Carcinoma de células renais na infância / Renal cell carcinoma in childhood

Os autores apresentam cinco casos de carcinoma de células renais em crianças. Relatam os aspectos encontrados na urografia excretora, ultrasonografia, angiografia e tomografia computadorizada e revisam e comparam-nos com dados clínicos, patológicos e radiológicos encontrados na literatura

Acridine orange flow cytometric analysis of renal cell carcinoma. Clinicopathologic implications of RNA content.

To explore the potential role that ribonucleic acid (RNA) content analysis may have in the assessment of primary renal cell carcinomas (RCC), biparametric flow cytometric (acridine orange) measurements for DNA/RNA were obtained on 108 fresh neoplastic specimens. RNA content was divided into low and high groups, based on the average RNA content in normal kidney controls. High RNA content was significantly correlated with aneuploidy, high proliferative index, high nuclear grade, cytoplasmic granularity, and large tumor size. No correlation was found between RNA content and patients' sex, race, and clinical stage of the carcinomas. When diploid RCCs were separately analyzed, high RNA content was correlated with high nuclear grade, large tumor size, high clinical stage, and cytoplasmic granularity. There was no correlation between RNA content and the patient's sex or race or the neoplasm's proliferative index. Of the 16 patients that relapsed (5 diploid and 11 aneuploid), four of the diploid and all 11 aneuploid neoplasms displayed high RNA content. The authors' data show that RNA may be a valuable objective and quantitative parameter in the clinicopathologic assessment of RCC.

Modulation of pro-epidermal growth factor, pro-transforming growth factor alpha and epidermal growth factor receptor gene expression in human renal carcinomas.

We have analyzed the expression of the genes for the precursors of epidermal growth factor (pro-EGF) and transforming growth factor alpha (proTGF-alpha) as well as for the EGF receptor in tissue specimens of a large number of adult patients with renal cell carcinoma. Since normal kidney tissue was available from the same patients we could directly compare the expression of these genes in tumors with that in adjacent normal renal tissue. Our experiments reveal underexpression of the proEGF gene in all tumors analyzed (21 of 21) and overexpression of the genes for proTGF-alpha (33 of 33 analyzed) and EGF receptor (22 of 23 analyzed) in tumor samples, when compared with normal kidney tissue. The expression of the proTGF-alpha gene appeared to depend on grade and differentiation of the tumor, since well differentiated tumors (grade 1) expressed more proTGF-alpha mRNA than the adjacent normal tissue but significantly less than poorly differentiated tumors (grade 2 or 3), which are the most aggressive ones. In none of these tissue specimens did we find, by Southern analysis, amplification of the proTGF-alpha or EGF receptor gene. Therefore, overexpression of these genes must be due to another effect, perhaps an alteration of their mRNA turnover. Although the EGF receptor gene (c-erbB1) is overexpressed in nearly all carcinomas analyzed, there was no linear coexpression with the proTGF-alpha gene. In contrast, transcription of the proEGF gene was completely turned off in tumor tissue. Although we have found by restriction fragment length polymorphism analysis, in one of three tumor samples, evidence for a somatic mutation within the proEGF gene, we do not know yet, due to the limited number of Southern analyses, whether this somatic mutation is causally involved in the decrease of proEGF mRNA expression and, hence, is representative of renal cell carcinoma. To our knowledge, this is the first observation on primary tumor tissue in humans that upon malignant transformation the gene for a polypeptide growth factor gene is underexpressed.

[Tumor heterogeneity of renal cell carcinoma as analyzed by flow cytometry].

