Skip to main content
SpringerLink
Log in

Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

  • Published:
Diseases of the Colon & Rectum

Purpose

Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer.

Methods

We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis.

Results

A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114).

Conclusions

Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. CE Dukes HJ Bussey (1958) ArticleTitleThe spread of rectal cancer and its effect on prognosis Br J Cancer 12 309–320 Occurrence Handle13596482 Occurrence Handle1:STN:280:DyaG1M%2FisFyrtg%3D%3D

    PubMed  CAS  Google Scholar 

  2. RC Newland PH Chapuis MT Pheils JG MacPherson (1981) ArticleTitleThe relationship of survival to staging and grading of colorectal carcinoma: a prospective study of 503 cases Cancer 47 1424–1429 Occurrence Handle7226068 Occurrence Handle10.1002/1097-0142(19810315)47:6<1424::AID-CNCR2820470630>3.0.CO;2-O Occurrence Handle1:STN:280:DyaL3M7osF2ktA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  3. PH Chapuis OF Dent R Fisher et al. (1985) ArticleTitleA multivariate analysis of clinical and pathological variables in prognosis after resection of large bowel cancer Br J Surg 72 698–702 Occurrence Handle4041728 Occurrence Handle10.1002/bjs.1800720909 Occurrence Handle1:STN:280:DyaL28%2FgtFanug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  4. LP Fielding RK Phillips JS Fry R Hittinger (1986) ArticleTitlePrediction of outcome after curative resection for large bowel cancer Lancet 2 904–907 Occurrence Handle2876336 Occurrence Handle10.1016/S0140-6736(86)90422-8 Occurrence Handle1:STN:280:DyaL2s%2FhtlKrsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  5. P Hermanek (1995) ArticleTitlepTNM and residual tumor classifications: problems of assessment and prognostic significance World J Surg 19 184–190 Occurrence Handle7754621 Occurrence Handle10.1007/BF00308624 Occurrence Handle1:STN:280:DyaK2M3nsVagsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  6. S Breitender-Geleff A Soleiman H Kowalski et al. (1999) ArticleTitleAngiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium Am J Pathol 154 385–394

    Google Scholar 

  7. JT Wigle G Oliver (1999) ArticleTitleProx1 function is required for the development of the murine lymphatic system Cell 98 769–778 Occurrence Handle10499794 Occurrence Handle10.1016/S0092-8674(00)81511-1 Occurrence Handle1:CAS:528:DyaK1MXmt1Grs70%3D

    Article  PubMed  CAS  Google Scholar 

  8. S Banerji J Ni SX Wang et al. (1999) ArticleTitleLYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan J Cell Biol 144 789–801 Occurrence Handle10037799 Occurrence Handle10.1083/jcb.144.4.789 Occurrence Handle1:CAS:528:DyaK1MXhvVWmsLc%3D

    Article  PubMed  CAS  Google Scholar 

  9. NJ Beasley R Prevo S Banerji et al. (2002) ArticleTitleIntratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer Cancer Res 62 1315–1320 Occurrence Handle11888898 Occurrence Handle1:CAS:528:DC%2BD38Xit1KhtLs%3D

    PubMed  CAS  Google Scholar 

  10. SM Maula M Luukkaa R Grenman D Jackson S Jalkanen R Ristamäki (2003) ArticleTitleIntratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region Cancer Res 63 1920–1926 Occurrence Handle12702584 Occurrence Handle1:CAS:528:DC%2BD3sXivFynsb4%3D

    PubMed  CAS  Google Scholar 

  11. PA Kayzas S Gellef A Batistatou NJ Agnantis D Stefanou (2005) ArticleTitleEvidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma J Pathol 206 170–177 Occurrence Handle10.1002/path.1776

    Article  Google Scholar 

  12. SF Schoppmann G Bayer K Aumayr et al. (2004) ArticleTitleAustrian Breast and Colorectal Cancer Study Group. Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer Ann Surg 240 306–312 Occurrence Handle15273556 Occurrence Handle10.1097/01.sla.0000133355.48672.22

