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Partial G-banded karyotypes showing a few examples of monosomy of chromosome 3p in conventional RCC: (a) del(3) (p13); (b) der(3)t(2;3)(p12;p13); (c) der(3)t(3;5)(p14;q22); (d) der (20)t(3;20)(q12;p13).
Source publication
Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdiv...
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Context 1
... associated with conventional RCC. Loss of the chromosomal material at 3p13 → pter is the characteristic chromosomal abnormality in conven- tional RCC. This partial monosomy of 3p can occur as a deletion (terminal or interstitial) of only the short arm (Fig. 5A) or may also involve a proximal region of the long arm of chromosome 3 (Fig. 5D). It may also occur as an unbalanced translocation between the 3p 14-21 region and another chromosomeal region (Fig. 5B), with 5q22 as the preferential partner region (Fig. 5C). In addition to the finding of partial monosomy of 3p, several recurrent ...
Context 2
... associated with conventional RCC. Loss of the chromosomal material at 3p13 → pter is the characteristic chromosomal abnormality in conven- tional RCC. This partial monosomy of 3p can occur as a deletion (terminal or interstitial) of only the short arm (Fig. 5A) or may also involve a proximal region of the long arm of chromosome 3 (Fig. 5D). It may also occur as an unbalanced translocation between the 3p 14-21 region and another chromosomeal region (Fig. 5B), with 5q22 as the preferential partner region (Fig. 5C). In addition to the finding of partial monosomy of 3p, several recurrent cytogenetic altera- tions associated with progression have been described. Numerical ...
Context 3
... chromosomal abnormality in conven- tional RCC. This partial monosomy of 3p can occur as a deletion (terminal or interstitial) of only the short arm (Fig. 5A) or may also involve a proximal region of the long arm of chromosome 3 (Fig. 5D). It may also occur as an unbalanced translocation between the 3p 14-21 region and another chromosomeal region (Fig. 5B), with 5q22 as the preferential partner region (Fig. 5C). In addition to the finding of partial monosomy of 3p, several recurrent cytogenetic altera- tions associated with progression have been described. Numerical changes that have been identi- fied are monosomy of chromosomes 8, 9, 13 and 14 and trisomy of chromosomes 12 and 20. ...
Context 4
... monosomy of 3p can occur as a deletion (terminal or interstitial) of only the short arm (Fig. 5A) or may also involve a proximal region of the long arm of chromosome 3 (Fig. 5D). It may also occur as an unbalanced translocation between the 3p 14-21 region and another chromosomeal region (Fig. 5B), with 5q22 as the preferential partner region (Fig. 5C). In addition to the finding of partial monosomy of 3p, several recurrent cytogenetic altera- tions associated with progression have been described. Numerical changes that have been identi- fied are monosomy of chromosomes 8, 9, 13 and 14 and trisomy of chromosomes 12 and 20. Non-random structural alterations involving 5q, 6q, 8p, 10q, ...
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Citations
... Most radiologically detected lesions are small and can be surveilled until the index tumor reaches 3 cm in size, at which malignant metastatic spread can occur (17). On purely histopathological criteria, precancerous and precursor lesions in the VHL kidney have been previously appreciated (18,19). ...
Using a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis.
... There are three main, well-defined, premalignant lesions of the kidney: the adenoma-carcinoma sequence of papillary renal cell carcinoma; the dysplastic changes within the cysts of the VHL syndrome; and the tubular dysplasia ("renal intratubular neoplasia" or RIN) [38][39][40]. Histologically CCCs differ from RIN. Their loc at i o n i s n ot on l y p er i t um or a l l i k e R I N , th e i r immunophenotype is of distal nephron, and more importantly, nuclear atypia is absent. ...
