High-grade Tumor Budding Research Articles

The Correlation of PD-L1 Overexpression With Tumor Budding In Cervical Carcinoma

Background: Several studies have proven the relationship between PD-L1, which is known as an immunotherapy target, and poor prognosis. The presence of a tumor budding (TB) group tumor outside the main tumor is also associated with a poor prognosis. The purpose of this study was to determine the relationship between PD-L1 and the grade of TB in cervical carcinoma. Methods: The design of this research is a case-control study with a retrospective approach. The sample is from a paraffin block of the primary cervical cancer tumor from the results of surgery in Balimed Denpasar Hospital between 2020 and 2023. From the statistical formula for the case-control study, a minimum sample of 15 is obtained for the case group with the criteria of high-grade TB, while 15 people were in the control group with low-grade TB. Immunohistochemistry (IHC) PD-L1 is positive if the membrane or cytoplasm is brown, and is negative if there is no brown color on the membrane or cytoplasm. Inferential statistics were used to evaluate the relationship between PD-L1 overexpression and low- and high-grade TB in cervical carcinoma using a chi-square test. Results: The results of this research revealed (p = 0.273) that there was no correlation between PD-L1 expression and high- and low-grade TB. Overexpression of PD-L1 was associated with a 2.250-fold increased risk of high-grade TB (OR = 2.250 with a 95% confidence interval of 0.103–1.915). Conclusions: The severity of TB does not correlate with PD-L1 expression. The functions of PD-L1 and other variables in the carcinogenesis of TB development are the cause of this weak association.

Potential predictor of prognosis in breast carcinoma: Tumor budding

ABSTRACT Background: Breast cancer is the most common cancer in women, with invasive breast carcinoma of no special type (IBC-NST) accounting for the majority of cases. Aim: This study aimed to evaluate the relationship between tumor budding (TB), which is the earliest histological indicator of tumor spread and represents epithelial–mesenchymal transition, and prognostic factors as well as the effect of TB on survival in patients with IBC-NST, thereby demonstrating its potential prognostic value. Materials and Methods: This study included 278 cases of breast resection diagnosed with IBC-NST from 2014 to 2019. Total tumor buds were counted in 10 high-power fields of a hematoxylin and eosin–stained section with the most infiltrative area at 400× magnification. The cutoff value for TB was obtained using receiver operating characteristic analysis for mortality and recurrence risk; this cutoff value was used to classify TB into two categories: low and high grades. The relationship between TB and prognostic factors and the effect of TB on the survival of patients were investigated. Results: This study revealed a statistically significant relationship between high-grade TB and increased tumor size, advanced pathological primary tumor (pT) category, lymph node metastasis, lymphatic invasion, blood vessel invasion, increased recurrence, and mortality as well as reduced overall and disease-free survival. Conclusion: TB in breast carcinomas may have significant predictive value for prognosis. It emerges as a simple, reproducible, and cost-effective histological marker. With the standardization of evaluation criteria, TB may be readily integrated into routine pathological examination, thereby increasing its value in clinical patient management.

Snail Expression as a Prognostic Factor in Colorectal Adenocarcinoma.

The aim of this study was to analyze the expression of Snail in the colorectal adenocarcinoma. This study used a cross-sectional design. Seventy four paraffin embedded block of Colorectal Adenocarcinoma were assessed using Snail rabbit polyclonal antibody and their expression were performed using Olympus CX-43 light microscope. The relationship between Snail expression with histopathological grading, tumor budding grading, lymphovascular invasion and metastases of colorectal adenocarcinoma ability were statistically analyzed by Mann Whitney tests and presented in tables using SPSS 27. From 74 samples examined, in samples with low grade tumor budding (n=11), there were 9 samples (81.8%) with weak expression, while those with strong expression were 2 samples (18.2%). In samples with intermediate grade tumor budding (n=28), there were 17 samples (60.7%) with weak expression, while those with strong expression were 11 samples (39.3%). In samples with high grade tumor budding (n=35), there were 13 samples (37.1%) with weak expression, while those with strong expression were 22 samples (62.9%). In samples with lymphovascular invasion (n=14), there were 10 samples (71.4%) with strong expression, while those with weak expression were 4 samples (28.6%). In samples with metastases (n=23), there were 16 samples (69.6%) with strong expression, while those with weak expression were 7 samples (30.4%). There was a significant relationship between the expression of Snail with tumor budding grade (p=0.003), lymphovascular invasion and metastases (p=<0.001), but there was no significant relationship with histopathological grade (p=0.942). The Snail expression can be used as a prognostic factor in colorectal adenocarcinoma.

