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During the 25-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in Ukraine has increased from 4.7 to 10.7 per 100,000 of the total population. Recent studies of our group have shown that increases in morbidity, aggressiveness, and proliferative activity of renal cell carcinomas (RCCs), especially clear-cell renal cell carcinoma (CCRCC), in Ukrainian patients continuously inhabiting the radio-contaminated areas could be explained by specific molecular changes influenced by the so-called "chronic persistent low-dose ionizing radiation" (CPLDIR) exposure. This study aimed to examine the role of angiogenesis in CCRCC carcinogenesis associated with CPLDIR in patients living more than 20 years in cesium 137 ((137)Cs) contaminated areas after the Chernobyl accident in Ukraine. Paraffin-embedded specimens of 106 CCRCs were studied: Control cases were 18 tumors from Spanish patients (group 1), 25 tumors from Ukrainian patients from so-called clean areas without known radio-contamination (group 2), and 63 tumors from Ukrainian patients from radio-contaminated areas (group 3). For intratumoral microvessel density (MVD) determination, anti-CD31 antibody was used. A computerized image analysis program was used to quantitatively calculate the vascular density. Seventy-three percent of group 3 and 72 % of group 2 CCRCCs displayed the highest MVD. A striking increase in MVD was seen in group 3 CCRCCs, in comparison with groups 1 and 2 (p 0.001). The majority of the hot spot vessels in group 3 was poorly differentiated. Moreover, MVD values for total vessels as well as for capillaries and tumor grade were strongly correlated. When we compared only tumor-node-metastasis tumor stages I and II, the differences remained statistically significant (p 0.1). The ratio of the average total vessels and capillaries in the Ukrainian groups combined was 1.65:1 in comparison to the Spanish group. Our results provide evidence that CPLDIR exposure increases MVD (particularly capillary) in CCRCCs and is associated with a higher histological grade.

The present study was carried out in order to examine molecular alterations of extracellular matrix (ECM), associated with cell-cell communication in conventional (clear-cell) renal cell carcinomas (cRCCs) influenced by persistent long-term, low-dose ionizing radiation (IR) exposure to patients living more than 19 years after the Chernobyl accident in Cesium 137 (137Cs)-contaminated areas of Ukraine. The ECM major components such as fibronectin, laminin, E-cadherin/beta-catenin complexes and p53 tumor suppressor gene protein, and transforming growth factor beta 1 (TGF-beta1) were immunohistochemically (IHC) evaluated in cRCCs from 59 Ukrainian patients, which represented 18 patients living in non-contaminated areas and 41 patients from 137Cs-contaminated areas. In contrast, a control group of 19 Spanish patients with analogue tumors were also investigated. For IHC evaluation, a tissue microarray technique was used. Decrease or loss and abnormal distribution of fibronectin, laminin, E-cadherin/beta-catenin complexes accompanied by elevated levels of p53 and TGF-beta1 were detected in the Ukrainian cRCCs from 137Cs-contaminated areas with statistically significant differences. Thus, our study suggests that chronic long-term, low-dose IR exposure might result in global remodeling of ECM components of the cRCCs with disruption in peri-epithelial stroma and epithelial basement membranes.

After the Chernobyl accident, the morbidity of renal-cell carcinomas in Ukraine increased gradually from 4.7 to 7.5 per 100,000 of the total population. Cesium 137 (137Cs) is responsible for 80-90% of the internal radioactivity in people living in radiocontaminated areas of Ukraine, and 90% of 137Cs is eliminated through the kidneys. Histological and immunohistochemical study of proliferating cell nuclear antigen (PCNA) and K-ras protein was performed in peritumoral kidney tissues of 167 Ukrainian patients (groups I-III, according to varying degrees of internal exposure to radiation), and of 85 analog Spanish patients, as a control group. Our data showed in the majority of Ukrainian patients a radiation sclerosing proliferative atypical nephropathy (RSPAN) in association with an increase in the incidences of tubular epithelial nuclear atypia and carcinoma in situ (CIS). Areas of epithelial nuclear atypia and CIS of the cortex and medulla showed significant PCNA expression with means of extent as 12, 14, and 15% of stained nuclei in groups I, II, and III respectively. K-ras expression of the same areas occurred in 67, 87, and 85% of cases in groups I, II, and III respectively. The present study points to a strong relationship between the long term of low-dose radiation exposure of the Ukrainian population and the development of RSPAN as a possible precursor of malignancy. In addition, it confirms the possible initiator, promoter, or progressor role of chronic low-level radiation of renal human carcinogenesis in Ukraine.

During the 13-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in Ukraine has increased from 4.7 to 7.5 per 100,000 of total population. Cesium 137 ( 137 Cs) accounts for 90% of the incorporated radioactivity in the Ukrainian population, which has been exposed to long-term, low dose ionizing radiation and 90% of the more labile pool of ( 137 Cs) is excreted via kidneys. The present study was performed to evaluate the histopathological features and the immunohistochemical status of proliferating cell nuclear antigen (PCNA) and K-ras in renal cell carcinomas (RCCs) of 236 Ukrainian patients (groups I to V), which represents a varying degrees of internal exposure to radiation and were operated in 2 different periods of time after the Chernobyl accident. The control group VI of 112 analog patients with RCCs was selected in Spain. The strong significant differences between the Ukrainian and Spanish groups were found in tumoral nuclear grade, in the percentage of sarcomatoid changes, the level of the peritumoral inflammatory response as well as in the peritumoral lesions. The dramatic increase of aggressivity and proliferative activity supported by strong PCNA and K-ras expression of RCCs from Ukrainian groups, associated with chronic radiation nephropathy of peritumoral kidney tissue, showed good correlation with the duration of radiation exposure and confirmed the influence of chronic but regular and sustained low dose of ionizing radiation on renal carcinogenesis of the Ukrainian population. Int. J. Cancer 87:880 ‐ 883, 2000. © 2000 Wiley-Liss, Inc.

