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Results for “Tissue Array Analysis”

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PubMed2006

TOP2A and HER2 gene amplification as predictors of response to anthracycline treatment in breast cancer.

The purpose of this study was to evaluate amplification of topoisomerase IIalpha (TOP2A) and HER2 genes as predictors of response to chemotherapy in advanced breast cancer. Gene copy number of TOP2A and HER2 were analysed with chromogenic in situ hybridization (CISH) on paraffin-embedded tissue sections from the primary tumour of 85 patients treated with anthracycline containing chemotherapy. TOP2A gene amplification was present in 14 (16%) and HER2 gene amplification in 38 (45%) of the primary tumours. Two of the 14 cases with TOP2A amplification were amplified without concurrent HER2 amplification. Neither TOP2A nor HER2 gene amplification were significantly associated with response to chemotherapy (p = 0.35 and p = 0.49, respectively).

Adult↗

PubMed2006

Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer.

Recent studies have suggested that K-ras play an important role in the induction of COX-2 expression in tumor cells. In the present study, tumor samples of 89 gastric cancer patients were prepared in tissue microarrays and they were stained by immunohistochemistry with antibodies against COX-2 and K-ras. We investigated the relationship between the protein expressions of COX-2 and K-ras in gastric cancer and their significance as prognostic markers in gastric cancer patients. The over expression rate of COX-2 and K-ras in gastric cancer was 61.8% and 61.8% (55/89) of all the patients, respectively. There was a significant positive correlation between COX-2 and K-ras expression in gastric cancer. COX-2 and K-ras positivity were correlated with depth of invasion and lymph node metastasis, respectively. K-ras positivity was correlated with growth pattern. Patients with COX-2 and K-ras positive tumors had a poorer prognosis than those with COX-2 and K-ras negative tumors. Over expression of COX-2 and K-ras were closely correlated to prognostic of patients with gastric cancer and they educed synergistic effect with carcinogenesis and development in gastric cancer.

Adult↗

PubMed2005

The tissue micro-array as a translational research tool for biomarker profiling and validation.

High-throughput molecular technologies have provided a wealth of putative biomarkers representing potential diagnostic, prognostic and therapeutic targets. Target validation commonly requires abundant and well-characterized tissue resources, as well as linked clinicopathologic data-sets. The tissue micro-array (TMA) is a validation and discovery platform of increasing popularity and necessity. TMAs provide a rapid means of examining in situ gene expression in a wide spectrum and large number of tissue samples. This paper describes the uses of TMAs as a translational research tool in biomarker profiling. The laboratory has performed numerous biomarker studies on several types of epithelial cancers. As an example, Epithelial Protein Cell Adhesion Molecule (EpCAM), a panepithelial antigen used to target tumours with immunotherapy, was examined in patients with renal cell carcinoma (RCC). EpCAM was an independent prognosticator for improved disease-specific survival in 318 clear cell RCCs examined, with a Cox proportional hazards multivariate hazard ratio of 0.63 (p=0.017; 95% confidence interval 0.43-0.92). Interestingly, despite a typically widespread epithelial expression, EpCAM is instead infrequently expressed in clear cell RCC, the most common type of renal cancer, making it a poor target for immunotherapy. In this capacity the TMA provided strong support for halting lengthy and costly clinical trials for this application.

Animals↗

PubMed2026

Profiling tumor immune microenvironment of epithelial ovarian carcinoma.

