Cellular organization and histogenesis of adenosquamous carcinoma of the pancreas: evidence supporting the squamous metaplasia concept.

Adenosquamous carcinoma of the pancreas (ASCAP) is characterized by conventional pancreatic ductal adenocarcinoma (PDAC) and squamous carcinoma components with at least 30% of the tumour showing squamous differentiation. To get further insight into the histogenesis of these lesions, we analysed the cellular organization of ASCAP compared to PDACs. Using Immunohistochemistry and triple immunofluorescence labelling studies for keratins, p63, p40, MUC1, MUC2, MUC5AC, Ki67, and EGFR we demonstrate that many ASCAPs contain a transitional zone between the K8/18-positive adenocarcinomatous component and the p63+ /p40+ /K5/K14+ squamous component initiated by the expression of p63 in K8/18+ adenocarcinomatous cells and the appearance of basally located p63+ K5/14+ cells. p63+ K5/14+ cells give rise to fully developed squamous differentiation. Notably, 25% of conventional PDACs without histologically recognizable squamous component contain foci of p63+ p40+ and K5/14+ cells similar to the transitional zone. Our data provide evidence that the squamous carcinoma components of ASCAPs originate from pre-existing PDAC via transdifferentiation of keratin K8/18-positive glandular cells to p63-, p40-, and keratin K5/14-positive squamous carcinoma cells supporting the squamous metaplasia hypothesis. Thus our findings provide new evidence about the cellular process behind squamous differentiation in ASCAPs.

Immunohistochemical and molecular profile of salivary gland cancer in children.

BACKGROUND: Pediatric salivary gland carcinomas (SGCs) are very rare. They differ from the adult SGCs in terms of epidemiologic and clinical behavior, being generally limited only to selected histotypes (e.g. low-grade mucoepidermoid [LG-MEC] and acinic cell cancer [AcCC]) and characterized by very good outcome. Our aim was to investigate therapeutic targets on a series of pediatric SGCs by immunohistochemical and molecular analysis. METHODS: A retrospective analysis was performed to search for cases of pediatric SGCs in the database of the Pediatric Oncology Unit at the Istituto Nazionale Tumori and in the Pathology database at the Gerhard-Seifert-Reference-Centre. The expressions of the most common tyrosine-kinase receptors (TKRs) reported in adult SGCs as EGFR, HER2, KIT and hormonal receptors (HRs) (estrogen α and ß, progesterone as well as androgen receptors) were investigated. CRTC1/MAML2 and MYB/NFIB were also analyzed in MEC and adenoid cystic carcinoma cases, respectively. RESULTS: Twenty-nine cases were identified: 22 MECs, 4 AcCCs, 1 adenoid cystic carcinoma (ACC), 1 adenocarcinoma not otherwise specified and 1 sialoblastoma. EGFR was the most expressed TKR, whilst HRs were negative in all cases except for ER-ß in four cases of MEC. CRTC1/MAML2 was present in 15 out of 17 evaluable MEC cases and MYB/NFIB was identified in the ACC case. CONCLUSIONS: The immunohistochemical and molecular profiles of pediatric SGCs analyzed in our series are similar to that observed in adults, especially for MEC, supporting a common biological background.

Intraobserver Agreement on Histopathologic Evaluations of Core Breast Biopsies.

