YOUNG AGE IS AN INDEPENDENT PROGNOSTIC FACTOR FOR SURVIVAL OF SPORADIC RENAL CELL CARCINOMA

0022-5347/04/1716-2160/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 171, 2160 –2165, June 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000125487.96469.2e

YOUNG AGE IS AN INDEPENDENT PROGNOSTIC FACTOR FOR SURVIVAL OF SPORADIC RENAL CELL CARCINOMA ´ NCHEZ-ORTIZ, CHARLES J. ROSSER, LYDIA T. MADSEN, DAVID A. SWANSON* RICARDO F. SA AND CHRISTOPHER G. WOOD† From the Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

ABSTRACT

Purpose: Compared to older adults with renal cell carcinoma (RCC) our subjective impression has been that younger adults present with more unfavorable histological features and yet respond more favorably to aggressive therapies. We reviewed our experience to validate these observations. Materials and Methods: We reviewed the medical records of 106 consecutive patients 40 years or younger and 145 consecutive 58 to 61-year-old patients referred for the surgical management of sporadic RCC between 1992 and 2002. Using univariate and multivariate analyses the pathological characteristics and outcome of the 2 groups were compared. Results: Mean age of the young adults was 34.7 years (range 14 to 40). Of younger adults 24% had tumors with unfavorable features, such as sarcomatoid differentiation, unclassified histology, medullary carcinoma and collecting duct carcinoma, compared with 12% of older adults (p ⬍0.02). However, older adults were more likely to have tumors of advanced local pathological stage (pT3a or greater) (46% vs 31%, p ⬍0.04). Whereas young adults had a higher incidence rate of lymph node metastases at presentation (25% vs 15%, p ⬍0.02), the rate of distant metastatic disease at presentation in young (34%) and older (28%) patients did not differ significantly (p ⫽ 0.33). Young age was independently associated with a higher 5-year actuarial disease specific survival rate on multivariate analysis at a median followup of 37 months (66% vs 52%, adjusted HR 2.64, 95% CI 1.45 to 4.79, p ⬍0.002). On multivariate analysis of patients without distant metastases at presentation young adults also had improved recurrence-free survival (median time to recurrence 32.4 vs 23.5 months, HR 2.23, 95% CI 1.04 to 4.78, p ⬍0.04). Conclusions: Young adults with RCC were more likely to have unfavorable histological features and a higher incidence of lymph node metastases than an older cohort of adults. Despite these differences on multivariate analysis young patients had improved disease-specific and recurrence-free survival following treatment. Whether age specific differences in host-tumor interaction exist in patients with RCC deserves further study. KEY WORDS: kidney; carcinoma, renal cell; lymph nodes; age groups; survival

Data from large epidemiological studies show that approximately 3.4% of patients with renal cell carcinoma (RCC) present at age 40 years or younger1 but the percent of young patients with RCC treated at our institution has been greater. After reviewing the records of 890 patients admitted to our cancer center between 1957 and 1976 Noronha et al observed an increase with time in the percent of patients 40 to 49 years old, namely 8.4% from 1957 to 1961, 13.9% from 1962 to 1966, 20.9% from 1967 to 1971 and 16.5% from 1972 to 1976.2 Although an association between cigarette smoking and renal cancer has been shown,3 the impact of the various epidemiological factors associated with renal cell carcinogenesis is not well understood. Our subjective clinical impression has been that adults 40 years or younger with RCC have a higher incidence of tumors with adverse pathological features. However, their response to aggressive surgical approaches has seemed more favorable than that of older patients treated with similar therapeutic strategies. To validate scientifically our clinical observations

we compared the pathological characteristics and survival of young adults with RCC to those of an older cohort of patients referred to a tertiary care comprehensive cancer center. MATERIALS AND METHODS

