Cells In Most Cases Research Articles

Immunohistochemical Expression of Tenascin-C in Canine Meningiomas.

In humans, tenascin-C (TN-C) expression has been detected in more aggressive neoplasms of the central nervous system, such as gliomas and meningiomas. No study has analyzed the immune expression of TN-C in canine meningioma. The current study aimed to investigate the immunohistochemical distribution of TN-C in different grades of canine meningiomas. Twenty-one cases of canine meningioma (12 grade I, 6 grade II, and 3 grade III) were analyzed. All samples were examined by immunohistochemistry with the following antibodies: TN-C, epithelial membrane antigen (EMA), Ki-67, pan-cytokeratin (Pan CK), and vimentin. The histopathological diagnosis of meningioma was reinforced with the positive labeling of vimentin (moderate to strong) and EMA (mild to moderate) in neoplastic cells in most cases, independently of its grade or subtype. The immunoreactivity of TN-C was irregular: mild in grade I, moderate in grade II, and moderate to severe in grade III neoplasms. Usually, immune positivity was observed in the stroma and perivascular space in all subtypes. In addition, the concentric whorls of neoplastic cells were labeled positive in some psammomatous and transitional meningiomas. The reaction to TN-C was more significant in grade II and III tumors. The immunohistochemical findings of the current study suggest that TN-C can act as a stromal marker, mainly in grade II or III meningiomas.

Granulation tissue-like spindle cell (sarcomatoid) carcinoma of the head and neck: a deceptively bland-looking underdiagnosed malignancy

The diagnosis of head and neck spindle cell squamous carcinoma (SC-SCC) is often challenging. Lesions with a prominent inflammatory infiltrate and reactive vessels may have a granulation tissue-like appearance, therefore being difficult to distinguish from reactive lesions, like contact ulcers, post-intubation granulomas, inflammatory pseudotumors, or benign vascular lesions. In this study, we analyzed the clinicopathological features of a series of 17 head and neck SC-SCC with granulation tissue-like appearance. All patients, but two, were males, ranging in age between 57 and 80 years. The larynx was the most frequently affected site (n = 12), followed by the tongue (n = 4). One tumor was hypopharyngeal. Most consult cases were submitted with benign suggestion or because of unexpected recurrences of granulation tissue polyps. Histologically, all lesions consisted of an ulcerated polypoid proliferation of moderately to markedly atypical spindle cells, with a minor component of conventional invasive or in situ squamous carcinoma. At least one cytokeratin cocktail was positive in 13 cases. The staining was limited to a few neoplastic cells in most cases. Positivity for p63, p40, and cytokeratins 5/6 was detected only in the conventional squamous cell carcinoma component, when present. ALK1 was negative in all cases. Sixteen cases were tested for p53 and all showed aberrant expression (12 diffusely positive and 4 of null-phenotype). The diagnosis of granulation tissue-like SC-SCC is challenging due to the close clinical and histological overlap with several benign conditions. Since the expression of epithelial markers is limited, the use of an immunohistochemical panel including p53 is recommended.

Organ Regeneration Without Relying on Regeneration-Dedicated Stem Cells.

The classic conception of tissue regeneration assumed the existence of tissue-proper regeneration stem cells that are set aside during normal tissue development and reserved as stem cells for regeneration. However, modern studies using cell tracing and other approaches have ruled out the presence of regeneration-proper stem cells in most cases in vertebrate tissue regeneration. The only experimentally validated regeneration-dedicated reserve cells are the satellite cells in skeletal muscle (e.g., Michele 2022) (see Sect. 5.2.3 ). Here, we will first discuss examples of large-scale tissue regeneration, liver regeneration in mammals, and lens and limb regeneration in newts. Then, attempts to widen the tissue regeneration capacity in mammals with exogenous transcription factor genes will be reviewed.

MEF2B is the ideal immunohistochemical marker to highlight neoplastic LP cells in nodular lymphocyte-predominant Hodgkin lymphoma.

MEF2B is the ideal immunohistochemical marker to highlight neoplastic LP cells in nodular lymphocyte-predominant Hodgkin lymphoma.