DNA content in renal cell carcinoma was investigated to examine the tumor heterogeneity and was correlated with their morphologic grades. A total number of 147 paraffin-embedded samples (2-6 samples with a mean of 5) from 30 tumors were analyzed by flow cytometry. DNA aneuploid patterns were demonstrated in 5 of 9 grade 1 tumors (56%), 15 of 18 grade 2 tumors (83%) and 3 of all grade 3 tumors (100%), while aneuploid DNA histograms were exhibited in 20 of 57 grade 1 samples (35%), 45 of 81 grade 2 samples (56%) and 8 of 9 grade 3 samples (89%). DNA aneuploid patterns were demonstrated more significantly in grade 2 and 3 samples than in grade 1 samples (p less than 0.02 and p less than 0.01, respectively). Consequently, 73 samples (50%) showed DNA aneuploid patterns and 74 samples exhibited DNA diploid patterns. Eleven tumors (37%) showed homogeneous DNA ploidy patterns (7 tumors were diploid and 4 tumors were aneuploid only), while 19 tumors (63%) showed DNA heterogeneity, 17 of these 19 tumors demonstrating diploid as well as aneuploid samples. DNA heterogeneity was not found when the tumor samples examined were fewer than 3 samples. However, 19 of 25 tumors (76%) in which more than 4 samples were examined showed DNA heterogeneity, the incidence of which tended to be increased with upgrading of the tumor--3 of 9 (33%) in grade 1 tumors, 13 of 18 (72%) in grade 2 tumors and 3 of all (100%) in grade 3 tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical demonstration of epidermal growth factor in human gastric cancer xenografts of nude mice.

Thirty-two surgical specimens and three cell lines of human gastric cancers were used for subcutaneous transplantation into nude mice, resulting in the establishment of eight (25%) xenografts from the surgical specimens and two (67%) from the cell lines. The localization of epidermal growth factor (EGF) in the surgical specimens and cell lines of the gastric cancers and their xenografts in nude mice was then investigated immunohistochemically. Epidermal growth factor was stained in the cytoplasm of the cancer cells, being detected in 16 (50%) of the 32 surgical specimens and in all of the cell lines. Seven (44%) of the sixteen EGF-positive surgical specimens and one (6%) of the 16 EGF-negative ones were tumorigenic in nude mice. All of the xenografts in nude mice were positive for EGF. The tumorigenicity of human gastric cancer xenografts in nude mice may, therefore, be correlated with the presence of EGF in cancer cells.

[Flow cytometric analysis of renal cell carcinoma].

Forty cases of renal cell carcinoma were studied retrospectively by flow cytometry and DNA contents of the cancer cells were measured. The results indicated that the incidence of aneuploid tumor was 57.5% (23/40), diploid tumor or quasi-diploid tumor 42.5% (17/40). DNA ploidy was strictly correlated to histopathological grade, clinical stage, cancer cell type and survival time. Therefore, analysis of cellular DNA ploidy of renal cell carcinoma is of prognostic value for renal cell carcinoma.

Tumour DNA content and skeletal metastases in renal cell carcinoma. A preliminary report.

The DNA content of the tumour cells in 10 patients with primary renal cell carcinomas was analysed; from six of the patients skeletal metastases were also studied. Four patients had homogenously diploid primary tumours, with solitary metastases. Six patients had aneuploid primary tumours, three with solitary and three with multiple metastases. In two patients radical excision of diploid metastases resulted in long disease-free intervals. Patients with diploid tumours survived significantly longer than patients with aneuploid tumours. These results indicate that tumour DNA content might be a useful prognostic indicator. The measurement of DNA content may be a suitable method of identifying those patients likely to survive long enough to benefit from major surgical resection and reconstruction.

Detection of drug resistance and P-glycoprotein in human renal cell carcinomas.

Expression of the multidrug-resistance gene product P-glycoprotein (P-170) was screened in 21 untreated human renal cell carcinomas using monoclonal antibodies (265/F4, C219) and immunoperoxidase staining. The inherent drug resistance of the same samples against doxorubicin was established by a short-term chemoresistance test in order to investigate the association between the expression of P-170 and intrinsic drug resistance in kidney cancers. P-glycoprotein could be demonstrated in 10 cases. Using the short-term test for predicting resistance, 17 resistant and 4 sensitive cancers were found. In vitro 10 of 17 resistant tumors revealed an increase of P-glycoprotein. On the other hand, in the sensitive tumor in vitro, an expression of P-glycoprotein could not be demonstrated. This investigation reveals that intrinsic drug resistance exists in many renal cell carcinomas and it is associated at least in part with increased expression of P-glycoprotein. The immunohistochemical results suggest that the presence of the P-glycoprotein may be useful as a marker for screening the multidrug-resistant phenotype in renal cell carcinomas and as an indicator of the therapeutic efficacy of multidrug-resistant kidney cancers.

