Skip to main content

Advertisement

Log in

Detection of lymphovascular invasion in early breast cancer by D2-40 (podoplanin): a clinically useful predictor for axillary lymph node metastases

  • Clinical Trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose The aim of this study was to investigate the use of D2-40 for the detection of lymphovascular invasion (LVI) in node positive and negative early breast cancer. LVI is associated with axillary lymph node metastases (ALNM) and a long-term prognostic factor. A precise identification of LVI would have a strong clinical impact for breast cancer patients. Methods Immunohistochemical staining with D2-40 and CD34 was performed on formalin-fixed, paraffin-embedded tissue sections of 254 invasive breast tumors of 247 patients with node negative and node positive early breast cancer. All slides were screened for the presence of LVI. Correlation with clinico-pathological factors including LVI as retrieved by routine haematoxylin and eosin (H.E.) stained sections and the eligibility for the prediction of ALNM was assessed. Results Using the D2-40 antibody for immunostaining, our results demonstrate a significant higher detection (P < 0.001) of LVI as compared with routine H.E.-staining in early breast cancer. LVI was correctly identified by D2-40 (D2-40+) in 70 out of 254 tumors (28%) as compared to 40 tumors (16%) by routine HE staining (HE+). There was a significant correlation between D2-40 + LVI and age, t-stage, nodal status, grading and hormonreceptor-status. Correlation between D2-40 + LVI and menopausal-status, HER2-status and histological type was not significant, while there was a significant correlation of D2-40 and so called “triple negative” tumors (ER/PR and HER2neu-negative). In a multivariate analysis D2-40+ was the strongest predictor for ALNM with an odds ratio of 3.489 and a P-value of P = 0.0003, followed only by T-stage and grading with odds ratios of 3.167 and 1.953 and P-values P = 0.0003 and P = 0.0352. Conclusion Immunostaining with D2-40 significantly increased the frequency of detection of lymphatic invasion compared to conventional H.E.-staining in early breast cancer. As LVI is a strong predictive and prognostic marker, the monoclonal antibody D2-40 has the potential to play a significant role in pathological routine workup of breast tumors. Further prospective studies are needed to prove the clinical impact of D2-40.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Jemal A et al (2006) Cancer statistics, 2006. CA Cancer J Clin 56(2):106–130

    Article  PubMed  Google Scholar 

  2. Glissmeyer M (2007) Reviewing prognostic factors in breast cancer management. Jaapa 20(5):42–46

    PubMed  Google Scholar 

  3. Mirza AN et al (2002) Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years. Ann Surg 235(1):10–26

    Article  PubMed  Google Scholar 

  4. Rosen PP et al (1989) Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 7(9):1239–1251

    PubMed  CAS  Google Scholar 

  5. Lee AK et al (1990) Prognostic significance of peritumoral lymphatic and blood vessel invasion in node-negative carcinoma of the breast. J Clin Oncol 8(9):1457–1465

    PubMed  CAS  Google Scholar 

  6. Lauria R et al (1995) The prognostic value of lymphatic and blood vessel invasion in operable breast cancer. Cancer 76(10):1772–1778

    Article  PubMed  CAS  Google Scholar 

  7. Pinder SE et al (1994) Pathological prognostic factors in breast cancer. III. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology 24(1):41–47

    Article  PubMed  CAS  Google Scholar 

  8. Rosen PP et al (1993) Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol 11(11):2090–2100

    PubMed  CAS  Google Scholar 

  9. Fitzgibbons PL et al (2000) Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124(7):966–978

    PubMed  CAS  Google Scholar 

  10. Hasebe T et al (2004) Histological characteristics of tumor in vessels and lymph nodes are significant predictors of progression of invasive ductal carcinoma of the breast: a prospective study. Hum Pathol 35(3):298–308