Bladder cancer selective chemotherapy with potent NQO1 substrate co-loaded prodrug nanoparticles

Currently, clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors. New formulations that can specifically and efficiently kill bladder cancer cells are in urgent need to overcome the low residence efficiency and dose limiting toxicity of current ones. The combination of mucoadhesive nanocarriers and cancer cell selective prodrugs can to great extent address these limitations. However, the insignificant endogenous stimulus difference between cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window. Herein, based on the statistically different NQO1 expression between cancerous and normal bladder tissues, the reactive oxygen species (ROS) activatable epirubicin prodrug and highly potent NQO1 substrate, KP372-1, was co-delivered using a GSH-responsive mucoadhesive nanocarrier. After endocytosis, epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372-1, thus specifically inhibiting the proliferation of bladder cancer cells. Since KP372-1 is much more potent than some commonly used NQO1 substrates, for example, β-lapachone, the cascade drug activation could occur under much lower drug concentration, thus greatly lowering the toxicity in normal cells and broadening the selectivity-window during intravesical bladder cancer chemotherapy.

Application of neural network to speed-up equilibrium calculations in compositional reservoir simulation

Compositional reservoir simulation is an important tool to model fluid flow in oil and gas reservoirs. Important investment decisions regarding oil recovery methods are based on simulation results, where hundred or even thousand of different runs are performed. In this work, a new methodology using artificial intelligence to learn the thermodynamic equilibrium is proposed. This algorithm is used to replace the classical equilibrium workflow in reservoir simulation. The new method avoids the stability test for single-phase cells in most cases and provides an accurate two-phase flash initial estimate. The classical and the new workflow are compared for a gas-oil mixing case, showing a simulation time speed-up of approximately 50%. The new method can be used in compositional reservoir simulations.

The ERM protein moesin regulates natural killer cell homeostasis in vivo

Moesin is a member of the ezrin–radixin–moesin (ERM) family of proteins that link plasma membrane proteins with actin filaments in the cell cortex. Hemizygous mutations in the X-linked moesin gene are associated with primary immunodeficiency with T and B cell lymphopenia, which also affects natural killer (NK) cells in most cases. We previously showed that moesin deficiency in mice substantially affects lymphocyte homeostasis, but its impact on NK cells remains unexplored. Here, we found that in moesin-deficient mice, NK cells were decreased in the peripheral blood and bone marrow but increased in the spleen. Analysis of female heterozygous mice showed a selective advantage for moesin-expressing NK cells in the blood. Moesin-deficient NK cells exhibited increased cell death and impaired signaling in response to IL-15, suggesting that moesin regulates NK cell survival through IL-15–mediated signaling. Our findings thus identify moesin as an NK cell homeostasis regulator in vivo.

PML-RARa of the Short but Not the Long/Variant Isoform Initiate from CD34+ TIM-3+ LSCs with Hierarchical Leukemic Organization

