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Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Risk factors associated with the progression and metastases of hindgut neuroendocrine tumors: a retrospective study

Authors: Yoichiro Okubo, Rika Kasajima, Masaki Suzuki, Yohei Miyagi, Osamu Motohashi, Manabu Shiozawa, Emi Yoshioka, Kota Washimi, Kae Kawachi, Yoichi Kameda, Tomoyuki Yokose

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

The worldwide incidence of neuroendocrine tumors (NETs) has increased remarkably, with the hindgut being the second most common site for such tumors. However, the mechanisms underlying progression and metastasis of hindgut NETs are unclear. A retrospective study was conducted to elucidate these mechanisms.

Methods

Clinicopathological data of cases of hindgut NET between April 1996 and September 2015 were analyzed, retrospectively. Patients with neuroendocrine carcinoma were excluded. Formalin-fixed paraffin-embedded tissues of hindgut NET cases were subjected to detailed morphometric and immunohistochemical analyses. Statistical analyses were performed using the non-parametric Mann-Whitney U test, Spearman’s correlation coefficient, and chi-squared test. Multivariate logistic regression analysis was conducted as appropriate for the data set.

Results

Fifty-six hindgut NET cases were considered. Microvessel density and lymphatic microvessel density were identified as significant risk factors for venous and lymphatic invasion. There was a positive correlation between microvessel density and the maximum tumor diameter. Multivariate logistic regression analysis revealed that the maximum tumor diameter alone was an independent predictor of lymph node metastasis, whereas lymphovascular invasion and MVD was not the predictor of lymph node metastasis. There were no significant correlations between the Ki-67 labeling index and any of the parameters evaluated including age, sex, the maximum tumor diameter, venous invasion, lymphatic invasion, microvessel density, lymphatic microvessel density, and lymph node metastasis.

