Uses and Limitations of Immunohistochemistry in Breast Pathology
Moderator: Dr. Anna Sapino and Dr. Nour Sneige
Section 4 -
Immunohistochemical Classification of Breast Cancer
Gerhard-Domagk-Institute of Pathology
University of Muenster
The classification of breast cancer can be done with a multitude of clinical, genetic and pathological
approaches. The presence of lymph node metastasis is at the present state of knowledge the most
Within the last years a series of studies verified the existence of different subclasses of invasive
breast cancer by means of global gene expression analysis. The differential expression patterns of
several low and high-molecular weight cytokeratins gave rise to the hypothesis of various breast cancer
subgroups with associated prognosis.
Interestingly, these expression parameters reflect on one hand tumour grade and established breast
cancer subtypes. On the other hand these expression patterns are associated with distinct genetic
alterations or alteration patterns. In detail, Sorlie and Perou
clearly demonstrated the
existence of a subgroup of invasive breast cancer cases, characterised by the expression of basal, high
molecular cytokeratins, including Ck 5 . This and previous works were able to demonstrate
that these rather rare tumours are associated with an inherited, BRCA1-related background
. Further cytogenetic, immunohistochemical analysis of a large series of invasive breast cancer
cases could furthermore clearly correlate cytokeratin expression with cytogenetic alteration patterns.
Especially the frequencies of chromosomal 16q-losses marked these carcinomas as an own, independent
subgroup, rather than the end stage of a dedifferentiation
With the definition of different subgroups of physiological breast cells, including Ck 5 positive
progenitor cells, it became obvious that a number of protein expression patterns of these physiological
breast cells demonstrate a large overlap with protein expression patterns of distinct breast cancer
As a consequence of these findings, different cellular compartments might therefore function as
different progenitors of invasive breast cancer and its suspected and proposed precursor lesions
In consequence the transfer of our knowledge about physiological breast differentiation onto the
level of breast carcinogenesis enables a feasible explanation for large heterogeneity of invasive breast
cancer, comprising well-differentiated glandular tumours on one end and poorly-differentiated carcinomas
on the other end of the morphological and immunohistochemical spectrum.
These results are a clear evidence for an important role of cellular subpopulations within the normal
breast functioning as cytogenetic pathway specific precursor cells of breast cancer
Whereas a carcinogenic hit of "early-progenitor cells" may cause the evolution of a poorly-differentiated
breast cancer, the tumour associated dedifferentiation of a glandular cell seems to be associated with a
lower tumour grade.
- Sorlie T, Perou C, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. U. S. A. 2001;98(19):10869-10874.
- Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. U. S. A 2003 Jul 8;100(14):8418-8423.
- Perou C, Sorlie T, Eisen M, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-752.
- Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J. Natl. Cancer Inst. 2003 Oct 1;95(19):1482-1485.
- van der GP, Bouter A, van der ZR, et al. Re: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl. Cancer Inst. 2004 May 5;96(9):712-713.
- Korsching E, Packeisen J, Agelopoulos K, et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest 2002 Nov;82(11):1525-1533.
- Wang ZC, Lin M, Wei LJ, et al. Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers. Cancer Res. 2004 Jan 1;64(1):64-71.
- Korsching E, Packeisen J, Liedtke C, et al. The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 2005 Aug;206(4):451-457.
- Boecker W, Moll R, Dervan P, et al. Usual ductal hyperplasia of the breast is a committed stem (progenitor) cell lesion distinct from atypical ductal hyperplasia and ductal carcinoma of the breast. J Pathol 2002;in press.
- Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003 May 15;17(10):1253-1270.
- Olsson H. Tumour biology of a breast cancer at least partly reflects the biology of the tissue/epithelial cell of origin at the time of initiation - a hypothesis. J Steroid Biochem. Mol. Biol. 2000 Nov 30;74(5):345-350.
- Li Y, Welm B, Podsypanina K, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl. Acad. Sci. U. S. A 2003 Dec 23;100(26):15853-15858.