Patients’ characteristics
Overall, there were 10410 patients who met the screening criteria between 2010 and 2015 based SEER database, of which 7161 (68.8%) were male, and 3249 (31.2%) were female. The median age of all patients was 64 years old. As for TNM stage, 1831 (17.6%) patients in T4 stage and 2301(30.7%) in N1 stage. There were 5713 (54.9%) patients with lung metastasis, 3920 (37.7%) patients with bone metastasis, 2034 (19.5%) patients with liver metastasis, and 1079 (10.4%) patients with brain metastasis. Patients with only one site occupied 50.6% (5268/10410) of RCC stage IV. Detailed clinical features of mRCC patients were displayed in Table1.
Table 1 Clinical features and metastasis sites for RCC
|
Lung metastasis (%)
|
|
Bone metastasis (%)
|
|
Liver metastasis (%)
|
|
Brain metastasis (%)
|
|
|
Yes
|
No
|
P
|
Yes
|
No
|
P Value
|
Yes
|
No
|
P Value
|
Yes
|
No
|
P Value
|
Age at diagnosis
|
63.7 ± 11.7
|
65.0 ± 12.2
|
<0.001
|
64.3± 11.9
|
64.2 ± 12.0
|
0.938
|
64.0 ± 12.2
|
64.3 ± 11.9
|
0.621
|
61.8 ± 10.3
|
64.5 ± 12.1
|
<0.001
|
Race
|
|
|
<0.001
|
|
|
0.044
|
|
|
<0.001
|
|
|
<0.001
|
White
|
4690(54.8)
|
3861(45.2)
|
|
3257(38.1)
|
5294(61.9)
|
|
1598(18.7)
|
6953(81.3)
|
|
924(10.8)
|
7627(89.2)
|
|
Black
|
554(50.4)
|
546(49.6)
|
|
402(36.5)
|
698(63.5)
|
|
292(26.5)
|
808(73.5)
|
|
72(6.5)
|
1028(93.5)
|
|
Other
|
455(62.2)
|
276(37.8)
|
|
256(35.0)
|
475(65.0)
|
|
139(19.0)
|
592(81.0)
|
|
82(11.2)
|
649(88.8)
|
|
Unknown
|
14(50.0)
|
14(50.0)
|
|
5(17.9)
|
23(82.1)
|
|
5(17.9)
|
23(82.1)
|
|
1(3.6)
|
27(96.4)
|
|
Gender
|
|
|
0.002
|
|
|
0.102
|
|
|
<0.001
|
|
|
0.665
|
Male
|
4002(55.9)
|
3159(44.1)
|
|
2734(38.2)
|
4427(61.8)
|
|
1321(18.4)
|
5840(81.6)
|
|
736(10.3)
|
6425(89.7)
|
|
Female
|
1711(52.7)
|
1538(47.3)
|
|
1186(36.5)
|
2063(63.5)
|
|
713(21.9)
|
2536(78.1)
|
|
343(10.6)
|
2906(89.4)
|
|
Grade
|
|
|
0.100
|
|
|
<0.001
|
|
|
<0.001
|
|
|
<0.001
|
Well
|
91(51.7)
|
85(48.3)
|
|
63(35.8)
|
113(64.2)
|
|
25(14.2)
|
151(85.8)
|
|
16(9.1)
|
160(90.9)
|
|
Moderately
|
496(51.1)
|
474(48.9)
|
|
297(30.6)
|
673(69.4)
|
|
118(12.2)
|
852(87.8)
|
|
98(10.1)
|
872(89.9)
|
|
Poorly
|
1185(54.5)
|
989(45.5)
|
|
680(31.3)
|
1494(68.7)
|
|
341(15.7)
|
1833(84.3)
|
|
180(8.3)
|
1994(91.7)
|
|
Undifferentiated
|
902(55.7)
|
718(44.3)
|
|
415(25.6)
|
1205(74.4)
|
|
243(15.0)
|
1377(85.0)
|
|
129(8.0)
|
1491(92.0)
|
|
Unknown
|
3039(55.6)
|
2431(44.4)
|
|
2465(45.1)
|
3005(54.9)
|
|
1307(23.9)
|
4163(76.1)
|
|
656(12.0)
|
4814(88.0)
|
|
Histology
|
|
|
<0.001
|
|
|
0.042
|
|
|
0.001
|
|
|
<0.001
|
Clear cell RCC
|
2615 (57.0)
|
1970 (43.0)
|
|
1625 (35.4)
|
2960 (64.6)
|
|
671 (14.6)
|
3914 (85.4)
|
|
503 (11.0)
|
4082 (89.0)
|
|
Papillary RCC
|
216 (41.6)
|
303 (58.4)
|
|
157 (30.3)
|
362 (69.7)
|
|
86 (16.6)
|
433 (83.4)
|
|
30 (5.8)
|
489 (94.2)
|
|
Chromophobe RCC
|
29 (34.5)
|
55 (65.5)
|
|
29 (34.5)
|
55 (65.5)
|
|
16 (19.0)
|
68 (81.0)
|
|
6 (7.1)
|
78 (92.9)
|
|
Sarcomatoid RCC