Eight conventional and six atypical oncocytomas in a series of 147 renal neoplasms were studied. Histopathologic findings revealed exclusively oncocytic cells, but cellular polymorphism was higher in the atypical tumors. Atypical oncocytomas presented focal necrosis, transcapsular invasion, or both. Electron microscopy showed similar findings in all cases. Immunohistochemistry of atypical oncocytomas had higher expression against proliferating cell nuclear antigen and more discontinuous immunostaining against laminin than typical ones. Flow cytometry revealed one or two aneuploid peaks in five typical and two atypical cases, although the latter had a higher proliferative fraction than typical oncocytomas. Cytogenetics of one typical oncocytoma showed a normal diploid karyotype; one atypical case resulted in a diploid karyotype but with endoreduplications in 13% of metaphases, and a second atypical oncocytoma became hypodiploid without structural anomalies. Based on the present results, the proposed distinction between conventional and atypical oncocytomas seems of limited clinical significance.

SUMMARY A case ofchromophobe renal cell carcinoma is reported in a 73 year-old man. Light microscopically, the tumor was composed of polygonal cells with a slightly eosinophilic and a fine reticular pattern, and a reaction of the cytoplasm with Hale's acid iron colloid. Ultrastructural analysis showed membranous microuesicles within the tumor cells, with degenerated mitochondria. Immunohistochemical profile against intermediate filaments was positive to cytokeratin 18 and negative against uimentin. Flow cytometry and cytogenetics revealed a predominant bypertriploid population. Few cases have been published with flow cytometry and cytogenetic findings. We report a new case.

We determined whether ubiquitylation and sumoylation processes are involved in conventional renal cell carcinogenesis associated with chronic, long-term, persistent low doses of ionizing radiation (IR) in patients living for more than 20 years in cesium-137 ((137)Cs)-contaminated areas after the Chernobyl accident in Ukraine. To this end, we assessed the immunohistochemical expression of ubiquitin (Ub), SUMO1, SUMO E2 conjugating enzyme Ubc9, and the cell cycle regulators p53, mdm2, and p14(ARF) in 38 conventional renal cell carcinomas from Ukrainian patients with different degrees of radiation exposure after the Chernobyl accident. As control cases, 18 conventional renal carcinoma (cRCC) tissues from a Spanish cohort were analyzed. No significant differences between the Ukrainian and Spanish groups were found regarding Ub overexpression, although being higher in the Ukrainian cases. Furthermore, this expression was inversely associated with SUMO1 and Ubc9, with no correlation with tumor nuclear grade. There was also a direct relationship between Ubc9 and inflammatory response. These findings do not allow us to consider the immunohistochemical expression of ubiquitylation and sumoylation as valuable markers for discriminating the effects of long-term, low-dose IR exposure in cRCC carcinogenesis.

Compared to the 19-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in the Ukraine has increased from 4.7 to 9.0 per 100,000 of the total population. Cesium 137 (

Our study was undertaken to better understand the role of G1/S transition abnormalities in the malignant progression of renal cell carcinomas (RCCs), exposed to long-term low doses of ionizing radiation (IR), from patients living in radiocontaminated areas of the Ukraine after the Chernobyl accident. We studied p16 and p15 gene alteration in association with oxidative stress markers, including inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). We analyzed 88 samples collected from 22 patients with RCCs and with different exposure to IR. Homozygous deletion of the p16 and p15 genes, as well as hypermethylation of the 5CpG island in the promoter region of the same genes, were analyzed by differential PCR and Methylation-Specific PCR respectively, in association with histopathology and immunohistochemical analysis of p16 and p15 proteins. COX2 and iNOS expression in the same tumors were likewise analyzed. Aberrant hypermethylation was observed in 7 (32%) and 5 (23%) cases accompanied, by immunohistochemical loss of expression for p16 and p15 genes respectively, in both high stage and grade tumors from patients living in radiocontaminated areas, this being especially outstanding for the p16 gene. An association with COX2 and less iNOS overexpression in the same tumors was observed. Our data suggest that inactivation of p16 gene, but not p15, induced by increased oxidative stress generated by persistent chronic exposure to IR, could be one of the major pathways responsible for RCCs malignant progression.

Cytogenetic analysis of a human renal oncocytoma revealed a near-haploid chromosome number of 36 with the loss of chromosomes 1, 2, 3, 6, 8, 9, 15, 17, 21, and 22. Review of the literature disclosed that this cytogenetic configuration is extremely rare in solid human tumors and that no renal oncocytomas with near-haploid stemline karyotype have been described. These results are compared with the other published cases of oncocytoma.

Three Bellini duct carcinomas (BDC) of the kidney were cytogenetically analyzed after short-term culture. All three had clonal chromosome abnormalities: 91-92,XXY,-Y, +12, +12, -15, -16, -18, +mar (case 1); 53,XY, +2,t(2;7)(p22;q11), +der (2)t (2;7)(p22;q11), +3, +r(3),add(5)(p15), +7, -8, +12, +17, +r(17), +20, -21 (case 2); and 44-47,X,-Y, +9, +16, -21/46,XY. Some of the numerical abnormalities are shared with papillary renal cell carcinomas (PRCC)(+7, +12, +16, +17, and +20) but not with transitional renal cell carcinomas. The present findings support the previous notion that BDC are different from other types of RCC.