Outcome of Renal Tumors in Young Adults

S. Siemer,* M. Hack, J. Lehmann, F. Becker and M. Stöckle From the Department of Urology, Saarland University, Germany

Purpose: Sporadic RCC is rare in young adults. We retrospectively reviewed the outcomes of patients 20 to 40 years old at our institution. Materials and Methods: Between 1975 and 2004, 2,710 patients were treated surgically for renal masses at our institution. We found 120 patients (4.4%) 20 to 40 years old. We analyzed the clinical presentation, pathological characteristics and outcome of these patients, and compared it to patients older than 40 years. Results: The mean age of 120 young adults was 34.1 years (range 20.4 to 39.8). Symptomatic presentation was documented in 49.5% of patients. RCC was found in 87 (72.5%) young adults. Young patients generally had a higher rate of organ confined tumors than patients older than 40 years (73.6% vs 59.3%, p Ͻ0.05). Histopathological characteristics, tumor size, lymph node metastases and distant metastatic disease did not differ significantly in young and older patients. Women were significantly more likely to have benign lesions (41% vs 20%, p Ͻ0.05). Mean followup for 120 patients was 80.6 months and 15 of 87 patients with RCC (17.2%) died of tumor related causes (mean followup 27.5 months). The 10-year cancer specific survival rate was 78% in young adults and 68% in older patients (p ϭ 0.22). Multivariate Cox regression analysis revealed lymph node metastases and tumor differentiation grade as independent prognostic parameters in young patients. Conclusions: Young patients are more likely to have symptomatic tumors at presentation. Nevertheless, they have more favorable pathological features and a definite trend to superior disease specific survival following surgical treatment. Organ sparing surgery should be considered in young women since benign lesions are frequent found in this population. Key Words: carcinoma, renal cell; age factors, survival rate

CC is the most common renal parenchymal malig- MATERIALS AND METHODS nancy and accounts for 3% to 6% of all adult malig- We analyzed the database of 2,710 patients referred to our R nancies.1 Although the incidence of renal cell institution for the treatment of renal masses between 1975 carcinoma has increased during recent years, patients are and 2004. Among those were 120 patients between the ages generally older than 40 years at diagnosis and the disease of 20 to 40 years. Patients with familial RCC syndromes, occurs predominantly in the sixth decade of life.1 Only 3% to 2 including von Hippel-Lindau disease, were excluded. Data 5% of all RCC are found in patients younger than 40 years. extracted from patient records included symptoms at pre- In other tumor entities it has been noted that young sentation, as well as radiographic and histopathological adults often have a less favorable prognosis than elderly characteristics. The pathological tumor stage was adapted patients with the same diagnosis, eg Varma and Sample according to the 2002 TNM classification.5 Patients were found an inferior survival rate for colorectal carcinoma pa- evaluated preoperatively by physical examination, labora- tients younger than 40 years old.3 However, an analysis of tory studies, ultrasonography and radiographic staging in- the Surveillance, Epidemiology and End Results database cluding chest x-ray, computerized tomography or magnetic could not confirm this finding. Indeed, young adults were resonance imaging. found to have less favorable tumor stages, but survival com- Univariate and multivariate (Cox regression modeling) parison for individual tumor stages did not reveal inferior analyses were performed to evaluate factors such as patient survival rates for the younger population.3,4 age, TNM pathological stage, tumor size, tumor histology We reviewed our experience with renal tumors in young and differentiation grade in regard to disease specific sur- adults between the age 20 and 40 years. We report on vival. Kaplan-Meier survival point estimates compared by a clinical characteristics at presentation, surgical procedures, log rank test were used for univariate survival data analy- pathological characteristics and survival data of these pa- sis. Data were analyzed using SPSS® software version 11.5. tients in comparison to older patients. RESULTS Of 2,710 patients presenting with renal masses at our insti- Submitted for publication May 2, 2005. tution 120 patients (4.4%) were between 20 to 40 years old. * Correspondence: Department of Urology and Pediatric Urology, The mean age of young adults was 34.1 year (range 20.4 to Saarland University, Kirrbergerstra␤e, 66421 Homburg/Saar, Ger- many (telephone: ϩ49 6841 1624700; FAX: ϩ49 6841 1624795; 39.8). Tumors were discovered incidentally in 61 (50.5%) vs e-mail: [email protected]). symptomatic presentation in 59 (49.5%) patients, with the

