Prognostic Significance Of Tumor Budding Research Articles

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.

Prognostic significance of tumor budding, desmoplastic reaction, and lymphocytic infiltration in patients with gastric adenocarcinoma

Prognostic significance of tumor budding, desmoplastic reaction, and lymphocytic infiltration in patients with gastric adenocarcinoma

Prognostic significance of tumor budding in pancreatic carcinoma: Digitalized image approach evaluation using artificial intelligence.

Introduction Pancreatic carcinoma (PC) is a highly malignant and lethal tumor characterized by a dismal prognosis which raised the need to identify other prognostic factors for better patient risk stratification. This study investigated the prognostic significance of tumor budding (TB) in pancreatic carcinoma using artificial intelligence. Methods In this retrospective multicenter study, we collected all cases of PC diagnosed (2008-2022). TB was assed using 2methods: manuel on hematoxylin-eosin (HE) slides and semi-automated using QUPATH software. The selected slide for each case was digitalized using NIS software version 4.00 connected to the microscope NIKON (Eclipse Ni-U). The pathological images were then incorporated into QUPATH. The budds were counted using cell count functionality based on the nucleus size and pixel variability, and TB scores were categorized as BUDD1(0-4), BUDD2(5-9) and BUDD3(≥10). We analyzed the association between the TB score and prognostic clinicopathological factors and overall survival. Results 25patients were included (mean age:62.3years;male-to-female ratio:2.57). TB was found in 100%of cases and a high TB score (BUDD2-3) was observed in 56%of cases (using QUPATH versus 48% using HE slides); statistical analysis showed no significant difference between the two methods(p=0.589). A high TB score was associated with older age(&gt;72 years), ductal histological subtype and advanced stage (pT&gt;2).53.8% of patients with lymph node metastasis or advanced stage had high TB score. Multivariate analysis revealed that TB score was strongly and independently associated with overall survival (OS), with a hazard ratio of 2.35. Conclusion TB is an additional prognostic factor in PC, and using artificial intelligence via QUPATH software offers a promising and accessible tool for pathologists to evaluate TB and to improve risk stratification in patients with PC.

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.

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 evaluation of tumour budding in oral squamous cell carcinoma: Evidenced by CD44 expression as a cancer stem cell marker

ObjectivesTumor budding is a sign of invasion and early step for metastasis of many cancers including oral squamous cell carcinoma (OSCC). Evidences suggest the presence of cancer stem cells in tumor buds. CD44 has been reported in tumor growth and metastasis as a cancer stem cell marker in OSCC. The study aims to highlight the prognostic significance of tumor budding in association with CD44 expression as a cancer stem cell marker in OSCC. MethodsA total of 60 radical neck dissection specimens of OSCC with and without lymph node metastasis were included in the study. The sections were evaluated for TB [Tumor Budding] in H&E and CD44 expression immunohistochemically. OSCC cases were then correlated with clinicopathologic and histomorphologic parameters such as age, gender, habit, site, staging, grading, recurrence, depth of invasion, pattern of invasion, and survival outcomes. Comparison of prognosis and CD44 expression were carried out by statistical methods. ResultsA high TB score was significantly correlated with grading (p = 0.037), POI [Pattern of invasion] (0.029), overall survival (p = 0.047). CD44 over expression showed strong correlations with POI (1HPF:p = 0.037;10HPF:p = 0.027), grading (p = 0.037), and overall survival (p = 0.047). Kaplan-Meier analysis revealed overall survival advantage for LTB [Low TB] (85 %) with OSCC compare to HTB [High TB] (75 %) for > 36 months. ConclusionAssessment of TB is effective in predicting prognosis of OSCC. Although CD44 expression has demonstrated strong prognostic influence, there were significant differences in its expression with the parameters.

Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients.

The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor-stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), "microcystic, elongated, fragmented" (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort (n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management.

