and organs. The association of VEGF with the same factors had significant impact with tumor stage, degree of local invasion and lymph node metastasis. Other histological changes revealed that only desmoplastic reaction had significant difference in relation to neuroendocrine differentiation. This study reached the conclusion that neuroendocrine cell hyperplasia is positively correlated with neuroendocrine differentiation and it has strong linkage in pathogenesis of colorectal adenocarcinoma. Neuroendocrine differentiation and VEGF expression are greatly correlated with progression and invasion of tumor to other tissues and organs, and this can be represented as an important parameter for poor prognosis of colorectal adenocarcinoma.


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Khalil KH, Al-Hassawi B, Abdo J. Correlation of Neuroendocrine Differentiation with Neuroendocrine Cell Hyperplasia and Vascular Endothelial Growth Factor in Colorectal Adenocarcinoma. Baghdad Sci.J [Internet]. 2021Mar.10 [cited 2021May9];18(1):0018. Available from:


Mármol I, Sánchez-de-Diego C, Pradilla D A, Cerrada E, Rodriguez Y M. Colorectal carcinoma: a general overview and future perspectives in colorectal cancer. Int J Mol Sci. 2017 Jan; 18(1): 197.

Bernick PE, Klimstra DS, Shia J, Minsky B, Saltz L, Shi W, et al. Neuroendocrine carcinomas of the colon and rectum. Dis Col Rect. 2004 Feb; 47(2): 163-9.

Kleist B, Poetsch M. Neuroendocrine differentiation: The mysterious fellow of colorectal cancer. World J Gastroenterol. 2015 Nov; 21(41): 11740-7.

Massironi S, Zilli A, Cavalcoli F, Conte D, Peracchi M. Chromogranin A and other enteroendocrine markers in inflammatory bowel disease. Neuropeptides. 2016 Aug; 1(58):127-34.

Mori M, Mimori K, Kamakura T, Adachi Y, Ikeda Y, Sugimachi K. Chromogranin positive cells in colorectal carcinoma and transitional mucosa. J Clinc Pathol. 1995 Aug1; 48(8): 754-8.

Klöppel G, Anlauf M, Perren A. Endocrine precursor lesions of gastroenteropancreatic neuroendocrine tumors. Endocrine Pathol. 2007 Sep; 18(3): 150-5.

Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. World Health Organization, 2010; 4th ed.

Shin SH, Kim SH, Jung SH, Jang JW, Kang MS, Kim SI, et al. High-Grade Mixed adenoneuroendocrine carcinoma in the cecum: A case report. Annals coloproctology. 2017 Feb; 33(1):39.

Woischke C, Schaaf CW, Yang HM, Vieth M, Veits L, Geddert H, et al. In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components. Modern Pathol. 2017 Jan; 30(1):95.

Sabnis A, Carrasco R, Liu SX, Yan X, Managlia E, Chou PM, et al. Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis. Neonat.. 2015; 107(3):191-8.

La Rosa S, Chiaravalli AM, Capella C, Uccella S, Sessa F. Immunohistochemical localization of acidic fibroblast growth factor in normal human enterochromaffin cells and related gastrointestinal tumours. Virch Archiv. 1997 Mar; 430(2): 117-24.

Khalid A, Javaid MA. Matrix Metalloproteinases: New Targets in Cancer Therapy. J Cancer Sci Ther. 2016; 8(6):143-53.

Ahmad A, Venizelos N, Hahn-Strömberg V. Prognostic Effect of Vascular Endothelial Growth Factor+ 936C/T Polymorphism on Tumor Growth Pattern and Survival in Patients Diagnosed with Colon Carcinoma. J Tumor Res. 2016; 2(1):1-6.

Kamel AA, Yossef WT, Mohamed M. Correlation of vascular endothelial growth factor expression and neovascularization with colorectal carcinoma: A pilot study. J Adenocarcinoma. 2016; 1(1): 5.

Ricci V, Ronzoni M, Fabozzi T. Aflibercept a new target therapy in cancer treatment: a review. Critical rev oncol / hematol. 2015 Dec; 96(3):569-76.

Kyriakopoulos, G, Mavroeidi, V, Chatzellis, E, Kaltsas, GA, Alexandraki, K I. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann Transl Med, 2018 Jun; 6(12). 1-13.

Shia J, Tickoo SK, Guillem JG, Qin J, Nissan A, Hoos A et al. Increased endocrine cells in treated rectal adenocarcinomas: a possible reflection of endocrine differentiation in tumor cells induced by chemotherapy and radiotherapy. Am J Surg Pathol. 2002 Jul; 26(7): 863-72.

