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Published in: Journal of Gastrointestinal Surgery 10/2016

01-10-2016 | Original Article

Extranodal Extension of Nodal Metastases Is a Poor Prognostic Indicator in Gastric Cancer: a Systematic Review and Meta-analysis

Authors: Nicola Veronese, Matteo Fassan, Laura D. Wood, Brendon Stubbs, Marco Solmi, Paola Capelli, Antonio Pea, Alessia Nottegar, Giuseppe Sergi, Enzo Manzato, Sara Carraro, Marco Maruzzo, Ivana Cataldo, Fabio Bagante, Mattia Barbareschi, Liang Cheng, Maria Bencivenga, Giovanni de Manzoni, Claudio Luchini

Published in: Journal of Gastrointestinal Surgery | Issue 10/2016

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Abstract

Introduction

The extranodal extension (ENE) of nodal metastases (the extension of neoplastic cells through the nodal capsule into the perinodal soft tissue) is a histological feature that has been considered a prognostic factor in several cancers, but the role in gastric cancer was not yet investigated. We aimed to investigate the prognostic role of ENE in patients affected by gastric cancer through a systematic review and meta-analysis.

Material and Methods

Two independent authors searched major databases until 09/30/2015 to identify studies providing data on gastric cancer patients’ prognostic parameters and comparing patients with ENE (ENE+) vs intra-nodal extension (ENE−). The data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) with 95 % confidence intervals (CI), adjusted for potential confounders.

Results

Nine studies followed up 3250 patients with gastric cancer (1064 ENE+ and 2186 ENE−). ENE+ was associated with a significantly higher risk of all-cause mortality (RR = 1.70; 95 % CI: 1.43–2.03, I 2 = 66 %; HR = 2.14; 95 % CI: 1.66–2.75, I 2 = 0 %), cancer-specific mortality (RR = 1.59; 95 % CI: 1.42–1.79; HR = 1.52; 95 % CI: 1.19–1.96), and disease recurrence (RR = 3.43, 95 % CI: 1.80–6.54, I 2 = 0 %).

