International Tumor Budding Consensus Conference Research Articles

Differential effect of tumor budding on the benefit of adjuvant chemotherapy in stage II colorectal cancer: a retrospective observational study.

Tumor budding (TB) has been shown to be a poor prognostic indicator after colorectal cancer (CRC) surgery. The aim of the present study is to evaluate the predictive role of morphological features (e.g., the number, structure, and location of tumor buds, and their reaction with the extracellular mesenchyme) in postoperative adjuvant chemotherapy in surgically resectable stage II CRC. Between 2016 and 2019, 336 patients with stage II CRC who underwent radical surgery were enrolled in this study. TB status was determined according to the criteria adopted at the 2016 International Tumor Budding Consensus Conference (ITBCC). We retrospectively recorded all the clinical and pathological data and assessed the effect of different types of TB status on patients' recurrence-free survival (RFS) and overall survival (OS). Of the 336 patients, 173, 88, and 75 were budding grade 1 (BD1), BD2, and BD3, respectively. The 5-year RFS rates were 84.6%, 81.2%, and 68.0% (P=0.01), and the 5-year OS rates were 91.0%, 83.3%, and 76.2% (P=0.007) in BD1, BD2, and BD3, respectively. TB grade was strongly associated with vascular invasion status and mucinous adenocarcinoma, and BD3 was detected in 51.7% of patients with positive vascular invasion. The multivariate analysis showed that only age, perineural invasion, and TB grade [BD2 vs. BD1, hazard ratio (HR) =1.468, 95% confidence interval (CI): 0.703-3.063, P=0.30; BD3 vs. BD1, HR =2.310, 95% CI: 1.154-4.625, P=0.01] had an independent effect on RFS. In addition, the Kaplan-Meier curve analysis showed that BD3 patients had the worst RFS (P=0.01). The OS of the adjuvant chemotherapy group was significantly improved compared to that of the surgery-only group in the BD1/2 patients (HR =0.278, 95% CI: 0.114-0.676, P=0.005) but not in the BD3 patients with significant interaction (Pinteraction=0.03). Our results indicate that TB could play a subsidiary role in selecting stage II CRC patients who could achieve a favorable prognosis with chemotherapy.

Immunohistochemical analysis of tumor budding in stage II colon cancer: exploring zero budding as a prognostic marker.

Tumor budding, a biomarker traditionally evaluated using hematoxylin and eosin (H&E) staining, has gained recognition as a prognostic biomarker for stage II colon cancer. Nevertheless, while H&E staining offers valuable insights, its limitations prompt the utilization of pan-cytokeratin immunohistochemistry (IHC). Consequently, this study seeks to evaluate the prognostic significance of tumor budding using IHC in a contemporary cohort of stage II colon cancer patients, aiming to deepen our understanding of this critical facet in cancer prognosis. We conducted a retrospective, population-based cohort study including 493 patients with stage II colon cancer and evaluated tumor budding using IHC, following the H&E-based guidelines proposed by the International Tumor Budding Consensus Conference Group. Correlation between H&E-based and IHC-based tumor budding was assessed using a four-tiered scoring system that included a zero budding (Bd0) category. Survival analyses explored the prognostic significance of tumor budding assessed by IHC and H&E. As expected, IHC-based tumor budding evaluation yielded significantly higher bud counts compared to H&E (p < 0.01). Interestingly, 21 patients were identified with no tumor budding using IHC. This was associated with significantly improved recurrence-free survival (HR = 5.19, p = 0.02) and overall survival (HR = 4.47, p = 0.04) in a multivariate analysis when compared to tumors with budding. The Bd0 category demonstrated a 100% predictive value for the absence of recurrence. In conclusion, IHC-based tumor budding evaluation in stage II colon cancer provides additional prognostic information. The absence of tumor budding is associated with a favorable prognosis and may serve as a potential marker for identifying patients with no risk of recurrence.

Tumor budding -a potential biomarker in low grade salivary gland carcinomas?

