Tumor Budding Research Articles

Endoscopic resection alone as a potential treatment method for low-risk deep invasive T1 colorectal cancer

Background and AimsAlthough T1b (deep submucosal invasion) is described as an indication of surgical resection with lymph node dissection for T1 colorectal cancer (CRC) in current guidelines, it has been reported to be a weaker correlation to the lymph node metastasis (LNM) than other risk factors (lymphovascular invasion, poorly differentiated or mucinous adenocarcinoma, tumor budding). “Low-risk T1b” CRC, which is defined as a lesion with only T1b and no other risk factors, may not require additional surgical resection. This study aimed to evaluate the necessity of surgeries in patients with low-risk T1b CRC from the point of the risk of LNM, recurrence and long-term outcome. MethodsFrom April 2001 to March 2019, 1,271 T1 CRCs were resected. Invasion depth and tumor budding were diagnosed according to the Japanese guideline, lymphovascular invasion was evaluated with special staining and immunostaining, and histological grade was diagnosed by the highest differentiation. Then, we analyzed 354 patients with low-risk T1b CRC. Among these, 105 patients were resected endoscopically without surgical resection (ER-alone group) and 249 patients were resected surgically (SR group). We examined the rate of LNM, the cumulative recurrence, and overall survival (OS) in each group. ResultsNo LNM was observed in both ER-alone group (0% (95%CI, 0-4.2%)) and SR group (0% (95% CI, 0-1.8%)). Five-year cumulative recurrence rate was 0% (95%CI, 0-9%) in ER-alone group and 0% (95% CI, 0-3%) in SR group. Five-year OS rate was 93% (95%CI, 90-96%) in ER-alone group and 95% (95% CI, 93-96%) in the SR group (p = 0.35). ConclusionsER alone without SR could be a potential treatment method for patients with low-risk T1b CRC.

Prognostic role of tumor budding in oral squamous cell carcinoma: a retrospective study

Background: Tumor budding (TB) is defined as a single cell or a cluster of up to five tumor cells at the invasion front of all oral squamous cell carcinoma (OSCC) cases. Tumor budding is considered a marker of many important events in oral carcinoma, including the epithelial-mesenchymal transition, invasion, metastasis, and for further prognosis. Methods: A total of 30 clinically and histopathologically diagnosed cases of OSCC were retrieved from the archival of the Department of Oral Pathology and Microbiology. After assessing the sections for the presence of TB, it is further categorized into high-intensity TB and low-intensity TB. Results: We found a strong association between lymph node metastasis, lymph node metastasis, and histopathological grading in the current study. There was no association between TB and a patient's survival rate. Conclusions: This study emphasizes the significance of tumor budding, its relevance to prognosis, and reproducibility, as well as the significance of its evaluation and incorporation into routine surgical pathology practice in the management of OSCC. As a result, we believe that tumor budding is a crucial factor in determining tumor behavior.

Can tumour budding change the future of pulmonary adenocarcinoma?

BackgroundPulmonary adenocarcinoma shows different prognosis even in the same pathological subtype and stage. In this study, it is aimed to investigate the relationship between tumour budding and known prognostic values and clinicopathological features in pulmonary adenocarcinoma. MethodsIn this study, there have been 77 patients diagnosed with primary pulmonary adenocarcinoma. In the evaluation process, the number of budding between 0 and 4 is accepted as low budding (Bd1), the number of budding between 5 and 9 is considered as medium budding (Bd2), and the number of budding above 10 is considered as high budding (Bd3). ResultsAccording to the findings of the study, it can be seen that there is a statistical difference between tumour budding and stromal fibrosis (p < 0.001). The presence of pleural invasion, lymph vascular invasion and perineural invasion in patients with Bd3 is found to be statistically higher than the patients with Bd1 (p = 0.048) (p = 0.041) (p = 0.029). ConclusionsTumour budding has been associated with pleural invasion, lymph vascular invasion, perineural invasion, and stromal fibrosis. This study is the first to show the relationship between tumour budding and stromal fibrosis in pulmonary adenocarcinomas. The role of tumour budding in lung cancers remains to be clarified.

Radiomics and machine learning analysis by computed tomography and magnetic resonance imaging in colorectal liver metastases prognostic assessment.

