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1.
Pathologie (Heidelb) ; 45(1): 42-49, 2024 Feb.
Article in German | MEDLINE | ID: mdl-38091082

ABSTRACT

Neuroendocrine neoplasms (NENs) originate from various epithelial or neuroectodermal tissues, can occur in any organ, including the pancreas, and are characterized by the expression of the neuroendocrine markers synaptophysin and chromogranin A. Pancreatic neuroendocrine tumors (PanNETs) are well-differentiated epithelial neoplasms with morphological and immunohistochemical features of neuroendocrine differentiation of low, intermediate, or high grade. Pancreatic neuroendocrine carcinomas (PanNECs) are clinically aggressive, high-grade (poorly differentiated) carcinomas with morphologic features suggesting neuroendocrine differentiation, a high proliferative rate (> 20 mitoses per 2 mm2 and Ki67 index > 20%), and immunohistochemical labeling for neuroendocrine markers. They include the small cell neuroendocrine carcinoma and the large cell neuroendocrine carcinoma categories.Neuroendocrine-like morphology coupled with immunohistochemical markers of neuroendocrine differentiation are highly specific. However, neuroendocrine markers may also be expressed in non-neuroendocrine neoplasms, which can therefore be confused with NENs. Mimickers of pancreatic NENs comprise a number of important pitfall tumors, including epithelial and non-epithelial neoplasms, such as acinar cell carcinomas, solid pseudopapillary neoplasms (SPNs), or even non-neoplastic lesions. All of these lesions have the expression of neuroendocrine markers in common, such as synaptophysin and chromogranin A, and although they are comparatively rare, they can cause considerable diagnostic problems. This review article deals with some of the most important mimickers of pancreatic neuroendocrine neoplasms and even non-neoplastic lesions, such as islet aggregation. The similarities and differences between these entities and pancreatic neuroendocrine neoplasms are highlighted, and key findings that facilitate the correct diagnosis are discussed.


Subject(s)
Carcinoma, Neuroendocrine , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Synaptophysin , Chromogranin A , Neuroendocrine Tumors/diagnosis , Pancreatic Neoplasms/diagnosis , Carcinoma, Neuroendocrine/diagnosis
2.
Oncoimmunology ; 5(4): e1106677, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27141391

ABSTRACT

Tumor-associated macrophages (TAM) play a controversial role in epithelial-mesenchymal transition (EMT) and prognosis of colorectal cancer (CRC). In particular, the microlocalization, polarization and prognostic impact of TAM in the immediate environment of invading CRC cells has not yet been established. To address this clinically relevant question, intraepithelial (iCD68) and stromal macrophages (sCD68), M1-macrophages (iNOS), M2-macrophages (CD163), cytokeratin-positive cancer cells (tumor buds) and expression of the anti-phagocytic marker CD47 were investigated in primary tumors of 205 well-characterized CRC patients. Cell-to-cell contacts between tumor buds and TAM were detected using high-resolution digital scans. The composition of the tumor microenvironment was analyzed with clinicopathological and molecular features. High CD68 counts predicted long term overall survival independent of microlocalization (iCD68 p=0.0016; sCD68 p=0.03), pT, pN, pM and post-operative therapy. CD68 infiltration correlated with significantly less tumor budding (iCD68 p=0.0066; sCD68 p=0.0091) and absence of lymph node metastasis (sCD68 p=0.0286). Cell-to-cell contact of sCD68 and invading cancer cells was frequent and ameliorated the detrimental prognostic effect of the tumor budding phenotype. Subgroup analysis identified long-term survival with CD47 loss and predominance of CD163+ M2 macrophages (p = 0.0366). CD163+ macrophages represented 40% of the total population, and positively correlated with total CD68 macrophage numbers (r[CD68/CD163] = 0.32; p = 0.0001). Strong CD163 infiltration predicted lower tumor grade (p = 0.0026) and less lymph node metastasis (p = 0.0056). This study provides direct morphological evidence of an interaction between TAM and infiltrating cancer cells. The prognostic impact of TAM is modulated by phenotype, microlocalization and the expression of anti-phagocytic markers in CRC.

3.
Oncotarget ; 6(16): 14300-17, 2015 Jun 10.
Article in English | MEDLINE | ID: mdl-25973543

ABSTRACT

Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvß5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvß5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvß5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.


Subject(s)
Colorectal Neoplasms/metabolism , Fibroblast Growth Factor 2/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Vitronectin/metabolism , src-Family Kinases/metabolism , Cell Adhesion/physiology , Cell Communication/physiology , Cell Movement/physiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , HEK293 Cells , HT29 Cells , Human Umbilical Vein Endothelial Cells , Humans , Neoplasm Invasiveness , Signal Transduction , Transcriptome
4.
Int J Cancer ; 125(7): 1532-41, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19488988

ABSTRACT

HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis.