Discussion

Judging from our results, ENE in gastric cancer patients should be considered for prognostic purposes from the gross sample to the pathology report.
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Literature
1.
go back to reference Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press, 2010. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press, 2010.
2.
3.
go back to reference Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English ed. Gastric Cancer 1998; 1:10–24.CrossRefPubMed Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English ed. Gastric Cancer 1998; 1:10–24.CrossRefPubMed
4.
go back to reference Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag, 2010. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag, 2010.
5.
go back to reference Roder JD, Bottcher K, Busch R, Wittekind C, Hermanek P, Siewert JR. Classification of regional lymph node metastasis from gastric carcinoma. German Gastric Cancer Study Group. Cancer 1998; 82:621–31.CrossRefPubMed Roder JD, Bottcher K, Busch R, Wittekind C, Hermanek P, Siewert JR. Classification of regional lymph node metastasis from gastric carcinoma. German Gastric Cancer Study Group. Cancer 1998; 82:621–31.CrossRefPubMed
6.
go back to reference Luchini C, Veronese N, Pea A, Sergi G, Manzato E, Nottegar A, Solmi M, Capelli P, Scarpa A. Extra-nodal extension in N1-adenocarcinoma of pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance. Eur J Gastroenterol Hepatol 2016; 28:205–9.PubMed Luchini C, Veronese N, Pea A, Sergi G, Manzato E, Nottegar A, Solmi M, Capelli P, Scarpa A. Extra-nodal extension in N1-adenocarcinoma of pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance. Eur J Gastroenterol Hepatol 2016; 28:205–9.PubMed
7.
go back to reference Veronese N, Nottegar A, Pea A, Solmi M, Stubbs B, Capelli P, Sergi G, Manzato E, Fassan M, Wood LD, Scarpa A, Luchini C. Prognostic impact and implications of extra-capsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis. Ann Oncol 2016; 27:42–8.CrossRefPubMed Veronese N, Nottegar A, Pea A, Solmi M, Stubbs B, Capelli P, Sergi G, Manzato E, Fassan M, Wood LD, Scarpa A, Luchini C. Prognostic impact and implications of extra-capsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis. Ann Oncol 2016; 27:42–8.CrossRefPubMed
8.
go back to reference Veronese N, Luchini C, Nottegar A, Kaneko T, Sergi G, Manzato E, Solmi M, Scarpa A. Prognostic impact and implications of extra-nodal extension in lymph-node positive thyroid cancers: a systematic review and meta-analysis. J Surg Oncol 2015; 112:828–33.CrossRefPubMed Veronese N, Luchini C, Nottegar A, Kaneko T, Sergi G, Manzato E, Solmi M, Scarpa A. Prognostic impact and implications of extra-nodal extension in lymph-node positive thyroid cancers: a systematic review and meta-analysis. J Surg Oncol 2015; 112:828–33.CrossRefPubMed
9.
go back to reference Luchini C, Nottegar A, Solmi M, Sergi G, Manzato E, Capelli P, Scarpa A, Veronese N. Prognostic implications of extra-nodal extension in node-positive squamous cell carcinoma of the vulva: a systematic review and meta-analysis. Surg Oncol 2016; 25:60–5.CrossRefPubMed Luchini C, Nottegar A, Solmi M, Sergi G, Manzato E, Capelli P, Scarpa A, Veronese N. Prognostic implications of extra-nodal extension in node-positive squamous cell carcinoma of the vulva: a systematic review and meta-analysis. Surg Oncol 2016; 25:60–5.CrossRefPubMed
10.
go back to reference Luchini C, Nottegar A, Pea A, Solmi M, Stubbs B, Capelli P, Sergi G, Manzato E, Fassan M, Wood LD, Scarpa A, Veronese N. Extra-nodal extension is an important prognostic parameter for both colonic and rectal cancer. Ann Oncol 2016; 27:955–6..PubMed Luchini C, Nottegar A, Pea A, Solmi M, Stubbs B, Capelli P, Sergi G, Manzato E, Fassan M, Wood LD, Scarpa A, Veronese N. Extra-nodal extension is an important prognostic parameter for both colonic and rectal cancer. Ann Oncol 2016; 27:955–6..PubMed
11.
go back to reference Wind J, Lagarde SM, Ten Kate FJ, Ubbink DT, Bemelman WA, van Lanschot JJ. A systematic review on the significance of extracapsular lymph node involvement in gastrointestinal malignancies. Eur J Surg Oncol 2007; 33: 401–8.CrossRefPubMed Wind J, Lagarde SM, Ten Kate FJ, Ubbink DT, Bemelman WA, van Lanschot JJ. A systematic review on the significance of extracapsular lymph node involvement in gastrointestinal malignancies. Eur J Surg Oncol 2007; 33: 401–8.CrossRefPubMed