|
311 (57.1)
|
234 (42.9)
|
|
210 (38.5)
|
335 (61.5)
|
|
117 (21.5)
|
428 (78.5)
|
|
46 (8.4)
|
499 (91.6)
|
|
Collecting duct RCC
|
42 (63.6)
|
24 (36.4)
|
|
28 (42.4)
|
38 (57.6)
|
|
13 (19.7)
|
53 (80.3)
|
|
2 (3.0)
|
64 (97.0)
|
|
T stage
|
|
|
<0.001
|
|
|
<0.001
|
|
|
<0.001
|
|
|
<0.001
|
T1
|
732(42.9)
|
974(57.1)
|
|
927(54.3)
|
779(45.7)
|
|
265(15.5)
|
1441(84.5)
|
|
165(9.7)
|
1541(90.3)
|
|
T2
|
994(64.1)
|
556(35.9)
|
|
619(39.9)
|
931(60.1)
|
|
279(18.0)
|
1271(82.0)
|
|
259(16.7)
|
1291(83.3)
|
|
T3
|
2143(64.4)
|
1186(35.6)
|
|
1059(31.8)
|
2270(68.2)
|
|
579(17.4)
|
2750(82.6)
|
|
311(9.3)
|
3018(90.7)
|
|
T4
|
815(44.5)
|
1016(55.5)
|
|
392(21.4)
|
1439(78.6)
|
|
439(24.0)
|
1392(76.0)
|
|
121(6.6)
|
1710(93.4)
|
|
Unknown
|
988(52.6)
|
890(47.4)
|
|
864(46.0)
|
1014(54.0)
|
|
452(24.1)
|
1426(75.9)
|
|
217(11.6)
|
1661(88.4)
|
|
N stage
|
|
|
<0.001
|
|
|
<0.001
|
|
|
<0.001
|
|
|
0.026
|
N0
|
3115(53.1)
|
2755(46.9)
|
|
2169(37.0)
|
3701(63.0)
|
|
931(15.9)
|
4939(84.1)
|
|
639(10.9)
|
5231(89.1)
|
|
N1
|
1869(58.4)
|
1332(41.6)
|
|
1179(36.8)
|
2022(63.2)
|
|
797(24.9)
|
2404(75.1)
|
|
293(9.2)
|
2908(90.8)
|
|
Unknown
|
729(54.4)
|
610(45.6)
|
|
572(42.7)
|
767(57.3)
|
|
306(22.9)
|
1033(77.1)
|
|
147(11.0)
|
1192(89.0)
|
|
Insurance
|
|
|
<0.001
|
|
|
0.384
|
|
|
0.633
|
|
|
0.002
|
Insured
|
5414(55.2)
|
4391(44.8)
|
|
3696(37.7)
|
6109(62.3)
|
|
1909(19.5)
|
7896(80.5)
|
|
1012(10.3)
|
8793(89.7)
|
|
Uninsured
|
237(57.5)
|
175(42.5)
|
|
160(38.8)
|
252(61.2)
|
|
88(21.4)
|
324(78.6)
|
|
58(14.1)
|
354(85.9)
|
|
Unknown
|
62(32.1)
|
131(67.9)
|
|
64(33.2)
|
129(66.8)
|
|
37(19.2)
|
156(80.8)
|
|
9(4.7)
|
184(95.3)
|
|
Married status
|
|
|
<0.001
|
|
|
0.079
|
|
|
0.025
|
|
|
0.013
|
Married
|
3382(56.3)
|
2628(43.7)
|
|
2238(37.2)
|
3772(62.8)
|
|
1125(18.7)
|
4885(81.3)
|
|
628(10.4)
|
5382(89.6)
|
|
Unmarried
|
2095(53.8)
|
1801(46.2)
|
|
1511(38.8)
|
2385(61.2)
|
|
814(20.9)
|
3082(79.1)
|
|
418(10.7)
|
3478(89.3)
|
|
Unknown
|
223(46.2)
|
260(53.8)
|
|
165(34.2)
|
318(65.8)
|
|
90(18.6)
|
393(81.4)
|
|
31(6.4)
|
452(93.6)
|
|
Abbreviations: RCC, renal cell carcinoma
Lung metastasis
Lung is the most common site of synchronous metastasis for mRCC patients among the cohort with metastatic disease. The mean age of cases without lung metastasis was 1.3 years elder than cases diagnosed with. White patients had higher proportion of lung metastasis than others in the ethnicity of patients. As compared to females, a larger percentage of males were lung metastasis. T3 patients had the highest rate of lung metastasis, and T1 had the lowest rate in the classification of T stage. For N stage classification, N1 had significantly higher rate of lung metastasis than N0, 58.4% vs. 53.1%, P < 0.001. Married and uninsured patients had a significantly higher than other types in metastatic rate specifically, both P < 0.001. Fuhrman grade did not show significant difference in lung metastasis.