The aim of this study was the evaluation radiomics analysis efficacy performed using computed tomography (CT) and magnetic resonance imaging in the prediction of colorectal liver metastases patterns linked to patient prognosis: tumor growth front; grade; tumor budding; mucinous type. Moreover, the prediction of liver recurrence was also evaluated. The retrospective study included an internal and validation dataset; the first was composed by 119 liver metastases from 49 patients while the second consisted to 28 patients with single lesion. Radiomic features were extracted using PyRadiomics. Univariate and multivariate approaches including machine learning algorithms were employed. The best predictor to identify tumor growth was the Wavelet_HLH_glcm_MaximumProbability with an accuracy of 84% and to detect recurrence the best predictor was wavelet_HLH_ngtdm_Complexity with an accuracy of 90%, both extracted by T1-weigthed arterial phase sequence. The best predictor to detect tumor budding was the wavelet_LLH_glcm_Imc1 with an accuracy of 88% and to identify mucinous type was wavelet_LLH_glcm_JointEntropy with an accuracy of 92%, both calculated on T2-weigthed sequence. An increase statistically significant of accuracy (90%) was obtained using a linear weighted combination of 15 predictors extracted by T2-weigthed images to detect tumor front growth. An increase statistically significant of accuracy at 93% was obtained using a linear weighted combination of 11 predictors by the T1-weigthed arterial phase sequence to classify tumor budding. An increase statistically significant of accuracy at 97% was obtained using a linear weighted combination of 16 predictors extracted on CT to detect recurrence. An increase statistically significant of accuracy was obtained in the tumor budding identification considering a K-nearest neighbors and the 11 significant features extracted T1-weigthed arterial phase sequence. The results confirmed the Radiomics capacity to recognize clinical and histopathological prognostic features that should influence the choice of treatments in colorectal liver metastases patients to obtain a more personalized therapy.

Tumour budding in cutaneous squamous cell carcinoma: A novel prognosis risk factor.

Most cutaneous squamous cell carcinomas (cSCC) have a good prognosis, there is a small group where metastasis and death occur and the evaluation of this risk is still cause for controversy. Tumour budding is a pattern of histological invasion that is an emerging risk factor in other solid tumours. To examine the association between tumour budding and other known high-risk predictors in cSCC. In addition, the impact of tumour budding on overall survival (OS) and disease-specific survival (DSS) was analysed. Retrospective study. It included patients with a diagnosis of non-genital cSCC by excisional biopsy at a university hospital, between 2010 and 2020. A pathologist re-analysed their histological slides and evaluated budding. Univariate and multivariate analyses were made to study the associations. 156 cSCC biopsies were found, and positive tumour budding was found in 13.5%. This correlated with worse DSS and OS. On univariate analysis, budding was correlated with the diameter, thickness of the tumour, histological grade, level of invasion, perineural and lymphovascular invasion, previous radiotherapy, recurrent tumours and lymph node metastasis (LNM). Multivariate analysis: tumour budding was associated with poorly differentiated tumours, prior radiotherapy and LNM. An association was found between tumour budding and most known risk factors in cSCC. We found findings that indicate that the presence of tumour budding is associated with a worse prognosis in terms of LNM, OS and DSS. This supports the results of previous work which has suggested that budding could be related to high-risk cSCC.

Intratumoral metabolic heterogeneity of colorectal cancer.

Although the metabolic phenotype within tumors is known to differ significantly from that of the surrounding normal tissue, the importance of this heterogeneity is just becoming widely recognized. Colorectal cancer (CRC) is often classified as the Warburg phenotype, a metabolic type in which the glycolytic system is predominant over oxidative phosphorylation (OXPHOS) in mitochondria for energy production. However, this dichotomy (glycolysis vs. OXPHOS) may be too simplistic and not accurately represent the metabolic characteristics of CRC. Therefore, in this review, we decompose metabolic phenomena into factors based on their source/origin and reclassify them into two categories: extrinsic and intrinsic. In the CRC context, extrinsic factors include those based on the environment, such as hypoxia, nutrient deprivation, and the tumor microenvironment, whereas intrinsic factors include those based on subpopulations, such as pathological subtypes and cancer stem cells. These factors form multiple layers inside and outside the tumor, affecting them additively, dominantly, or mutually exclusively. Consequently, the metabolic phenotype is a heterogeneous and fluid phenomenon reflecting the spatial distribution and temporal continuity of these factors. This allowed us to redefine the characteristics of specific metabolism-related factors in CRC and summarize and update our accumulated knowledge of their heterogeneity. Furthermore, we positioned tumor budding in CRC as an intrinsic factor and a novel form of metabolic heterogeneity, and predicted its metabolic dynamics, noting its similarity to circulating tumor cells and epithelial-mesenchymal transition. Finally, the possibilities and limitations of using human tumor tissue as research material to investigate and assess metabolic heterogeneity are discussed.