Acute promyelocytic leukemia (APL) is successfully treated with PML-RARa-targeted therapies. APL is divided into two groups with distinct PML-RARa subtypes: Long/variant (the L/V type) and short (the S type) isoforms. The L/V type PML-RARa is observed ~70% of APL patients, whereas the S type isoform, which lacks nucleus localization sequence located in exon6 of PML gene, is involved in ~30% of APL cases. PML-RARa contributes to leukemogenesis presumably by repressing transcriptional activities via its DNA binding properties in nucleus. However, recent studies have shown that PML-RARa mainly localizes in nucleus in the L/V type APL, whereas it dominantly distributes in cytoplasms in the S type APL. This study was planned to clarify difference in the role of PML-RARa in leukemogenesis in APL patients with the L/V or the S type.We performed the transcriptome analysis of APL blast cells from 4 cases each of the L/V type and the S type. Surprisingly, APL cells of the L/V and the S type showed significantly different gene expression pattern by gene set enrichment analysis. For example, pathways for apoptosis involving BCL-2, prostaglandin and T lymphocyte maturation were enriched only in the S type APL, whereas cytokine pathways were mainly enriched in the L/V type APL. More interestingly, the gene sets associated with functional leukemic stem cells (LSCs) (K.Eppert, et al. Nat Med, 2011) were enriched in the S type APL (NES 1.72, FDR q-value 0.083).In most AML of FAB types except for M3 (APL), self-renewing LSCs are concentrated in the CD34+CD38- population, and transplantation of CD34+CD38- LSCs of AML patients resulted in reconstitution of human AML in xenograft models. Based on this data, it is widely accepted that AML is hierarchically organized and is maintained by LSCs, like normal hematopoiesis is initiated from normal HSCs. However, it has been reported that reconstitution of human APL is usually difficult in xenograft models (D.Thomas and R.Majeti. Blood, 2017), although human APL was reconstituted in rare cases by a recent report (S.Patel, et al. Leukemia, 2012). We have reported that self-renewing AML LSCs express TIM-3, a signaling molecule activating the β-catenin pathway (Y.Kikushige, et al. Cell Stem Cell, 2015), but TIM-3 expression was negative in leukemic cells in most cases of APL. However, because the S type but not the L/V type APL has LSC signatures by transcriptome analysis, we revisited to test the LSC activity of the S type APL.By FACS analysis, CD34+CD38- cells were rarely found in the L/V type APL patients, and they largely lacked TIM-3 expression and did not have PML-RARa transcript (n=10), suggesting that these CD34+CD38-TIM-3- cells may be residual normal hematopoietic stem cells (HSCs). In contrast, CD34+CD38- cells from the S type APL strongly expressed TIM-3 and PML-RARa transcript (n=12), suggesting that they may be functional LSCs. We then tested whether CD34+ cells of the S type APL can reconstitute human APL in a xenograft model. Purified 0.4-3.0 x106 CD34+ APL cells were transplanted into sublethally irradiated NSG mice. Strikingly in the S type APL, CD34+ but not CD34- cells reconstituted human PML-RARa+ APL in NSG mice in 3 out of 5 patient tested, whereas in the L/V type APL, CD34+ cells were incapable of reconstitution in all 3 cases tested. The hCD45+CD34+TIM-3+ cells harvested from the primary NSG recipients again reconstituted the S type APL in serial xenotransplantion experiments. These results collectively suggest that the S type APL have LSCs capable of self-renewal within the CD34+ leukemic population, and may use TIM-3 signaling for self-renewal as in other FAB types of AML.Thus, APL with the S type, but not the L/V type PML-RARa have expression signature related to LSCs, and have functional LSCs with TIM-3 expression. Therefore, the leukemic hematopoiesis of APL with the S type is hierarchically organized as in case of AML of other FAB types. The mechanisms by which these 2 types of PML-RARa exert different functions to the LSC property should be critical to understand pathogenesis of APL. DisclosuresNo relevant conflicts of interest to declare.

3DeeCellTracker, a deep learning-based pipeline for segmenting and tracking cells in 3D time lapse images.

Despite recent improvements in microscope technologies, segmenting and tracking cells in three-dimensional time-lapse images (3D + T images) to extract their dynamic positions and activities remains a considerable bottleneck in the field. We developed a deep learning-based software pipeline, 3DeeCellTracker, by integrating multiple existing and new techniques including deep learning for tracking. With only one volume of training data, one initial correction, and a few parameter changes, 3DeeCellTracker successfully segmented and tracked ~100 cells in both semi-immobilized and 'straightened' freely moving worm's brain, in a naturally beating zebrafish heart, and ~1000 cells in a 3D cultured tumor spheroid. While these datasets were imaged with highly divergent optical systems, our method tracked 90-100% of the cells in most cases, which is comparable or superior to previous results. These results suggest that 3DeeCellTracker could pave the way for revealing dynamic cell activities in image datasets that have been difficult to analyze.

Co-expression patterns of chimeric antigen receptor (CAR)-T cell target antigens in primary and recurrent ovarian cancer

ObjectiveChimeric antigen receptor (CAR)-T cell strategies ideally target a surface antigen that is exclusively and uniformly expressed by tumors; however, no such antigen is known for high-grade serous ovarian carcinoma (HGSC). A potential solution involves combinatorial antigen targeting with AND or OR logic-gating. Therefore, we investigated co-expression of CA125, Mesothelin (MSLN) and Folate Receptor alpha (FOLRA) on individual tumor cells in HGSC. MethodsRNA expression of CA125, MSLN, and FOLR1 was assessed using TCGA (HGSC) and GTEx (healthy tissues) databases. Antigen expression profiles and CD3+, CD8+ and CD20+ tumor-infiltrating lymphocyte (TIL) patterns were assessed in primary and recurrent HGSC by multiplex immunofluorescence and immunohistochemistry. ResultsAt the transcriptional level, each antigen was overexpressed in >90% of cases; however, MSLN and FOLR1 showed substantial expression in healthy tissues. At the protein level, CA125 was expressed by the highest proportion of cases and tumor cells per case, followed by MSLN and FOLRA. The most promising pairwise combination was CA125 and/or MSLN (OR gate), with 51.9% of cases containing ≥90% of tumor cells expressing one or both antigens. In contrast, only 5.8% of cases contained ≥90% of tumor cells co-expressing CA125 and MSLN (AND gate). Antigen expression patterns showed modest correlations with TIL. Recurrent tumors retained expression of all three antigens and showed increased TIL densities. ConclusionsAn OR-gated CAR-T cell strategy against CA125 and MSLN would target the majority of tumor cells in most cases. Antigen expression and T-cell infiltration patterns are favorable for this strategy in primary and recurrent disease.

