Prognostic role of histological necrosis for nonmetastatic clear cell renal cell carcinoma: correlation with pathological features and molecular markers.

PURPOSE: We defined the prognostic role of tumor necrosis and its extent in nonmetastatic clear cell renal cell carcinoma. Also, we further investigated its pathogenesis by correlating this tumor feature with other pathological characteristics and molecular markers related to the von Hippel Lindau-hypoxia inducible factor pathway and to tumor proliferation. MATERIALS AND METHODS: A total of 213 patients with nonmetastatic clear cell renal cell carcinoma were evaluated. Mean followup was 66 months. The presence and extent of histological necrosis were correlated with clinicopathological factors, Ki-67 antigen expression calculated by the MIB-1 (Ki-67 antibody) index, pVHL, HIF-1alpha, the tumor infiltrating lymphocyte subset and cancer specific survival. RESULTS: Histological necrosis was present in 63.8% of clear cell renal cell carcinoma cases. Necrosis was significantly associated with grade and the degree of tumor infiltrating lymphocytes, while its extent correlated significantly with grade, the degree of tumor infiltrating lymphocytes and stage. Tumor necrosis was a significant prognostic factor, which was confirmed even when limiting analysis to patients with intracapsular renal cell carcinoma. On multivariate analysis histological necrosis was not an independent predictor of cancer specific survival. The extent of tumor necrosis was not a significant prognostic factor. The presence and extent of histological necrosis was not associated with high Ki-67 expression and it did not correlate with pVHL expression or with nuclear and cytoplasmic HIF-1alpha expression. CONCLUSIONS: Based on our results we cannot support histological necrosis and its extent as prognostic factors for clear cell renal cell carcinoma. Efforts should be made to develop nomograms that use routinely available and objective predictor variables. The precise mechanism that causes tumor necrosis remains unknown but the host immune response might significantly contribute to its development.

Nuclear expression of hypoxia-inducible factor-1alpha in clear cell renal cell carcinoma is involved in tumor progression.

OBJECTIVES: The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-1alpha (HIF-1alpha); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1alpha activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1alpha pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1alpha proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis. MATERIALS AND METHODS: Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1alpha were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74 mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS). RESULTS: A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1alpha. All pVHL-negative cases were associated with high HIF-1alpha expression. pVHL negativity and HIF-1alpha nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-1alpha nuclear expression were independent predictors of TSS. CONCLUSIONS: The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1alpha alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.

Intracapsular clear cell renal carcinoma: ploidy status improves the prognostic value of the 2002 TNM classification.

PURPOSES: The TNM classification has been revised for the 2002 edition of the UICC publication to better stratify patients with intracapsular renal cell carcinoma (RCC) but few studies have been published to date to validate this new classification. Moreover, additional prognostic factors seem to be necessary to improve the prediction of intracapsular tumor aggressiveness and the definition of patient subgroups at high risk for metastases. We report the long-term results of the new TNM scheme. We evaluated the impact of DNA content, S-phase and MIB-1 (Dako, Glostrup, Denmark) score. MATERIALS AND METHODS: A total of 136 patients with intracapsular clear cell RCC and a mean followup of 74 months were reclassified. Tumor specific survival (TSS) was compared with nuclear grade (NG), DNA content and proliferative status (S-phase fraction and MIB-1 score). RESULTS: TSS was 92%, 81.1% and 40.1% for pT1a, pT1b and pT2, respectively (p <0.05). TSS according to DNA ploidy status (diploid vs aneuploid) was pT1a-95.2% vs 68.6% (p <0.05), pT1b-90% vs 46.7% (p <0.05) and pT2-49.2% vs 25% (p not significant). DNA ploidy was also significantly associated with survival when adjusted for NG. There was no significant association between TSS and MIB-1 score or tumor S-phase fraction. CONCLUSIONS: The 2002 TNM classification is a useful prognostic factor for evaluating organ confined RCC of the clear cell subtype. Evaluation of the DNA content in clear cell RCC appears to significantly improve the predictive value of the TNM staging system, especially in the pT1a and pT1b categories. Fuhrman NG alone or combined should be routinely used in such patients.

