Tumor-stroma Ratio Research Articles

Tumour-stroma ratio to predict pathological response to neo-adjuvant treatment in rectal cancer

IntroductionManagement of rectal cancer has advanced, with an increasing use of neoadjuvant chemoradiotherapy (nCRT). This opens options for organ preserving treatment for those with a major response to nCRT. However, the degree of clinical response, based on MRI and post-treatment biopsies, only poorly matches the degree of actual pathological response. In order to select patients with major pathological response without surgical resection, it is of importance to define tumour markers predicting the degree of pathological response to nCRT. The intra-tumoural tumour-stroma ratio (TSR) might be this marker. MethodsTSR in pre-treatment biopsies was estimated according to the method described by van Pelt et al. The degree of pathological response was assessed on the tumour resection according to tumour regression grading (TRG) by Mandard. The primary endpoint of this study was the difference in pathological response to nCRT between TSR-high and TSR-low groups. ResultsWe found that 26.2% of patients with major response was classified as TSR-high, while 73.8% of patients were classified as TSR-low. A high TSR in pre-treatment biopsies was associated with a lower chance of major-response to nCRT (OR = 0.37, 95%CI; 0.19–0.73), p = 0.004), independent of tumour stage and time between nCRT and surgery. ConclusionIn rectal cancer, TSR in pre-treatment biopsies predicts pathologic response to nCRT, with a high TSR bringing twice the risk of poor to no response compared to low TSR. In future, assessment of TSR may fulfil a role in a therapeutic algorithm identifying patients who will or will not respond to nCRT prior to treatment initiation.

Exploring the combination of tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding with WHO histopathological grading on early-stage oral squamous cell carcinoma prognosis.

While the relevance of the World Health Organization histopathological grading system as a prognostic tool for oral squamous cell carcinoma has received many critics, other histopathological features such as tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding are displaying promising results. Here, we evaluated the prognostic impact of the incorporation of tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding into World Health Organization histopathological grading for patients with oral squamous cell carcinoma. A total of 95 patients with early-stage oral squamous cell carcinoma were enrolled in the study, and World Health Organization tumor grading, tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding were evaluated in surgical slides stained with hematoxylin and eosin. Survival analyses for cancer-specific survival and disease-free survival were performed using Cox regression models, and receiver operating characteristic curves were applied for assessment of the performance of the combinations. Tumor-stroma ratio (stroma-rich) was significantly and independently associated with both shortened cancer-specific survival and poor disease-free survival, individually and in combination with World Health Organization histopathological grading. The combination of tumor-stroma ratio with World Health Organization grading did not improve the discriminatory ability compared to tumor-stroma ratio alone. Although low tumor-infiltrating lymphocytes were associated with shortened cancer-specific survival, the association did not withstand multivariate analysis. However, in combination with World Health Organization grading, low tumor-infiltrating lymphocytes were independently associated with poor cancer-specific survival. The combination of tumor-infiltrating lymphocytes and World Health Organization histopathological grading displayed a better discrimination of poor cancer-specific survival than tumor-infiltrating lymphocytes alone, but not at a significant level. Our findings support tumor-stroma ratio as a potential prognostic marker for patients with oral squamous cell carcinoma, and the incorporation of tumor-infiltrating lymphocytes into the World Health Organization grading system improves the prognostic ability of the tumor grading alone.

Novel Correlations among the Histopathological Components of Oral Squamous Cell Carcinoma

Background: Oral squamous cell carcinoma (OSCC) is an aggressive tumor with high mortality and morbidity rates.
 Aims:In this study, we aimed to probe whether there is association between stromal histopathological parameters with patient data, as well as, the correlation of these parameters with each other.
 MaterialsandMethods:This study was performed at University of Duhok, College of Dentistry, the practical section was carried out between February 2022 and June 2022 as follow:A group of 86 formalin fixed paraffin embedded (FFPE) samples of OSCC and 20 FFPE samplesof healthy gingiva were stained with Hematoxylin and eosin(H&E) and Mason’s trichrome (MT)stains. Tumor/ stroma ratio(TSR), stromal tumor-infiltrating lymphocytes(sTIL), budding activity (BA), cell nest size (CNS), orientation and packing of collagen fibers and collagen fibercontent(CFC) were evaluated. These histomorphological parameters were correlated with clinicopathological characteristics and with each other.
 Statistical Analysis Used: Chi square test, fisher exacts test and spearman’s rank correlation coefficient were used for analyzing our study data.
 Results: Tumor/ stroma ratio, BA, CNS, orientation and packing of collagen fibers, and CFC were significantly associated with pT stage of the tumor. Moreover, significant correlations were observed among TSR, BA, CNS and CFC. In addition, orientation and packing of collagen fibers were significantly correlated with each other.
 Conclusions: Novel correlations were found between collagen fiber features with TSR, BA, and CNS in an easy and cost- effective methods.