BACKGROUND: Epithelial ovarian carcinoma (EOC) comprises five main histological subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), mucinous (MOC), and endometrioid (ENOC). Each histotype harbors specific genomic alterations and clinical outcome. Few studies systematically compared the tumor immune microenvironment across the five subtypes. METHODS: We performed 7-plex (CD45, CD8, CD68, CD163, FoxP3, CD20, and cytokeratin) sequential immunohistochemistry on a clinically annotated tissue microarray including 139 EOC representing the five subtypes and 26 borderline tumors (serous and mucinous). Digital pathology was used to quantify immune cell abundance, their spatial distribution (stroma vs tumor core), and correlation with survival. RESULTS: Immune cells were dominated by macrophages and more abundant in the stroma than tumor core across the five subtypes, consistent with immune excluded pattern. Compared to HGSOC, CCOC displayed the highest infiltration by CD45+ leukocytes and CD68+ macrophages, particularly M2-like CD163+ cells, suggesting a macrophage-rich, immunosuppressive phenotype. LGSOC exhibited the highest infiltration by intraepithelial FoxP3+ regulatory T cells. Comparison of borderline tumors with invasive carcinoma (LGOSC and MOC) revealed that malignant progression is accompanied by loss of CD8+ T cells, enrichment in regulatory T cells and increase of CD163+/CD68+ ratio, consistent with immune evasion during tumorigenesis. There was a trend toward better survival in HGSOC highly infiltrated by lymphocytes, either intraepithelial (CD8+ and FoxP3+) or stromal (FoxP3+ and CD20+). CONCLUSIONS: EOC is characterized by histotype-specific immune milieux defined by macrophage dominance, epithelial immune exclusion and dynamic immune remodeling during progression from borderline tumors to invasive carcinomas.

Humans↗

PubMed2005

CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target.

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in >90% mortality for Barrett-associated adenocarcinomas. To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform. We identified 560 transcripts with >3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had >5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels. These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.

Adenocarcinoma↗

PubMed2004

Focal adhesion kinase overexpression in endometrial neoplasia.

Focal adhesion kinase (FAK) is a protein tyrosine kinase that is a critical mediator of signaling events between cells and their extracellular matrix. Elevations in FAK mRNA and protein overexpression have been linked to tumor cell capacity for invasion and metastasis. FAK expression has been shown to be elevated in a variety of solid tumors. The purpose of this study was to evaluate for FAK upregulation in endometrial neoplasia. Tissue microarray blocks were made from formalin-fixed, paraffin-embedded archival tissue, including 115 carcinoma (100 endometrioid, 10 serous, and 5 clear cell), 28 hyperplasia, and 38 normal specimens using 1-mm punches. The tissue was immunostained with monoclonal antibody for FAK and p53. Immunoreactivity was scored by intensity (0-4+ scale) and percent positive staining. FAK overexpression was categorized as 4+ cytoplasmic intensity in more than 90% of neoplastic cells. Positive p53 was categorized at least 2+ nuclear intensity in more than 10% of neoplastic cells. Higher rates of FAK upregulation were identified in endometrial hyperplasia (P = 0.025) and carcinoma (P < 0.001) versus normal endometrium. FAK overexpression in carcinoma correlated with higher FIGO grade (P = 0.025) and p53 overexpression (P < 0.001). FAK was consistently overexpressed in high-grade tumors regardless of subtype, including 8 of 10 serous tumors, 4 of 5 clear cell tumors, and 16 of 23 grade 3 endometrioid tumors. In conclusion, upregulation of FAK is seen in both endometrial hyperplasia and carcinoma, implying that FAK may play an important role in endometrial carcinogenesis. FAK overexpression in endometrial carcinoma correlates with higher FIGO grade and p53 overexpression.

Carcinoma, Endometrioid↗

PubMed2005

HER2 positivity in breast carcinoma: a comparison of chromogenic in situ hybridization with fluorescence in situ hybridization in tissue microarrays, with targeted evaluation of intratumoral heterogeneity by in situ hybridization.