Outcomes of noncurative endoscopic submucosal dissection for T1 colorectal cancer: Prospective, multicenter, cohort study in Japan.

This study investigated the incidence of lymph node metastasis and long-term outcomes in patients with T1 colorectal cancer where endoscopic submucosal dissection (ESD) resulted in noncurative treatment. It is focused on those with deep submucosal invasion, a factor considered a weak predictor of lymph node metastasis in the absence of other risk factors. This nationwide, multicenter, prospective study conducted a post-hoc analysis of 141 patients with T1 colorectal cancer ≥20 mm where ESD of the lesion resulted in noncurative outcomes, characterized by poor differentiation, deep submucosal invasion (≥1000 μm), lymphovascular invasion, high-grade tumor budding, or positive vertical margins. Clinicopathologic features and patient prognoses focusing on lesion sites and additional surgery requirements were evaluated. Lymph node metastasis incidence in the low-risk T1 group, identified by deep submucosal invasion as the sole high-risk histological feature, was assessed. Lymph node metastasis occurred in 14% of patients undergoing additional surgery post-noncurative endoscopic submucosal dissection for T1 colorectal cancer. In the low-risk T1 group, in the absence of other risk factors, the frequency was 9.7%. The lymph node metastasis rates in patients with T1 colon and rectal cancers did not differ significantly (14% vs. 16%). Distant recurrence was observed in one patient (2.3%) in the ESD only group and in one (1.0%) in the additional surgery group, both of whom had had rectal cancer removed. The risk of lymph node metastasis or distant occurrence was not negligible, even in the low-risk T1 group. The findings suggest the need for considering additional surgery, particularly for rectal lesions (Clinical Trial Registration: UMIN000010136).

Risk Factors of Lymph Node Metastasis and Prognosis in 891 Chinese Patients With Submucosal Early Gastric Carcinoma, Emphasizing Differences Between Gastric Cardiac and Noncardiac Origins.

Differences in risk factors (RF) of lymph node metastasis (LNM) and prognosis between submucosal early gastric cardiac (SEGCC) and noncardiac (SEGNCC) carcinomas remain unclear. In this study, we investigated and compared RF of LNM and prognosis in 891 patients with radical gastrectomy for SEGCC (n=217) or SEGNCC (n=674). Compared with SEGNCC, SEGCC displayed significantly higher proportion of elderly patients (70y or above), the elevated macroscopic type, well/moderately differentiated tubular and low-grade papillary adenocarcinomas, as well as low-grade tumor budding, but lower prevalence of the depressed macroscopic type, poorly differentiated tubular adenocarcinoma, mixed adenocarcinoma, poorly cohesive carcinoma, lymphovascular invasion (LVI), perineural invasion, and high-grade tumor budding. By univariate analysis, significant RF for LNM of the cohort included female sex, poor differentiation, SM2 invasion, LVI, intermediate-grade and high-grade tumor budding, whereas tumor size, histology type, and perineural invasion were the significant RF for LNM in SEGNCC. By multivariate analysis, significant independent RF for LNM included female sex and LVI in SEGCC but were female sex, mixed adenocarcinoma, LVI, and high-grade tumor budding in SEGNCC. The 5-year overall survival was significantly worse in SEGCC than in SEGNCC for patients with LNM, but not for those without. For overall survival, LNM was the only significant independent RF in SEGCC, whereas age 70 years or above and LNM were independent RF in SEGNCC. The results of our study provided the clinicopathologic evidence for individualized clinical management strategies for these 2 groups of patients and suggested different pathogenesis mechanisms between SEGCC and SEGNCC.