0022-5347/06/1754-1240/0 1240 Vol. 175, 1240-1244, April 2006 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/S0022-5347(05)00696-8 OUTCOME OF RENAL TUMORS IN YOUNG ADULTS 1241

TABLE 1. Characteristics of 120 patients 20 to 40 years old with renal tumors Mean age (range) 34.1 (20.4–39.8) No. RCC (%) 87 (72.5) No. sex (%): Male 81 (67.5) Male with benign disease 16 (20) Female 39 (32.5) Female with benign disease 17 (44) No. tumor side (%): Lt 55 (45.8) Rt 56 (46.7) Synchronous 9 (7.5) No. symptoms (%): Hematuria 27 (22.5) Flank pain 22 (18.3) Others 10 (8.7) None 61 (50.5)

main symptom being hematuria in 27 of 59 (46%) followed by flank pain in 22 of 59 (37%) patients (table 1). There were about twice as many males than females in this cohort (66% vs 34%). Differences in regard to age (34.4 vs 33.6 years, p ϭ 0.42), tumor size (5.3 vs 6.6 cm, p ϭ 0.19) and symptoms (50.5% vs 29%, p ϭ 0.53) were not significant FIG. 1. Overall survival of 120 patients 20 to 40 years old with renal tumors. between women and men. However, women were signifi- cantly more likely to have benign lesions (41% vs 20%, p Ͻ0.05). Survival analysis was performed in 120 patients with Surgery was performed through a lumbar incision in 115 renal tumors (fig. 1). Throughout the followup of up to 290.4 patients (96.0%). Nephron sparing surgery was performed in months (mean 80.6) 21 patients died (mean followup 50.4 40 of 120 (33.3%) patients, whereas in benign lesions the months), 15 of them died related to their tumor disease with rate of organ preserving surgery was significantly higher (24 a mean followup 27.5 months. The overall and cancer spe- of 33 or 72%, p Ͻ0.05). There was no difference in the cific 5-year survival rate was 72% and 78%, respectively. The number of organ sparing procedures (nephrectomy vs 10-year cancer specific survival rate in younger patients (87) nephron sparing surgery) associated with patient age. with RCC was higher than in older patients (2,164, fig. 2). Table 2 lists the pathological characteristics of patients However, this difference did not reach statistical signifi- 20 to 40 years old and patients older than 40 years. Whereas cance (78% vs 68%, p ϭ 0.22). older adults were more likely to have locally advanced tu- Univariate analysis was performed to evaluate the influ- mors (pT3a or greater), there were no significant differences ence of clinical and pathological variables on disease specific in the incidence of lymph node metastases, distant meta- static disease, tumor differentiation and tumor size between both groups.

TABLE 2. Histological findings in patients 20 to 40 years and older than 40 years with RCC Older Than 20–40 Yrs 40 Yrs p Value

No. pts 87 2,164 No. TNM classification (%): pT1 44 (50.6) 988 (45.8) pT2 20 (23.0) 293 (13.5) pT3 20 (23.0) 781 (36.0) pT4 3 (3.4) 102 (4.7) Ͻ0.05* No. pNϩ (%) 11 (12.6) 188 (8.6) 0.45 No. pMϩ (%) 6 (6.9) 296 (13.7) 0.36 No. grade (%): GI 15 (17.3) 241 (13.1) GII 43 (49.4) 1,061 (57.5) GIII 29 (33.3) 541 (29.4) 0.87 No. conventional (%) 68 (77.9) 1,733 (80.1) No. chromophobe (%) 8 (9.2) 197 (9.1) No. papillary (%) 7 (8.0) 134 (6.2) No. sarcomatoid (%) 4 (4.6) 24 (1.1) No. others (%) - 76 (3.5) 0.78 Mean cm tumor size 5.75 (0.1–25) 6.16 (0.1–38) 0.31 (range) ϩ ϩ FIG. 2. Cancer specific survival in 87 patients 20 to 40 years old vs * pT1 2vspT3 4. 2,164 patients older than 40 years. 1242 OUTCOME OF RENAL TUMORS IN YOUNG ADULTS

