الفهرس 
AcknowledgmentOnly 14 pages are availabe for public view
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Abstract
Tumor budding, Poorly differentiated clusters and Desmoplastic stromal reaction are a group of the most promising novel histopathological features currently studied in CRC in the hope for solving survival heterogeneity dilemma of CRC patients and to establish more accurate CRC prognostic factors. Our herein study provides a set of the most robust candidates for a promising CRC survival prediction and accurate risk stratification. These novel, simple, reproducible, and cost-effective parameters might be included in the routine reporting checklist for CRC. In this study, we retrospectively analyzed 135 CRC mixed- stage cohort of CRC patients who underwent surgical radical resection from January 2015 to December 2018 at South Egypt Cancer Institute (SECI). We examined the proposed new assessment methods of TB, PDCs and DR at the invasive front of CRC, assessed their feasibility in practice and also examined the conventional pathological parameters (TNM stage, PNI and LVI) and investigated their association with (TB, PDCs and DR). Thus, this study not only examined and compared the prognostic significance of known histopathologic markers in CRC through their recommended assessment methodologies, but also, we present one of the few studies to examine and compare TB, PDC and DR in different CRC stages. Furthermore, to evaluate the prognostic power of these novel invasive front markers and to clarify if their assessment add value to the current conventional prognostic factors, we performed a 2-year survival analysis. TB scores were strongly associated with PNI (p=0.012), pathologic N stage classification (p=0.017), PDC (p<0.001) and DR (p<0.001), thus it could be a good predictor of lymph node metastasis. There was statistically significant correlation between PDC grades and LVI (p=0.018), PNI (p=0.002) and DR (p<0.001). Strong significant association was observed between DR types and tumor size (p=0.007), LVI (P=0.011) and PNI (p<0.001). All of TB, PDC and DR affected the OS significantly, yet only TB could stratify survival rates independently from the conventional TNM stage and WHO tumor grade. Patient group with BD3 had a higher risk of worse prognosis equaling seven and half times. Conclusion The results of the present study show that TB, PDC and DR are promising factors, simple to use in practice and can be assessed using routine light microscopy on H&E stained slides. These factors turn to be good candidates to construct the basis of a new staging system that is expected to be less subjective and more informative for prognostic prediction compared with conventional tumor grading systems and TNM staging, furthermore, it can contribute in the effective stratification of patients who can benefit from adjuvant therapy. TB assessment according to the ITBCC guidelines resulted in a robust prognostic prediction value, independent of the AJCC tumor staging factors and other conventional histopathologic prognostic factors. Besides, we found that tumor budding might be a reliable predictor of LN metastasis in CRC patients. Further validation studies such as we present here aim to encourage more widespread integration of the ITBCC standardized method in reporting of tumor budding in CRC. We believe multi-institutional studies to validate our results and evaluate diagnostic reproducibility are needed for embracement of these novel histopathologic parameters in routine pathologic practice. Recommendations Additional multi-institutional studies are required- including prospective ones- to evaluate the diagnostic reproducibility of TB, PDC and DR in CRC. Further molecular studies are needed to better understand these novel histopathologic phenomena-including their pathogenesis and if they are correlated to each other- and investigate their exact impact on CRC microenvironment. As TB, PDC and DR also need an urgent standardized internationally used assessment methods to solve the current heterogeneity of methodology, which may be the reason hindering their integration into daily routine practice. Further studies are recommended to investigate the optimal approach for the evaluation of these invasive front prognostic markers whether in combination or in isolation. Further studies are required to determine if PDC grading has a role in the post-neoadjuvant setting.