    Article  PubMed  Google Scholar 

  13. P Bono VM Wasenius P Heikkila J Lundin DG Jackson H Joensuu (2004) ArticleTitleHigh LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer Clin Cancer Res 10 7144–7149 Occurrence Handle15534085 Occurrence Handle10.1158/1078-0432.CCR-03-0826 Occurrence Handle1:CAS:528:DC%2BD2cXpsVKltLs%3D

    Article  PubMed  CAS  Google Scholar 

  14. Y Nakamura H Yasuoka M Tsujimoto et al. (2005) ArticleTitleLymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer Breast Cancer Res Treat 91 125–132 Occurrence Handle15868440 Occurrence Handle10.1007/s10549-004-5783-x Occurrence Handle1:CAS:528:DC%2BD2MXjvVWjsr4%3D

    Article  PubMed  CAS  Google Scholar 

  15. O Straume DG Jackson LA Akslen (2003) ArticleTitleIndependent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma Clin Cancer Res 9 250–256 Occurrence Handle12538477 Occurrence Handle1:CAS:528:DC%2BD3sXnt1OktQ%3D%3D

    PubMed  CAS  Google Scholar 

  16. SS Dadras T Paul J Bertoncini et al. (2003) ArticleTitleTumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival Am J Pathol 162 1951–1960 Occurrence Handle12759251

    PubMed  Google Scholar 

  17. FT Hall JL Freeman SL Asa DG Jackson NJ Beasley (2003) ArticleTitleIntratumoral lymphatics and lymph node metastases in papillary thyroid carcinoma Arch Otolaryngol Head Neck Surg 129 716–719 Occurrence Handle12874070 Occurrence Handle10.1001/archotol.129.7.716

    Article  PubMed  Google Scholar 

  18. H Yasuoka Y Nakamura H Zuo et al. (2005) ArticleTitleVEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma Mod Pathol 18 1127–1133 Occurrence Handle15803188 Occurrence Handle10.1038/modpathol.3800402 Occurrence Handle1:CAS:528:DC%2BD2MXmtlCrsro%3D

    Article  PubMed  CAS  Google Scholar 

  19. N Weidner J Folkman F Pozza et al. (1992) ArticleTitleTumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma J Natl Cancer Inst 84 1875–1887 Occurrence Handle1281237 Occurrence Handle10.1093/jnci/84.24.1875 Occurrence Handle1:STN:280:DyaK3s%2FpsFWhtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  20. N Weidner JP Semple WR Welch J Folkman (1991) ArticleTitleTumor angiogenesis and metastasis-correlation in invasive breast carcinoma N Engl J Med 324 1–8 Occurrence Handle1701519 Occurrence Handle1:STN:280:DyaK3M%2FnsVWquw%3D%3D Occurrence Handle10.1056/NEJM199101033240101

    Article  PubMed  CAS  Google Scholar 

  21. LH Sobin CH Wittekind (2002) International Union Against Cancer. TNM classification of malignant tumors EditionNumber6 Wiley-Liss New York

    Google Scholar 

  22. InstitutionalAuthorNameJapanese Society for Cancer of the Colon and Rectum. (1998) General rules for clinical and pathological studies on cancer of the colon, rectum and anus EditionNumber6 Kanehara & Co Ltd Tokyo

    Google Scholar 

  23. TA Partanen K Alitalo M Miettinen (1999) ArticleTitleLack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors Cancer 86 2406–2412 Occurrence Handle10590384 Occurrence Handle10.1002/(SICI)1097-0142(19991201)86:11<2406::AID-CNCR31>3.0.CO;2-E Occurrence Handle1:STN:280:DC%2BD3c%2FlvFGqtQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  24. K Akagi Y Ikeda M Miyazaki et al. (2000) ArticleTitleVascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues Br J Cancer 83 887–891 Occurrence Handle10970690 Occurrence Handle10.1054/bjoc.2000.1396 Occurrence Handle1:CAS:528:DC%2BD3cXntFGjtLc%3D