Expression Status of BCL-6 and Syndecan-1 Identifies Distinct Histogenetic Subtypes of Hodgkin's Disease

The tumor cells in most cases of Hodgkin's disease (HD) have been recently recognized to originate from the B-cell lineage, but their precise differentiation stage is not fully clarified. Recently, we have reported that the histogenesis of B-cell lymphomas may be assessed by monitoring the expression pattern of BCL-6, a transcription factor expressed in germinal center (GC) B cells, and CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation. In this study, we have applied these two markers to the study of HD histogenesis. We have found that in nodular lymphocyte predominance HD (NLPHD) tumor cells consistently display the BCL-6+/syn-1− phenotype, indicating their derivation from GC B cells. Conversely, classic HD (CHD) is heterogeneous because the tumor cells of a fraction of CHD display the BCL-6−/syn-1+ phenotype of post-GC B-cells, whereas another fraction of CHD is constituted by a mixture of tumor cells reflecting the GC (BCL-6+/syn-1−) or post-GC (BCL-6−/syn-1+) phenotypes. BCL-6−/syn-1+ tumor cells of CHD are mostly found surrounded by T cells expressing CD40L, consistent with the observation that CD40 signaling downregulates BCL-6 expression. These data indicate that tumor cells of NLPHD uniformly display a GC B-cell phenotype, whereas the phenotype of tumor cells of CHD appears to be modulated by the surrounding cellular background, particularly CD40L+ reactive T cells.

Transforming growth factor beta type 1 (TGF-β) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells.

Galectin-9 is one of the key proteins employed by a variety of human malignancies to suppress anti-cancer activities of cytotoxic lymphoid cells and thus escape immune surveillance. Human cancer cells in most cases express higher levels of galectin-9 compared to non-transformed cells. However, the biochemical mechanisms underlying this phenomenon remain unclear.Here we report for the first time that in human cancer as well as embryonic cells, the transcription factors hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are involved in upregulation of transforming growth factor beta 1 (TGF-β1) expression, leading to activation of the transcription factor Smad3 through autocrine action. This process triggers upregulation of galectin-9 expression in both malignant (mainly in breast and colorectal cancer as well as acute myeloid leukaemia (AML)) and embryonic cells. The effect, however, was not observed in mature non-transformed human cells. TGF-β1-activated Smad3 therefore displays differential behaviour in human cancer and embryonic vs non-malignant cells. This study uncovered a self-supporting biochemical mechanism underlying high levels of galectin-9 expression operated by the human cancer and embryonic cells employed in our investigations. Our results suggest the possibility of using the TGF-β1 signalling pathway as a potential highly efficient target for cancer immunotherapy.

LINC-05. PRIMARY CENTRAL NERVOUS SYSTEM EWING SARCOMA IN PEDIATRIC AND AYA PATIENTS: 2 INSTITUTIONS EXPERIENCE IN BUENOS AIRES ARGENTINA