Expression of transforming growth factor alpha in normal human adult kidney and enhanced expression of transforming growth factors alpha and beta 1 in renal cell carcinoma.

Normal kidney and renal cell carcinoma tissues from ten patients were studied for mRNA and DNA for both transforming growth factors alpha and beta 1. Northern and Southern hybridizations were conducted on samples extracted from the solid tumor and surrounding normal tissues and two tumor-derived cell lines. Low levels of constitutive expression of TGF-alpha mRNA were detected in all normal kidney tissues; six of the ten patients, however, demonstrated an increased (2- to 8-fold) expression of TGF-alpha in the tumor versus normal kidney as determined by densitometry of RNA blots. All ten patients had elevated mRNA levels for TGF-beta 1 in the tumor (2.5-to 22-fold increase) relative to normal kidney. Two tumor-derived cell lines also expressed TGF-alpha and TGF-beta 1 mRNA. Southern blot hybridization of the DNA extracted from the normal tumor pairs revealed no gene amplification or gross rearrangement for either the TGF-alpha or TGF-beta 1 genes. These results demonstrate the expected constitutive expression of TGF-beta 1 by normal kidney; however, the constitutive expression of TGF-alpha by Northern blot analysis in normal adult human kidney is previously unreported. Enhanced expression of TGF-alpha and TGF-beta 1 mRNA in solid tumor may be related to the development of renal cell carcinoma.

[The study of plasminogen activator in renal cell carcinoma with special remarks on urokinase type plasminogen activator].

Plasminogen activators (PA) have been reported to be associated with fibrinolysis. The amounts of PA in urine, plasma, and tissues of patients with renal cell carcinoma were determined by measuring the amounts of two kinds of antigens, urokinase type (u-PA) antigen and tissue type (t-PA) antigen, by highly sensitive enzyme-immunoassay. The u-PA antigen level in urine showed neither daily variation nor age-relationship. It was, however, significantly higher (164.2 +/- 93.5 x 10(2) U/gCr) in patients with renal cell carcinoma than in healthy subjects (56.8 +/- 22.4 x 10(2) U/gCr) (p less than 0.01). The amount of u-PA antigen in urine tended to be higher in patients with high grade or stage cancer than in those with cancer of low grade or stage, though not statistically significant. The u-PA antigen content in tissues appeared elevated in tumors (8.90 +/- 6.00 x 10(-1) U/g wet tissue) in comparison to normal renal cortex and medulla. However, the difference was not significant, as the cancer samples consisted of various tissue components including necrotic or hemorrhagic tissue in addition to cancer cells. Although the t-PA antigen content in urine was too immeasurably small in 29% cases by the present method, there was no significant difference between patients with renal cell carcinoma and healthy subjects. The plasma level of t-PA antigen tended to be elevated in renal cell carcinoma group (7.87 +/- 5.60 U/ml) compared to the control group (5.7 +/- 2.19 U/ml), but no significant difference was present between them.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of the 1 alpha, 25-dihydroxyvitamin D3 receptor concentration and the DNA content in renal cell carcinomas.

A role has been suggested for 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in cell proliferation and differentiation. Therefore the concentration of the 1,25-(OH)2D3 receptors and DNA-ploidy was measured in 22 renal cell carcinomas. No relation was found, the mean 1,25-(OH)2D3 receptor concentration being 8.4 fmol/mg of protein (range 2.8-15.9) in diploid tumors and 7.0 fmol/mg of protein (range 0-27.8) in DNA aneuploid tumors. The aneuploid tumors (11 out of 22) had a heterogeneous DNA content in 9 out of 11 cases. At the time of operation, no patient had metastases. In this prospective study, one out of 9 patients with DNA aneuploid tumor had died of renal cell carcinoma (observed 33-58 months, median 42 months). None of 10 patients with diploid tumors had died (observed 40-56 months, median 52 months).

