Analytical Cellular Pathology - Volume 29, issue 1

Authors: López de Silanes, Isabel | Paz Quesada, María | Esteller, Manel

Article Type: Research Article

Abstract: The messenger RNA 3′-untranslated region (3′UTR) is emerging as critically important in regulating gene expression at posttranscriptional levels. The 3′UTR governs gene expression via orchestrated interactions between mRNA structural components (cis-elements) and specific trans-acting factors (RNA-binding proteins and non-coding RNAs). Alterations in any of these components can lead to disease. Here, we review the mutations in 3′UTR regulatory sequences as well as the aberrant levels, subcellular localization, and posttranslational modifications of trans-acting factors that can promote or enhance the malignant phenotype of cancer cells. A thorough understanding of these alterations and their impact upon 3′UTR-directed posttranscriptional gene regulation will uncover …promising new targets for therapeutic intervention. Show more

Keywords: Post-transcriptional gene regulation, RNA-binding proteins, non-coding RNAs, miRNAs, AU-rich elements (ARE), ribonomics, cis-elements, trans-acting factors

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 1-17, 2007

Authors: Casparie, M. | Tiebosch, A.T.M.G. | Burger, G. | Blauwgeers, H. | van de Pol, A. | van Krieken, J.H.J.M. | Meijer, G.A.

Article Type: Research Article

Abstract: Since 1991, a nationwide histopathology and cytopathology network and archive is in operation in The Netherlands under the name PALGA, encompassing all sixty-four pathology laboratories in The Netherlands. The overall system comprises decentralized systems at the participating laboratories, a central databank, and a dedicated communication and information exchange tool. Excerpts of all histopathology and cytopathology reports are generated automatically at the participating laboratories and transferred to the central databank. Both the decentralized systems and the central system perform checks on the quality and completeness of excerpts. Currently, about 42 million records on almost 10 million patients are stored in the …central databank. Each excerpt contains patient identifiers, including demographic data and the so-called PALGA diagnosis. The latter is structured along five classification axes: topography, morphology, function, procedure, and diseases. All data transfer and communication occurs electronically with encryption of patient and laboratory identifiers. All excerpts are continuously available to all participating pathology laboratories, thus contributing to the quality of daily patient care. In addition, external parties may obtain permission to use data from the PALGA system, either on an ongoing basis or on the basis of a specific permission. Annually, 40 to 60 applications for permission to use PALGA data are submitted. Among external users are the Dutch cancer registry, population-based screening programs for cancer of the uterine cervix and breast cancer in The Netherlands, and individual investigators addressing a range of research questions. Many scientific papers and theses incorporating PALGA data have been published already. In conclusion, the PALGA system is a unique system that requires a minimal effort on the part of the participating laboratories, while providing them a powerful tool in their daily practices. Show more

Keywords: Central pathology archive, histopathology, cytopathology, information exchange, PALGA, cancer registry, cancer screening, biobanking

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 19-24, 2007

Authors: Janssen, Emiel A.M. | Søiland, Håvard | Skaland, Ivar | Gudlaugson, Einar | Kjellevold, Kjell H. | Nysted, Arne | Søreide, Jon-Arne | Baak, Jan P.A.