Clinicopathological features and prognosis of sporadic mismatch repair deficient colorectal cancer

Objective: To investigate the clinicopathological characteristics and prognostic factors of sporadic mismatch repair deficient (dMMR) colorectal cancer. Methods: A total of 120 cases of sporadic dMMR colorectal cancer from July 2015 to April 2021 were retrospectively collected in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Patients with Lynch syndrome; synchronous multiple colorectal cancers; preoperative anti-tumor treatments such as chemotherapy and radiotherapy; and those with incomplete follow-up information were excluded based on family history and next-generation sequencing (NGS) test results. Immunohistochemical stains were used to detect the expression of mismatch repair proteins, methylation-specific PCR for methylation testing, and fluorescent PCR for BRAF V600E gene mutation detection. The clinical and pathological data, and gene mutation status were analyzed. Follow-up was done to assess survival and prognosis including progression-free survival and overall survival rate. Results: Sporadic dMMR colorectal cancer occurred more frequently in the right side of the colon, in females, and in the elderly. Morphologically, it was mostly moderately-differentiated, and most patients had low-grade tumor budding. In terms of immunohistochemical expression, MLH1 and PMS2 loss were dominant, and there were age and location-specificities in protein expression. MLH1 methylation was commonly detected in elderly female patients and rare in young male patients; while MLH1 and PMS2 deficiency, and BRAF V600E mutation occurred more often on the right side (P<0.05). The 3-year and 5-year progression-free survival rates were 90.7% and 88.7% respectively, and the 3-year and 5-year overall survival rates were 92.8% and 90.7% respectively. Tumor budding status was an independent risk factor affecting patient recurrence (hazard ratio=3.375, 95% confidence interval: 1.060-10.741, P=0.039), patients with low-grade tumor budding had better prognosis, and those with medium or high-grade tumor budding had poor prognosis. Conclusion: For dMMR colorectal cancer patients, tumor budding status is an independent risk factor for recurrence.

Tumor Budding as a Prognostic Marker in Primary Colon Cancer - A Single Center Experience.

Introduction: Tumor budding (TB) is considered to be a morphological and prognostic factor relevant to colon cancer (CC). The aim of our study is to assess the TB and to evaluate its relationship to clinicopathological findings within stage II and III CC patients as a single center experience. Materials and methods: A total of 120 CC patients operated between 2018 and 2021 at the University Clinic of Digestive Surgery in Skopje, the Republic of North Macedonia were included in this retrospective, single center study. TB was evaluated by the magnification of 200x along the invasive front of the primary tumor on H&E and CKAE1/AE3 immunohistochemically stained sections. Two grades were used: low grade (TB1, 0-4 TBs) and high-grade, which includes intermediate (TB2, 5-9 TBs) and high grade (TB3 ≥10TBs) of TBs. Results: A statistically significant correlation has been identified between high-grade TB and age (p=0.05) of the patients. There was also a significantly higher occurrence of high-grade TB in patients within stage III CC. Statistically significant correlations were also found in lymph node status (p<0.01), vascular invasion (p<0.05), lymphatic invasion (p<0.01), postoperative relapse (p<0.01), and death (p<0.01). Tumor relapse and death were significantly more frequent in patients with high-grade TB than those with low-grade TB. Patients with registered high-grade TB demonstrated significantly lower relapse-free survival (RFS) and overall survival (OS) rates than patients with low-grade TB over the observation period (RFS: 53.8% vs. 98.5%, p<0.001; OS: 65.4% vs. 97.1%, p<0.001, respectively). Patients with lung and liver postoperative relapses had higher percentage of cases with high-grade TB (94.1%). Conclusion: Our results are highly suggestive that TB should be included as a histological biomarker in the pathology report of patients with stage II and stage III CC, because of its prognostic value.

Risk factors for lymph node metastasis in T2 colorectal cancer: a systematic review and meta-analysis.

