Abstract
BackgroundTumour budding (TB), lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) have shown promise as prognostic factors in colorectal cancer (CRC) but reproducibility using conventional histopathology is challenging. We demonstrate image analysis methodology to quantify the histopathological features which could permit standardisation across institutes and aid risk stratification of Dukes B patients.MethodsMultiplexed immunofluorescence of pan-cytokeratin, D2-40 and DAPI identified epithelium, lymphatic vessels and all nuclei respectively in tissue sections from 50 patients diagnosed with Dukes A (n = 13), Dukes B (n = 29) and Dukes C (n = 8) CRC. An image analysis algorithm was developed and performed, on digitised images of the CRC tissue sections, to quantify TB, LVD, and LVI at the invasive front.ResultsTB (HR =5.7; 95% CI, 2.38-13.8), LVD (HR =5.1; 95% CI, 2.04-12.99) and LVI (HR =9.9; 95% CI, 3.57-27.98) were successfully quantified through image analysis and all were shown to be significantly associated with poor survival, in univariate analyses. LVI (HR =6.08; 95% CI, 1.17-31.41) is an independent prognostic factor within the study and was correlated to both TB (Pearson r =0.71, p <0.0003) and LVD (Pearson r =0.69, p <0.0003).ConclusionWe demonstrate methodology through image analysis which can standardise the quantification of TB, LVD and LVI from a single tissue section while decreasing observer variability. We suggest this technology is capable of stratifying a high risk Dukes B CRC subpopulation and we show the three histopathological features to be of prognostic significance.
Highlights
Tumour budding (TB), lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) have shown promise as prognostic factors in colorectal cancer (CRC) but reproducibility using conventional histopathology is challenging
A wealth of original studies, systematic and metaanalysis reviews have been published on the subject of lymphatic vessel invasion (LVI) [5,6,7], lymphatic vessel density (LVD) [8,9,10] and tumour budding (TB) [11,12,13,14,15] in CRC prognosis [16,17]
LVI and TB have been shown to be significantly prognostic in most of these studies they are not, along with LVD, routinely reported in the clinical pathology report and are not included within the minimum core data set compiled by the Royal College of Pathologists [1], wherein only TB is listed as a non-core data item
Summary
Tumour budding (TB), lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) have shown promise as prognostic factors in colorectal cancer (CRC) but reproducibility using conventional histopathology is challenging. There exist subtypes of colorectal cancer (CRC), defined by disrupted molecular pathways, in clinical practice prognosis and recommendation for adjuvant therapy relies upon histopathological analysis of haematoxylin and eosin (H&E) stained tissue sections and the consequent TNM or Dukes staging of the tumour [1,2]. A wealth of original studies, systematic and metaanalysis reviews have been published on the subject of lymphatic vessel invasion (LVI) [5,6,7], lymphatic vessel density (LVD) [8,9,10] and tumour budding (TB) [11,12,13,14,15] in CRC prognosis [16,17]. Semi-quantitative scoring employed in these studies is subjective, open to variability and time consuming
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