Article Type: Research Article

Abstract: Background: The prognostic value of the PI3K/Akt/mTOR pathway and PTEN in invasive breast cancer (IBC) is controversial. Cell proliferation, especially the Mitotic Activity Index (MAI), is strongly prognostic in lymph node-negative (LNneg) invasive breast cancer. However, its prognostic value has not been compared with the value of Akt and PTEN expression. Material and methods: Prognostic comparison of Her2Neu, p110alpha (PIK3CA), Akt, mTOR, PTEN, MAI and cell-cycle regulators in 125 LNneg patients aged <55 years with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based adjuvant systemic chemotherapy. Results: Twenty-one (17%) patients developed distant metastases=DMs (median follow-up: 134 months). p110alpha correlated (p=0.01) with pAkt but …only in PTEN-negatives; pAkt correlated (p=0.02) with mTOR. PTEN-negativity correlated with high MAI, high grade and ER-negativity (p=0.009). The MAI was the strongest prognosticator (Hazard Ratio=HR=2.9, p=0.01). Her2Neu/p110α/Akt/mTOR features have no additional prognostic value to the MAI. PTEN had additional value but only in MAI<3 (39/125=31%; 8% DMs). 19/39=49% of the MAI<3 patients have combined MAI<3 / PTEN+ with 0% DMs, contrasting 15% DMs in MAI<3 / PTEN− (p=0.03). Conclusions: In T1−3 N0 M0 adjuvant CMF-treated breast cancer patients aged <55 years, MAI was the strongest survival predictor. The PI3K/Akt/mTOR pathway and cell-cycle regulator characteristics had no additional prognostic value, but PTEN has. Patients with combined MAI<3 & PTEN-positivity had 100% survival. The small subgroup of MAI<3 patients that died were PTEN-negative. Show more

Keywords: Breast cancer, cell proliferation, Mitotic Activity Index, Akt pathway, PTEN

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 25-35, 2007

Authors: Horree, N. | Heintz, A.P.M. | Sie-Go, D.M.D.S. | van Diest, P.J.

Article Type: Research Article

Abstract: Background: Cell cycle proteins and HIF-1α with downstream factors are often abberrantly expressed in (pre)neoplastic tissue. Methods: Paraffin-embedded specimens of inactive endometrium with TM (n=15), ovarian inclusion cysts (n=6), cervix with TM (tubal metaplasia) (n=3), Fallopian tubes (n=7), cycling endometrium (n=9) and a ciliated cell tumor of the ovary were stained for p16 and LhS28. 39 Endometrioid endometrial carcinomas and 5 serous endometrial carcinomas were stained for p16. Additionally, inactive endometrium (n=15) was immunohistochemically stained for p21, p27, p53, cyclin A, cyclin D1, cyclin E, HIF-1α, CAIX, Glut-1 and MIB-1. Results: A mosaic pattern of expression of p16 was seen …throughout in all cases of endometrial TM (15/15), in 2/6 of the ovarian inclusion cysts with TM, in all (3/3) cervical TM and focal in 5/7 of Fallopian tube cases. Mosaic expression was also seen in a ciliated cell tumor of the ovary and in 18/39 of endometrioid endometrial carcinomas, and diffuse p16 expression was seen in 5/5 serous carcinomas. In comparison with normal endometrium, TM areas in the endometrium showed significantly increased expression of HIF-1α, cyclin E, p21 and cyclin A, and decreased expression of p27. Membranous expression of CAIX and Glut-1 was only seen in TM areas, pointing to functional HIF-1α. Conclusion: As p16 is consistently expressed in TM, less and only patchy expressed in the normal Fallopian tube, is paralleled by aberrant expression of cell cycle proteins, HIF-1α, CAIX and Glut-1 and resembles the pattern of p16 expression frequently seen in endometrial carcinomas, we propose endometrial TM to be a potential premalignant endometrial lesion. Show more

Keywords: Tubal metaplasia, immunohistochemistry, p16, endometrium, cervix, ovary, carcinogenesis, hypoxia

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 37-45, 2007

Authors: Montironi, Rodolfo | Scarpelli, Marina | Lopez-Beltran, Antonio | Mazzucchelli, Roberta | Alberts, David | Ranger-Moore, James | Bartels, Hubert G. | Hamilton, Peter W. | Einspahr, Janine | Bartels, Peter H.