An accurate and reproducible assay method for determining HER2 status is crucial, as a positive HER2 gene status is an eligibility requirement for Herceptintrade mark therapy. Although immunohistochemical (IHC) assessment is both practical and inexpensive, a worrying trend of high false-positive rates has been reported. Fluorescence in situ hybridization (FISH) is the universally accepted gold standard for confirming IHC 2+ cases and ambiguous results but is costly and requires specialized equipment and technical expertise. Chromogenic in situ hybridization (CISH) amalgamates the practical advantages of IHC with the reproducibility of FISH, and high concordance between the CISH and FISH methods has been reported in conventional sections. Tissue microarrays (TMAs) allow high throughput of specimens, and HER2 status assessment in TMA cores using IHC and FISH has correlated well with scores in conventional sections. The authors used TMA technology to compare the efficacy of ZYMED(R) CISH with PathVysiontrade mark FISH in a cohort of 119 archival breast resection cases and investigated possible intratumoral heterogeneity in a "mini-array" of 21 HercepTest "equivocal"/2+ cases. Concordance between FISH and CISH in TMA sections was 99%. All prescored 2+ HercepTest cases were nonamplified. Four 3+ HercepTest cases were classed as potential false-positives. The authors suggest that confirmatory ISH should be performed on all positive HercepTest cases. CISH was easier to perform and quicker to enumerate than FISH. The authors conclude that CISH is a practical alternative to FISH as a confirmatory tool for HER2 gene amplification status. Intratumoral heterogeneity did not affect the patient's HER2 status.

Aneuploidy↗

PubMed2005

Differential immunoprofiles of hepatocellular carcinoma, renal cell carcinoma, and adrenocortical carcinoma: a systemic immunohistochemical survey using tissue array technique.

The differential diagnoses of hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and adrenocortical carcinoma (ACC) are sometimes difficult due to their overlapping histologic features. Immunohistochemistry is a helpful adjunct in supporting the histologic diagnosis. In this study, the authors used the tissue array technique to systemically analyze the efficacy of different immunohistochemical panels in discerning these neoplasms. Immunohistochemical stains were performed on a total of 895 tumors (including 170 HCCs, 176 RCCs, and 40 ACCs) using monoclonal antibodies against hepatocyte antigen (HPA), CD10, RCC marker, vimentin, alpha-inhibin, keratins (KL-1, CAM 5.2, 7, and 20), epithelial membrane antigen, and polyclonal antibodies against carcinoembryonic antigen (pCEA) and alpha-fetoprotein, and antibodies Melan-A (A103), MOC31, and BG8. HPA immunostain alone detected 85.9% of HCCs, and the addition of canalicular pattern of pCEA and CD10 immunostains raised the sensitivity to 94.7%. RCC marker was positive in 54.5% of RCCs but was negative in all non-RCC tumors. Using positive CD10 and negative HPA and pCEA together with RCC marker increased the sensitivity to 74.4%. Immunoreactivity for alpha-inhibin and A103 could be detected in 67.5% and 55% of ACCs, respectively. When the two antibodies were combined, 82.5% of ACCs were labeled. Proper selection of immunohistochemical stains aid in the differential diagnosis of the three neoplasms. Using the tissue array technique, the authors also showed an effective model for comprehensive antibody testing.

Adrenal Cortex Neoplasms↗

PubMed2005

Immunohistochemical detection of NRSA on small cell lung cancer with a monoclonal antibody (MAG-1) that recognizes the carboxyl terminus of provasopressin.

A single monoclonal antibody (MAG-1) directed against the C-terminal 18-amino acid region (VAGc18) of provasopressin was examined as an agent for recognizing the tumor-specific NRSA marker common to small cell lung cancer (SCLC) in formalin-fixed tissues with ABC immunohistochemistry. SCLC tumors were obtained from several tissue locations and included primary, metastatic, and recurrent disease. Positive staining was found in 91% of cases (53/58). All five of the unreactive tumors were of the lungs or chest wall, and there did not appear to be an association of this negativity with disease stage, age, or sex. Alternatively, almost all primary lesions, almost all metastatic lesions, and all recurrent lesions examined gave a positive reaction with MAG-1. For this study, vasopressin-producing cells of the human anterior hypothalamus served as a positive control, while negative controls comprised normal lung tissue, tumor that received MAG-1 in the presence of an excess of antigen (VAGc18 peptide), or tumor reacted with a commercial IgG1 isotype as primary antibody. All of the results indicate that MAG-1 can be effectively used to selectively identify the NRSA marker on almost all SCLC tumors, at all disease stages, and at all locations. Since all four tumors tested showing no reactivity with MAG-1 gave a positive reaction for synaptophysin, it is proposed that a combined use of MAG-1 with synaptophysin antibodies could allow all SCLC tumors to be detected by ABC immunohistochemistry.