Lymph node metastasis (LNM) occurs in 20-25% of patients with T2 colorectal cancer (CRC). Identification of risk factors for LNM in T2 CRC may help identify patients who are at low risk and thereby potential candidates for endoscopic full-thickness resection. We examined risk factors for LNM in T2 CRC with the goal of establishing further criteria of the indications for endoscopic resection. MEDLINE, CENTRAL, and EMBASE were systematically searched from inception to November 2023. Studies that investigated the association between the presence of LNM and the clinical and pathological factors of T2 CRC were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Certainty of evidence (CoE) was assessed using the GRADE approach. Fourteen studies (8349 patients) were included. Overall, the proportion of LNM was 22%. The meta-analysis revealed that the presence of lymphovascular invasion (OR, 5.5; 95% CI 3.7-8.3; high CoE), high-grade tumor budding (OR, 2.4; 95% CI 1.5-3.7; moderate CoE), poor differentiation (OR, 2.2; 95% CI 1.8-2.7; moderate CoE), and female sex (OR, 1.3; 95% CI 1.1-1.7; high CoE) were associated with LNM in T2 CRC. Lymphatic invasion (OR, 5.0; 95% CI 3.3-7.6) was a stronger predictor of LNM than vascular invasion (OR, 2.4; 95% CI 2.1-2.8). Lymphovascular invasion, high-grade tumor budding, poor differentiation, and female sex were risk factors for LNM in T2 CRC. Endoscopic resection of T2 CRC in patients with very low risk for LNM may become an alternative to conventional surgical resection. PROSPERO, CRD42022316545.

A Cross-Sectional Study of Tumor Budding in Correlation with Clinicopathological Parameters in Invasive Breast Carcinoma

Introduction: Breast carcinoma is the largest cause of mortality from cancer among women in India. Tumor budding is usually defined as isolated single cancer cells or clusters of up to four cancer cells located at the invasive tumor front. Tumor budding is associated with poor clinicopathological characteristics, such as Tumor size, tumor differentiation, lymph node invasion, lymphatic or vascular invasion etc. Aim: To study tumor budding and its association with known clinicopathological parameters and hormone receptor status in invasive breast carcinoma. Methods : A Cross-sectional study was conducted after approval from the ethics committee. The duration of study was 1.5 years (Jan 2022- June 2023). Results: A total of fifty cases of invasive breast carcinomas were included in this study. 70% (35cases) were &gt;50yrs of age, 65% (33cases) were of T2 (tumor size) category. 82%(41cases) of Invasive duct carcinoma, No specific type, 12% (6 cases) of mixed carcinomas followed by three cases, one is invasive lobular carcinoma(6%), others are high grade papillary duct carcinoma(6%) and mucinous carcinoma (6%). 76%(38cases) showed presence of lymphovascular invasion, 74%(37cases) showed absence of necrosis, 54%(27 cases) are categorized as grade 2. High grade tumor budding was seen in 54% (27 cases). Conclusion: The following variables had a significant association with the tumor budding in present study: Tumor size, TNM staging, treatment status, lymphovascular invasion showing a p-value of &lt;0.05. ER positive tumors are also associated with high grade tumor budding. Keywords: Breast Carcinoma, Clinicopathological Variables, Lymphovascular Invasion, Tumor Budding

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 tumour budding in noncolorectal gastrointestinal tract and pancreatobiliary tract: a systematic review and meta-analysis.

Tumour budding shows promise as a prognostic factor in various cancers, but its widespread application is hindered by the lack of large, validated studies and standardized criteria. This meta-analysis aims to review and examine the prognostic role of tumour budding specifically in noncolorectal gastrointestinal and pancreatobiliary tract cancers, broadening our perspective on its clinical relevance. The literature review was conducted through PubMed, Embase, and Web of Science from inception till 20 February 2023. Pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the relation between tumour budding and clinicopathologic features, as well as overall survival. Each study was evaluated using the Newcastle-Ottawa Scale and both heterogeneity and publication bias were analysed. In this meta-analysis of 57 studies across various cancer types, multivariate HR revealed worse overall survival in oesophageal squamous cell carcinoma (HR 3.34 [95% CI 2.21-5.04]), gastric adenocarcinoma (2.03 [1.38-2.99]), pancreatic ductal adenocarcinoma (2.56 [2.02-3.25]), and biliary tract adenocarcinoma (3.11 [2.46-3.93]) with high-grade tumour budding. Additionally, high-grade tumour budding consistently correlated with adverse clinicopathological features, including lymph node metastasis, lymphovascular invasion, and distant metastasis without any observed inverse association. High heterogeneity was noted. Our study suggests that tumour budding is a valuable prognostic marker in various cancers. Nonetheless, standardized criteria tailored to specific organ types are necessary to enhance its clinical utility.

