Breast Cancer Research and Treatment

, Volume 135, Issue 3, pp 693–703

Is there ‘progression through grade’ in ductal invasive breast cancer?

  • Barbara Schymik
  • Horst Buerger
  • Annika Krämer
  • Ulli Voss
  • Petra van der Groep
  • Wolfgang Meinerz
  • Paul J. van Diest
  • Eberhard Korsching
Preclinical Study


Recent molecular data pointed towards the possibility of a stepwise dedifferentiation in a subgroup of invasive breast cancer (BC) cases. It was hypothesized that oestrogen receptor positive (ER+) grade 3 (G3) ductal invasive BCs are the end stage of a dedifferentiation process of luminal BC. A progression of luminal A towards luminal B BCs associated with a ‘progression through grade’ and an increased cell proliferation seemed the obvious explanation. In order to verify this hypothesis on a morphological and immunohistochemical level, we investigated 865 invasive BC cases. All cases were reviewed for the presence of intratumoural heterogeneity in grade of the invasive cancer and the presence of associated ductal carcinoma in situ (DCIS). With the use of tissue microarrays, the molecular subtype was determined and correlated with clinico-pathological features. In addition, all cases were stained for p21, p27, Ki-67, Cyclin D1, bcl-2, p53, and p16 and the results subjected to a biomathematical dependency analysis. The frequency of ER-positivity decreased with tumour size. The frequency of luminal A BC decreased as well, whereas the number of luminal B BCs remained constant. A gradual increase of the frequency of basal-like, HER2-driven and non-expressor BCs with tumour size was seen. In only 1 out of 865 BC cases, both a G1 and a G3 invasive cancer component was seen within the same BC. In two cases, a ductal invasive G1 carcinoma was associated with a poorly-differentiated DCIS. The frequency of columnar cell lesions was evenly distributed over ER+ and ER− ductal invasive G3 carcinomas. The biomathematical analysis gave striking hints against an obligate progression of BC trough grade. In conclusion, our results show that a morphological recognizable striking ‘progression through grade’ at least in its extreme form from G1 towards G3 is a very rare event in the natural course of invasive BC, including luminal BC.


Breast cancer Breast cancer progression Estrogen receptor 


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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Barbara Schymik
    • 1
    • 2
  • Horst Buerger
    • 2
    • 3
    • 4
  • Annika Krämer
    • 3
  • Ulli Voss
    • 3
  • Petra van der Groep
    • 4
  • Wolfgang Meinerz
    • 1
    • 2
  • Paul J. van Diest
    • 4
  • Eberhard Korsching
    • 5
  1. 1.Clinics of GynecologySt. Vincenz HospitalPaderbornGermany
  2. 2.Cooperative Breast Center PaderbornPaderbornGermany
  3. 3.Institute of PathologyPaderbornGermany
  4. 4.Department of PathologyUniversity of UtrechtUtrechtThe Netherlands
  5. 5.Institute of BioinformaticsUniversity Hospital of Muenster, University of MuensterMuensterGermany

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