The prognostic significance of tumor budding and the expression of focal adhesion kinase and survivin in lung adenocarcinoma

ObjectivesAdenocarcinoma is the tumor group with the highest incidence among lung cancers with poor prognosis. Tumor budding (TB) is the migration of single tumor cells or small clusters of cells from the neoplastic epithelium to the invasive front of the tumor. Focal adhesion kinase (FAK) and survivin are considered as poor prognostic factors in several tumors. Hence, we investigated TB, FAK, and survivin expression in lung adenocarcinoma. MethodsThe study included 103 cases of lung adenocarcinoma in the resection materials. In tumoral tissues; TB was counted and scored in one high-power field (HPF), as low if <5 in 1 HPF and high if ≥5 in 1 HPF. FAK and survivin were studied immunohistochemically. ResultsThe mean number of TB in 1 HPF is 3.96 ± 2.8. Low-grade TB was observed in 45 (43.7 %) and high-grade TB was observed in 58 (56.3 %) patients. There was a positive correlation between TB and pT stage (p = 0.017), clinical stage (p = 0.002), lymphovascular invasion (p = 0.001), and perineural invasion (p = 0.045). The 4-year survival rate in patients was 90 % in those with low-grade TB and 60 % in those with high-grade TB (p = 0.001). FAK and survivin expressions were significantly increased in tumors with high-grade TB (p < 0.05). ConclusionA significant correlation was found between the grade of TB and pT stage, clinical stage, lymphovascular and perineural invasion in lung adenocarcinoma. TB can be considered as a histological parameter showing poor prognosis. It is thought that high expression of FAK and survivin also affect the prognosis in these patients by increasing TB.

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.

Histomorphological Evaluation of Desmoplastic Tumor Stroma in Malignant Ovarian Surface Epithelial Tumors.

Ovarian cancer is the 8th most common cancer in women worldwide. Tumor budding is defined as a type of invasive growth in carcinomas with either a single tumor cell or a cluster of up to four cells at the invasive tumor front and is associated with epithelial-mesenchymal transition. A reactive stroma rich in cancer-associated fibroblasts is associated with higher tumor grade and poorer prognosis in breast, colorectal, and oral cancers. The present study was conducted to highlight the prognostic significance of tumor budding and fibrotic cancer stroma in malignant ovarian surface epithelial tumors with known prognostic parameters. This was a retrospective cross-sectional study conducted over a 2-year period, in which all histologically diagnosed cases of malignant ovarian surface epithelial tumors who underwent surgery were included. The fibrotic stroma was classified into three distinct categories - mature, intermediate, and immature. The number of tumor buds was counted at the invasive front of the tumor and graded based on the number of buds - 0-5, 5-9, and ≥10 buds. Among the 50 cases, 32% (16 cases) had mature stroma, whereas 30% (15 cases) and 38% (19 cases) had intermediate and immature stroma, respectively. Although a significant association could not be established between tumor budding and stroma grade, a fair agreement was established between them. A significant association could be established between histological grade with both tumor budding (P = 0.03) and fibrotic stroma grade (P = 0.02). The study highlighted the role of stromal response in malignant surface epithelial tumors of the ovary since a higher-grade tumor was associated with an immature stroma, whereas a lower-grade tumor was associated with a mature stroma.

Prognostic significance of tumor budding in melanoma

Cutaneous melanoma is an aggressive neoplasm with growing incidence and continuous research is undertaken for novel prognostic factors. This current research aims to determine if tumor budding is an independent factor that correlates with the survival of patients with melanoma. A total of 742 cases of melanoma were evaluated. A receiver operating curve (ROC) was performed to analyze tumor budding impact on survival, identifying a cutoff point associated with death. Subsequently, two groups of participants were created based on that result. Participants within the two groups were compared for clinicopathologic characteristics and survival analysis. Also, a multivariate analysis was performed. Of the total, 447 (60.2%) melanomas occurred in women and 295 in men. The mean age was 57.5 years + 15.75. The most common location was in acral areas (68.2%) followed by trunk (16.7%) and head and neck (15.1%). At presentation, 142 cases (19.1%) presented as stage I, 307 (41.4%) as stage II, 269 (36.3%) as stage III, and 24 (3, 2%) in stage IV. Regarding tumor budding, 586 (79%) cases showed tumor budding (at least one bud in 0.785 mm 2 ), with a median of 5. From the ROC curve, 4.5 tumor buds/0.785 mm 2 was the best cutoff point for correlation with death, grouping the series in low budding (0-4 buds/0.785 mm 2 ) and high budding ( > 5 buds/0.785 mm 2 ). Cases with high tumor budding were associated with older age, acral location, advanced clinical stages, ulceration, recurrence, and death. High tumor budding was associated with a significant decrease in 5-year overall survival (94.4% vs. 55.5%, P < 0.001). In the multivariate analysis, the factors remaining as independent predictors of survival were acral location, clinical stage IV, recurrence during clinical follow-up, and high tumor budding. High tumor budding (>5 buds in 0.785 mm 2 ) independently correlates with 5-year overall survival rates and is associated with older age, acral location, advanced clinical stages, ulceration, recurrence, and death.