Epidermal growth factor receptor gene expression in normal human kidney and renal cell carcinoma.

The epidermal growth factor receptor (EGFr) is a transmembrane glycoprotein detected on many cells and tissues including neoplastic and normal kidney. EGFr binds the mitogenic polypeptide hormone epidermal growth factor (EGF) as well as EGF-related transforming growth factor-alpha (TGF-alpha). Increases in EGFr gene expression and protein production have been implicated in the development of the malignant phenotype for certain cancers. To determine if alterations in EGFr gene expression are present in human renal cell carcinoma, paired samples of normal and neoplastic renal tissue from ten patients with advanced renal cell carcinoma were analyzed for EGFr mRNA content by Northern blot hybridization. The EGFr gene was constitutively expressed in 90% of normal kidney samples. In seven out of nine evaluable patients, tumors expressed 1.7 to 8.4 times more EGFr mRNA than corresponding normal tissue. Two patients showed no elevation of tumor EGFr mRNA and one patient had no identifiable EGFr transcripts in either neoplastic or normal kidney. Expression of EGFr mRNA was also detected in three tumor-derived and two established renal cell carcinoma cell lines. EGFr transcripts were not found in tumor infiltrating lymphocytes (TIL). These findings suggest that overexpression of EGFr mRNA may be associated with malignant transformation in renal cell carcinomas.

Monoclonal antibody against rat renal cell tumor-associated antigen as a new tool for the analysis of renal tumorigenesis.

A monoclonal antibody, NR-2 MAb, against one of the rat renal cell tumor-associated antigens was developed. NR-2 MAb belonged to IgM class and recognized a polypeptide of 81,000 daltons designated as NR-2 antigen, which is of non-glycoprotein nature with a pI of 4.6. NR-2 MAb was employed to probe the histogenesis of renal cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine followed by trisodium nitrilotriacetate monohydrate. Immunohistochemical analysis indicated that NR-2 antigen was expressed in simple hyperplasia, adenomatous hyperplasia and renal cell tumors. Both clear cells and basophilic cells of the simple hyperplasia showed equally strong positive reactions with NR-2 MAb, whereas the vacuolated epithelium was negative. Furthermore, the proximal tubules in nontumorous areas also expressed NR-2 antigen, suggesting that the hyperplastic lesions which eventually lead to renal cell tumors may derive from epithelia of proximal tubules and not directly from vacuolated epithelium. Such NR-2 antigen-positive epithelia of proximal tubules seem to be initiated cells. NR-2 MAb also cross-reacted with preneoplastic liver lesions.

Estrogen and progesterone binding sites in renal cell carcinoma.

Twenty-five renal cell carcinomas were assayed for estrogen and progesterone receptor levels. Estrogen specific binding was present in only 4 patients (16%) and progesterone specific binding in 7 patients (28%). In all cases these receptors were present in very low titers, less than 10 fm/mg. We believe that earlier reports citing significant estrogen and progesterone binding activity may reflect high levels of nonspecific protein binding.

MDR1 RNA levels in human renal cell carcinomas: correlation with grade and prediction of reversal of doxorubicin resistance by quinidine in tumor explants.

We examined the distribution of RNA levels expressed by the multidrug-resistance gene (MDR1, also known as PGY1) in 42 renal cell carcinoma (RCC) samples (38 primary and four metastatic lesions). The median MDR1 RNA level for the 38 primary lesions, expressed relative to the level for KB-3-1 cells, was approximately one-half of the level in multidrug-resistant KB-8-5 cells. Elevated MDR1 RNA levels were also observed in three of the four metastatic lesions. The mean MDR1 RNA level was higher in well-differentiated RCCs than in those that were poorly differentiated, suggesting that the increased expression of the MDR1 gene in RCCs originates from the increased expression in renal proximal tubule cells. To clarify the association of the MDR1 protein product P-glycoprotein with natural resistance to doxorubicin (ADR) in RCCs, we evaluated the effects of quinidine on in vitro sensitivity to ADR in 16 RCC samples, using a [3H]thymidine incorporation assay. The enhancing effect of quinidine (7.5 micrograms/mL) on sensitivity to ADR was statistically significant only in the group with high MDR1 RNA levels. Similar enhancement by quinidine of sensitivity to ADR was also observed in the established RCC cell lines in which MDR1 RNA levels were high. These results suggest that P-glycoprotein is active in the natural resistance of RCCs to ADR.