Low-grade salivary gland carcinoma is regularly treated with surgical therapy of the salivary gland without elective neck dissection in T1/2 carcinomas, either alone or with adjuvant radiation therapy. However, occult metastasis and locoregional recurrence influence therapy and outcome. Tumor budding is an emerging prognostic pathological factor in many carcinomas, but has not yet been adequately considered in salivary gland carcinomas. We conducted a retrospective single-center study of 64 patients diagnosed with low-grade carcinoma of the major salivary glands treated between 2003 and 2017. Pathological risk factors and TNM classification were thoroughly assessed for each case. All hematoxylin and eosin (HE)-stained histological specimens underwent careful examination, and tumor budding was identified following the guidelines set forth by the International Tumor Budding Consensus Conference in 2016. Tumor budding was not statistically significant concerning 5-year survival rate (5-YSR) (p=0.969) and mean overall survival (log-rank p=0.315). Whereas 5-year disease-free survival rate (5-YDFSR) was 87% in the low tumor budding group and 61.1% in the intermediate and high tumor budding group (p=0.021). Mean disease-free survival accounted for 100.2 months (CI: 88.6;111.9) in the low budding score group and 58.7 months (CI: 42.8;74.6) in the other group (log-rank p=0.032). Notably, pT1/2 showed significantly lower tumor buds than pT3/4 stages (2.43 tumor buds/0.785 mm2 vs. 4.19 tumor buds/0.785 mm2, p=0.034). Similar findings were noted comparing nodal-positive and nodal-negative patients, as well as patients with and without lymphovascular invasion and perineural invasion (each p<0.05). Tumor budding might be used as an additional prognostic factor for recurrence in low-grade salivary gland carcinoma, seemingly associated with a higher nodal metastasis rate and advanced tumor stages and a worse 5-YDFSR. Consequently, the evaluation of tumor budding in resection specimens of low-grade salivary gland tumor may prove valuable in decision-making for neck dissection and follow-up strategy.

Tumor budding is a meaningful prognostic marker in patients with hepatocellular carcinoma after curative hepatectomy

AbstractAimTumor budding (TB) has excellent prognostic value in many solid tumors, but there is little research on it in hepatocellular carcinoma (HCC). This study assessed the prognostic value of TB in patients with HCC who received hepatectomy.MethodsThis retrospective study included 210 patients with HCC who received curative hepatectomy at the First Affiliated Hospital of Xi'an Jiaotong University, between 2016 and 2018. TB was evaluated on hematoxylin‐ and eosin‐stained slides according to the criteria established by the 2016 International Tumor Budding Consensus Conference. t‐tests, Chi‐squared tests, and rank‐sum tests were used to correlate the extent of TB with clinicopathological parameters. Prognostic analysis was performed using Cox regression models and the Kaplan–Meier method.ResultsThe positive detection rate of TB was 45.2% (95/210) in 210 patients with HCC. Patients positive for TB always exhibit lower tumor differentiation, higher hepatitis B virus DNA levels, and more severe liver fibrosis. Multivariate Cox analysis identified TB (hazard ratio [HR]: 2.232, 95% confidence interval [CI]: 1.479–3.368, p &lt; 0.001) as an independent prognostic factor for patients' recurrence‐free survival (RFS), similar to tumor size (HR: 1.070, 95% CI: 1.070–1.142, p = 0.042) and satellite nodule (HR: 2.266, 95% CI: 1.298–3.956, p = 0.004). Kaplan–Meier analysis also demonstrated that TB‐positive patients had a significantly worse RFS. Interestingly, subgroup analysis revealed that among HCC patients with negative microvascular invasion (MVI), TB was also strongly associated with RFS (HR: 3.206, 95% CI: 1.667–6.168, p &lt; 0.001). These findings suggest that TB may serve as a supplemental prognostic biomarker for HCC‐negative MVI.ConclusionsTB is an adverse prognostic biomarker for HCC, particularly in patients negative for MVI. TB evaluation should be considered in the postoperative pathological examination of HCC in clinical practice.

