Correlation between subsets of tumor-infiltrating immune cells and risk stratification in patients with cervical cancer.
ABSTRACT: Aim:To investigate the correlation between clinicopathological features and risk stratification in cervical cancer patients, and evaluate the feasibility of tumor-infiltrating immune cells as prognostic biomarkers in clinical practice. Methods:CD3+ tumor infiltrating T cells (TILs), CD45RO+ TILs, CD4+ TILs, CD8+ TILs, FOXP3+ TILs (regulatory T cells, Tregs), CD68+ tumor associated macrophages (TAMs), CD163+ TAMs, and PD-L1+ tumor cells were immunostained in formalin-fixed paraffin-embedded (PPFE) tissues from 96 cervical cancer patients. Immunostaining density and other clinicopathological features such as age, FIGO stage, histopathologic type, Ki67 index, HPV status, lymhovasular invasion status (LVI), lymph node metastasis, tumor size, stromal invasion status, surgical margin status, and parametrial invasion, were evaluated for their roles in risk stratification of cervical cancer patients. Results:The results showed that significant differences of lymph node metastasis (p = 0.003), surgical margin status (p = 0.020), and stromal invasion status (p = 0.004) existed between lVI(-) and LVI(+) patients. CD3+ TILs in the central tumor area (p = 0.010), CD4+ TILs in the central tumor area (p = 0.045), CD8 + TILs in the central tumor area (p = 0.033), and CD8+ TILs in the invasive margin area (p = 0.004) showed significant differences between lVI(-) and LVI(+) patients. When patients were grouped by status of lymph node metastasis, significant differences of FIGO stage (p = 0.005), LVI status (p = 0.003), CD3+ TILs in the central tumor area (p = 0.045), CD45RO+ TILs in the central tumor area (p = 0.033), and CD45RO+ TILs in the invasive margin area (p = 0.028) were also observed. After the patients were stratified into low-, intermediate-, and high risk groups, significant differences of FIGO stage (p = 0.018), status of lymph node metastasis (p = 0.000), LVI status (p = 0.000), parametrial invasion status (p=0.012), stromal invasion status (p = 0.000), tumor growth pattern (p = 0.015) and tumor size (p = 0.000) were identified among 3 groups of patients, while only CD45RO+ TILs in the invasive margin area (p = 0.018) and FOXP3+ TILs in the central tumor area (p = 0.009) were statistically different among three groups of patients. Spearman's correlation analysis demonstrated that FIGO stage, LVI status, status of lymph node metastasis, parametrial invasion, stromal invasion status, and tumor size positively correlated with risk stratification (P = 0.005, 0.020, 0.000, 0.022, 0.000, and 0.000 respectively), while CD45RO+ TILs in the invasive margin area and FOXP3+ TILs in the central tumor area showed statistically negative correlation with risk stratification (P = 0.031, 0.009 respectively). Conclusion:Our study suggested that CD45RO+ TILs in the invasive margin area and FOXP3+ TILs in the central tumor area might be useful biomarkers for risk stratification in cervical cancer patients. Large cohort studies of cervical cancer patients are required to validate our hypothesis.
Project description:The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) reflects an active inflammatory tumor microenvironment. High density of TILs as well as presence of TLS is associated with improved survival in various solid cancer types. We aimed to describe the density and distribution of TILs and TLS in pulmonary metastases (PMs) from primary colorectal cancer (CRC) and its correlation with clinicopathological variables. Fifty-seven CRC pulmonary metastasectomy specimen (PM) and 31 matched primary CRC specimen were included. Cluster of differentiation (CD)3+, CD8+, CD45RO+ and FoxP3+ TILs were evaluated by immunohistochemistry and density was scored semiquantitatively. TLS were evaluated based on morphological criteria. Survival time was defined from pulmonary metastasectomy to death or last follow up. A marked infiltration with CD3+, CD8+, CD45RO+ and FoxP3+ TILs was evident in CRC PM and matched primary CRC. Further assessment of the immune infiltrate in PM showed that a high density of FOXP3+ TILs at the invasive margin [HR 2.40 (1.11-6.96); P = 0.031] and low density of CD8+ cells in TLS [HR 0.30 (0.14-0.79); P = 0.016] were associated with a worse prognosis in univariate analysis. Moreover, a low CD8/FoxP3-ratio of TILs at the invasive margin (P = 0.042) and in TLS (P = 0.027) conferred an impaired prognosis after pulmonary metastasectomy. Our findings suggest that CRC PM harbor an immune active microenvironment. The balance of CD8+ and FoxP3+ T-cells at the tumor border and in TLS provides prognostic information in patients with CRC PM.
