[Peculiarities of angiogenesis in clear cell renal cancer]. / Osobennosti angiogeneza pri svetlokletochnom rake pochki.

A literature search was conducted to review papers on the results of studies of clear cell renal cancer (CCRC) vascularization. Numerous data on the relationship between tumor pathogenesis and its vascularization have been revealed, which indicates the multifactorial nature of CCRC development and the significant role of angiogenesis in this process. It should be taken into account that patients with CCRC may have impaired vessel formation even before tumor development. To evaluate normal and pathologic angiogenesis, a pathohistologic study using immunohistochemistry is certainly necessary. Due to the significant role of angiogenesis in the development and course of CCRC, the use of drugs that suppress the formation of the vascular network in the tumor is relevant and advisable. To date, many drugs have been developed and introduced into clinical practice to inhibit angiogenesis. However, such drugs have not lived up to the expectations placed due to the frequent and rapidly developing drug resistance. Timely detection of pre-tumor and tumor processes, as well as effective treatment of cancer, including CCRC, is possible only with close cooperation between pathomorphologists and oncologists.

Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma.

Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two-dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three-dimensional light-sheet microscopy. Here, we used the diagnosing immunolabeled paraffin-embedded cleared organs pipeline for tissue clearing, immunolabeling, and three-dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE-1, which targets lymphatic vessels, were examined by calculating three-dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin-fixed paraffin-embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three-dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K-mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High-end tissue clearing techniques and volumetric immunohistochemistry enable three-dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

Depiction rate of feeding arteries of renal cell carcinoma on four-dimensional computed tomography angiography.

PURPOSE: To retrospectively evaluate the depiction rate of feeding arteries in biopsy-proven clear cell renal cell carcinoma (CCRCC) on four-dimensional computed tomography angiography (4D-CTA) images. MATERIALS AND METHODS: This study included 22 patients with 22 CCRCC and 30 feeding arteries treated with transcatheter renal artery embolization. The depiction rate of the feeding arteries on preprocedural 4D-CTA was evaluated. Images were acquired by 320-row multi-detector computed tomography (CT) 15‒36 s after starting to inject a contrast agent (600 mg/kg iodine) intravenously into patients at 2.1 s intervals (11 phases). Two board-certified radiologists retrospectively assessed the feeder depiction rate in all 11 phases with reference to the procedural images as the gold standard. Discrepancies were resolved by consultation with a third radiologist. RESULTS: Among the feeders, 11 (36.7%) were segmental or lobar, and 19 (63.3%) were interlobar or arcuate arteries. The feeder depiction rate was the highest (25 [83.3%] of 30) in the 5th phase (delay, 23.4 s) where the gap in contrast enhancement between the renal artery and cortex was the largest. This was followed by the 6th (23 [76.7%] of 30), 4th (22 [73.3%] of 30]), and 7th (21 [70.0%] of 30) phases. The overall rate of depicting feeding arteries in the 11 phases of 4D-CTA was 28 (93.3%) of 30. CONCLUSIONS: The depiction rate of CCRCC feeding arteries including lobar or smaller artery branches by 4D-CTA was favorable. The feeding arteries were optimally visualized during the phase with the largest contrast gap between the renal artery and cortex.

Analysis of various potential prognostic markers and survival data in clear cell renal cell carcinoma

ABSTRACT Purpose Clear cell renal cell cancers frequently harbor Von Hippel-Lindau gene mutations, leading to stabilization of the hypoxia-inducible factors (HIFs) and their target genes. In this study, we investigated the relationship between vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α, p53 positivity, microvessel density, and Ki-67 rates with prognostic histopathologic factors (Fuhrman nuclear grade, stage, and sarcomatoid differentiation) and survival in clear cell renal cell carcinomas. Material and Methods Seventy-two nephrectomy specimens diagnosed as clear cell renal cell carcinoma between 2000 and 2012 were reevaluated. Immunohistochemically VEGF, HIF-1α, HIF-2α, p53, CD34 (for microvessel density evaluation), and Ki-67 antibodies were applied to the tumor areas. The relationships of these antibodies with prognostic factors and survival rates were evaluated with statistical analyses. Results Mean survival time was 105.6 months in patients with ccRCC. Patients with high expression of VEGF, HIF-1α and HIF-2α positivity, a high Ki-67 proliferation index, and a high microvessel density evaluation score had a shorter survival time (p<0.05). Conclusions Our findings supported that with the use of these immunohistochemical markers, prognosis of renal cell carcinoma may be predicted at the first step of patient management. New treatment modalities targeted to HIF-1α and HIF-2α might be planned as well as VEGF-targeted therapies in the management of clear cell renal cell carcinomas.

Metastatic renal cell carcinoma management: [review]

PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC) patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

Significance of intratumoral microscopic vascular invasion in patients with renal cell carcinoma / Significado da invasäo vascular microscópica intratumoral nos pacientes com carcinoma de células renais

Objetivo: Estudar a presença da invasäo vascular microscópica intratumoral e a evoluçäo dos pacientes submetidos à nefrectomia devido ao câncer renal. Material e métodos: De Janeiro/88 a Julho/99, 115 pacientes submeteram-se ao tratamento cirúrgico para o carcinoma de células renais. Um único patologista revisou todas as amostras anátomo-patológicas, procurando células neoplásicas na microcirculaçäo do tumor. Resultado: O tamanho do tumor variou de 0,5 a 19,5 cm (5,9 ñ 2,9). Três tumores mediam até 4 cm (7 por cento), 9 (21 por cento) entre 4,1 e 7 cm, 8 (42 por cento) entre 7,1 e 10 cm, e 6 (50 por cento) mediam mais do que 10 cm (p<0,001). Invasäo vascular microscópica foi observada em 23 por cento dos casos, sendo 7 por cento em tumores diagnosticados incidentalmente e 39 por cento em tumores sintomáticos (p<0,001). Até o final do estudo, houve 5 casos de progressäo da doença e 8 mortes, nos casos onde havia invasäo vascular microscópica. Na ausência da invasäo, apenas 1 progressäo e 2 mortes foram observadas. Conclusäo: Nesta série, a presença de invasäo vascular microscópica associou-se a um aumento importante da morbimortalidade. Essa descoberta representa um outro fator prognóstico das taxas de sobrevida dos pacientes com carcinoma de células renais.