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Temporal Change in Risk of Metachronous Contralateral Renal Cell Carcinoma: Influence of Tumor Characteristics and Demographic Factors

From the Departments of Urology and Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Farhang Rabbani, MD, Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: rabbanif{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the relative risk (RR) of developing a metachronous contralateral renal tumor after an initial diagnosis of renal cell carcinoma (RCC), with stratification by renal tumor characteristics, demographic factors, and follow-up duration, in order to develop an improved risk-based surveillance strategy.

PATIENTS AND METHODS: The 1973 to 1997 Surveillance, Epidemiology, and End Results database was used to determine the observed and expected number of metachronous contralateral renal tumors developing after an initial diagnosis of RCC.

RESULTS: A total of 43,483 patients had a first diagnosis of RCC. Contralateral RCC developed subsequently in 155 (0.4%) of 40,049 patients with follow-up who had no synchronous diagnosis of RCC, with 10.81 expected cases (RR, 14.3; 95% CI, 12.2 to 16.8). The respective RRs (and 95% CIs) for contralateral RCC for white men and women were 16.0 (11.1 to 22.3) and 13.7 (7.7 to 22.6) at less than 2 years, 8.8 (5.0 to 14.3) and 10.5 (5.0 to 19.3) at 2 to 5 years, 13.5 (8.1 to 21.0) and 5.1 (1.4 to 13.2) at 5 to 10 years, and 13.0 (6.2 to 23.9) and 13.7 (5.0 to 29.9) at 10 years, respectively. The RRs were significantly higher in black compared with white men for the first 5 years, with the RRs (and 95% CIs) in the former group of 95.3 (58.2 to 146.7) at less than 2 years and 41.9 (16.8 to 86.3) at 2 to 5 years.

CONCLUSION: The incidence of metachronous contralateral RCC is stable on long-term follow-up, suggesting that surveillance of the contralateral kidney should remain rigorous on extended follow-up. Black men are at a significantly higher risk of developing contralateral RCC in the first 5 years of follow-up.

	INTRODUCTION

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OVER THE PAST decade, a shift has occurred toward advocating partial nephrectomy over radical nephrectomy to manage a solitary renal tumor of low stage in patients with a normal contralateral kidney.^1-5 An argument used to support this approach has been that the risk of developing a metachronous contralateral renal tumor is not negligible, while the risk of ipsilateral recurrence is low.^1-4 However, little data are available in the literature on the risk factors influencing the development of a contralateral renal tumor, which may aid in selecting patients at higher risk for whom a partial nephrectomy may be a more suitable option. Furthermore, we have no information on the temporal risk of when metachronous contralateral tumors will occur; such information may be useful in devising an appropriate follow-up strategy for patients undergoing radical or partial nephrectomy.

The incidence of bilateral renal cell carcinoma (RCC) has generally been reported to be 2% to 6%,^4,6-9 with an incidence as high as 12% in an autopsy series.¹⁰ One study with long-term follow-up of 13 to 21 years (mean, 14.5 years) reported metachronous contralateral cancers in four (12.9%) of 31 patients with RCC and one additional patient with an adenoma.¹¹ A rising incidence of RCC has been reported in the Surveillance, Epidemiology, and End Results (SEER) database by Chow et al,¹² likely due to the widespread use of computed tomography, ultrasonography, and magnetic resonance imaging for imaging. The resultant stage migration has led to an increased incidence of "incidentalomas," with longer survival from the index cancer, which makes the issue of metachronous contralateral tumors even more important.

Using the 1973 to 1997 SEER database,¹³ we sought to determine the temporal risk of developing a metachronous contralateral RCC in patients with an initial diagnosis of RCC, with stratification by tumor stage and demographic factors. The advantage of population-based over hospital-based studies for this purpose is that the former have a large group of patients with long follow-up, allowing for more stable estimates of relative risk (RR) as well as evaluation of the temporal changes in RR.