Occurrence of Distant Metastasis During Bladder Presevation in T1 high-grade Bladder Cancer: Report of Three Cases

We report three patients with T1 high-grade (HG) bladder cancer who suffered from distant metastasis during bladder preservation. The patients were a 48-year-old female (Case 1), a 75-year-old female (Case 2) and an 82-year-old male (Case 3) with the chief complaint of asymptomatic gross hematuria. The histopathological diagnoses of the initial transurethral resection of the bladder tumor (TURBT) and second TURBT were urothelial carcinoma, pT1, HG and no malignancy in all three patients. Bladder tumors of all patients revealed sessile growth pattern and no presence of carcinoma in situ. Case 2 and 3 did not receive BCG vesical instillation after the second TURBT. Lymph node metastases appeared in Case 1 and Case 2 and lung metastasis appeared in Case 3. Tumor budding (TB) was positive in Case 1 and Case 2. Variant histology (VH) of nested morphology was detected in Case 1 and VH of inverted morphology in Case 2 and Case 3. Twenty-four months after the initial TURBT, Case 1 died due to cancer progression after cisplatin-based chemotherapy and pembrolizumab therapy. Thirty-three and 11 months after the initial TURBT, Case 2 and Case 3 were alive without cancer progression after cisplatin-based chemotherapy and/or pembrolizumab therapy, respectively. The two patients with T1 HG bladder cancer with TB had lymphatic metastasis and the patient without TB had hematogenous metastasis. Nested morphology is reportedly categorized as high-risk disease and inverted morphology as low-risk disease. TB might be correlated with lymphatic metastasis in T1 HG bladder cancer, and TB should be considered in the management of T1 HG bladder cancer. In the case of VH, the guidelines should be followed during the treatment decision of T1 HG bladder cancer.

Mismatch repair deficiency as prognostic factor for stage III small bowel adenocarcinoma: A multicentric international study.

Small bowel adenocarcinoma (SBA) is a rare cancer with an aggressive behavior. No study has specifically addressed the putative prognostic role of mismatch repair status in stage III SBAs. We aimed to investigate whether mismatch repair deficiency is associated with cancer-specific survival in a Western cohort of patients with stage III SBAs. In this retrospective multicentric international cohort study, we enrolled 70 patients who underwent surgically resection for stage III SBAs and we analyzed the frequency of mismatch repair deficiency, tested by immunohistochemistry for mismatch repair proteins and by polymerase chain reaction for microsatellite instability, and its association with cancer-specific survival and other clinic-pathologic factors. We found sixteen (23%) patients with mismatch repair deficient adenocarcinoma, without discordance between immunohistochemical and polymerase chain reaction for microsatellite instability analyses. Mismatch repair deficiency proved to be associated with a better outcome both at univariable analysis (hazard ratio: 0.28, 95% confidence interval: 0.08-0.91, p: 0.035) and in bivariable models adjusted for patient age or gender, tumor site, pT4 stage, tumor budding, and perineural invasion. This study highlights the importance of testing mismatch repair status to improve prognostic stratification in stage III SBAs.

Predictive value of tumor budding in head and neck squamous cell carcinoma: an update.

Head and neck squamous cell carcinoma forms an anatomically and functionally complex group of malignancies. The significant local aggressiveness and frequent regional relapses motivate ongoing research to identify more reliable and sensitive prognostic and predictive biomarkers. One emerging area of cancer biology is the evaluation of tumor budding at the advancing invasive front of various types of epithelial cancers. Recent studies suggest that tumor budding is a relatively common phenomenon in cancer progression and that it may have important prognostic implications for patients due to its potential to provide valuable insights into the biology and clinical behavior of head and neck cancer. In this review, we aim to provide information about tumor budding in head and neck squamous cell carcinoma. Thus, we hope to shed light on the complex biology of these malignancies, as well as aiding diagnostic, classification, and better characterization and thereby, looking for new avenues for improving patient outcomes.

Clinico-Pathological Features, Outcomes and Impacts of COVID-19 Pandemic on Patients with Early-Onset Colorectal Cancer: A Single-Institution Experience.

The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic. We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old. A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%). EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determined.