Fondevila C, Metges JP, Fuster J, Grau JJ, Palacin A, Castells A, et al. p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer. 2004 Jan; 90(1): 206-15.

Gulubova M, Vlaykova T. Chromogranin A‐, serotonin‐, synaptophysin‐and vascular endothelial growth factor‐positive endocrine cells and the prognosis of colorectal cancer: an immunohistochemical and ultrastructural study. Journal of gastroenterology and hepatology. 2008 Oct;23(10):1574-85.

Chen Y, Liu F, Meng Q, Ma S. Is neuroendocrine differentiation a prognostic factor in poorly differentiated colorectal cancer. World J Surg Oncol. 2017 Dec; 15(1): 71.

Slovin SF. Neuroendocrine differentiation in prostate cancer: a sheep in wolf's clothing? Nature Rev Urol. 2006 Mar; 3(3): 138-44.

Schron D S, Gipson T, Mendelsohn G. The histogenesis of small cell carcinoma of the prostate an immunohistochemical study. Cancer. 1984; 53: 2478-80.

Schonhoff SE, Giel-Moloney M, Leiter AB. Minireview: Development and differentiation of gut endocrine cells. Endocrinol. 2004 Jun; 145(6): 2639-44.

Bonkhoff H. Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status. Prostate. 1998; 36(S8): 18-22.

Sauer CG, Roemer A, Grobholz R. Genetic analysis of neuroendocrine tumor cells in prostatic carcinoma. Prostate. 2006 Feb; 66(3): 227-34.

Johnson LR. Regulation of gastrointestinal mucosal growth. Physiol Rev. 1988 Apr; 68(2): 456-502.

El-Salhy M, Solomon T, Hausken T, Gilja OH, Hatlebakk JG. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. World J Gastroenterol. 2017 Jul; 23(28): 5068.

Nascimbeni R, Villanacci V, Di Fabio F, Gavazzi E, Fellegara G, Rindi G. Solitary microcarcinoid of the rectal stump in ulcerative colitis. Neuroendocrinol. 2005; 81(6): 400-4.

Barral M, Dohan A, Allez M, Boudiaf M, Camus M, Laurent V, et al. Gastrointestinal cancers in inflammatory bowel disease: An update with emphasis on imaging findings. Critical rev oncol /hematol. 2016 Jan; 1(97): 30-46.

Wang H, Steeds J, Motomura Y, Deng Y, Verma-Gandhu M, El-Sharkawy RT, et al. CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection. Gut. 2007 Jul; 56(7): 949-57.

Volante M, Marci V, Andrejevic-Blant S, Tavaglione V, Sculli MC, Tampellini M, et al. Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas. Virch Archiv. 2010 Nov; 457(5): 521-7.

Liu Y, He J, Xu J, Li J, Jiao Y, Bei D, et al. Neuroendocrine differentiation is predictive of poor survival in patients with stage II colorectal cancer. Oncol let. 2017 Apr; 13(4): 2230-6.

Suresh PK, Sahu KK, Pai RR, Sridevi HB, Ballal K, Khandelia B, et al. The prognostic significance of neuroendocrine differentiation in colorectal carcinomas: our experience. J Clinic Diag Res: (JCDR). 2015 Dec; 9(12): EC01.

Hamada Y, Oishi A, Shoji T, Takada H, Yamamura M, Hioki K, et al. Endocrine cells and prognosis in patients with colorectal carcinoma. Cancer. 1992; 69: 2641-6.

Zlobec I, Steele R, Compton CC. VEGF as a predictive marker of rectal tumor response to preoperative radiotherapy. Cancer: Interdisci. Int J Am Cancer Soc. 2005 Dec; 104(11): 2517-21.

Ismail NH. mRNA in situ Hybridization Analysis of Vascular Endothelial Growth Factor and Matrix Metalloproteinase-1 in Colorectal Cancer. Al-Mustan. J Pharma Sci. 2016 Dec; 16(2): 62-9.

Eefsen RL, Engelholm L, Willemoe GL, Van den Eynden GG, Laerum OD, Christensen IJ, et al. Microvessel density and endothelial cell proliferation levels in colorectal liver metastases from patients given neo‐adjuvant cytotoxic chemotherapy and bevacizumab. International journal of cancer. 2016 Apr; 138(7): 1777-84.

Lazaris A, Amri A, Petrillo SK, Zoroquiain P, Ibrahim N, Salman A, et al. Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti‐angiogenic therapies. The J Pathol: Clinic Res. 2018 Jul; 4(3): 184-92.