The number of performed core biopsies of the breast as diagnostic workup is increasing in many European countries. We measured the intraobserver variability in pathological assessment of breast core biopsies. Furthermore, we studied potential modifiers of agreement between the assessments. Two hundred and fifty-six breast biopsies were evaluated twice in a blinded fashion by two pathologists. We calculated the observed and the chance-corrected (weighted) intraobserver agreement (kappa) using the B-categorization scheme (B1: normal or not interpretable, B2: benign, B3: benign but of uncertain biological potential, B4: suspicious of malignancy, B5: malignant). The observed agreement between the first and the second assessments were 0.80 (95% CI: 0.75-0.85) for pathologist 1 and 0.81 (95% CI: 0.76-0.86) for pathologist 2. The chance-corrected agreements were 0.85 (95% CI: 0.80-0.89) and 0.81 (95% CI: 0.76-0.87), respectively. The most frequent disagreement was between B1 and B2 for pathologist 1 (N = 34 out of 50 disagreements, 68%) and between B2 and B3 for pathologist 2 (N = 23 out of 48 disagreements, 48%). Our study shows that the chance-corrected agreement between the histopathological evaluations of breast biopsies based on the B-categorization scheme is almost perfect. The level of agreement is modified by biopsy technique and by the level of suspicion of the mammographic lesion.

Straight Vessel Pattern and Rapid Filling Time: Characteristic Findings on Contrast-Enhanced Sonography of Testicular Lymphoma.

Six patients with 7 lesions that were histologically confirmed as primary testicular lymphoma were preoperatively investigated with a standardized sonographic protocol including contrast-enhanced sonography. Duplex and contrast-enhanced sonography showed marked hypervascularization in all 7 lesions. On contrast-enhanced sonography, the filling time of lymphomatous lesions was significantly shorter than the filling time of a size-matched sample of 10 patients with seminomas (P < .0001). The sonographic hallmarks of testicular lymphoma in our case series were as follows: (1) sharply demarcated homogeneous hypoechoic testicular lesions with marked hypervascularization; (2) a rapid (<7 seconds) filling time of contrast bubbles; and (3) a straight and parallel course of intralesional vessels on contrast-enhanced sonography.

Uterine fibroids: do we deal with more than one disease?

Uterine fibroids rank among the most frequent symptomatic human tumors at all. Recent data suggest that mutations of the mediator subcomplex 12 gene (MED12) and rearrangements of the gene-encoding high-mobility group protein AT-hook 2 (HMGA2) characterize major genetic subtypes of these tumors, which, for example, differ by their average size. Herein, we have investigated a total of 289 fibroids from 120 patients. Of these fibroids, 256 were fully genetically analyzed. Of the latter group, 20 (7.8%) fibroids had a chromosomal rearrangement of 12q14-15 reflecting a rearranged allele of HMGA2 and 179 (69.9%) fibroids had a mutation of MED12. The remaining tumors had either another genetic abnormality or no detectable abnormality at all. We were able to demonstrate that tumors of both groups also display striking differences of their frequency in individual patients. Whereas 70.0% (14/20) HMGA2-mutated fibroids made their appearance as solitary nodules, 85.5% (153/179) MED12-mutated fibroids occurred as multiple nodules as a rule of independent clonal origin, as reflected by different MED12 mutations. These findings are likely to point to a different pathogenesis of both types of fibroids. In the predominant of these groups so far, an unknown "mutator" may cause independent mutations of MED12, resulting in an independent clonal outgrowth of nodules. Furthermore, the low but existing risk of MED12-mutated fibroids to undergo malignant transformation after a leiomyoma-STUMP (smooth muscle tumors of uncertain malignant potential)-leiomyosarcoma sequence excludes the latter mutation as a suitable stand-alone marker for benign growth.

MED12 mutations occurring in benign and malignant mammalian smooth muscle tumors.

Mutations of the mediator subcomplex 12 gene (MED12) recently have been described in a large group of uterine leiomyomas (UL) but only in a single malignant uterine smooth muscle tumor. To further address the occurrence of fibroid-type MED12 mutations in smooth muscle tumors, we have analyzed samples from 34 leiomyosarcomas (LMS), 21 UL, two extrauterine leiomyomas (EL), and 10 canine genital leiomyomas for the presence of MED12 mutations of the UL-type. Interestingly, besides UL MED12 mutations were found in one uterine LMS, one EL, and two canine vaginal leiomyomas. The results confirm the occurrence of fibroid-type MED12 mutations in malignant uterine smooth muscle tumors thus suggesting a rare but existing leiomyoma-LMS sequence. In addition, for the first time MED12 mutations are reported in smooth muscle tumors in a non-primate mammalian species.