Subject(s)
Biomarkers, Tumor/metabolism , Homeodomain Proteins/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Transcription Factors/metabolism , Cell Differentiation , Cell Transformation, Neoplastic/metabolism , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , Humans , Immunohistochemistry , Kaplan-Meier Estimate , MicroRNAs/metabolism , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , Predictive Value of Tests , Prognosis , Transcription Factors/genetics
5.
Am J Clin Pathol ; 129(6): 899-906, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18480006

ABSTRACT

Several studies have shown that glypican 3 (GPC3) could be a useful diagnostic marker for hepatocellular carcinoma (HCC) and for differentiating HCC from nonneoplastic and preneoplastic liver disease. To systematically investigate the epidemiology of GPC3 expression in the liver and in other organs and tissues, we used tissue microarray technology comprising 4,387 tissue samples from 139 tumor categories and 36 nonneoplastic and preneoplastic tissue types. The immunohistochemical expression of GPC3 was assessed semiquantitatively using a 10% cutoff score and was detected in 9.2% of nonneoplastic liver samples (11/119), 16% of preneoplastic nodular liver lesions (6/38), and 63.6% of HCCs (140/220), underlining the role of GPC3 in hepatocarcinogenesis. Furthermore, several other tumors revealed consistent expression of GPC3, including squamous cell carcinoma of the lung (27/50 [54%]), testicular nonseminomatous germ cell tumors (32/62 [52%]), and liposarcoma (15/29 [52%]).


Subject(s)
Biomarkers, Tumor/metabolism , Glypicans/metabolism , Neoplasms/metabolism , Precancerous Conditions/metabolism , Tissue Array Analysis , Carcinoma, Embryonal/metabolism , Carcinoma, Embryonal/pathology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Female , Humans , Liposarcoma/metabolism , Liposarcoma/pathology , Liver/metabolism , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Neoplasms/pathology , Precancerous Conditions/pathology , Predictive Value of Tests , Testicular Neoplasms/metabolism , Testicular Neoplasms/pathology
6.
Methods ; 44(3): 255-61, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18314057

ABSTRACT

Cell death induction by apoptosis is an important process in the maintenance of tissue homeostasis as well as tissue destruction during various pathological processes. Consequently, detection of apoptotic cells in situ represents an important technique to assess the extent and impact of cell death in the respective tissue. While scoring of apoptosis by histological assessment of apoptotic cells is still a widely used method, it is likely biased by sensitivity problems and observed-based variations. The availability of caspase-mediated neo-epitope-specific antibodies offers new tools for the detection of apoptosis in situ. Here, we discuss the use of immunohistochemical detection of cleaved caspase 3 and lamin A for the assessment of apoptotic cells in paraffin-embedded liver tissue. Furthermore, we evaluate the effect of tissue pretreatment and antigen retrieval on the sensitivity of apoptosis detection, background staining and maintenance of tissue morphology.


Subject(s)
Apoptosis , Caspase 3/analysis , Laminin/analysis , Animals , Caspase 3/immunology , Epitopes , Female , Immunohistochemistry , Laminin/immunology , Mice , Mice, Inbred C57BL , fas Receptor/physiology
7.
Hum Pathol ; 39(4): 536-42, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18234275

ABSTRACT

Extranodal marginal zone B-cell lymphomas (mucosa-associated lymphoid tissue [MALT] lymphomas) of the gastrointestinal tract have been known to have characteristic chromosomal aberrations including trisomies of chromosomes 3, 12, and 18. However, knowledge of the clinical significance of cytogenetic changes in MALT lymphomas is still limited. In the present study, the frequency of the numeric and structural aberrations of the chromosomes 1, 3, 12, 18 and X and of the MALT1 gene as well as their potential clinical significance were analyzed by using fluorescent in situ hybridization on a tissue microarray containing 257 tissue samples from 203 cases of surgically resected primary gastric lymphomas including 115 cases of MALT lymphomas, 88 cases of diffuse large B-cell lymphomas (DLBCLs, 75 with an associated MALT lymphoma, so-called ex-MALT DLBCL, and 13 de novo), and 54 controls cases of Helicobacter pylori-associated chronic gastritis. Clinical follow-up information was available in 137 cases. Trisomies 1, 3, 12, and 18 were detected in 3.3%, 44.4%, 12.3%, and 19.2% of MALT lymphomas and in 11.1%, 42.2%, 26.5%, and 22.0% of ex-MALT DLBCLs, respectively. In addition, we found gains of the X chromosome in 36.4% of MALT lymphomas, in 34.5% of ex-MALT DLBCLs, and in 36.4% of de novo DLBCLs. Structural and/or numeric abnormalities of the MALT1 gene were observed in 37.0% of MALT lymphomas and in 22.2% of ex-MALT DLBCLs. In de novo DLBCL, trisomies for chromosomes 3, 12, 18, and X were found in 42.9%, 10.0%, 11.1%, and 36.4%, respectively, whereas alterations of MALT1 (namely, translocations) were found in 20.0% of the cases. An unexpected high and previously unreported gain of chromosome X in gastric MALT lymphomas was found. This tumor appears, therefore, to be a genetically unstable neoplasia. Our results point out that t(11;18) and aneuploidy may be both involved in lymphomagenesis and that at least a subset of MALT lymphomas may progress toward high-grade neoplasia.


Subject(s)
Chromosomal Instability , Gastric Mucosa , Lymphoma, B-Cell, Marginal Zone/genetics , Stomach Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Aneuploidy , Caspases/genetics , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 18/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Neoplasm Proteins/genetics , Tissue Array Analysis , Translocation, Genetic
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