Conclusions

Angiogenic mechanisms may play important roles in the progression of hindgut NET. Otherwise, the maximum tumor diameter alone was an independent predictor of lymph node metastasis in hindgut NETs. Moreover, our study raises the question of whether the presence of lymphovascular invasion, in endoscopically obtained hindgut NET tissues, is an absolute indication for additional surgery or not.
Literature
1.
go back to reference Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD, Knowledge N. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer. 2014;21:R153–63.CrossRefPubMed Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD, Knowledge N. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer. 2014;21:R153–63.CrossRefPubMed
3.
go back to reference Sevilla I, Segura A, Capdevila J, Lopez C, Garcia-Carbonero R, Grande E, et al. Management of controversial gastroenteropancreatic neuroendocrine tumour clinical situations with somatostatin analogues: results of a Delphi questionnaire panel from the NETPraxis program. BMC Cancer. 2016;16:858.CrossRefPubMedPubMedCentral Sevilla I, Segura A, Capdevila J, Lopez C, Garcia-Carbonero R, Grande E, et al. Management of controversial gastroenteropancreatic neuroendocrine tumour clinical situations with somatostatin analogues: results of a Delphi questionnaire panel from the NETPraxis program. BMC Cancer. 2016;16:858.CrossRefPubMedPubMedCentral
4.
go back to reference Okubo Y, Motohashi O, Nakayama N, Nishimura K, Kasajima R, Miyagi Y, et al. The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure. Diagn Pathol. 2016;11:128.CrossRefPubMedPubMedCentral Okubo Y, Motohashi O, Nakayama N, Nishimura K, Kasajima R, Miyagi Y, et al. The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure. Diagn Pathol. 2016;11:128.CrossRefPubMedPubMedCentral
5.
go back to reference Kim ST, Ha SY, Lee J, Hong SN, Chang DK, Kim YH, et al. The Clinicopathologic features and treatment of 607 hindgut neuroendocrine tumor (NET) patients at a single institution. Medicine (Baltimore). 2016;95:e3534.CrossRef Kim ST, Ha SY, Lee J, Hong SN, Chang DK, Kim YH, et al. The Clinicopathologic features and treatment of 607 hindgut neuroendocrine tumor (NET) patients at a single institution. Medicine (Baltimore). 2016;95:e3534.CrossRef
7.
go back to reference Okubo Y, Yokose T, Motohashi O, Miyagi Y, Yoshioka E, Suzuki M, et al. Duodenal rare neuroendocrine tumor: Clinicopathological characteristics of patients with Gangliocytic Paraganglioma. Gastroenterol Res Pract. 2016;2016:5257312.CrossRefPubMedPubMedCentral Okubo Y, Yokose T, Motohashi O, Miyagi Y, Yoshioka E, Suzuki M, et al. Duodenal rare neuroendocrine tumor: Clinicopathological characteristics of patients with Gangliocytic Paraganglioma. Gastroenterol Res Pract. 2016;2016:5257312.CrossRefPubMedPubMedCentral
8.
go back to reference Okubo Y, Wakayama M, Nemoto T, Kitahara K, Nakayama H, Shibuya K, et al. Literature survey on epidemiology and pathology of gangliocytic paraganglioma. BMC Cancer. 2011;11:187.CrossRefPubMedPubMedCentral Okubo Y, Wakayama M, Nemoto T, Kitahara K, Nakayama H, Shibuya K, et al. Literature survey on epidemiology and pathology of gangliocytic paraganglioma. BMC Cancer. 2011;11:187.CrossRefPubMedPubMedCentral
9.
go back to reference Ebata T, Shimoi T, Ishiwata T, Iwasawa S, Bun S, Yunokawa M, et al. Amrubicin Monotherapy for patients with platinum-pretreated non-gastrointestinal non-pancreatic Extrapulmonary neuroendocrine carcinoma. Oncology. 2017; Ebata T, Shimoi T, Ishiwata T, Iwasawa S, Bun S, Yunokawa M, et al. Amrubicin Monotherapy for patients with platinum-pretreated non-gastrointestinal non-pancreatic Extrapulmonary neuroendocrine carcinoma. Oncology. 2017;
10.
go back to reference Jesinghaus M, Konukiewitz B, Keller G, Kloor M, Steiger K, Reiche M, et al. Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas. Mod Pathol. 2017;30:610–9.CrossRefPubMed Jesinghaus M, Konukiewitz B, Keller G, Kloor M, Steiger K, Reiche M, et al. Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas. Mod Pathol. 2017;30:610–9.CrossRefPubMed
11.
go back to reference Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014;120:2814–23.CrossRefPubMed Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014;120:2814–23.CrossRefPubMed