The radiomorphological appearance of the invasive margin in pancreatic cancer is associated with tumor budding

PurposePancreatic cancer (PDAC) is characterized by infiltrative, spiculated tumor growth into the surrounding non-neoplastic tissue. Clinically, its diagnosis is often established by magnetic resonance imaging (MRI). At the invasive margin, tumor buds can be detected by histology, an established marker associated with poor prognosis in different types of tumors.MethodsWe analyzed PDAC by determining the degree of tumor spiculation on T2-weighted MRI using a 3-tier grading system. The grade of spiculation was correlated with the density of tumor buds quantified in histological sections of the respective surgical specimen according to the guidelines of the International Tumor Budding Consensus Conference (n = 28 patients).Results64% of tumors revealed intermediate to high spiculation on MRI. In over 90% of cases, tumor buds were detected. We observed a significant positive rank correlation between the grade of radiological tumor spiculation and the histopathological number of tumor buds (rs = 0.745, p < 0.001). The number of tumor buds was not significantly associated with tumor stage, presence of lymph node metastases, or histopathological grading (p ≥ 0.352).ConclusionOur study identifies a readily available radiological marker for non-invasive estimation of tumor budding, as a correlate for infiltrative tumor growth. This finding could help to identify PDAC patients who might benefit from more extensive peripancreatic soft tissue resection during surgery or stratify patients for personalized therapy concepts.

The prognostic value of tumor budding in a thoroughly characterized stage II colon cancer population in the context of a national screening program

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.

Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer.

Tumor budding (TB) has emerged as a promising independent prognostic biomarker in colorectal cancer (CRC). The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC. However, existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies. Consequently, this study investigated the correlation among TB categories, clinicopathological features, and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification. To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC. The clinical data of 547 CRC patients were collected for this retrospective study. Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines. Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy (P = 0.004), clinical stage IV (P < 0.001), ≥ 4 regional lymph node metastases (P = 0.004), left-sided colonic cancer (P = 0.040), and Bd 2-3 (P = 0.002) were independent prognostic factors in patients with stage III-IV CRC. Moreover, the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3, both in the tumor stroma and its invasive margin. TB has an independent predictive prognostic value in patients with stage III-IV CRC. It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Effects of tumour budding on adjuvant chemotherapy in colorectal cancer.

High tumour budding has been indicated as a risk factor of poor survival in colorectal cancer. This study aimed to investigate the impact of tumour budding grades and the use of adjuvant chemotherapy on prognosis in patients with colorectal cancer. This study included consecutive colorectal cancer patients who underwent radical surgery for primary colorectal adenocarcinoma at The Sixth Hospital of Sun Yat-sen University between 2009 and 2019. Tumour budding was assessed based on the recommendations of the International Tumor Budding Consensus Conference using haematoxylin and eosin (H&E)-stained slides with tumour samples. The primary outcome of interest was to correlate tumour budding with disease-free survival and overall survival; the secondary outcome was investigation of the impact of adjuvant therapy on different tumour budding grades. In addition, a subgroup analysis was performed for the effects of lymphocytic infiltration on adjuvant chemotherapy in patients with Bd3. Of 709 eligible patients, 412 with colorectal cancer were included. According to the International Tumor Budding Consensus Conference, 210 (50.9 per cent), 127 (30.8 per cent) and 75 (18.2 per cent) were classified as low budding (Bd1), intermediate budding (Bd2) and high budding (Bd3) respectively. Patients with Bd1, Bd2 and Bd3 had 5-year disease-free survival rates of 82.9 per cent, 70.1 per cent and 49.3 per cent respectively, and 5-year overall survival rates of 90 per cent, 79.5 per cent and 62.7 per cent respectively (P <0.001). Adjuvant chemotherapy yielded a significant survival benefit in patients with Bd3 (5-year disease-free survival, 65 per cent versus 31.4 per cent, P <0.001; 5-year overall survival, 84.4 per cent versus 63.1 per cent, P <0.001), but not in those with Bd1 or Bd2. In patients with Bd3, the benefit of adjuvant chemotherapy was maintained in those with low, but not high lymphocytic infiltration. High grade of tumour budding was strongly correlated with poorer survival outcomes in colorectal cancer. Patients with Bd3 benefited from adjuvant chemotherapy, with the exclusion of patients with high lymphocytic infiltration.

