Annals of Surgical Oncology

, Volume 24, Issue 4, pp 1077–1084 | Cite as

Perineural Invasion is a Major Prognostic and Predictive Factor of Response to Adjuvant Chemotherapy in Stage I–II Colon Cancer

  • J. A. CienfuegosEmail author
  • P. Martínez
  • J. Baixauli
  • C. Beorlegui
  • S. Rosenstone
  • J. J. Sola
  • J. Rodríguez
  • J. L. Hernández-Lizoáin
Colorectal Cancer



Perineural invasion (PNI) in colon cancer (CC) has been associated with poorer prognosis even in stage II disease (T3–4 N0 M0). The aim of this study is to analyze prognostic histopathologic factors in stage II colon cancer in patients treated with curative surgery as established in National Comprehensive Cancer Network guidelines.


From a prospective database of CC cases, 507 patients with stage I–II disease who had undergone curative resection from January 2000 and December 2012 were identified. Of these patients, 17 % received 5-flurouracil-based adjuvant chemotherapy. Together with demographic and anatomic variables, we also studied perineural and lymphovascular invasion, degree of differentiation, and their correlation with disease-free survival.


Perineural invasion was identified in 57 patients (11.2 %) and lymphovascular invasion (LVI) in 82 (16.2 %) of the 507 patients. Perineural invasion was associated with LVI, the depth of invasion of the wall of the colon, and location of the tumor. Overall and disease-free survival of the complete series at 5 and 10 years was 89.5, 85.2, 83.2 and 81.6 %, respectively. In the PNI positive patients, disease-free survival at 5 years was significantly lower than in those without PNI (73.5 vs 88.6 %; p = 0.02). Multivariate analysis showed the presence of PNI to be a significant independent prognostic factor for disease-free survival (p = 0.025). Adjuvant chemotherapy reversed the impact of PNI on 5- to 10-year disease-free survival.


PNI a major prognostic and predictive factor in stage II colon cancer, and our results support the use of adjuvant chemotherapy in patients with PNI.


Overall Survival Colon Cancer Adjuvant Chemotherapy National Comprehensive Cancer Network National Comprehensive Cancer Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



All authors the have read and approved the manuscript and it is not under consideration for publication elsewhere. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of the manuscript


