Budding Score Research Articles

Potentials of pretreatment [18F]FDG PET/CT for non-invasive prediction of the tumor unfavorable pathological indices and microenvironment in NSCLC

PurposeTo investigate pretreatment [18F]FDG PET/CT in predicting tumor pathological features and microenvironment.MethodologyFifty-one patients with histo-pathologically proven non-small cell lung cancer (NSCLC) underwent pretreatment [18F]FDG PET/CT, and their clinicopathological data were collected. PET-derived biomarkers (SUVmax, mean, MTV, and TLG), consolidation-to-tumor ratio (CTR), and histopathological data (tumor grade, differentiation, tumor histological subtype, tumor-infiltrating lymphocytes (TILs), degree of desmoplasia, degree of necrosis, tumor budding, and nuclear grade), as well as a proposed risk stratification pathological scoring system, were all assessed.ResultsA CTR cut-off point of 0.34 was able to discriminate between low- and high-grade tumors with a sensitivity and specificity of 75.9% and 68.2%, respectively (p = 0.012). Low CTR was significantly associated with the tumor pathological subtype “adenocarcinoma,” low nuclear grade, negative tumor necrosis, and low pathological scores, respectively (p < 0.05). No significant associations were observed for CTR with tumor budding score, desmoplasia score, or TILs% (p-values > 0.05). High SUVmax (> 12.64) and high SUVmean (> 4.28) values were significantly associated with SCC tumors (p = 0.023 and 0.04, respectively). SUVmean was significantly associated with cytological differentiation (p = 0.023). A statistical trend was noted for SUVmax concerning nuclear grade and desmoplasia scores (p = 0.068 and 0.061, respectively). No statistically significant associations were revealed for MTV and TLG concerning different pathological features (p-values > 0.05). Primary lung tumors positive for desmoplasia revealed higher metabolic activity regarding SUVmax, with a statistical trend observed (p = 0.072). No statistically significant associations were observed concerning other metabolic parameters (p-values > 0.05).ConclusionPET/CT-derived biomarkers appear promising for predicting tumor unfavorable pathological features and microenvironment in NSCLC.

Correlation of tumor budding with a novel and other established prognostic parameters in patients with invasive breast carcinoma.

Breast cancer is the most common malignancy among women. Established prognostic markers in breast carcinomas include tumor size, histologic grade, nodal status, lymphovascular invasion, perineural invasion, hormone receptor status, HER-2 status, and age. To correlate peripheral tumor budding (pTB) with stromal tumor-infiltrating lymphocytes (sTILs) and established prognostic factors in invasive breast carcinoma. It is a retrospective study conducted at multiple centers including a tertiary care center. 100 cases were included over a period of 2.5 years. All cases of invasive breast carcinoma (IBC) in which excision specimens with lymph node dissection were available were studied. Slides were reviewed for pTB and sTILs. Tumor budding of ≤20/10 hpf was considered low tumor budding, and >20 buds/10 hpf was considered high tumor budding. Tumor budding was correlated with age, tumor size, lymphovascular invasion, perineural invasion, tumor stage (pT, pN), stromal tumor-infiltrating lymphocytes, tumor grade, ductal carcinoma in situ, hormonal receptors, and HER2neu. Fisher exact test and Chi-square test were used. We found that high tumor budding was seen in 34 cases and low tumor budding in 66 cases. There was a statistically significant association between high tumor budding and tumor size (P = 0.007), lymphovascular invasion (P < 0.001), perineural invasion (P = 0.004), tumor staging/pT (P = 0.006), nodal staging/pN (P = 0.001), and low sTILs (P < 0.001). However, the association of high tumor budding with parameters like age (P = 0.979), histological type (P = 0.243), tumor grade (P = 0.052), DCIS (P = 0.478), and ER (P = 0.633), and PR (P = 0.544), HER2Neu status (P = 0.171) was not significant. This study suggests tumor budding score can be used as a prognostic indicator for breast cancer.

