PARANEOPLASTIC SIGNS AND SYMPTOMS OF RENAL CELL CARCINOMA: IMPLICATIONS FOR PROGNOSIS HYUNG L. KIM, ARIE S. BELLDEGRUN,* DANIELO G. FREITAS, MATTHEW H. T. BUI, KEN-RYU HAN, FREDERICK J. DOREY AND ROBERT A. FIGLIN From the Departments of Urology (HLK, ASB, DGF, MHTB, KH, RAF), Biostatistics and Medicine (FJD), University of California School of Medicine, Los Angeles, California ABSTRACT Purpose: Renal cell carcinoma (RCC) can present with a wide range of signs and symptoms. To our knowledge we report the first study to describe the frequency of paraneoplastic findings in a modern RCC series and assess the prognostic significance of each finding. Materials and Methods: Using the kidney cancer database at our institution 1,046 patients undergoing nephrectomy for RCC between 1989 and 2001 were assessed. The prognostic signif- icance of symptoms present at diagnosis and findings on preoperative laboratory evaluation were examined in a univariate analysis as well as on multivariate analysis controlling for TNM stage, Fuhrman grade and Eastern Cooperative Oncology Group performance status (ECOG-PS). Results: Mean followup to date of death or last contact for all patients was 40.3 months. Median time to death was 19.3 months. Most paraneoplastic signs and symptoms correlated with poor survival, although on multivariate analysis hypoalbuminemia, weight loss, anorexia and malaise predicted shorter survival. The frequency of each of these findings was 19.9%, 22.9%, 10.6% and 19.1%, respectively. Cachexia, defined as the presence of at least 1 of these findings, was noted in 35.3% of patients. Cachexia did not predict a higher recurrence rate in patients with localized disease and only malaise correlated with a decreased likelihood of responding to immunotherapy. Conclusions: Cachexia, defined as hypoalbuminemia, weight loss, anorexia or malaise, predicts worse survival after controlling for well established indicators of prognosis (TNM stage, Fuhr- man grade and ECOG-PS). Consideration should be given to expanding the ECOG-PS to include measures for cachexia when applied to patients with RCC. KEY WORDS: kidney; carcinoma, renal cell; signs and symptoms; cachexia; prognosis Renal cell carcinoma (RCC) is the third most common genitourinary malignancy. 1 It is estimated that more than 30,000 new cases were diagnosed in 2002. Approximately 20% of patients diagnosed with RCC present with paraneo- plastic symptoms. 2 Another 10% to 40% of patients have paraneoplastic symptoms during the disease course. The paraneoplastic syndrome represents a constellation of signs and symptoms that result from the release of various tumor associated proteins rather than as a consequence of local invasion. Proteins responsible for the paraneoplastic effects may be elaborated directly by the tumor cells or by the immune system in response to the tumor. With the widespread use of radiological imaging RCC is being detected at earlier stages. In modern series approxi- mately 15% to 48% of RCC cases are diagnosed incidentally during evaluation for an unrelated disorder. 3, 4 However, to our knowledge the frequency of paraneoplastic signs and symptoms in a modern series has never been reported. Further- more, paraneoplastic findings at presentation have been as- sumed to indicate a poor prognosis, although to our knowledge the implications for prognosis have never been clearly defined. Many previous studies have examined presenting symp- toms in the context of incidentally diagnosed RCC. 3, 4 The hypothesis for these studies was that incidentally discovered tumors are more likely to be diagnosed at a lower stage and, therefore, they carry a better prognosis. Patients presenting with symptoms were grouped together to serve as the control group and no attempt was made to discriminate among symptoms. In this study we examined the assumption that all symp- tomatic tumors are similar. The frequency of various para- neoplastic signs and symptoms in a modern RCC series is reported and their prognostic significance is assessed. This information may allow for a better determination of progno- sis and better patient selection for standard as well as exper- imental treatments. PATIENTS AND METHODS Patients and definitions. Using the kidney cancer data- base at our institution 1,046 patients were identified who underwent partial or a radical nephrectomy for RCC be- tween 1989 and 2001. Presenting signs and symptoms were determined at the time of preoperative history and physical examination using a standard patient question- naire. Hypertension was defined as new hypertension or worsening of existing hypertension, as determined by the primary physician. Weight loss was defined as an unin- tended decrease of at least 5 pounds within 3 months. Hematuria included gross and microscopic hematuria. Flank or abdominal masses were noted by the patient or examining physician. Fever, chills, night sweats, anorexia and malaise were reported by the patient. Anorexia was defined as a loss of appetite and malaise was defined a prolonged decrease in energy level. Hematuria, flank pain and flank mass are part of the classic triad of presenting symptoms for RCC and, therefore, they were included in the study, although it is unlikely that they represent para- neoplastic effects. Accepted for publication June 13, 2003. * Corresponding author: Department of Urology, CHS 66-188, University of California School of Medicine, 10833 Le Conte Ave., Los Angeles, California 90095 (telephone: 310-206-1434; FAX: 310- 206-5343; e-mail: abelldegrun@mednet.ucla.edu). 0022-5347/03/1705-1742/0 Vol. 170, 1742–1746, November 2003 THE JOURNAL OF UROLOGY ® Printed in U.S.A. Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1097/01.ju.0000092764.81308.6a 1742