	PATIENTS AND METHODS

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Patients
Between January 1973 and December 1997, 43,483 individuals had an initial diagnosis of RCC in the SEER database.¹³ Patients with renal parenchymal neoplasms (International Classification of Diseases, ninth revision, code 189.0) were considered to have RCC if the histology was not transitional cell carcinoma (International Classification of Diseases –Oncology [ICD-O] morphology codes 8120 to 8130) or a mesenchymal or Wilms’ tumor (ICD-O morphology code 8590). A total of 357 patients had a synchronous RCC, and 3,111 patients had no follow-up after the diagnosis of RCC; these patients were excluded from the analysis. Follow-up ranging from 0.08 to 24.9 years (median, 2.25 years) was available in the 40,049 patients who form the subject of analysis.

Patient age ranged from 1 to 115 years (median, 65 years). There were 25,201 male patients (63%) and 14,848 female patients (37%). Patient race was white in 34,570 patients (86.3%), black in 3,507 patients (8.8%), and other or unknown origin in 1,972 patients (4.9%). RCC stage was classified in the SEER database as localized in 18,952 patients (47.3%), regional (including extrarenal extension) in 8,325 patients (20.8%), metastatic in 10,084 patients (25.2%), and unknown in 2,688 patients (6.7%). Although suboptimal, this classification is used by the SEER database for the early years of the study.

Calculations of SEER Data
A patient with an initial diagnosis of RCC was considered at risk for developing a contralateral RCC until the date of last follow-up or death. The 1973 to 1997 SEER data were used to determine the age-, sex-, race-, and calendar year–specific incidence rates for each year for RCC.¹³ The age-, sex-, race-, and calendar year–specific numbers of person-years at risk¹⁴ were calculated for varying follow-up periods (< 2 years, 2 to 5 years, 5 to 10 years, and 10 years), using 5-year age groups from less than 5 years to 80 to 84 as well as more than 85 years. The expected number of contralateral RCCs was obtained by multiplying the incidence rates by the number of person-years at risk in each category, with these products summed over the different age groups and calendar years. The RR was calculated as the observed number of occurrences of contralateral RCC divided by the expected number.

Statistical Analyses
Statistical significance was assigned with the assumption that the observed number of contralateral tumors follows a Poisson distribution. This is a valid assumption because the study population was relatively large and the occurrence of a contralateral RCC was an infrequent event.¹⁵ The Poisson model assumes that the observed number of contralateral tumors, x, takes on the values x = 0, 1, 2, 3, . . . with probabilities

equation

where µ is the expected number of contralateral tumors.¹⁵ Exact Poisson limits were used to calculate 95% confidence intervals (CIs).¹⁶ Assuming a relative risk of 14.3, for a two-sided P < .05 with a power of 80%, the expected number of cases would need to be 0.20.¹⁷

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Metachronous contralateral RCC developed in 155 (0.4%) of 40,049 patients followed up who had an initial diagnosis of RCC with no synchronous contralateral RCC. With a total follow-up of 166,059 person-years, the expected number of metachronous contralateral RCCs would be 10.8, with an RR of 14.3 (95% CI, 12.2 to 16.8). There was a relatively even distribution of person-years of follow-up over time: 55,527 person-years (33%) for less than 2 years, 47,459 person-years (29%) for 2 to 5 years, 39,351 person-years (24%) for 5 to 10 years, and 23,723 person-years (14%) for 10 years. Table 1 shows the observed and expected numbers of metachronous contralateral tumors and the corresponding RRs (with 95% CIs) stratified by race, sex, and duration of follow-up.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Controversy exists over the surgical management of low-stage renal tumors in patients with a normal contralateral kidney. Proponents of partial nephrectomy have argued that the incidence of metachronous contralateral tumor (2% to 6%)^4,6-9 is similar to that of ipsilateral tumor recurrence (< 5%).^1,2,4 As most of these data comes from hospital-based series from tertiary care centers, there is a potential for overestimation of the true incidence due to referral bias or underestimation due to short follow-up in most reported series. To date, no study has quantified the risk of metachronous contralateral renal tumor development in patients with RCC as a function of time as well as demographic factors such as sex and race. Identification of patients at increased risk of developing a metachronous contralateral tumor may allow for closer surveillance with contralateral renal imaging in this population.