Treatment strategy for cervical lymph node metastases from early-stage tongue and floor of the mouth squamous cell carcinoma using tumour budding and depth of invasion as predictors

ObjectivesThis study aimed to determine whether elective neck dissection can help improve outcomes in early-stage tongue and floor squamous cell carcinoma (SCC) by statistically analysing the relationship between information obtained from biopsy specimens and the incidence and prognosis of cervical lymph node metastasis (CLM).Materials and methodsBiopsy specimens of 103 patients diagnosed with early cT1–T2 cancer of the tongue and floor of the mouth were included.ResultsMultivariate analysis showed that the three parameters significantly correlated with CLM, and univariate analyses showed that budding score (BS) ≥ 5 and pathological depth of invasion (pDOI) ≥ 5 mm were independent risk factors for CLM. There were significant differences in the 5-year cumulative disease-specific survival between the BS < 5 and BS ≥ 5 groups, the pDOI < 5 mm and pDOI ≥ 5 mm groups, and the positive and negative budding and depth of invasion (BD) score groups.ConclusionIn early-stage tongue and floor of the mouth cancers with maximum tumour diameter ≤ 20 mm, it may be necessary to treat occult CLM during initial surgery based on the following preoperative criteria: pDOI ≥ 5 mm or BS ≥ 5 in biopsy specimens and DOI ≥ 8 mm on imaging. The BD model exhibited the highest specificity and proved helpful for CLM prediction.Clinical relevancepDOI ≥ 5 mm and BS ≥ 5 were independent predictors of CLM and prognosis in early-stage tongue and floor of the mouth cancers with a maximum tumour diameter of 20 mm.

Multicenter Study on Tumor Budding in Lung Squamous Cell Carcinoma: Comparison Between Biopsy and Resection With Interobserver Variability Assessment

Grading lung squamous cell carcinoma (LUSC) is controversial and not universally accepted. The histomorphologic feature of tumor budding (TB) is an established independent prognostic factor in colorectal cancer, and its importance is growing in other solid cancers, making it a candidate for inclusion in tumor grading schemes. We aimed to compare TB between preoperative biopsies and resection specimens in pulmonary squamous cell carcinoma and assess interobserver variability. A retrospective cohort of 249 consecutive patients primarily resected with LUSC in Bern (2000-2013, n = 136) and Lausanne (2005-2020, n = 113) with available preoperative biopsies was analyzed for TB and additional histomorphologic parameters, such as spread through airspaces and desmoplasia, by 2 expert pathologists (M.M., C.N.). Results were correlated with clinicopathologic parameters and survival. In resection specimens, peritumoral budding (PTB) score was low (0-4 buds/0.785 mm2) in 47.6%, intermediate (5-9 buds/0.785 mm2) in 27.4%, and high (≥10 buds/0.785 mm2) in 25% of cases (median bud count, 5; IQR, 0-26). Both the absolute number of buds and TB score were similar when comparing tumor edge and intratumoral zone (P = .192) but significantly different from the score obtained in the biopsy (P < .001). Interobserver variability was moderate, regardless of score location (Cohen kappa, 0.59). The discrepant cases were reassessed, and consensus was reached in all cases with identification of causes of discordance. TB score was significantly associated with stage (P = .002), presence of lymph node (P = .033), and distant metastases (P = .020), without significant correlation with overall survival, tumor size, or pleural invasion. Desmoplasia was significantly associated with higher PTB (P < .001). Spread through airspaces was present in 34% and associated with lower PTB (P < .001). To conclude, despite confirming TB as a reproducible factor in LUSC, we disclose areas of scoring ambiguity. Preoperative biopsy evaluation was insufficient in establishing the final TB score of the resected tumor.

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

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

Evaluation of the Immunohistochemical Scoring System of CDX2 Expression as a Prognostic Biomarker in Colon Cancer.

