Assessing Tumour Budding in Lung Squamous Cell Carcinoma: A Comparative Analysis of Digital Whole-Slide Imaging and Light Microscopy

Validation of the International Tumor Budding Consensus Conference (ITBCC) 2016 recommendation in squamous cell carcinoma of the lung-a single-center analysis of 354 cases.

594 Background: Tumor budding, defined as single tumor cells or small clusters of four or less tumor cells at the invasive front, has been shown to be a strong and independent prognostic factor in colorectal cancer (CRC). However, widespread reporting of tumor budding has been held back largely due to a lack of consensus on scoring methods. 23 experts from the United States, Canada, Japan and Europe participated at the International Tumor Budding Consensus Conference (ITBCC), held in April 2016 in Bern, Switzerland, and agreed on a set of recommendations for assessing and reporting tumor budding in CRC. The aim of this study was to validate the method proposed by ITBCC in the clinically relevant scenario of Stage II CRC. Methods: In 151 Stage II CRC patients, tumor budding was assessed on scanned H&E-stained slides in a single hot spot measuring 0.785mm2. Cutoffs as defined by ITBCC were used: Low (Bd1): 0-4 buds, intermediate (Bd2): 5-9 buds, high (Bd3): ≥ 10 buds. Statistical analysis for associations with clinicopathological features, disease free survival (DFS) and overall survival (OS) was performed. Results: The average number of buds/hotspot was 6.8 (median 5.0). 43.1% of cases were Bd1, 27.2% Bd2 and 29.8% Bd3. Tumor budding as a continuous variable was associated with extramural venous invasion (EMVI) (p = 0.05). Tumor budding was associated with poorer OS in univariate analysis (p = 0.0386, HR 1.048, 95%CI 1.002-1.095). For 3- and 5- year DFS, Bd3 was associated with significantly worse survival in comparison with Bd1/2 (p = 0.0031 and p = 0.0025, respectively). In multivariate analysis adjusting for pT, tumor grade and EMVI, tumor budding retained its adverse prognostic effect for DFS (p = 0.006, HR 3.293, 95%CI 1.66-6.53). Conclusions: This study provides promising data on tumor budding assessed by the ITBCC method in the Stage II scenario. Especially Bd3 shows a detrimental adverse impact on DFS in comparison to Bd1/Bd2. Based on the ITBCC, tumor budding has the potential to strongly affect the management of Stage II CRC patients and should be therefore included in reporting guidelines and staging systems in CRC.

Tumor budding in colorectal carcinoma: An institutional interobserver reliability and prognostic study of colorectal adenocarcinoma cases

Introduction: Artifacts are often introduced during tissue collection and processing, slide preparation, and/or when generating whole slide images (WSI). The presence of artifacts has a negative impact on the digital pathology workflow as artifacts may hinder diagnostic reporting and can lead to false positive and false negative results when using image analysis algorithms or computer-aided diagnosis systems. Manual quality control of WSI is a time-consuming procedure and therefore automated quality control tools, which report and exclude artifacts, are highly desirable to streamline digital pathology workflows. To automate the quality control step, we developed SlideQC, an AI-based quality control tool that automatically detects, reports, and outlines artifacts such as air bubbles, dust/debris, folds, out-of-focus,and pen marks, in both research and clinical workflows. Methods: SlideQC was trained with a DenseNet-based network using 1984 annotations for artifacts including air bubbles, dust/debris, folds, out-of-focus, and pen markers, across 254 Haematoxylin and Eosin (H&E) stained WSI from more than 9 tissue types. A set of 2048 annotations from synthetically generated out-of-focus images was added to supplement the training data. The performance of the SlideQC was evaluated on an external test cohort of 49 WSI H&E images sourced from the open-source database ‘HistoQCRepo’, across 375 annotations (tissue and artifact), and compared with the performance of HistoQC, an open-source quality control tool for digital pathology slides. Results: On the external test cohort, SlideQC showed high sensitivity, specificity, and F1-score with average values of 0.93, 0.99, and 0.93, across the five artifact types. In the same cohort, HistoQC attained an average sensitivity, specificity, and F1-score of 0.65, 0.79, and 0.54, respectively. Conclusions: SlideQC achieved high sensitivity, specificity, and F1-score on an external test cohort. SlideQC can add efficiency gains to a workflow by performing quality control on 100% of slides rather than the currently manually performed on only a subset of the slides in clinical pathology departments. SlideQC can allowthe triaging and alerting of slides containing a high level of artifact within a digital pathology workflow. The tool can also be used to exclude the artifact region from downstream analysis by subsequent image analysis algorithms. Citation Format: Daniela Rodrigues, Stefan Reinhard, Therese Waldburger, Daniel Martin, Suzana Couto, Inti Zlobec, Peter Caie, Erik Burlingame. SlideQC: An AI-based tool for automated quality control of whole-slide digital pathology images. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5442.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016.