We reviewed the medical records of 131 consecutive 13 to 40-year-old patients referred to our institution between 1992 and 2002 for the surgical management of parenchymal renal masses. Patients with a history of hereditary renal tumor syndromes were excluded. Of these 131 young adults 106 had a final diagnosis of RCC, representing 10.5% of all patients (106 of 1,007) with RCC who underwent surgical management at our institution during the same period. The pathological characteristics and clinical outcome of patients in this cohort were compared with those of a group of 145 consecutive patients 58 to 61 years old with RCC referred during the same period. Age ranges for young and old patients were defined a priori before data analysis. The definition of young patients was determined to be 40 years or younger based on published data from the colorectal cancer literature,4 –7 suggesting differences in tumor biology in young patients defined as such. We defined older patients as all consecutive patients between ages 58 and 61 years for several reasons. This represents the median age for RCC for patients in most contemporary RCC

Accepted for publication January 23, 2004. Study received institutional review board approval. * Financial interest and/or other relationship with AstraZeneca, Kidney Cancer Association, Steba-Biotech and Chiron. † Correspondence: Department of Urology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 446, Houston, Texas 77030 (telephone: 713-792-3250; FAX: 713-794-4824; e-mail: [email protected]). 2160

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RENAL CANCER IN YOUNG ADULTS

series.8 –12 We did not include middle-aged patients between ages of 40 and 57 years to avoid masking any potential differences in tumor biology between young and old patients. Lastly, we did not include patients older than 61 years to prevent competing comorbidities (eg death from cardiovascular disease) from affecting our assessment of the natural history of RCC in this older population. All patients had undergone a thorough history, physical examination, radiographic staging with computerized tomography or magnetic resonance imaging of the abdomen and pelvis, chest radiography and laboratory studies. Bone scans and brain imaging were performed if warranted by patient symptoms, physical examination findings or laboratory studies. Survival was assessed by retrospective chart review. The clinical characteristics recorded were patient sex, age, performance status, ethnicity, body mass index, incidental or symptomatic disease presentation, history of hypertension, history of smoking, family history of malignancy, and disease specific and recurrence-free survival. The pathological characteristics recorded were tumor size, location, histology, grade, local tumor pathological stage and nodal or distant metastases at presentation. The Student t or Mann-Whitney test was used to evaluate differences between the younger and older groups, and the Fisher exact test was used in the analysis of data involving cross tabulations as indicated with p ⬍0.05 considered significant. Univariate and multivariate Cox regression analyses were performed to evaluate the relationship between disease specific and recurrence-free survival, and patient age, performance status, TNM pathological stage, tumor histology and grade, and type of systemic therapy. Kaplan-Meier actuarial survival was calculated with SPSS software (SPSS, Inc., Chicago, Illinois). RESULTS

Table 1 lists the clinical characteristics of patients in the 2 age groups. The mean age of young adults was 34.7 years (range 14 to 40). Four patients were younger than 20 years (14, 17, 18 and 18 years old, respectively). Compared with older patients young adults were more likely to be female (42% vs 29%) and to have symptoms at presentation (81% vs 57%), and less likely to have a history of smoking (37% vs 55%) or hypertension (15% vs 47%) (p ⬍0.01). There were no differences in mean tumor size (7.9 cm), tumor location, performance status, ethnicity (77% white), family history of cancer, body mass index