PROGNOSTIC SIGNIFICANCE OF TUMOR-STROMA RATIO IN HEAD AND NECK SQUAMOUS CELL CARCINOMA: A SYSTEMATIC REVIEW

<h3>Objectives</h3> To understand the role of the tumor-stroma ratio (TSR) in head and neck squamous cell carcinoma (HNSCC) and to evaluate its prognostic value. <h3>Study Design</h3> An electronic search was performed in PubMed/Medline, Web of Science, Science Direct, Scopus, Embase, and Cochrane Collaboration Library databases. Articles that assessed the relationship between TSR and HNSCC prognosis through analysis of global and/or disease-specific survival were included in the assessment. The quality of evidence was assessed using the Newcastle-Ottawa scale. <h3>Results</h3> After applying the inclusion and exclusion criteria, 9 articles were included. Data from present systematic review indicate that, in squamous cell carcinomas (SCC) of the esophagus and oral cavity, stromal-rich tumors showed lower survival, being TSR associated with high recurrence rates locoregional in the oral cavity and considered an independent prognostic factor for esophageal disease-free survival. Furthermore, a high proportion of stroma in oral SCC was significantly associated with the depth of invasion, pattern of tumor invasion, perineural invasion, location, and size of the primary tumor. <h3>Conclusions</h3> This study demonstrated a strong relationship between TSR and the prognosis in SCC of esophagus and oral cavity.

Correlation between apparent diffusion coefficient and tumor-stroma ratio in hybrid 18F-FDG PET/MRI: preliminary results of a rectal cancer cohort study.

BackgroundTo explore possible correlations between the tumor-stroma ratio (TSR) and different imaging features of fluorine-18-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) in untreated rectal cancer patients.MethodsA patients with rectal cancer were included in this study. All participants were examined preoperatively with whole-body 18F-FDG PET/MRI. Two pathologists evaluated the TSR of tumors together. Apparent diffusion coefficient (ADC) values and PET-related parameters of the primary lesions were measured and compared between the stroma-high and stroma-low groups. Pearson’s correlation or Spearman’s rank correlation were used to evaluate the correlation between the ADC values, PET-related parameters, and pathological indices.ResultsOur results showed that in the untreated rectal cancer patients, the ADC mean values correlated with the TSR (r=0.327; P=0.007), and stroma-high (low TSR) rectal cancer corresponded to relatively lower ADC mean values (813.54±88.68 vs. 879.92±133.18; P=0.018). The ADC mean and ADC minimum (ADCmin) values were found to be negatively correlated with the pathological T stages (r=−0.384, P=0.001; r=−0.416, P=0.001, respectively) as well as the largest tumor diameters (r=−0.340, P=0.005; r=−0.314, P=0.010, respectively) of rectal cancer. In addition, the pathological T stages correlated with all PET-related metabolic parameters, including mean standard uptake value (SUV), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) (r=0.338, P=0.006; r=0.350, P=0.004; r=0.326, P=0.007; and r=0.472, P<0.001, respectively). Our results also identified associations between the ADCmin values and SUVmean, SUVmax, and TLG (r=−0.335, P=0.006; r=−0.343, P=0.005; and r=−0.343, P=0.005, respectively). However, there were no statistical correlations between the PET/MRI parameters and the immunohistochemical (IHC) results.ConclusionsThis study indicated that the intratumoral heterogeneity measured by PET/MRI may reflect characteristics of the tumor microenvironment. Hence, PET/MRI parameters might be helpful in predicting tumor aggressiveness and prognosis.