Influence of immunohistochemistry on the final diagnosis of breast biopsies.

AIMS: Because of the introduction of mammography screening programmes in Europe, the number of breast biopsies performed is increasing. We investigated the influence of immunohistochemistry (IHC) on the final diagnosis of breast biopsies by comparing the primary diagnoses (based on the results of haematoxylin and eosin staining only) with the final diagnoses (based on the additional information provided by IHC). METHODS AND RESULTS: We analysed the breast biopsies which were performed at the University of Halle-Wittenberg between 2006 and 2010 and for which the pathologist requested IHC for making the final diagnosis. According to the B-categorization scheme, the primary diagnosis changed in 37 of a total of 429 biopsies (8.6%). In 18 of these biopsies (48.6%) the category changed from B1-B2 to B3-B5 or vice versa, which would imply a different work-up. Only 77% of the primary diagnoses of breast cancer in situ were confirmed. CONCLUSION: IHC has a considerable influence on the final diagnosis of breast biopsies in several situations, including those in which the biopsied women are at risk of inadequate therapeutic intervention. The influence is particularly notable among those biopsies for which IHC is performed in order to assess the suspicion of breast cancer in situ.

MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups.

Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates ß-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a "fibroid-type mutation" in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.

Mammographic density and inter-observer variability of pathologic evaluation of core biopsies among women with mammographic abnormalities.

BACKGROUND: As high percentage of mammographic densities complicates the assessment of imaging findings, mammographic density may influence the histopathological evaluation of core-biopsies of the breast. We measured the influence of mammographic density on the inter-observer variability of histopathological findings of breast biopsies. METHODS: Histological slides of 695 women who underwent core biopsies of the breast at University of Halle between 2006 and 2008 were evaluated in a blinded fashion by two pathologists using the five levels of the B-categorization scheme (B1-B5). To quantify mammographic density, we used a computer-based threshold method (Madena). We calculated observed and chance-corrected agreements (weighted kappa) and 95% confidence intervals (95% CI) according to four categories of mammographic density (<10%, 10<25%, 25<50%, ≥50%). RESULTS: The weighted kappa decreased monotonically from 89.6% (95% CI: 85.8%, 93.3%) among women with less than 10% of mammographic density to 80.4% (95% CI: 69.9%, 90.9%) for women with more than 50% of mammographic density, respectively. Results of a kappa regression analysis showed that agreement of pathologists on clinically relevant categories (B1-B2 versus B3-B5) decreased with mammographic density. CONCLUSIONS: Mammographic density is a relevant modifier of the agreement between pathologists who assess breast biopsies using the B-categorization scheme. The influence of mammographic density on the inter-observer variability can be explained to some extent by varying prevalences of histological entities across B categories that have typically different inter-observer agreement. Women with high mammographic density are at higher risk of inter-observer variability compared to women with low mammographic density and should possibly undergo a second pathology review.

Anti-thyroid peroxidase antibodies are associated with the absence of distant metastases in patients with newly diagnosed breast cancer.