Article Type: Research Article

Abstract: Background: A preceding exploratory study (J. Clin. Pathol. 57(2004), 1201–1207) had shown that a karyometric assessment of nuclei from papillary urothelial neoplasms of low malignant potential (PUNLMP) revealed subtle differences in phenotype which correlated with recurrence of disease. Aim of the study: To validate the results from the exploratory study on a larger sample size. Materials: 93 karyometric features were analyzed on haematoxylin and eosin-stained sections from 85 cases of PUNLMP. 45 cases were from patients who had a solitary PUNLMP lesion and were disease-free during a follow-up period of at least 8 years. The other 40 were from patients …with a unifocal PUNLMP, with one or more recurrences in the follow-up. A combination of the previously defined classification functions together with a new P-index derived classification method was used in an attempt to classify cases and identify a biomarker of recurrence in PUNLMP lesions. Results: Validation was pursued by a number of separate approaches. First, the exact procedure from the exploratory study was applied to the large validation set. Second, since the discriminant function 2 of the exploratory study had been based on a small sample size, a new discriminant function was derived. The case classification showed a correct classification of 61% for non-recurrent and 74% for recurrent cases, respectively. Greater success was obtained by applying unsupervised learning technologies to take advantage of phenotypical composition (correct classification of 92%). This approach was validated by dividing the data into training and test sets with 2/3 of the cases assigned to the training sets, and 1/3 to the test sets, on a rotating basis, and validation of the classification rate was thus tested on three separate data sets by a leave-k-out process. The average correct classification was 92.8% (training set) and 84.6% (test set). Conclusions: Our validation study detected subvisual differences in chromatin organization state between non-recurrent and recurrent PUNLMP, thus allowing a very stable method of predicting recurrence of papillary urothelial neoplasms of low malignant potential by karyometry. Show more

Keywords: Urothelium, papillary urothelial neoplasm of low malignant potential, recurrence

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 47-58, 2007

Authors: Pisacane, A.M. | Picciotto, F. | Risio, M.

Article Type: Research Article

Abstract: Introduction: Vasculogenic mimicry, as previously described in aggressive melanoma, is characterized by the de novo generation of intratumoral patterned vascular channels, composed of PAS-positive basement membrane in the absence of endothelial cells, providing additional microcirculation, in support to the classic tumoral angiogenesis. Methods: We investigated the immunohistochemical expression of two endothelial markers, CD31 and CD34, in tumoral cells of 60 melanomas (45 primary cutaneous and 15 metastatic) as possible evidence of vasculogenic mimicry. In addition we investigated the relationship between CD31 and CD34 expression and three pathological markers such as Clark's level, and skin ulceration, predictive of melanoma's aggressive behaviour, …and mitotic index. Results: No cases of common melanocytic nevi immunoreacted with CD31 or CD34. Random CD31 immunoreactivity was present in 6% of Clark's level I/II, 50% of Clark's level III and 80% Clark's level IV/V. CD34 was negative in Clark's level I/II but randomly stained the 20% and 55% of level III and IV/V respectively. 66% (10/15) of metastatic melanomas were CD31 positive showing a canalicular immunostaining pattern, conversely CD34 expression was never found. 7/8 cutaneous ulcerated melanomas immunostained for CD31 and 4/8 for CD34. CD31 immunostained 88% high/intermediate MI, and 53% of low MI melanomas. CD34 decorated the 29% of high/intermediate and 38% of low MI melanomas. Conclusions: CD31 and CD34 immunoreactivity closely parallel both the different morphologic steps of melanocytic tumor progression and the presence of histological parameters related to the aggressive behaviour. Their expression could be related to endothelial transdifferentiation of melanoma cells although a consequent functional role has not been demonstrated yet. Show more

Keywords: Malignant melanoma, vasculogenic mimicry, tumor-cell plasticity

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 59-66, 2007

Authors: Ao, Ping

Article Type: Other

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 67-69, 2007

Authors: Duesberg, Peter | Li, Ruhong | Fabarius, Alice | Hehlmann, Ruediger

Article Type: Other

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 71-72, 2007

Authors: Postma, C. | Terwischa, S. | Hermsen, M.A.J.A. | van der Sijp, J.R.M. | Meijer, G.A.

Article Type: Other

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 73-75, 2007

Article Type: Other

Citation: Analytical Cellular Pathology, vol. 29, no. 1, pp. 77-77, 2007