Characterization of the immunophenotype of the tumor budding and its prognostic implications in squamous cell carcinoma of the lung

Tumor budding is a valuable prognostic marker in oral tongue squamous cell carcinoma (OTSCC) but lacks a standardized scoring system. The aim of this study was to evaluate the prognostic value of tumor budding for OTSCC patients based on the scoring system recommended by the International Tumor Budding Consensus Conference (ITBCC) 2016. Tumor budding was scored as ITBCC recommended in 255 patients with OTSCC. Then, associations between tumor budding and clinicopathologic parameters were examined. Among them, 136 patients with follow-up data available were used to evaluate overall survival (OS) by the Kaplan-Meier method. Prognostic value of tumor budding was assessed by Cox regression analysis. The inter-observer and intra-observer agreement was calculated by the kappa statistic. Tumor budding score was associated with lymph node metastasis, differentiation, invasive pattern, lymphoid infiltrate, tumor relapse, invasive depth, and reduced OS in OTSCC patients. The Cox analysis showed high budding score was an independent prognostic factor in patients with all clinical stage and patients with clinical early-stage OTSCC. The high kappa values were achieved in intra-observer and inter-observer. International Tumor Budding Consensus Conference scoring system is a simple, reliable, and reproducible method to measure tumor budding in OTSCC, which should be included in the routine pathological report.

Tumor budding as a prognostic marker in colorectal cancer has not previously been investigated in a cohort of screened stage II colon cancer patients. We assessed the prognostic significance of tumor budding in a thoroughly characterized stage II colon cancer population comprising surgically resected patients in the Region of Southern Denmark from 2014 to 2016. Tumors were re-staged according to the 8th edition of UICC TNM Classification, undergoing detailed histopathological evaluation and tumor budding assessment following guidelines from the International Tumor Budding Consensus Conference. Prognostic evaluation utilized Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models for time to recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS).Out of 497 patients, 20% were diagnosed through the national colorectal cancer screening program. High-grade tumor budding (Bd3) was found in 19% of tumors and was associated with glandular subtype, perineural invasion, mismatch repair proficient tumors, and tumor recurrence (p < 0.001, p < 0.001, p = 0.045, and p = 0.007 respectively). In multivariable Cox regression, high-grade budding was a significant prognostic factor for TTR compared to low-grade (Bd3 HR 2.617; p = 0.007). An association between tumor budding groups and RFS was observed, and the difference was significant in univariable analysis for high-grade compared to low-grade tumor budding (Bd3 HR 1.461; p = 0.041). No significant differences were observed between tumor budding groups and OS.High-grade tumor budding is a predictor of recurrence in a screened population of patients with stage II colon cancer and should be considered a high-risk factor in a shared decision-making process when stratifying patients to adjuvant chemotherapy.