INTRODUCTIONEwing Sarcoma (ES) is defined by molecular markers, being t(11;22)(q24;q12) the most frequent. Intracranial ES usually shows as metastases from extracranial sites. Primary central nervous system (CNS) lesions are extremely rare.MATERIAL AND METHODSRetrospective review of clinical records from patients with primary CNS ES, assessed at 2 institutions in Argentina between 2007–2019. Translocation was evidenced in all cases through molecular testing. Clinical characteristics, imaging, histopathology, and treatment response were evaluated. Extracranial and osseous lesions were excluded.RESULTS15 patients. Median age at beginning of symptoms: 8 yo (2–20). Most patients had intracranial hypertension syndrome (14/15). In brain MRI, 5/15 supratentorial lesions, 4/15 posterior fosa, 1/15 medullary, 2/15 supra and infratentorial, and 3/15 lesions diffuse leptomeningeal infiltration. Histopathologic findings showed diffuse pattern with small round blue cells in most cases, other patterns were also described. CD99 marked positive in all cases. Misdiagnosis with glial tumors (4/15), medulloblastoma (6/15) and infectious diseases (3/15); led to median delay to accurate diagnosis of 3 months (range 0–67). After correct diagnosis patients were treated with standard ES treatment (6 VIDE cycles plus radiotherapy) in 14/15 patients. Vincristine, irinotecan and temozolamide was used as second line treatment in all relapse cases whenever possible. EFS was 22 months (2- 65). OS at 5 years of follow-up was 46,67% (mean OS 31 mo).CONCLUSIONEven though molecular assessment led to accurate diagnosis in all cases, treatment response and outcome showed two different groups of patients with long and very short survival. Adaptative therapy should be considered.

BIOFILM FORMATION BY SALMONELLA ENTERITIDIS STRAINS IN PRESENCE OF SIGNAL QUINOLON SYNTHETIC ANALOGUES

Aim. Study of the biofilm formation of S. enteritidis in presence of original derivatives of 2-heptyl-3-hidroxy-4-quinolon with different length of alkyl chain. Methods. Test strain cells were incubated in 96-well plates in presence 20, 40 and 80 µM of discovered compounds. The compounds were divided into two groups – with shortened length of alkyl chain then in PQS, and with extended length of alkyl chain then in PQS. Planktonic culture growth was determined spectrophotometrically on the wave length 600 nm. Biofilm formation was studded by CV-test (crystal violet-test) spectrophotometrically on the wave length 592 nm. Results. Obtained results showed that in presence of the PQS analogs with shortened length of alkyl chain decreased content of planktonic cells in most cases. In the same time PQS analogues with extended length of alkyl chain stimulated planktonic cells accumulation. PQS and its analogues with shortened length of alkyl chain were not active, or moderately stimulate biofilm formation of S. enteritidis test-strains. In the other hand, PQS analogues with extended alkyl chain significantly decrease S. enteritidis biofilm mass approximately by 50–70% and higher compare the control. Conclusions. It was shown that analogues of Pseudomonas aeruginosa signal quinolone with the extended alkyl chain are the effective inhibitors of biofilm formation by different strains of S. enteritidis.

P120 CATENIN EXPRESSION AND ITS CORRELATION WITH E-CADHERIN IN SALIVARY GLAND NEOPLASMS

P120 catenin loss or altered localization has been associated with E-cadherin inactivation and poor patient prognosis in several cancers. Objectives The purposes of this study were to investigate the expression of P120 catenin in salivary gland neoplasms in correlation with E-cadherin, and examine the relationships between levels of expression and pathologic characteristics. Materials and Methods Fifty-two cases of salivary gland neoplasms, including 25 mucoepidermoid carcinomas (MEC), 13 adenoid cystic carcinomas (ACC), 12 pleomorphic adenomas (PA) and 2 polymorphous adenocarcinoma (PAC) were investigated for P120 catenin and E-cadherin expression immunohistochemically. The immunoreactivity was categorized as low expression or high expression group, based on whether the positive staining was below or higher than 10% of the neoplastic cells, respectively. Findings Overall, the expression of both proteins was common in salivary gland neoplasms. P120 catenin primarily localized to the membrane of neoplastic cells in most cases. A significant correlation between levels of expression of both proteins was noted in MECs with no relationship with pathologic characteristics. In ACCs and PA, ductal cells showed positive immunoreactivity, whereas myoepithelial cells variably expressed both proteins. Overexpression of P120 catenin was detected in solid subtype of ACCs. Conclusion The cadherin-catenin complex is maintained in neoplasms of salivary gland. The differential expression of both P120 catenin and E-cadherin in this group of neoplasms appears to represent the heterogeneous population of neoplastic cells present in each tumor type.

Immunohistochemical Study of Non-Epithelial Cells in Spiradenoma.