Antibodies, Monoclonal↗

PubMed2005

Utility of syndecan-1 (CD138) expression in the diagnosis of undifferentiated malignant neoplasms: a tissue microarray study of 1,754 cases.

Syndecan-1, a heparan sulfate-rich membrane glycoprotein, is expressed in plasma cells and is considered a reliable marker of plasmacytic differentiation. However, it has not been widely tested in non-hematolymphoid tissues, and thus its utility in the setting of an undifferentiated malignant neoplasm has not been evaluated. The authors conducted an extensive study of CD138 staining in over 1,700 normal, benign, and malignant non-hematolymphoid tissues, using five tissue microarrays. Immunohistochemical staining was performed with two commercially available CD138 monoclonal antibodies directed against syndecan-1 (Serotec, Oxford, UK, and DAKO, Carpenteria, CA). In addition to the specific membrane staining, many normal tissues and epithelial tumors showed strong cytoplasmic immunoreactivity. A small subset of mesenchymal neoplasms also showed membrane and cytoplasmic immunoreactivity. In squamous cell carcinoma of the head and neck, renal cell carcinoma, and prostate adenocarcinoma, the intensity of CD138 staining inversely correlated with the histologic grade of the carcinoma. However, statistically significant staining differences and their correlation with histologic grades differed depending on whether the Serotec or the DAKO antibody was used. These results indicate that CD138 immunoreactivity is widespread in normal and neoplastic epithelial tissues, as well as a variety of undifferentiated epithelial and mesenchymal processes. The authors conclude that the expression of syndecan-1, although relatively specific to plasma cells within the hematolymphoid system, should be interpreted with extreme caution in the setting of an undifferentiated neoplasm. Furthermore, the two commercially available monoclonal CD138 antibodies tested in this study showed significant differences in their immunoreactivity in different tumor types.

Adult↗

PubMed2005

High-resolution immunophenotyping of subcellular compartments in tissue microarrays by enzyme metallography.

Ultrasensitive bright field in situ hybridization assays using enzyme metallography (EnzMet) have been developed and validated, but little is known regarding the applicability of EnzMet for immunophenotypic detection of protein via IHC. Superior resolution via discrete metallographic deposits offers the potential for enhancing high-resolution immunophenotyping. Using high-complexity tissue microarrays (TMAs), 88 common solid tumors were evaluated by automated EnzMet (Nanoprobes and Ventana). Targets were chosen to assess the ability of EnzMet to specifically localize encoded antigens in the nucleus (estrogen receptor), cytoplasm (cytokeratins), and cytoplasmic membrane (HER2) in TMAs. Results were compared with conventional IHC diaminobenzidine (DAB) immunostaining. There was full concordance between the EnzMet and conventional IHC results. Furthermore, the EnzMet reaction products did not appreciably diffuse, were dense and sharply defined, and provided excellent high-resolution differentiation of cellular compartments in paraffin sections for the nuclear, cytoplasmic, and cell membrane-localized antigens evaluated. The higher density of elemental silver deposited during enzyme metallography permitted evaluation of core immunophenotypes at a relatively low magnification, allowing more tissue to be screened in an efficient manner. This preliminary study shows the utility of using enzyme metallography for high-resolution immunophenotyping in TMAs.