    Article  PubMed  Google Scholar 

  11. Kato T et al (2003) The combination of angiogenesis and blood vessel invasion as a prognostic indicator in primary breast cancer. Br J Cancer 88(12):1900–1908

    Article  PubMed  CAS  Google Scholar 

  12. Shoup M et al (1999) Predictors of axillary lymph node metastases in T1 breast carcinoma. Am Surg 65(8):748–752; discussion 752–753

    Google Scholar 

  13. Chua B et al (2001) Frequency and predictors of axillary lymph node metastases in invasive breast cancer. ANZ J Surg 71(12):723–728

    Article  PubMed  CAS  Google Scholar 

  14. Neville AM et al (1992) Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group. J Clin Oncol 10(5):696–705

    PubMed  CAS  Google Scholar 

  15. Van den Eynden GG et al (2006) Distinguishing blood and lymph vessel invasion in breast cancer: a prospective immunohistochemical study. Br J Cancer 94(11):1643–1649

    PubMed  Google Scholar 

  16. Obermair A et al (1995) Microvessel density and vessel invasion in lymph-node-negative breast cancer: effect on recurrence-free survival. Int J Cancer 62(2):126–131

    Article  PubMed  CAS  Google Scholar 

  17. Weninger W et al (1999) Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells. Lab Invest 79(2):243–251

    PubMed  CAS  Google Scholar 

  18. Breiteneder-Geleff S et al (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154(2):385–394

    PubMed  CAS  Google Scholar 

  19. Birner P et al (2001) Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer. Int J Cancer 95(1):29–33

    Article  PubMed  CAS  Google Scholar 

  20. Birner P et al (2001) Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer. Clin Cancer Res 7(1):93–97

    PubMed  CAS  Google Scholar 

  21. Birner P et al (2000) Lymphatic microvessel density in epithelial ovarian cancer: its impact on prognosis. Anticancer Res 20(5A):2981–2985

    PubMed  CAS  Google Scholar 

  22. Partanen TA, Alitalo K, Miettinen M (1999) Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer 86(11):2406–2412

    Article  PubMed  CAS  Google Scholar 

  23. Schacht V et al (2005) Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol 166(3):913–921

    PubMed  CAS  Google Scholar 

  24. Kahn HJ, Marks A (2002) A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab Invest 82(9):1255–1257

    PubMed  Google Scholar 

  25. Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8(3):138–140

    PubMed  CAS  Google Scholar 

  26. Gombos Z et al (2005) Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res 11(23):8364–8371

    Article  PubMed  CAS  Google Scholar 

  27. Walgenbach-Bruenagel G et al (2006) Detection of lymphatic invasion in early stage primary colorectal cancer with the monoclonal antibody D2-40. Eur Surg Res 38(5):438–444

    Article  PubMed  CAS  Google Scholar 

  28. Fukunaga M (2005) Expression of D2-40 in lymphatic endothelium of normal tissues and in vascular tumours. Histopathology 46(4):396–402

    Article  PubMed  CAS  Google Scholar 

  29. Arnaout-Alkarain A et al (2007) Significance of lymph vessel invasion identified by the endothelial lymphatic marker D2-40 in node negative breast cancer. Mod Pathol 20(2):183–191

    Article  PubMed  CAS  Google Scholar 

  30. Choi WW et al (2005) Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol 18(1):143–152

    Article  PubMed  CAS  Google Scholar 

  31. Van der Auwera I et al (2005) Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin Cancer Res 11(21):7637–7642

    Article  PubMed  CAS  Google Scholar 

  32. Van der Auwera I et al (2004) Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification. Clin Cancer Res 10(23):7965–7971

    Article  PubMed  Google Scholar 

  33. Nime FA et al (1977) Prognostic significance of tumor emboli in intramammary lymphatics in patients with mammary carcinoma. Am J Surg Pathol 1(1):25–30