Intratumoral lymphocytes are a defining feature of spiradenoma; however, there have only been a few reports on the phenotypic features of non-epithelial cells. Spiradenomas also contain numerous cells positive for S-100 protein and the nature of these cells is still controversial. We performed a clinicopathological and immunohistochemical study of ten cases of spiradenoma. The study included seven men and three women. On histopathological examination, spiradenoma could be divided into two types: the vascular proliferating (VP) type (five cases) that featured granulation tissue with edema, vascular proliferation, and inflammatory cell infiltration into the stroma, and the common type (five cases), which did not include any of the aforementioned features. Immunohistochemical staining demonstrated a large number of cells positive for S-100 protein. These included cells with large pale nuclei, dendritic cells, and a few cells with small dark nuclei that were also positive for α-smooth muscle actin. Most of the cells infiltrating the parenchymata of these lesions were CD3-positive. The proportions of CD4-positive and CD8-positive cells were almost equal or CD8-positive cells were predominant. CD20+ cells were observed in five spiradenomas. In painful lesions, there were numerous nerve fibers near the tumor. In spiradenoma, CD3+ T cells were mainly seen in the parenchyma and CD8+ cells were predominant over CD4+ cells in most cases. CD20+ cells showed focal infiltration of the parenchyma and stroma, especially in VP-type lesions. S-100 protein-positive cells in spiradenoma contained not only Langerhans cells, but also cells with myoepithelial differentiation.

Ovarian stromal cells as a source of cancer-associated fibroblasts in human epithelial ovarian cancer: A histopathological study.

Fibroblasts are a major component of cancer tissue and known to contribute to cancer progression. However, it remains unknown whether they are derived from local fibroblasts or of other origin. This study was designed to identify the contribution of local stromal cells to cancer stroma in human epithelial ovarian cancer. Seventy-six cases of surgically resected primary ovarian carcinoma (48 cases confined to the ovaries and 28 cases with distant metastases) and 17 cases of secondary ovarian tumor (e.g. colon cancer metastasized to the ovary) were enrolled in this study. The tissues were immunostained for forkhead box protein L2 (FOXL2), a transcription factor crucial for ovarian development and function, and markers for cancer-associated fibroblasts (CAFs) and inflammatory cells. Under normal condition, FOXL2 expression was restricted to ovarian stromal cells and some other types of cells in female genital tracts and never found in other sites of the body. FOXL2-positive cells were found in all primary and secondary tumors in the ovary, and were the dominant stromal cells in most cases. In contrast, only a few FOXL2-positive cells were found in peritoneal seeding sites of four serous carcinoma cases, and all the other tumors at extraovarian sites had no FOXL2-positive cells. FOXL2-positive cells in the ovarian lesion variably expressed CAFs markers, such as alpha-smooth muscle actin and fibroblast activating protein, as determined by double immunostaining. Background inflammation, but not histological subtype or origin of the neoplasm seemed to correlate with the proportion of FOXL2-positive cells. These results suggest that ovarian stromal cells are the main source of cancer stroma in the ovary but do not seem to move to distant sites via circulation together with tumor cells. Our results also support the hypothesis that cancer-associated fibroblasts may originate locally, which was previously demonstrated using animal models.

P120 catenin expression and its correlation with E-cadherin in salivary gland neoplasms

ObjectivesAltered P120 catenin expression has been associated with E-cadherin loss and poor prognosis in several cancers. The objectives of this study were to examine the P120 catenin expression in salivary gland neoplasms in correlation with E-cadherin and assess the relationships between their expression levels and pathologic characteristics. MethodsFifty-two cases of salivary gland neoplasms, i.e. 25 mucoepidermoid carcinomas (MEC), 13 adenoid cystic carcinomas (ACC), 12 pleomorphic adenomas (PA) and 2 polymorphous adenocarcinomas (PAC) were included. The expression of P120 catenin and E-cadherin was investigated immunohistochemically. ResultsBoth P120 catenin and E-cadherin were overexpressed in salivary gland neoplasms, compared to normal tissue. P120 catenin was primarily detected on the membrane of neoplastic cells in most cases. A significant correlation between levels of expression of both proteins was noted in MECs. In ACCs and PA, ductal cells showed positive immunoreactivity, whereas myoepithelial cells variably expressed both proteins. Increased P120 catenin expression was significantly associated with the solid subtype of ACCs. ConclusionsThe cadherin-catenin complex is preserved in the heterogenous tumor cell population in salivary gland neoplasms. Overexpression of P120 catenin may be involved in the progression to solid ACCs.

