International Journal of Colorectal Disease

, Volume 33, Issue 9, pp 1183–1193 | Cite as

The prognostic value of signet ring cell histology in stage I/II colon cancer—a population-based, propensity score-matched analysis

  • Christoph Jakob Ackermann
  • Ulrich Guller
  • Wolfram Jochum
  • Bruno M. Schmied
  • Rene WarschkowEmail author
Original Article



Previous research associated signet ring cell histology in colon cancer patients with poor survival outcomes. The aim of this study was to analyze the prognostic significance of signet ring cell histology on overall and cancer-specific survival in patients with localized colon cancer.


Stage I and II colon cancer patients treated with surgical resection between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were assessed using risk-adjusted Cox proportional hazards regression models and propensity score methods.


Eighty-eight thousand nine hundred fifty-eight stage I–II colon cancer patients were identified. Overall, 446 (0.5%) showed signet ring cell histology. In unadjusted analyses, the 5-year OS and CSS rates of patients with signet ring cell histology were 65.8 and 83.1%, respectively, compared with 74.3 and 88.7% in patients with non-signet ring cell adenocarcinoma (p values: OS, p < 0.001; CSS, p < 0.001). Neither in risk-adjusted Cox proportional hazard regression analysis (OS: hazard ratio (HR), 0.96 (95% CI, 0.82–1.12%) p = 0.616; CSS: HR, 1.01 (95% CI, 0.79–1.28%) p = 0.946) nor with propensity score matching (OS: HR, 0.96 (95% CI, 0.82–1.14%) p = 0.669 and CSS: HR: 1.09 (95% CI: 0.84–1.40%) p = 0.529), a survival disadvantage was found for signet ring cell histology.


This is the first propensity score-adjusted population-based investigation on exclusively stage I and II colon cancer patients providing compelling evidence that signet ring cell histology does not negatively impact survival in stage I and II colon cancer after risk-adjusting for known prognostic factors. Therefore, standard treatment strategies can be applied in these patients.