Project description:Objective:To investigate the association between programmed death-ligand 1 (PD-L1) coupled with CD8+ tumor-infiltrating lymphocytes (TILS) and the clinicopathological features, along with prognosis of cervical squamous cell carcinoma (CSCC). Methods:95 patients of CSCC received tumor resection at the Department of Pathology of the First Affiliated Hospital of University of Science and Technology of China (USTC) from 2015 to 2020. Full-automatic immunohistochemistry was applied to measure PD-L1 expression and CD8+ TILS density. Our literature deeply assessed the links between PD-L1 expression, clinicopathological features, and the influences of combination of PD-L1 and CD8+ TILS (PD-L1+/CD8+ TILS) on the prognosis of CSCC. Results:64.21% of CSCC patients (61/95) expressed PD-L1, and PD-L1 expression was related to the Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, invasion depth, differentiation degree, metastasis of lymph node, and vascular invasion (P < 0.05). Dramatic correlation between PD-L1 expression and CD8+ TILS density was illustrated in CSCC patients (r = -0.461, P < 0.001). Obvious differences in differentiation degree, FIGO stage, infiltration depth, and lymph node metastasis were shown between patients with PD-L1 coupled with high-density of CD8+ TILS and those with PD-L1 coupled with low-density of CD8+ TILS (P < 0.05). Patients with PD-L1 negative expression exhibited better prognosis compared with those with PD-L1 positive expression (P < 0.05). Patients with PD-L1 coupled with high-density of CD8+ TILS showed better prognostic status, while those with PD-L1 coupled with low-density of CD8+ TILS had worse prognostic condition (P < 0.05). Differentiation, metastasis of lymph node, and FIGO stage were substantive impact elements of a CSCC patient's overall survival (OS) by Cox multivariate analysis. Conclusions:CD8+ TILS density is related to PD-L1 expression in carcinoma. PD-L1/CD8+ TILS density can be regarded as evaluation for the prognosis of patients with CSCC, providing a new therapeutic target in clinical application.
Project description:Cholangiocarcinoma is a malignancy arising from the biliary tract epithelial cells with poor prognosis. Tumor infiltrating lymphocytes (TIL)s and programmed cell death receptor ligand 1 (PD-L1) have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Tumor samples from 44 patients with resected and histologically verified extrahepatic cholangiocarcinoma were evaluated for CD8, CD45RO and PD-L1 expression, and their correlations with clinicopathological data and survival data were analyzed. Total 44 extrahepatic cholangiocarcinoma tissues were evaluated. CD8+ tumor infiltrating lymphocytes (TIL)s were observed in 30 (68%) tumors. Among them, 14 had CD8+CD45RO+ TILs. PD-L1 was expressed on cancer cells in 10 (22.7%) tumors in 34 evaluable extrahepatic cholangiocarciniomas. The presence of CD8+ TILs or CD8+CD45RO+ TILs was not associated with clinical staging or tumor differentiation. Extrahepatic cholangiocarcinoma with CD8+CD45RO+ TILs had longer overall survival (OS) on univariate (P = 0.013) and multivariate (P = 0.012) analysis. Neither CD8+TIL nor PD-L1 expression on cancer cells correlated significantly with OS. These results add to the understanding of the clinical features associated with CD8 TILs and PD-L1 expression in extrahepatic cholangiocarcinoma, and they support the potential rationale of using PD-1 blockade immunotherapy in cholangiocarcinoma.
