Annals of Surgical Oncology

, Volume 22, Issue 5, pp 1504–1512 | Cite as

Histologic Categorization of Desmoplastic Reaction: Its Relevance to the Colorectal Cancer Microenvironment and Prognosis

  • Hideki UenoEmail author
  • Eiji Shinto
  • Hideyuki Shimazaki
  • Yoshiki Kajiwara
  • Takahiro Sueyama
  • Junji Yamamoto
  • Kazuo Hase
Colorectal Cancer



Although the essential roles of stromata in tumor development have been recognized, the morphologic classification of desmoplastic reaction (DR) in colorectal cancer (CRC) is unclear.


In this study, DRs were histologically classified into three patterns based on the products of activated fibroblasts (i.e., keloid-like collagen and myxoid stroma). The prognostic impact of DRs was evaluated in two independent cohorts of stages 2 and 3 CRC patients: cohort 1 (880 patients) and cohort 2 (474 patients). The association of DR and the local environment was investigated immunohistochemically.


In cohort 1, mature DR was shown by 413 patients, intermediate DR by 275 patients, and immature DR by 192 patients. Categorization of DR was significantly associated with tumor location, pT and pN stages, tumor differentiation, venous invasion, tumor budding, and Crohn’s-like lymphoid reaction (P ≤ 0.0001–0.008). Immature DR was relevant to the high incidence of recurrence in the liver, lung, lymph nodes, peritoneum, and locoregional areas (P ≤ 0.0001–0.002). The 5-year disease-free survival rate was highest in the mature group (87 %), followed by the intermediate group (72 %) and the immature group (49 % (P < 0.0001). In the multivariate analysis, DR showed an impact on survival outcome independent of conventional prognostic factors, including pT and pN stages. These results were similarly observed in cohort 2. Immature DR was associated with normal MutL homologue 1 (MLH1)/MutS homologue 2 (MSH2) immunoreactivity, a smaller number of infiltrating CD8+ T cells and tumor-associated macrophages, a decreased microvessel count, and positive expression of tenascin-C and fibronectin.


The proposed histologic DR categorization directly reflects tumor behavior in a modulating stromal environment and could provide valuable prognostic information for CRC patients.


Venous Invasion Mature Group Immature Group Desmoplastic Reaction Microvessel Count 
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.


Conflicts of interest

There are no conflicts of interest.


  1. 1.
    Pietras K, Östman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316:1324–31.CrossRefPubMedGoogle Scholar
  2. 2.
    McAllister SS, Weinberg RA. Tumor–host interactions: a far-reaching relationship. J Clin Oncol. 2010;28:4022–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.CrossRefPubMedGoogle Scholar
  5. 5.
    Östman A, Augsten M. Cancer-associated fibroblasts and tumor growth-bystanders turning into key players. Curr Opin Genet Dev. 2009;19:67–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Peña C, Céspedes MV, Lindh MB, et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 2012;73:1287–87.CrossRefPubMedGoogle Scholar
  7. 7.
    Hewitt RE, Powe DG, Carter GI, Turner DR. Desmoplasia and its relevance to colorectal tumour invasion. Int J Cancer. 1993;53:62–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Ueno H, Jones A, Jass JR, Talbot IC. Clinicopathological significance of the “keloid-like” collagen and myxoid stroma in advanced rectal cancer. Histopathology. 2002;40:327–34.CrossRefPubMedGoogle Scholar
  9. 9.
    Ueno H, Jones AM, Wilkinson KH, Jass JR, Talbot IC. Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut. 2004;53:581–6.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour “budding” as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology. 2004;127:385–94.CrossRefPubMedGoogle Scholar
  12. 12.
    Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol. 2009;17:1–29.CrossRefGoogle Scholar
  13. 13.
    Graham DM, Appelman HD. Crohn’s-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod Pathol. 1990;3:332–5.PubMedGoogle Scholar
  14. 14.
    Ueno H, Hashiguchi Y, Shimazaki H, et al. Objective criteria for Crohn-like lymphoid reaction in colorectal cancer. Am J Clin Pathol. 2013;139:434–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Hiraoka K, Miyamoto M, Cho Y, et al. Concurrent infiltration by CD8+T cells and CD4+T cells in a favorable prognostic factor in non–small-cell lung carcinoma. Br J Cancer. 2006;94:275–80.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Ioachim E, Michael M, Stavropoulos NE, Kitsiou E, Salmas M, Malamou-Mitsi V. A clinicopathological study of the expression of extracellular matrix components in urothelial carcinoma. BJU Int. 2005;95:655–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Kressner U, Lindmark G, Tomasini-Johansson B, et al. Stromal tenascin distribution as a prognostic marker in colorectal cancer. Br J Cancer. 1997;76:526–30.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    McDonald LT, LaRue AC. Hematopoietic stem-cell-derived carcinoma-associated fibroblasts: a novel origin. Int J Clin Exp Pathol. 2012;5:863–73.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Prall F. Tumour budding in colorectal carcinoma. Histopathology. 2007;50:151–62.CrossRefPubMedGoogle Scholar
  21. 21.
    Bran GM, Goessler UR, Hormann K, Riedel F, Sadick H. Keloids: current concepts of pathogenesis (review). Int J Mol Med. 2009;24:283–93.CrossRefPubMedGoogle Scholar
  22. 22.
    Desmoulière A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol. 2004;48:509–17.CrossRefPubMedGoogle Scholar
  23. 23.
    Hanamura N, Yoshida T, Matsumoto E, Kawarada Y, Sakakura T. Expression of fibronectin and tenascin-C mRNA by myofibroblasts, vascular cells, and epithelial cells in human colon adenomas and carcinomas. Int J Cancer. 1997;73:10–15.CrossRefPubMedGoogle Scholar
  24. 24.
    Guttery DS, Shaw JA, Lloyd K, Pringle JH, Walker RA. Expression of tenascin-C and its isoforms in the breast. Cancer Metastasis Rev. 2010;29:595–606.CrossRefPubMedGoogle Scholar
  25. 25.
    Lieubeau B, Heymann MF, Henry F, Barbieux I, Meflah K, Grégoire M. Immunomodulatory effects of tumor-associated fibroblasts in colorectal-tumor development. Int J Cancer. 1999;81:629–36.CrossRefPubMedGoogle Scholar
  26. 26.
    Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989;339:58–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Hasan J, Byers R, Jayson GC. Intra-tumoural microvessel density in human solid tumours. Br J Cancer. 2002;86:1566–77.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18:4266–76.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Wright CL, Stewart ID. Histopathology and mismatch repair status of 458 consecutive colorectal carcinomas. Am J Surg Pathol. 2003;27:1393–406.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Hideki Ueno
    • 1
    Email author
  • Eiji Shinto
    • 1
  • Hideyuki Shimazaki
    • 2
  • Yoshiki Kajiwara
    • 1
  • Takahiro Sueyama
    • 1
  • Junji Yamamoto
    • 1
  • Kazuo Hase
    • 1
  1. 1.Department of SurgeryNational Defense Medical CollegeTokorozawaJapan
  2. 2.Department of Laboratory MedicineNational Defense Medical College HospitalTokorozawaJapan

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