Eszter Székely

Leiomyosarcomas of great vessels.

Sarcomas of the great vessels are rare. Altogether 400 such cases have been described in the aorta, the pulmonary artery, and inferior vena cava. The clinical symptoms are generally related to embolic phenomena, aneurysm formation, and widespread metastases, especially to bones. With improved diagnostic modalities more cases are diagnosed and treated surgically. Resection of the tumor may prolong the patient’s life. In this paper authors present two cases of such rare sarcomas. In our first case a tumor has developed in the thoracic aorta with symptoms of imminent aortic dissection. The tumorous nature of the lesion was revealed only histologically, since neither the operation, nor macroscopic picture gave any clue to its tumorous nature. The second case was a male patient with a huge retroperitoneal tumor arising from the inferior vena cava, which was clinically suspected to be a carcinomaarising in the adrenal gland.

Leiomyosarcoma of the female breast.

Leiomyosarcomas of the breast are rare tumors. Less than 15 such cases have been reported in the literature so far. In this paper authors describe a case of leiomyosarcoma of a female breast presenting as a firm lobulated mass, mimicking a phylloid tumor radiographically. By fine needle aspiration biopsy, on the smears discohesive malignant looking cells were conclusive to a poorly differentiated invasive ductal carcinoma of the breast. The mastectomy specimen contained a lobulated mass, microscopically showing a partly epithelioid spindle cell tumor, immunoreactive for vimentin, desmin, smooth muscle actin antibodies, and negative for epithelial markers, hormone and growth factor receptors. Axillary lymph nodes were free of tumor. A primary leiomyosarcoma of the breast was diagnosed.

Pretreatment MicroRNA Level and Outcome in Sorafenib-treated Hepatocellular Carcinoma

Sorafenib represents the first effective targeted therapy for advanced stage hepatocellular carcinoma (HCC); however, adequate patient stratification regarding sorafenib-responsiveness is still missing. Our aim was to analyse the association between the pretreatment microRNA profile of HCC and patient survival under sorafenib treatment. Total RNA was extracted from diagnostic fine-needle aspiration biopsy (FNAB) cytological smears of 20 advanced stage HCC patients collected between June 2008 and July 2012. All patients underwent sorafenib administration after FNA. Clinicopathological and survival data were recorded. Fourteen frequently deregulated miRNAs in HCC (miR-17-5p, miR-18a, miR-21, miR-34a, miR-122, miR-195, miR-210, miR-214, miR-221, miR-222, miR-223, miR-224, miR-140, miR-328) were tested by qRT-PCR. NormFinder software was used to select proper miR (mir-140) as a reference. Satisfactory amount of total RNA was obtained from all the considered samples (mean 10.8 ± 9.3 µg, range 0.2–32.2 µg). Among the analysed miRNAs, high miR-214 expression was associated with smaller tumor size (p=0.019), whereas high miR-17-5p expression correlated with better Eastern Cooperative Oncology Group performance status (p=0.003). The survival analysis revealed that high miR-224 expression was associated with increased progression-free and overall survival (PFS p=0.029; OS p=0.012). Pretreatment microRNA profiling, especially miR-224 expression, might serve as an ancillary tool for the better assessment of expected survival rates for patients under sorafenib treatment.

β-catenin expression and claudin expression pattern as prognostic factors of prostatic cancer progression

To investigate the patterns of expression of the junctional proteins β‐catenin and claudins in different prognostic groups of patients with prostatic cancer, to determine their value as prognostic markers.

Expression of Claudins and Their Prognostic Significance in Noninvasive Urothelial Neoplasms of the Human Urinary Bladder

The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.