Breast Neoplasms↗

PubMed2006

Sarcomas often express constitutive nitric oxide synthases (NOS) but infrequently inducible NOS.

Nitric oxide (NO) has a dual action in tumors, with both pro-tumor and anti-tumor activities. NO is produced by nitric oxide synthases (NOS). There are three enzyme isoforms: two of them are constitutively produced (neuronal or brain NOS and endothelial NOS), and one is an inducible form (iNOS). NOS expression has been shown in several epithelial tumors, but there is no report addressing NOS expression in sarcomas. The authors evaluated the expression of NOS in 97 cases of various sarcomas spotted in duplicate in a tissue array paraffin block. Eighty-four of the 97 tumor specimens (86.6%) expressed nNOS, and most of them showed a strong expression of the isoenzyme. Only chondrosarcomas and liposarcomas had significant numbers of negative cases, and all pleomorphic sarcomas, alveolar soft part sarcomas, angiosarcomas, gastrointestinal stromal tumors, and synovial sarcomas showed some degree of positivity. Forty-three cases (44.4%) showed eNOS immunostaining, but only 15.5% showed a strong signal, with emphasis on angiosarcomas, chondrosarcomas, alveolar soft part sarcomas, and synovial sarcoma. Strong expression of iNOS was observed in only 9 cases (9.3%), with weak expression in another 26 cases (26.8%). Strong expression of iNOS was found in malignant peripheral nerve sheet tumors, liposarcomas, pleomorphic sarcomas, fibrosarcomas, chondrosarcomas, and synovial sarcomas. Apparently alveolar soft part sarcomas are unusual in their capacity of expression of NOS isoforms, and in a very peculiar pattern. In conclusion, sarcomas in general commonly express constitutive NOS, and only a few types of sarcomas can express iNOS, the isoenzymes capable of releasing large amounts of NO. More comprehensive studies should be performed to better understand the clinical importance of NOS expression and NO production in sarcomas.

Humans↗

PubMed2006

Aberrant expression of the Rb pathway proteins in soft tissue sarcomas.

Cell cycle regulation depends on a fine balance between cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) that block the cycle progression. Alterations of the cell cycle regulators are a common feature of many malignant tumors, and some have been shown to have prognostic significance. In this study, 152 cases of different types of soft tissue sarcomas were evaluated for alterations of cell cycle regulator proteins that control the cell cycle progression from G1 to S phase and govern the Rb pathway. Immunohistochemical stains for proteins Rb, E2F1, cyclin D1, CDK4, CDK6, p16, and p27 were carried out on tissue microarrays. The relationship between the expression of these proteins and the histologic grade of the sarcomas was assessed. Altered expression for Rb and p16 proteins was identified in 67.8% and 65.1% of the cases, respectively. Overexpression of E2F1, cyclin D1, CDK4, and CDK6 was detected in 50.7%, 24.3%, 92.1%, and 10.5%, respectively. Overexpression of E2F1 was associated with altered expression of Rb protein. Overexpression of cyclin D1, CDK4, and CDK6 showed an association with normal Rb expression. CDK6 expression revealed a positive correlation with the histologic grade of the sarcoma, and p27 expression was inversely correlated with sarcoma grade. These results suggest that alterations of the Rb pathway proteins are common in soft tissue sarcomas and may participate in their tumorigenesis. CDK6 and p27 showed correlation with the histologic grade of the sarcomas, suggesting that these proteins could be used as prognostic markers.

Biomarkers, Tumor↗

PubMed2006

Human Papillomavirus DNA and P16INK4A are not detected in renal tumors with immunohistochemistry and signal-amplified in situ hybridization in paraffin-embedded tissue.