Survival Colon cancer Adenocarcinoma Signet ring carcinoma, Surveillance, Epidemiology, and End Results Program SEER Propensity score 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomark Prev 19(8):1893–1907CrossRefGoogle Scholar
  3. 3.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386CrossRefPubMedGoogle Scholar
  4. 4.
    Bosman FT et al (2010) 4th Edition of the WHO classification of tumours of the digestive system. International Agency for Research on Cancer, GenevaGoogle Scholar
  5. 5.
    Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, Rodriguez-Bigas MA, Cormier JN, Chang GJ (2012) Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann Surg Oncol 19(9):2814–2821CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mizushima T, Nomura M, Fujii M, Akamatsu H, Mizuno H, Tominaga H, Hasegawa J, Nakajima K, Yasumasa K, Yoshikawa M, Nishida T (2010) Primary colorectal signet-ring cell carcinoma: clinicopathological features and postoperative survival. Surg Today 40(3):234–238CrossRefPubMedGoogle Scholar
  7. 7.
    Hugen N, Verhoeven RH, Lemmens VE, van Aart CJ, Elferink MA, Radema SA, Nagtegaal ID, de Wilt JH (2015) Colorectal signet-ring cell carcinoma: benefit from adjuvant chemotherapy but a poor prognostic factor. Int J Cancer 136(2):333–339CrossRefPubMedGoogle Scholar
  8. 8.
    Lee DW, Han SW, Lee HJ, Rhee YY, Bae JM, Cho NY, Lee KH, Kim TY, Oh DY, Im SA, Bang YJ, Jeong SY, Park KJ, Park JG, Kang GH, Kim TY (2013) Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy. Br J Cancer 108(10):1978–1984CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Benedix F et al (2013) Influence of mucinous and signet-ring cell differentiation on epidemiological, histological, molecular biological features, and outcome in patients with colorectal carcinoma. Zentralbl Chir 138(4):427–433PubMedGoogle Scholar
  10. 10.
    National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER) Research Data (1973–2015) released April 2018, based on the November 2017 submission. available at (Last accessed April 29, 2018). 2017
  11. 11.
    Wingo PA, Jamison PM, Hiatt RA, Weir HK, Gargiullo PM, Hutton M, Lee NC, Hall HI (2003) Building the infrastructure for nationwide cancer surveillance and control—a comparison between the National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology, and End Results (SEER) Program (United States). Cancer Causes Control 14(2):175–193CrossRefPubMedGoogle Scholar
  12. 12.
    Fritz A et al (2000) International classification of disease for oncology (ed. 3). World Health Organization, Geneva, SwitzerlandGoogle Scholar
  13. 13.
    Ho DE et al (2011) MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw 42:1–28CrossRefGoogle Scholar
  14. 14.
    Joffe MM, Rosenbaum PR (1999) Invited commentary: propensity scores. Am J Epidemiol 150(4):327–333CrossRefPubMedGoogle Scholar
  15. 15.
    Rosenbaum PR (1987) Model-based direct adjustment. J Am Stat Assoc 82:387–394CrossRefGoogle Scholar
  16. 16.
    Inamura K, Yamauchi M, Nishihara R, Kim SA, Mima K, Sukawa Y, Li T, Yasunari M, Zhang X, Wu K, Meyerhardt JA, Fuchs CS, Harris CC, Qian ZR, Ogino S (2015) Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. Ann Surg Oncol 22(4):1226–1235CrossRefPubMedGoogle Scholar
  17. 17.
    Nitsche U, Zimmermann A, Späth C, Müller T, Maak M, Schuster T, Slotta-Huspenina J, Käser SA, Michalski CW, Janssen KP, Friess H, Rosenberg R, Bader FG (2013) Mucinous and signet-ring cell colorectal cancers differ from classical adenocarcinomas in tumor biology and prognosis. Ann Surg 258(5):775–782 discussion 782–3CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Nitsche U, Friess H, Agha A, Angele M, Eckel R, Heitland W, Jauch KW, Krenz D, Nüssler NC, Rau HG, Ruppert R, Schubert-Fritschle G, Wilhelm D, Werner J, Engel J (2016) Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort. J Cancer Res Clin Oncol 142(11):2357–2366CrossRefPubMedGoogle Scholar
  19. 19.
    Chew MH, Yeo SAE, Ng ZP, Lim KH, Koh PK, Ng KH, Eu KW (2010) Critical analysis of mucin and signet ring cell as prognostic factors in an Asian population of 2,764 sporadic colorectal cancers. Int J Color Dis 25(10):1221–1229CrossRefGoogle Scholar
  20. 20.
    Catalano V, Loupakis F, Graziano F, Bisonni R, Torresi U, Vincenzi B, Mari D, Giordani P, Alessandroni P, Salvatore L, Fornaro L, Santini D, Baldelli AM, Rossi D, Giustini L, Silva RR, Falcone A, D'Emidio S, Rocchi M, Luzi Fedeli S (2012) Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer. Ann Oncol 23(1):135–141CrossRefPubMedGoogle Scholar
  21. 21.
    Du W et al (2004) Incidence and survival of mucinous adenocarcinoma of the colorectum: a population-based study from an Asian country. Dis Colon rectum 47(1):78–85Google Scholar
  22. 22.
    Borger ME et al (2007) Signet ring cell differentiation in mucinous colorectal carcinoma. J Pathol 212(3):278–286CrossRefPubMedGoogle Scholar
  23. 23.
    Kakar S, Aksoy S, Burgart LJ, Smyrk TC (2004) Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival. Mod Pathol 17(6):696–700CrossRefPubMedGoogle Scholar
  24. 24.
    Karahan B et al (2015) Relationship between MLH-1, MSH-2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. Int J Clin Exp Pathol 8(4):4044–4053PubMedPubMedCentralGoogle Scholar
  25. 25.
    Leopoldo S, Lorena B, Cinzia A, Gabriella DC, Angela Luciana B, Renato C, Antonio M, Carlo S, Cristina P, Stefano C, Maurizio T, Luigi R, Cesare B (2008) Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann Surg Oncol 15(5):1429–1439CrossRefPubMedGoogle Scholar
  26. 26.
    Sinicrope FA, Sargent DJ (2012) Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res 18(6):1506–1512CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yoon YS, Kim J, Hong SM, Lee JL, Kim CW, Park IJ, Lim SB, Yu CS, Kim JC (2015) Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer. Color Dis 17(8):O161–O167CrossRefGoogle Scholar
  28. 28.
    Twelves C, Wong A, Nowacki MP, Abt M, Burris H III, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, van Hazel G, Zaluski J, Scheithauer W (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352(26):2696–2704CrossRefPubMedGoogle Scholar
  29. 29.
    Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ (2005) Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 23(34):8671–8678CrossRefPubMedGoogle Scholar
  30. 30.
    Andre T et al (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27(19):3109–3116CrossRefPubMedGoogle Scholar
  31. 31.
    Andre T et al (2018) Three versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage iii colon cancer: disease-free survival results from a randomized, open-label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J Clin Oncol 36(15):1469-1477Google Scholar
  32. 32.
    Benson AB 3rd et al (2004) American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22(16):3408–3419CrossRefPubMedGoogle Scholar
  33. 33.
    Labianca R et al (2013) Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(Suppl 6):vi64–vi72CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Medical Oncology and HematologyKantonsspital St. GallenSt. GallenSwitzerland
  2. 2.University Clinics for Visceral Surgery and Medicine, University Hospital BerneBerneSwitzerland
  3. 3.Institute of PathologyKantonsspital St. GallenSt. GallenSwitzerland
  4. 4.Department of SurgeryKantonsspital St. GallenSt. GallenSwitzerland
  5. 5.Institute of Medical Biometry and InformaticsUniversity of HeidelbergHeidelbergGermany

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