A. Schlichter

Nephron sparing surgery for renal cell carcinoma 4 cm. or less in diameter: indicated or under treated?

PURPOSE Although radical nephrectomy is the standard treatment for localized unilateral renal cell carcinoma with a normal contralateral kidney, there is ongoing interest in the use of nephron sparing surgery or partial nephrectomy in such cases. The extent of radical surgery in such cases has also been reconsidered in view of the uncertainty regarding the malignant or benign nature. MATERIALS AND METHODS Of 14,793 autopsies in Jena from 1985 until 1995 there were 260 renal cell carcinomas. Of the 260 renal cell carcinomas the diameter was 40 mm. or less in 104. These 104 tumors were divided into group 1-20 mm. or less (33 cases), group 2-21 to 30 mm. (28) and group 3-31 to 40 mm. (43). RESULTS Grade 1 renal cell carcinomas decreased in frequency with increasing tumor diameter, while an opposite result was noted for grade 3. Lymph node and distant metastases were well correlated with tumor size. With an increase in tumor size the frequency of venous involvement increased as well. Significantly more multifocal malignant renal cell carcinomas were seen in tumors between 21 and 40 mm. compared to those 20 mm. or less in diameter. CONCLUSIONS The metastatic potential and biology of these small nodules are not yet known. To lower the risk of local recurrence the results of our study suggest that nephron sparing surgery might be advisable in patients with renal cell carcinoma 20 mm. or less in diameter.

Real Indications for Adrenalectomy in Renal Cell Carcinoma

Objectives: Adrenalectomy is a part of radical nephrectomy because of the surgical oncology principle of a ‘wide margin beyond the malignancy’ and due to concern over possible metastases to the ipsilateral adrenal gland, especially in upper pole tumors. But, neither the frequency, predisposing factors of the renal cell carcinoma nor mechanisms of involvement of the adrenal gland are well defined. We assessed the ipsilateral adrenal involvement in renal cell carcinoma to determine whether ipsilateral adrenalectomy during radical nephrectomy is essential. Material and Method: In a series of 15,347 autopsies in Jena from 1985 through 1996, 272 renal cell carcinoma with 24 adrenal metastases were found. In the same period 9 adrenal metastases were found in 639 radical nephrectomies. Contralateral and bilateral metastases were seen in 15 cases of the autopsy series and in 2 cases of the operative series. Results: The risk of adrenal metastases correlated with multifocal tumors, pleomorphic cell type, anaplastic growth pattern and tumors that were larger than 2.5 cm. Of the 24 renal cell carcinomas with adrenal metastases in the autopsy series, 23 had evidence of widespread disease and 22 had lymph node metastases. A preoperative abdominal computerized tomography was performed in all 9 patients of the operative series with renal cell carcinoma and adrenal involvement. The adrenal gland was considered abnormal in 8 of the 9 cases (88.9%). Only in 1 patient was the computerized tomography incorrectly interpreted as negative. Conclusion: We think adrenalectomy should only be performed if there is radiographic evidence of metastases in the adrenal gland or adrenal infiltration by a large upper-pole tumor is possible. Macroscopically normal adrenal glands should not be removed during tumor nephrectomy because the need and benefit of routine adrenalectomy are extremely limited.

Where Are the Limits of Elective Nephron– Sparing Surgery in Renal Cell Carcinoma?

Objectives: The indication for elective nephron–sparing surgery (NSS) in renal cell carcinoma (RCC) is still controversial. The presented study was performed to determine limitations for NSS regarding to multifocality and to characterize the biological importance of these small tumor lesions.Methods: In 372 patients who underwent radical nephrectomy for RCC consecutively, nephrectomy specimens were investigated by using 3–mm parenchyma sections regarding to local tumor spread and multifocality. To characterize multifocal tumors, we performed cytogenetic and molecular genetic investigations.Results: Serial sections of 372 nephrectomy specimens revealed a total of 92 multifocal tumors in 61 specimens (16.4%). The correlation between tumor size and multifocality is shown as follows: tumor diameter 1–20 mm: 12.5%; 21–30 mm: 23.4%; 31–40 mm: 10.2%; >40 mm: 16.7%. The mean diameter of the multifocal tumors was 8.8×9.1×6.1 mm and the mean distance to the primary tumor was 26.4 mm (5–84 mm). Using cytogenetic and moleculargenetic analysis, in nearly one third of all cases a concordance of chromosomal aberrations in primary and secondary tumors was found.Conclusions:Multifocality of renal cell carcinoma occurs independently from primary tumor size. The evidence of structural and/or numeric aberrations, found in additional tumor foci, obviously is an argument for their malignant potential. This findings have to be considered in preparation of nephron–sparing surgery for patients with renal cell carcinoma.