Objective: To investigate the role of tumor budding (TB) in predicting lymph node metastasis of intestinal-type early gastric adenocarcinoma, and to determine the optimal cutoff value of TB number. Methods: A total of 202 patients with intestinal-type early gastric adenocarcinoma, who underwent surgical operation at the Affiliated Wuxi People's Hospital of Nanjing Medical University, Jiangsu, China from 2008 to 2018 were included. According to the International Tumor Budding Consensus Conference (ITBCC) criteria, the number of TB for each case was assessed. The receiver operating characteristic (ROC) curve was employed to determine the optimal cutoff value of TB number for predicting lymph node metastasis, and multivariate logistic regression was used to analyze whether a high TB number was an independent risk factor for lymph node metastasis. In addition, in the patients, who met the indications for endoscopic resection and developed lymph node metastasis, the association of a high number of TB with lymph node metastasis was examined. Results: TBs were observed in 63.4% (128/202) of intestinal-type early gastric adenocarcinomas. Using ROC curve, 4 TBs was found as the optimal cutoff value to predict lymph node metastasis (area under the curve 0.767; sensitivity 0.657; specificity 0.780). Therefore, the 202 cases were divided into two groups: the high-budding (≥4 TBs) group (n=60) and the low-budding (<4 TBs) group (n=142). The high-budding group exhibited a higher rate of lymph node metastasis than that of the low-budding group (41.7% vs 9.1%, P<0.01), and ≥4 TBs was associated with deeper invasion and lymph vessel invasion (P<0.01). The multivariate regression model showed that ≥4 TBs was an independent risk factor for lymph node metastasis (Hazard ratio=8.760, 95%CI 2.648-28.987; P<0.01). Meanwhile, 4 TBs as the cutoff value could better predict lymph node metastasis than the cutoff value advised by the ITBCC. In addition, 3 cases were found to have developed lymph node metastasis even that they met the expanded indications for endoscopic resection, and 2 of these 3 cases exhibited a higher TB number (≥4 TBs). Conclusions: More than 4 TBs are a useful indicator for predicting lymph node metastasis in intestinal-type early gastric adenocarcinoma. It may be used to as an endoscopic resection criterion for patients with a high risk of lymph node metastasis.

Tumor budding was suggested as a valuable prognostic factor in oral squamous cell carcinoma (OSCC) but lacks a standardized scoring system. This study evaluates tumor budding in OSCC using the scoring system recommended by the International Tumor Budding Consensus Conference (ITBCC) 2016. The study included 114 patients with resected OSCC. Tumor budding was evaluated according to ITBCC criteria and assigned to three categories (low, intermediate, and high tumor budding). The associations between tumor budding and clinicopathological parameters were examined and survival rate analyses were performed by the Kaplan-Meier method. The prognostic value of tumor budding was assessed by Cox regression analysis. Significant correlations of tumor budding with clinicopathological parameters including lymph node metastasis, grade, stage, perineural and lymphovascular invasion, and local recurrence were found. Intermediate and high tumor budding were significantly and independently associated with worse disease-free survival. High tumor budding was identified as an independent prognostic factor for disease-specific and overall survival. The ITBCC scoring system represents a simple, feasible, and reproducible method to evaluate tumor budding in OSCC. Tumor budding, according to ITBCC criteria, showed its prognostic value in resected OSCC, and its incorporation into the histopathological reporting guidelines should be considered.

Validation of the International Tumor Budding Consensus Conference 2016 recommendations on tumor budding in stage I-IV colorectal cancer

Aim: In our study, we aimed to reveal the effect of tumor budding(TB) on prognosis in urothelial carcinomas and to compare the most commonly used alternative method (AM) and the International Tumor Budding Consensus Conference (ITBCC) system. TB can be easily assessed on routine hematoxylin and eosin-stained slides. In studies, TB was found to be associated with prognostic parameters in many organs. TB assessment in many organ cancers is based on ITBCC or alternatively different values used by different authors. Material and Method: Forty-eight urothelial cancers were obtained from 2010 to 2016 that was comprised of those having undergone surgical staging with a cystectomy or cystoprostatectomy and at least 5 years followed up. All hematoxylin and eosin-stained slides were re-evaluated for the status of TB according to ITBCC and AM. Results: According to ITBCC TB was not correlated with pT, lymphovascular invasion, lymph node involvement (LNI), tumor stage and 5-year mortality (p=0.102, p=0.722, p=0.165, p=0.431, p=0.524). According to AM, TB was more frequent as pT advanced, and was marginally associated with LNI (p=0.027, p=0.058). There was no relationship between TB and overall survival (p=0.130). Conclusion: We found the cut-off value in AM more useful than ITBCC recommendations. Although the association of TB with some of the prognostic parameters suggests that it may also be associated with prognosis, no relationship was found with overall survival. This may be related to the number of our cases.

