Microvessel density is high in clear-cell renal cell carcinomas of Ukrainian patients exposed to chronic persistent low-dose ionizing radiation after the Chernobyl accident.

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.

[Multidisciplinary approach to the endolymphatic sac tumour]. / Abordaje multidisciplinar al tumor de saco endolinfático.

INTRODUCTION: Papilar adenocarcinoma of endolymphatic sac is related with Von Hippel Lindau disease at 15% of cases, has a slow growing with a high local aggressiveness, and doesn't metastasize. It causes symptoms of Meniere's syndrome due to the compression that produces at endolymphatic duct. When it presents with hearing loss is usually sudden and irreversible manner. The diagnostic is made with image tests and analysis of its structure with immunohistochemical tests. The elective treatment is surgical remove, and its main complication the perioperative bleeding it can be avoided with preoperative embolization or stereotactic radiation. CASE REPORT: A case of endolymphatic sac tumour is presented, in a 17-years-old male with unilateral deafness and crisis of rotate vertigo, with family history of Von Hippel-Lindau disease. Perceptive deafness and right vestibular arreflexia are detected at technical exploration. In a petrous bone computer tomography appears a mass at vestibular aqueduct. We performed a petrosectomy with presigmoidal approach and saving of inner ear. Pathological analysis revealed an endolymphatic sac tumour. DISCUSSION: In patients with a family history of Von Hippel Lindau disease and clinical symptoms of vertigo and normal hearing or with slight hearing loss we should suspect the presence of endolymphatic sac tumor. The clinical presentation of hearing loss can be sudden and irreversible even with negative or inconclusive images. Therefore, a quick action is important for the preservation of this function.

Abordaje multidisciplinar al tumor de saco endolinfático / Multidisciplinary approach to the endolymphatic sac tumour

Introducción. El adenocarcinoma papilar de saco endolinfático se asocia a la enfermedad de Von Hippel Lindau en el 15% de los casos, tiene un crecimiento lento pero elevada agresividad local, y no metastatiza. Clínicamente produce un Síndrome de Menière derivado de la compresión que provoca en el conducto endolinfático. Cuando debuta con pérdida de audición suele ser de forma brusca e irreversible. Se diagnostica con técnicas de imagen y el análisis de su estructura con inmunohistoquímica. Su tratamiento electivo es la exéresis quirúrgica, y su principal complicación el sangrado perioperatorio, que se puede evitar con embolización o radiación estereotáctica preoperatorio.Caso clínico. Presentamos un caso de un tumor de saco endolinfático en un paciente de 17 años aquejado de sordera unilateral y crisis de vértigo rotatorio, con antecedentes familiares de enfermedad de Von Hippel Lindau. Las pruebas complementarias mostraron una hipoacusia neurosensorial y una arreflexia vestibular derechas. En tomografía computarizada de peñascos se apreciaba una lesión en el acueducto vestibular. Se sometió al paciente a una petrosectomía con abordaje presigmoideo y preservación de laberinto, realizándose una exéresis total de la lesión. Se diagnosticó de tumor del saco endolinfático en el análisis anatomopatológico.Discusión. Ante un paciente con antecedentes familiares de enfermedad de Von Hippel Lindau y un cuadro clí-nico de vértigo incluso sin hipoacusia, o siendo esta leve, habría que pensar en la presencia de un tumor del saco endolinfático. La presentación clínica de sordera puede ser brusca e irreversible, incluso con imágenes negativas o poco concluyentes, por lo que una rápida actuación es importante para la preservación de esta función (AU)

Introduction. Papilar adenocarcinoma of endolymphatic sac is related with Von Hippel Lindau disease at 15% of cases, has a slow growing with a high local aggressiveness, and doesn’t metastasize. It causes symptoms of Meniere’s syndrome due to the compression that produces at endolymphatic duct. When it presents with hearing loss is usually sudden and irreversible manner. The diagnostic is made with image tests and analysis of its structure with immunohistochemical tests. The elective treatment is surgical remove, and its main complication the perioperative bleeding it can be avoided with preoperative embolization or stereotactic radiation.Case report. A case of endolymphatic sac tumour is presented, in a 17-years-old male with unilateral deafness and crisis of rotate vertigo, with family history of Von Hippel-Lindau disease. Perceptive deafness and right vestibular arreflexia are detected at technical exploration. In a petrous bone computer tomography appears a mass at vestibular aqueduct. We performed a petrosectomy with presigmoidal approach and saving of inner ear. Pathological analysis revealed an endolymphatic sac tumour.Discussion. In patients with a family history of Von Hippel Lindau disease and clinical symptoms of vertigo and normal hearing or with slight hearing loss we should suspect the presence of endolymphatic sac tumor. The clinical presentation of hearing loss can be sudden and irreversible even with negative or inconclusive images. Therefore, a quick action is important for the preservation of this function (AU)