or type of treatment between young adults and the older cohort (ethnicity and body mass index data not shown). Young adults had a significantly higher percent of tumors with unfavorable features, such as sarcomatoid differentiation, unclassified histology, medullary carcinoma or collecting duct carcinoma, than older adults (24% vs 12%, p ⫽ 0.02, table 2). After excluding the 6 patients with collecting duct carcinoma, medullary carcinoma or rhabdoid carcinoma from analysis younger patients persisted with a higher incidence of tumors with sarcomatoid differentiation compared with the older cohort (20% or 20 of 102 vs 10% or 14 of 143, p ⫽ 0.038). There was a trend for young patients to have a higher incidence of Fuhrman grade 4 histology compared with older patients (31% or 32 of 102 vs 22% or 31 of 143), but this difference did not achieve statistical significance (p ⫽ 0.13). Whereas young adults had a higher incidence of lymph node metastases at presentation (25% vs 15%, p ⬍0.02), older adults were more likely to have tumors of advanced local pathological stage (pT3a or greater) (46% vs 31%, p ⫽ 0.03, table 3). There was no difference in the rate of distant metastatic disease at presentation between young (34%) and older (28%) adults (p ⫽ 0.33). Of all young and old patients with nodal or distant metastases, 78% received additional therapy with immunotherapy, tumor vaccines or conventional chemotherapy. A similar proportion of patients in the 2 groups received interleukin-2 or interferon immunotherapy (table 4). Table 5 shows univariate Cox regression analysis to evaluate the relationship between clinical and pathological variables and disease specific survival. Although there was only a trend toward longer disease specific survival in young adults on univariate analysis (p ⫽ 0.10), young age emerged as an independent predictor of improved survival on multivariate analysis after adjusting for the TNM stage, tumor grade, performance status, adjuvant therapy and histology (adjusted HR 2.64, 95% CI 1.45 to 4.79, p ⫽ 0.001, tables 5 and 6). Kaplan-Meier survival analysis of all study patients (TanyNanyMany) revealed a 5-year actuarial disease specific survival rate of 66% (median 155 months, 95% CI 49.1 to 261.9) for young adults compared with 52% for older adults (median 60.5 months, 95% CI 40.9 to 80.0) at a median followup of 37.3 months (range 1 to 235) (p ⬍0.01, fig. 1). There was no relationship between survival and patient sex,

TABLE 1. Characteristics of younger and older patients with RCC Young Group No. pts Age: Mean Median 95% CI Range % Female (No.) % Presentation (No.): Incidental Flank pain Hematuria Palpable mass Symptomatic metastasis % Performance status: 0 1 % Family Ca history (No.): None RCC Nonrenal Ca % RCC treatment (No.): Systemic therapy alone Partial nephrectomy Open radical nephrectomy Hand assisted radical nephrectomy Laparoscopic radical nephrectomy

106

p Value

145

34.7 37 33.7–35.9 14–40 42 (44) 19 33 27 3 18

Older Group

(20) (35) (29) (3) (19)

59.4 59 59.2–59.6 58–61 29 (42) 43 23 17 1.5 15.5

(62) (34) (24) (2) (22)

0.0001

0.044 0.001

0.62 86 (91) 14 (15)

90 10

(131) (14)

39 (41) 2 (2) 59 (58)

51 4 45

(70) (6) (62)

5 (5) 17 (18) 74 (79) 3 (3)

0 14 81 3

(20) (118) (4)

2

(3)

0.16

0.10

1

(1)

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RENAL CANCER IN YOUNG ADULTS TABLE 2. RCC histological characteristics in young and older adults % Age 14–40 (No.)

No. pts Histology: Conventional Papillary Mixed papillary ⫹ clear cell Chromophobe RCC Unclassified RCC Collecting duct Ca Medullary Ca Fuhrman grade: 1 2 3 4 Not graded Sarcomatoid differentiation Rhabdoid features Unfavorable histology (sarcomatoid, rhabdoid, unclassified, medullary or collecting duct)

106

% Age 58–61 (No.)

p Value

145 0.18

75.5 (80) 7.5 (8) 3.8 (4) 4.7 (5) 4.7 (5) 2.9 (3) 0.9 (1)

84.8 (123) 9.7 (14) 2 (3) 1.4 (2) 1.4 (2) 0.7 (1) 0

4.7 (5) 32.1 (34) 26.4 (28) 32.1 (34) 4.7 (5) 17.9 (19) 0 23.6 (25)

1.4 30.3 42.1 24.1 2.1 9.7 0.7 11.7

0.21 (2) (44) (61) (35) (3) (14) (1) (17)

