Stromal Lymphocyte Infiltration Research Articles

Differential analysis of histopathological and genetic markers of cancer aggressiveness, and survival difference in EBV-positive and EBV-negative prostate carcinoma

Several studies have shown an association between prostate carcinoma (PCa) and Epstein-Barr virus (EBV); however, none of the studies so far have identified the histopathological and genetic markers of cancer aggressiveness associated with EBV in PCa tissues. In this study, we used previously characterized EBV-PCR-positive (n = 39) and EBV-negative (n = 60) PCa tissues to perform an IHC-based assessment of key histopathological and molecular markers of PCa aggressiveness (EMT markers, AR expression, perineural invasion, and lymphocytic infiltration characterization). Additionally, we investigated the differential expression of key oncogenes, EMT-associated genes, and PCa-specific oncomiRs, in EBV-positive and -negative tissues, using the qPCR array. Finally, survival benefit analysis was also performed in EBV-positive and EBV-negative PCa patients. The EBV-positive PCa exhibited a higher percentage (80%) of perineural invasion (PNI) compared to EBV-negative PCa (67.3%) samples. Similarly, a higher lymphocytic infiltration was observed in EBV-LMP1-positive PCa samples. The subset characterization of T and B cell lymphocytic infiltration showed a trend of higher intratumoral and tumor stromal lymphocytic infiltration in EBV-negative tissues compared with EBV-positive tissues. The logistic regression analysis showed that EBV-positive status was associated with decreased odds (OR = 0.07; p-value < 0.019) of CD3 intratumoral lymphocytic infiltration in PCa tissues. The analysis of IHC-based expression patterns of EMT markers showed comparable expression of all EMT markers, except vimentin, which showed higher expression in EBV-positive PCa tissues compared to EBV-negative PCa tissues. Furthermore, gene expression analysis showed a statistically significant difference (p < 0.05) in the expression of CDH1, AR, CHEK-2, CDKN-1B, and CDC-20 and oncomiRs miR-126, miR-152-3p, miR-452, miR-145-3p, miR-196a, miR-183-3p, and miR-146b in EBV-positive PCa tissues compared to EBV-negative PCa tissues. Overall, the survival proportion was comparable in both groups. The presence of EBV in the PCa tissues results in an increased expression of certain oncogenes, oncomiRs, and EMT marker (vimentin) and a decrease in CD3 ITL, which may be associated with the aggressive forms of PCa.

Correlation between stromal Th and Tc lymphocytes and PD-L1 expression in early breast cancer tumors.

Prognostic and predictive value of PD-L1 as a biomarker in breast cancer remains controversial. While some studies suggest its association with negative prognostic parameters, others reported a highly significant association between PD-L1 expression and tumor-infiltrating lymphocytes, which are known to be an independent favorable prognostic factor. The aim of present study is to examine the relationship between immune response markers and PD-L1 expression in early breast cancer. Immunohistochemical expression of PD-L1, along with density and composition of stromal lymphocytic infiltrate and peritumoral lymphoid aggregates was analyzed in 95 samples of invasive breast cancer. A strong positive correlation between PD-L1 expression and the density of stromal lymphocytic infiltrate and peritumoral lymphoid aggregates was identified and a cut-off value of 53% coverage of tumor stroma by lymphocytes, with which PD-L1 positivity can be predicted with excellent diagnostic accuracy, was determined for the first time using statistical methods. Additionally, PD-L1 positivity was observed significantly more often in tumors with higher absolute number of both CD4 and CD8 T-lymphocytes in the stromal infiltrate. No significant correlation with molecular subtype of breast cancer was found. Our results indicate that the density of stromal lymphocytic infiltrate might be a better predictor of PD-L1 positivity in early breast cancer than the molecular subtype and that the key to the optimization of PD-L1 as a biomarker in breast cancer lies in its interpretation in the context of other immune response markers.

Tumor Budding Should Be in Oral Cavity Cancer Reporting: A Retrospective Cohort Study Based on Tumor Microenvironment.

The utility of histological grading, which is useful in predicting prognosis in many tumors, is controversial for oral squamous cell carcinoma (OSCC). Therefore, new histopathological parameters should be added to histopathology reports of OSCCs. The study aimed to evaluate the parameters of worst invasion pattern (WPOI) and tumor budding in patients with OSCC, to compare them with other histopathological parameters, clinical data and overall survival, and to evaluate these results within the literature. A total of 73 OSCC cases with excisional biopsies were included in this study. WPOI, tumor budding, cell nest size, tumor-stroma ratio, stromal lymphocyte infiltration and stroma type, as well as classical histopathological parameters, were evaluated on hematoxylin-eosin-stained sections. Perineural invasion, lymph node metastases, advanced stage, presence of more than five buds and single cell invasion pattern in univariate survival analyses are characterized by a shortened overall survival time. While there was no significant difference between WPOI results and survival in the survival analysis, WPOI 5 was associated with more frequent lymph node metastasis and advanced stage at the time of diagnosis compared to WPOI 4. We concluded that tumor budding and single-cell invasion should be considered prognostic histopathologic parameters in OSCC.

Clinical Meaning of Stromal Tumor Infiltrating Lymphocytes (sTIL) in Early Luminal B Breast Cancer

Luminal breast cancer (BC) is associated with less immune activation, and the significance of stromal lymphocytic infiltration (sTIL) is more uncertain than in other BC subtypes. The aim of this study was to investigate the predictive and prognostic value of sTIL in early luminal BC. The study was performed with an observational design in a prospective cohort of 345 patients with predominantly high-risk luminal (hormone receptor positive, HER2 negative) BC and with luminal B features (n = 286), in which the presence of sTIL was analyzed with validated methods. Median sTIL infiltration was 5% (Q1–Q3 range (IQR), 0–10). We found that sTIL were associated with characteristics of higher biological and clinical aggressiveness (tumor and lymph node proliferation and stage, among others) and that the percentage of sTIL was predictive of pathologic complete response in patients treated with neoadjuvant chemotherapy (OR: 1.05, 95%CI 1.02–1.09, p &lt; 0.001). The inclusion of sTIL (any level of lymphocytic infiltration: sTIL &gt; 0%) in Cox regression multivariable prognostic models was associated with a shorter relapse-free interval (HR: 4.85, 95%CI 1.33–17.65, p = 0.016) and significantly improved its performance. The prognostic impact of sTIL was independent of other clinical and pathological variables and was mainly driven by its relevance in luminal B BC.

Immunoexpression of SIRT1, 6, and 7 in oral leukoplakia and oral squamous cell carcinoma.

Sirtuins (SIRTs) are a family of proteins involved in the metabolic process responsible for extending the lifespan. The role of SIRT1, 6, and 7 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OLP), one of its precursors, is still elusive. In this study, 82 OLP and 77 OSCC were immunohistochemically examined for SIRT1, 6, and 7. Stained sections were thoroughly scanned and evaluated using a digital image analysis program. The SIRT1, 6, and 7 expressions were detected in the nuclei of epithelial and carcinoma cells in various degrees. Afterward, any correlations among SIRTs, including associations with clinicopathological features and the Kaplan-Meier curves were analyzed. OSCC demonstrated significantly higher SIRT1 expression than OLP, while non-dysplastic lesions showed significantly higher SIRT6 expression than other lesions. A strong correlation was observed between SIRT6 and 7 in OLP, SIRT1 and 6 in in OSCC and in SIRT6 and 7 when all lesion types were considered. There were no significant differences between SIRTs reactivity and the clinical features in OLP. For OSCC, SIRT1 and 6 was found to be directly associated with site of the lesion, while SIRT7 showed a direct relationship between gender, stromal lymphocytic infiltration, and depth of the invasion. OSCC with high SIRT7 expression revealed a slightly lower survival probability, although not statistically significant (p = 0.1019). Our findings suggest that SIRT1, 6, and 7 may play correlated and diverse roles in the development and advancement of OSCC.

Tumor-infiltrating lymphocytes predict survival in ≥ pT2 urothelial bladder cancer

Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in several types of cancers, including genitourinary cancers. However, multiple different scoring methods used to assess TILs complicate the comparison of different studies and are not always suitable for daily practice. In 2014, the International TILs Working Group (ITWG) proposed a simple and robust assessment method for a more standardized evaluation of TILs. Here, we validated this system in muscle-invasive urinary bladder cancer (MIBC). Patient history and histologic specimens from 203 patients with MIBC were retrospectively analyzed. The stromal TIL (sTIL) score was determined using the ITWG system and 3 groups were defined according to the degree of stromal lymphocytic infiltration: low (0–10%), intermediate (10–55%) and high (55–100%). Associations between sTIL score, clinicopathological variables, tumor-specific survival (TSS), overall survival (OS), and disease-free survival (DFS) were analyzed. High stromal lymphocytic infiltration was associated with significantly higher OS, TSS and DFS when compared to low grade sTILs. The survival benefit remained statistically significant in multivariate analyses, confirming that sTILs are a strong independent positive prognostic factor in patients with MIBC. In summary, the degree of sTILs as defined by the ITWG robustly predicts survival in MIBC patients. Prospective studies with larger case numbers are needed to determine whether sTILs should be included in staging guidelines and how they could aid in therapeutic decision making.

A Novel Subset of Triple-Negative Breast Cancers with Unique Histology and Immunohistochemical Expression.

Background & Objective:Triple-Negative Breast Carcinoma (TNBC) is characterized by an absence of estrogen receptor, progesterone receptor and HER2 neu expression, with distinct molecular, histological and clinical features, aggressive clinical course and a poor prognosis. The objective was to evaluate the expression of Cytokeratin5/6 (CK 5/6), Epidermal Growth Factor Receptor 1 (EGFR 1), E-cadherin and Androgen receptor in tissue sections of TNBC. Methods:All modified radical mastectomy samples received negative for the three markers were subjected to further studies with CK5/6, EGFR 1, E- cadherin and Androgen receptor staining. The clinical and pathological data were tabulated and statistically analysed using the Chi-square test, and cross-tabulation was done to assess the correlation between these markers.Results:Of 94 samples classified as TNBC, 31 (33%) were positive for CK 5/6, 47 (50%) for EGFR, 32 (34%) for E Cadherin and Androgen receptor, respectively. We had one positive patient for all four markers, 13 patients were negative for all four. Thirty-five cases were positive for only one marker, 32 were positive for two markers, and 13 were positive for three markers. Analysis revealed certain interesting patterns, namely - E cadherin was the most common isolated marker expressed in our cohort of TNBC with 15 of 35 positives. Conclusion:This study highlights the presence of a unique subtype of TNBC, which are negative for all the four markers studied here, with unique histomorphology of absent tumour necrosis and stromal lymphocytic infiltration being unique.

Association of pathological clinical characteristics, PD L 1 receptor expression (sp 142), with tumor lymphocytic infiltration cells (TILs) in patients (pts) with triple negative breast cancer (TNBC) in Tucumán, Argentina.

e13049 Background: Breast cancer (BC) is the most prevalent tumor in women and the leading cause of cancer death in women. TNBC has the worst prognosis among BC subtypes and limited treatment options, mainly including chemotherapy. The efficacy of immunotherapy is clear for immunogenic tumors, such as melanoma, kidney cancer, non-lung cancer small cell, among others. BC seems to be less immunogenic. Basal-type TNBC present a prominent infiltration of inflammatory cells, suggesting that an immune pathway plays a role in tumorogenesis. The development of immunotherapy (IO)has reached an important turning point in the history of cancer treatment based on the use of the immune system itself to fight tumor cells. PD-L1 overexpression is the only predictive response biomarker for anti-PD-1 / PD-L1 therapy that is accepted in TNBM. Methods: Retrospectively, 68 cases of TNBC from the Pathological Anatomy Service of the Ntra. Sra. De las Mercedes Maternity Institute, of Tucumán, between 2010 and 2016 were analyzed. VENTANA anti PDL1 sp142 assay platform was used. Tumor-infiltrating immune cells (IC) are scored as the proportion of tumor area that is occupied by PD-L1 staining IC of any intensity. A specimen should be considered to have PD-L1 expression if the specimen exhibits ≥ 1% IC. In addition, carcinomas with a proportion greater than 50% of lymphocytic infiltration and its association with the expression of PD L1 were studied according to the recommendations of the International TILs Working group. Results: The median age of the patients was 56 years (21-80). The predominant histological type was non-specific type ductal carcinoma, reported in 45/68 cases (66%), following the medullar 9 / 68 (13%) lobular in 8/68 (11%), metaplastic 3/68 (4%) and other 4%. The tumor grade (G), half of the cases were G 3 with 34/68 (50%), G 2 with 42%. The largest proportion of pts, 42%, had no lymph node (LN) involvement, 33% had between 1 to 3 positive LN and 25% showed 4 or more LN. Stage II 39/68 patients (58%) in stage III 20/68 (30%), I (9%, 6) and IV (3%, 2). 16% (11/68) of the patients were PD-L1 positive. Tumors with lymphocytic infiltration between 0% and 10% expressed 24% (2/37), no expression was observed in tumors with TIls between 10 and 50% and in cases with lymphocytic infiltration greater than 50% expression of PD L was observed 1 in 9/18 cases (50%) (Fisher's exact test, p &lt; 0.0001). Conclusions: It was demonstrated that there is an association between the stromal lymphocytic infiltrate (TILs) and the expression of PD-L1 in tumor cells, in this population of women from Tucumán, which would help to select patients as candidates for anti PD L1 therapies.

Presence of myxoid stromal change and fibrotic focus in pathological examination are prognostic factors of triple-negative breast cancer: Results from a retrospective single-center study.

Stromal reaction is an important prognostic factor in several cancers, and the presence of myxoid change was assessed as a poor prognostic factor in colorectal cancer. However, the prognostic significance of myxoid change in triple-negative breast cancer (TNBC) remains unknown. This study aimed to determine the prognostic significance of myxoid change and fibrotic focus (FF), which is a fibrotic area within the tumor and considered a poor prognostic indicator in patients with TNBC. We enrolled 62 patients with TNBC and reviewed the surgically resected specimens to evaluate myxoid change and FF in the tumor using previously outlined criteria. We evaluated tumor-infiltrating lymphocytes (TILs) using hematoxylin and eosin slides. Overall survival (OS) and relapse-free survival (RFS) were compared based on the presence of myxoid change and/or FF, and the risk factors for RFS were analyzed. Myxoid change and FF were observed in 25.8% and 33.9% of specimens, respectively. Based on stromal lymphocyte infiltration, 19 patients (30.6%) had high TILs, while the remaining 43 patients (69.4%) had low/intermediate TILs. Presence of myxoid change was significantly correlated with poor OS and RFS (p = 0.040 and 0.031, respectively). FF was also significantly correlated with poor OS and RFS (p = 0.012 and 0.028, respectively). The combination of myxoid change and FF was an independent and poor prognostic factor according to the multivariate analysis (HR 11.61; 95% CI 1.027-131.2; p = 0.048). Presence of myxoid change and FF were significantly associated with low/intermediate TILs in the stroma (p = 0.013). Histopathological assessment of myxoid change and FF in TNBC may be a useful, practical, and easily assessable method for predicting prognosis in patients with TNBC, which should be confirmed in larger prospective studies. Diagnostic criteria for the establishment of myxoid change and FF in TNBC must be established, and their underlying molecular events must be clarified.

Molecular Subtyping of Triple Negative Breast Cancer by Surrogate Immunohistochemistry Markers.

Triple negative breast cancer (TNBC) is a heterogeneous disease and an attempt was made to classify TNBCs into surrogate molecular subtypes using immunohistochemical markers. Tissue microarrays were constructed for 245 cases of TNBCs. For classification of TNBCs immunohistochemistry was done on tissue microarrays for cytokeratin 5/6, 4/14 (CK5/6, CK4/14), epidermal growth factor receptor (EGFR), vimentin, E-cadherin, claudin 3 and 7, androgen receptor (AR) and aldehyde dehydrogenase1A. The TNBCs were classified into basal-like 1 (BL1) type (CK5/6+, CK4/14+, EGFR- n=32; 13.1%), basal-like 2 (BL2) type (EGFR+, n=4; 1.6%), mesenchymal type (Vimentin+, E-cadherin ̅, claudin 3-and 7-, n=70; 28.6%), luminal androgen type (AR+, n=41; 16.7%), mixed type (n=37; 15.1%), and unclassified type (n=61; 24.9%). Luminal androgen receptor subtype showed apocrine features, and was associated with older age group, lower proliferation index and high frequency of lymph node metastasis. Basal subtype was cellular with rich stromal lymphocytic infiltrate. Mesenchymal stem like subtype was associated with younger age group with metaplastic and mesenchymal features. Mesenchymal stem like and unclassified subtype had shorter overall survival with median of 68.2 and 69.2 months, respectively, and the BL2 had median disease-free survival of 35.4 months. On immunohistochemistry TNBC is a heterogeneous entity composed of 6 major subtypes. Immunohistochemical subtyping of TNBC can provide information on prognostication and selection of appropriate targeted therapy for these patients.

Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients.

Circulating tumor cells (CTCs) and the immune infiltration of tumors are closely related to clinical outcomes. This study aimed to verify the influence of stromal lymphocyte infiltration and the immune context of tumor microenvironment on the hematogenous spread and prognosis of 282 chemotherapy naïve primary BC patients. To detect the presence of mesenchymal CTCs, RNA extracted from CD45-depleted peripheral blood was interrogated for the expression of mesenchymal gene transcripts. Tumor-infiltrating lymphocytes (TILs) were detected in the stromal areas by immunohistochemistry, using CD3, CD8, and CD45RO antibodies. The concentrations of 51 plasma cytokines were measured by multiplex bead arrays. TILs infiltration in mesenchymal CTC-positive patients significantly decreased their progression-free survival (HR = 4.88, 95% CI 2.30–10.37, p < 0.001 for CD3high; HR = 6.17, 95% CI 2.75–13.80, p < 0.001 for CD8high; HR = 6.93, 95% CI 2.86–16.81, p < 0.001 for CD45ROhigh). Moreover, the combination of elevated plasma concentrations of transforming growth factor beta-3 (cut-off 662 pg/mL), decreased monocyte chemotactic protein-3 (cut-off 52.5 pg/mL) and interleukin-15 (cut-off 17.1 pg/mL) significantly increased the risk of disease recurrence (HR = 4.838, 95% CI 2.048–11.427, p < 0.001). Our results suggest a strong impact of the immune tumor microenvironment on BC progression, especially through influencing the dissemination and survival of more aggressive, mesenchymal CTC subtypes.

Radiation and immunotherapy: emerging mechanisms of synergy.

Immunotherapy (IO) has become a standard treatment in patients with metastatic and locally advanced non-small cell lung cancer (NSCLC), and is now being tested in patients with early stage disease. IO agents currently in use for lung cancer target PD-1, PD-L1, and CTLA-4. While survival and tumor control have improved with IO, many patients have limited or short responses to IO. Therefore, methods to improve the systemic response to IO are needed. Radiation therapy (RT) is an integral component of lung cancer treatment, and may improve systemic response to IO by increasing antigen presentation, increasing co-stimulatory signaling, increasing T-cells recruitment, upregulating PD-L1, increasing tumor stromal lymphocyte infiltration, and altering the microenvironment. IO after definitive chemoradiation is now standard treatment in unresectable stage III NSCLC following publication of the PACIFIC clinical trial. For early stage NSCLC, IO is being investigated in conjunction with stereotactic body radiotherapy (SBRT). The benefit of adding RT to IO in patients with metastatic disease may be especially pronounced in patients with low baseline PD-L1 expression, potentially when delivered as a short course of SBRT, as supported by the PEMBRO-RT clinical trial. Current and ongoing clinical trials are evaluating the optimal radiation dose, timing, and sequencing of RT with IO.

Prognostic significance of immune checkpoints in the tumour–stromal microenvironment of sebaceous gland carcinoma

BackgroundImmune checkpoint blockade strategies have gained attention in the treatment/prognosis of cancers by targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway alone or in combination with cytotoxic T-lymphocyte-associated antigen...

Lymphoepithelioma-like Gastric Carcinoma a Rare Condition: A case report

Background: Lymphoepithelioma-like gastric carcinoma (LELGC) is a rare type of gastric cancer characterized by a carcinoma with intense stromal lymphocytic infiltration. It comprises approximately 4% of all gastric neoplasms and occurs mainly in men and in the proximal stomach. LELGCs have a better prognosis than other gastric carcinomas due to its lower invasive and metastatic capacity. Unfortunately, there is a lack of diagnostic criteria that help identifying this tumor and differentiating it from medular and tubular adenocarcinoma with lymphoid stroma. Epstein-Barr Virus (EBV) and microsatellite instability have a predominant role in the physiopathology of the disease. The clinical manifestations are similar to those of other gastric neoplasms.

Novel biomarkers for risk stratification of Barrett\u2019s oesophagus associated neoplastic progression\u2013epithelial HMGB1 expression and stromal lymphocytic phenotype

BackgroundThe incidence of oesophageal adenocarcinoma is increasing globally. Barrett’s oesophagus (BO) is a pre-malignant condition with no biomarker to risk stratify those at highest risk of dysplasia and malignant transformation.MethodsSubcellular epithelial protein (HMGB1, p53, RUNX3) expression, alongside expression of CD20, CD4, CD8 and Foxp3 to characterise stromal B lymphocyte, and helper, cytotoxic and regulatory T-lymphocyte cell infiltrate, respectively, was assessed by immunohistochemistry in 218 human tissue samples including normal oesophageal/gastric biopsies (n = 39), BO (non-dysplasia, dysplasia, non-dysplastic background from progressors to dysplasia or cancer, n = 121) and oesophageal adenocarcinoma (n = 58).ResultsThere is a dynamic subcellular epithelial expression of HMGB1 (loss of nuclear, emergence of cytoplasmic), associated with epithelial p53 expression and differential immune cell phenotype in oesophageal neoplastic progression. We identify a protein signature and lymphocyte infiltrate in non-dysplastic BO when progressive disease (dysplasia or adenocarcinoma) is present but not histologically represented in the biopsied field. There is a dynamic stromal lymphocytic infiltrate in oesophageal neoplastic progression.ConclusionsThis data reveals novel insights into the microenvironment of BO and progression towards cancer and identifies a novel high-risk biomarker of disease progression to aid surveillance strategies to identify early progression and impact future incidence of oesophageal cancer.

&lt;p&gt;Association of ki67 and tumor marker p53 in locally advanced breast cancer patients and evaluation of response to neoadjuvant chemotherapy: a survey in South Iran&lt;/p&gt;

PurposeHeterogeneity of breast cancer, the most common cancer in women, complicates approach to its treatment. Neoadjuvant chemotherapy (NAC) in the treatment of locally advanced breast cancer (LABC) with the endpoint of achieving pathologic complete response (pCR) is not always successful. The purpose of this study was to evaluate the clinicopathologic characteristics, biomarker status and response of LABCs to NAC.Patients and methodsCore biopsies and post-surgical specimens of LABC patients were evaluated after receiving NAC. Their lymph node involvement, tumor staging, grading, size, tumoral and stromal lymphocytic infiltration (TLI, SLI), hormonal status, ki67, p53 and HER2 expression were evaluated. Response to NAC was assessed using pCR, Miller-Payne grading and residual cancer burden.ResultsIn a total of 71 patients, pCR rate was 5.6%. Strong association was observed between ki67 positivity and p53 expression (P-value˂0.001). Also ki67, TLI and SLI showed association with triple negative tumor subtype (P-value 0.011, 0.002 and 0.014). Good response to NAC was associated with p53 expression. Nodal metastatic residue was also associated with primary tumor’s nuclear grade.ConclusionStrong correlation of ki67 and p53 can suggest probable interchangeability of both markers in the prognosis of LABC. In this study p53 even showed superiority to ki67 having association with good response. Strong association of ki67, TLI and SLI with triple negative tumor subtype can be parallel to an overall better response rate of this subtype. We can also propose the effectiveness of defining nuclear grade as a prognostic factor towards residual lymph node involvement post NAC.

Stromal lymphocyte infiltration is associated with tumour invasion depth but is not prognostic in high-grade T1 bladder cancer

IntroductionAssessment of tumour-infiltrating lymphocytes (TILs) can provide important prognostic information in various cancers and may be of value in predicting response to immunotherapy. The objective of the present study was to investigate the association of stromal lymphocytic infiltration with clinicopathological parameters and their correlation with outcomes in patients with high-grade pT1 non–muscle-invasive bladder cancer (NMIBC). Materials and methodsWe retrospectively analysed clinical data and formalin-fixed paraffin-embedded (FFPE) tissues of 147 patients with primary high-grade pT1 NMIBC who underwent transurethral resection of the bladder. The stromal TIL density was scored as percentage of the stromal area infiltrated by mononuclear inflammatory cells over the total intratumoural stromal area. The main end-point was correlation with cancer-specific survival (CSS). ResultsMedian follow-up was 8.2 years (6.1–9.5). Induction Bacillus Calmette–Guérin therapy was undergone by 126 patients (86%). Stromal TILs were high (≥10%) in 82 tumours (56%) and were positively associated with the tumour invasion depth (p = 0.01) and cancers with variant histology (p = 0.01). For the CSS analysis, high (≥10%) versus. low (<10%) stromal TIL hazard ratio (95% confidence interval) was 1.70 (0.7–3.9, p = 0.2). ConclusionsA higher density of stromal TILs was associated with the tumour invasion depth in pT1 NMIBC. The level of TILs was not associated with survival outcomes. These data suggest that tumour aggressiveness is associated with an increased adaptive immune response in pT1 NMIBC. Characterisation of T-cell subtypes along with B-cells may be critical to enhance our knowledge of the host immune response in patients with high-risk NMIBC.

Interobserver Variability in Scoring Percentages of Tumor-Infiltrating Lymphocytes in Breast Core Needle Biopsies

Recent research has shown that tumor-infiltrating lymphocytes (TILs) are correlated with improved survival in a continuous fashion in primary breast cancers. Additionally, the TIL score on breast core biopsies has been shown to correlate with higher rates of pathological complete response after neoadjuvant chemotherapy. In 2014, an International TIL Working Group created a standardized evaluation method for scoring TILs. We sought to determine the interobserver variability in scoring TILs after training among three pathologists with different levels of experience. Fifty-five cases of diagnostic core biopsies from 2010 to 2012 of primary breast carcinoma were selected for the cohort. Prior to scoring the breast biopsies, the evaluators reviewed the standardized scoring method from the 2014 TIL Working Group. The biopsies were assessed for the average percent of stromal lymphocytes in increments of 5%. Each of the cases was scored by the three pathologists who were blinded to the other’s results. The scores were then tabulated and Kendall’s correlation coefficient was calculated using SPSS software from IBM. Values of Kendall’s concordance less than 0.4 can be considered poor agreement, values between 0.4 and 0.59 are fair, between 0.6 and 0.74 are good, and above 0.75 is excellent agreement. The stromal TIL scores ranged from 1% to 90%. The calculated Kendall’s correlation coefficients varied from 0.704 to 0.762 between the three evaluators. Minor interobserver disagreements were attributed to heterogeneity within the tumor, with alternating areas of relatively scant and dense stromal lymphocytic infiltration. The data show that with adequate training, a high degree of correlation is possible between observers at varying levels of experience on core needle biopsies. Scoring TILs on core needle biopsy may be used as an additional biomarker to estimate a patient’s response to neoadjuvant therapy.

Chemosensitivity, tumor infiltrating lymphocytes (TILs), and survival of postpartum PABC patients treated by neoadjuvant chemotherapy

BackgroundPregnancy-associated breast cancer (PABC) refers to breast cancers (BC) diagnosed during pregnancy or shortly after birth. Although the inflammatory environment of post-partum PABC cases (designed as PP-PABC) may be deleterious, so far PP-PABC have scarcely been distinguished from breast cancers diagnosed during pregnancy. Furthermore, whether PP-PABC cases have an enhanced immune infiltration remains unknown. We investigated chemosensitivity, immune infiltration and survival of PP-PABC patients treated by neoadjuvant chemotherapy (NAC) compared to non-PABC matched BC patients. Materials and methodsWe identified PP-PABC cases among a cohort of 1199 invasive BC treated with NAC between 2002 and 2012. Each PP-PABC case was matched with 3 non-PABC controls, according to age and pathological breast cancer subtype. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival (DFS) was assessed by univariate and multivariate analyses. ResultsOur final population study was composed of 116 patients (29 PP-PABC and 87 non-PABC). Median follow-up was of 49.0 and 29.3 months, respectively. After NAC, pCR rates (p = 0.64), post-NAC immune infiltration (stromal TILs: p = 0.67; intratumoral TILs: p = 0.14), and DFS rates (p = 0.17) were comparable between PP-PABC and non-PABC patients in global population. Similar results were found after stratification by pathological subtype. ConclusionWe observed similar patterns between postpartum PABC and control tumors in terms of chemosensitivity, immune infiltration, and prognostic. Our results enhance the idea that PP-PABC should receive the same standard of care treatment as other patients, including neoadjuvant chemotherapy.

1137 - Stromal lymphocyte infiltration is associated with tumor invasion depth but is not prognostic in high-grade T1 bladder cancer

1137 - Stromal lymphocyte infiltration is associated with tumor invasion depth but is not prognostic in high-grade T1 bladder cancer