BACKGROUND: The presence of thyroid peroxidase antibodies (TPOab) are reported to be associated with improved outcome among breast cancer patients. We evaluated the correlation between TPOab and diagnostic parameters among newly diagnosed breast cancer patients. METHODS: Three hundred and fourteen newly diagnosed patients with breast cancer, diagnosed and treated in Bethesda Essen between January 2002 and June 2006, were included in this study; 258 (82.2%) without TPOab (≤100 IU/mL) and 56 (17.8%) with TPOab (>100 IU/mL). Blood analysis was performed to measure serum levels of carcinoembryonic antigen (CEA), cancer antigen 15-3 (CA-15-3), free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and TPOab by radioimmunoassay. Data regarding age, tumor size, grading, TNM classification, receptor status, lymph node, and distant metastases were collected and analyzed from patient reports. Statistics were performed using Pearson's χ2-test and logistic regression analysis. RESULTS: There were no incidences of distant metastasis among 56 patients with TPOab, whereas 17 (6.6%) of 258 cases without TPOab displayed distant metastases (p=0.04). Logistic regression showed an inverse association of TPOab with CA-15-3 and CEA levels (p<0.001, respectively). Both groups, with and without TPOab, revealed no significant differences with respect to age, tumor size, grading, TNM classification, fT3, fT4, and receptor status. TPOab positive patients had higher TSH levels (2.55±3.58), compared to TPOab negative cases (1.20±1.15) (p<0.001). CONCLUSIONS: TPOab occurrence is associated with significantly lower frequency of distant metastases in breast cancer. TPOab level inversely correlates with the conventional tumor markers CA-15-3 and CEA.

Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms.

Recent studies have shown that the recurrent t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma results in a novel fusion of the MYB proto-oncogene with the transcription factor gene NFIB. To determine the frequency of this finding, we used RT-PCR assays of the MYB and MYB-NFIB fusion transcripts, and immunohistochemistry for the MYB protein, to study adenoid cystic carcinomas and other epithelial tumors of the salivary glands, and head and neck region. MYB-NFIB fusion transcript was detected in 25 of 29 (86%) frozen adenoid cystic carcinoma tumor samples, and in 14 of 32 (44%) formalin-fixed paraffin-embedded adenoid cystic carcinoma tumor specimens. In contrast, the MYB-NFIB fusion was not expressed in non-adenoid cystic carcinoma neoplasms of the head and neck, confirming the high specificity of the MYB-NFIB fusion. Adenoid cystic carcinomas from various anatomic sites, including salivary gland, sinonasal cavity, tracheobronchial tree, larynx, breast, and vulva were repeatedly fusion-positive, indicating that adenoid cystic carcinomas located in different anatomic sites not only have important morphologic features in common, but also probably evolve through activation of the same molecular pathways. Studies of the expression of MYB revealed that 89% of the tumors, including both fusion-positive and fusion-negative cases, overexpressed MYB RNA. Similarly, 82% of adenoid cystic carcinomas stained positive for MYB protein, compared with 14% of non-adenoid cystic carcinoma neoplasms, indicating that MYB immunostaining may be useful for the diagnosis of adenoid cystic carcinoma, but that neoplasms sometimes in the differential diagnosis are also labeled. The latter are, however, fusion-negative. In summary, our studies show that MYB activation through gene fusion or other mechanisms is a major oncogenic event in adenoid cystic carcinoma occurring at various anatomic sites. In addition to being a diagnostically useful biomarker for adenoid cystic carcinoma, MYB and its downstream effectors are also novel potential therapeutic targets.

Glycoconjugate expression in adenoid cystic carcinoma of the salivary glands: up-regulation of L1 predicts fatal prognosis.

AIMS: The up-regulation of the cell adhesion molecule L1 has been associated with impaired prognosis in several cancers. This study aimed to identify potential prognostic markers, including L1, in adenoid cystic carcinoma of the salivary glands (ACCs), which might give additional insight into the molecular mechanisms underlying malignant progression. METHODS AND RESULTS: The expression of L1 was analysed in 34 primary ACCs (nine tubular, 15 cribriform, nine solid, one mixed) and correlated with recurrence, metastasis, overall survival and clinicopathological parameters. Independent of the histological subtype, intense L1 expression in the primary tumours was associated significantly with metastasis (P = 0.02) and death (P = 0.044). In the subgroup of cribriform ACCs, 10 of 15 tumours contained pseudocysts, which were associated with significantly lower recurrence rates (P = 0.003), lower metastasis rates (P = 0.009) and a prolonged overall survival (P =0.004). CONCLUSIONS: Determination of L1 expression in primary ACCs improves risk estimations. As up-regulation of L1 expression predicts fatal prognosis, L1 might be involved functionally in growth and spread of ACC and might thus present a molecular target for future therapeutic strategies.