Tumor budding (TB), a histopathological manifestation of epithelial-mesenchymal transition, is an important step in cancer invasion and metastasis development. TB has been considered a strong prognostic indicator in colorectal cancer. The International Tumor Budding Consensus Conference (ITBCC) scoring system is the standardized method used for patient outcome prediction in several human tumors. We investigated the clinicopathological implications and applicability of TB measured using the ITBCC scoring system in gallbladder cancer (GBC). The TB grades assigned to the 78 GBC patients were as follows: Bd1 (low TB), 41 (52.6%) patients; Bd2 (intermediate TB), 22 (28.2%) patients; and Bd3 (high TB), 15 (19.2%) patients. A higher TB grade correlated with a poorer histological differentiation (P< 0.000), higher pT category (P< 0.000), the involvement of surgical resection margin (P= 0.005), presence of nodal metastasis (P< 0.000), lymphatic and venous invasion (P< 0.000), and perineural invasion (P= 0.004). Univariate Cox regression analysis revealed that a poor histological grade, high pT category, lymphatic invasion, perineural invasion, and intermediate to high TB grades were associated with worse 5-year overall survival and disease-free survival. TB was not significantly associated with death or recurrence risk in multivariate Cox analysis. The interobserver agreement of TB grading was substantial. This study is the first to apply the ITBCC scoring system and suggest the prognostic value of TB in GBC.

Breast cancer is one of the most common cancers globally, with an increasing incidence rate. It is a heterogeneous disease, and early metastasis remains a challenge. Tumor budding, defined as single tumor cells or small clusters at the invasive front, has been suggested as a prognostic marker in various cancers, including breast cancer. This study aims to evaluate tumor budding in invasive breast carcinoma using the International Tumor Budding Consensus Conference (ITBCC) scoring system and explore its association with pathological characteristics and prognosis. A retrospective study was conducted on 100 mastectomy specimens of histopathologically confirmed invasive breast carcinoma, excluding cases that underwent chemotherapy or radiotherapy. Tumor budding was classified as low, intermediate, or high based on the ITBCC scoring method, and associations with clinicopathological features were analyzed using appropriate statistical tests. Tumor budding was classified as high in 52% of cases. A significant association was found between high tumor budding and higher tumor grade (P<0.001), negative estrogen receptor and progesterone receptor status (P<0.001), positive HER2neu status (P=0.003), and high Ki-67 levels (P<0.001). High tumor budding was also linked to higher T stage, and dermal lymphovascular invasion (P=0.001). Our findings support previous studies showing that high tumor budding is associated with poor prognostic factors such as higher tumor grade, negative hormone receptor status, and higher T stage. Tumor budding is a potential prognostic marker in breast cancer, associated with more aggressive tumor characteristics.

Tumour budding in colorectal cancer, defined as single tumour cells or small clusters containing four or fewer tumour cells, is a robust and independent biomarker of aggressive tumour biology. On the basis of published data in the literature, the evidence is certainly in favour of reporting tumour budding in routine practice. One important aspect of implementing tumour budding has been to establish a standardised and evidence-based scoring method, as was recommended by the International Tumour Budding Consensus Conference (ITBCC) in 2016. Further developments have aimed at establishing methods for automated tumour budding assessment. A digital approach to scoring tumour buds has great potential to assist in performing an objective budding count but, like the manual consensus method, must be validated and standardised. The aim of the present review is to present general considerations behind the ITBCC scoring method, and a broad overview of the current situation and challenges regarding automated tumour budding detection methods.