Clear cytoplasm is a major characteristic feature of most malignant renal neoplasms. Benign clear cells in the renal parenchyma, usually histiocytes, can occasionally be found, but they are infrequently of an epithelial nature. We report histological, immunohistochemical, ultrastructural, and cytogenomic features of clear epithelial cell clusters incidentally found in four kidney specimens. Multiple microscopic clear cell clusters were present in the cortex, often in subcapsular location. They were composed of large epithelial cells with strikingly clear cytoplasm, without nuclear atypia, arranged in solid nests, and some tubules with narrow lumina. Immunohistochemically, they were positive for AE1AE3, PAX 8, EMA, kidney-specific cadherin, cytokeratin 7, E cadherin, and CD117, with focal immunoreactivity for CD10. Carbonic anhydrase IX, vimentin, and markers related to apoptosis and proliferation were negative. Ultrastructurally, the cytoplasms were enlarged and poor in organelles, showing ballooning degeneration. Array comparative genomic hybridization showed no chromosomal gains or losses. Clear cell clusters constitute a rare finding in the kidney and must be differentiated from benign lesions (ectopic adrenal tissue, osmotic tubulopathy, histiocytic clusters, renal adenomas) and renal cell carcinomas. Clear cell clusters appear to be generated from “endocrine-type” atrophic tubules whose cells are enlarged due to intracellular oedema. Immunohistochemistry shows a distal nephron phenotype with a limited expression of a proximal marker, CD10. Coexisting chronic renal disease or ischemic conditions seem to be related to the development of clear cell clusters. Pathological, ultrastructural, and cytogenomic features do not support a preneoplastic nature of this lesion, at least in the cases studied here.
... Shrewsbury et al. [11] estimated that around 2-7% of patients with ESRD develop RCC. Approximately 20% of patients with chronic kidney disease (CKD) who are treated with dialysis end up having acquired cystic kidney disease (ACKD) [11,12]. These patients have an increased risk of developing RCC and in clinical settings it has been described that 5% who undergo transplantation after dialysis develop RCC in their native kidneys [8,[13][14][15]. ...
Purpose
End-stage renal disease (ESRD) is a known risk factor for the development of renal cell carcinoma (RCC). This case-control study was performed to assess the risk in a nationwide cohort and evaluate tumor characteristics and survival in the ESRD-RCC population.
Methods
In this study, 9,299 patients with RCC identified in the National Swedish Kidney Cancer Register from 2005 until 2014 and 93,895 matched controls were linked to the Swedish Renal Registry and the National Patient Register. ESRD was defined as chronic kidney disease stage 5, kidney transplantation or kidney dialysis 0–40 years before the diagnosis of RCC.
Results
A total of 117 patients with ESRD and subsequent RCC were identified and compared with 9,087 patients with RCC. There was a 4.5-times increased risk for RCC among ESRD patients (95% CI = 3.6–5.6; p < 0.001) compared to matched controls. Longer time with ESRD increased the risk of RCC (ESRD > 9 years, OR = 10.2, 95% CI = 7.0–14.8). The ESRD-RCC patients were younger (p = 0.002), had smaller tumors (p < 0.001) and had lower tumor stage (p = 0.045). The incidence of papillary and chromophobe RCC was higher and clear cell RCC lower among the ESRD patients (p < 0.001). The 5-year overall survival was 50% in ESRD-RCC patients and 63% in RCC-only patients (p < 0.05).
Conclusion
More than 9 years with ESRD increased the risk of developing RCC 10-times compared to individuals without ESRD and the tumors showed a different histopathological pattern. Despite a less advanced tumor stage at diagnosis, the overall survival in ESRD-RCC patients was lower compared to patients with RCC-only.
... Bu nedenle birçok genitoüriner malignitenin aksine, böbrekte premalign değişiklikler konusunda tartışmalar mevcuttur. Premalign böbrek kanseri lezyonu olarak renalintratubulerneoplazi ve vonHippel-Lindausendromlu hastalarda izlenen kistlerin displastik değişiklikleri uzun yıllar önce tanımlanmıştır (24,25). Ancak bu tür lezyonların son derece nadir görülmeleri sebebiyle, klinik önemleri ve prognozları ile alakalı yeterli kanıt bulunmamaktadır. ...