Association of circulating tumor DNA (ctDNA) molecular disease (MRD) detection with lymph node metastasis after local excision of pathological T1 colorectal cancer: First results from DENEB, a CIRCULATE-Japan GALAXY substudy.

23 Background: Patients with pathological T1 (pT1) colorectal cancer (CRC) at high risk for lymph node metastasis (LNM) after complete local resection are recommended to receive additional intestinal resection along with lymph node dissection. However, the existing pathological criteria for risk stratification of LNM are inadequate, such that ~90% of patients without LNM are exposed to potentially unnecessary treatment. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective substudy within the GALAXY observational study, to explore the ability of predicting LNM using circulating tumor DNA (ctDNA) detection compared to the standard pathological criteria. Methods: This study included patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk-stratification criteria for LNM. The additional surgery was indicated for patients meeting any of the following criteria: (1) depth of submucosal invasion (&gt;1000µm); (2) lymphovascular invasion; (3) poorly differentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous carcinoma; and (4) high-grade tumor budding (BD2/3) at the site of deepest invasion according to the Japanese guideline. ctDNA was analyzed from plasma samples collected within 4 weeks before the additional intestinal resection using a personalized, tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay). The study assessed the diagnostic concordance rate between ctDNA detection and the occurrence of LNM. Results: Of 208 CRC patients enrolled between July 2021 and May 2023 in DENEB, 166 patients met the inclusion criteria. Of these, 22 (13.3%) were ultimately diagnosed with pStage III due to the presence of LNM in additional intestinal resection. Among the 166 patients, 6 patients tested ctDNA-positive; all 6 had LNM, yielding a positive predictive value of 100.0%. On the other hand, 160 patients had ctDNA-negative results, 144 of whom did not have LNM, resulting in a negative predictive value of 90.0%. The overall diagnostic concordance rate for ctDNA in detecting LNM was 90.4% (95% confidence interval, 84.8% to 94.4%). All 6 patients with a ctDNA-positive result and LNM had left-sided colorectal cancer and a tumor diameter greater than 13 mm. Conclusions: This analysis showed that ctDNA testing has the potential to improve risk stratification of LNM in patients with pT1 CRC who underwent complete local resection. Clinical trial information: UMIN000039205 .

Study of tumor budding and its association with clinicopathological parameters in breast carcinoma.

Tumor budding is a phenomenon in which the tumor cells detach from the main mass and are present at the invasive front. The present study was conducted to study tumor budding in invasive breast carcinoma and to correlate it with clinicopathological parameters and molecular subtypes. The study was conducted over a period of 1 year, and tumor budding was studied as a single or group of cells at the invasive front of breast carcinoma counted in a high-power field (40×). The grading was statistically correlated with tumor size, grade, lymph node status, lymphovascular invasion, pathological TNM staging, molecular subtype, and survival of patients. A total of 50 cases of invasive breast carcinoma were included, out of which 66% (n=33) showed high-grade tumor budding, which was statistically significantly higher in grade 2 invasive ductal carcinoma (p<0.05). High tumor budding was associated with lymphovascular invasion, lymph node metastasis, and a high Ki-67 proliferative index. All cases showing low-grade budding were alive until 6 months of diagnosis, but there was no statistically significant association between stage and budding. Tumor buds are significantly higher in grade 2 invasive ductal carcinoma with lymphovascular invasion, lymph node metastasis, and a high Ki-67 proliferative index. Immunohistochemistry may prove helpful in distinguishing tumor buds from their mimickers. Further studies with extended follow-up are recommended to predict tumor budding as a prognostic marker in breast carcinoma, which may play an important role in cancer therapy.