The Emerging Impact of Tumor Budding in Oral Squamous Cell Carcinoma: Main Issues and Clinical Relevance of a New Prognostic Marker.

Simple SummaryThe results of tumor budding are an independent prognostic factor of locoregional recurrences in many solid cancers, including colorectal, nasopharyngeal, esophageal, and lung cancer. Regarding oral squamous cell carcinoma, tumor budding predicts poor survival outcomes regardless of the tumor subsite and the pathological stage. Several detection methods for tumor budding have been proposed in the literature in order to reach an agreement on a standardized scoring system. However, the lack of a standardized assessment method prevents its evaluation in a multidisciplinary setting. In this context, this study aims to critically review the literature data regarding the prognostic role of tumor budding in oral squamous cell carcinoma. The validation of a tumor budding detection method based on tumor stage and site could be relevant to improving risk stratification and planning the clinical management of patients. Moreover, tumor budding could be included in daily pathological practice to better predict the patient’s outcomes.Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor–stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site.

Tumor-Stroma Ratio and Programmed Cell Death Ligand 1 Expression in Preoperative Biopsy and Matched Laryngeal Carcinoma Surgical Specimen.

Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic and immune cells in the tumor microenvironment. Tumor to stroma ratio (TSR) has been associated with prognosis in different malignancies. The aims of this exploratory investigation were to analyze for the first time the: (i) association between TSR, PD-L1 expression and other clinical–pathological features in laryngeal squamous cell carcinoma (LSCC) biopsies and paired surgical specimens; (ii) prognostic and predictive role of TSR and PD-L1. TSR, PD-L1 expression (in terms of combined positive score [CPS]), and other clinical–pathological features were analyzed in biopsies and surgical specimens of 43 consecutive LSCC cases. A CPS < 1 evaluated on surgical specimens was associated with a low TSR (stroma rich) on both biopsies and surgical specimens (p = 0.0143 and p = 0.0063). Low TSR showed a significant negative prognostic value when evaluated on both biopsies and surgical specimens (HR = 8.808, p = 0.0003 and HR = 11.207, p = 0.0002). CPS ≥ 1 appeared to be a favorable prognostic factor (HR = 0.100, p = 0.0265). The association between bioptic and surgical specimen TSR and PD-L1 expression should be further investigated for a potential impact on targeted treatments, also with regard to immunotherapeutic protocols.

Intratumoral Budding in Pretreatment Biopsies, among Tumor Microenvironmental Components, Can Predict Prognosis and Neoadjuvant Therapy Response in Colorectal Adenocarcinoma.

Background and Objectives: The prediction of the prognosis and effect of neoadjuvant therapy is vital for patients with advanced or unresectable colorectal carcinoma (CRC). Materials and Methods: We investigated several tumor microenvironment factors, such as intratumoral budding (ITB), desmoplastic reaction (DR), and Klintrup–Mäkinen (KM) inflammation grade, and the tumor–stroma ratio (TSR) in pretreatment biopsy samples (PBSs) collected from patients with advanced or unresectable CRC. A total of 85 patients with 74 rectal carcinomas and 11 colon cancers treated at our hospital were enrolled; 66 patients had curative surgery and 19 patients received palliative treatment. Results: High-grade ITB was associated with recurrence (p = 0.002), death (p = 0.034), and cancer-specific death (p = 0.034). Immature DR was associated with a higher grade of clinical tumor-node-metastasis stage (cTNM) (p = 0.045), cN category (p = 0.045), and cM category (p = 0.046). The KM grade and TSR were not related to any clinicopathological factors. High-grade ITB had a significant relationship with tumor regression in patients who received curative surgery (p = 0.049). Conclusions: High-grade ITB in PBSs is a potential unfavorable prognostic factor for patients with advanced CRC. Immature DR, TSR, and KM grade could not predict prognosis or therapy response in PBSs.