TABLE 3. Multivariate Cox regression analysis of 87 patients 20 to 40 years old with RCC pT pN pM Grade Tumor Size

Coefficient 0.022 2.631 0.130 1.062 0.162 SE 0.024 0.713 0.821 0.543 0.101 p Value 0.361 0.000 0.873 0.004 0.109 R 0.000 0.370 0.000 0.151 0.081 Risk ratio 1.02 13.89 1.14 2.89 1.18 95% CI 0.97–1.07 3.43–56.2 0.22–5.69 1.01–8.23 0.96–1.43

survival in young patients. TNM stage, grading and tumor Several authors describe classic prognostic factors such size are significant prognostic factors (detailed data not as staging, grading, patient age, tumor size, symptoms and shown). Multivariate Cox regression analysis including anemia in patients with RCC.15,16 Multivariate Cox regres- significant factors from univariate analysis revealed that sion analysis performed in our patient population revealed only distant metastases and histological tumor grade were only tumor grading and lymph node metastases as signifi- independent factors in regard to cancer specific survival cant independent prognostic factors. Pathological stage, gen- (table 3). erally known as one of the most important prognostic factors in patients with RCC was not determined as an independent prognostic factor (p ϭ 0.36), which may be related to the DISCUSSION relatively low number of patients analyzed. To our knowledge this is the largest published series of Despite the fact that the rate of metastases, tumor size patients with renal tumors (2,710) comparing the symptoms and tumor grading was comparable in young and old adults at presentation, pathological characteristics and outcome in (table 2), we found a significantly higher incidence of favor- patients 20 to 40 years old and patients older than 40 years. able pathological stages (pT1aϩb, pT2) in the younger group We found in 4.4% patients 20 to 40 years old with renal (73.6% less than 40 years vs 59.3% more than 40 years, p tumors and 87 of 2,164 (4.0%) with renal cell carcinomas. We Ͻ0.05). Gillett et al also found in his study a significantly observed an increased rate of young patients when compar- higher incidence of pT1-2 tumors in patients 18 to 40 years ing two different time intervals (3.9% from 1975 to 1980 and old compared with those 60 to 70 years old (82.7% vs 69.9%, 4.8% from 2000 to 2003). Other authors have reported rates p ϭ 0.02).7 A high rate of pT1, pT2 tumors was also reported of young adults between 3.5% und 7.3%.6,7 by Eggener et al (89%) and Abbou el Fettouh et al (75%).11,17 Recent studies have revealed that the incidence of RCC This imbalance of more favorable tumor stages in younger over the last years has increased about 2% annually. The patients could explain their superior survival despite a com- age standardized incidence is currently at 5 to 6 per 100.000 parable number of patients with metastatic disease in both individuals.8 Tate et al reported that between 1978 and 1997 age groups. the overall age standardized incidence rate for RCC in En- In contrast to these results, Sanchez-Ortiz et al observed gland increased by 86%.8 Similarly, the incidence rate in the an association between young age and renal cell carcinomas United States increased about 126%.9 One explanation is of more unfavorable histological features and a higher inci- the increased detection rate of RCC because of the wide- dence of lymph node metastases when comparing the patho- spread use of modern imaging techniques such as ultra- logical characteristics and survival rates of sporadic RCC in sonography and computerized tomography. Furthermore, young adults with those in older patients.13 Results on the potential etiological causes including hypertension, smok- frequency of lymph node and distant metastases differ ing, diet, obesity may have a role.8–10 across various reports. We found distant metastases in 6.9% In our retrospective analysis, survival of young adults and lymph node metastases in 12.6% of the young patients, with renal tumors was superior to that