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Tibor Tot

Intratumoral heterogeneity - IHC and ISH analysis


Handout (pdf 103 p)

Handout(pdf 26p)


Breast cancer is a heterogeneous disease with individual cases varying in morphology, clinical and radiological manifestations, prognosis, and therapy response. Heterogeneity is frequently seen within the same tumor and in general refers to co-existence of more than one tumor cell subpopulations with regard to histological tumor type and grade, protein expression or genetic characteristics. This intratumoral heterogeneity may manifest in three different patterns: the deviating tumor cells may form a distinct cluster, they can be scattered among the other cells of the tumor, or intermingle with the rest of the tumor cells in a mosaic-like pattern. HER2 heterogeneity is seen in up to 40% of the analyzed invasive breast carcinomas in some series (1). Multifocality is an important issue in breast cancer and differences between the tumor foci may also be substantial. Foci deviating from one another with regard to their estrogen and progesterone receptor status are seen in approximately 10% of multifocal carcinomas similar to differences in HER2 over-expression. Variations in Ki67 proliferation index are also frequent. Heterogeneity may potentially lead to discordant results dependent on which part of the tumor is embedded and examined. This problem is even more obvious in core biopsy – surgical specimen correlation and in relation of primary tumors and metastatic foci. More importantly, the different subpopulations may influence the assessment of the tumors’ molecular phenotype and potentially may lead to under-treatment of the patients. According to the results of our research team, patients with multifocal tumors showing molecular intertumoral heterogeneity have worse survival compared to patients with homogeneous multifocal cases (2). In practice, all the classifications systems allow for intratumoral and intertumoral heterogeneity defining cut-off levels in a percentage of positive tumor cells. The proportion of positive cells may have a substantial impact on the tumors´ response to therapy. Assessing and reporting the percentage of the tumor cells expressing a biomarker at scanning microscopic magnification is an essential routine. Tricolor BDISH method for assessing HER-2 positivity has the advantage of demonstrating all the needed structures within the same histology slide (3).

  1. Hanna WM at al. Mod Pathol 2014; 27:4-18.                                                                                                
  2. Pekar G et al. Cancer 2014; 120:26-34.
  3. Nitta H et al. Diagn Pathol 2012; 7:60


Tibor Tot is associate professor of pathology at the University of Uppsala, Sweden and head of Laboratory Medicine Dalarna and its Department of Pathology and Clinical Cytology at the County Hospital in Falun, Sweden. He is breast cancer expert of the Swedish Board of Welfare and is regular course director of its breast pathology program. The last years he is also one of the three faculty members in the breast pathology arm of the European School of Pathology, invited faculty member in European School of Radiology and one of the scientific directors in the European School of Oncology Certificate of Competence in Breast Cancer program. In addition to more than 80 journal articles and 20 book chapters, he published the book Practical Breast Pathology (Thieme 2002, second edition 2014), which has become official teaching material of the European School of Pathology. He is also co-author of the Thieme Series on Art and Science of Mammography. Recently, he edited two Springer books related to modern breast cancer diagnostics. With radiological – pathological correlation of breast diseases as his main field of interest, he is repeatedly invited lecturer at the European Congress of Radiology, European Congress of Pathology, and other international and national congresses, symposia, and teaching courses all over the world. He is member of the Editorial Board of Virchows Archiv, the official journal of the European Society of Pathology, Vojnosanitetski pregled (Belgrade), the Journal of OncoPathology, and the Journal of Solid Tumors, one of the editors of Case Reports in Pathology, member of the European Working Groups for Breast Cancer Screening Pathology and the past chair of the Working Group for Breast Pathology of the European Society of Pathology.

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