Tumor Budding Assessment with Cytokeratin and Its Significance in Laryngeal Squamous Cell Carcinomas.

There is a need for novel prognostic parameters in assessing laryngeal squamous cell carcinoma (LSCC). Tumor budding is an instrumental parameter, which has hardly been studied before in this organ. This study aimed to assess tumor budding in LSCCs with routine hematoxylin and eosin (H&E) stain as well as cytokeratin (CK) immunohistochemistry (IHC). Objectives were to compare the effectiveness of both these methods to assess tumor budding, to investigate the association of tumor budding and clinicopathologic features, and to determine the prognostic significance of tumor budding in LSCCs. Fifty laryngectomy specimens were included. Tumor budding was counted (20x) on slides stained with IHC-CK, and highest count per slide was noted. The cases were classified as positive (> 1 buds) or negative (no buds present). The budding index was categorized as low (< 5 buds) or high (> 5 buds). Tumor budding on H&E was absent, low and high grade in 28%, 30% and 42% cases respectively, when compared to CK-IHC in 17%, 24% and 59% of cases, respectively. Presence of lymphoplasmacytic infiltration significantly correlated with tumor budding and higher grade. Transglottic location of tumor and pT stage was associated with high budding. Presence of lymphoplasmacytic infiltrate significantly correlated with worse prognosis. Tumor budding, an easily assessable, inexpensive histopathologic parameter has seldom been studied in LSCCs. Presence of lymphoplasmacytic infiltrate in routine preoperative biopsy reporting could be useful in prognostication. CK-IHC is helpful to detect especially cases with low-grade tumor budding.

Prognostic significance of tumor budding, poorly differentiated cluster, and desmoplastic reaction in endometrioid endometrial carcinomas

The tumor budding (TB); poorly differentiated cluster (PDC); desmoplastic reaction (DR); and microcystic, elongated, and fragmented (MELF) patterns of invasion are pathological findings at the tumor invasion front associated with epithelial-to-mesenchymal transition. This study aimed to clarify the clinical significance of the TB, PDC, DR, and MELF patterns in endometrioid endometrial carcinomas (EEC). Two hundred and eight cases of histologically proven EEC retrieved from the archives of the Department of Pathology, Fukui Prefectural Hospital, and diagnosed between January 2000 and August 2020 were retrospectively analyzed. The TB, PDC, DR, and MELF patterns were identified in 29 (13.9%), 47 (22.6%), 45 (21.6%), and 23 (11.1%) cases, respectively. Kaplan-Meier curve analysis with log-rank test demonstrated that TB, PDC, and DR were associated with a lower progression-free survival (p=0.010, 0.002, and <0.0001, respectively), whereas the MELF pattern did not show any association (p=0.668). In multivariate analyses, only DR was significantly associated with lower progression-free survival (p=0.034). Moreover, only PDC was associated with lower overall survival in univariate analysis (p=0.018), but the association lost significance in multivariate analysis. The present study revealed that the histological confirmation of TB, PDC, and DR at the tumor invasive front predicts poor prognosis in EEC. However, the MELF pattern was not a predictor of poor prognosis in EEC.