12.
go back to reference Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008–12.CrossRefPubMed Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008–12.CrossRefPubMed
13.
go back to reference Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339:b2700.CrossRefPubMedPubMedCentral Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339:b2700.CrossRefPubMedPubMedCentral
15.
16.
go back to reference Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21:1539–58.CrossRefPubMed Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21:1539–58.CrossRefPubMed
17.
go back to reference Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50:1088–101.CrossRefPubMed Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50:1088–101.CrossRefPubMed
19.
go back to reference Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56:455–63.CrossRefPubMed Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56:455–63.CrossRefPubMed
20.
go back to reference Alakus H, Hölscher AH, Grass G, Hartmann E, Schulte C, Drebber U, Baldus SE, Bollschweiler E, Metzger R, Mönig SP. Extracapsular lymph node spread: a new prognostic factor in gastric cancer. Cancer 2010; 116:309–15.CrossRefPubMed Alakus H, Hölscher AH, Grass G, Hartmann E, Schulte C, Drebber U, Baldus SE, Bollschweiler E, Metzger R, Mönig SP. Extracapsular lymph node spread: a new prognostic factor in gastric cancer. Cancer 2010; 116:309–15.CrossRefPubMed
21.
go back to reference Choi WH, Kim S, Shen J, Cheong JH, Hyung WJ, Kim YI, Choi SH, Noh SH, Park CI. Prognostic significance of perinodal extension in gastric cancer. J Surg Oncol 2007; 95:540–5.CrossRefPubMed Choi WH, Kim S, Shen J, Cheong JH, Hyung WJ, Kim YI, Choi SH, Noh SH, Park CI. Prognostic significance of perinodal extension in gastric cancer. J Surg Oncol 2007; 95:540–5.CrossRefPubMed
22.
go back to reference Di Giorgio A, Botti C, Sammartino P, Mingazzini P, Flammia M, Stipa V. Extracapsular lymphnode metastases in the staging and prognosis of gastric cancer. Int Surg 1991; 76:218–21.PubMed Di Giorgio A, Botti C, Sammartino P, Mingazzini P, Flammia M, Stipa V. Extracapsular lymphnode metastases in the staging and prognosis of gastric cancer. Int Surg 1991; 76:218–21.PubMed
23.
go back to reference Lee IS, Park YS, Ryu MH, Song MJ, Yook JH, Oh ST, et al. Impact of extranodal extension on prognosis in lymph node-positive gastric cancer. Br J Surg 2014; 101:1576–84.CrossRefPubMed Lee IS, Park YS, Ryu MH, Song MJ, Yook JH, Oh ST, et al. Impact of extranodal extension on prognosis in lymph node-positive gastric cancer. Br J Surg 2014; 101:1576–84.CrossRefPubMed
24.
go back to reference Nakamura K, Ozaki N, Yamada T, Hata T, Sugimoto S, Hikino H, Kanazawa A, Tokuka A, Nagaoka S. Evaluation of prognostic significance in extracapsular spread of lymph node metastasis in patients with gastric cancer. Surgery 2005; 137:511–7.CrossRefPubMed Nakamura K, Ozaki N, Yamada T, Hata T, Sugimoto S, Hikino H, Kanazawa A, Tokuka A, Nagaoka S. Evaluation of prognostic significance in extracapsular spread of lymph node metastasis in patients with gastric cancer. Surgery 2005; 137:511–7.CrossRefPubMed
25.
go back to reference Nakamura K, Ogoshi K, Makuuchi H. Subclassification of extranodal involvement in gastric cancer patients. Hepatogastroenterology 2010; 57:968–74.PubMed Nakamura K, Ogoshi K, Makuuchi H. Subclassification of extranodal involvement in gastric cancer patients. Hepatogastroenterology 2010; 57:968–74.PubMed
26.
go back to reference Okamoto T, Tsuburaya A, Kameda Y, Yoshikawa T, Cho H, Tsuchida K, Hasegawa S, Noguchi Y. Prognostic value of extracapsular invasion and fibrotic focus in single lymph node metastasis of gastric cancer. Gastric Cancer 2008; 11:160–7.CrossRefPubMed Okamoto T, Tsuburaya A, Kameda Y, Yoshikawa T, Cho H, Tsuchida K, Hasegawa S, Noguchi Y. Prognostic value of extracapsular invasion and fibrotic focus in single lymph node metastasis of gastric cancer. Gastric Cancer 2008; 11:160–7.CrossRefPubMed
27.
go back to reference Oscar Tapia OE, Villaseca MH, Araya JC, Roa JC. Compromiso ganglionar extracapsular en pacientes con cáncer gástrico: determinación del valor pronóstico. Rev Med Chile 2011; 139: 992–7.CrossRef Oscar Tapia OE, Villaseca MH, Araya JC, Roa JC. Compromiso ganglionar extracapsular en pacientes con cáncer gástrico: determinación del valor pronóstico. Rev Med Chile 2011; 139: 992–7.CrossRef