Encoded by the CDX2 homeobox gene, the CDX2 protein assumes the role of a pivotal transcription factor localized within the nucleus of intestinal epithelial cells, orchestrating the delicate equilibrium of intestinal physiology while intricately guiding the precise development and differentiation of epithelial tissue. Emerging research has unveiled that positive immunohistochemical expression of this protein shows that the CDX2 gene exerts a potent suppressive impact on tumor advancement in colorectal cancer, impeding the proliferation and distant dissemination of tumor cells, while the inhibition or suppression of CDX2 frequently correlates with aggressive behavior in colorectal cancer. In this study, we conducted an immunohistochemical assessment of CDX2 expression on a cohort of 43 intraoperatively obtained tumor specimens from patients diagnosed with colon cancer at Colțea Clinical Hospital in Bucharest, between April 2019 and December 2023. Additionally, we shed light on the morphological diversity within colon tumors, uncovering varying differentiation grades within the same tumor, reflecting the variations in CDX2 expression as well as the genetic complexity underlying these tumors. Based on the findings, we developed an innovative immunohistochemical scoring system that addresses the heterogeneous nature of colon tumors. Comprehensive statistical analysis of CDX2 immunohistochemical expression unveiled significant correlations with known histopathological parameters such as tumor differentiation grades (p-value = 0.011) and tumor budding score (p-value = 0.002), providing intriguing insights into the complex involvement of the CDX2 gene in orchestrating tumor progression through modulation of differentiation processes, and highlighting its role in metastatic predisposition. The compelling correlation identified between CDX2 expression and conventional histopathological parameters emphasizes the prognostic significance of the CDX2 biomarker in colon cancer. Moreover, our novel immunohistochemical scoring system reveals a distinct subset of colon tumors exhibiting reserved prognostic outcomes, distinguished by their "mosaic" CDX2 expression pattern.

Analyzing Tumor Budding Scores in Invasive Breast Carcinoma: A Tertiary Care Center Study in South India

ABSTRACT Introduction and Aim: Tumor budding is a distinctive phenomenon which involves the presence of small clusters or individual cancer cells at the invasive front of tumors. Tumor budding has garnered attention due to its potential implications for prognosis, treatment strategies, and our understanding of cancer progression. Our aim is to study the distribution of tumor buds and its scoring in patients with infiltrating breast carcinoma and to associate with other histopathological parameters like the size of the tumor, its grade, lymphovascular invasion, and lymph node metastasis. Materials and Methods: This was a study analyzing the data of 70 resected specimens of primary breast carcinomas and providing a descriptive overview. Tumor budding was recognized, counted, and graded in hematoxylin and eosin slides. The cases were classified as low (0–4), intermediate (5–9), and high (≥10 buds) based on the count of tumor buds. Tumor budding has significant correlation with tumor grade and tumor size. Results: Of the 70 cases, 60 cases (85.71%) were diagnosed as invasive ductal carcinoma NOS. The majority [38 (54.28%)] of the cases showed an intermediate tumor budding score of 5–9/10 HPF. Conclusion: Evaluation of tumor budding allows pathologists and oncologists to gather valuable information about the tumor’s biological aggressiveness and potential for metastasis. It also helps in better risk stratification of patients, enabling a more personalized and tailored approach to treatment planning. In conclusion, assessing tumor budding in breast carcinoma holds significant clinical importance in the management and prognosis of this disease.

Unraveling a Histopathological Needle-in-Haystack Problem: Exploring the Challenges of Detecting Tumor Budding in Colorectal Carcinoma Histology

Background: In this study focusing on colorectal carcinoma (CRC), we address the imperative task of predicting post-surgery treatment needs by identifying crucial tumor features within whole slide images of solid tumors, analogous to locating a needle in a histological haystack. We evaluate two approaches to address this challenge using a small CRC dataset. Methods: First, we explore a conventional tile-level training approach, testing various data augmentation methods to mitigate the memorization effect in a noisy label setting. Second, we examine a multi-instance learning (MIL) approach at the case level, adapting data augmentation techniques to prevent over-fitting in the limited data set context. Results: The tile-level approach proves ineffective due to the limited number of informative image tiles per case. Conversely, the MIL approach demonstrates success for the small dataset when coupled with post-feature vector creation data augmentation techniques. In this setting, the MIL model accurately predicts nodal status corresponding to expert-based budding scores for these cases. Conclusions: This study incorporates data augmentation techniques into a MIL approach, highlighting the effectiveness of the MIL method in detecting predictive factors such as tumor budding, despite the constraints of a limited dataset size.