5ʹ-Ectonucleotidase CD73/NT5E supports EGFR-mediated invasion of HPV-negative head and neck carcinoma cells

BackgroundEpithelial-to-mesenchymal transition (EMT) of malignant cells is a driving force of disease progression in human papillomavirus-negative (HPV-negative) head and neck squamous cell carcinomas (HNSCC). Sustained hyper-activation of epidermal growth factor receptor (EGFR) induces an invasion-promoting subtype of EMT (EGFR-EMT) characterized by a gene signature (“‘EGFR-EMT_Signature’”) comprising 5´-ectonucleotidase CD73. Generally, CD73 promotes immune evasion via adenosine (ADO) formation and associates with EMT and metastases. However, CD73 regulation through EGFR signaling remains under-explored and targeting options are amiss.MethodsCD73 functions in EGFR-mediated tumor cell dissemination were addressed in 2D and 3D cellular models of migration and invasion. The novel antagonizing antibody 22E6 and therapeutic antibody Cetuximab served as inhibitors of CD73 and EGFR, respectively, in combinatorial treatment. Specificity for CD73 and its role as effector or regulator of EGFR-EMT were assessed upon CD73 knock-down and over-expression. CD73 correlation to tumor budding was studied in an in-house primary HNSCC cohort. Expression correlations, and prognostic and predictive values were analyzed using machine learning-based algorithms and Kaplan–Meier survival curves in single cell and bulk RNA sequencing datasets.ResultsCD73/NT5E is induced by the EGF/EGFR-EMT-axis and blocked by Cetuximab and MEK inhibitor. Inhibition of CD73 with the novel antagonizing antibody 22E6 specifically repressed EGFR-dependent migration and invasion of HNSCC cells in 2D. Cetuximab and 22E6 alone reduced local invasion in a 3D-model. Interestingly, combining inefficient low-dose concentrations of Cetuximab and 22E6 revealed highly potent in invasion inhibition, substantially reducing the functional IC50 of Cetuximab regarding local invasion. A role for CD73 as an effector of EGFR-EMT in local invasion was further supported by knock-down and over-expression experiments in vitro and by high expression in malignant cells budding from primary tumors. CD73 expression correlated with EGFR pathway activity, EMT, and partial EMT (p-EMT) in malignant single HNSCC cells and in large patient cohorts. Contrary to published data, CD73 was not a prognostic marker of overall survival (OS) in the TCGA-HNSCC cohort when patients were stratified for HPV-status. However, CD73 prognosticated OS of oral cavity carcinomas. Furthermore, CD73 expression levels correlated with response to Cetuximab in HPV-negative advanced, metastasized HNSCC patients.ConclusionsIn sum, CD73 is an effector of EGF/EGFR-mediated local invasion and a potential therapeutic target and candidate predictive marker for advanced HPV-negative HNSCC.

Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets.

Colorectal cancer (CRC) is a major health burden worldwide and is the third most common type of cancer. The early detection and diagnosis of CRC is critical to improve patient outcomes. This review explores the intricate interplay between the tumor microenvironment, stromal interactions, and the progression and metastasis of colorectal cancer. The review begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and the implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. This review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.

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.

Clinicopathological and prognostic significance of PD-L1 expression in colon adenocarcinoma tumor budding

ObjectiveIn this study, we investigated the relationship between programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in colon adenocarcinoma tumor budding. MethodsThis study included 122 patients with colon adenocarcinomas. The largest sample of formaldehyde-fixed paraffin-embedded tumor tissues was selected for analysis. Expression of membranous PD-L1 (clone 22C3) and the Combined Positive Score (CPS) in tumor tissues was calculated and graded according to the percentages of peritumoral and intratumoral tumor cells (0 %, 1 %, 1–5 %, >5 %). The effects of these factors on the prognosis were analyzed. ResultsTumor budding was associated with adverse clinicopathological features and poor overall survival. PD-L1 (CPS%) peritumoral tumor budding (1 %/<1 %) was statistically significant in the univariate model (p = 0.004). Age, organ metastases (liver, lung, liver, lung, and peritoneum), and metastases were statistically significant in the multivariate model (p = 0.001, p = 0.004, p = 0.001, p = 0.002, p = 0.004, and p = 0.032, respectively). PD-L1 positive staining was mostly observed around the tumor and during tumor budding. PD-L1 peritumoral tumor budding rates and patients' survival rates differed significantly (log-rank = 12.07, p = 0.007). ConclusionWe found that patients with PD-L1 (CPS%) > 1 % in tumor budding had a shortened life expectancy and demonstrated the importance of including tumor budding areas in the samples used for biomarker evaluation. We previously reported that PD-L1 expression in tumor budding is associated with more aggressive cancer biology and poor survival, although overall survival is of limited statistical significance.

Buds, clusters, and transitions in 21st century colorectal carcinoma: revolution or reinvention?†.