Digital image analysis provides robust tissue microenvironment-based prognosticators in patients with stage I-IV colorectal cancer

In patients with colorectal cancer (CRC), a promising marker is tumor-stroma ratio (TSR). Quantification issues highlight the importance of precise assessment that might be solved by artificial intelligence-based digital image analysis systems. Some alternatives have been offered so far, although these platforms are either proprietary developments or require additional programming skills. Our aim was to validate a user-friendly, commercially available software running in everyday computational environment to improve TSR assessment and also to compare the prognostic value of assessing TSR in 3 distinct regions of interests, like hotspot, invasive front, and whole tumor. Furthermore, we compared the prognostic power of TSR with the newly suggested carcinoma percentage (CP) and carcinoma-stroma percentage (CSP). Slides of 185 patients with stage I-IV CRC with clinical follow-up data were scanned and evaluated by a senior pathologist. A machine learning-based digital pathology software was trained to recognize tumoral and stromal compartments. The aforementioned parameters were evaluated in the hotspot, invasive front, and whole tumor area, both visually and by machine learning. Patients were classified based on TSR, CP, and CSP values. On multivariate analysis,TSR-hotspot was found to be an independent prognostic factor of overall survival (hazard ratio for TSR-hotspotsoftware: 2.005 [95% confidence interval (CI): 1.146-3.507], P=.011, for TSR-hotspotvisual: 1.781 [CI: 1.060-2.992], P=.029). Also, TSR was an independent predictor for distant metastasis and local relapse in most settings. Generally, software performance was comparable to visual evaluation and delivered reliable prognostication in more settings also with CP and CSP values. This study presents that software-assisted evaluation is a robust prognosticator. Our approach used a less sophisticated and thus easily accessible software without the aid of a convolutional neural network; however, it was still effective enough to deliver reliable prognostic information.

Tumor-stroma ratio, neoangiogenesis and prognosis in laryngeal carcinoma. A pilot study on preoperative biopsies and matched surgical specimens

ObjectivesThe interaction between tumor cells and stroma is critical in tumorigenesis, tumor neo–angiogenesis and cancer progression. The aims of this study were to: (i) evaluate the concordance between tumor-stroma ratio (TSR) and microvascular density (MVD) on paired biopsy and surgical specimens of laryngeal carcinoma (LSCC); (ii) investigate the association of TSR with angiogenesis (CD105- and CD31-assessed MVD); (iii) assess the prognostic role of TSR and MVD evaluated on preoperative biopsies and paired surgical specimens. MethodsTSR, CD105- and CD31-assessed MVD were analyzed in paired biopsies and surgical specimens of 43 consecutive cases. ResultsTSR showed good agreement between biopsies and surgical specimens (AC1 statistic: 0.7957). In biopsies, TSR low/stroma-rich cases showed higher CD105-assessed MVD (p = 0.0380). In surgical specimens both median CD105- and CD31-assessed MVD were significantly higher in TSR low/stroma-rich than in TSR high/stroma-poor patients (p = 0.0089 and p = 0.0391). In the univariate Cox’s model, TSR predicted disease-free survival (DFS) in both biopsies and surgical specimens (p = 0.0003 and p = 0.0002). DFS was associated with CD105- and CD31-assessed MVD in biopsies (p < 0.0001 for both) and surgical specimens (p < 0.0001 for both). Considering biopsies, the multivariate analysis found both TSR (p = 0.0032; HR = 6.112, 95%CI: 1.833–20.378) and CD105-assessed MVD (p = 0.0002; HR = 1.201, 95%CI: 1.090–1.322) as DFS predictor. In paired surgical specimens, both TSR (p = 0.0074; HR = 6.137, 95%CI: 1.626–23.172) and CD105-assessed MVD (p = 0.0005; HR = 1.172 95 %CI 1.071–1.282) retained their significance in multivariate analysis. ConclusionsIf confirmed by large prospective studies, TSR and MVD could be proposed as prognostic biomarkers of LSCC for a possible treatment intensification or targeted therapy.

Prognostic role of tumor stroma ratio, tumor-infiltrating lymphocytes, and tumor budding in patients with intestinal-type gastric cancer after radical resection.