Prognostic significance of tumor budding in patients with pancreatic invasive ductal carcinoma who received neoadjuvant therapy

Neoadjuvant therapy is commonly used for invasive pancreatic ductal carcinoma (PDAC). Tumor budding and high podoplanin expression in cancer-associated fibroblasts (CAFs) are prognostic factors in patients with various carcinomas including PDAC who have not received neoadjuvant therapy. In this study, we investigated whether tumor budding and podoplanin-positive CAFs are associated with outcomes in Japanese PDAC patients with neoadjuvant therapy. Histopathological findings of surgically resected PDACs with neoadjuvant therapy from 2005 to 2018 were reviewed (n = 97). With reference to International Tumor Budding Consensus Conference recommendations, tumors were evaluated for budding at 20 × magnification (/0.785 mm2) and at 40 × magnification (/0.237 mm2; mean number of fields: 3) for podoplanin expression in CAFs (%). Overall survival, disease-free survival, and disease-specific survival (DSS) were analyzed using the log-rank test and Cox proportional hazards model. After adjusting for T category, N category, resection margin, and adjuvant therapy, multivariate analyses demonstrated that tumor budding at 40 × magnification was an independent prognostic factor for worse DSS (hazard ratio: 2.41, p = 0.022). Tumor budding at 20 × magnification and podoplanin-positive CAFs tended to be associated with worse DSS; however, these findings were not statistically significant. Our findings indicate that tumor budding is an independent prognostic factor in PDAC patients with neoadjuvant therapy.

Prognostic Significance of Intratumoral and Peritumoral Budding in Distal Extrahepatic Bile Duct Carcinoma

Introduction: Although tumor budding (TB) has been recognized as a representative adverse prognosticator in gastrointestinal malignancies, it is not well elucidated in distal extrahepatic bile duct carcinoma (DBDC). Herein, we investigated the prognostic significance of peritumoral (PTB) and intratumoral (ITB) budding according to the modified DBDC staging of the 8th edition of the American Joint Committee on Cancer. Methods: PTB and ITB were independently evaluated in a cohort of DBDC patients (n = 410) based on the 2016 International Tumor Budding Consensus Conference. Results: High levels of PTB (PTBHigh, ≥ grade-2) and ITB (ITBHigh, ≥ grade-3) were identified in 316 (77%) and 238 (58%) cases, respectively. In univariate analysis, PTBHigh and ITBHigh, larger size and sclerosing tumor growth pattern, higher histologic grade, extrapancreatic location, adenocarcinomas unrelated to intraductal papillary neoplasm of the bile duct, pancreatic, duodenal, and lymphovascular invasion, perineural invasion, cancer involvement of the bile duct resection margin, nodal metastasis, and higher T and N categories and disease stages were associated with shorter patient overall survival (OS) times. In multivariate analysis, PTBHigh and ITBHigh remained poor independent prognostic indicators of OS in DBDC patients. Specifically, ITBHigh could predict poor prognosis in patients with stage I (T1N0) DBDC. Conclusions: Both PTBHigh and ITBHigh were strong prognostic indicators in patients with DBDC. Thus, ITB could be used to predict worse prognoses in patients with DBDC, in which PTB is difficult to assess, especially for patients with stage I (T1N0) DBDC.

Tumor Budding Assessment in Colorectal Carcinoma: Normalization Revisited.

Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.785mm 2 ) rather than objective lens and a normalization factor is applied for this purpose. However, the validity of this approach is yet to be tested. We sought to validate the ITBCC method with a particular emphasis on normalization as a tool for standardization. In a cohort of 365 stage I-III CRC, both normalized and non-normalized TB were significantly associated with disease-specific survival and recurrence-free survival ( P <0.0001). Examining both 0.95 and 0.785mm 2 field areas in a subset of patients (n=200), we found that normalization markedly overcorrects TB counts: Counts obtained in a 0.95mm 2 hotspot field were reduced by an average of 17.5% following normalization compared with only 3.8% when counts were performed in an actual 0.785mm 2 field. This resulted in 45 (11.3%) cases being downgraded using ITBCC grading criteria following normalization, compared with only 5 cases (1.3%, P =0.0007) downgraded when a true 0.785mm 2 field was examined. In summary, the prognostic value of TB was retained regardless of whether TB counts in a 0.95mm 2 field were normalized. Normalization resulted in overcorrecting TB counts with consequent downgrading of most borderline cases. This has implications for risk stratification and adjuvant treatment decisions, and suggests the need to re-evaluate the role of normalization in TB assessment.

Relationship of HER2 with age, gender, location of the tumor, and tumor budding in colorectal adenocarcinoma at H. Adam Malik General Hospital, Medan, Indonesia

Link of Video Abstract: https://youtu.be/_B_bL8gi7hU Background: Colorectal carcinoma is one of the most common malignancies and is one of the leading causes of cancer-related death worldwide. The incidence of colorectal carcinoma in Indonesia is reported to be 12.8 per 100,000 adult population, accounting for 9.5% of all cancer-related deaths. Assessment of Human Epidermal Growth Factor Receptor 2 (HER2) expression is used to help predict tumor behavior and the effect of anti-HER2 receptor therapy. This study aims to analyze the relationship between HER2 immunohistochemical expression with age, gender, tumor location, and tumor budding in this malignancy. Methods: This study is a cross sectional analytic study of 45 samples diagnosed with colorectal carcinoma at H. Adam Malik General Hospital Medan. Tumor budding was assessed for tumor invasiveness based on the International Tumor Budding Consensus Conference (ITBCC) 2016 in a field area of ​​0.785 mm2 with a 20x objective lens using a three-level scoring system, which was categorized into low budding (0-4 buds), intermediate budding (5-9 buds), and high budding (≥10 buds). Staining was performed using immunohistochemistry of the monoclonal anti-human HER2 anti-human DBS manufacturer, which would appear positive on the tumor cell membrane at a dilution of 1:100. HER2 expression was assessed using the HERACLES criteria. The results are presented as a score of 0, 1+, 2+, 3+, then categorized into negative (score 0-2+) and positive (score 3+). Data were analyzed using SPSS version 25.0 for Windows. Results: There was no significant relationship between HER2 and clinicopathological parameters such as age (p=0.755), gender (p&gt;0.05) and tumor location (p&gt;0.05). However, there was a significant relationship between HER2 and tumor budding histopathological parameters with a value of p=0.011 in a positive direction (the greater the number of budding, the more positive HER2 expression, and vice versa). Conclusion: HER2 is not significantly related to age, gender and tumor location. However, it is significantly associated with tumor budding. HER2 plays a role in the proliferation and differentiation of colorectal carcinoma tumor cells.