12.
go back to reference Spychalski M, Koptas W, Zelga P, Dziki A. Role of endoscopic submucosal dissection in treatment of rectal gastroenteropancreatic neuroendocrine neoplasms. Prz Gastroenterol. 2017;12:17–21.PubMed Spychalski M, Koptas W, Zelga P, Dziki A. Role of endoscopic submucosal dissection in treatment of rectal gastroenteropancreatic neuroendocrine neoplasms. Prz Gastroenterol. 2017;12:17–21.PubMed
13.
go back to reference Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934–59.CrossRefPubMed Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934–59.CrossRefPubMed
14.
go back to reference Yamagishi D, Matsubara N, Noda M, Yamano T, Tsukamoto K, Kuno T, et al. Clinicopathological characteristics of rectal carcinoid patients undergoing surgical resection. Oncol Lett. 2012;4:910–4.PubMedPubMedCentral Yamagishi D, Matsubara N, Noda M, Yamano T, Tsukamoto K, Kuno T, et al. Clinicopathological characteristics of rectal carcinoid patients undergoing surgical resection. Oncol Lett. 2012;4:910–4.PubMedPubMedCentral
15.
go back to reference Dellaportas D, Koureas A, Contis J, Lykoudis PM, Vraka I, Psychogios D, et al. Contrast-enhanced color Doppler ultrasonography for preoperative evaluation of sentinel lymph node in breast cancer patients. Breast Care (Basel). 2015;10:331–5.CrossRef Dellaportas D, Koureas A, Contis J, Lykoudis PM, Vraka I, Psychogios D, et al. Contrast-enhanced color Doppler ultrasonography for preoperative evaluation of sentinel lymph node in breast cancer patients. Breast Care (Basel). 2015;10:331–5.CrossRef
16.
go back to reference Haga T, Fukuoka M, Morita M, Cho K, Tatsumi KA. Prospective analysis of the efficacy and complications associated with deep sedation with midazolam during Fiberoptic bronchoscopy. J Bronchology Interv Pulmonol. 2016;23:106–11.CrossRefPubMed Haga T, Fukuoka M, Morita M, Cho K, Tatsumi KA. Prospective analysis of the efficacy and complications associated with deep sedation with midazolam during Fiberoptic bronchoscopy. J Bronchology Interv Pulmonol. 2016;23:106–11.CrossRefPubMed
17.
go back to reference Akimoto J, Fukuhara H, Suda T, Nagai K, Ichikawa M, Fukami S, et al. Clinicopathological analysis in patients with neuroendocrine tumors that metastasized to the brain. BMC Cancer. 2016;16:36.CrossRefPubMedPubMedCentral Akimoto J, Fukuhara H, Suda T, Nagai K, Ichikawa M, Fukami S, et al. Clinicopathological analysis in patients with neuroendocrine tumors that metastasized to the brain. BMC Cancer. 2016;16:36.CrossRefPubMedPubMedCentral
18.
go back to reference Legakis I, Saif MW, Syrigos K. Therapeutic challenges in neuroendocrine tumors. Anti Cancer Agents Med Chem. 2017; Legakis I, Saif MW, Syrigos K. Therapeutic challenges in neuroendocrine tumors. Anti Cancer Agents Med Chem. 2017;
19.
go back to reference Legakis I, Mantzouridis T, Bouboulis G, Chrousos GP. Reciprocal changes of serum adispin and visfatin levels in patients with type 2 diabetes after an overnight fast. Arch Endocrinol Metab. 2016;60:76–8.CrossRefPubMed Legakis I, Mantzouridis T, Bouboulis G, Chrousos GP. Reciprocal changes of serum adispin and visfatin levels in patients with type 2 diabetes after an overnight fast. Arch Endocrinol Metab. 2016;60:76–8.CrossRefPubMed
20.
go back to reference Guo X, Zheng L, Jiang J, Zhao Y, Wang X, Shen M, et al. Blocking NF-kappaB is essential for the immunotherapeutic effect of recombinant IL18 in pancreatic cancer. Clin Cancer Res. 2016;22:5939–50.CrossRefPubMed Guo X, Zheng L, Jiang J, Zhao Y, Wang X, Shen M, et al. Blocking NF-kappaB is essential for the immunotherapeutic effect of recombinant IL18 in pancreatic cancer. Clin Cancer Res. 2016;22:5939–50.CrossRefPubMed
21.
go back to reference Xiao G, Zhu F, Wang M, Zhang H, Ye D, Yang J, et al. Diagnostic accuracy of APRI and FIB-4 for predicting hepatitis B virus-related liver fibrosis accompanied with hepatocellular carcinoma. Dig Liver Dis. 2016;48:1220–6.CrossRefPubMed Xiao G, Zhu F, Wang M, Zhang H, Ye D, Yang J, et al. Diagnostic accuracy of APRI and FIB-4 for predicting hepatitis B virus-related liver fibrosis accompanied with hepatocellular carcinoma. Dig Liver Dis. 2016;48:1220–6.CrossRefPubMed
22.