Immunohistochemical Expression of Immune Checkpoints; CTLA-4, LAG3, and TIM-3 in Cancer Cells and Tumor-infiltrating Lymphocytes (TILs) in Colorectal Carcinoma.

Colorectal cancer is considered the third most prevalent cancer in both sexes. Immune checkpoint receptors that regulate T-cell response, stimulation, and development include lymphocyte activating gene 3 (LAG-3), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and T-cell immunoglobulin and mucin domain 3 (Tim-3). In addition, they are crucial for the advancement of cancer and tumor immune escape. This work's aim was to assess the immunohistochemistry expression of Tim-3, CTLA-4, and LAG-3 in cancer cells and tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) and the correlation between these markers and clinicopathological variables and survival data. This study involved 206 CRC specimens processed for CTLA-4, LAG3, and TIM-3 immunohistochemistry and correlated with the clinicopathological and survival parameters of the patients. High CTLA-4 epithelial expression was highly related to the old age group, large tumor size, low tumor-stroma ratio (TSR), high grade, advanced stage, the presence of distant metastasis (DM), perineural invasion (PNI), necrosis, lymphovascular invasion (LVI), relapse, mortality, overall survival (OS), and disease-free survival (DFS), while negative CTLA-4 TILs expression was highly linked with the presence of gross perforation, low TSR, high tumor budding (TB) score, high grade, advanced stage, the existence of lymph node (LN) metastasis, DM, necrosis, LVI, PNI, DFS, mortality, and OS. Positive LAG-3 TILs expression was highly correlated with large tumor size, gross perforation, low TSR, high TB score, high grade, advanced phase, the presence of LN, necrosis, LVI, PNI, relapse DFS, mortality, and OS. High Tim-3 epithelial expression was extremely linked with low TSR, advanced phase, the presence of LN, LVI, PNI, relapse, DFS, mortality, and OS, while positive Tim-3 TILs expression was related to gross perforation, low TSR, high TB score, advanced stage, the presence of LN, DM, necrosis, relapse, DFS, mortality, and OS. The patients' poor prognosis may be related to the immunohistochemistry expression of LAG-3, Tim-3, and CTLA-4 in CRC cancer tissue and TILs. Poor patient consequences can result from the CTLA-4, Tim-3, and LAG-3 co-expression, but CTLA-4 TILs' expression of these proteins may inhibit the growth of tumors.

New Histopathologic Risk Model for Early T-stage Oral Squamous Cell Carcinoma: Focusing on a Modified Worst Pattern of Invasion System and a New Tumor Budding Score.

Oral squamous cell carcinoma (OSCC) is treated based on the TNM staging. However, early T-stage OSCC still exhibits substantial nodal metastasis and death rates. Recent literature highlights the independent prognostic value of worst pattern of invasion (WPOI) and tumor budding in OSCC. Nevertheless, WPOI-5 is uncommon in early T-stage OSCC, and the definitions of tumor budding and WPOI-4 overlap. Moreover, WPOI assessment is subjective, and tumor budding evaluation varies across studies. To address these limitations, we aimed to develop a modified WPOI system and a novel tumor budding scoring system that assesses single cells and high-density tumor budding. We also evaluated a new histopathologic risk model for early T-stage OSCC. The study cohort comprised 37 pT1 and 64 pT2 OSCCs. The modified WPOI demonstrated superior interobserver agreement compared with the original system (κ value: 0.98 vs. 0.53). In the multivariate analysis, modified WPOI and tumor budding score were independent prognostic factors for nodal metastasis and disease-free survival, while modified WPOI predicted disease-specific survival. By integrating these factors, our risk model stratified the patients into 3 groups. Notably, the intermediate-risk and high-risk groups exhibited significantly higher rates of nodal metastasis, recurrence, and tumor-related death. Conversely, none in the low-risk group had nodal metastasis or succumbed to the disease. Our model offered simplified scoring and potentially improved prognostic predictions. In conclusion, we've developed a modified WPOI system, a new tumor budding scoring system, and a reliable risk model that classifies early T-stage OSCC patients into distinct risk groups with significant prognostic differences.