    Article  PubMed  CAS  Google Scholar 

  34. Goldhirsch A et al (2005) Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16(10):1569–1583

    Article  PubMed  CAS  Google Scholar 

  35. Goldhirsch A et al (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18(7):1133–1144

    Article  PubMed  CAS  Google Scholar 

  36. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456

    Article  PubMed  CAS  Google Scholar 

  37. Evangelou E, Kyzas PA, Trikalinos TA (2005) Comparison of the diagnostic accuracy of lymphatic endothelium markers: Bayesian approach. Mod Pathol 18(11):1490–1497

    Article  PubMed  CAS  Google Scholar 

  38. Saigo PE, Rosen PP (1987) The application of immunohistochemical stains to identify endothelial-lined channels in mammary carcinoma. Cancer 59(1):51–54

    Article  PubMed  CAS  Google Scholar 

  39. Lee AK, DeLellis RA, Wolfe HJ (1986) Intramammary lymphatic invasion in breast carcinomas. Evaluation using ABH isoantigens as endothelial markers. Am J Surg Pathol 10(9):589–594

    Article  PubMed  CAS  Google Scholar 

  40. Acs G et al (2007) Extensive retraction artifact correlates with lymphatic invasion and nodal metastases and predicts poor outcome in early stage breast carcinoma. Am J Surg Pathol 31(1):129–140

    Article  PubMed  Google Scholar 

  41. Irie J et al (2007) Artefact as the pathologist's friend: peritumoral retraction in in situ and infiltrating duct carcinoma of the breast. Int J Surg Pathol 15(1):53–59

    Article  PubMed  Google Scholar 

  42. Tezuka K et al (2007) Prognostic significance of lymphovascular invasion diagnosed by lymphatic endothelium immunostaining in breast cancer patients. Oncol Rep 17(5):997–1003

    PubMed  Google Scholar 

  43. Dent R et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434

    Article  PubMed  Google Scholar 

  44. Russo J et al (1987) Predictors of recurrence and survival of patients with breast cancer. Am J Clin Pathol 88(2):123–131

    PubMed  CAS  Google Scholar 

  45. Fisher B et al (1983) Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer 52(9):1551–1557

    Article  PubMed  CAS  Google Scholar 

  46. Karlsson P et al (2007) The role of the number of uninvolved lymph nodes in predicting locoregional recurrence in breast cancer. J Clin Oncol 25(15):2019–2026

    Article  PubMed  Google Scholar 

  47. Cody HS 3rd, Borgen PI, Tan LK (2004) Redefining prognosis in node-negative breast cancer: can sentinel lymph node biopsy raise the threshold for systemic adjuvant therapy? Ann Surg Oncol 11(3 Suppl):227S–230S

    PubMed  Google Scholar 

  48. Rivadeneira DE et al (2000) Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients. J Am Coll Surg 191(1):1–6; discussion 6–8

    Google Scholar 

  49. Anan K et al (2000) Axillary lymph node metastases in patients with small carcinomas of the breast: is accurate prediction possible? Eur J Surg 166(8):610–615

    Article  PubMed  CAS  Google Scholar 

  50. O'Rourke S et al (1994) Local recurrence after simple mastectomy. Br J Surg 81(3):386–389

    Article  PubMed  Google Scholar 

  51. EBCTCG (2000) Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 355(9217):1757–1770

    Google Scholar 

  52. Wallgren A et al (2003) Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group trials I through VII. J Clin Oncol 21(7):1205–1213

    Article  PubMed  CAS  Google Scholar 

  53. Clarke M et al (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366(9503):2087–2106

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Braun.

Additional information

M. Braun and U. Flucke contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Braun, M., Flucke, U., Debald, M. et al. Detection of lymphovascular invasion in early breast cancer by D2-40 (podoplanin): a clinically useful predictor for axillary lymph node metastases. Breast Cancer Res Treat 112, 503–511 (2008). https://doi.org/10.1007/s10549-007-9875-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-007-9875-2

Keywords

Navigation