Breast Cancer Research and Treatment

, Volume 84, Issue 2, pp 117–130

Prognostic Significance of Periodic Acid-Schiff-Positive Patterns in Primary Breast Cancer and its Lymph Node Metastases

  • Jeroen T. Buijs
  • Anne-Marie Cleton
  • Vincent T.H.B.M. Smit
  • Clemens W.G.M. Löwik
  • Socrates E. Papapoulos
  • Gabri van der Pluijm


Invasive ductal carcinoma is by far the largest histological subtype of breast cancer, but clinical behavior can differ greatly. Reliable morphological markers are, therefore, of invaluable help to distinguish between patients with good and poor prognosis. Histological patterns stained with periodic acid-Schiff (PAS) were previously shown to be of prognostic significance in cutaneous and uveal melanoma. In this study, we examined the presence of different PAS-positive (PAS+) structures in 54 women with infiltrating ductal adenocarcinoma of the breast and at least one axillary lymph node metastasis but no distant metastases who were followed for at least 11 years. We found that the complexity of the thin PAS+ patterns in lymph node metastases is associated with a shorter period of disease free survival (DFS) as well as of total survival (Kaplan–Meier curves). Furthermore, the presence of PAS+ networks – the most complex thin PAS+ pattern – in lymph node metastases is one of the two independent factors associated with the occurrence of a distant metastasis (multivariate Cox model). Moreover, the presence of PAS+ networks in positive lymph nodes is the feature most strongly associated with DFS. In conclusion, the presence of PAS+ networks in lymph node metastases is a new, reliable and convenient indicator for prognosis of breast cancer patients.