The association between human papillomavirus (HPV) infection and carcinogenesis has long been established in literature, with the strongest evidence for its role in cervical carcinoma. The role of HPV in urological tumors has been investigated and sporadic reports have linked HPV infection to bladder, prostate, renal, penile, and testicular cancer. Although less rigorously studied, there are a few conflicting results about the role of HPV in the development of malignant renal tumors. Moreover, no data are available for association of HPV DNA and expression of P16 in benign renal tumors. Formalin-fixed, paraffin-embedded tissues from 62 renal tumors (40 clear cell, 9 papillary, and 3 chromophobe renal cell carcinomas, 1 collecting duct carcinoma, 2 urothelial carcinoma of renal pelvis and 7 oncocytomas) were immunostained with low-risk and high-risk HPV DNA (6, 11, 16, 18, 31, 33, 42, 51, 52, 56, 58). Tissue microarray sections of 62 tumors were stained with P16 by immunohistochemistry. Signal amplified colorimetric in situ hybridization was performed on microarray sections using biotinylated probes for HPV subtypes 6, 11, 16, 18. A nuclear dot-like signal was considered positive for low-risk and high-risk HPV by immunohistochemistry and in situ hybridization and nuclear or cytoplasmic staining is considered positive for P16. No staining for HPV DNA and P16 was found in any type of renal tumors. Our results support that HPV does not seem to play a role in the development of benign and malignant renal tumors.

Adenoma, Oxyphilic↗

PubMed2006

Automation of manual components and image quantification of direct dual label fluorescence in situ hybridization (FISH) for HER2 gene amplification: A feasibility study.

Determination of HER2 status by fluorescence in situ hybridization (FISH) in breast carcinoma correlates well with response to targeted therapy and prognosis. However, manual time consuming methods and quantification aspects of the procedure may be challenging for some laboratories. We examined the feasibility of automating these components of the FISH assay using a tissue microarray (TMA-118 clinically annotated cases) and a series of 41 whole sections. An in situ hybridization automated staining workstation was used to automate a programmed overnight start, on line baking, deparaffinization, cell conditioning, protease digestion, and prehybridization buffer washing. Dual label probe/target codenaturation/hybridization and stringency washing were done off line. The HER2 and CEP17 spot counts were quantified, and the HER2/CEP17 ratio calculated, via an imaging workstation. Results were benchmarked against manual counts for whole sections, and bright field in situ hybridization [silver in situ hybridization (SISH)] for the TMA. Automated FISH results using whole sections correlated well with manual results: HER2/CEP17 ratio correlation coefficient r = 0.9154, r = 0.8380, P < 0.0001. Correlation between automated and manual TMA FISH results was also excellent, and disease-free survival was significantly shorter (P < 0.001) for the HER2 amplified cases. Automation of the laborious manual prehybridization and image quantification components of FISH using directly labeled probes is feasible. Operational gains and enhanced consistency are inherent in this automated approach to HER2 clinical FISH testing.

Automation↗

PubMed2005

Fluorescence in situ hybridization for the detection of t(X;18)(p11.2;q11.2) in a synovial sarcoma tissue microarray using a breakapart-style probe.

Synovial sarcomas (SSs) account for 5% of soft tissue tumors and carry a balanced translocation t(X;18)(p11.2;q11.2), detectable in over 90% of cases. This translocation brings together portions of two genes: SYT and SSX. Detecting interruption of the SYT gene on chromosome 18 would be useful as a diagnostic tool. We describe a scoring method to detect disruption of SYT with breakapart probe fluorescence in situ hybridization (FISH) and the application of this method for identification of SS within a sarcoma tissue microarray. After optimization, SYT disruption was identified in 22 of 23 (96%) of known SS tumor samples but was not in 23 of 23 (100%) of non-SS sarcoma samples. Ten of 11 (91%) blinded test SS tumor samples were also correctly identified. For comparison, commercially available FISH and chromogenic in situ hybridization (CISH) probes were tested. The commercial FISH probes identified SYT disruption in 81% of the SS tumor samples but in none of the non-SS samples. The CISH probes produced signals too weak to interpret. The use of breakapart FISH probes is a relatively quick procedure for detection of synovial sarcoma translocations and can be applied to archival specimens in tissue microarrays.