go back to reference Boskoski I, Volkanovska A, Tringali A, Bove V, Familiari P, Perri V, et al. Endoscopic resection for gastrointestinal neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2013;7:559–69.CrossRefPubMed Boskoski I, Volkanovska A, Tringali A, Bove V, Familiari P, Perri V, et al. Endoscopic resection for gastrointestinal neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2013;7:559–69.CrossRefPubMed
23.
go back to reference Konishi T, Watanabe T, Nagawa H, Oya M, Ueno M, Kuroyanagi H, et al. Treatment of colorectal carcinoids: a new paradigm. World J Gastrointest Surg. 2010;2:153–6.CrossRefPubMedPubMedCentral Konishi T, Watanabe T, Nagawa H, Oya M, Ueno M, Kuroyanagi H, et al. Treatment of colorectal carcinoids: a new paradigm. World J Gastrointest Surg. 2010;2:153–6.CrossRefPubMedPubMedCentral
24.
go back to reference Wang YZ, Diebold A, Boudreaux P, Raines D, Campeau R, Anthony L, et al. Surgical treatment options for rectal carcinoid cancer: local versus low radical excision. Am Surg. 2014;80:31–5.PubMed Wang YZ, Diebold A, Boudreaux P, Raines D, Campeau R, Anthony L, et al. Surgical treatment options for rectal carcinoid cancer: local versus low radical excision. Am Surg. 2014;80:31–5.PubMed
25.
go back to reference Nakamura K, Osada M, Goto A, Iwasa T, Takahashi S, Takizawa N, et al. Short- and long-term outcomes of endoscopic resection of rectal neuroendocrine tumours: analyses according to the WHO 2010 classification. Scand J Gastroenterol. 2016;51:448–55.CrossRefPubMed Nakamura K, Osada M, Goto A, Iwasa T, Takahashi S, Takizawa N, et al. Short- and long-term outcomes of endoscopic resection of rectal neuroendocrine tumours: analyses according to the WHO 2010 classification. Scand J Gastroenterol. 2016;51:448–55.CrossRefPubMed
26.
go back to reference Kwon MJ, Kang HS, Soh JS, Lim H, Kim JH, Park CK, et al. Lymphovascular invasion in more than one-quarter of small rectal neuroendocrine tumors. World J Gastroenterol. 2016;22:9400–10.CrossRefPubMedPubMedCentral Kwon MJ, Kang HS, Soh JS, Lim H, Kim JH, Park CK, et al. Lymphovascular invasion in more than one-quarter of small rectal neuroendocrine tumors. World J Gastroenterol. 2016;22:9400–10.CrossRefPubMedPubMedCentral
27.
go back to reference Kitagawa Y, Ikebe D, Hara T, Kato K, Komatsu T, Kondo F, et al. Enhanced detection of lymphovascular invasion in small rectal neuroendocrine tumors using D2-40 and Elastica van Gieson immunohistochemical analysis. Cancer Med. 2016;5:3121–7.CrossRefPubMedPubMedCentral Kitagawa Y, Ikebe D, Hara T, Kato K, Komatsu T, Kondo F, et al. Enhanced detection of lymphovascular invasion in small rectal neuroendocrine tumors using D2-40 and Elastica van Gieson immunohistochemical analysis. Cancer Med. 2016;5:3121–7.CrossRefPubMedPubMedCentral
28.
go back to reference Okubo Y, Okubo T, Okubo Y, Ishiwatari T. Neuroendocrine differentiation in breast cancer: Clinicopathological significance of Bcl-2 positive solid papillary carcinoma. Case Rep Med. 2016;2016:9501410.CrossRefPubMedPubMedCentral Okubo Y, Okubo T, Okubo Y, Ishiwatari T. Neuroendocrine differentiation in breast cancer: Clinicopathological significance of Bcl-2 positive solid papillary carcinoma. Case Rep Med. 2016;2016:9501410.CrossRefPubMedPubMedCentral
29.
go back to reference Okubo Y, Nemoto T, Wakayama M, Tochigi N, Shinozaki M, Ishiwatari T, et al. Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan. BMC Cancer. 2015;15:269.CrossRefPubMedPubMedCentral Okubo Y, Nemoto T, Wakayama M, Tochigi N, Shinozaki M, Ishiwatari T, et al. Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan. BMC Cancer. 2015;15:269.CrossRefPubMedPubMedCentral
30.
go back to reference Okubo Y. Gangliocytic Paraganglioma: a diagnostic pitfall of rare neuroendocrine tumor. Endocr Pathol. 2017;28:186.CrossRefPubMed Okubo Y. Gangliocytic Paraganglioma: a diagnostic pitfall of rare neuroendocrine tumor. Endocr Pathol. 2017;28:186.CrossRefPubMed
31.
go back to reference Ishiwatari T, Okubo Y, Tochigi N, Wakayama M, Nemoto T, Kobayashi J, et al. Remodeling of the pulmonary artery induced by metastatic gastric carcinoma: a histopathological analysis of 51 autopsy cases. BMC Cancer. 2014;14:14.CrossRefPubMedPubMedCentral Ishiwatari T, Okubo Y, Tochigi N, Wakayama M, Nemoto T, Kobayashi J, et al. Remodeling of the pulmonary artery induced by metastatic gastric carcinoma: a histopathological analysis of 51 autopsy cases. BMC Cancer. 2014;14:14.CrossRefPubMedPubMedCentral