    Article  PubMed  CAS  Google Scholar 

  25. JD White PW Hewett D Kosuge et al. (2002) ArticleTitleVascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma Cancer Res 62 1669–1675 Occurrence Handle11912138 Occurrence Handle1:CAS:528:DC%2BD38XisVSisLc%3D

    PubMed  CAS  Google Scholar 

  26. M Ohno T Nakamura K Kunimoto K Nishimura C Chung-Kang Y Kuroda (2003) ArticleTitleLymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer Oncol Rep 10 939–943 Occurrence Handle12792749 Occurrence Handle1:CAS:528:DC%2BD3sXltFGlt74%3D

    PubMed  CAS  Google Scholar 

  27. S Onogawa Y Kitadai S Tanaka T Kuwai S Kimura K Chayama (2004) ArticleTitleExpression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma Cancer Sci 95 32–39 Occurrence Handle14720324 Occurrence Handle10.1111/j.1349-7006.2004.tb03167.x Occurrence Handle1:CAS:528:DC%2BD2cXhvFOrtLg%3D

    Article  PubMed  CAS  Google Scholar 

  28. JS Reis-Filho FC Schmitt (2003) ArticleTitleLymphangiogenesis in tumors: what do we know? Microsc Res Tech 60 171–180 Occurrence Handle12539171 Occurrence Handle10.1002/jemt.10255

    Article  PubMed  Google Scholar 

  29. RK Jain BT Fenton (2002) ArticleTitleIntratumoral lymphatic vessels: a case of mistaken identity or malfunction? J Natl Cancer Inst 94 417–421 Occurrence Handle11904313

    PubMed  Google Scholar 

  30. S Breiteneder-Geleff K Matsui A Soleiman et al. (1997) ArticleTitlePodoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis Am J Pathol 151 1141–1152 Occurrence Handle9327748 Occurrence Handle1:CAS:528:DyaK2sXmvFGmu7s%3D

    PubMed  CAS  Google Scholar 

  31. Y Kitadai M Kodama S Cho et al. (2005) ArticleTitleQuantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes Int J Cancer 115 388–392 Occurrence Handle15688374 Occurrence Handle10.1002/ijc.20859 Occurrence Handle1:CAS:528:DC%2BD2MXkt1Clur8%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Yuko Ueda, Hitomi Arimasu, and Miyuki Fujioka for technical assistance.

Author information

Authors and Affiliations

  1. Department of Surgery 1, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Kentaro Matsumoto M.D., Yoshifumi Nakayama M.D., Ph.D., Yuzuru Inoue M.D., Ph.D., Noritaka Minagawa M.D., Ph.D., Takefumi Katsuki M.D., Kazunori Shibao M.D., Ph.D., Yosuke Tsurudome M.D., Ph.D., Keiji Hirata M.D., Ph.D. & Naoki Nagata M.D., Ph.D.

Authors
  1. Kentaro Matsumoto M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshifumi Nakayama M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuzuru Inoue M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noritaka Minagawa M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takefumi Katsuki M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazunori Shibao M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yosuke Tsurudome M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Keiji Hirata M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Naoki Nagata M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideaki Itoh M.D., Ph.D.*
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

*Deceased.

The Poster presentation at the meeting of the Japanese Society of Gastroenterology, Sapporo, Japan, October 11 to 14, 2006.

Reprints are not available.

About this article

Cite this article

Matsumoto, K., Nakayama, Y., Inoue, Y. et al. Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer. Dis Colon Rectum 50, 308–314 (2007). https://doi.org/10.1007/s10350-006-0792-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10350-006-0792-y

Key words

Search

Navigation