Premalign lezyonlar, normal dokuya göre daha fazla malign değişim riski ile karakterize
lokal lezyonlardır. Genitoüriner sistemde prostatik intra epitelyal neoplazi, mesane karsinoma in situ ve testis in situ germ hücre neoplazisi gibi kanser öncülü olabileceği kanıtlanmış lezyonlar mevcut olmakla birlikte; moleküler, epidemiyolojik ve morfolojik çalışmalara rağmen birçok lezyonun premalign potansiyeli için tartışmalar devam etmektedir. Genitoüriner sistemde premalign oluşumların ayrıcı tanıda akla getirilmesi, olası malign lezyonların erken tespiti için ciddi önem arzetmektedir.
... Раніше дослідникам вдалося не тільки виявити осередки інтратубулярної епітеліальної дисплазії в перитуморальній тканині при нирково-клітинному раку, а й описати скупчення попередників пухлинних клітин у вигляді карциноми in situ [14,31]. Сформульована та розвинута проблема ренальної інтратубулярної неоплазії як передраку нирки [22,26,31]. На підставі проведених імуногістохімічних реакцій на панцитокератин (цитоплазматичний антиген) і PCNA (ядерний антиген) виявили, що найбільша експресія зазначених антигенів супроводжує епітеліальні клітини НТ перитуморальної тканини при СКРН. ...
The aim was to investigate in a comparative plan the ultrastructural peculiarities of cells, cellular and noncellular elements of renal intratubular neoplasia of peritumoral tissue with highly, average and low grades of differentiation at clear cell renal cell carcinoma (CCRCC). Material and methods. Material for conducting transmission electron microscopic researches was postoperative biopsies of the peritumoral tissue at highly differentiated CCRCC (G1) – five cases; at an average grade of differentiation (G2) – five cases; at low grade of differentiation (G3) – six cases. The renal tubules (RT) and tangential stroma elements with different differentiation (G1, G2, G3) in peritumoral tissue at the ultrastructural level were investigated. Results. It was revealed that in RT of peritumoral tissue at highly differentiated CCRCC (G1) and the average degree of differentiation (G2) cells of renal intratubular neoplasia zones are represented mainly in the average electronic density by little-differentiated epithelial cells with a large nuclear-cytoplasmic ration. Epithelial cells with small nuclear-cytoplasmic ratio, the cytoplasm of which is filled with disorganized small mitochondria, Mallory bodies, glycogen granules and autophagosomes, are present in separate cells zones of the renal intratubular neoplasia with the CCRCC of the indicated degrees of differentiation. Peritumoral tissue at highly differentiated CCRCC (G1) and the average degree of differentiation (G2) contains hemocapillaries, small venules, clusters of fibroblasts, macrophages, plasmocytes. A characteristic ultrastructural feature of peritumoral tissue with a low degree of differentiation (G3) at CCRCC is the presence of a small diameter RT coated with very thick and simultaneously flaky basal membranes. Typical for separate small differentiated epithelial cells of renal intratubular neoplasia zones RT of peritumoral tissue at CCRCC of low degree of differentiation (G3) is the presence in their cytoplasm of a very large size, spherical form of Mallory body with the electron-density, connected with the outer membrane of the nuclear shell. It was also revealed that in the conditions of renal intratubular neoplasia, a number of zones of renal intratubular neoplasia RT of peritumoral tissue are filled with epithelial cells, the cytoplasm of which contains a giant size of the autophagosome and electron-density cluster of glycogen granules. The autophagosome contains small lipid drops of insignificant electron density and approximately the same size of a very high electron density spherical formation of unspecified nature. Conclusions. Epithelial cells of the renal intratubular neoplasia zones of peritumoral tissue at CCRCC of low degree of differentiation (G3), in the comparative plan with similar epithelial cells of the renal intratubular neoplasia zones of peritumoral tissue with high (G1) and the average (G2) degrees of differentiation, have cytoplasm, which is the most saturated Mallory bodies, autophagosomes, electron-density clusters of granules of glycogen.