Project description:The consensus of endoscopic therapy for early gastric cancer (EGC) mainly depends on its clinicopathological features. However, the roles of tumor-associated neutrophils (TANs) in EGC remain uncertain. Here, we explored its predictive role for lymph node metastasis (LNM) in EGC. Three hundred twenty-two patients who underwent radical gastrectomy for EGC were enrolled. Preoperative peripheral blood was used to analyze the neutrophil-to-lymphocyte ratio (NLR), and the different status of TANs was determined by hematoxylin-and-eosin staining (H&E) and immunohistochemistry (IHC). TANs, rather than NLR, were positively associated with tumor size, Lauren classification, lymphovascular invasion (LVI), and LNM. Univariate analysis revealed that TANs were associated with LNM as well as tumor size, depth of invasion, Lauren classification, histological classification, LVI, and perineural invasion. In addition to histological classification and LVI, TANs were found to be an independent risk factor for LNM in EGC (P = 0.013). Stratification analysis by depth of invasion showed LVI in SM1 tumor, and both LVI and TANs (P = 0.042) in SM2 tumor were independent risk factors for LNM. In conclusion, TANs in EGC can predict LNM, and TANs may help to estimate LNM precisely in addition to the current criteria.
Project description:Lymphovascular invasion (LVI) is the primary and essential step in the systemic dissemination of cancer cells. The aim of our study was to assess the independent prognostic role of LVI for pT1 urothelial carcinoma with squamous differentiation in bladder cancer. We retrospectively analyzed the clinical and pathological information of 206 patients diagnosed pT1 urothelial carcinoma with squamous differentiation. Of the 206 patients, LVI was detected in 57 (27.6%) patients. The 5 year cancer specific survival (CSS) rates were 87.2% in LVI (-) and 52.4% in LVI (+) (p < 0.001). According to univariate analysis, tumor multiplicity, tumor size, recurrence and LVI were the prognostic factors associated with CSS. Additionally, tumor size and LVI significantly influenced the CSS in multivariate analysis. TURBT had shorter median CSS than RC in recurred patients with LVI (+). Our study suggested that LVI is an important predictor for survival of pT1 urothelial carcinoma with squamous differentiation. LVI positive status and tumor size ≥3 cm led to a higher risk of death. RC should be routinely performed in recurred LVI (+) bladder cancer patients of pT1 urothelial carcinoma with squamous differentiation.
Project description:BACKGROUND: The effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery. METHODS: We studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A ?2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated. RESULTS: A total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P < 0.001), LVI (P?=?0.026), pN stage (N1 vs. N0: P?=?0.018; N3 vs. N0: P < 0.001), and luminal B (P?=?0.001) and HER-2 (P < 0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P < 0.001), pN stage (P?=?0.003), and HER-2 subtype (P < 0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P?=?0.031). CONCLUSIONS: The HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.
Project description:INTRODUCTION:This study aimed to evaluate whether lymphovascular invasion (LVI) can replace lymph node (LN) involvement as a prognostic marker in patients who do not undergo lymph node dissection (LND) during surgery in patients with upper tract urothelial carcinoma (UTUC). METHODS:A total of 505 patients who underwent radical nephroureterectomy (RNU) were recruited from four academic centres and divided into four groups: node negative (N0, Group 1); node positive (N+, Group 2); no LND without LVI (NxLVI-, Group 3); and no LND with LVI (NxLVI+, Group 4). RESULTS:Patients in Group 2 had larger tumours, a higher incidence of left-sided involvement, more aggressive T stage and grade, and a higher positive surgical margin rate than patients in other groups. Pathological features (T stage and grade) were poorer in Group 4 than in Groups 1 and 3. Compared to other groups, Group 2 had the worst prognostic outcomes regarding locoregional/distant metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). LVI and LN status in Group 4 was not associated with MFS in multivariate analysis. Among Nx diseases, LVI was not an independent predictor of MFS or CCS. The small number of cases in Groups 2 and 4 is a major limitation of this study. CONCLUSIONS:Clinical outcomes according to LVI did not correlate with those outcomes predicted by LN involvement in patients with UTUC. Therefore, LVI may not be used as a substitute for nodal status in patients who do not undergo LND at the time of surgery.