Colorectal Carcinomas: Searching for New Histological Parameters Associated with Lymph Node Metastases.

Background and Objectives: Colorectal cancer (CRC) continues to be an essential public health problem. Our study aimed to evaluate the prognostic significance of classic prognostic factors and some less-studied histopathological parameters in CRC. Materials and Methods: We performed a retrospective study on 71 colorectal carcinoma patients who underwent surgery at the "Pius Brînzeu" County Clinical Emergency Hospital in Timișoara, Romania. We analyzed the classic parameters but also tumor budding (TB), poorly differentiated clusters (PDCs) of cells, tumor-infiltrating lymphocytes (TILs), and the configuration of the tumor border on hematoxylin-eosin slides. Results: A high degree of malignancy (p = 0.006), deep invasion of the intestinal wall (p = 0.003), an advanced stage of the disease (p < 0.0001), lymphovascular invasion (p < 0.0001), perineural invasion (p < 0.0001), high-grade TB (p < 0.0001), high-grade PDCs (p < 0.0001), infiltrative tumor border configuration (p < 0.0001) showed a positive correlation with lymph node metastases. Conclusions: The analyzed parameters positively correlate with unfavorable prognostic factors in CRC. We highlight the value of classic prognostic factors along with a series of less-known parameters that are more accessible and easier to evaluate using standard staining techniques and that could predict the risk of relapse or aggressive evolution in patients with CRC.

Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy

IntroductionGlycogen synthase kinase 3 (GSK-3) has been proposed as a novel cancer target due to its regulating role in both tumor and immune cells. However, the connection between GSK-3 and immunoevasive contexture, including tumor budding (TB) has not been previously examined. Methods: we investigated the expression levels of total GSK-3 as well as its isoforms (GSK-3β and GSK-3α) and examined their potential correlation with TB grade and the programmed cell death-ligand 1 (PD-L1) in colorectal cancer (CRC) tumor samples. Additionally, we compared the efficacy of GSK-3-inhibition with PD-1/PD-L1 blockade in humanized patient-derived (PDXs) xenografts models of high-grade TB CRC. Resultswe show that high-grade (BD3) TB CRC is associated with elevated expression levels of total GSK-3, specifically the GSK-3β isoform, along with increased expression of PD-L1 in tumor cells. Moreover, we define an improved risk stratification of CRC patients based on the presence of GSK-3+/PD-L1+/BD3 tumors, which are associated with a worse prognosis. Significantly, in contrast to the PD-L1/PD-1 blockade approach, the inhibition GSK-3 demonstrated a remarkable enhancement in the antitumor response. This was achieved through the reduction of tumor buds via necrosis and apoptosis pathways, along with a notable increase of activated tumor-infiltrating CD8+ T cells, NK cells, and CD4- CD8- T cells. Conclusionsour study provides compelling evidence for the clinical significance of GSK-3 expression and TB grade in risk stratification of CRC patients. Moreover, our findings strongly support GSK-3 inhibition as an effective therapy specifically targeting high-grade TB in CRC.

High-grade tumor budding is a risk factor for survival in patients with laryngeal squamous cell carcinoma

ObjectiveWith the increasing incidence and mortality of laryngeal squamous cell carcinoma worldwide, researchers continue to search for novel prognostic factors and treatment methods for preventing early laryngeal squamous cell carcinoma from becoming advanced laryngeal squamous cell carcinoma. This study aims to determine if tumor budding is an independent risk factor associated with the survival of patients with laryngeal squamous cell carcinoma. Methods268 cases of laryngeal squamous cell carcinoma were studied, and tumor budding was analyzed for associations with clinicopathological features and clinical outcomes. ResultsTumor budding was divided into low-grade tumor budding (0–6/0.785 mm2) and high-grade tumor budding (≥7/0.785 mm2) based on the results of the receiver operating characteristics curve analysis. Logistic regression analysis showed that smaller tumor cell nests, the low levels of tumor-infiltrating lymphocytes, and higher pathological T staging were the risk factors for high-grade tumor budding (p < 0.05). In the low-grade tumor budding group, there was no statistic difference in survival between patients without tumor budding and those with 1–6/0.785 mm2 tumor budding. Multivariate survival analysis showed high-grade tumor budding (p < 0.001) was independent prognostic factors for disease-free survival and overall survival in laryngeal squamous cell carcinoma. High-grade tumor budding was also an independent prognostic factor for disease-free survival (p = 0.037) and overall survival (p = 0.009) in T1-2N0 laryngeal squamous cell carcinoma. ConclusionsSmaller tumor cell nests, the low levels of tumor-infiltrating lymphocytes, and higher pathological T staging were closely associated with high-grade tumor budding in laryngeal squamous cell carcinoma. High-grade tumor budding may be an adverse risk factor that affects not only the disease-free survival and overall survival of laryngeal squamous cell carcinoma patients but also the survival of T1-2N0 laryngeal squamous cell carcinoma patients. Level of EvidenceLevel 4.