Prognostic value of histopathological grading systems in lip and tongue squamous cell carcinoma

We evaluated the prognostic value of 3 histopathological grading systems in lower lip squamous cell carcinoma (LLSCC) and oral tongue SCC (OTSCC) cases. We examined 62 OTSCC cases and 69 LLSCC cases using the tumor budding/depth (BD), tumor-stroma ratio (TSR), and TSR/tumor budding models and analyzed the relationship between clinicopathological parameters and patient prognosis based on overall survival (OS) and disease-free survival (DFS). In OTSCC cases, T3 and T4 tumors were significantly associated with 5 or more tumor buds and a high BD score. In LLSCC cases, tumor budding was significantly associated with OS, BD score (OS and DFS, P < .001), and TSR/tumor budding score (OS, P=.002; DFS, P=.012). Invasion depth was also associated with OS in LLSCC (P=.019). Multivariate analysis revealed that tumor budding in LLSCC remained significantly associated with OS and BD risk score with DFS, demonstrating their independent prognostic value. The BD grading system was associated with clinicopathologic parameters of greater aggressiveness in OTSCC, whereas the BD and TSR/tumor budding systems showed prognostic value in LLSCC. These findings suggest the potential use of these grading systems as adjuvant methods for prognostic analysis in patients with OTSCC and LLSCC.

Effect of microsatellite instability on histopathological parameters and prognosis in colon cancers

Purpose: The aim of this study was to compare the clinicopathological features, while evaluating the frequency of MSI, and the survival rates in these patients in our patient group with MSI and microsatellite stabil (MSS) colorectal carcinomas (CRCs).Materials and Methods: We retrospectively enrolled 146 patients who underwent colon resection between the years of 2014-2022. The expression of MSI status was evaluated by immunohistochemistry. The association of MSI status, presense of tumor-infiltrating lymphocytes (TILs), and tumor budding score with a patient’s survival was assessed by the Kaplan–Meier method and Cox regression analysis.Results: There were 104 (71.2%) MSS cases and, 42 (28.8%) MSI cases. 15 (10.3%) MSI tumors were found to be MSI-low, and 27 (18.5%) to be MSI-high. MSI tumors were significantly associated with younger patients (&amp;lt;50), earlier stage (T1-T2), right localization, lower rate of lymph node metastasis, presence of mucinous component and TILs response. The Cox-regression model revealed TILs, tumor budding score, and MSI are variables that significantly affect survival. The presence of TILs exhibited a protective effect (Hazard ratio (HR)=0.446), which decreased the mortality risk by 2.24 times for the follow-up period, while the presence of high TBS increased the risk of mortality by HR=3.22.Conclusion: This study revealed that patients with MSI CRCs may show unique clinicopathological features and should be evaluated using some guiding parameters that will improve survival.

Semi-Supervised Learning to Automate Tumor Bud Detection in Cytokeratin-Stained Whole-Slide Images of Colorectal Cancer

Tumor budding is a histopathological biomarker associated with metastases and adverse survival outcomes in colorectal carcinoma (CRC) patients. It is characterized by the presence of single tumor cells or small clusters of cells within the tumor or at the tumor-invasion front. In order to obtain a tumor budding score for a patient, the region with the highest tumor bud density must first be visually identified by a pathologist, after which buds will be counted in the chosen hotspot field. The automation of this process will expectedly increase efficiency and reproducibility. Here, we present a deep learning convolutional neural network model that automates the above procedure. For model training, we used a semi-supervised learning method, to maximize the detection performance despite the limited amount of labeled training data. The model was tested on an independent dataset in which human- and machine-selected hotspots were mapped in relation to each other and manual and machine detected tumor bud numbers in the manually selected fields were compared. We report the results of the proposed method in comparison with visual assessment by pathologists. We show that the automated tumor bud count achieves a prognostic value comparable with visual estimation, while based on an objective and reproducible quantification. We also explore novel metrics to quantify buds such as density and dispersion and report their prognostic value. We have made the model available for research use on the grand-challenge platform.