Bone metastasis
As for bone metastasis, there was no difference between male and female patients. The same phenomenon occurred in diagnostic age, insurance status, and married status. White patients had higher percentages of bone metastasis than black patients and other races. T1 patients accounted for the largest proportion in T stage classification in bone metastasis. Unlike the results of lung metastasis, N0 had higher percentages of bone metastasis. For Fuhrman grade, undifferentiated (grade IV) presented the lowest rate.
Liver metastasis
There are many different results in liver metastasis compared to bone and lung metastasis. For ethnicity, black patients had a higher percentage than other races, which did not happen in above metastasis. Regardless of gender and married status, the opposite results were shown in liver metastasis, as females were much more than males and unmarried patients were more than married. Patients in T4 were the most common types in T stage classification in liver metastasis. In terms of N stage classification, patients in N1 had higher liver metastasis than other kinds. Insurance state and diagnostic age showed no statistically significant difference.
Brain metastasis
Some features for patients with brain metastasis resemble those with lung metastasis, involving age at diagnosis, ethnicity, and T stage classification. N0 patients presented significant difference with N1 in brain metastasis. Unexpectedly, patients with uninsured and unmarried had higher percentage than those insured and married, both P < 0.05. Undifferentiated differentiated tumors had lower brain metastatic rate than well, moderately, and poorly tumors. There was no significant difference between males and females.
Combination of metastases
There were many patients suffered more than one metastasis. Except for one-site metastasis, 11 combinations of metastases were found in Table 2. As shown in Figure 1, Venn diagram was used to illustrate the distribution of the mRCC patients. The patients of bone and lung metastasis were the highest frequency in the two-site metastasis, which achieving to 10.82% (1126/10410). Only 12 patients had bone and brain and liver metastasis, which was the least common in metastatic mRCC. There were still 91 patients had all four sites metastasis.
Table 2 Frequencies of combination metastasis and 3, 5-y OS
|
Number (%)
|
3-y OS
|
5-y OS
|
Median OS (mo)
|
One site
|
|
|
|
|
Only Lung
|
2796 (26.86)
|
9.05%
|
1.54%
|
11
|
Only Bone
|
1719 (16.51)
|
10.99%
|
2.27%
|
12
|
Only Liver
|
534 (5.13)
|
6.74%
|
0.75%
|
5
|
Only Brain
|
219 (2.10)
|
7.76%
|
1.37%
|
9
|
Two sites
|
|
|
|
|
Bone and brain
|
97 (0.93)
|
2.06%
|
0
|
5
|
Bone and liver
|
232 (2.22)
|
3.45%
|
0
|
4
|
Bone and lung
|
1126 (10.82)
|
4.62%
|
0.44%
|
6
|
Brain and liver
|
23 (0.22)
|
0
|
0
|
3
|
Brain and lung
|
337 (3.24)
|
3.56%
|
0.30%
|
6
|
Liver and lung
|
641 (6.16)
|
2.18%
|
0.16%
|
4
|
Three sites
|
|
|
|
|
Bone and brain and liver
|
12 (0.12)
|
0
|
0
|
3
|
Bone and brain and lung
|
221 (2.12)
|
1.81%
|
0
|
4
|
Bone and liver and lung
|
422 (4.05)
|
1.81%
|
0
|
3
|
Brain and liver and lung
|
79 (0.76)
|
1.27%
|
0
|
3
|
Four sites
|
|
|
|
|
Bone and brain and liver and lung
|
91 (0.87)
|
0
|
0
|
3
|
Abbreviations: OS: overall survival
Pathological distribution
Patients were grouped by the most frequent pathotype in SEER database, the distribution of distant metastases were shown in Figure 2. In terms of the type of clear cell RCC and chromophobe RCC, the percentage of exclusive lung metastasis was higher to lung and other metastases. The Same phenomenon of clear cell RCC were reappeared in bone and liver metastasis. It is interesting that liver metastasis showed differences between pathological types. Except for clear cell RCC, the liver plus other metastases possessed higher percentage than exclusive liver (Figure 2c). As expected, brain and other metastases were much more than exclusive brain metastasis, and it had no statistical significance between pathological types (Figure 2d).