Evaluation of renal function and upper urinary tract morphology in the ileal orthotopic neobladder with no antireflux mechanism.

PURPOSE: Long-term renal function is crucial in orthotopic bladder substitutions, and can be influenced by several factors including ureteral obstruction, urinary infection and reflux. In this study we investigated the prevalence of renal functional impairment and the incidence of morphological alterations of the upper urinary tract in patients who had a low pressure ileal neobladder constructed with no antireflux mechanism. MATERIALS AND METHODS: From 1996 to 2002, 70 men received a W-shaped neobladder using refluxing ureterointestinal anastomoses and short afferent limb. Final evaluation of patient status was in November 2003. A total of 20 patients died during followup and mean followup of the remaining 50 patients was 50 months (range 21 to 89). Kidney morphology was evaluated using technetium diethylenetetraminepentaacetic acid nuclear renography and ultrasonography. Total and separate renal function were evaluated by measuring plasma creatinine and glomerular filtration rate (GFR), the latter measured as the renal clearance of technetium diethylenetetraminepentaacetic acid. Measured values of GFR were compared with the results from a group of healthy subjects of the same age. RESULTS: The anastomotic stricture rate was 4%, 2 severe strictures occurred 2 and 4 months after surgery, while 2 moderate strictures were detected with renal scans during the study. Renal scintigraphy revealed an excretory phase within the normal range in 67 of 99 renoureteral units (68%), a short delay in collecting system drainage associated with mild and transient pelvicaliceal dilatation in 23 (23%), and dilatation of the upper urinary tract in the remaining 9 (9%) including obstructive in 2 (2%) and not obstructive in 7 (7%). Mean (+SD) total GFR of the patients was 89.7 (19.6) ml per minute per 1.73 m. Mean total GFR of the control group was 90.6 (11.4) ml per minute per 1.73 m. The comparison between measured GFR of patients and the control group showed no statistically significant difference. CONCLUSIONS: Our medium-term data support the assumption that the lack of any antireflux mechanism in orthotopic neobladder, per se, has no detrimental effect on renal function.

Mixed germ cell tumor after bilateral orchidopexy in persistent Müllerian duct syndrome with transverse testicular ectopia.

The persistent müllerian duct syndrome is characterized by the retention of müllerian derivatives (fallopian tubes, uterus) in patients otherwise normally virilized, usually with cryptorchidism or an inguinal hernia. Very rarely, this syndrome is associated with transverse testicular ectopia, which designates the condition when both testes descend through the same inguinal canal into the same scrotal sac. We report on a patient with both conditions, who had T1N2M0 scrotal mixed germ cell tumor of the testis (teratoma and embryonal carcinoma), 18 years after bilateral orchidopexy. The literature concerning this uncommon association is reviewed.

Solitary floating vena caval thrombus as a late recurrence of renal cell carcinoma.

We report an unusual case of solitary thrombus floating in the inferior vena cava (IVC) in a patient who underwent radical nephrectomy for a renal cell carcinoma (RCC) of the right kidney extended into the renal vein with no capsular and perinephric tissue invasion (pT3b). Twenty months after surgery, a routine computed tomography scan identified an intraluminal mass floating in the IVC. Cavotomy and thrombectomy with no caval resection were successfully performed. A review of the literature showed only three previous published cases of RCC recurring in the IVC only, with no local recurrence or distant metastases. We outline the possible etiology of these unusual and solitary recurrences in the IVC and we emphasize the need for a strict surveillance for all patients with RCC and especially for those with pT1b, pT2 and pT3 disease. An early diagnosis of this rare recurrence can permit an easy removal of the thrombus with no caval resection and graft replacement, making this disease potentially curable by surgery.