Factors influencing the agreement on histopathological assessments of breast biopsies among pathologists.

AIMS: It has been recommended that the histopathology results of core biopsies of the breast are categorized according to the B-categorization scheme. We measured the interobserver variability of the B-categorization of core biopsies of the breast. METHODS AND RESULTS: Core biopsies were taken among 765 women at the University of Halle between 2006 and 2008. All histological slides were reviewed in a blinded fashion by two experienced breast pathologists. We calculated observed and chance-corrected agreements (kappa) and 95% confidence intervals (CI). The prevalence of B3-B5 biopsies was 41.6%. The observed and weighted kappa agreement of the five-level B-categorization scheme was 0.87 (95% CI: 0.84 -0.89) and 0.89 (95% CI: 0.89-0.91), respectively. The most frequent disagreement was between B2 and B3 (47 of 103 disagreements, 45.6%). Overall, 49.5% of all disagreements were clinically relevant disagreements that would imply different therapeutic strategies. Agreement was modified by referral group, Breast Imaging Reporting and Data System (BIRADS) level, radiological breast density, imaging guidance and application of immunohistological staining. CONCLUSIONS: Interobserver agreement of the B-categorization scheme was high and was modified by referral status, level of radiological suspicion of breast cancer, breast density, imaging guidance of core biopsies and requirement of additional immunohistological staining.

Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology.

OBJECTIVE: Testing for human papillomavirus (HPV) has been shown to increase the sensitivity and negative predictive value for detection of high-grade cervical intraepithelial neoplasia (CIN2+), either when used in conjunction with Pap cytology testing or alone. However, there is no satisfying clinical management algorithm for women testing Pap negative/HPV positive. We therefore evaluated the clinical utility of a novel dual biomarker-based approach (p16/Ki-67 Dual-stained cytology) for the identification of CIN2+ in women with Pap negative/HPV positive screening results, without the need to refer all women to immediate colposcopy. METHODS: All women aged ≥30 enrolled during 2007/2008 into a regional prospective Pap/HPV co-testing screening pilot project and tested Pap negative, but positive for HPV (n=425) were included in the analysis. p16/Ki-67 Dual-stained cytology was performed from residual cellular material available from the liquid-based cytology vial collected during the initial Pap/HPV co-testing screening visit. Results were correlated to the presence of CIN2+ confirmed during preliminary follow-up. RESULTS: p16/Ki-67 Dual-stained cytology tested positive at baseline in 108 out of 425 (25.4%) Pap negative/HPV positive cases. Sensitivity of Dual-stain testing for the detection of biopsy-confirmed CIN2+ during preliminary follow-up within the group of Pap negative/HPV positive women was 91.9% for CIN2+ (34/37 cases), and 96.4% for CIN3+ (27/28 cases). Specificity was 82.1% for CIN2+ on biopsy, and 76.9% for CIN3+, respectively. CONCLUSIONS: Triaging Pap negative/HPV positive screening test results with p16/Ki-67 Dual-stained cytology may identify women with a high probability of underlying CIN2+ and may efficiently complement HPV-based screening programs to prevent cervical cancer.

Mucoepidermoid carcinoma of the salivary glands revisited with special reference to histologic grading and CRTC1/3-MAML2 genotyping.