Tumor budding in colorectal adenocarcinoma using cytokeratin 20 immunostaining

Introduction: Colorectal cancer is the third most common cancer worldwide and second most common fatal cancer. Tumor budding is an emerging prognostic indicator in cancers. Though tumor budding can be assessed using Hematoxylin and Eosin stain, sometimes peritumoral inflammation and reactive stromal fibrosis obscures the tumor buds. The present study aimed to assess tumor budding using cytokeratin 20 immunohistochemistry in colorectal cancers. Methods: This is a cross sectional study which included 30 cases of colorectal carcinomas. cytokeratin 20 stained slides of colorectal carcinoma were assesed for tumor budding using International Tumor Budding Consensus Conference (ITBCC) 2016 consensus criteria and compared with AJCC cancer stage. Results: Demographic analysis showed peak incidence of colorectal cancer in the age group of 55-64 years (33.3%) and male: female ratio of 1.14:1. Majority of the tumors with score 1(23.3%) showed stage I. While tumors with score 2 had similar incidence of stage I (16.6%) and II (16.6%) and lesser incidence of stage III (3.33%). Most of the tumors with score 3 tumor budding had stage III tumors (26.67%). The p value is &lt; 0.0001, which is statistically significant. Tumor budding signifies the biological and molecular phenomenon of epithelial-mesenchymal transition in the tumor microenvironment. Loss of E-cadherin, alterations in transcription factors including SNAIL, ZEB, TWIST etc and switching of CMS2 to CMS4 are some of the recorded molecular profiles responsible for tumor budding. Conclusion: This study concludes that the tumor stage increases with tumor budding and thus is a reliable marker in predicting the prognosis. This study also states that immunohistochemical study gives objective scoring of tumor buds in colorectal cancers. Keywords: tumor budding; colorectal cancer; cytokeratin 20; prognostic marker

The relationship between microsatellite instability in colorectal adenocarcinoma and tumor budding and histopathological parameters.

This study aims to investigate the correlation between the presence of microsatellite instability (MSI) and tumor budding, as well as their relationship with histopathological parameters in patients diagnosed with colorectal adenocarcinoma. The study encompassed patients who underwent curative surgery to treat colorectal cancer. These patients were classified into groups based on their MSI status. The International Tumor Budding Consensus Conference (ITBCC) 2016 guidelines were utilized to identify tumor budding. Demographics, clinical data, tumor budding, and histopathological attributes were assessed across study groups. The study analyzed 268 patients, out of which 32 (11.9%) were identified as having MSI. Microsatellite Stable (MSS) patients were placed in Group 1, and those with MSI were classified into Group 2. The average age was lower in Group 2 compared to Group 1 (55.9 years vs. 61.4 years, p=0.034). Tumor localizations in the caecum (5.9% vs. 18%) and the ascending colon (11.9% vs. 25%) were more prevalent in Group 2 (p=0.019). The occurrence of tumor budding (75% vs. 62.5%, p=0.133) and the budding degree in those with tumor budding were comparable between the groups. Poorly differentiated tumors were more prevalent in Group 2 (5.5% vs. 25%, p=0.001). Additionally, the tumor diameter was larger in Group 2 (3.58 cm vs. 4.35 cm, p=0.007). MSI is a significant biomarker, possessing diagnostic, prognostic, and predictive value in colorectal cancer (CRC). Understanding the connection between MSI and tumor budding in CRC may provide clinicians with insights to enhance patient management.

Tumor budding as a predictor of disease-free survival in patients with cholangiocarcinoma.

Background: Tumor budding is considered a prognostic factor in several solid cancer types. However, we lack comprehensive information on the importance of tumor budding in cholangiocarcinoma. Therefore, we aimed to assess the prognostic value of tumor budding in intrahepatic and extrahepatic cholangiocarcinomas and to evaluate its correlations with other clinicopathological parameters. Methods: We monitored 219 patients who underwent surgery for intrahepatic or extrahepatic cholangiocarcinoma at the Pusan National University Hospital between 2012 and 2021. Tumor budding was evaluated using the International Tumor Budding Consensus Conference scoring system. Tumor budding was classified into low (0-4), intermediate (5-9), and high (≥10). For statistical analysis, tumor budding was divided into two groups based on the cut-off value of 10 (lower: 0-9 vs. higher: ≥10). The correlations between clinicopathological parameters were examined using the chi-square and Fisher's exact test. The prognostic values of the variables were analyzed using the log-rank test and Cox regression analysis. Results: Low, intermediate, and high tumor buddings were identified in 135 (61.6%), 63 (28.8), and 21 (9.6%), patients, respectively. Higher tumor budding was related to the presence of lymphatic invasion (p = 0.017), higher tumor grade (p = 0.001), higher N category (p = 0.034). In the univariable and multivariable analyses, higher tumor budding was associated with shorter disease-free survival in 97 (44.3%) patients who underwent R0 resection (p < 0.001 and p = 0.011). Tumor budding did not significantly correlate with disease-specific survival in entire patients. Conclusion: Tumor budding may serve as a prognostic factor for intrahepatic and extrahepatic cholangiocarcinomas treated with R0 resection.