Analysis of Histological Prognostic Factors in Colorectal Carcinoma and Relationship of VEGF and E-Cadherin Expression in Prognostic Assessment

Colorectal carcinomas (CRC) are associated with several histopathological and molecular factors of prognostic and hence therapeutic implications, including for epithelial mesenchymal transition (EMT) and angiogenesis. Downregulation of E-cadherin is a crucial step in EMT, directly related to tumor progression, invasion, and metastasis. Vascular endothelial growth factor (VEGF) induces angiogenesis and thereby tumour progression and metastases. Our objective was to analyse VEGF and E-cadherin expression in patients with CRC and to effectively assess the relationship of these with histopathological factors. 50 cases of CRC obtained over eighteen months duration, were included in the study. Haematoxylin and Eosin-stained sections were studied for histopathological factors. Immunohistochemistry with E-Cadherin and VEGF were performed on representative sections and evaluated. Histopathological features of importance noted were low grade tumour budding (55.5%), Infiltrative invasive front (83%), lympho-vascular invasion (50%). Preserved expression of E-Cadherin was seen in 66% of the cases, and 34% reduced expression, predominantly noted in patients above the age of 50, increased tumour size, mucinous variants, advanced TNM stage, lymph node involvement and high-grade tumour budding. VEGF staining was seen in 64% of the cases with varying intensity. Increased VEGF expression was noted in poorly differentiated tumours, advanced Duke’s stage and with lymph node metastasis. Colorectal carcinomas with high grade tumour budding were associated with lymph vascular invasion, infiltrative invasive front and significantly correlated with TNM stage. High grade tumours and adverse histopathological prognostic factors revealed a reduced E-cadherin expression and increased VEGF expression.

High grade tumor budding is associated with poor survival in pathologic stage I lung adenocarcinoma

AimTumor budding is a significant prognostic parameter that has been related to aggressive behavior in early-stage tumors of various origins. The aim of this study was to evaluate the clinicopathological significance of tumor budding in pathologic stage (pStage) I lung adenocarcinomas. MethodsThis study comprised 107 patients who underwent curative resection for pStage I lung adenocarcinomas at our hospital between December 2010 and January 2016. We examined tumor budding on routine hematoxylin and eosin (H&E) slides from resected specimens. Tumors were categorized into two groups based on the degree of tumor budding: low grade (grade 0–1) and high grade (grade 2–3). We evaluated the relationship between tumor budding and overall survival (OS), disease-free survival (DFS) and clinicopathological parameters. ResultsThere is a significant difference (p = 0.002) between the 5-year DFS rates of the high-grade and the low-grade tumor budding group, which were 70 % and 90 %, respectively. High-grade tumor budding positive patients from the same pathological stage (p < 0.001; HR = 2.93 [1.51–5.68]) and clinical stage (p = 0.002) had poorer cumulative survival rates than low grade tumor budding positive patients. High grade tumor budding was positively associated with spread through air spaces (STAS) (p < 0 0.001), lymphovascular invasion (LVI) (p < 0.001), tumor necrosis (p < 0.001), high SUVmax value (SUVmax>3.0) (p < 0.001), and tumor size >20 mm (p = 0.024). High-grade tumor budding was significant prognostic factor of OS (p < 0.006) and DFS (p < 0.001) on univariate Cox regression hazard model analysis. However, it did not show significance in the multivariate analysis (p > 0.05). ConclusionsHigh-grade tumor budding is an independent prognostic factor and associated with adverse clinicopathological features and poor survival rates. We proposed that high-grade tumor budding should be recognized as a new prognostic parameter and will be beneficial in predicting the clinical course in pStage I lung adenocarcinomas.