in the older popula- with no significant difference compared to the group of older tion. Of 87 patients 15 (17.2%) with RCC died during a mean patients. Eggener et al report 4.4% distant and lymph node followup of 27.5 months. The 5 and 10-year cancer specific metastases.11 In the study from Abbou El Fettouh et al 16% survival rate was 78%, respectively. In a recent study by of patients had distant metastases and 3% of patients had Eggener et al cancer specific survival was 84.9% at 5 years in lymph node metastases at the time of diagnosis.17 In con- young adults.11 A group from the Mayo Clinic reported a trast Sanchez-Ortiz et al described a significant higher in- similar 5-year cancer specific survival rate of 75.3%. Pa- cidence rate of lymph node metastases at presentation in tients in the older age group between 60 and 70 years old younger vs older patients (25% vs 15%, p Ͼ0.02).13 However, had a lower 5-year cancer specific survival rate of 71.9%, they noticed a better outcome of young adults as previously which also was not significantly different (p ϭ 0.127).7 Ro- mentioned. driguez et al found a 69%, and Sanchez-Ortiz et al a 66% Superior survival rates in younger adults are interpreted 5-year cancer specific survival rate, respectively.12,13 Yusim by some authors as related to distinct histopathological sub- et al reported a distinctly better prognosis for a small group types and growth patterns. Gillett et al as well as Cao et al of 15 young adults experiencing a cancer specific survival noticed a significantly lower number of conventional clear rate of 93% at 5 years.14 When comparing these survival cell RCCs in younger patients.6,7 Furthermore, a high pro- rates to a group of older patients, all of the previously men- portion of cystic components in these tumors seems to influ- tioned studies, found a trend toward a more favorable out- ence their prognosis. But it is not clear whether the presence come in young patients but a significant difference was only of such cystic components is associated with a better out- shown by Yusim et al and Sanchez-Ortiz et al.13,14 come than that for solid tumors. In our retrospective inves- OUTCOME OF RENAL TUMORS IN YOUNG ADULTS 1243 tigation cystic growth patterns had not been documented for 5. Sobin, L. H. and Wittekind, Ch.: TNM classifications: Kidney. a subsequent statistical analysis. In: TNM Classifications of Malignant Tumours, 6th ed. New A high rate of symptomatic tumors seems contradictory York: Wiley, 2002 to the relatively better prognosis of young RCC patients as 6. Cao, Y., Paner, G. P., Perry, K. T., Flanigan, R. C., Campbell, several authors reported a less favorable outcome for symp- S. C. and Picken, M. M.: Renal neoplasms in younger adults: analysis of 112 tumors from a single institution according to tomatic RCC at presentation.10,18,19 Regarding the mode of the new 2004 World Health Organization classification and presentation, we found that young adults were more likely 2002 American Joint Committee on Cancer Staging System. to present with symptoms than older adults (49.5% vs 33%, Arch Pathol Lab Med, 129: 487, 2005 p Ͻ0.05). Despite modern imaging techniques the rate of 7. Gillett, M. D., Cheville, J. C., Karnes, R. J., Lohse, C. M., Kwon, symptomatic tumors at presentation in young adults did not E. D., Leibovich, B. C. et al: Comparison of presentation and decrease during recent years, whereas the incidence of inci- outcome for patients 18 to 40 and 60 to 70 years old with solid dental tumors was growing in patients older than 40 renal masses. J Urol, 173: 1893, 2005 years.10,18 One potential reason is that a younger and gen- 8. Tate, R., Iddenden, R., Harnden, P., Morris, E., Craigs, C., erally healthier population rarely presents for tumor screen- Bennett, C. et al: Increased incidence of renal parenchymal ing. In accordance with our observation, Eggener et al found carcinoma in the Northern and Yorkshire region