Hemangiopericitoma congénito / Congenital hemangioparicytoma

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Disruption of basement membrane, extracellular matrix metalloproteinases and E-cadherin in renal-cell carcinoma.

UNLABELLED: A retrospective study was performed to determine the prognostic value of Basement Membrane (BM) integrity, Matrix Metalloproteinases (MMPs) and E-Cadherin expression in renal cell carcinoma (RCC). MATERIALS AND METHODS: An immunohistochemical study on laminin and collagen IV, MMPs 1 and 2, and E-Cadherin was carried out on 71 RCCs. BM fragmentation was considered taking 75% as a cut-off. MMP 1 and MMP2 immunostaining, as well as E-Cadherin was considered taking 25% as a cut-off. RESULTS: An inverse relationship was seen between E-Cadherin with laminin, collagen IV and MMPs. More than 75% loss of laminin, collagen IV and E-Cadherin, as well as higher expression of MMPs, were associated with symptoms, tumoral size and worse grade. Loss of collagen IV and E-Cadherin were of prognostic value. CONCLUSION: Both BM and E-Cadherin are good prognostic markers. MMPs patterns show a relationship between BM proteins and E-Cadherin, but evaluation is more time-consuming and provide no better prognostication; consequently they are not useful in routine clinical applications.

[Assessment of the basal membrane status as prognostic factor in renal carcinoma]. / Valoración del estado de la membrana basal como factor pronóstico en el carcinoma renal.

OBJECTIVES: To know the basal membrane (BM) integrity in renal cell carcinoma (RC) and its importance as prognostic factor. MATERIAL AND METHODS: 73 patients with RC were selected. Immunohistochemistry with monoclonal antibodies against basal proteins laminin and collagen IV was performed. Percentage for BM fragmentation in the whole tumour was considered taking 75% as cut off. RESULTS: Follow-up was 6.3 +/- 4.3 years and 27 patients progressed. Correlation between laminin and collagen IV was significative (p = 0.000). A BM fragmentation expressed with laminin bigger than 75% was related to tumoural symptoms (p = 0.019), worse grade (p = 0.004) and necrosis in more than 10% of the tumour (p = 0.000). Fragmentation observed with collagen IV was associated to tumours greater than 7 cm (p = 0.014). Those patients whose tumours displayed more than 75% of BM fragmentation, measured with collagen IV, presented worse survival (p = 0.042). A similar trend was observed in the case of laminin, but it did not reach statistic significance (p = 0.119). In the unvariated analysis grade III-IV, more than 10% of necrosis within the tumour, tumoural symptoms and BM fragmentation bigger than 75% measured with collagen IV were prognostic, while only grade and necrosis did so in the multivariate analysis. CONCLUSIONS: Collagen IV and laminin represent nicely, with a similar expression pattern, the BM fragmentation in RC. Within a battery of immunohistochemical markers to study RC at least one of them should be included because their prognostic implication.

Valoración del estado de la membrana basal como factor pronóstico en el carcinoma renal / Significance of basal membrane status as a prognostic factor in renal carcinoma