Mucoepidermoid carcinoma (MEC) is the most common carcinoma of the salivary glands. Here, we have used two large patient cohorts with MECs comprising 551 tumors to study clinical, histological, and molecular predictors of survival. One cohort (n = 167), with known CRCT1/3-MAML2 fusion status, was derived from the Hamburg Reference Centre (HRC; graded with the AFIP and Brandwein systems) and the other (n = 384) was derived from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW; graded with the AFIP system). The reliability of both the AFIP and Brandwein grading systems was excellent (n = 155). The weighted kappa for inter-rater agreement was 0.81 (95% CI 0.65-0.97) and 0.83 (95% CI 0.71-0.96) for the AFIP and Brandwein systems, respectively. The 5-year relative survival was 79.7% (95% CI 73.2-86.2%). Although the Brandwein system resulted in a higher rate of G3-MECs, survival in G3-tumors (AFIP or Brandwein grading) was markedly worse than in G1/G2-tumors. Survival in > T2 tumors was markedly worse than in those with lower T-stage. Also, fusion-negative MECs had a worse 5-year progression-free survival. The frequency of fusion-positive MECs in the HRC cohort was 78.4%, of which the majority (86.7%) was G1/G2-tumors. In conclusion, the AFIP and Brandwein systems are useful in estimating prognosis and to guide therapy for G3-MECs. However, their significance regarding young age (≤ 30 years) and location-dependent heterogeneity of in particular G2-tumors is more questionable. We conclude that CRTC1/3-MAML2 testing is a useful adjunct to histologic scoring of MECs and for pinpointing tumors with poor prognosis with higher precision, thus avoiding overtreatment.

A link between the expression of the stem cell marker HMGA2, grading, and the fusion CRTC1-MAML2 in mucoepidermoid carcinoma.

Recently, the concept of cancer stem cells and their expression of embryonic stem cell markers has gained considerable experimental support. In this study, we examined the expression of one such marker, the high-mobility group AT-hook 2 gene (HMGA2) mRNA, in 53 formalin-fixed, paraffin-embedded mucoepidermoid carcinomas (MEC) and four normal parotid tissues using quantitative real-time RT-PCR (qPCR). MECs are often characterized by the fusion gene CRTC1-MAML2, the detection of which is an important tool for the diagnosis and prognosis of MEC. For detection of the CRTC1-MAML2 fusion transcript, we performed RT-PCR. The mean expression level of HMGA2 was higher in fusion negative (302.8 +/- 124.4; n = 14) than in positive tumors (67.3 +/- 13.1; n = 39). Furthermore, the fusion-negative tumors were often high-grade tumors and the HMGA2 expression level rose with the tumor grade (low: 43.7 +/- 11.0, intermediate: 126.2 +/- 28.3, and high: 271.2 +/- 126.5). A significant difference was found in the HMGA2 expression levels between the different grading groups (one-way ANOVA, P = 0.04) and among the fusion-negative and -positive tumors (t-test, P = 0.05), indicating that the expression level of HMGA2 was closely linked to grading, the presence/absence of the CRTC1-MAML2 fusion, and the tumor behavior of MECs. These findings offer further evidence for the theory that the MEC group comprises two subgroups: one group with the CRTC1-MAML2 fusion, which is a group with a moderate aggressiveness and prognosis, and the other group lacking that fusion corresponding to an increased stemness, and thus, higher aggressiveness and worse prognosis.

Copy number gain at 8q12.1-q22.1 is associated with a malignant tumor phenotype in salivary gland myoepitheliomas.

Salivary gland myoepithelial tumors are relatively uncommon tumors with an unpredictable clinical course. More knowledge about their genetic profiles is necessary to identify novel predictors of disease. In this study, we subjected 27 primary tumors (15 myoepitheliomas and 12 myoepithelial carcinomas) to genome-wide microarray-based comparative genomic hybridization (array CGH). We set out to delineate known chromosomal aberrations in more detail and to unravel chromosomal differences between benign myoepitheliomas and myoepithelial carcinomas. Patterns of DNA copy number aberrations were analyzed by unsupervised hierarchical cluster analysis. Both benign and malignant tumors revealed a limited amount of chromosomal alterations (median of 5 and 7.5, respectively). In both tumor groups, high frequency gains (> or =20%) were found mainly at loci of growth factors and growth factor receptors (e.g., PDGF, FGF(R)s, and EGFR). In myoepitheliomas, high frequency losses (> or =20%) were detected at regions of proto-cadherins. Cluster analysis of the array CGH data identified three clusters. Differential copy numbers on chromosome arm 8q and chromosome 17 set the clusters apart. Cluster 1 contained a mixture of the two phenotypes (n = 10), cluster 2 included mostly benign tumors (n = 10), and cluster 3 only contained carcinomas (n = 7). Supervised analysis between malignant and benign tumors revealed a 36 Mbp-region at 8q being more frequently gained in malignant tumors (P = 0.007, FDR = 0.05). This is the first study investigating genomic differences between benign and malignant myoepithelial tumors of the salivary glands at a genomic level. Both unsupervised and supervised analysis of the genomic profiles revealed chromosome arm 8q to be involved in the malignant phenotype of salivary gland myoepitheliomas.