... The von Hippel-Lindau (VHL) disease is characterized by the heterozygous inactivation of a single VHL allele, which predisposes to benign and malignant tumour de- van velopment in many organ systems [1]. In the kidney, biallelic VHL inactivation results in the formation of numerous benign cysts in ∼75% of the patient population [2]. It is thought that clear cell renal cell carcinoma (ccRCC, 35-75% prevalence) develops from cells lining these premalignant renal tubular cysts; however, not all cysts develop ccRCC, and not all cases of ccRCC are preceded by cysts [3][4][5]. ...
Background:
von Hippel-Lindau (VHL) disease is characterized by the development of benign and malignant tumours in many organ systems, including renal cysts and clear cell renal cell carcinoma. It is not completely understood what underlies the development of renal pathology, and the use of murine Vhl models has been challenging due to limitations in disease conservation. We previously described a zebrafish model bearing inactivating mutations in the orthologue of the human VHL gene.
Methods:
We used histopathological and functional assays to investigate the pronephric and glomerular developmental defects in vhl mutant zebrafish, supported by human cell culture assays.
Results:
Here, we report that vhl is required to maintain pronephric tubule and glomerulus integrity in zebrafish embryos. vhl mutant glomeruli are enlarged, cxcr4a+ capillary loops are dilated and the Bowman space is widened. While we did not observe pronephric cysts, the cells of the proximal convoluted and anterior proximal straight tubule are enlarged, periodic acid schiff (PAS) and Oil Red O positive, and display a clear cytoplasm after hematoxylin and eosine staining. Ultrastructural analysis showed the vhl-/- tubule to accumulate large numbers of vesicles of variable size and electron density. Microinjection of the endocytic fluorescent marker AM1-43 in zebrafish embryos revealed an accumulation of endocytic vesicles in the vhl mutant pronephric tubule, which we can recapitulate in human cells lacking VHL.
Conclusions:
Our data indicates that vhl is required to maintain pronephric tubule and glomerulus integrity during zebrafish development, and suggests a role for VHL in endocytic vesicle trafficking.
... In this study it was noticed within the adjacent renal parenchyma in four cases, ranging from mild to severe intraepithelial cytological atypia, similar to carcinoma in situ; interestingly, this lesion has been found occasionally in the contralateral kidney as well. Premalignant precursor lesions of RCC are not well characterized, but intratubular epithelial dysplasia defined morphologically by crowded, enlarged and pleomorphic nuclei has been described by other authors [18]. However, this finding remains understudied and outside the current recommendations for the pathological reporting of RCC. ...
Experimental renal cancer caused by ochratoxin A (OTA) in rats was first defined in the US National Toxicology Program (1989) and raised questions about any aetiological role in human urinary tract tumours. A review of histopathology in several rat kidney tumours from dietary OTA in recently described London studies, augmented by clinical immunohistochemistry for the first time for this mycotoxin, establishes their renal tubular cell origin. It had been assumed that the toxin might cause the human urothelial tumours associated with Balkan endemic nephropathy, but the present study could not support this. Comparison with a similar review of a metastasising renal tumour from a female rat of the NTP study consistently shows the kidney as the primary carcinogenic site for OTA. Morphological heterogeneity of these kidney tumours as epithelioid and/or sarcomatoid is revealed. Leiomyosarcoma was also diagnosed, and rhabdomyosarcoma differentiation was observed in the exceptionally aggressive NTP female tumour. The present pilot study involving immunohistochemistry indicates need for wider review of archived tumours for experimental evidence before formulating any epidemiological basis from a rat model for OTA’s relevance to idiopathic human renal cell carcinoma. Although the NTP study concluded that females are less sensitive to OTA than males, some female tumours still had heterogeneous morphology.