4055 Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (&gt; 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]

Update to role of the neutrophil lymphocyte ratio in patients with advanced NSCLC undergoing immunotherapy.

e21041 Background: The tumor microenvironment TME is a heterogeneous mixture of different tumor cells, necrotic cells and immune infíltrate.Furthermore nerves and vasculature immersed in the surrounding stroma. The TME cells have different immunological phenotypes. The infiltrating lymphocytes of the tumor stroma (tils) and neutrophil lymphocyte ratio (NLR) are a reflection of the state of “inflammation” in the TME and his systemic repercussion. In our institution we have carried out several research studies studying different markers of inflammation, such as BMI, TILs and NLR in different solid tumors. We conclude that these markers of inflammation have a role in tumor behavior, prognosis and response to treatment. The main objective was investigated the relationship between as NLR and progression-free survival (PFS).in patients with NSCLC who received immunotherapy. The secondary objective was to analyze if there is a relationship between ORR and NLR in patients with NSCLC. Methods: Retrospective and analytical study of patients of Instituto Oncológico de Córdoba. Patients with stage IV NSCLC were analyzed. Were included patient who performed IT alone or in combination with another immunomodulator or platinum-based chemotherapy. The cut-off value for NLR &gt; or &lt; 3 was taken. ORR was evaluated by RECIST criteria. For the statistical analysis of survival, Chi-Square test and Kaplan-Meyer test were used. Results: 52 pts with NSCLC were selected, the average age was 67 years. Of the total number of subjects analyzed, 75% (39) presented non-squamous histology and 25% (13) presented squamous histology. All performed IT (anti PD1) alone or in combination with another immunomodulator (Ipilimumab) or platinum-based CT. Of total patients analized, 27 pts had a NLR &lt; 3; and 25 pts NLR &gt; 3. The median overall survival (OS)was 8.5 months for general population. Patients with an NLR &lt; 3, the median PFS was 14.9 months and those with an NLR &gt; 3 was 5.5 months (p: 0.01). When analyzed the ORR in pts with NLR &lt; 3 it was 21% and those with NLR &gt; 3 the ORR was 4% with statistically significant differences (p:0.02). All patients had follow-up of at least 1 year4 patients (8%)with NLR &lt; 3 had disease progression at 6 months in differencies with patients with NLR &gt; 3 that had progression 13 pts (25%)(p:0.01) and these differences were maintained when we evaluated the PFS at year. Conclusions: Patients with NLR &lt; 3 had better progression-free survival and ORR. It is possible that NLR is a very useful and easily accessible predictive factor in patients with NSCLC undergoing immunotherapy.

Tumor Stroma Ratio and Its Significance in Locally Advanced Colorectal Cancer.

Colorectal cancer is the third leading cause of cancer-related death, and its incidence is rising in the younger patient population. In the past decade, research has unveiled several processes (underlying tumorigenesis, many of which involve interactions between tumor cells and the surrounding tissue or tumor microenvironment (TME). Interactions between components of the TME are mediated at a sub-microscopic level. However, the endpoint of those interactions results in morphologic changes which can be readily assessed at microscopic examination of biopsy and resection specimens. Among these morphologic changes, alteration to the tumor stroma is a new, important determinant of colorectal cancer progression. Different methodologies to estimate the proportion of tumor stroma relative to tumor cells, or tumor stroma ratio (TSR), have been developed. Subsequent validation has supported the prognostic value, reproducibility and feasibility of TSR in various subgroups of colorectal cancer. In this manuscript, we review the literature surrounding TME in colorectal cancer, with a focus on tumor stroma ratio.

Is the tumor-stroma ratio a prognostic factor in gallbladder cancer?

This study aimed to examine the prognostic effect of the tumor-stroma ratio, which has been shown to have prognostic value in various cancers, in patients with gallbladder cancer who have undergone curative resection. The records of gallbladder cancer patients who underwent surgical treatment in our clinic between December 2005 and March 2021 were analyzed retrospectively. The hematoxylin and eosin-stained sections representing the tumors were evaluated under light microscopy to determine tumor-stroma ratio, and based on the results, <50% was defined as the stroma-rich and ≥50% as the stroma-poor groups. A total of 28 patients, including 20 females and 8 males, with a mean age of 64.6 years, were included in this study. Stroma-poor and stroma-rich tumors were detected in 15 and 13 patients, respectively. There was no statistically significant relationship identified between tumor-stroma ratio and advanced age, gender, serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen, incidental or nonincidental diagnosis, jaundice, adjacent organ or structure resection, tumor location, grades 1-2 or 3, T1/T2 or T3/T4, N0 or N1/N2, M stage, American Joint Committee on Cancer stage, lymphovascular invasion, and perineural invasion. The stroma-poor and stroma-rich groups had a 5-year survival rate of 30% and 19.2% and a median overall survival of 25.7 and 15.1 months, respectively, with no statistically significant difference between the groups (p=0.526). A low tumor-stroma ratio tended to be a poor prognostic factor in gallbladder cancer, although not to a statistically significant degree. This can be considered one of the preliminary studies, as further studies involving larger groups are needed.