Lectin- and immunohistochemical studies on acquired cystic kidney and associated renal cell carcinoma.

Nine specimens of acquired cystic kidney were studied by means of lectin- and immunohistochemistry. The cysts appeared to originate from any part of the nephron, but mostly from the proximal tubule. The cause of multicyst formation is still unclear, but the results of this study suggested that obstruction of the lower nephron might play an important role. Many microscopic carcinomas or dysplastic epithelial cells were observed in the cyst wall. All these carcinomas originated from the proximal tubule, except for one which was of Bellini duct origin and showed papillary growth. The reasons why almost all of the carcinomas originated from the proximal tubule were: 1) the majority of the cysts originated from the proximal tubule, and 2) dysplastic epithelial cells in the cysts originating from the proximal tubules were more frequent in number than those in cysts originating from other parts of the nephron. Histological observation showed that stimulation due to oxalate crystals in the proximal cysts was one of the causes of dysplastic epithelial cell hyperplasia.

Immunohistochemistry of capillary hemangioblastoma. Immunoperoxidase-labeled antibody staining resolves the differential diagnosis with metastatic renal cell carcinoma, but does not explain the histogenesis of the capillary hemangioblastoma.

We used a battery of antigens to determine whether immunohistochemistry can (a) contribute to resolving the histogenesis of the stromal component of the capillary hemangioblastoma, and (b) answer cases of difficult pathologic differential diagnosis with metastatic clear cell carcinoma. The stromal cells of the capillary hemangioblastoma are antigenically polymorphous and may express immunoreactive erythropoietin, renin, keratin, Leu M1, Leu 7, actin, neuron-specific enolase, S100 protein, and glial fibrillary acidic protein. However, the use of epithelial membrane antigen allows certain histopathologic distinction between capillary hemangioblastoma and metastatic clear cell carcinoma.

Expression of lacto series type 2 antigens in human renal cell carcinoma and its clinical significance.

We performed immunohistochemical examination of serial sections of human fetal and adult renal tissue as well as human renal carcinoma tissue, using monoclonal antibodies T5A7, 1B2, FH2, FH4, and FH6. These monoclonal antibodies were directed to lacto series type 2 antigens with sugar-chain structures: lactosylceramide, lactoneotetraosylceramide (paragloboside), Lex (a chemically well-defined fucosyl carbohydrate antigen), difucosyl Lex, and sialosyl-difucosyl Lex, respectively. The staining pattern in fetal renal tissue changed significantly according to the stage of organogenesis. In addition, expression of the antigens, especially paragloboside and sialosyl-difucosyl Lex, was closely related to the prognosis of the patient. These results suggest that the expression of a series of oncofetal antigens in development or differentiation of organs is reflected in the reversion to an immature pattern of antigenic expression in tumor tissue. The pattern of antigen expression in renal tumors offers a good criterion for ascertaining the degree of tumor differentiation and malignancy and is valuable for determining prognosis.

Genetic variation of haptoglobin and transferrin in relation to DNA content and stage in renal cell carcinoma.

Four genetic marker systems were investigated in 102 patients with renal cell carcinoma. The previously observed excess of the transferrin (TF) variant C3 among male patients was confirmed. Interestingly, an excess of TFC3 and a deficit of the haptoglobin heterozygote, HP2-1, were associated with diploid tumor DNA content and Stage I, particularly in male patients. The results are discussed in terms of a possible genetic influence on tumor progression.