Abstract
Nucleolar morphometric features have a potential role in the assessment of the aggressiveness of many cancers. However, the role of nucleoli in invasive breast cancer (BC) is still unclear. The aims of this study were to investigate the optimal method for scoring nucleoli in IBC and their prognostic significance, and to refine the grading of breast cancer (BC) by incorporating nucleolar score. Digital images acquired from haematoxylin and eosin-stained sections from a large BC cohort were divided into training (n=400) and validation (n=1200) sets for use in this study. Four different assessment methods were evaluated in the training set to identify the optimal method associated with the best performance and significant prognostic value. These were: (i) a modified Helpap method; (ii) counting prominent nucleoli (size ≥2.5µm) in 10 field views (FVs); (iii) counting prominent nucleoli in five FVs; and (iv) counting prominent nucleoli in one FV. The optimal method was applied to the validation set and to an external validation set, i.e. data from The Cancer Genome Atlas (n=743). Scoring prominent nucleoli in five FVs showed the highest interobserver concordance rate (intraclass correlation coefficient of 0.8) and a significant association with BC-specific survival (P<0.0001). A high nucleolar score was associated with younger age, larger tumour size, and higher grade. Incorporation of nucleolar score in the Nottingham grading system resulted in a higher significant association with survival than the conventional grade. Quantification of nucleolar prominence in five FVs is a cost-efficient and reproducible morphological feature that can predict BC behaviour and can provide an alternative to pleomorphism to improve BC grading performance.
Highlights
Histological grade of invasive breast cancer (IBC), using the Nottingham grading system, is one of the strongest prognostic indices to guide management [1,2,3]
This study included two cohorts of IBC: 1) the Nottingham cohort (n=1600 cases) split into: a) a training set comprising 400 cases scored by four observers using four different scoring methods and b) a validation set (n=1200), which was scored by counting nucleoli in 5 field views (FVs) by two observers. 2) an external validation cohort; The Cancer Genome Atlas (TCGA) cohort (n= 743) to assess the performance of the optimal scoring method
Assessment of nucleoli in the training set demonstrated that counting nucleoli in 5 FVs (0.5mm2) using digitesd whole slide images was the optimal method
Summary
Histological grade of invasive breast cancer (IBC), using the Nottingham grading system, is one of the strongest prognostic indices to guide management [1,2,3]. MATERIALS AND METHODS Study Cohorts Nottingham Cohort This study was conducted on a large series (n=1600) of primary operable BC presented to Nottingham City Hospital, Nottingham, United Kingdom between 1999-2006 This is a well-characterised cohort with long term clinical follow-up (median 138 months, range 0-216 months) and detailed clinico-pathological data including patient’s age at diagnosis, primary tumor histological grade, tumor size and histological tumor type, Nottingham Prognostic Index (NPI), molecular subtypes and outcome data. The latter includes breast cancer specific survival (BCSS), defined as time (in months) from the date of the primary surgery to the time of death from BC and distant metastasis free survival (DMFS), and defined as the time (in months) from the primary surgery until the first event of distant metastasis. P- values < 0.05 (two-tailed) were considered as statistically significant
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