Histologic variants of renal cell carcinoma: does tumor type influence outcome?

Each histologic type of renal cell carcinoma (RCC) has different pathologic and clinical parameters; however, the independent role of histologic type in outcome prediction remains contested. Most studies show relevance for outcome of each histologic type when correlated with survival by univariate analysis, whereas few studies show differences in outcome once other key prognostic factors, such as stage and grade, are considered. These studies highlight the challenges to prove outcome relevance. Despite the contested independent value of type for outcome prediction, separation of RCC into types is well accepted and can be substantiated on clinical, pathologic, molecular, and general outcome differences.     

Multicentricity in renal cell carcinoma: can primary tumor location serve as a co-determinant of surgical treatment?

OBJECTIVE: To assess the incidence of multicentricity in our series of renal cell carcinoma (RCC) patients and to investigate whether certain clinicopathological parameters could assist the selection of the appropriate surgical modality. METHODS: We performed a retrospective analysis of 235 RCC specimens that had been resected by radical nephrectomy at our institution from June 1995 to 2001. RESULTS: Twenty-six (11%) kidneys contained at least one small accompanying nodule. Fourteen (6%) kidneys exhibited satellite tumors that were histologically consistent with the adenomas, while "true" multicentricity was detected in 12 (5%) specimens. In the latter, the number of concomitant foci was independent of the size of the primary tumor. No correlation was observed between histological pattern and multifocality. In five out of seven (71%) specimens that contained the main tumor mass within the upper or middle portion of the kidney, satellite lesions were found to be located at the mid-kidney, whereas specimens with lower-pole RCC demonstrated no restriction in the distribution of accompanying nodules. All patients had been screened pre-operatively by ultrasonography and CT scanning. CONCLUSIONS: Our findings may be suggestive of a putative link between primary tumor location and multicentricity, although this relation could not be statistically confirmed. The 5% incidence of multicentricity renders the biological significance of satellite adenomas and/or adenocarcinomas unclear.     

Nephron-sparing surgery for renal cell carcinoma--is tumor size a suitable parameter for indication?

Objectives. Because patients with small renal cell carcinomas (RCC) are being treated by nephron-sparing surgery with increased frequency, a generally accepted parameter giving additional information as to which kind of tumor is suitable for this treatment is urgently required. Methods. In a retrospective analysis of 245 patients who underwent radical nephrectomy for RCC, we investigated whether tumor size could provide the necessary information. We analyzed the association of tumor size with pTNM classification, grade, and the findings of the flow cytometric analysis of the DNA content analyzing the DNA index (DI). Results. Stage pT1 was found in 23 patients (9.4%), pT2 in 100 (40.8%), pT3 in 109 (44.5%), and pT4 in 13 patients (5.3%). Grade 1 was found in 87 patients (35.5%), grade 2 in 120 (49.0%), and grade 3 in 38 patients (15.5%). A low DI was found in 71%, a moderately increased DI in 20%, and a high DI in 9%. Lymph node metastases were detected in 14% and distant metastases in 22%. Closer examination of the tumors less than 2.5 cm (n = 23) revealed a significantly lower incidence (P <0.001) of infiltration of the renal capsule (n = 0) than in the rest of the group. Positive lymph nodes or distant metastases could not be found in this subgroup. A multifocal appearance of RCC was detected in only 2 (8.7%) of the 23 patients; it was detected in 67 (30.2%) of the 222 patients in the rest of the group. None of the 23 patients had grade 3 tumors (P <0.05). Fifty-two percent of the tumors were grade 1 and 48% grade 2. None of the 23 had a high DI; a moderately increased DI was found in 1 patient and a low DI in 22 of the 23 patients. Detailed examination of the tumors between 2.5 and 4 cm (n = 29) revealed an infiltration of the renal capsule in 11 (38%); lymph node metastases were found in 2 (6.9%) and metastases in 4 (13.8%). A multifocal appearance was found in 4 (13.9%) of the 29 patients; grade 3 tumors were detected in 3 (10.3%) of 29 patients, grade 2 tumors in 12 (41.4%), and grade 1 tumors in 14 (48.3%). In this subgroup, a high DI was found in 14% (not significant). The examination of tumors larger than 4 cm in size revealed worse results in the pTNM classification, grade, and flow cytometric results. Conclusions. Only tumors smaller than 2.5 cm should be considered suitable for nephron-sparing surgery in patients eligible for elective surgery. In patients in whom nephron-sparing surgery is imperative, even tumors between 2.5 and 4 cm appear to be suitable. In patients requiring extensive resection, however, the risk of local recurrence seems to be higher because of the higher incidence of multifocality.     