FUNDAMENTOS: Conocer el estado de la membrana basal (MB) en el carcinoma renal (CR) y su importancia como factor pronóstico. MATERIAL Y MÉTODOS: Se seleccionaron 73 pacientes con CR. Se realizó inmunohistoquímica con anticuerpos monoclonales contra las proteínas basales laminina y colágeno IV. La valoración de los resultados consideró la integridad de la MB dentro del tumor tomando como punto de corte un 75 por ciento de basales fragmentadas en el tumor.RESULTADOS: El seguimiento fue de 6.3 ñ 4,3 años, durante el cual hubo progresión de la enfermedad en 27 pacientes. La correlación en la expresión de ambas moléculas fue significativa (p=0,000). La fragmentación de la MB en más del 75 por ciento del tumor expresada con laminina se relacionó con una presencia de clínica por el tumor (p=0,019), con un peor grado de diferenciación celular (p=0,004) y con más del 10 por ciento de necrosis (p=0,001). Una fragmentación mayor del 75 por ciento expresada con colágeno IV se asoció a tumores mayores de 7 cm (p=0,014). Se observó una peor supervivencia en aquellos pacientes con tumores con más del 75 por ciento de fragmentación de la MB medida con colágeno IV (p=0,042), mientras que con la laminina se apreció una tendencia similar que no alcanzó la significación estadística (p=0,1 19). En el análisis univariado resultaron factores pronósticos el grado III-IV, la presencia de más de un 10 por ciento de necrosis en el tumor, la presentación clínica del tumor y con una fragmentación de la MB mayor del 75 por ciento analizada con colágeno IV, persistiendo los dos primeros en el análisis multivariado.CONCLUSIONES: Colágeno IV y laminina representan correctamente y de forma paralela el grado de fragmentación de la MB en el CR. Dentro de una batería de factores imnunohistoquímicos en CR se debería incluir al menos una de ellas por su implicación pronóstica (AU)

Radiation sclerosing proliferative atypical nephropathy of peritumoral tissue of renal-cell carcinomas after the Chernobyl accident in Ukraine.

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.

Pathology and proliferative activity of renal-cell carcinomas (RCCS) and renal oncocytomas in patients with different radiation exposure after the Chernobyl accident 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.

Expression of type I interferon receptor in renal cell carcinoma.

Immunohistochemical analysis of INF-R was performed on 110 renal tumors, 25 peritumoral kidney tissues and 10 lymph node metastases. Pathological material was previously studied and classified according to predominant cell type, stage and grade. A statistical analysis was made in order to determine to what extent the immunoexpression of INF-R differed in relation to the histological variables studied. All peritumoral kidney sections, 89/110 tumors and 9/10 metastases proved positive. Membranous expression was related to clear cell carcinomas. Type I INF-R is expressed in RCC, independent of tumor stage and grade, as well as sex, age and survival. INF-R is widely expressed in RCC in any tumoral type, and its expression is preserved in metastatic disease, which may help to target those patients who could benefit from INF therapy.

Proliferating cell nuclear antigen (PCNA) as a prognostic factor in renal cell carcinoma.

BACKGROUND: A retrospective study was performed on patients with renal cell carcinoma to determine whether tumoral proliferating cell nuclear antigen (PCNA) is a predictive factor. METHODS: We studied immunohisto-chemical PCNA expression with pc10 monoclonal antibody in 109 renal tumor paraffin sections. These tumors were previously classified according to cellular type by Thoenes, Furman's grading and Robson's staging, Moreover, we counted the number of mitoses in 10 high power fields (HPF) and also evaluated the tumoral necrosis percentage. Ten year survival curve of Kaplan and Meier was obtained for 90 patients. RESULTS: Nuclear immunostaining for PCNA showed a statistical correlation with Robson's stage, cellular type and nuclear grade. Moreover, the number of positive nuclei was higher in tumors presenting an elevated mitosis count and higher in degree of necrosis. Survival was significantly poorer in patients whose PCNA index was greater than 5%. Nuclear PCNA immunostaining was shown to be an independent prognostic factor in patients with Robson stage I and also in those who had high cytological grading. CONCLUSIONS: These results show PCNA to be a prognostic marker for RCC.

Chromophobe renal cell carcinoma. Pathologic, ultrastructural, immunohistochemical, cytofluorometric and cytogenetic findings.

A case of chromophobe 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 microvesicles within the tumor cells, with degenerated mitochondria. Immunohistochemical profile against intermediate filaments was positive to cytokeratin 18 and negative against vimentin. Flow cytometry and cytogenetics revealed a predominant hypertriploid population. Few cases have been published with flow cytometry and cytogenetic findings. We report a new case.

A singular case of near-haploid stemline karyotype in a renal oncocytoma.

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.

Cytogenetic analysis of three primary Bellini duct carcinomas.

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.

DNA-ploidy, morphometric-stereological and P-glycoprotein study of superficial bladder carcinomas.