Project description:Little is known concerning the prognostic significance of the degree of lymphatic vessel invasion in pancreatic head cancer. To address this gap in knowledge, we retrospectively examined 60 patients with locally advanced, surgically resectable pancreatic head cancer who underwent pancreaticoduodenectomy and lymph node (LN) dissection.All cases were histopathologically diagnosed as ductal adenocarcinoma, stage II (25 pT3N0 cases, 35 pT3N1 cases). The following variables were investigated: age; sex; neoadjuvant therapy; adjuvant therapy; tumor size; tumor grade; invasion into the serosa, retropancreatic tissue, duodenum, bile duct, portal venous system and perineural area; cut margins; LN metastasis; and the number of invaded lymphatic vessels (LVI-score).Univariate analysis demonstrated that LN metastasis and an LVI-score ?5 were significantly associated with poor disease-free survival. Multivariate Cox regression analysis confirmed that LN metastasis and an LVI-score ?7 were significantly associated with poor disease-free survival. Additionally, LVI-scores ?9 and ?10 were comparable to or surpassed the significance of LN metastasis based on the hazard ratio. Univariate analysis demonstrated that tumor size >30?mm, duodenal invasion, LN metastasis and an LVI-score ?2 were significantly associated with poor overall survival. Multivariate Cox regression analysis confirmed that LN metastasis and LVI-scores ?9 and ?10 were significantly associated with poor overall survival, and an LVI-score ?10 was comparable to or surpassed the significance of LN metastasis based on the hazard ratio.Our study strongly suggests that a high degree of lymphatic vessel invasion is associated with a poor prognosis in patients with locally advanced, surgically resectable pancreatic head cancer.
Project description:Tumor-infiltrating lymphocytes (TILs) are vital in limiting cancer progression and may supplement the TNM classification. CD45RO(+) memory TILs show major prognostic impact in various malignancies but have not been extensively explored in non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate their potential in a NSCLC TNM-Immunoscore. Tissue microarrays were constructed from tumor tissue samples from two cohorts including in total 536 patients (University Hospital of North Norway, n = 285; Nordland Hospital, n = 251) with primary resected stage I to IIIA NSCLC. The density of CD45RO(+) and CD8(+) TILs in tumor epithelial and stromal compartments of the tumors was evaluated by immunohistochemistry. In univariate analyses, intraepithelial CD45RO(+) TIL density (T-CD45RO) was a significant prognostic factor for disease-specific survival (P = .007), limited to the squamous cell carcinoma (SCC) histology subgroup (P < .001), where it was significant in both cohorts (University Hospital of North Norway, P = .003; Nordland Hospital, P = .022). Combining T-CD45RO and stromal CD8(+) TIL density (S-CD8) increased the prognostic impact in SCC (P < .001) and showed a significant impact within all pathological stages (I, P = .025; II, P < .001; III, P = .001). In the multivariate analysis, T-CD45RO was an independent positive prognostic factor for SCC (hazard ratio 2.65, 95% confidence interval 1.64-4.28, P < .001), and in combination with S-CD8, the prognostic impact increased vastly (high + high versus low + low: hazard ratio 6.50, 95% confidence interval 3.54-11.91, P < .001). In conclusion, T-CD45RO was an independent prognostic factor for SCC NSCLC. When combined with S-CD8, the prognostic impact increased and was significant within each pathological stage. We propose CD45RO as a candidate marker for TNM-Immunoscore in SCC NSCLC.
Project description:BACKGROUND:Lymphovascular invasion (LVI) has never been revealed by preoperative scans. It is necessary to use digital mammography in predicting LVI in patients with breast cancer preoperatively. METHODS:Overall 122 cases of invasive ductal carcinoma diagnosed between May 2017 and September 2018 were enrolled and assigned into the LVI positive group (n?=?42) and the LVI negative group (n?=?80). Independent t-test and ?2 test were performed. RESULTS:Difference in Ki-67 between the two groups was statistically significant (P?=?0.012). Differences in interstitial edema (P?=?0.013) and skin thickening (P?=?0.000) were statistically significant between the two groups. Multiple factor analysis showed that there were three independent risk factors for LVI: interstitial edema (odds ratio [OR]?=?12.610; 95% confidence interval [CI]: 1.061-149.922; P?=?0.045), blurring of subcutaneous fat (OR?=?0.081; 95% CI: 0.012-0.645; P?=?0.017) and skin thickening (OR?=?9.041; 95% CI: 2.553-32.022; P?=?0.001). CONCLUSIONS:Interstitial edema, blurring of subcutaneous fat, and skin thickening are independent risk factors for LVI. The specificity of LVI prediction is as high as 98.8% when the three are used together.