Cyclooxygenase-2 expression: Does it have a probable role in tumorigenesis mechanisms of renal cell carcinoma?

Objectives The purpose of this study was to evaluate the correlation between the levels of cyclooxygenase-2 (COX-2) expression with clinicopathologic features and determine the impact on prognosis in patients with renal cell carcinoma (RCC). Methods Expression of COX-2 was evaluated immunohistochemically in RCC tissues from 62 patients who underwent radical nephrectomy between 1996 and 2004. Percentage of COX-2 staining was scored as 0 (negative), 1 (1–24%), 2 (25–49%), 3 (50–74%), and 4 (75–100%). Immunohistochemical COX-2 staining score (ISS) was defined as summation of intensity and percentage of COX-2 staining. Results Twenty-seven patients (43.5%) with a median follow-up of 47.8 (25–115) months stained positively for COX-2. COX-2 expression was positive in 37.1%, 50%, and 66.7% of patients with stages 1, 2, and 3, respectively (P = 0.46). Correlation between ISS and pathological stage was statistically significant (P = 0.005). Multivariate regression analysis revealed no clinicopathologic parameter as independent predictors of progression. Kaplan–Meier analysis revealed statistically significant different survival rates in tumor stage, grade, and ISS. Conclusion Although COX-2 expression is not an independent predictor of progression in patients with RCC, patients with higher ISS values have significantly shorter progression-free survival rates. These results might be important to the clinician because positive COX-2 expression of a certain RCC might necessitate early adjuvant systemic therapy to delay the progression of RCC. For this reason, there is a need for innovative, prospective, and randomized studies in patients with positive COX-2 expression that will display the impact of systemic therapies in these patients.     

Multifocality in renal cell carcinoma: A bilateral event?

OBJECTIVES: The major disadvantage of nephron-sparing surgery for renal cell carcinoma is the risk of local recurrence. This is most likely a manifestation of undetected small additional tumors in the renal remnant. To define more clearly the incidence and nature of unilateral and bilateral multifocal tumors, an autopsy study was undertaken. MATERIALS AND METHODS: In a series of 14,793 autopsies from 1985 to 1995, 260 renal cell carcinomas were found. In all cases of renal cell carcinoma a search for small renal lesions was performed in the apparently normal-appearing portion of the kidneys. Every kidney was serially and systematically cut (5 mm) to probe for intraparenchymal lesions. RESULTS: Of the 260 renal cell carcinomas 36 cases (13.85%) had multifocal malignant and/or benign nodules. The number of the additional nodules ranged from 2 to 18. 12% of the malignant multifocal carcinomas were limited to the ipsilateral kidney and 88% were bilateral. The average size of the multifocal renal lesions was 8.7 x 9.0 x 9.5 (range 3-23) mm. Renal cell carcinomas with low stage and good grading have a higher incidence of multifocal nodules. No significant difference was found with regard to metastasized and nonmetastasized renal cell carcinomas. In 38.1% of all chromophilic renal cell carcinomas additional nodules were found. CONCLUSIONS: Multifocality in renal cell carcinomas cannot be predicted reliably, although the papillary histological pattern, good grading and low staging seems to be associated with a higher incidence of multifocality. Nearly 90% of the multifocal nodules were bilateral.     

CD44 immunoreactivity in the developing human kidney: a marker of renal progenitor stem cells?

Abstract

CD44 is a transmembrane adhesion glycoprotein, functioning as a hyaluronan receptor and participating in the uptake and degradation of hyaluronan. Recently, CD44 has been proposed in the adult kidney as a marker of activated glomerular parietal epithelial cells, the putative niche stem cells that, in case of damage to podocytes, might migrate inside the glomerular tuft and undergo transition to podocytes. Here, immunoreactivity for CD44 was tested in 18 human fetuses and newborns with a gestational age ranging from 11 to 39 weeks. CD44 immunoreactivity was observed in all but one developing kidneys, being localized in several renal cell types including intraglomerular, capsular, cortical and medullary interstitial cells and nerve cells. In some cases, CD44 marked scattered cells in nephrogenic subcapsular zone. Our data indicate that CD44 is involved in human nephrogenesis, probably marking a subset of progenitor/stem cells involved in early phases of kidney development and, putatively, in podocyte and/or interstitial cell differentiation.     