Prognostic value of tumor-stroma ratio in oral carcinoma: Role of cancer-associated fibroblasts.

Tumor-stroma ratio (TSR) is a promising parameter representing the abundance of the stroma which has been validated in many solid tumors. However, it is still not clear which part of stroma mainly contribute to the prognostic value of TSR. The aim of this study is to confirm the prognostic value of TSR in a large cohort of oral squamous cell carcinoma (OSCC) and further demonstrated that cancer-associated fibroblasts (CAFs)-stroma ratio (CSR) contributed to the prognostic value of TSR. TSR was evaluated on hematoxylin and eosin stained tissue samples from 581 patients with OSCC, which divides patients into high (>50%) and low (<50%) stroma. Then, CSR was estimated on immunohistochemical staining slides of 100 patients selected from 581patients. In multivariate analysis, TSR was identified as an independent prognostic factor for disease-free survival (DFS) (p<0.001) and oral cancer-specific survival (OCSS) (p<0.001). The interaction term reached statistical significance for histological grade for DFS and OCSS separately. Furthermore, the high-stroma group had a higher CSR than the low-stroma group. The prognostic value of TSR is validated in OSCC particularly in moderate and high differentiation, and CSR plays its part in the prognosis of TSR.

Calculated Tumor-Associated Neutrophils Are Associated with the Tumor-Stroma Ratio and Predict a Poor Prognosis in Advanced Gastric Cancer.

The tumor-associated neutrophils (TANs) value and tumor—stroma ratio (TSR) are promising prognostic parameters in the tumor microenvironment. We aimed to evaluate the prognostic role and relationship of TANs and TSR in gastric cancer. Our study comprised 157 patients who underwent gastrectomy for advanced gastric cancer. TANs were assessed by immunohistochemical staining (CD15 and CD66b) and were analyzed with an image analyzer. TANs have been known to have different functional subpopulations of N1 (anti-tumor) and N2 (pro-tumor). We developed “calculated TANs with pro-tumor function (cN2; CD15 minus CD66b)”. The TSR was evaluated using hematoxylin and eosin staining. High-grade CD15-positive, cN2 in the tumor center, and TSR were significantly related to poor disease-free survival (DFS). TSR and cN2 were independent prognostic factors for DFS (hazard ratio (HR) = 2.614; p = 0.001, HR = 3.976; p = 0.002) and cN2 in the tumor center showed a positive correlation with TSR (R = 0.179, p = 0.025). While CD66b stained both N1 and N2, CD15 detected most of N2. Combining both markers revealed a novel cN2, which was an independent marker of poor prognosis. The transformation from N1 to N2 predominantly occurred in the tumor center, and was associated with TSR.

The prognostic significant of tumor budding, tumor stroma ratio and tumor-infiltrating lymphocytes in gallbladder adenocarcinoma