0.02 0.02

TABLE 3. RCC pathological characteristics in young and older adults Age 14–40

Age 58–61

p Value

No. pts 106 145 % Tumor location (No.): 0.59 Rt kidney 54.7 (58) 51 (74) Lt kidney 44.3 (47) 44.8 (65) Bilat 0.9 (1) 4.1 (6) Renal mass size (cm): 0.99 Mean 7.9 7.9 Median 6.7 7.0 95% CI 6.9–8.9 7.1–8.7 % pT stage (No.): pTX* 4.7 (5) 0 pT1 39.6 (42) 39.3 (57) pT2 25.5 (27) 14.5 (21) pT3a 15.1 (16) 22.1 (32) pT3b 11.3 (12) 20.7 (30) pT3c 0 1.4 (2) pT4 3.8 (4) 2.1 (3) % pT stage categorized (No./total No.): 0.03 pT2 or less 68.7 (68/99) 53.8 (78) pT3a or greater 31.3 (32/99) 46.2 (67) % N stage (No.): 0.012 NX 5.7 (6) 0.7 (1) N0 69.8 (74) 84.8 (123) N1 6.6 (7) 2.8 (4) N2 17.9 (19) 11.7 (17) % M stage (No.): 0.33 M0 66.0 (70) 72.4 (105) M1 34.0 (36) 27.6 (40) * Five young patients with metastatic sarcomatoid carcinoma did not undergo nephrectomy due to metastases progression in the liver (3), lung and spine with cord compression (1), and brain (1).

TABLE 4. Systemic therapies administered to patients with nodal or distant metastases % Age 14–40 (No.)

% Age 58–61 (No.)

p Value

No. pts 50 54 None 22 (11) 22 (12) 0.28 Interleukin-2 alone 2 (1, ⫹ vaccine) 11 (6, ⫹ vaccines in 5) Interferon alone 16 (8, ⫹ vaccine in 1, chemotherapy in 6*) 15 (8, ⫹ chemotherapy in 4) Interferon ⫹ interleukin-2 26 (13, ⫹ chemotherapy in 10, vaccines in 2) 24 (13, ⫹ chemotherapy in 8, vaccine in 1) Chemotherapy alone* 24 (12) 26 (14, ⫹ vaccines in 10) Tumor vaccine alone 10 (5) 2 (1)* * Protocol chemotherapy regimens were highly variable and included 5-fluorouracil, paclitaxel, gemcitabine, vinblastine, doxorubicin, ifosfamide, cisplatin, retinoic acid, thalidomide, Xeloda, CISCA, methotrexate, vinblastine, doxorubicin and cisplatin, and etoposide.

ethnicity, tumor location, history of smoking, history of hypertension, performance status, family history of malignancy or type of systemic therapy (in patients with metastatic disease). Performance status was not independently predictive of survival, likely because all patients had a performance status of 1 or less with 85% having a performance status of zero. In the younger age group there were no differences by gender in tumor size, stage, grade, histology, or the incidence of regional or distant metastases. Multivariate Cox regression analysis of recurrence-free

survival in patients without distant metastases at presentation (TanyNanyM0) revealed that older age was independently associated with a higher risk of recurrence after adjusting for histology, tumor grade, performance status and TNM stage (adjusted HR 2.23, 95% CI 1.04 to 4.78, p ⬍0.04). Furthermore, on Kaplan-Meier analysis young patients had a higher recurrence-free survival rate at 5 year than the older cohort (73.1% vs 59.8%, log rank p ⬍0.05, fig. 2) with a median time to recurrence of 32.4 and 23.5 months, respectively. The latest recurrence in the older cohort of patients occurred 9

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RENAL CANCER IN YOUNG ADULTS TABLE 5. Univariate Cox regression analysis of disease specific survival in patients with RCC Age: Young (14–40) Older (58–61) Histology: Chromophobe Conventional Papillary Mixed clear cell ⫹ papillary Collecting duct or medullary Unclassified Fuhrman grade: 1 2 3 4 Sarcomatoid differentiation: No Yes Systemic therapy: Interleukin-2 and/or interferon* No immunotherapy Performance status: 0 1 pT stage: pT1 pT2 pT3a pT3b, T3c pT4 Nodal status: N0 N1 N2 M status: M0 M1 * Many patients 2 therapies.

