Size and Shape Filtering of Malignant Cell Clusters within Breast Tumors Identifies Scattered Individual Epithelial Cells as the Most Valuable Histomorphological Clue in the Prognosis of Distant Metastasis Risk.

Velicko Vranes,Marko Radulovic,Xingyu Li,Ksenija Kanjer,Nebojša T Milošević,Jelena Milovanović,Konstantinos N Plataniotis,Nemanja Rajković,Nataša Todorović Raković

doi:10.3390/cancers11101615

Abstract

Survival and life quality of breast cancer patients could be improved by more aggressive chemotherapy for those at high metastasis risk and less intense treatments for low-risk patients. Such personalized treatment cannot be currently achieved due to the insufficient reliability of metastasis risk prognosis. The purpose of this study was therefore, to identify novel histopathological prognostic markers of metastasis risk through exhaustive computational image analysis of 80 size and shape subsets of epithelial clusters in breast tumors. The group of 102 patients had a follow-up median of 12.3 years, without lymph node spread and systemic treatments. Epithelial cells were stained by the AE1/AE3 pan-cytokeratin antibody cocktail. The size and shape subsets of the stained epithelial cell clusters were defined in each image by use of the circularity and size filters and analyzed for prognostic performance. Epithelial areas with the optimal prognostic performance were uniformly small and round and could be recognized as individual epithelial cells scattered in tumor stroma. Their count achieved an area under the receiver operating characteristic curve (AUC) of 0.82, total area (AUC = 0.77), average size (AUC = 0.63), and circularity (AUC = 0.62). In conclusion, by use of computational image analysis as a hypothesis-free discovery tool, this study reveals the histomorphological marker with a high prognostic value that is simple and therefore easy to quantify by visual microscopy.

Highlights

Cancer diagnosis, prognosis, and treatment are the main challenges in oncology
Selection of breast cancer patients was retrospective and based on the absence of systemic treatments with hormonal or cytotoxic drugs. This was according to recommendations for lower risk patients effective in the year 1993 for the smaller size tumors classified as pT1 and pT2, grade 1 and grade 2, and without lymph node involvement or metastasis (N0M0) breast carcinoma (Table 1)
Our findings show that malignant cell clusters in breast tumors provide prognostic information by their count, size, and shape

Summary

Introduction

Prognosis, and treatment are the main challenges in oncology. The primary breast tumor is not life-threatening until the disease becomes systemic by its metastatic spread. As most patients do not incur metastasis even without cytotoxic chemotherapy [1], it may be that many are unnecessarily exposed to toxic side effects of chemotherapy treatment [2]. This could be resolved by prescribing less intense treatments to those at low risk and more intense chemotherapy to those reliably prognosticated at high metastasis risk. Clinicopathological parameters with prognostic value include tumor size, lymph node spread and metastasis (TNM staging) age, histologic grade, steroid receptor status [3], and gene signatures such as Mammaprint and OncotypeDX [4]. For early breast cancer patients with negative lymph node spread and distant metastasis, this staging system is not anymore prognostically reliable because it only contains information on tumor size. New prognostic markers are needed in patients with N0M0 disease in order to compensate for the reduced prognostic value of TNM as the major prognostic marker

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