Expression of Jun and Fos proteins in ovarian tumors of different malignant potential and in ovarian cancer cell lines.

Jun and Fos proteins form the transcription factor activating protein 1 (AP-1). They play a role in cell proliferation, malignant transformation and invasion in various tumors. The aim of the current study was to characterize the role of AP-1 in ovarian cancer. Fifty-six ovarian tumors of different invasive potential including 13 metastases as well as 5 ovarian cancer cell lines were analyzed by Western blot analysis regarding their expression of pc-Jun, Jun B, Jun D, c-Fos, Fos B, Fra-1 and Fra-2. In addition, invasion, cell proliferation and migration assays were performed. The expression of pc-Jun, Jun B, Jun D and Fra-2 was higher in invasive cancer compared to benign tumors. In metastases, c-Fos and Fos B expression was significantly lower than in the respective primary ovarian carcinomas. The invasive and proliferative potential of the cells was not associated with AP-1 protein expression. These results suggest that AP-1 proteins are differentially expressed in benign ovarian tumors, tumors with low malignant potential and epithelial ovarian carcinomas and metastases. No correlation with the proliferative and invasive potential of ovarian cancer cell lines could be found.

Expression and prognostic value of activating transcription factor 2 (ATF2) and its phosphorylated form in mammary carcinomas.

BACKGROUND: The transcription factor ATF2 is overexpressed in various tumors, but its role in breast cancer is still not understood. MATERIALS AND METHODS: In a study of mammary carcinomas, the expression of ATF2 and its phosphorylated active forms was analyzed by Western blot analysis (WB; pThr69/pThr71-ATF2, n=134) and immunohistochemistry (IHC; p-ATF2-Thr6, n=110). Results were correlated with histological and clinical data, survival data, expression of ERK1/2 and two matrix metalloproteinases. RESULTS: Patients with high ATF2 expression as detected by WB had a significantly shorter overall survival (p = 0.038). This tendency was corroborated by IHC. In contrast, high p-ATF2 expression as found by WB correlated significantly with a well-differentiated phenotype, but not with prognosis. Immunohistochemically detected p-ATF2 overexpression was even associated with prolonged survival (p = 0.047). CONCLUSION: Although high ATF2 expression is associated with a poor prognosis, our data do not point to an oncogenic role of active p-ATF2 in mammary carcinomas.

A new type of MAML2 fusion in mucoepidermoid carcinoma.

The present study reports for the first time a CRTC3-MAML2 fusion gene in a mucoepidermoid carcinoma, as determined by RT-PCR and sequencing. We screened a total of 67 formalin-fixed, paraffin-embedded mucoepidermoid carcinomas for the presence of chimeric genes. In one of these samples, a CRTC3-MAML2 fusion gene was detected. Thus, this report demonstrates the existence of a fusion of MAML2 with CREB regulated transcriptional coactivator CRTC3 additional to the already known fusion of MAML2 and CRTC1. Both gene fusions seem to result in an identical tumor phenotype and the fusion genes CRTC1-MAML2 and CRTC3-MAML2 may play a similar role in the development of mucoepidermoid carcinomas.