The Chart Diagnostic System Improves the Diagnostic Accuracy of Cervical Lymph Node Metastasis in Oral Squamous Cell Carcinoma

Purpose: To establish a diagnosis method based on imaging findings and histopathological factors associated with cervical lymph node metastasis. Methods: A total of 1587 cervical lymph nodes that were detected using imaging tools in 73 OSCC patients who underwent surgical treatment were enrolled to evaluate the association between imaging findings (long diameter, short diameter, long–short ratio, US findings (hilum and internal echo), contrast effect with enhanced CT, standardized uptake value (SUV) max and SUV average with 18F FDG-Positron Emission Tomography (PET)) and metastatic cervical lymph nodes. In 57 OSCC patients, biopsy specimens were evaluated for histopathologic factors (budding score, lymphatic invasion, vascular invasion, nerve invasion, and YK classification) and the presence of cervical lymph node metastases. Cervical lymph node metastasis was determined based on histopathological examination of the lymph nodes of patients with no metastasis observed 3 years after primary surgery. Results: In total, 22 of the 73 patients had cervical lymph node metastasis pathologically. In the comparison of the presence of metastatic lymph nodes, univariate analysis showed significant differences in cervical lymph node long and short diameter, long/short ratio, internal echo, rim enhancement, SUV max, SUV average, budding score, and vascular invasion. Multivariable analysis showed significant differences in internal echo, rim enhancement, SUV max, and budding score. Conclusions: We propose a chart diagnostic system that combines imaging and histopathological findings to improve the diagnosis of cervical lymph node metastasis.

Associations of Complete Blood Count Parameters with Disease-Free Survival in Right- and Left-Sided Colorectal Cancer Patients.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Some complete blood count (CBC) parameters are found to be associated with CRC prognosis. In this study, ninety-seven pretreated CRC patients were included, and the patients were divided into two groups: left-sided and right-sided, depending on the anatomical location of the tumor. Based on clinicopathologic features including tumor budding, disease stages, and tumor anatomical location, levels of CBC parameters were compared, and disease-free survivals (DFS) were determined. There were differences between patients with different tumor budding scores for only three parameters, including red cell distribution width (RDW), numbers of platelets, and mean platelet volume (MPV). Furthermore, numbers of WBCs, monocytes, and MPV in CRC patients with early disease stages were higher than those with advanced stages. However, levels of eosinophil in CRC patients with advanced stages were higher than those with early stages. Depending on the tumor anatomical location, we observed that numbers of red blood cells (RBCs), hemoglobin (Hgb), and hematocrit (Hct) in CRC patients with left-sided tumors were higher than those with right-sided tumors. We found that low levels of MPV were associated with shorter DFS. However, high levels of eosinophils were associated with shorter DFS in all CRC patients. When patients were divided based on the tumor anatomical location, higher levels of MPV, MCHC, and Hgb were associated with better DFS in the left-sided but not right-sided CRC patients. However, left-sided, but not right-sided, CRC patients with high levels of eosinophil and RDW had shorter DFS. Furthermore, right-sided, but not left-sided, CRC patients with high levels of platelets tended to have a shorter DFS. Our data show that MPV and eosinophils could serve as potential prognostic biomarkers in pre-treatment CRC patients, regardless of the tumor anatomical location. Additionally, lower levels of MPV, MCHC, and Hgb, and high levels of eosinophils and RDW could be negative predictive biomarkers in left-sided CRC patients.

Tumoral and Parenchymal Morphological Assessment in Liver Metastases of Colorectal Carcinoma: Micrometastasis, Peritumoral Lymphocytes, Tumor Budding and Differentiation are Potential Prognostic Factors.