We carried out a DNA-ploidy, morphometric-stereologic and P-glycoprotein study on 40 newly diagnosed superficial bladder cancer patients (G1-G2), correlating the results with histological grade and clinical outcome. Variations in the number of patients who present recurrences, progression or remain tumor-free during the whole follow-up period (at least 5 years) were not significant when related to nuclear size, proliferative diploid index, presence of aneuploidy and expression of P-glycoprotein. It is striking how the majority of disease-free subjects showed a proliferative diploid index higher than 10%. Moreover, 3 of them presented an aneuploid cell population. In our study, only histological grade showed a significant discriminatory level in terms of progression versus no progression in patients with superficial bladder cancer.

Behavior of epithelial differentiation antigens (carcinoembryonic antigen, epithelial membrane antigen, keratin and cytokeratin) in transitional cell carcinomas of the bladder.

Results of an immunohistochemical study in normal urothelium and transitional cell carcinomas of the bladder are presented. Paraffin-embedded material was confronted with immunoantisera against carcinoembryonic antigen (CEA), keratin (K), cytokeratin (CK) and epithelial membrane antigen (EMA). Immunohistochemical findings confirm the changes in reactivity of dysplastic urothelium and carcinoma in situ for CEA, CK and EMA, in comparison with normal urothelium. Statistically significant differences were also found, depending upon tumor stage, in staining of transitional cell carcinomas for K and CK. Expression of CK correlated with the tumor differentiation grade: normal urothelium and well-differentiated carcinomas showed a specific pattern of immunostaining for the basal cells, this pattern being lost in poorly differentiated carcinomas.

Morphometric and immunohistochemical characterization of bladder carcinoma in situ and its preneoplastic lesions.

We performed a morphometric and immunohistochemical study of 26 bladder carcinoma in situ (Cis) specimens, compared with normal urothelium and urothelial preneoplastic lesions. The following morphometric parameters were evaluated: nuclear area, nuclear perimeter and maximum nuclear diameter. For the immunohistochemical study we used five lectins, antibodies against four epithelial differentiation antigens, and antibodies against blood group isoantigens. A progressive increase in nuclear size from normal urothelium to dysplastic urothelium and Cis was detected. Nuclear size values in Cis and in high-grade, high-stage bladder carcinomas were similar. The most relevant immunohistochemical results were obtained with CEA, CK, UEA-1 and ABH isoantigens, which show significant immunoreactivity changes in preneoplastic urothelium and Cis when compared with normal urothelium. We conclude that bladder Cis behaves morphometrically and immunohistochemically as an invasive bladder carcinoma, and we emphasize the usefulness of these techniques for detecting flat dysplastic and neoplastic lesions in random bladder biopsies.

Correlation between serum values of prostatic acid phosphatase and morphometric analysis in the cytologic diagnosis of prostatic carcinoma.

We studied 78 men with suspicion of prostatic carcinoma, who underwent transrectal aspiration biopsy, diagnosing 46 adenocarcinoma, 13 chronic prostatitis and 19 benign prostatic hyperplasia. Moreover, we determined prostatic acid phosphatase (PAP) by enzyme immunoanalysis, resulting in 9/78 false-positives and 18/78 false-negatives. Also, we carried out a morphometric analysis of the cytologic samples which showed good correlation with the cytologic diagnosis except in the moderately differentiated carcinomas. We found a good correlation between PAP values, cytologic diagnosis and nuclear size as well as the percentage of the binucleolated cells.

[The Ask-Upmark kidney: a form of reflux nephropathy]. / El riñón de ASK-Upmark: una forma de nefropatía del reflujo.

We present six female patients aged 14 to 47, all diagnosed histopathologically as suffering from Ask-Upmark Kidney and who had clinical manifestations of severe arterial tension associated with urinary infection in four cases. Mictional Cystourethrography was carried out in all cases, and four of them displayed vesicoureteral reflux in the small kidney. Although this pathology has classically been considered a congenital malformation in the context of renal hypoplasias (segmental hypoplasia), the observation of glomerular traces with PAS staining in the renal segments regarded classically as "aglomerular" and the frequent association of this pathology with vesicoureteral reflux point significantly towards Ask-Upmark Kidney being a form of reflux nephropathy. Nephrectomy cured the arterial hypertension in half the cases, and the factors with prognostic importance in this respect are commented upon.