of England, a rate of 55.9% with symptomatic presentation in young 1978-1997. Eur J Cancer, 39: 961, 2003 9. Pantuck, A. J., Zisman, A. and Belldegrun, A. S.: The changing adults with renal tumors.11 The high rate of symptomatic natural history of renal cell carcinoma. J Urol, 166: 1611, RCC was found equally in young males (50.5%) as well as 2001 females (49%), with a comparable distribution of tumor size 10. Siemer, S., Uder, M., Humke, U., Lindenmeier, T., Moll, V., and age in both groups. Rudenauer, E. et al: Value of ultrasound in early diagnosis of Histopathological review found a significantly higher pro- renal cell carcinoma. Urologe A, 39: 149, 2000 portion of benign lesions in young females. The reason for 11. Eggener, S. E., Rubenstein, J. R., Smith, N. D., Nadler, R. B., this finding remains unclear. Eggener et al also report a Kontak, J., Flanigan, R. C. et al: Renal tumors in young significantly higher rate of benign tumors in women (36.0% adults. J Urol, 171: 106, 2004 vs 9.5%, p Ͻ0.01).11 A distinctly different proportion of his- 12. Rogriguez, A., Tazi, H., Patard, J. J. and Lobel, B.: Renal cell tological findings was also noted between younger vs older carcinoma in adults less than 40 years of age: a particular cancer? Incidence, outcome and review of the literature. Ann patients by Cao et al, reporting a higher incidence of benign 6 Urol (Paris), 37: 155, 2003 tumors in women. Cytogenetical and immunohistochemical 13. Sanchez-Ortiz, R. F., Rosser, C. J., Madsen, L. T., Swanson, studies may be warranted in the future to reveal factors D. A. and Wood, C. G.: Young age is an independent prognos- accounting for this finding. From a clinical perspective, an tic factor for survival of sporadic renal cell carcinoma. J Urol, organ sparing approach should be strongly considered when 171: 2160, 2004 treatment for renal tumors in young females is performed. 14. Yusim, I., Mermershtain, W., Neulander, E., Eidelberg, I., Gusakova, I. and Kaneti, J.: Influence of age on the prognosis CONCLUSIONS of patients with renal cell carcinoma (RCC). Onkologie, 25: 548, 2002 Similar to the experience in the older age group, renal 15. Ficarra, V., Prayer-Galetti, T., Novella, G., Bratti, E., Maffei, masses presenting in young adults are predominantly renal N., Dal Bianco, M. et al: Incidental detection beyond patho- cell carcinomas. We report our series of RCC in young adults logical factors as prognostic predictor of renal cell carcinoma. in comparison to older patients including a long-term fol- Eur Urol, 43: 663, 2003 16. Siemer, S., Lehmann, J., Loch, A., Becker, F., Stein, U., Schnei- lowup of more than 15 years. The predominant prognostic der, G. et al: Current TNM classification of renal cell carci- factors for survival in younger patients are tumor grade and noma evaluated: revising stage T3a. J Urol, 173: 33, 2005 lymph node status. Although more likely to be symptomatic 17. Abbou El Fettouh, H. I., Cherullo, E. E., El Jack, M., Al Masla- at the time of presentation, RCC in young adults is usually mani, Y. and Novick, A. C.: Sporadic renal cell carcinoma in organ confined and the prognosis is more favorable than in young adults: presentation, treatment, and outcome. Urol- older adults. Organ sparing surgery should be considered in ogy, 60: 806, 2002 young women, since benign lesions are a frequent finding in 18. Sweeney, J. P., Thornhill, J. A., Graiger, R., McDermott, T. E. this particular population. and Butler, M. R.: Incidentally detected renal cell carcinoma: pathological features, survival trends and implications for treatment. Br J Urol, 78: 351, 1996 19. Tsui, K.-H., Shvarts, O., Smith, R. B., Figlin, R., deKernion, Abbreviations and Acronyms J. B. and Belldegrun, A.: Renal cell carcinoma: prognostic RCC ϭ renal cell carcinoma significance of incidentally detected tumors. J Urol, 163: 426, 2000

REFERENCES EDITORIAL COMMENT

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