Tumor Budding and Poor Prognosis in Oral Cancer: A Systematic Review and Meta-Analysis.

Tumor budding (TB) has been investigated in several types of solid tumors. In oral cancer, studies show its association with survival. However, for its implementation in routine histological analyses, results with a high certainty of evidence are needed. Therefore, the aim of this systematic review is to explore the association between tumor budding and overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in oral cancer. A search was performed in Embase, PubMed, Scopus, Livivo, Web of Science, and Google Scholar. We adopted the following inclusion criteria: studies that evaluate tumor budding in oral cancer, that investigate survival, and presenting cohort design. We excluded reviews and studies without hazard-ratio (HR) data. This systematic review included 22 studies and showed an association between TB and survival. High-grade TB is associated with a worse OS in univariate analysis (HR = 3.11; 95% CI: 2.06-4.69, p<0.01) and multivariate analysis (HR = 2.62; 95% CI: 1.64-4.20, p<0.01); with a poorer DSS in univariate (HR = 2.43; 95% CI: 1.94-3.03, p<0.01) and multivariate analysis (HR = 2.01; 95% CI: 1.43-2.83, p< 0.01); and with a worse DFS in univariate (HR = 1.94; 95% CI: 1.44-2.62, p<0.01) and multivariate analysis (HR = 2.15; 95% CI: 1.31-3.53, p< 0.01). Sensitivity analysis showed that the results are robust, and no significant publication bias was identified in univariate analysis for DFS (Egger's test: p = 0.94). The certainty of the evidence was graded as low or very low. Our findings indicate that TB is an independent prognostic factor of OS, DSS, and DFS in oral cancer. However, further studies are needed to increase the certainty of the evidence.

Prognostic Factors Among Colonic Adenocarcinomas Invading Into the Muscularis Propria.

Depth of invasion through the intestinal wall, categorized as primary tumor stage (pT), is an important prognostic factor in colorectal cancer. However, additional variables that may affect clinical behavior among tumors involving the muscularis propria (pT2) have not been examined at length. We evaluated 109 patients with pT2 colonic adenocarcinomas (median age: 71y, interquartile range: 59 to 79y) along various clinicopathologic parameters, including invasion depth, regional lymph node involvement, and disease progression after resection. Tumors extending to the outer muscularis propria (termed pT2b) were associated in multivariate analysis with older patient age ( P =0.04), larger tumor size ( P <0.001), higher likelihood of lymphovascular invasion (LVI; P =0.03) and higher lymph node stage (pN; P =0.04), compared with tumors limited to the inner muscle layer (pT2a), and LVI was the single most important variable predicting regional lymph node metastasis at resection in these tumors ( P =0.001). The Kaplan-Meier analysis during a median clinical follow-up of 59.7 months (interquartile range: 31.5 to 91.2) revealed that disease progression was more likely in pT2 tumors that exhibited, at the time of staging: size >2.5cm ( P =0.039), perineural invasion (PNI; P =0.047), high-grade tumor budding ( P =0.036), higher pN stage ( P =0.002), and distant metastasis ( P <0.001). Proportional hazards (Cox) regression identified high-grade tumor budding ( P =0.02) as independently predicting shorter progression-free survival in pT2 tumors. Finally, among cases that would not ordinarily be candidates for adjuvant treatment (ie, pT2N0M0), the presence of high-grade tumor budding was significantly associated with disease progression ( P =0.04). These data suggest that, during the diagnosis of pT2 tumors, pathologists may wish to pay particular attention and ensure adequate reporting of certain variables such as tumor size, depth of invasion within the muscularis propria (ie, pT2a vs. pT2b), LVI, PNI, and, especially, tumor budding, as these may affect clinical treatment decisions and proper patient prognostication.