breast neoplasms neoplasm metastasis neovascularization pathologic periodic acid-Schiff reaction prognosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Orr RK: The impact of prophylactic axillary node dissection on breast cancer survival-a Bayesian meta-analysis. Ann Surg Oncol 6: 109–116, 1999Google Scholar
  2. 2.
    Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27–31, 1995Google Scholar
  3. 3.
    Risau W: Mechanisms of angiogenesis. Nature 386: 671–674, 1997Google Scholar
  4. 4.
    Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364, 1996Google Scholar
  5. 5.
    Rak J, Kerbel RS: Treating cancer by inhibiting angiogenesis: new hopes and potential pitfalls. Cancer Metastasis Rev 15: 231–236, 1996Google Scholar
  6. 6.
    Kumar R, Fidler IJ: Angiogenic molecules and cancer metastasis. In vivo 12: 27–34, 1998Google Scholar
  7. 7.
    de Jong JS, van Diest PJ, Baak JP: Hot spot microvessel density and the mitotic activity index are strong additional prognostic indicators in invasive breast cancer. Histopathology 36: 306–312, 2000Google Scholar
  8. 8.
    Engels K, Fox SB, Harris AL: Angiogenesis as a biologic and prognostic indicator in human breast carcinoma. EXS 79: 113–156, 1997Google Scholar
  9. 9.
    Gasparini G, Harris AL: Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol 13: 765–782, 1995Google Scholar
  10. 10.
    Harris AL, Zhang H, Moghaddam A, Fox S, Scott P, Pattison A, Gatter K, Stratford I, Bicknell R: Breast cancer angiogenesis-new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting. Breast Cancer Res Treat 38: 97–108, 1996Google Scholar
  11. 11.
    Clarijs R, Otte-Holler I, Ruiter DJ, de Waal RM: Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma. Invest Ophthalmol Vis Sci 43: 912–918, 2002Google Scholar
  12. 12.
    Folberg R, Pe'er J, Gruman LM, Woolson RF, Jeng G, Montague PR, Moninger TO, Yi H, Moore KC: The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: a matched case-control study. Hum Pathol 23: 1298–1305, 1992Google Scholar
  13. 13.
    Thies A, Mangold U, Moll I, Schumacher U: PAS-positive loops and networks as a prognostic indicator in cutaneous malignant melanoma. J Pathol 195: 537–542, 2001Google Scholar
  14. 14.
    Folberg R, Rummelt V, Parys-Van Ginderdeuren R, Hwang T, Woolson RF, Pe'er J, Gruman LM: The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 100: 1389–1398, 1993Google Scholar
  15. 15.
    Warso MA, Maniotis AJ, Chen X, Majumdar D, Patel MK, Shilkaitis A, Gupta TK, Folberg R: Prognostic significance of periodic acid-Schiff-positive patterns in primary cutaneous melanoma. Clin Cancer Res 7: 473–477, 2001Google Scholar
  16. 16.
    Foss AJ, Alexander RA, Hungerford JL, Harris AL, Cree IA, Lightman S: Reassessment of the PAS patterns in uveal melanoma. Br J Ophthalmol 81: 240–246, 1997Google Scholar
  17. 17.
    McLean IW, Keefe KS, Burnier MN: Uveal melanoma. Comparison of the prognostic value of fibrovascular loops, mean of the ten largest nucleoli, cell type, and tumor size. Ophthalmology 104: 777–780, 1997Google Scholar
  18. 18.
    Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ: Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155: 739–752, 1999Google Scholar
  19. 19.
    van den Broek LJ, van de Vijver MJ: Assessment of problems in diagnostic and research immunohistochemistry associated with epitope instability in stored paraffin sections. Appl Immunohistochem Mol Morphol 8: 316–321, 2000Google Scholar
  20. 20.
    Hazelbag HM, van den Broek LJ, van Dorst EB, Offerhaus GJ, Fleuren GJ, Hogendoorn PC: Immunostaining of chainspecific keratins on formalin-fixed, paraffin-embedded tissues: a comparison of various antigen retrieval systems using microwave heating and proteolytic pre-treatments. J Histochem Cytochem 43: 429–437, 1995Google Scholar
  21. 21.
    Valtola R, Salven P, Heikkila P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, deWaal R, Alitalo K: VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 154: 1381–1390, 1999Google Scholar
  22. 22.
    Lee HD, Yoon DS, Koo JY, Suh CO, Jung WH, Oh KK: Breast conserving therapy in stage I & II breast cancer in Korea. Breast Cancer Res Treat 44: 193–199, 1997Google Scholar
  23. 23.
    Noguchi M, Yagasaki R, Kawahara F, Minami M, Tsuyama H, Earashi M, Kinoshita K, Taniya T, Miwa K, Nishijima H, Takanaka T, Kawashima H, Takashima C, Kanno M, Nakamura S, Mizukami Y, Nonomura A, Michigishi T, Yokoyama K: Breast conserving treatment versus modified radical mastectomy in Japanese patients with operable breast cancer. Int Surg 82: 289–294, 1997Google Scholar
  24. 24.
    van Tienhoven G, Voogd AC, Peterse JL, Nielsen M, Andersen KW, Mignolet F, Sylvester R, Fentiman IS, van der SE, van Zijl K, Blichert-Toft M, Bartelink H, van Dongen JA: Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group. Eur J Cancer 35: 32–38, 1999Google Scholar
  25. 25.
    Petersen OW, Lind NH, Gudjonsson T, Villadsen R, Ronnov-Jessen L, Bissell MJ: The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion. Breast Cancer Res 3: 213–217, 2001Google Scholar
  26. 26.
    Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454, 2002Google Scholar
  27. 27.
    Dandachi N, Hauser-Kronberger C, More E, Wiesener B, Hacker GW, Dietze O, Wirl G: Co-expression of tenascin-C and vimentin in human breast cancer cells indicates phenotypic transdifferentiation during tumour progression: correlation with histopathological parameters, hormone receptors, and oncoproteins. J Pathol 193: 181–189, 2001Google Scholar
  28. 28.
    Sharma N, Seftor RE, Seftor EA, Gruman LM, Heidger Jr PM, Cohen MB, Lubaroff DM, Hendrix MJ: Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate 50: 189–201, 2002Google Scholar
  29. 29.
    Hendrix MJ, Seftor EA, Kirschmann DA, Seftor RE: Molecular biology of breast cancer metastasis. Molecular expression of vascular markers by aggressive breast cancer cells. Breast Cancer Res 2: 417–422, 2000Google Scholar
  30. 30.
    McDonald DM, Munn L, Jain RK: Vasculogenic mimicry: how convincing, how novel, and how significant? Am J Pathol 156: 383–388, 2000Google Scholar
  31. 31.
    Folberg R, Hendrix MJ, Maniotis AJ: Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156: 361–381, 2000Google Scholar
  32. 32.
    Fausto N: Vasculogenic mimicry in tumors. Fact or artifact? Am J Pathol 156: 359, 2000Google Scholar
  33. 33.
    Bissell MJ: Tumor plasticity allows vasculogenic mimicry, a novel form of angiogenic switch. A rose by any other name? Am J Pathol 155: 675–679, 1999Google Scholar
  34. 34.
    Sood AK, Seftor EA, Fletcher MS, Gardner LM, Heidger PM, Buller RE, Seftor RE, Hendrix MJ: Molecular determinants of ovarian cancer plasticity. Am J Pathol 158: 1279–1288, 2001Google Scholar
  35. 35.
    Shirakawa K, Wakasugi H, Heike Y, Watanabe I, Yamada S, Saito K, Konishi F: Vasculogenic mimicry and pseudocomedo formation in breast cancer. Int J Cancer 99: 821–828, 2002Google Scholar
  36. 36.
    Shirakawa K, Tsuda H, Heike Y, Kato K, Asada R, Inomata M, Sasaki H, Kasumi F, Yoshimoto M, Iwanaga T, Konishi F, Terada M, Wakasugi H: Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res 61: 445–451, 2001Google Scholar
  37. 37.
    Ruoslahti E: Specialization of tumour vasculature. Nat Cancer Rev 2: 83–90, 2002Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Jeroen T. Buijs
    • 1
  • Anne-Marie Cleton
    • 2
  • Vincent T.H.B.M. Smit
    • 2
  • Clemens W.G.M. Löwik
    • 1
  • Socrates E. Papapoulos
    • 1
  • Gabri van der Pluijm
    • 1
  1. 1.Department of EndocrinologyLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of PathologyLeiden University Medical CenterLeidenThe Netherlands

Personalised recommendations