  1. 1.
    GLOBOCAN cancer fact sheets: Colorectal cancers. Accessed 5 Apr 2016.
  2. 2.
    Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2016. doi: 10.1136/gutjnl-2015-310912.Google Scholar
  3. 3.
    American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York: Springer New York; 2010.CrossRefGoogle Scholar
  4. 4.
    Andre T, de Gramont A, Vernerey D, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015;33:4176–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Quasar Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet. 2007;370:2020–9.CrossRefGoogle Scholar
  6. 6.
    Shah MA, Renfro LA, Allegra CJ, et al. Impact of patient factors on recurrence risk and time dependency of oxaliplatin benefit in patients with colon cancer: Analysis from modern-era adjuvant studies in the adjuvant colon cancer end points (ACCENT) database. J Clin Oncol. 2016;34:843–53.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    O’Connor ES, Greenblatt DY, LoConte NK, Gangnon RE, Liou JI, Heise CP, Smith MA. Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J Clin Oncol. 2011;29:3381–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tournigand C, Andre T, Bonnetain F, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the multicenter international study of oxaliplatin, fluorouracil, and leucovorin in the adjuvant treatment of colon cancer trial. J Clin Oncol. 2012;30:3353–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Benson AB 3rd, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408–19.CrossRefPubMedGoogle Scholar
  10. 10.
    Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Quah HM, Chou JF, Gonen M, et al. Identification of patients with high-risk stage II colon cancer for adjuvant therapy. Dis Colon Rectum. 2008;51:503–7.CrossRefPubMedGoogle Scholar
  12. 12.
    NCCN clinical practice guidelines in oncology. Updated 2016. Accessed 5 October 2016.
  13. 13.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775–81.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dalerba P, Sahoo D, Paik S, et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med. 2016;374:211–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937–44.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Maak M, Simon I, Nitsche U, et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg. 2013;257:1053–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Phipps AI, Limburg PJ, Baron JA, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015;148:77–87.e2.CrossRefPubMedGoogle Scholar
  19. 19.
    Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L. Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol. 2004;22:3395–407.CrossRefPubMedGoogle Scholar
  20. 20.
    Tournigand C, de Gramont A. Chemotherapy: is adjuvant chemotherapy an option for stage II colon cancer? Nat Rev Clin Oncol. 2011;8:574–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Andre T, Sargent D, Tabernero J, et al. Current issues in adjuvant treatment of stage II colon cancer. Ann Surg Oncol. 2006;13:887–98.CrossRefPubMedGoogle Scholar
  22. 22.
    Fang SH, Efron JE, Berho ME, Wexner SD. Dilemma of stage II colon cancer and decision making for adjuvant chemotherapy. J Am Coll Surg. 2014;219:1056–69.CrossRefPubMedGoogle Scholar
  23. 23.
    American Society of Anesthesiologists. New classification of physical status. Anesthesiology. 1963;24:111.Google Scholar
  24. 24.
    West NP, Hohenberger W, Weber K, Perrakis A, Finan PJ, Quirke P. Complete mesocolic excision with central vascular ligation produces an oncologically superior specimen compared with standard surgery for carcinoma of the colon. J Clin Oncol. 2010;28:272–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Chang GJ, Kaiser AM, Mills S, Rafferty JF, Buie WD, Standards Practice task force of the American Society of Colon and rectal surgeons. practice parameters for the management of colon cancer. Dis Colon Rectum. 2012;55:831–43.CrossRefPubMedGoogle Scholar
  26. 26.
    Washington MK, Berlin J, Branton P, et al. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med. 2009;133:1539–51.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Jass JR, O’Brien J, Riddell RH, Snover DC, Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of surgically resected specimens of colorectal carcinoma: association of directors of anatomic and surgical pathology. Am J Clin Pathol. 2008;129:13–23.CrossRefPubMedGoogle Scholar
  28. 28.
    American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed. New York: Springer New York; 2006:294.Google Scholar
  29. 29.
    Hamilton S, Bosman F, Boffetta P, et al. Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban R, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on Cancer; 2010:134–46.Google Scholar
  30. 30.
    Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol. 1985;94:426–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Liebig C, Ayala G, Wilks J, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol. 2009;27:5131–7.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: A review of the literature. Cancer. 2009;115:3379–91.CrossRefPubMedGoogle Scholar
  33. 33.
    Betge J, Langner C. Vascular invasion, perineural invasion, and tumour budding: Predictors of outcome in colorectal cancer. Acta Gastroenterol Belg. 2011;74:516–29.PubMedGoogle Scholar
  34. 34.
    Sato T, Ueno H, Mochizuki H, et al. Objective criteria for the grading of venous invasion in colorectal cancer. Am J Surg Pathol. 2010;34:454–62.CrossRefPubMedGoogle Scholar
  35. 35.
    Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352:476–87.CrossRefPubMedGoogle Scholar
  36. 36.
    Yothers G, Song N, George TJ, Jr. Cancer hallmark-based gene sets and personalized medicine for patients with stage II colon cancer. JAMA Oncol. 2016;2:23–4.CrossRefPubMedGoogle Scholar
  37. 37.
    Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22:1797–806.CrossRefPubMedGoogle Scholar
  38. 38.
    Niedzwiecki D, Bertagnolli MM, Warren RS, et al. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011;29:3146–52.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    McKenzie S, Nelson R, Mailey B, et al. Adjuvant chemotherapy improves survival in patients with American Joint Committee on Cancer stage II colon cancer. Cancer. 2011;117:5493–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yothers G, O’Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013;31:4512–9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. 2011;29:4611–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Kopetz S, Tabernero J, Rosenberg R, et al. Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist. 2015;20:127–33.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gao S, Tibiche C, Zou J, Zaman N, Trifiro M, O’Connor-McCourt M, Wang E. Identification and construction of combinatory cancer hallmark-based gene signature sets to predict recurrence and chemotherapy benefit in stage II colorectal cancer. JAMA Oncol. 2016;2:37–45.CrossRefPubMedGoogle Scholar
  45. 45.
    Poeschl EM, Pollheimer MJ, Kornprat P, et al. Perineural invasion: Correlation with aggressive phenotype and independent prognostic variable in both colon and rectum cancer. J Clin Oncol. 2010;28:358–60; author reply e361–2.Google Scholar
  46. 46.
    Huh JW, Kim HR, Kim YJ. Prognostic value of perineural invasion in patients with stage II colorectal cancer. Ann Surg Oncol. 2010;17:2066–72.CrossRefPubMedGoogle Scholar
  47. 47.
    Huh JW, Lee JH, Kim HR, Kim YJ. Prognostic significance of lymphovascular or perineural invasion in patients with locally advanced colorectal cancer. Am J Surg. 2013;206:758–63.CrossRefPubMedGoogle Scholar
  48. 48.
    Desolneux G, Burtin P, Lermite E, Bergamaschi R, Hamy A, Arnaud JP. Prognostic factors in node-negative colorectal cancer: A retrospective study from a prospective database. Int J Colorectal Dis. 2010;25:829–34.CrossRefPubMedGoogle Scholar
  49. 49.
    Yang Y, Huang X, Sun J, et al. Prognostic value of perineural invasion in colorectal cancer: A meta-analysis. J Gastrointest Surg. 2015;19:1113–22.CrossRefPubMedGoogle Scholar
  50. 50.
    Knijn N, Mogk SC, Teerenstra S, Simmer F, Nagtegaal ID. Perineural invasion is a strong prognostic factor in colorectal cancer: a systematic review. Am J Surg Pathol. 2016;40:103–112.CrossRefPubMedGoogle Scholar
  51. 51.
    Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466–74.CrossRefPubMedGoogle Scholar
  52. 52.
    Suzuki T, Suwa K, Ogawa M, et al. Adjuvant chemotherapy for the perineural invasion of colorectal cancer. J Surg Res. 2015;199:84–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Ballman KV. Biomarker: Predictive or prognostic? J Clin Oncol. 2015;33:3968–71.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang JX, Song W, Chen ZH, et al. Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis. Lancet Oncol. 2013;14:1295–306.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • J. A. Cienfuegos
    • 1
    Email author
  • P. Martínez
    • 1
  • J. Baixauli
    • 1
  • C. Beorlegui
    • 2
  • S. Rosenstone
    • 1
  • J. J. Sola
    • 3
  • J. Rodríguez
    • 4
  • J. L. Hernández-Lizoáin
    • 1
  1. 1.Department of General Surgery, Clínica Universidad de Navarra, School of MedicineUniversity of NavarraPamplonaSpain
  2. 2.Department of Histology and Pathology, School of MedicineUniversity of NavarraPamplonaSpain
  3. 3.Department of PathologyHospital San PedroLogroño (La Rioja)Spain
  4. 4.Department of Oncology, Clínica Universidad de Navarra, School of MedicineUniversity of NavarraPamplonaSpain

Personalised recommendations