28.
go back to reference Zacho A, Fischermann K, Sorensen BL. Prognostic role of breach of lymph node capsule in nodal metastates from gastric carcinoma. Acta Chir Scand 1963; 125:365–9.PubMed Zacho A, Fischermann K, Sorensen BL. Prognostic role of breach of lymph node capsule in nodal metastates from gastric carcinoma. Acta Chir Scand 1963; 125:365–9.PubMed
29.
go back to reference Tanaka T, Kumagai K, Shimizu K, Masuo K, Yamagata K. Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; extranodal invasion is a significant risk factor for peritoneal metastasis. J Surg Oncol 2000; 75:165–71.CrossRefPubMed Tanaka T, Kumagai K, Shimizu K, Masuo K, Yamagata K. Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; extranodal invasion is a significant risk factor for peritoneal metastasis. J Surg Oncol 2000; 75:165–71.CrossRefPubMed
30.
go back to reference Kumagai K, Tanaka T, Yamagata K, Yokoyama N, Shimizu K. Liver metastasis in gastric cancer with particular reference to lymphatic advancement. Gastric Cancer 2001; 4:150–5.CrossRefPubMed Kumagai K, Tanaka T, Yamagata K, Yokoyama N, Shimizu K. Liver metastasis in gastric cancer with particular reference to lymphatic advancement. Gastric Cancer 2001; 4:150–5.CrossRefPubMed
31.
go back to reference Sergeant G, Ectors N, Fieuws S, Aerts R, Topal B. Prognostic relevance of extracapsular lymph node involvement in pancreatic ductal adenocarcinoma. Ann Surg Oncol 2009; 16:3070–9.CrossRefPubMed Sergeant G, Ectors N, Fieuws S, Aerts R, Topal B. Prognostic relevance of extracapsular lymph node involvement in pancreatic ductal adenocarcinoma. Ann Surg Oncol 2009; 16:3070–9.CrossRefPubMed
32.
go back to reference Nakamura K, Okamoto Y, Matsui H, Makuuchi H, Ogoshi K. Impact of difference in the definition of extranodal spread on the outcome of node-positive patients with gastric cancer. Langenbecks Arch Surg 2010; 395:211–6.CrossRefPubMed Nakamura K, Okamoto Y, Matsui H, Makuuchi H, Ogoshi K. Impact of difference in the definition of extranodal spread on the outcome of node-positive patients with gastric cancer. Langenbecks Arch Surg 2010; 395:211–6.CrossRefPubMed
33.
go back to reference Luchini C, Capelli P, Fassan M, Simbolo M, Mafficini A, Pedica F, Ruzzenente A, Guglielmi A, Corbo V, Scarpa A. Next generation histopathologic diagnosis: a lesson from a hepatic carcinosarcoma. J Clin Oncol 2014; 32:e63-66.CrossRefPubMed Luchini C, Capelli P, Fassan M, Simbolo M, Mafficini A, Pedica F, Ruzzenente A, Guglielmi A, Corbo V, Scarpa A. Next generation histopathologic diagnosis: a lesson from a hepatic carcinosarcoma. J Clin Oncol 2014; 32:e63-66.CrossRefPubMed
34.
go back to reference Luchini C, Veronese N, Solmi M, Cho H, Kim JH, Chou A, Gill AJ, Faraj SF, Chaux A, Netto GJ, Nakayama K, Kyo S, Lee SY, Kim DW, Yousef GM, Scorilas A, Nelson GS, Köbel M, Kalloger SE, Schaeffer DF, Yan HB, Liu F, Yokoyama Y, Zhang X, Pang D, Lichner Z, Sergi G, Manzato E, Capelli P, Wood LD, Scarpa A, Correll CU. Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis. Oncotarget 2015; 6:39088–97.PubMedPubMedCentral Luchini C, Veronese N, Solmi M, Cho H, Kim JH, Chou A, Gill AJ, Faraj SF, Chaux A, Netto GJ, Nakayama K, Kyo S, Lee SY, Kim DW, Yousef GM, Scorilas A, Nelson GS, Köbel M, Kalloger SE, Schaeffer DF, Yan HB, Liu F, Yokoyama Y, Zhang X, Pang D, Lichner Z, Sergi G, Manzato E, Capelli P, Wood LD, Scarpa A, Correll CU. Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis. Oncotarget 2015; 6:39088–97.PubMedPubMedCentral
Metadata
Title
Extranodal Extension of Nodal Metastases Is a Poor Prognostic Indicator in Gastric Cancer: a Systematic Review and Meta-analysis
Authors
Nicola Veronese
Matteo Fassan
Laura D. Wood
Brendon Stubbs
Marco Solmi
Paola Capelli
Antonio Pea
Alessia Nottegar
Giuseppe Sergi
Enzo Manzato
Sara Carraro
Marco Maruzzo
Ivana Cataldo
Fabio Bagante
Mattia Barbareschi
Liang Cheng
Maria Bencivenga
Giovanni de Manzoni
Claudio Luchini
Publication date
01-10-2016
Publisher
Springer US
Published in
Journal of Gastrointestinal Surgery / Issue 10/2016
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI
https://doi.org/10.1007/s11605-016-3199-7

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