Abstract 5069: Inflammatory cytokine localization in the prostate tumor microenvironment and their association with prostate cancer racial disparities

Abstract Prostate cancer (PCa) is the 3rd leading cause of cancer-related deaths in American men. The major risk factors for PCa development include advanced age, family history and African ancestry. Chronic inflammation has been implicated as a major contributor to PCa and genes involved in inflammatory pathways are reported as more prevalent in tumors from African American (AA) versus Caucasian American (CA) men. Specifically, interleukin-1β (IL1β), IL6, IL8, and IL10 have been identified as over-expressed in the tumor microenvironment of AA men. These interleukins are in involved in the attraction, activation or maintenance of innate immune cells such as neutrophils and macrophages. However, it is not well understood where these interleukins are expressed in the prostate and what cell types produce them. We aim to address these specific questions in this study. The expression pattern and cellular localization of IL1β, IL6, IL8 and IL10 were evaluated using a highly specific RNA in situ hybridization (RISH) assay to analyze formalin-fixed paraffin-embedded tissues of low grade (Gleason ≤ 3+4) and higher grade (Gleason ≥ 4+3) PCa from AA and CA men. IL8 expression was additionally assessed by RISH in two unique tissue microarray (TMA) sets; i) primary prostate tumors obtained by radical prostatectomy from AA and CA men, matched for patient age, tumor grade and stage; ii) distant metastatic tissues obtained by autopsy. Immunohistochemical analysis of neutrophils (CD66ce) and RISH for macrophages (CD68) was used to assess the expression pattern of these immune cells within the same cohorts. Limited IL1β and IL10 expression was observed across all cases. IL6 expression was largely confined to the stromal compartment in endothelial cells and areas of acute inflammation. Modest IL6 expression was observed in atrophic epithelial cells. IL6 was never seen in tumor cells. IL8 was the most abundantly detected cytokine within our cohort and was significantly increased in higher grade cases. In benign regions, IL8 expression was predominantly observed in epithelial cells in regions of prostatic atrophy and in areas surrounding corpora amylacea. We observed marked IL8 expression in urothelial cells in most cases. IL8 expression was also apparent in multiple tumors, both in tumor cells and infiltrating immune cells. Tumor-infiltrating macrophages were markedly increased within a subset of tumors, but did not appear to express IL8. Conversely, a subset of neutrophils expressed IL8. Neutrophils were significantly increased in benign tissues from men with higher grade PCa, particularly in AA men. IL8 expression was also observed in a subset of distant metastases, particularly in liver metastases. There is differential expression of cytokines among men with PCa, and IL8 is the most abundant among the ones we analyzed. Our future studies aim to determine a role for IL8 in prostate carcinogenesis. Citation Format: Janielle P. Maynard, Onur Ertunc, Angelo M. De Marzo, Karen S. Sfanos. Inflammatory cytokine localization in the prostate tumor microenvironment and their association with prostate cancer racial disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5069.

Esophageal carcinosarcoma comprised of minimally invasive squamous cell carcinoma and undifferentiated pleomorphic sarcoma: A collision cancer?

Esophageal carcinosarcoma is a rare neoplasm with components of squamous cell carcinoma and sarcomatous spindle cell stroma. The latter may show overt mesenchymal differentiation but is thought to be derived from carcinoma cells in most cases. Here, we report a case of esophageal carcinosarcoma that appeared to be comprised of different origins of epithelial and mesenchymal tumor cells. The sarcomatous component formed an intralumial pedunculated large mass lesion that consisted of pleomorphic atypical histiocyte-like cells. The squamous epithelium exhibited features of mostly dysplasia with minor foci of microinvasive squamous cell carcinoma. The invasive carcinoma was apart from the sarcoma, and no transitions were observed between the epithelial and sarcomatous cells. Immunohistochemistry showed that the sarcoma cells did not express any lineage-specific markers, including those for epithelial cells and histiocytes, which lead to the diagnosis of undifferentiated pleomorphic sarcoma. Although cyclin D1 was overexpressed in the carcinoma cells, it was nearly negative in the sarcoma cells. These findings indicate that the tumor may be a collision carcinosarcoma. It is highly likely that the patient's history of heavy smoking and alcohol consumption were relevant to the pathogenesis, at least for the epithelial component, of the tumor.