0022-5347/95/1533-0917$03.00/0 TliE JOLJRNAI. OF UROLOGY Copyright 0 1995 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 153,917-918, March 1995 Printed in U S A .

Editorial

BIOLOGICAL AND THERAPEUTIC CHALLENGES OF RENAL CARCINOMA

Renal cell carcinoma continues to intrigue investigators, and the biological, molecular and therapeutic challenges of this lesion are amply illustrated by the 4 contributions presented in this special issue of the Journal.

Tumor size is an important but ambiguous parameter of neoplastic growth, since it encompasses a variety of cell populations and tissue compartments, including prolifer- ating cells, viable but nonproliferating cells, necrotic cells and areas of hemorrhage, necrosis and edema. Therefore, it is unclear how tumor dimensions of the magnitude re- ported by Guinan et al (page 901) in their thorough and careful study relate to tumor stage and to the metastatic process, since neovascularization and access to systemic dissemination are acquired well before the dimensions of the lesions reported are achieved. Similarly and in order to reach a diameter of only 2 to 3 cm., transformed cells must undergo more than 30 doublings (assuming no cell loss) or approximately 70% of the total growth of a tumor. Al- though the observations of Guinan et a1 suggest that in some cases aggregate assessment of tumor size may have prognostic value, little insight into basic aspects of renal cancer biology is provided by such descriptive measure- ments. Moreover, tumor size is an inconsistent prognostic variable when patients are stratified according to stage and only among patients with stage I1 lesions does size appear to be a reliable prognostic factor. Despite these concerns, this study is important and it amplifies other investigations, including those demonstrating that renal tumors less then 5.0 cm. in diameter and particularly those detected incidentally have a survival advantage.

In contrast, the contribution by Kletscher et a1 (page 904) calls attention to putative field changes in the renal tubular epithelium occurring in sporadic cases of renal adenocarcinoma and to temporal variability in the expres- sion of the malignant phenotype. While the investigators demonstrate a concordance between the histological pat- tern of the primary and secondary lesions and a lesser similarity between the grade of the primary and secondary lesions, i t is likely that the observations reported reflect multifocal disease arising in a committed epithelium. However, determination of the true incidence of multifo- cality requires further study, since information concerning the status of the contralateral kidney, that is metachro- nous contralateral renal carcinoma, is not provided. In patients undergoing nephrectomy for sporadic hyper- nephroma carcinoma subsequently develops in the con- tralateral kidney in less than 1% and, therefore, it would be of interest to learn whether patients with multifocal sporadic renal cancer have an increased incidence of syn- chronous or asynchronous contralateral renal cancer, thereby suggesting a diathesis of the tubular epithelium. Furthermore, the ability to predict multicentric carcinoma preoperatively with only imaging techniques is of concern, since imaging methods detected this condition in only 62% of patients. This incidence is similar to that reported by Walther e t a1 and reflects the limitations of imaging in consistently detecting small renal lesions.

Although uncommon, heritable or familial variants of renal adenocarcinoma provide opportunity for elucidating

fundamental mechanisms in the malignant transforma- tion of the renal tubular epithelium, which may also have implications for cancer control and progression. Indeed, and among urological malignancies, renal cell carcinoma may be unique, since it appears that specific phenotypes correlate with consistent chromosomal aberrations. Thus, while trisomy 17 and trisomy or tetrasomy 7 are found in the papillary variant of renal carcinoma, structural rear- rangements of the short arm of chromosome 3 are custom- arily seen in the more common histological patterns of renal carcinoma, thereby, providing correlation between karyotypic changes and morphological expression.

The article by Zbar e t a1 (page 907) extends their initial findings, documents a familial variant of papillary renal carcinoma in 10 different families and suggests that cyto- genetic studies of this lesion should be informative. In addition and when compared to other forms of renal ade- nocarcinoma, papillary carcinoma, at least in its sporadic form, has been reported to have unique pathological, ra- diological and clinical features, and information concern- ing these aspects of familial as contrasted to sporadic papillary renal carcinoma would be of interest. However, it would appear that patients with the familial form of pap- illary renal cancer have a poorer prognosis than patients with the sporadic variety, although this may relate to the multicentricity, bilaterality and apparent inexorable pro- gression of the former lesion. In addition to raising provoc- ative scientific issues pertinent to the malignant process and to newer therapies, for example gene therapy, these studies suggest clinical and ethical issues relating to the identification and surveillance of individuals a t risk, and to the counseling and optimal management of these indi- viduals.

In contrast to the therapy of sporadic renal carcinoma, the therapy of patients with hereditary forms of renal carcinoma offers unique and novel challenges. In this re- gard, surgical treatment with purely curative intent may not always be realistic as illustrated by the study of Walther et a1 (page 913). Thus, heritable and familial variants of renal carcinoma may, as in patients with von Hippel-Lindau disease, be accompanied by additional re- nal lesions as well as by other potentially lethal systemic manifestations. While renal cancer in these patients may initially manifest a low malignant potential, their ominous significance is reflected by an ability to progress, to me- tastasize and to recur throughout the life of the patient. Walther et a1 reported new solid renal lesions in 36% of patients and in 36% of kidneys during a 26-month followup period, and of the lesions resected fully 38% were not detected by preoperative studies.

The indications for parenchymal or nephron sparing sur- gery continue to undergo investigation but nephron spar- ing surgery appears to at least have a role in the definitive therapy of patients with a small localized lesion in a soli- tary kidney. However, in patients with von Hippel-Lindau disease in whom existing involvement of multiple organ systems may prove fatal, the use of nephron sparing sur- gery may be particularly relevant. In view of this and of the clinical problems associated with dialysis, and assum-

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918 RENAL CARCINOMA

ing that cancer control can be achieved, it is possible that nephron sparing surgery, despite the need for repeat sur- gical intervention as new lesions evolve, becomes a reason- able, albeit temporizing, therapeutic option. In these pa- tients nephron sparing surgery of lesions at a stage when they are a t low risk for dissemination seems legitimate particularly when quality of life issues are considered. In contrast, among patients with hereditary papillary renal carcinoma when involvement of other organ systems by competing lesions is often not the cause of death, the role of nephron sparing surgery must perhaps be more care- fully considered. While evolving surgical techniques ex- pand the therapeutic armamentarium, indications for

their use must be titrated to clearly defined goals, includ- ing cure, long-term palliation and quality of life.

In summary, these contributions document important aspects in the biology and therapy of renal adenocarci- noma, and emphasize challenging problems relevant to this lesion. However, and perhaps most significantly, they suggest appropriate areas for continuing fundamental in- vestigation.

Gerald Sufrin Department of Urology State University of New York Buffalo, New York