Marked Increase in CYP24A1 Gene Expression in Human Papillary Thyroid Cancer

The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25-D3) inhibits cell growth and induces cell differentiation and apoptosis in numerous tumors, such as colon, breast, and prostate cancers (1–3). However, the anticancer effect of 1,25-D3 cannot always be seen in a clinical setting. In case of colon cancers, a marked increase in the expression of the 1,25D3 inactivating enzyme, the 24-hydroxylase (CYP24A1), has been observed (4). The role of 1,25-D3 in the development of thyroid carcinomas has not yet been established. However, Sharma et al. (5) observed the correlation of high baseline CYP24A1 and relatively low stimulation after calcitriol treatment (compared with sensitive cells) with lack of growth inhibition in numerous thyroid cancer cell lines. We have also examined the gene expression of the inactivating CYP24A1 and the activating 1-alpha-hydroxylase (CYP27B1) enzyme in human thyroid cancers. To date, gene expression analysis of thyroid samples (both normal and papillary tumor tissue of the same patient) was carried out in six unrelated, consecutive, Hungarian, Caucasian patients at our Thyroid Clinic. All surgically removed thyroid tissue samples underwent histological examination, and papillary tumor was identified in all cases. The study was approved by the Regional Committee of Science and Research Ethics, Semmelweis University (SOTE-TUKEB 1160-0/20101018EKU), and all patients gave written informed consent. Total RNA was isolated from each sample with Roche High Pure Total RNA Isolation kit. Five hundred nanograms of total RNA was reverse-transcribed to cDNA. The expression differences of selected genes were analyzed by Taqman probe-based quantitative real-time reverse transcriptase– polymerase chain reaction. Relative quantification was carried out from collected data (threshold cycle numbers) by Applied Biosystems 7500 System SDS software 1.3. CYP24A1 mRNA expression was markedly increased in all but one papillary cancer compared with that of normal thyroid tissue, sometimes reaching 300-fold elevation (Supplementary Fig. S1; Supplementary Data are available online at www.liebertonline.com/thy). No significant alteration was seen in CYP27B1 gene activity between neoplastic and normal tissues. There was no significant difference in serum 25-OHvitamin D3 concentrations among patients (mean: 28.03 ng/ mL, range: 22.7–31.9 ng/mL). In this letter, we report marked increases in the 1,25-D3neutralizing CYP24A1 gene expression in human papillary thyroid cancer. The tumor cell growth-inhibiting role of vitamin D3 has been extensively studied in different malignancies (1–3). The interest in the association of vitamin-D3 serum levels with various cancer incidences has dramatically increased. However, only very limited data are available on the relationship between serum vitamin D3 concentrations and malignant thyroid conditions (6,7). The pilot study of Laney et al. showed levels of vitamin D and rates of vitamin D deficiency to be similar between patients with thyroid nodules, thyroid cancer in remission, and active thyroid cancer (8). However, the results of Stepien et al. revealed significantly lower calcitriol concentrations in patients with papillary, follicular, and anaplastic thyroid cancers (7). This finding could be attributable to higher CYP24A1 levels cleaving calcitriol, as there were no differences in serum 25-OH-vitamin D3. Earlier, calcitriol had also been shown to attenuate thyrotropinstimulated growth and iodide uptake by rat thyroid cells (FRTL-5) (9,10). Papillary cancer is the most common thyroid malignancy. The role of vitamin D3 in the prevention or development of this disorder has to be yet determined. The increase in CYP24A1 expression in this cancer type could be a ‘‘protective’’ mechanism against the well-known anticancer effect of calcitriol. The observation of Sharma et al. (5) regarding increased expression of CYP24A1 in thyroid cancer cell lines corroborates this notion. One of the cell lines they used was human papillary thyroid carcinoma cell line, whereas the other ones showed the features of human anaplastic thyroid carcinoma. Also, the most resistant cell lines to calcitriol had the highest baseline levels of CYP24A1. In our study at this stage, the number of examined tumor tissues does not allow drawing of statistically significant conclusion about the correlation of tumor histopathological stage or aggressiveness with CYP24A1 levels. Khadzkou et al. demonstrated enhanced 1-alphahydroxylase expression but concluded that this elevation did not show large differences in CYP27B1 expression in papillary thyroid cancer and its metastasis compared with normal

Trabecular angiomyolipoma mimicking hepatic cell carcinoma.