The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma

ObjectiveTo evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). MethodsIn total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000–2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. Results60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. ConclusionTumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.

Prognostic value of tumor budding in patients with stage II and III colon cancer: A single-institution experience.

247 Background: Tumor budding has recently been recognized as one important prognostic factor for recurrence in patients with localized colon cancer. Nevertheless, not all guidelines consider tumor budding in the decision-making process for selecting patients for adjuvant chemotherapy. We aim to assess the prognostic value of tumor budding in a cohort of patients with stage II and III colon cancer. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz and tumor budding assessment available, from October 2016 to August 2021. Tumor budding was reported following the recommendations from the 2016 International Tumour Budding Consensus Conference. Results: A total of 390 patients were included. Patients were predominantly men (55%) and had a median age of 75 (35-95). Fifty percent of the patients were stage II and 50% were localized in the right colon. Tumor budding was reported as low, intermediate, and high in 186 (48%), 110 (28%), and 94 (24%) patients, respectively. After a median follow up of 18 months, 63 recurrences and 73 deaths were observed. Time to recurrence was significantly worse for patients with high tumor budding. At 24 months, 91%, 79%, and 67% of patients with low, intermediate and high budding were recurrence-free. Median TTR was not reached in any of the three cohort (P &lt;0.001). Comparing high vs low or intermediate budding, the hazard ratio (HR) for recurrence was 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P &lt; 0.001]. We performed a univariate analysis with the most relevant clinic-pathological features. T4, N2, R1, bowel obstruction or perforation, positive resection margins (R1), lymphovascular or perineural invasion, and mismatch repair protein status were found to be statistically associated with TTR and entered the multivariate analysis. T4, N2, R1 and high tumor budding (HR: 0.48 [CI95%: 0.28 to 0.84], P = 0.011) were independent prognostic factors for recurrence at the multivariate analysis. Conclusions: High tumor budding is an adverse independent prognostic factor for recurrence in patients with stage II and III colon cancer and should be acknowledge when considering adjuvant chemotherapy.

Evaluation and prognostic significance of tumor budding in pancreatic ductal adenocarcinomas.

In this study, it was aimed to investigate the prognostic importance of Tumor budding (TB) in Pancreatic ductal adenocarcinomas(PDAC) and its correlation with histopathological findings according to the International Tumor Budding Consensus Conference(ITBCC) grading. A total of 75 patients diagnosed with PDAC were included in this study. The demographic features of the cases (age, sex) and the macroscopic features of the tumors (localization,size) were obtained from the electronic archive system. All Hematoxylin-Eosin-stained sections were re-evaluated in terms of differentiation, presence of lymphovascular (LVI) and perineural invasion(PNI), surgical margin positivity, primary tumor(pT), lymph node metastasis(LNM) and tumor budding. Statistically, Chi-square test, cox-regression and Kaplan-Meier test were performed. Thirty four of the cases were female and 41 were male. The mean age was 64.21±9.71years. The degree of TB was TB-few in 17 cases, TB-moderate in 25cases, and TB-high in 33cases. LVI, PNI, LNM and TB-high were poor prognostic factors. Moreover, TB-high was related with poor differantiation,LVI,PNI,LNM and short survival time. Tumor budding was independent negative prognostic factor in multivariable model analyzes. ITBCC scoring can also be used in PDACs. In addition, high tumor budding was a poor prognostic feature and might be a target for tumor-specific treatments as it could be a predictive finding for the locally invasive character of the tumor. Evaluation and grading of TB thought to represent EMT may be a histological feature that can be used in tumor selection for advanced molecular methods to identify subtypes that may be associated with poor prognosis and drug resistance.