Tumour budding (TB) describes single or small groups of neoplastic cells that lack continuity with an advancing tumour front. Poorly differentiated clusters (PDCs) are larger and qualitatively different. TB grade and PDCs may predict a worse outcome in colorectal carcinoma and other cancers and fall into the category of 'invasive front prognostic markers' that also includes intratumoural stroma type. Epithelial-mesenchymal transition (EMT) allows the adoption by epithelial cells of mesenchymal characteristics such as dyscohesion, migration, and stromal invasion. TB and PDCs harbor alterations in EMT-related proteins and RNAs and may be morphological manifestations of EMT. However, persistence of epithelioid features and absence of a full complement of typical alterations in TB and PDCs may indicate 'partial EMT', i.e. an intermediate/hybrid state. Recently, Pavlič et al asserted that TB and PDCs in colorectal cancer represent different manifestations of partial EMT and, perhaps controversially, that TB is closer than PDCs to complete transition. In clinical practice, low inter-observer agreement for invasive front prognostic markers is a potential problem. The UK colorectal cancer pathology dataset advises assessment of TB and recommends the use of an international consensus system, but time will tell if we are adopting reliable prognostic markers or reinventing the wheel. Additional studies of TB, PDCs, and EMT will presumably allow greater insight into their role in tumour development and progression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Proposal of a grading system for squamous cell carcinoma of the lung - the prognostic importance of tumour budding, single cell invasion, and nuclear diameter.

The prognostic markers of lung squamous cell carcinoma (LSCC) are less investigated. The aim of our study was to evaluate tumour budding (TB), minimal cell nest size, nuclear diameter (ND), and spread through air spaces (STAS) among patients with resected LSCC, semi-quantitatively. Furthermore, we aimed to identify a grading system for the best prognostic stratification of LSCC. Patients who underwent surgical resection at the Department of Surgery, University of Szeged between 2010 and 2016 were included. Follow-up data were collected from medical charts. Morphological characteristics were recorded from histologic revision of slides. Kaplan-Meier analysis, log rank test and Cox proportional-hazards model, ROC curve analysis, and intraclass correlation were utilised. Altogether 220 patients were included. In univariate analysis, higher degree of TB, infiltrative tumour border, larger ND, the presence of single cell invasion (SCI) and STAS were associated with adverse prognosis. Based on our results, we proposed an easily applicable grading scheme focusing on TB, ND, and SCI. In multivariate analysis, the proposed grading system (pOS< 0.001, pRFS< 0.001) and STAS (pOS= 0.008, pRFS< 0.001) were independent prognosticators. Compared to the previously introduced grading systems, ROC curve analysis revealed that the proposed grade had the highest AUC values (AUCOS: 0.83, AUCRFS: 0.78). Each category of the proposed grading system has good (ICC: 0.79-0.88) reproducibility. We validated the prognostic impact of TB, SCI, ND, and STAS in LSCC. We recommend a reproducible grading system combining TB, SCI, and ND for proper prognostic stratification of LSCC patients. Further research is required for validation of this grading scheme.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes

BackgroundGrading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. ObjectiveTo develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. Design, setting, and participantsTissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. Outcome measurements and statistical analysisGGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. Results and limitationsIntegration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. ConclusionsWe propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. Patient summaryWe developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

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.

Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection.

Up to 15% of colorectal polyps are amenable for conventional polypectomy. Advanced endoscopic resection techniques are introduced for the treatment of those polyps. They provide higher en bloc resection rates compared with conventional techniques, while helping patients to avoid the complications of surgery. Note that 20 mm is considered as the largest size of a polyp that can be resected by polypectomy or endoscopic mucosal resection (EMR) in an en bloc fashion. Endoscopic submucosal dissection (ESD) is recommended for polyps larger than 20 mm. Intramucosal carcinomas and carcinomas with limited submucosal invasion can also be resected with ESD. EMR is snare resection of a polyp following submucosal injection and elevation. ESD involves several steps such as marking, submucosal injection, incision, and dissection. Bleeding and perforation are the most common complications following advanced endoscopic procedures, which can be treated with coagulation and endoscopic clipping. En bloc resection rates range from 44.5 to 63% for EMR and from 87.9 to 96% for ESD. Recurrence rates following EMR and ESD are 7.4 to 17% and 0.9 to 2%, respectively. ESD is considered enough for the treatment of invasive carcinomas in the presence of submucosal invasion less than 1000 μm, absence of lymphovascular invasion, well-moderate histological differentiation, low-grade tumor budding, and negative resection margins.

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.