Aim: Tumor microenvironment plays an important role in onset and progression of the cancer. Tumor budding (TB), tumor stroma and tumor-infiltrating lymphocytes are component of the tumor microenvironment. It was aim to determine the relationship of TB, tumor stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs) with clinicopathological prognostic parameters in gallbladder adenocarcinoma. Materials and Methods: Thirty cholecystectomy cases that were diagnosed as adenocarcinoma between 2010 and 2020, that did not receive neoadjuvant therapy and of which archive slides could be accessed, were included in the study. TB, TSR and TILs were evaluated. A p&amp;lt;0.05 value was statistically significant. Results: High TB score was significantly associated with higher histological grade (p=0.008), higher pT stage, lymphovascular invasion (LVI) (p=0.038), lymph node metastasis (p=0.046) and distant metastasis (p=0.036) . Patients with high TB scores had a shorter overall survival (p&amp;lt;0.001). In the high TILs group, lower histological grade (p=0.004), less LVI (p=0.029), fewer distant metastases (p=0.021) and lower TSR (p=0.008) were detected. Increased TCR was associated with higher histological grade (p=0.015) and increased distant metastasis (p=0.013). There was no significant effect of TCR on overall survival (p=0.239). Conclusion: TB can be used as a novel prognostic histological characteristic in the gallbladder cancer patients. We have concluded that it is early to recommend TILs and TSR as the prognostic indicators in gallbladder cancers. In the future, further studies can be conducted on a larger number of GBC cases with a multicenter participation to clarify the prognostic value of TILs and TSR.

A classification based on tumor-stroma ratio and tumor budding for patients with muscle-invasive bladder cancer

Background Tumor-stroma ratio (TSR) and tumor budding (TB) play important roles in muscle-invasive bladder cancer (MIBC). We developed a rating system (TSR-TB type) based on the morphological evaluation of TSR and TB for predicting patient outcome and using individualized care. Research design and methods TSR and TB were assessed in publicly accessible MIBC tumor slides from the TCGA database. MIBC patients were classified as low stromal type or high stromal type based on TSR, and high stromal type was further classified as compartmentalized stromal type or mixed stromal type based on TB. Results TSR-TB type was an independent adverse prognostic factor for OS in MIBC (P<0.001). Low stromal type had a greater prognosis than the other subtypes (P<0.001) and were enriched for FGFR3 mutations (P=0.001), which could be susceptible to targeted therapy. The mixed stromal type was distinguished by increased M2 macrophage penetration (P<0.001), anti-tumor immune activity, DNA repair pathway mutations, and poor survival. GSEA showed that certain cancer-related pathways, such as mitotic spindle, PI3K-AKT-MTOR signaling, and the G2M checkpoint, were hyperactivated in high stromal type (all FDR<0.05). Furthermore, mixed stromal type demonstrated enhanced activation of epithelial mesenchymal transformation (EMT), inflammatory response, KRAS signaling, and angiogenesis (all FDR<0.05). Conclusion TSR and TB-based MIBC classification coincides with patient survival and molecular alterations. The identified subtypes may have important implications for individualized MIBC therapy.

Emerging histopathologic markers in early-stage oral tongue cancer: A systematic review and meta-analysis.

Although there are many histopathologic prognosticators, grading of early oral tongue squamous cell carcinoma (OTSCC) is still based on morphological cell differentiation which has low prognostic value. Here we summarize the emerging histopathological markers showing powerful prognostic value, but are not included in pathology reports. Using PubMed, Scopus, Ovid Medline, and Web of Science databases, a systematic literature search was preformed to identify early OTSCC studies that investigated the prognostic significance of hematoxylin–eosin‐based histopathologic markers. Our meta‐analysis showed that tumor budding was associated with overall survival (hazard ratio [HR] 2.32; 95% CI 1.40–3.84; p < 0.01) and disease‐specific survival (DSS) (1.89; 95% CI 1.13–3.15; p = 0.02). Worst pattern of invasion was associated with disease‐free survival (DFS) (1.95; 95% CI 1.04–3.64; p = 0.04). Tumor–stroma ratio was also associated with DFS (1.75, 95% CI 1.24–2.48; p < 0.01) and DSS (1.69; 95% CI 1.19–2.42; p < 0.01). Tumor budding, worst pattern of invasion, and tumor–stroma ratio have a promising prognostic value in early OTSCC. The evaluation and reporting of these markers is cost‐effective and can be incorporated in daily practice.

Integrative analysis identifies activated anti-tumor immune microenvironment in lung metastasis of pancreatic cancer.

Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup. We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (n = 22), peritoneal (n = 18), and liver (n = 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features. We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4: P < 0.001/P = 0.015, CD8: P < 0.001/P = 0.038, CD45RO: P = 0.022/P = 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (P = 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (P = 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (P < 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites. We identified that lung metastasis revealed an immunologically "hot" tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup.