Intratumoral Lymphocytic Infiltrate 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.

Abstract B014: Immuno-modulation of the tumor microenvironment of pancreatic adenocarcinoma following isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT)

Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest tumors. Unlike other tumors, the progress of systemic therapies has been very slow, mainly due to the peculiar and resistant tumor microenvironment (TME) of PDAC. The addition of ablative stereotactic body radiation therapy (SBRT) in a total neoadjuvant strategy is promising for the treatment of localized PDAC and is currently being explored in several clinical trials. However, if radiation therapy possesses the ability to modulate the TME, the impact of high-dose SBRT is still poorly known in PDAC. Here, we aim to characterize by immunohistochemistry (IHC) and RNA sequencing (RNAseq) analysis the immuno-modulations of the TME following isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT). MATERIAL: Paraffin-embedded residual tumoral tissues of 50 localized PDAC resected between 2011 and 2020 were used: seventeen patients had surgery first, seventeen received an induction chemotherapy with FOLFIRINOX (FFX) only and sixteen with FFX followed by an iHD-SBRT designed to individually maximize the dose prescribed to the tumor and vessels interfaces up to Dmax(0.5cc)&amp;lt;53Gy in 5 fractions. RESULTS: We found that although collagen deposition increases significantly after iHD-SBRT (COL1: 83.27 vs 78.60 vs 68.04%, p&amp;lt;0.001 for iHD-SBRT, FFX and treatment naïve cohort respectively), the intra-tumoral lymphocyte infiltration is globally not altered, including for cytotoxic CD8+ lymphocytes. Only the IHC expression of CD4+ T helper population is significantly decreased after iHD-SBRT. Using gene set enrichment analysis (GSEA) of the KEGG pathway, the IL-17 signaling pathway related to the T17 cells is particularly significantly increased after iHD-SBRT compared to FFX only. After iHD-SBRT, the IHC expression levels of FOXP3+ cells and PD-L1 are significantly increased. No difference is observed for CD68+ expression however, cell type enrichment analysis from our RNA-seq data using xCell algorithm shows that the M2-polarized CD68+ cells are increased after iHD-SBRT compared to FFX alone. PD-1 expression is significantly decreased after iHD-SBRT. Furthermore, RNAseq data revealed that iHD-SBRT is associated with significant enrichment in basaloid cells (p&amp;lt;0.0024), a subtype of basal–like cells associated with immunomodulatory stroma and better clinical outcomes. GSEA canonical pathway analysis further revealed metabolism-related pathways such as oxidative phosphorylation and gluthathione metabolism significantly enriched in iHD-SBRT treated group, suggesting the potential of mitochondrial inhibitors as candidates for combination therapy. CONCLUSIONS: iHD-SBRT is able to durably immuno-modulate the TME of PDAC. If the overall T-cell infiltration is preserved, we have identified some increased pro-tumoral cells and pathways after iHD-SBRT that could improve the development of better-oriented combination trials involving high-dose SBRT. Citation Format: Christelle Bouchart, Oier Azurmendi Senar, Julie Navez, Laurine Verset, Anaïs Boisson, Matthieu Hein, Nicky D’Haene, Dirk Van Gestel, Luigi Moretti, Pieter Demetter, Jean-Baptiste Bachet, Karen Willard-Gallo, Rémy Nicolle, Tatjana Arsenijevic, Jean-Luc Van Laethem. Immuno-modulation of the tumor microenvironment of pancreatic adenocarcinoma following isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B014.

Intra-tumoral lymphocytic infiltration in colorectal liver metastasis as a marker of improved overall survival

Intra-tumoral lymphocytic infiltration in colorectal liver metastasis as a marker of improved overall survival

Tumor-infiltrating lymphocytes, PD-L1, and MMR-deficiency combined characterization may identify subgroups of rectal cancer patients who would benefit from immunotherapy

IntroductionMismatch repair deficiency, immunological fertility, and PD-L1 expression status are key histopathological and molecular features defining tumor responsiveness to immunotherapy and, eventually, prognosis. These were investigated in a series of locally advanced rectal cancer patients treated with postoperative chemotherapy and radiotherapy. Materials and methodsTumor-infiltrating lymphocyte (TIL) density was assessed in hematoxylin-eosin tissue sections. PD-L1 expression and the expression of MMR proteins (MLH1, PSM2, MSH2, and MSH6) were assessed with immunohistochemistry. Their association with histopathological variables (node involvement and tumor budding) and prognosis was assessed. ResultsThe TIL-density was significantly higher in the invading tumor front and was inversely related to tumor budding and directly with better overall survival (OS) and distant metastasis-free survival (DMFS) (p = 0.02 and 0.02, respectively). Cancer cell PD-L1 expression was related to high TIL-density (p < 0.01) but not to prognosis, although its overexpression defined a trend for poorer OS in patients with high TIL-density. High PD-L1 expression by stroma infiltrating immune cells was linked with better OS and DMFS (p = 0.007 and 0.001, respectively. MMR deficiency was recorded in 26.2 % of cases, and this was linked with higher TIL-density, but not with prognosis. ConclusionsDense intratumoral lymphocytic infiltration relates to a better prognosis in rectal cancer, although it is also linked with PD-L1 expression that may adversely modulate the anti-tumor effects of TILs. This latter subgroup of patients (high TIL-density/high cancer cell PD-L1 expression) could be an additional target for anti-PD-1/PD-L1 immunotherapy, along with the established subgroup of MMR deficient patients.

Peritumoral Immune-suppressive Mechanisms Impede Intratumoral Lymphocyte Infiltration into Colorectal Cancer Liver versus Lung Metastases.

Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites in MSS colorectal cancer. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer.

Clinical and Imaging Research in the Diagnosis of Anorectal Melanoma with Surgical Outcome: A Case Report and Literature Review

Abstract Objective This study aims to report the case of a 69-year-old female patient with a diagnosis of anorectal melanoma (AM) established by immunohistochemistry. Methods Clinical case report, a descriptive and qualitative study. Results The patient had a nodular and ulcerative lesion in the anal region, the imaging exams revealed an expansive lesion that affected the rectum and the vaginal wall. The chosen course of treatment was initial surgical intervention, the surgery and postoperative course progressed without complications, and the anatomopathological examination confirmed the diagnosis of invasive malignant melanoma of the distal rectum of anorectal transition. The anatomopathological examination confirmed the diagnosis of invasive malignant melanoma located in the distal rectum of the anorectal transition. Immunohistochemistry analysis showed infiltrative melanoma with microsatellites, as well as peri and intratumoral lymphocytic infiltrate, angiolymphatic invasion, and perineural invasion. The surgical resection margins, ovaries, posterior vaginal wall, and parametrium showed no signs of neoplastic involvement. Following the surgery, the patient began immunotherapy, which she is still undergoing. Conclusions The survival rate of AM can be improved through various diagnostic and therapeutic modalities. However, further exploration of this topic through clinical studies is necessary to enhance both diagnosis and treatment.

Intratumoral Microbiota Changes with Tumor Stage and Influences the Immune Signature of Oral Squamous Cell Carcinoma.

Characterization of the oral microbiota profile through various studies has shown an association between the microbiome and oral cancer; however, stage-specific determinants of dynamic changes in microbial communities of oral cancer remain elusive. Additionally, the influence of the intratumoral microbiota on the intratumoral immune system remains largely unexplored. Therefore, this study aims to stratify microbial abundance in the early-onset and subsequent stages of oral cancer and analyze their influence on clinical-pathological and immunological features. The microbiome composition of tissue biopsy samples was identified using 16S rRNA amplicon sequencing, while intratumoral and systemic immune profiling was done with flow cytometry and immunohistochemistry-based analysis. The bacterial composition differed significantly among precancer, early cancer, and late cancer stages with the enrichment of genera Capnocytophaga, Fusobacterium, and Treponema in the cancer group, while Streptococcus and Rothia were enriched in the precancer group. Late cancer stages were significantly associated with Capnocytophaga with high predicting accuracy, while Fusobacterium was associated with early stages of cancer. A dense intermicrobial and microbiome-immune network was observed in the precancer group. At the cellular level, intratumoral immune cell infiltration of B cells and T cells (CD4+ and CD8+) was observed with enrichment of the effector memory phenotype. Naive and effector subsets of tumor-infiltrating lymphocytes (TILs) and related gene expression were found to be distinctly associated with bacterial communities; most importantly, highly abundant bacterial genera of the tumor microenvironment were either negatively correlated or not associated with the effector lymphocytes, which led to the conclusion that the tumor microenvironment favors an immunosuppressive and nonimmunogenic microbiota. IMPORTANCE The gut microbiome has been explored extensively for its importance in the modulation of systemic inflammation and immune response; in contrast, the intratumoral microbiome is less studied for its influence on immunity in cancer. Given the established correlation between intratumoral lymphocyte infiltration and patient survival in cases of solid tumors, it was pertinent to explore the extrinsic factor influencing immune cell infiltration in the tumor. Modulation of intratumoral microbiota could have a beneficial effect on the antitumor immune response. This study stratifies the microbial profile of oral squamous cell carcinoma starting from precancer to late-stage cancer and provides evidence for their immunomodulatory role in the tumor microenvironment. Our results suggest combining microbiome study with immunological signatures of tumors for their prognostic and diagnostic application.

Potential predictors for CDX2 expression loss and mismatch repair deficiency in colorectal cancer.

CDX2 expression loss is commonly associated with mismatch repair deficiency (dMMR) in colorectal cancer (CRC). However, there are only a few studies that have attempted to correlate CDX2 expression loss with specific MMR genes (MLH1, MSH2, MSH6, PMS2). This is a retrospective study of 327 patients who underwent surgery due to CRC. Nine patients (2.9%) had two synchronous CRCs, making the total sample 336 CRC. Histopathological data such as tumor type, tumor grade, perineural, lymphatic, and vascular invasion, pT stage, pN stage, peritumoral and intratumoral lymphocytic infiltration were collected and recorded in the database. After immunohistochemical analysis, CDX2 expression, MLH1, MSH2, MSH6, and PMS2 deficiency were also recorded. CDX2 expression loss was detected in 19 out of 336 CRCs (5.9%) and was associated with ascending colon CRC, partially mucinous adenocarcinoma, poorly differentiated carcinoma, and dMMR. Forty-four (13.1%) of CRCs were dMMR. We found a statistically significant association between CDX2 expression loss and MLH1 and PMS2 deficiency. Considering that most expression phenotypes include pairs of MMR genes, we analyzed MLH1/PMS2 and MSH2/MSH6 as heterodimers. Analysis of heterodimers showed a similar result, namely, that MLH1/PMS2 heterodimer deficiency was significantly associated with CDX2 expression loss. We also constructed a regression model for CDX2 expression loss and for dMMR. Poor tumor differentiation and MLH1/PMS2 heterodimer deficiency have been identified as potential predictors for CDX2 expression loss. CRC in the ascending colon and CDX2 expression loss have been identified as positive potential predictors of dMMR with rectal cancer as negative potential predictor of dMMR. Our study showed a significant association between CDX2 expression loss and MLH1 and PMS2 deficiency in CRC. We also managed to produce a regression model for CDX2 expression and showed that poor tumor differentiation and MLH1/PMS2 heterodimer deficiency are independent factors for CDX2 expression loss. We were the first to include CDX2 expression in a regression model for dMMR and showed that CDX2 expression loss can be used as a predictive factor for dMMR, which should be confirmed by further studies.

DNA Mismatch Repair Deficiency in Colorectal Adenocarcinoma by a Two-Antibody Immunohistochemical Approach and its Association with Clinicopathological Features among Bangladeshi Patients

Background: Defective DNA Mismatch Repair (dMMR) genes cause dMMR/Microsatellite Instability (MSI)-related Colorectal Cancers (CRC) in humans which are different from Microsatellite Stable (MSS) tumors in terms of biological behavior, therapeutic response, and prognosis. We aimed to determine the frequency of dMMR CRCs by a two-antibody (PMS2 and MSH6) immunohistochemical approach and to evaluate their association with clinicopathological parameters to document the ever first report of such cases in Bangladesh. Methods: Fifty histopathologically confirmed resected bowel specimens of CRC were studied over a period of two years at a tertiary-level hospital in Bangladesh. Histopathological parameters like morphologic variants, histologic subtypes, grade, stage, Lymphovascular Invasion (LVI), intratumoral lymphocytic infiltrate, and Crohn-like peritumoral reaction were assessed. Immunohistochemistry using PMS2 and MSH6 was performed on representative paraffin blocks by DAKO EnVision method. Expression of both of the markers was evaluated in classified groups. Results: Mean age of study population was 48.60±14.6 years with a male to female ratio of 1.8:1. dMMR was recorded in 32% of cases. Expression of PMS2 and MSH6 were lost in 20% and 12% of cases, respectively. dMMR status was significantly associated with mucinous histology (p=0.014), lower pN staging (p=0.042), low LVI (p=0.002), exhibited intra-tumoral lymphocytosis (p=0.001), and Crohn like peritumoral reaction (p=0.001). No significant association with gender, age, right-sided location, histologic type, pT stage or grade was observed. Conclusion: Frequency of dMMR CRCs was comparatively higher in the Bangladeshi population than in other races. Identification of dMMR tumors by their protein expression pattern using at least two, preferably four antibodies is proposed for routine screening of CRC cases.

Peritumoral and Intratumoral Lymphocytic Infiltration and Stromal Reaction in High-Risk Endometrioid Carcinomas

Peritumoral and Intratumoral Lymphocytic Infiltration and Stromal Reaction in High-Risk Endometrioid Carcinomas

Study of Mismatch Repair Protein Expression by Using Immunohistochemistry in Various Carcinomas with Special Reference to Colorectal Adenocarcinomas - At a Tertiary Referral Laboratory in India

Background: DNA mismatch repair (MMR) is an important process during the DNA replication for correcting DNA replication errors. Deficient MMR (dMMR) leads to increased mutational burden and has been associated with several carcinomas and cancer syndromes like Lynch syndrome. The absence of MMR protein by immunohistochemistry is a surrogate marker for microsatellite instability. The aim of the study is to present our datas of MMR deficient tumors and the pattern of MMR protein loss by using immunohistochemistry,also to highlight the technical issues of tissue processing that interfere in result interpretation. Material &amp; Method: 318 cases of various carcinomas were analysed for mismatch repair proteins viz. MLH1, MSH2, MSH6 and PMS2 using immunohistochemistry.Result: Out of total 318 cases,47 cases showed deficient MMR proteins. Among the MMR deficient cases colonic adenocarcinoma cases has the highest percentage with loss of MMR proteins. Regarding pattern of MMR protein loss the simultaneous loss of both MLH1 and PMS2 is the most common pattern. In 5 cases (1.5%) of total cases we could not interpret the result. In compare to MMR proficient colorectal adenocarcinomas, the MMR deficient tumors are predominantly right sided and on histopathology they shows high grade histology,intratumoral lymphocytic infiltration, peritumoral lymphocytic infilatration,,mucinous and signet cell components. Conclusion: Evaluation of MMR proteins using immunohistochemistry is relatively easy to institute in the routine testing as it is a useful predictive and prognostic marker in various carcinomas,also it helps screening the cases of lynch syndrome. This study also highlight the need of using standard protocols for tissue fixation and processing before evaluating for MMR proteins.

Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma

Although PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL). Subcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment. Our results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy. In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

BackgroundColorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with...

176P Type of TP53 alteration may correlate with the extent of lymphocytic infiltration in high-grade serous ovarian carcinomas

176P Type of TP53 alteration may correlate with the extent of lymphocytic infiltration in high-grade serous ovarian carcinomas

PD-L1 Expression in Different Segments and Histological Types of Ovarian Cancer According to Lymphocytic Infiltrate.

Background and Objectives: Ovarian cancer is the leading cause of death among gynecological tumors. PD-1/PD-L1 immunoregulatory mechanism is activated in ovarian cancers. Lymphocyte infiltration is a significant factor that affects its expression. We analyzed the correlation between localization of lymphocytic infiltrate and PD-L1 expression in epithelial ovarian tumors. Materials and Methods: PD-L1 expression was analyzed in 328 subjects, 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. Expression in central and invasive tumor parts in epithelial ovarian carcinoma was combined with the most pronounced lymphocyte reaction. Immunohistochemical analysis was performed using the tissue microarray and correlated with a set of histopathology parameters. Results: PD-L1 expression was most prominent in epithelial ovarian carcinoma with different levels of expression observed between invasive and central tumor segments. A high level of PD-L1 expression on tumor cells was more frequently present in the invasive than in the central tumor parts (p < 0.001) only in high-grade serous ovarian carcinoma (HGSC). There was no significant correlation between peritumoral lymphocytic infiltrate and PD-L1 expression regardless of tumor segment. In the central tumor parts of HGSC, there was a correlation of intratumoral lymphocytic infiltrate with a higher level of PD-L1 expression (p = 0.003). Conclusions: The most prominent PD-L1 expression was observed in the invasive tumor parts of HGSC. Only the central parts of the HGSC exhibited significant PD-L1 expression in association with considerable intratumoral lymphocytic infiltrate.

Nanoparticle delivery of recombinant IL-2 (BALLkine-2) achieves durable tumor control with less systemic adverse effects in cancer immunotherapy

Recent strategies in cancer immunotherapy based on interleukin-2 (IL-2) are generally focused on reducing regulatory T cell (Treg) development by modifying IL-2 receptor alpha (IL-2Rα) domain. However, the clinical utility of high-dose IL-2 treatment is mainly limited by severe systemic toxicity. We find that peritumorally injectable ‘BALLkine-2’, recombinant human IL-2 (rIL-2) loaded porous nanoparticle, dramatically reduces systemic side effects of rIL-2 by minimizing systemic IL-2 exposure. Notably, in cynomolgus monkeys, subcutaneous (SC)-injection of BALLkine-2 not only dramatically reduces systemic circulation of rIL-2 in the blood, but also increases half-life of IL-2 compared to IV- or SC-injection of free rIL-2. Peritumorally-injected BALLkine-2 enhances intratumoral lymphocyte infiltration without inducing Treg development and more effectively synergizes with PD-1 blockade than high-dose rIL-2 administration in B16F10 melanoma model. BALLkine-2 could be a highly potent therapeutic option due to higher anti-tumor efficacy with lower and fewer doses and reduced systemic toxicity compared to systemic rIL-2.

High-risk morphological features are less prevalent among small (&lt;5mm) papillary thyroid microcarcinomas compared to larger (≥5mm) tumors: a study of 206 cases

AbstractIntroduction: Papillary thyroid microcarcinoma (PTMC) is defined as a PTC measuring 1 cm or less, incidentally discovered. The aim of this study was to determine whether small (&lt;5mm) tumors by contrast with large (≥5mm) ones are less frequently associated with high-risk morphological features, predictive of tumor aggressiveness.Materials and methods: All consecutive PTMC cases registered at the Department of Pathology, Târgu-Mureş Emergency County Hospital between 2003-2014 were reviewed. The following have been assessed: tumor size, subcapsular versus nonsubcapsular location, extrathyroidal extension/invasion into the perithyroidal adipose tissue, multifocality, resection margins, lymph node involvement, histological variant, tumor border, stromal reaction (fibrosis/desmoplasia/sclerosis), presence of plump pink cells, nuclear features of the tumor cells, intratumoral lymphocytic infiltrate, multinucleated giant cells, psammoma bodies and stromal calcification. The cases were split in two categories: small (&lt; 5mm) and large (≥ 5mm) PTMCs and the pathological features were evaluated in comparison.Results: Our study included 206 cases, 91 large and 115 small PTMCs, respectively. Large PTMCs were significantly associated with the presence of plump pink cells (p=0.002), well developed PTC nuclear features (p=0.003), stromal reaction (fibrosis/desmoplasia/sclerosis) (p&lt;0.001), infiltrative tumor border (p=0.011), subcapsular location (p&lt;0.001), positive resection margins (p=0.022), stromal calcifications (p&lt;0.001) and intratumoral multinucleated giant cells (p&lt;0.001). Small PTMCs were generally well circumscribed and nonsubcapsular.Conclusions: Our results have shown that small (&lt;5mm) PTMCs are less frequently associated with high-risk morphological features, predictive of tumor aggressiveness compared with large (≥5mm) tumors and could thus be considered as low-risk cancers.

Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma

BackgroundTertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but...

The Oncocytic Variant of Poorly Differentiated Thyroid Carcinoma Shows a Specific Immune-Related Gene Expression Profile

Poorly differentiated thyroid cancer (PDTC) is a rare, follicular cell-derived neoplasm with an unfavorable prognosis. The oncocytic variant of PDTC may be associated with even more adverse outcome than classical PDTC cases, but its specific molecular features are largely unknown. Our aim was to explore the immune-related gene expression profile of oncocytic and classical PDTC, in correlation with clinical and pathological characteristics (including programmed death ligand 1 [PD-L1] expression) and outcome, and in comparison with a control group of well-differentiated follicular carcinomas (WDFCs), including conventional follicular carcinomas (FTCs) and Hürthle cell carcinomas (HCCs). A retrospective series of 48 PDTCs and 24 WDFCs was analyzed by means of NanoString technology employing the nCounter PanCancer Immune Profiling panel. Gene expression data were validated using quantitative real-time polymerase chain reaction. Oncocytic PDTCs showed a specific immune-related gene expression profile, with higher expression of LAIR2, CD274, DEFB1, IRAK1, CAMP, LCN2, LY96, and APOE, and lower expression of NOD1, as compared to conventional PDTCs. This molecular signature was associated with increased intratumoral lymphocytic infiltration, PD-L1 expression, and adverse outcome. Three of these genes, CD274, DEFB1, and IRAK1, as well as PD-L1 expression, were also the hallmarks of HCCs as compared to FTCs. By contrast, the panel of genes differentially regulated in PDTCs as compared to WDFCs was unrelated to the oncocytic phenotype. Our results revealed a distinctive immune-related gene expression profile of oncocytic PDTC and confirmed a more aggressive outcome in this cancer subtype. These findings may provide guidance when exploring novel immunotherapeutic options for oncocytic PDTC patients.