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 × 9.0 × 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.

Clonal Origin of Multifocal Renal Cell Carcinoma as Determined by Microsatellite Analysis

PURPOSE The reported incidence of satellite tumor lesions in renal cell carcinoma (7% to 25%) suggests that there is a risk of local recurrence after nephron sparing surgery. It remains largely unknown whether small satellite tumors show malignant features and whether they are metastases from the primary tumor. Therefore, we determined the clonality of multifocal tumors by molecular genetic analysis. MATERIALS AND METHODS A total of 19 multifocal clear cell renal cell carcinomas were investigated by microsatellite analysis using 6 markers for chromosome 3p, namely D3S1560, D3S1289, D3S1766, D3S1300, D3S1566 and D3S1663. Polymerase chain reaction was performed according to standard protocols, followed by gel electrophoresis and automated analysis using an automated DNA sequencer (Li-Cor, Lincoln, Nebraska). RESULTS All primary clear cell tumors were characterized by loss of heterozygosity on 3p. Multifocal tumors showed identical microsatellite alterations with at least 1 marker in 17 of the 19 cases. In 2 cases different microsatellite patterns were detected in tumors from the same kidney. CONCLUSIONS Identical loss of heterozygosity and shift patterns detected in different tumors in the same kidney strongly suggest that multifocal clear cell renal cell carcinomas have a common clonal origin in most cases. These findings indicate that satellite tumors are the result of intrarenal metastasis from the primary tumor. The clinical implications of these results must be correlated with the clinical disease course in patients with multifocal renal cell carcinoma.

How Accurate Is Diagnostic Imaging in Determination of Size and Multifocality of Renal Cell Carcinoma as a Prerequisite for Nephron-Sparing Surgery?

Background: The indication for elective nephron-sparing surgery (NSS) in renal cell carcinoma (RCC) is under discussion in the urological literature. The main problem of NSS is the multifocality of RCC. The presented study was performed to asses the accuracy of pre- and intraoperative ultrasound (US), and computerized tomography (CT) in determination of tumor size and detection of multifocal lesions. Materials and Methods: Tumor size was measured by preoperative US and CT and compared with the tumor diameters in gross sections of the neoplastic kidneys. Multifocality was determined by 3-mm step sectioning of the nephrectomy specimen, and the results were correlated with preoperative US and CT on the one hand, and the ex situ sonography of the nephrectomized kidney on the other hand. Results: US and CT show similar results in the determination of the tumor size. In only 22.9%, preoperative US and CT were able to detect multifocal tumors. Ex situ sonography had a sensitivity of 40.0% and a specificity of 87.2% in this regard. Conclusions: In preparation for nephron-sparing surgery of renal cell carcinoma, neither preoperative routine imaging, nor intraoperative ultrasound can safely predict multifocal lesions of renal cell carcinoma.

Computerized contrast angiosonography:a new diagnostic tool for the urologist?

Objectives To evaluate the diagnostic potential of echo‐enhanced ultrasonography (US) for depicting the vascularization pattern of renal cell carcinoma (RCC), and calculating the first‐pass effect using harmonic imaging, against that obtained by triphasic helical computed tomography (CT).

Serum Transforming Growth Factor-beta 1 in Patients With Renal Cell Carcinoma

PURPOSE A major problem of renal cell carcinoma is the prediction of metastases via tumor prognostic markers. Therefore, much effort has been committed to the development of new prognostic markers. MATERIALS AND METHODS The level of transforming growth factor-beta1 was measured by enzyme-linked immunosorbent assay in serum samples collected from patients with renal cell carcinoma before radical nephrectomy. RESULTS In serum samples from 21 patients with renal cell carcinoma and 21 healthy controls mean transforming growth factor-beta1 levels were 177 +/- 54.1 versus 65.6 +/- 15.8 ng./ml., respectively. This difference was statistically significant (Mann-Whitney U test p <0.001). CONCLUSIONS Increased levels of transforming growth factor-beta1 are common in serum of patients with renal cell carcinoma.