Bilateral RCC generally has a reported incidence of 2% to 6%^4,6-9 with autopsy series¹⁰ and studies with long-term follow-up¹¹ showing a higher incidence of 12% to 13%. The higher incidence of bilateral RCC in the reported hospital-based studies compared with our study may be due to the referral bias that may exist in hospital-based studies. Accurate estimates of the long-term risk of contralateral renal tumor development are difficult to obtain because studies with long-term follow-up are small and represent a highly selected population.¹¹ In the absence of these data, some authors have recommended obtaining only a history and physical examination with no imaging after 5 years of follow-up.¹⁸

Our study, to our knowledge, represents the first to quantify as a standard incidence ratio the temporal risk of metachronous contralateral tumor after an initial diagnosis of RCC as a function of patient demographic factors and tumor characteristics. With the person-years methodology,¹⁴ the cumulative risk of contralateral tumor over time can be more easily appreciated. Although the median follow-up in our study was 2.25 years, 11,757 (29%) of 40,049 patients had follow-up for more than 5 years, and 14% of the person-years of risk were beyond 10 years after the diagnosis of RCC. This provides our study with significant power in detecting changes in RR on long-term follow-up beyond 10 years. With the exception of a higher RR of metachronous contralateral RCC in black males for less than 5 years of follow-up after the initial diagnosis of RCC, the RRs were relatively constant over time. This implies that the frequency of imaging of the contralateral kidney should not be altered beyond 10 years.

The increased incidence of renal cancer developing in the contralateral kidney in black men in the first 5 years of follow-up has not previously been reported in the literature. Further, the finding of a higher incidence of synchronous bilateral renal tumors in black men suggests that these tumors developing in the first 5 years may be due to detection bias secondary to increased imaging surveillance.

Chow et al¹² recently reported on the rising incidence of RCC, with a greater rise seen in blacks compared with whites. The racial difference in the rising incidence of RCC in the SEER database reported by Chow et al illustrates the importance of the use of age-, sex-, race-, and calendar year–specific incidence rates when calculating the expected number of metachronous contralateral RCCs, as we have done in our study. Chow et al reported incidence rates of 9.6 and 4.4 versus 11.1 and 4.9 per 100,000 person-years, respectively, for white men and women versus black men and women in the 1975 to 1995 SEER database. Our use of race-specific incidence rates when calculating the expected number of contralateral cancers takes this overall higher incidence of RCCs in blacks into account. Furthermore, the use of calendar year–specific incidence rates prevents an artificial bias from the temporal increase in incidence of RCC, as this would otherwise result in a higher risk in those with shorter follow-up who would be those diagnosed in the latter years.

Although an investigator may speculate that an environmental or genetic factor may contribute to this racial difference in the risk of bilateral RCC, no data suggest a role for any particular risk factor. Acquired cystic kidney disease is more common in blacks,¹⁹ and renal medullary carcinoma occurs almost exclusively in blacks with sickle cell trait or hemoglobin SC disease²⁰; however, these are uncommon causes of renal tumor. The incidence of cigarette smoking, a known risk factor for RCC,²¹ in men over 45 years of age is higher in black versus white men across all years of the study: in 1974, 57.8% versus 41.2% for ages 45 to 64 years and 29.7% versus 24.3% for ages greater than 65 years; in 1985, 46.1% versus 32.1% for ages 45 to 64 years and 27.7% versus 18.9% for ages greater than 65 years; and in 1997, 39.4% versus 26.5% for ages 45 to 64 years and 26.0% versus 11.5% for ages greater than 65 years.²² Blacks also have a higher incidence of obesity and hypertension,^23,24 both of which are risk factors associated with RCC.^25-28 However, little data are available on the racial differences in the use of diuretics and antihypertensive agents, which have also been implicated as risk factors for RCC.²⁸

Dechet et al⁶ reported that the tumor-node-metastasis stage is a significant predictor of contralateral tumor recurrence as well as tumor multifocality. However, our study did not identify tumor stage as having a significant influence on the risk of development of metachronous contralateral tumors. Stage as assigned in the SEER database is the clinical stage for patients treated conservatively and the pathologic stage for patients treated with surgery. Because some patients with localized clinical stage may actually have regional disease or extrarenal extension at surgery, use of the SEER stage may have masked a difference in RR for the different stages. Since details regarding cancer-specific surgery where pathologic stage may be determined are available only for 1983 to 1997, limiting analyses to patients undergoing partial or radical nephrectomy would preclude assessment of RR on long-term follow-up ( 10 years).