Chromosomes, Human, Pair 11↗

PubMed2006

The incidence and anatomic site specificity of chromosomal translocations in primary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in North America.

Several balanced translocations have been identified in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but there are few data regarding their frequency in different anatomic sites or the frequency of translocations involving BCL6 or kappa or lambda immunoglobulin light chain genes (IGK or IGL), particularly in patients from geographic regions other than Europe and Japan. One hundred thirty-three paraffin-embedded North American primary MALT lymphoma specimens from diverse anatomic sites were studied by fluorescence in situ hybridization (FISH) using probes for API2-MALT1, IGH-MALT1, IGH-BCL10, IGH-FOXP1, IGH, +/- centromeres 3, 7, 12, and 18, and a subset (n=74) were analyzed using FISH probes for IGK, IGL, and BCL6. Translocations were mutually exclusive and were detected in 26% of cases (17% API2-MALT1, 5% IGH-MALT1, 3% IGH-unknown translocation partner, and 1% IGH-BCL10). Aneuploidy was associated with IGH-MALT1 and IGH-BCL10 but only rarely with API2-MALT1. There was striking site specificity, with API2-MALT1 showing a marked predilection for lung and intestine, and IGH-MALT1 and IGH-BCL10 occurring almost exclusively in lung. Twenty-three percent of translocation-negative primary MALT lymphomas from diverse sites showed complete/partial trisomy 18. No MALT lymphomas with translocations involving IGK, IGL, BCL6, or FOXP1 were identified. This FISH panel detected cytogenetic abnormalities in half of all MALT lymphomas, and translocations arose preferentially in MALT lymphomas of the lung and gastrointestinal tract. Differences in incidence and anatomic site specificity of translocations between North American and non-North American cases may reflect geographic variability of infectious or other etiologic factors.

Adaptor Proteins, Signal Transducing↗

PubMed2007

Nonsmall cell lung carcinoma with neuroendocrine differentiation--an entity of no clinical or prognostic significance.

The existence of non-small cell lung carcinoma with neuroendocrine differentiation as a distinct entity and its relevance for prognostic and treatment purposes is controversial. This study assesses the frequency and biologic and prognostic significance of neuroendocrine (NE) expression of synaptophysin (SNP), chromogranin (Ch), and neural cell adhesion molecule (N-CAM) using tissue microarray (TMA) and immunohistochemistry. Six hundred nine nonsmall cell lung carcinomas (NSCLCs) were reviewed for subclassification. TMA blocks were made using duplicate 0.6-mm-diameter tissue cores and slides stained with SNP, Ch, and N-CAM. Immunoreactivity was considered if 1% or more of tumor cells were positive. Hematoxylin and eosin-stained sections were subclassified as: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (carcinosarcoma, giant cell carcinoma). Positivity for either marker was identified in 13.6% of NSCLC (76/558). NSCLC showed reactivity for Ch in 0.4% of cases (2/524), for SNP in 7.5% of cases (39/521) and for N-CAM in 8.6% of cases (44/511), whereas only 0.2% of cases (1/517) showed coexpression of SNP and Ch and none of all 3 markers. The assessment of NE differentiation in NSCLC is unnecessary and expensive and is of no clinical or prognostic significance. SNP or N-CAM stains a small minority of NSCLC, whereas Ch immunoreactivity is less common. Positivity for any 2 NE markers is rare. SNP is more likely to be expressed in adenocarcinoma (P=0.01) and N-CAM in squamous-cell carcinoma (P=0.008). Otherwise there was no correlation between immunoreactivity and tumor morphology. Disease specific and overall survival is not influenced by NE differentiation and therefore non-small cell lung carcinoma with neuroendocrine differentiation should not be a subclass distinct from the other NSCLC.

Biomarkers, Tumor↗