Prognostic significance of tumor budding in muscle invasive urothelial carcinomas of the urinary bladder

ObjectiveThe aim of the present study was to analyze the prognostic significance of tumor budding in muscle-invasive urothelial carcinomas of the urinary bladder, and also to determine an optimal threshold value in evaluation. Patients and methodsThe study included 108 patients diagnosed with muscleinvasive conventional urothelial carcinoma between 2010 and 2020. Tumor budding was evaluated on H&E-stained slides. The critical tumor budding number was determined with the “receiver operating characteristics (ROC)” curve. Cases with a tumor budding number of ≤6 were categorized as low, and cases with >6 as high tumor budding. ResultsThe univariate Cox proportional hazards regression model for recurrence-free survival showed that lymphovascular invasion (P = 0.001), tumor budding (P = 0.012), pT stage (T4 vs. T2) (P = 0.005), and lymph node metastasis (P = 0.009) were significantly associated with recurrence-free survival. The multivariate Cox proportional hazards regression model utilizing backward stepwise (wald) method revealed that only LVI (P = 0.001) was independent risk factor for recurrence-free survival. The univariate Cox analysis showed that lymphovascular invasion (P = 0.001), tumor budding (P = 0.004), pT stage (T4 vs. T2) (P = 0.003), and lymph node metastasis (P = 0.001) were significantly associated with overall survival. The multivariate Cox analysis (backward stepwise (wald) method) revealed that tumor focality (P = 0.018), pT stage (T4 vs. T2) (P = 0.015), and lymphovascular invasion (P = 0.002) were independent factors for overall survival. ConclusionsOur findings suggested that the evaluation of tumor budding may be a useful parameter for predicting outcome in patients with muscle-invasive bladder cancer.

Joint Tumor Bud-MMP/TIMP Count at the Invasive Front Improves the Prognostic Evaluation of Invasive Breast Carcinoma.

Background: Tumor budding is a histological phenomenon consisting of the formation of small clusters of one to five undifferentiated malignant cells detached from the main tumor mass which are observed in the tumor stroma. In the present study, we investigated the prognostic significance of tumor budding in breast cancer and its relationship with the expressions of matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs). Methods: The number of buds was counted in whole-tissue sections from 153 patients with invasive ductal carcinomas who underwent a long follow-up period. In addition, an immunohistochemical study of MMP-9, -11, and -14 TIMP-1 and -2 expression by cell types at the invasive tumor front was carried out. Results: There was a wide variability in the number of buds among tumors, ranging from 0 to 28 (median = 5). Tumor budding count ≥ 4 was the optimal cut-off to predict both relapse-free and overall survival. High-grade tumor budding was associated with MMP/TIMP expression by cancer-associated fibroblasts. In addition, we found that the combination of tumor budding grade with MMP/TIMP expression by stromal cells, and especially with MMP-11 expression by mononuclear inflammatory cells, significantly improved the prognostic evaluation. Conclusion: High-grade tumor budding is associated with a more aggressive tumor phenotype, which, combined with MMP/TIMP expression by stromal cells at the invasive front of the tumor, identifies patients with poor prognosis.

Tumor budding in upper urinary tract urothelial carcinoma: a putative prognostic factor for extraurothelial recurrence and overall survival.

Tumor budding, defined as a single cancer cell or clusters of fewer than five cancer cells observed at the tumor invasion front, has been reported to be associated with poor prognosis in various types of cancers. However, limited information regarding the pathological and prognostic significance of tumor budding in upper urinary tract urothelial carcinoma (UUTUC) is available. We investigated 135 consecutive patients with newly diagnosed invasive UUTUCs (73 with renal pelvic cancers and 62 with ureteral cancers) treated with nephroureterectomy or partial ureterectomy between 1999 and 2018 in our hospital. Under a × 200 magnification, tumors with 10 or more budding foci were defined as "high tumor budding". The median follow-up period was 53.6months. Among the 135 patients, 41 (30%; 16 with renal pelvic cancers and 25 with ureteral cancers) showed high tumor budding. High tumor budding was related to adjuvant chemotherapy status, higher pathological T stage, lymphovascular invasion, lymph node metastasis, tumor location, concomitant variant histology, and non-papillary gross finding. The multivariate Cox analysis revealed that LVI and high tumor budding were independent predictors for extraurothelial recurrence (P = 0.039 and 0.014, hazard ratio = 2.50 and 2.88, respectively), and high tumor budding was an independent predictor for overall survival (P = 0.024, hazard ratio = 2.33). Tumor budding can be easily introduced in clinical practice with no need for immunohistochemical analysis, may be an important clinicopathological factor of UUTUC, and is suggested to be useful as a novel predictive prognostic factor of patients with invasive UUTUC.

Predictive significance of tumor budding in postoperative liver metastasis of pancreatic neuroendocrine tumors.