HR

95% CI

r Value

1.00 (reference) 1.47

0.92–2.31

0.103

1.00 (reference) 2.42 2.74 3.44 9.51 15.3

0.34–17.6 0.33–22.9 0.38–30.9 0.97–92.4 1.69–138.5

0.38 0.35 0.27 0.053 0.015

1.00 (reference) 0.69 1.16 3.92

0.18–2.59 0.32–4.26 1.09–14.1

0.58 0.82 0.036

1.00 (reference) 3.03

1.86–4.94

0.0001

1.00 0.88

0.48–1.56

0.66 0.89

1.00 0.92

0.61–1.10

1.00 (reference) 2.14 7.30 8.40 44.2

1.14–6.46 3.44–15.5 3.89–18.2 15.3–127.8

0.024 0.0001 0.0001 0.0001

1.00 (reference) 2.77 5.19

1.10–6.99 3.14–8.58

0.008 0.0001

1.00 (reference) 6.73

4.23–10.73

⬍0.0001

TABLE 6. Multivariate Cox regression analysis of disease specific survival in patients with RCC Age: Young (14–40) Older (58–61) Histology: Conventional, papillary, mixed or chromophobe Collecting duct or medullary Ca Unclassified Ca Fuhrman grade: 1–3 4 Sarcomatoid differentiation: No Yes pT stage: pT1 pT2 pT3a pT3b, T3c pT4 Nodal status: N0 N1 N2 M status: M0 M1

Adjusted HR

95% CI

p Value

1.00 (reference) 2.64

1.45 –4.79

0.001

1.00 (reference) 0.24 5.15

0.27 –2.17 1.62 –20.1

0.21 0.02

1.00 (reference) 1.30

0.72 –2.35

0.36

1.00 (reference) 2.03

1.08 –3.80

0.027

1.00 (reference) 3.25 5.53 5.35 30.8

1.21 –8.75 2.30 –13.3 2.08 –13.7 7.34–128.2

0.02 0.0001 0.0001 0.0001

1.00 (reference) 1.91 1.96

0.64 –5.69 1.01 –3.81

0.25 0.047

1.00 (reference) 3.70

2.12 –6.45

0.0001

years after diagnosis. Five young adults had recurrences after 12 years, including 2 at 17.6 and 18.6 years, respectively. Four of these recurrences were distant and 1 represented a new renal mass in the same kidney. None of these patients had nodal metastases at initial presentation. DISCUSSION

In our retrospective study of patients with RCC young adults presented with renal tumors that had more unfavor-

able histological features and had a higher incidence of lymph node metastases than older adults. Nevertheless, young age was independently associated with higher disease specific and recurrence-free survival rates on multivariate analysis. Whether these survival differences are a result of age related differences in tumor biology or in immunological host response is not well understood. Lieber et al presented the first comprehensive review of RCC in young adults more than 20 years ago.13 After review-

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RENAL CANCER IN YOUNG ADULTS

FIG. 1. Disease specific survival in 106 young (red) and 145 older (green) patients with renal cell carcinoma (multivariate analysis p ⫽ 0.001).

FIG. 2. Recurrence-free survival in 70 young (red) and 105 older (green) patients with renal cell carcinoma without distant metastases at presentation (TanyNanyM0) (multivariate analysis p ⫽ 0.04).