... Kidney Von Hippel Lindau Renal intraepithelial lesions (RIL) Poppel et al. 2000 Ovary SCOUT Secretory cell outgrowth (serous) ...
Where does cancer come from? Although the cell-of-origin is difficult to pinpoint, cancer clones harbor information about their clonal ancestries. In an effort to find cells before they evolve into a life-threatening cancer, physicians currently diagnose premalignant diseases at frequencies that substantially exceed those of clinical cancers. Cancer risk prediction relies on our ability to distinguish between which premalignant features will lead to cancer mortality and which are characteristic of inconsequential disease. Here, we review the evolution of cancer from premalignant disease, and discuss the concept that even phenotypically normal cell progenies inherently gain more malignant potential with age. We describe the hurdles of prognosticating cancer risk in premalignant disease by making reference to the underlying continuous and multivariate natures of genotypes and phenotypes and the particular challenge inherent in defining a cell lineage as "cancerized."
... In humans, preneoplastic lesions of the kidney are scarcely described morphologically. Van Poppel reported " intratubular epithelial dysplasia " as a common precursor of sporadic RCC [14]. Nevertheless, only multiple cystic clear cell lesions in relation to the von Hippel-Lindau (VHL) disease are accepted as premalignant conditions [14, 15, 16]. ...
... Van Poppel reported " intratubular epithelial dysplasia " as a common precursor of sporadic RCC [14]. Nevertheless, only multiple cystic clear cell lesions in relation to the von Hippel-Lindau (VHL) disease are accepted as premalignant conditions [14, 15, 16]. These cysts reveal crucial genetic alterations like VHL gen mutations or allel deletion and an overexpression of the Hypoxia-inducible factor (HIF) [17, 18], which is a well-known oncogenic pathway in RCC [19]. ...
Activation of the PI3K/AKT/mTOR pathway is a crucial molecular event in human clear cell renal cell carcinoma (ccRCC), and is also upregulated in diabetic nephropathy. In diabetic rats metabolic changes affect the renal distal tubular epithelium and lead to glycogen-storing Armanni-Ebstein lesions (AEL), precursor lesions of RCC in the diabetes induced nephrocarcinogenesis model. These lesions resemble human sporadic clear cell tubules (CCT) and tumor cells of human ccRCC.
Human sporadic CCT were examined in a collection of 324 nephrectomy specimen, in terms of morphologic, metabolic and molecular alterations, and compared to preneoplastic CCT and RCC developed in the rat following streptozotocin-induced diabetes or N-Nitrosomorpholine administration. Diabetic and non-diabetic rats were subjected to the dual PI3K/mTOR inhibitor, NVP/BEZ235.
Human sporadic CCT could be detected in 17.3% of kidney specimens. Human and rat renal CCT display a strong induction of the PI3K/AKT/mTOR pathway and related metabolic alterations. Proteins involved in glycolysis and de novo lipogenesis were upregulated. In in vivo experiments, dual inhibition of PI3K and mTOR resulted in a reduction of proliferation of rat diabetes related CCT and increased autophagic activity.
The present data indicate that human sporadic CCT exhibit a pattern of morphologic and metabolic alterations similar to preneoplastic lesions in the rat model. Activation of the PI3K/AKT/mTOR pathway in glycogenotic tubuli is a remarkable molecular event and suggests a preneoplastic character of these lesions also in humans.
... Premalignant alterations in the kidney have been described previously. These lesions were suggested to be named as renal intratubular neoplasia (RIN) by a consensus committee of the World Health Organisation [32]. RIN was considered to be precancerous abnormalities in the sequence of changes by which RCC develops from normal kidney tubules [18,19,32,33]. ...
... These lesions were suggested to be named as renal intratubular neoplasia (RIN) by a consensus committee of the World Health Organisation [32]. RIN was considered to be precancerous abnormalities in the sequence of changes by which RCC develops from normal kidney tubules [18,19,32,33]. Similar molecular alterations are found in some putative premalignant changes. ...