Introduction: Various potential prognostic histopathologic factors for colorectal carcinoma liver metastasis have been proposed. However, there is still no consensus on pathological reporting of colorectal carcinoma liver metastasis resection materials. The aim of this study was to investigate the relation between selected tumoral and parenchymal histopathologic features and prognostic factors for better characterization and prognostic prediction of the patients with colorectal carcinoma liver metastasis. Methods: Hematoxylin-eosin stained slides from 100 patients who underwent hepatic resection were evaluated. Pathologic characteristics; including number of tumor nodules, largest tumor size, status of surgical margin, tumor distance to closest margin, tumor necrosis, the presence of tumor capsule, tumor differentiation, perineural and lymphovascular invasion, micrometastasis, tumor budding, peritumoral lymphocytic infiltrate and parenchymal features including steatosis, steatohepatitis, lobular inflammation, confluent necrosis, hepatocyte ballooning, portal inflammation were assessed. For 49 patients who were treated with preoperative chemotherapy, tumor regression grade and chemotherapy-related parenchymal changes such as sinusoidal damage, venous obstruction, nodular regenerative hyperplasia, steatosis and steatohepatitis were also evaluated. Results: The presence of lymphovascular invasion (p < 0.001), micrometastasis (p=0.004), absent or mild peritumoral lymphocytic infiltration (p =0.013), high tumor budding score (p=0.033) and moderate/poor differentiation (p=0.022) were significantly associated with shorter overall survival. Lymphovascular invasion (p < 0.001) was an independent predictor of mortality in multivariate analysis. Conclusions: We conclude that tumor differentiation, lymphovascular invasion, micrometastasis, peritumoral lymphocytic reaction and tumor budding score are potential prognostic histopathological features and candidates for inclusion in pathology reports of colorectal carcinoma liver metastasis resections.

Tumour budding in colorectal carcinoma: Association with other histopathological prognostic parameters

Colorectal carcinoma (CRC) is the third leading cancer in India. Pathologists play a crucial role in assessing stage, analyzing surgical margins and documenting the histopathologic prognostic parameters. Tumour budding is one such prognostic parameter, defined as single cells or small groups of tumour cells (up to 4 cell clusters) at the invasive front of the tumour. The aim of this study is to examine the association of tumour budding with other histopathological prognostic parameters in patients with colorectal carcinoma.TheHematoxylin &amp; Eosin (H &amp;E) stained slides of 52 histopathologically diagnosed CRC resection specimens were reviewed and tumour budding (BD) was assessed into four grades under 200x power. Other histopathological prognostic parameters like tumour size, site, grade, laterality, lymphovascular invasion, perineural invasion, T and N stage were analyzed using descriptive statistics and Chi-square test with Software SPSS version 23.A higher BD score is seen to be more often associated with grade 3 tumour morphology, presence of perineural invasion, tumour size of 5cm or more and tumours located in the sigmoid colon or rectum. No association of tumour budding is seen with TIL’s or tumour of size &amp;#60; 5cm.Tumour budding is a practical and significant histological index for identification of high malignant potential and poor outcome in CRC patients with rectal or sigmoid colon location, size more than 5cm, perineural invasion and higher histological grade. Tumour budding may help identify patients who need a more intensive postoperative follow up and the possibility of adjuvant therapy.

Tumor Budding Score Is a Strong and Independent Prognostic Factor in Patients With Pancreatic Ductal Adenocarcinoma: An Evaluation of Whole Slide Pathology Images of Large Sections.

ObjectiveWe aimed to develop the tumor budding (TB) score and to explore the association between the TB score and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC).MethodsIn this retrospective study, 130 consecutive patients with PDAC underwent surgical resection between July 2016 and March 2019. The location and counts of TB were assessed based on the digitalized whole slide hematoxylin and eosin images. The TB score was achieved using the Cox regression equation. The cutoff point for the TB score was determined by X-tile. Univariate and multivariate Cox regression models were used to analyze the association between the TB score and OS.ResultsThe TB score was 0.49 (range = 0–1.08), and the best cutoff for the TB score was 0.62. The duration of survival in individuals with a low TB score [median = 21.8 months, 95% confidence interval (CI) = 15.43–25.50] was significantly longer than that in those with a high TB score (median = 11.33 months, 95% CI = 9.8–14.22). Univariate analysis revealed that the TB score was significantly associated with OS [hazard ratio (HR) = 2.71, 95% CI = 1.48–4.96, p = 0.001]. Multivariate analysis revealed a strong and independent association between the TB score and OS (HR = 2.35, 95% CI = 1.27–4.33, p = 0.03). The high TB score group had a 2.14 times higher mortality than the low TB score group.ConclusionThe TB score is strongly and independently associated with the risk of OS in PDAC.