ing the pathological characteristics of 89 consecutive patients between ages 20 and 40 years who underwent nephrectomy at the Mayo Clinic they concluded that RCC followed a similar course in young adults and older patients with overall mean 3 and 5-year survival rates of 60% and 55%, respectively. However, their data on young adults were compared with historical controls from RCC series. Perhaps the higher 5-year Kaplan-Meier survival rate in our series (66%) can be explained by our use of disease specific rather than overall survival as an end point. The fact that the percent of young adults with regional or distant metastatic disease (46%) in this study from 1981 was similar to that in our contemporary series (44%) is likely related to our referral pattern as a tertiary care cancer center. Our population includes a high percent of patients with locally advanced and metastatic disease who are referred for novel therapies. Schiff et al identified 37 patients 40 years or younger of 523 with RCC in the Yale University medical center tumor registry.14 As in our experience, young adults displayed a higher incidence rate of regional spread (32%) than patients older

than 40 years (12%). No difference was seen in the incidence of distant metastatic disease (25% in young and older patients). We believe that the fact that younger patients had a higher incidence of nodal metastases despite having a lower local stage reflects potential differences in tumor biology between these 2 groups of patients. Perhaps this could be explained by the higher incidence of tumors of unfavorable histology in the younger group, even in patients with small tumors. Four of these patients had evidence of lymph node or distant metastasis despite having tumors smaller than 4.5 cm. Despite the presence of regionally advanced disease at presentation in young patients the 5-year survival rate in young patients with stages I–III disease was also almost twice that of older adults. To our knowledge whether younger patients have a more vigorous immunological tumor response remains to be studied. Patients with stage IV disease fared equally poorly regardless of age. Rainwater et al from the Mayo Clinic performed the first study comparing prognostic pathological variables in a group of 41 patients 40 years or younger with those of a cohort of 34 who were 80 years or older.15 Although no differences between groups were observed with regard to sex, tumor grade or DNA ploidy pattern, young patients had a higher incidence of papillary histology. There was no difference in survival rates at 5 and 10 years between young patients (73% and 67%) and older patients (74% and 60%, respectively). However, they acknowledged that survival comparisons were difficult because of the high rate of death due to nonrenal causes in the older cohort. Similar findings were reported by Boykin et al in a small descriptive series of 18 patients between ages 20 and 40 years.16 While there were no differences in tumor histology or the overall survival rate between young and older patients, younger patients with stage I or II disease had an excellent overall prognosis with an 85% survival rate at 10 years. Our observed association between young age and renal cell carcinomas of unfavorable histology has been described previously. In a review of 24 renal cell carcinomas in children and young adults ages 6 to 29 years (mean 21 years) between 1958 and 1998 Renshaw et al also identified a higher than expected percentage of female patients (58%) and an association between younger age and high-grade and advanced pathologic stage.17 As in the Mayo Clinic series15 but not our study, an increased incidence of papillary histology was observed. In a more contemporary series Abou El Fettouh et al reviewed their experience with 101 consecutive patients between ages of 20 and 40 years at the Cleveland Clinic.18 At a mean followup of 48 months the overall and cancer specific survival rates were 61% and 67%, respectively. These findings are consistent with our data showing a disease specific survival rate of 66% at 5 years. Although they concluded that young adults had survival rates comparable to those of older adults, their study did not include a contemporary control group of older patients for comparison. Our data evaluating the patterns of recurrence in this cohort of healthy young adults provide useful information on the natural history of surgically treated RCC. In particular, a subset analysis of young patients without regional or distant metastases at presentation (TanyN0M0) shows that local or distant recurrences may develop as late as 18 years after surgery. This value for late recurrence is consistent with prior case reports suggesting that patients with RCC may be at risk for recurrence up to 24 years after presentation.19 Our data underscore the need for lifelong followup of young patients with RCC regardless of pathological stage. CONCLUSIONS

To our knowledge we report the largest study to date comparing the pathological characteristics and survival rates of sporadic RCC in young adults with those in older patients.

RENAL CANCER IN YOUNG ADULTS

Young adults had tumors with more unfavorable histological features and they had a higher incidence of lymph node metastases than older adults. Nevertheless, young patients had higher disease specific and recurrence-free survival rates after adjusting for clinical and pathological variables on multivariate analysis. These data support the study of potential biological differences in host-tumor interactions between younger and older patients with RCC.

10.

11.

12.

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