Wilms tumor—a renal stem cell malignancy?

Wilms’ tumor (WT; nephroblastoma) is the most common pediatric renal malignancy and rated fourth in overall incidence among childhood cancers. It is viewed as a prototype of differentiation failure in human neoplasia as it recapitulates the histology of the nephrogenic zone of the growing fetal kidney. The cellular origin of WT is unclear. However, recent genomic, genetic and epigenetic studies point to an early renal stem/progenitor cell that undergoes malignant transformation as the source for WT. In this context, classical WT shares genes and pathways activated in progenitors committed to the renal lineage. However, direct proof and characterization of the WT initiating cell have remained elusive. Novel methodologies recently adopted from the cancer stem cell scientific field, including the analysis of sorted single human tumor cells, have been applied to WT. These have enabled the identification of cell sub-populations that show similarities—in terms of molecular marker expression—to human fetal kidney progenitors and are, therefore, likely to be derivatives of the same lineage. Further elucidation of the WT cancer stem cell or the cell of origin in human tumors and in transgenic mouse models that generate murine tumors may not only provide novel therapeutic targets but also shed light on the normal kidney stem cell.     

Elevated concentrations of γ-enolase in renal cell tumors in rats: similarity to renal cell carcinoma in man

Concentrations of enolase isozymes in normal kidney and renal cell tumors in rats were determined using a highly sensitive enzyme immunoassay, and the isozymes were immunohistochemically localized in tissue sections. Levels of -enolase in renal cell turnors were significantly lower than in normal kidney, whereas those of -enolase were significantly elevated (mean ±SD:211±129 ng/mg protein, n=15, as compared to 27.1±2.9 ng/mg protein, n=7). The proportion of -enolase in the total enolases in the tumor tissues (1.6±0.5%) was significantly higher than in normal kidney (0.15±0.005). Immunohistochemistry revealed epithelial cells of all nephron segments to be positive for the -isozyme, whereas -enolase staining was strongly positive only in the loops of Henle, being faint in the distal tubules and absent in the proximal tubules. Both - and -enolases demonstrated positive immunostaining in all of the seven renal cell tumors studied. These findings indicate that an isozyme switch from - to -enolase occurs during rat kidney carcinogenesis, taking into account the derivation from proximal tubules, consistent with the findings for renal cell carcinomas in man.     

Cystic renal cell carcinomas in adults. Is preoperative recognition of multilocular cystic renal cell carcinoma possible?

PURPOSES: We correlated clinicopathological and imaging features of multilocular cystic renal cell carcinoma (MCRCC) to propose preoperative criteria for therapeutic modalities. MATERIALS AND METHODS: A total of 24 RCCs with a chiefly cystic component were identified from 1993 to 2002. In each case histological slides and available imaging studies were retrieved. Two tumor groups were defined, namely MCRCC and clear RCC with cystic change (CRCC) by intrinsic growth or necrotic degeneration. Radiological correlation using computerized tomography and magnetic resonance imaging was performed considering criteria such as an expansile nodule, cyst wall thickness and septa. RESULTS: On imaging MCRCC presented as a multilocular cystic mass lacking an expansile nodule, and with regular thin cyst wall and septa. On pathological study MCRCC presented as complex, multilocular cystic carcinoma with septa covered by low nuclear grade clear renal tumor cells without a grossly expansile nodule. They were staged pT1 with a free clinical course. In contrast, CRCC was identified on imaging with an expansile nodule (5 mm or greater), thick, irregular cyst wall and septa. On pathological study CRCC was characterized by a grossly expansile nodule in the septa and/or cyst wall. Nuclear grade and TNM stage were higher in CRCC. CONCLUSIONS: Preoperative recognition of MCRCC is possible using strict computerized tomography and/or magnetic resonance imaging criteria. The current study confirms the low malignant potential of MCRCC. Nephron sparing surgery should be proposed when MCRCC is suspected.