The role and relationship between programmed death ligand 1 and cytotoxic T lymphocyte-associated antigen-4 immunohistochemical expression in colorectal carcinoma patients: an impact on outcome.

BackgroundGlobally, colorectal carcinoma (CRC) is the third most common cancer diagnosed in both men and women. Programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are immune checkpoints that induce tumour immune escape.AimThis study aimed to evaluate the immunohistochemical expression of PD-L1 and CTLA-4 in CRC and their relationship with clinicopathological parameters and survival data.ResultThis study included 103 CRC, 22 adenoma and 21 non-neoplastic specimens. High PD-L1 epithelial expression was in favour of CRC and high-grade dysplastic adenoma compared to normal specimens. High PD-L1 epithelial expression was associated with larger sized tumours, perforation, advanced T stage, infiltrative tumour border configuration (TBC), high tumour budding (TB) score, low tumour-stroma ratio (TSR) and absence of peritumoural lymphocytes. High PD-L1+ tumour infiltrating lymphocytes (TILs) showed an association with absence of perforation, early T stage, pushing TBC, lower TB score, high TSR and presence of peritumoural lymphocytes. High epithelial CTLA-4 expression was in favour of adenocarcinoma, high-grade dysplastic adenoma and low-grade dysplastic adenoma compared to normal specimens. High CTLA-4 epithelial score showed an association with positive lymph nodes (LNs), presence of an infiltrative TBC and absence of peritumoural lymphocytes. Low CTLA-4+ TILs showed a significant association with advanced tumour stage and increased number of positive LNs. Prolonged survival was associated with low epithelial PD-L1 and CTLA-4, high PD-L1+ TILs and high CTLA-4+ TILs. By multivariate Cox regression analysis, PD-L1+ TILs immunoreactivity score (p = 0.020) and CTLA-4+ TILs H. score (p = 0.036) were independent prognostic factors affecting overall survival among the other prognostic factors.ConclusionPD-L1 and CTLA-4 expression by tumour cells could cooperate with each other in enhancing progression of CRC leading to poor patient outcome, while their expression by TILs could stand against tumour progression.

Expression and localisation of methylthioadenosine phosphorylase (MTAP) in oral squamous cell carcinoma and their significance in epithelial-to-mesenchymal transition

Methylthioadenosine phosphorylase (MTAP) is a rate-limiting enzyme in the methionine salvage pathway, which recycles one carbon unit that is lost during polyamine synthesis back into the methionine cycle. Although MTAP deficiency has been reported in various tumours, MTAP is overexpressed and might promote oncogenesis in other cancers, including prostate and colon cancer. Currently, little is known about the MTAP status of oral squamous cell carcinoma (OSCC). In this study, we immunohistochemically examined the expression of MTAP in surgically resected oral epithelial dysplasia (OED, n=7), carcinoma in situ (CIS) (n=16), and OSCC (n=118). In the normal epithelium, MTAP was only weakly expressed in the cytoplasm of the basal layer cells. In OED, CIS, and OSCC, MTAP was uniformly expressed in the cytoplasm of the dysplastic and cancer cells. In addition to cytoplasmic MTAP expression, 45 of 118 cases (38.1%) exhibited increased nuclear expression of MTAP in the cancer cells at the invasive front. Statistical analysis showed that the concomitant nuclear and cytoplasmic expression of MTAP was associated with a high budding score (p=0.0023); poor differentiation (p=0.0044); aggressive invasion patterns (p=0.0001); and features of epithelial-to-mesenchymal transition (EMT), such as loss of E-cadherin expression (p=0.0003) and upregulated expression of vimentin (p=0.0002), slug (p=0.0002), and laminin 5 (p<0.0001). High expression of protein arginine methyltransferase 1 or 5, the functions of which are reported to be inhibited in MTAP-deficient cancer, was associated with the concomitant nuclear and cytoplasmic expression of MTAP (p<0.0001). Concomitant nuclear and cytoplasmic expression of MTAP was marginally significantly associated with worse 5-year relapse-free survival (p=0.045). These findings suggest that MTAP not only plays a role in the oncogenesis of OSCC, but that it might also make it more aggressive by inducing EMT through its activity in the methionine salvage pathway.