32.
go back to reference Okubo Y, Wakayama M, Kitahara K, Nemoto T, Yokose T, Abe F, et al. Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: morphometric and immunohistochemical analysis of six autopsy cases. Diagn Pathol. 2011;6:27.CrossRefPubMedPubMedCentral Okubo Y, Wakayama M, Kitahara K, Nemoto T, Yokose T, Abe F, et al. Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: morphometric and immunohistochemical analysis of six autopsy cases. Diagn Pathol. 2011;6:27.CrossRefPubMedPubMedCentral
33.
go back to reference Okubo Y, Ishiwatari T, Izumi H, Sato F, Aki K, Sasai D, et al. Pathophysiological implication of reversed CT halo sign in invasive pulmonary mucormycosis: a rare case report. Diagn Pathol. 2013;8:82.CrossRefPubMedPubMedCentral Okubo Y, Ishiwatari T, Izumi H, Sato F, Aki K, Sasai D, et al. Pathophysiological implication of reversed CT halo sign in invasive pulmonary mucormycosis: a rare case report. Diagn Pathol. 2013;8:82.CrossRefPubMedPubMedCentral
34.
go back to reference Sun X, Gong Y, Talamonti MS, Rao MS. Expression of cell adhesion molecules, CD44s and E-cadherin, and microvessel density in carcinoid tumors. Mod Pathol. 2002;15:1333–8.CrossRefPubMed Sun X, Gong Y, Talamonti MS, Rao MS. Expression of cell adhesion molecules, CD44s and E-cadherin, and microvessel density in carcinoid tumors. Mod Pathol. 2002;15:1333–8.CrossRefPubMed
35.
go back to reference Okubo Y, Tochigi N, Wakayama M, Shinozaki M, Nakayama H, Ishiwatari T, et al. How histopathology can contribute to an understanding of defense mechanisms against cryptococci. Mediat Inflamm. 2013;2013:465319.CrossRef Okubo Y, Tochigi N, Wakayama M, Shinozaki M, Nakayama H, Ishiwatari T, et al. How histopathology can contribute to an understanding of defense mechanisms against cryptococci. Mediat Inflamm. 2013;2013:465319.CrossRef
36.
go back to reference Aki K, Okubo Y, Nanjo H, Ishiwatari T, Nihonyanagi Y, Tochigi N, et al. Genomic analysis of single nucleotide polymorphisms Asp299Gly and Thr399Ile in Japanese patients with invasive Aspergillosis. Jpn J Infect Dis. 2015;68:330–2.CrossRefPubMed Aki K, Okubo Y, Nanjo H, Ishiwatari T, Nihonyanagi Y, Tochigi N, et al. Genomic analysis of single nucleotide polymorphisms Asp299Gly and Thr399Ile in Japanese patients with invasive Aspergillosis. Jpn J Infect Dis. 2015;68:330–2.CrossRefPubMed
37.
go back to reference Okubo Y, Shinozaki M, Wakayama M, Nakayama H, Sasai D, Ishiwatari T, et al. Applied gene histopathology: identification of Fusarium species in FFPE tissue sections by in situ hybridization. Methods Mol Biol. 2013;968:141–7.CrossRefPubMed Okubo Y, Shinozaki M, Wakayama M, Nakayama H, Sasai D, Ishiwatari T, et al. Applied gene histopathology: identification of Fusarium species in FFPE tissue sections by in situ hybridization. Methods Mol Biol. 2013;968:141–7.CrossRefPubMed
38.
go back to reference Shinozaki M, Okubo Y, Sasai D, Nakayama H, Murayama SY, Ide T, et al. Identification of Fusarium species in formalin-fixed and paraffin-embedded sections by in situ hybridization using peptide nucleic acid probes. J Clin Microbiol. 2011;49:808–13.CrossRefPubMedPubMedCentral Shinozaki M, Okubo Y, Sasai D, Nakayama H, Murayama SY, Ide T, et al. Identification of Fusarium species in formalin-fixed and paraffin-embedded sections by in situ hybridization using peptide nucleic acid probes. J Clin Microbiol. 2011;49:808–13.CrossRefPubMedPubMedCentral
39.
go back to reference Williams CS, Leek RD, Robson AM, Banerji S, Prevo R, Harris AL, et al. Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer. J Pathol. 2003;200:195–206.CrossRefPubMed Williams CS, Leek RD, Robson AM, Banerji S, Prevo R, Harris AL, et al. Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer. J Pathol. 2003;200:195–206.CrossRefPubMed
Metadata
Title
Risk factors associated with the progression and metastases of hindgut neuroendocrine tumors: a retrospective study
Authors
Yoichiro Okubo
Rika Kasajima
Masaki Suzuki
Yohei Miyagi
Osamu Motohashi
Manabu Shiozawa
Emi Yoshioka
Kota Washimi
Kae Kawachi
Yoichi Kameda
Tomoyuki Yokose
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3769-4

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