Although pancreatic neuroendocrine tumors (PNETs) are considered indolent tumors, nearly half of cases metastasize to the liver, which can be lethal. However, effective indicators to predict aggressive behavior have not been well-established. In the current study, we explored the prognostic significance of tumor budding in Grade 1-2 PNETs. Hematoxylin-eosin and immunohistochemically stained slides of surgically removed Grade 1-2 PNETs were evaluated. Tumor budding, a histomorphological parameter that corresponds to single cells or small cell clusters (<5 cells), was classified as low (0-10 buds) and high (>10 buds) grade. We observed that tumor budding was correlated with aggressive histopathological parameters, such as T stage, lymph node status, metastasis, and vascular invasion (p < .05). Univariate and multivariate analyses showed that high-grade budding was an independent predictive factor for postoperative liver metastasis (p = .012). Moreover, Grade 1-2 PNETs with high-grade budding was associated with worse overall survival and disease-free survival (p = .0015 and p = .0041, respectively). We conclude that tumor budding may serve as a valuable parameter in the risk stratification of postoperative liver metastasis and that incorporating tumor budding into histopathological reports may aid in appropriate clinical management.

Interobserver Variability in the Assessment of Tumor Budding in pT 3/4 Colon Cancer: Improvement by Supporting Immunohistochemistry?

The prognostic significance of tumor budding in colon cancer is unequivocally documented, and the recommendations of the International Tumor Budding Consensus Conference (ITBCC) are currently the accepted basis for its assessment. Up to now, it is unknown whether the general use of a supporting cytokeratin immunohistochemistry can improve the interobserver variability and prognostic significance. Six investigators with different levels of experience reassessed 229 cases of colon carcinoma (pT3/4, N+/−, M0) with a supporting cytokeratin immunohistochemistry. The results were compared to previous assessments, which have been performed only on H & E. Bd3 was significantly associated with the occurrence of distant metastases according to the assessments of three out of six investigators (p < 0.05). Only one single investigator reached significant results concerning the cancer specific survival (p = 0.01). The pairwise kappa values range between a poor and moderate level of agreement (range 0.17–0.45; median 0.21). In conclusion, the results show no superiority of the use of an additional cytokeratin immunohistochemistry compared to the conventional analysis on sole H & E slides. Therefore, the general supporting use of a cytokeratin immunohistochemical staining seems to be inadvisable in colon cancer in consideration of necessary resources and costs.

A modular cGAN classification framework: Application to colorectal tumor detection

Automatic identification of tissue structures in the analysis of digital tissue biopsies remains an ongoing problem in digital pathology. Common barriers include lack of reliable ground truth due to inter- and intra- reader variability, class imbalances, and inflexibility of discriminative models. To overcome these barriers, we are developing a framework that benefits from a reliable immunohistochemistry ground truth during labeling, overcomes class imbalances through single task learning, and accommodates any number of classes through a minimally supervised, modular model-per-class paradigm. This study explores an initial application of this framework, based on conditional generative adversarial networks, to automatically identify tumor from non-tumor regions in colorectal H&E slides. The average precision, sensitivity, and F1 score during validation was 95.13 ± 4.44%, 93.05 ± 3.46%, and 94.02 ± 3.23% and for an external test dataset was 98.75 ± 2.43%, 88.53 ± 5.39%, and 93.31 ± 3.07%, respectively. With accurate identification of tumor regions, we plan to further develop our framework to establish a tumor front, from which tumor buds can be detected in a restricted region. This model will be integrated into a larger system which will quantitatively determine the prognostic significance of tumor budding.

The relationship between tumor budding and survival in colorectal carcinomas.

Tumor budding is a parameter that is increasingly understood in colorectal carcinomas. We aimed to investigate the relationship between tumor budding, prognostic factors, and survival. A total of 185 patients who had undergone colorectal surgery were observed. Tumor budding, the tumor budding score, and the relationship between these and prognostic factors, and survival investigated. Tumor budding was found in 91 (49.2%) cases. The relationship between the tumor budding score and histological grade, lymphovascular invasion, perineural invasion, pathological lymph node stage, and mortality rates were significant. In our study, the relationship between tumor budding and survival is very strong. Considering these findings and the literature, the prognostic significance of tumor budding becomes clear and should be stated in pathology reports.