Prognostic Impact of Tumor Budding on Moroccan Gastric Cancer Patients.

Tumor budding (TB) has been defined as an independent prognostic factor in many carcinomas like colon adenocarcinoma, but its prognostic impact on gastric cancer patients remains not well established. In the present study, we aimed to highlight the correlation of tumor budding with clinicopathological features and predict its survival outcomes in gastric cancer patients for the first time in the Moroccan population. This study was conducted on 83 patients who underwent surgery for gastric adenocarcinoma from 2014 to 2020. The patient's clinico-pathological characteristics were obtained from the pathological and clinical records of each patient. Tumor budding was assessed on HES slides, according to the 2016 International Tumor Budding Consensus Conference criteria. The association of tumor budding grades with categorical and continuous variables were respectively assessed by the χ2-test and the unpaired t-test. Survival analysis was performed by the Kaplan-Meier method, the log-rank test. Patients consisted of 65.1% of men and 34.9% of women with a median age of 61.2 years. Histologically, the majority of the tumors were adenocarcinoma (65.1%). Among all cases, 18.1% were classified as Bud1 (15/83), (27/83) 32.5% as Bud 2, and 49.4% (41/83) as Bud 3 grades. High-grade tumor budding (BUD 3) was found to be significantly associated with special clinicopathological features including older age (P = .02), unradical resection (R1/R2) (P = .03), and the presence of vascular invasion (P = .05), and perineural invasion (P = .04). Furthermore, tumors with high-grade tumor budding were significantly associated with a low rate of resected lymph nodes (P = .04) and advanced TNM stage (P = .02). Among all stages, high-grade tumor budding was correlated with shorter overall survival in univariate and multivariate analysis (P = .04). Patients with high-tumor budding had worse relapse-free survival compared with patients with low-tumor budding grade (P = .01). According to our study, the high-tumor budding grade was correlated with unfavorable clinicopathological features and poorer survival. The present study findings suggest that tumor budding should be considered in the treatment and prognosis of gastric cancer patients.

High-yield areas to grade tumor budding in colorectal cancer: A practical approach for pathologists

BackgroundTumor budding (TB) has significant prognostic implication in stage II colorectal cancer (CRC) and is graded based on the International Tumor Budding Consensus Conference (ITBCC) protocol. In the current study, we evaluate tumor budding and its relationship to multiple histologic features in 104 tumors. MethodsOne-hundred four resected CRC cases were retrieved. Tumor bud count and TB grade were compared to the final tumor bud count/TB grade of the tumor per ITBCC protocol. The following high-yield co-features were assessed in each slide: highest T stage, presence of benign mucosa, presence of a precursor lesion, and highest tumor volume. ResultsTwenty-nine (28 %) cases had discrepancies between slide TB grade and final TB grade. The least discrepancies were seen in slides with benign mucosa (7 %) and precursor lesions (7 %). Among stage II patients without high-risk features, no discrepancies were observed in slides with benign mucosa. Slides with deepest invasion (rs = 1.000, p = 0.01) and benign mucosa (rs = 0.957, p < 0.001) had the strongest correlation with final tumor bud count in the same stage II subgroup. Similar relationships were observed when comparing final TB grade. Deepest invasion, tumor volume, as well as lymphovascular invasion, when present, also showed strong correlations with final TB grade in the entire cohort (rs = 0.828–0.845, p < 0.001). ConclusionOur study is the first study to evaluate the relationship between TB grade and co-existing histologic features. We highlight the benefit of focusing on slides with high-yield co-features, with the strongest correlation seen in slides with adjacent benign mucosa and precursor lesions.