Hepatic angiomyolipomas are rare tumors, especially in comparison with those occurring in the kidney. Nevertheless, it is important to be aware of their existence, especially when occurring in the liver, where they might have different subtypes. Not infrequently they are composed of rather irregular cells with epithelioid appearance. In these cases hepatocellular carcinoma or the possibility of other malignant tumors has to be ruled out, with the aid of numerous immunohistochemical reactions. The authors present a case of a female patient, whose liver lesion was first diagnosed on cytological examination as a hepatocellular carcinoma. Based on the preoperative cytological diagnosis, a large liver lobe resection was performed. Histological examination found an angiomyolipoma of the above-mentioned type, and the final diagnosis was ascertained with the aid of vimentin, smooth muscle actin (SMA), and HMB-45.

Expression of p21waf1/cip1, p27kip1, p63 and Androgen Receptor in Low and High Gleason Score Prostate Cancer

The aim of this study was to investigate the expression of p21waf1/cip1, p27kip1, p63 and androgen receptor proteins in relation to serum prostate specific antigen levels in low and high Gleason score prostate cancers. Biopsies of patients suffering from prostate adenocarcinoma of low (3 + 3 to 3 + 4) and high (5 + 4 to 5 + 5) Gleason scores (13 cases each group) were immunostained for positive regulators of cell cycle control (p21waf1/cip1 and p27kip1), and essential markers of normal prostate gland ontogeny (p63) and growth (androgen receptor) to find differentially expressed markers of malignant progression. Serum prostate specific antigen levels were also monitored at the time of biopsy and following anti-androgen therapy. All cases except one in each group were androgen receptor positive. P63 and p21waf1/cip1 proteins detected in normal basal cell nuclei were lost in all but one studied tumors respectively. P27kip1 protein, however, was detected in all low Gleason score prostate cancers, but it was found in only 7/13 high score cases. Prostate specific antigen levels, either pre- or post-treatment, did not show strict correlation with the p27kip1 results. The low to high grade dedifferentiation of prostate adenocarcinoma is accompanied with the down-regulation of p27kip1 protein, which may be an important molecular sign of the lost cell cycle control.

E-Cadherin Expression in Transitional Cell Carcinomas

The authors analyzed the expression of E-cadherin, one of the most important cell adhesion molecules, on paraffin sections of tumors of bladder cancer patients. The aim of the study was to see whether there is any association between E-cadherin expression and tumor grade, stage, age and gender of the patients, number of recurrences, or overall survival. The samples were examined in 51 primary bladder transitional cell carcinomas (TCC) of 50 patients, resected by transurethral resection (TUR) between January 1, 1996 and January 1, 1997. Immunoreactions were performed with monoclonal anti-human E-cadherin antibody. Forty of the fifty patients could be clinically followed. The analysis of the results on these forty patients was performed by contingency analysis and significance was assessed by Ξ2 test. No significant association between E-cadherin expression and tumor grade, stage, age or gender of the patients, the number of recurrences, or overall survival could be seen. (Pathology Oncology Research Vol 12, No 2, 73–77)

Claudins and Ki-67: Potential Markers to Differentiate Low- and High-Grade Transitional Cell Carcinomas of the Urinary Bladder

Updated classification of urothelial cell cancer differentiates low-grade and high-grade cancers, which determines potential clinical outcome. Substantial interobserver variability necessitates new biomarkers to ensure classification. Claudins’ specific expression pattern characterizes normal tissues, different tumor types, and defined grades of tumor differentiation. The aim of this study was to examine the expression pattern of claudins and proliferation marker Ki-67 in low-grade and high-grade urothelial cell cancers compared with independent control samples of non-tumorous urothelium, as well as to reveal the predictive usefulness of claudins. The expression of claudins-1, -2, -3, -4, -5, -7, and -10 and Ki-67 was studied with quantitative immunohistochemistry and real-time RT-PCR with relative quantification in 103 samples: 86 urothelial cell cancers (27 low grade, 59 high grade) and 17 non-tumorous urothelia. Results were analyzed regarding overall survival and recurrence-free period as well. High-grade tumors overall showed significantly higher claudin-4 and Ki-67 and significantly lower claudin-7 expression when compared with low-grade ones. High-grade tumors revealed significantly shorter overall survival in Kaplan-Meier analysis. Claudin-4, claudin-7, and Ki-67 might be used as potential markers to differentiate low-grade and high-grade urothelial cell cancers, thereby possibly enhancing accuracy of pathological diagnosis and adding further information to clinical outcome.