Over the past decade, an evolution in our understanding of renal cortical tumors has taken place.²⁹ Study of kindreds of patients with familial RCC, which accounts for 5% of patients with renal cortical tumors, has identified distinct genetic alterations in different histologic subtypes of RCC. Furthermore, recognition of these cytogenetic alterations has led to the description of a new classification³⁰ of renal tumors that more accurately reflects the underlying genetic alterations. Since this Heidelberg classification of RCC was described only recently,³⁰ we did not evaluate histologic type as a variable in our analysis because the histologic codes in the SEER database reflect the older classification. Grimaldi et al,⁷ using the newer Heidelberg classification, did not identify a difference in the distribution of histologies between those with bilateral and unilateral RCC in a series of 698 patients with RCC, of whom 33 had bilateral disease. This finding is consistent with the similar incidences of bilateral renal tumor ( 5%) reported for papillary RCC³¹ and oncocytoma.^32,33 Given the lack of detail with respect to family history of RCC in the SEER database, as well as the use of the older classification, other factors may be associated with an increased risk of metachronous contralateral RCC within the SEER population that we are not able to detect. Studies of hospital-based series where these details are available may allow identification of the histologic subtypes and, ultimately, the underlying genetic alterations associated with an increased risk of metachronous contralateral RCC.

In summary, our study illustrates the relatively constant incidence of metachronous contralateral tumor developing over time, except for black men in the first 5 years of follow-up, in whom the incidence is higher. As this observation of a higher RR in black men in the first 5 years has not, to our knowledge, been previously reported, it generates a hypothesis for further testing in an independent data set. This observation, if confirmed by independent data, implies that imaging of the contralateral kidney should continue beyond 10 years of follow-up with a greater frequency in black men in the first 5 years of follow-up. We did not identify sex or tumor stage as factors that can be used to modulate the frequency of contralateral renal imaging.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Lee CT, Katz J, Shi W, et al: Surgical management of renal tumors 4 cm or less in a contemporary cohort. J Urol 163: 730-736, 2000[CrossRef][Medline]

2. Hafez KS, Fergany AF, Novick AC: Nephron sparing surgery for localized renal cell carcinoma: Impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 162: 1930-1933, 1999[CrossRef][Medline]

3. Lau WK, Blute ML, Weaver AL, et al: Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 75: 1236-1242, 2000[Abstract]

4. Lerner SE, Hawkins CA, Blute ML, et al: Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol 155: 1868-1873, 1996[CrossRef][Medline]

5. Novick AC: Nephron-sparing surgery for renal cell carcinoma. Br J Urol 82: 321-324, 1998[Medline]

6. Dechet CB, Blute ML, Zincke H: Nephron-preserving surgery for unilateral renal cell carcinoma: Which pathologic variables contribute to contralateral renal tumor recurrence? J Urol 159: 169, 1998 (suppl, abstr)

7. Grimaldi G, Reuter V, Russo P: Bilateral non-familial renal cell carcinoma. Ann Surg Oncol 5: 548-552, 1998[CrossRef][Medline]

8. Kessler OJ, Livne PM, Servadio C: Bilateral asynchronous renal cell carcinoma: Treatment approach. Isr J Med Sci 29: 721-725, 1993[Medline]

9. Morgan WR, Zincke H: Progression and survival after renal-conserving surgery for renal cell carcinoma: Experience in 104 patients and extended follow-up. J Urol 144: 852-857, 1990[Medline]

10. Wunderlich H, Schlichter A, Zermann D, et al: Multifocality in renal cell carcinoma: A bilateral event? Urol Int 63: 160-163, 2000

11. Henriksson C, Geterud K, Aldenborg F, et al: Bilateral asynchronous renal cell carcinoma. Eur Urol 22: 209-212, 1992[Medline]

12. Chow W-H, Devesa SS, Warren JL, et al: Rising incidence of renal cell cancer in the United States. JAMA 281: 1628-1631, 1999[Abstract/Free Full Text]

13. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, Cancer Statistics Branch: SEER Cancer Incidence Public-Use Database 1973-1997. Bethesda, MD, Information Management Services, 2000

14. Schoenberg BS, Myers MH: Statistical methods for studying multiple primary malignant neoplasms. Cancer 40: 1892-1898, 1977[CrossRef][Medline]

15. Bailar JC, Ederer F: Significance factors for the ratio of a Poisson variable to its expectation. Biometrics 20: 639-643, 1964[CrossRef]

16. Breslow NE, Day NE: Statistical Methods in Cancer Research: Volume II. The Design and Analysis of Cohort Studies. Lyon, France, International Agency for Research on Cancer, 1987, pp 69-72

17. Breslow NE, Day NE: Statistical Methods in Cancer Research: Volume II. The Design and Analysis of Cohort Studies. Lyon, France, International Agency for Research on Cancer 1987, p 278

18. Montie JE: Follow-up after partial or total nephrectomy for renal cell carcinoma. Urol Clin North Am 21: 589-592, 1994[Medline]

19. Matson MA, Cohen EP: Acquired cystic kidney disease: Occurrence, prevalence, and renal cancers. Medicine 69: 217-226, 1990[Medline]

20. Davis CJ Jr, Mostofi FK, Sesterhenn IA: Renal medullary carcinoma: The seventh sickle cell nephropathy. Am J Surg Pathol 19: 1-11, 1995[Medline]

21. McLaughlin JK, Hrubec Z, Heinemann EF, et al: Renal cancer and cigarette smoking in a 26-year followup of U.S. veterans. Public Health Rep 105: 535-537, 1990[Medline]

22. Eberhardt MS, Ingram DD, Makuc DM, et al: Urban and Rural Health Chartbook: Health, United States, 2001. Hyattsville, MD, National Center for Health Statistics, 2001

23. Flegel KM, Carroll MD, Kuczmarski RJ, et al: Overweight and obesity in the United States: Prevalence and Trends, 1960-1994. Int J Obesity 22: 39-47, 1998[CrossRef][Medline]

24. Eisner GM: Hypertension: Racial differences. Am J Kidney Dis 16: 35-40, 1990 (suppl)[Medline]

25. Yu MC, Mack TM, Hanisch R, et al: Cigarette smoking, obesity, diuretic use, and coffee consumption as risk factors for renal cell carcinoma. J Natl Cancer Inst 77: 351-356, 1986

26. Yuan J-M, Castwlao JE, Gago-Dominguez M, et al: Hypertension, obesity and their medications in relation to renal cell carcinoma. Br J Cancer 77: 1508-1513, 1998[Medline]

27. Benichou J, Chow J-H, McLaughlin JK, et al: Population attributable risk of renal cell cancer in Minnesota. Am J Epidemiol 148: 424-430, 1998[Abstract/Free Full Text]

28. McLaughlin JK, Blot WJ, Devesa SS, et al: Renal cancer, in Schottenfeld D, Fraumeni JF Jr (Eds): Cancer Epidemiology and Prevention ( ed 2 ). New York, NY, Oxford University Press, 1996, pp 1142-1155

29. Russo P: Evolving understanding and surgical management of renal cortical tumors. Mayo Clin Proc 75: 1233-1235, 2000 (editorial)[Medline]

30. Kovacs G, Akhtar M, Beckwith BJ, et al: The Heidelberg classification of renal cell tumors. J Pathol 183: 131-133, 1997[CrossRef][Medline]

31. Amin MB, Corless CL, Renshaw AA, et al: Papillary (chromophil) renal cell carcinoma: Histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 62 cases. Am J Surg Pathol 21: 621-635, 1997[CrossRef][Medline]

32. Amin MB, Crotty TB, Tickoo SK, et al: Renal oncocytoma: A reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 21: 1-12, 1997[CrossRef][Medline]

33. Dechet CB, Bostwick DG, Blute ML, et al: Renal oncocytoma: Multifocality, bilateralism, metachronous tumor development and coexistent renal cell carcinoma. J Urol 162: 40-42, 1999[CrossRef][Medline]

Submitted August 16, 2001; accepted December 19, 2001.

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