New Cut-Off Point between T1 and T2 Renal Cell Carcinoma – Necessary for a Better Discriminatory Power of the TNM Classification

Purpose: We evaluated the pathological features of tumor size, lymph node and distant metastases, cell type, growth pattern, infiltration pattern, histological grade, local invasion and venous involvement of organ-confined renal carcinomas. The aim of this study was the re-evaluation of the TNM classification and the tumor cut-off point between T1 and T2 for renal cell carcinomas from the 1987 to the 1997 versions. Materials and Methods: (1) Patients with renal cell carcinoma who had been operated between October 1992 and August 2001 were evaluated. 437 of 691 patients showed T1 and T2 tumors. These organ-confined tumors have been divided into five groups: group 1: tumor-size of 20 mm or less (n = 16), group 2: 21–30 mm (n = 79); group 3: 31–40 mm (n = 83; group 4: 41–70 mm (n = 184), and group 5: more than 70 mm in diameter (only T2, n = 75). Follow-up ranged from 0 to 100 months (average 28.63 months). (2) Of 15,347 autopsies performed in Jena between 1985 and 1996, 272 renal cell carcinomas were revealed. In 145 of these 272 cases renal cell carcinomas were limited to the kidney. These 145 tumors were divided accordingly into 5 groups: group 1: 20 mm or less (n = 33), group 2: 21– 30 mm (n = 31); group 3: 31–40 mm (n = 29); group 4: 41–70 mm (n = 42), and group 5: T2 (n = 10). Clinicopathological criteria examined were lymph node and distant metastases, cell type, growth pattern, infiltration pattern, histological grade, local invasion and venous involvement. To identify the optimal cut-off point between T1 and T2 disease the χ2 test was used. Results: (1) In the clinical series only 1.8% (n = 8) of all cases showed lymph node metastases. Distant metastases were shown in 57 cases (13.04%); within group 1: 0%, group 2: 7.59%, group 3: 1.20%, group 4: 15.76%, group 5: 28%. The tumor grading was statistically correlated with tumor size. (2) In the pathological series 94 of the evaluated 145 patients were downstaged from T21987 to T11997. Lymph node and distant metastases were well correlated with tumor size. Lymph node metastases were seen in 0, 12.9, 31, 29.3 and 40% (group 1 to group 5) and distant metastases in 12.1, 25.8, 41.4, 47.7 and 60%. There were no statistically significant differences between T21997 and T13–7 cm. The tumor grading was statistically correlated with tumor size (grade 1: in 66.7, 25.8, 17.2, 9.5 and 0%). Conclusion: Our data suggest that the current cut-off diameter between T1 and T2 renal cell carcinomas (7 cm) is too high. Lowering the cut-off level will result in better discriminatory power of the TNM classification. From our data, we conclude that the cut-off diameter should be lowered to 3.5 cm (p < 0.001).

Lymphocyte transformation test (LTT) – a model for testing the cytokine-induced immunomodulatory capacity of renal cell carcinoma

SummaryWe investigated the immunomodulatory capacity of cytokines produced by renal cell carcinoma in vitro by analyzing their effects on mitogen-induced T-lymphocyte blast cell transformation. All of the tested 70 cell cultures, derived from 70 tumor areas in 33 patients, had immunomodulatory capacity. In addition to suppression in the lymphocyte transformation test (max. 44/70; 63 %) there was also superinduction (max. 37/70; 53 %). We found no significant correlation with the stage and grade of primary tumors. However, the suppression of mitogen-induced T-lymphocyte blast cell transformation was significant in multifocal tumors (0.08 % TCM, P < 0.001) and non-significant in metastatic tumors. The production of the assayed cytokines IL-6, IL-10, IL-11, and TGF beta 1 was variable and there was no significant correlation to the immunomodulatory capacity of the tumors.ZusammenfassungZur Untersuchung von immunmodulatorischen Effekten der von Nierenzellkarzinomzellen in vitro abgegebenen Zytokine wurde im allogenen Lymphozytentransformationstest (LTT) der Einfluß von Nierenzellkarzinom-Kulturüberständen auf die mitogeninduzierte T-Lymphozytentransformation geprüft. Für alle untersuchten 70 Zellkulturen aus verschiedenen Tumorarealen von 33 Patienten konnte ein immunmodulatorischer Effekt nachgewiesen werden. Dabei kam neben der Hemmung im LTT (max. 44/70; 63 %, abhängig von der Konzentration) auch eine Aktivierung der T-Lymphozytentransformation vor (max. 37/70; 53 %). Der immunmodulatorische Effekt der Kulturüberstände der untersuchten Tumorareale zeigte keine signifikante Korrelation mit der lokalen Ausdehnung und dem Differenzierungsgrad des Primärtumors (T- bzw. G-Stadium). Bei multifokalem Tumorwachstum (12 Patienten) war die Hemmung im LTT jedoch statistisch hoch signifikant (0,08 % TCM, p < 0,001) verstärkt, bei metastasierenden Tumoren (5 Patienten) tendentiell. Für keines der von den Tumorzellen sehr variabel produzierten Zytokine IL-6; IL-10; IL-11 sowie TGF beta 1 ergab sich ein signifikanter Zusammenhang mit der immunmodulatorischen Potenz des Tumors.