Univariate survival analysis of distant metastases sites
In Table 3, we took the variables included the metastatic site, ethnicity, gender, grade, T stage, N stage, insurance status, and married status. All the variables were regarded as prognostic factors relating to overall survival apart from insurance status. Liver metastasis informed the worst OS in one-site metastasis of four metastatic sites. Among the cohort, bone metastasis presented the minimum hazard ratio (HR). Black patients exhibited worse prognosis with white patients in OS (P < 0.001). Compared to males, there were worse prognosis in females. The interesting phenomenon was observed in Fuhrman grade that patients with moderately differentiated grade appeared better OS than well differentiated grade (P = 0.003). Similarly, patients of T3 seemed to exhibit survival advantage compared to patients of T1. As we expected, patients of N1 had worse prognosis than those of N0. As for histology, Sarcomatoid RCC owned the worst OS than the RCC originated from epithelium. The significant difference in married status was observed, the unmarried patients were prone to worse outcome. We utilized Kaplan-Meier analysis to create survival curves among the patients with single metastasis and two-site metastasis (Figure3a, 3b). As for the patients with three-site metastasis, the log-rank tests showed that no significant difference between them (Figure3c).
Table 3 Univariate survival analysis of patients with four single metastases
Characteristics
|
Overall survival
|
|
HR (95% CI)
|
p-value
|
Metastatic site
|
|
<0.001
|
Lung
|
1
|
Ref.
|
Bone
|
0.969 (0.901-1.042)
|
0.393
|
Liver
|
1.490 (1.341-1.655)
|
<0.001
|
Brain
|
1.118 (0.948-1.319)
|
0.185
|
Race
|
|
<0.001
|
White
|
1
|
Ref.
|
Black
|
1.151(1.071-1.238)
|
<0.001
|
Other
|
0.930(0.850-1.018)
|
0.115
|
Gender
|
|
0.020
|
Male
|
1
|
Ref.
|
Female
|
1.060(1.009-1.113)
|
0.020
|
Grade
|
|
<0.001
|
Well
|
1
|
Ref.
|
Moderate
|
0.734(0.597-0.903)
|
0.003
|
Poorly
|
1.076(0.886-1.308)
|
0.460
|
Undifferentiated
|
1.358(1.115-1.653)
|
0.002
|
Histology
|
|
< 0.001
|
Clear cell RCC
|
1
|
Ref.
|
Papillary RCC
|
1.327 (1.188-1.482)
|
< 0.001
|
Chromophobe RCC
|
0.896 (0.679-1.181)
|
0.435
|
Sarcomatoid RCC
|
2.513 (2.273-2.778)
|
< 0.001
|
Collecting duct RCC
|
2.110 (1.607-2.770)
|
<0.001
|
T stage
|
|
<0.001
|
T1
|
1
|
Ref.
|
T2
|
1.092 (1.005-1.186)
|
0.038
|
T3
|
0.905(0.843-0.972)
|
0.006
|
T4
|
1.222(1.130-1.322)
|
<0.001
|
N stage
|
|
<0.001
|
N0
|
1
|
Ref.
|
N1
|
1.770(1.682-1.862)
|
<0.001
|
Insurance status
|
|
0.111
|
Insured
|
1
|
Ref.
|
Uninsured
|
1.096(0.979-1.228)
|
0.111
|
Married status
|
|
<0.001
|
Married
|
1
|
Ref.
|
Unmarried
|
1.241(1.184-1.301)
|
<0.001
|
Abbreviations: HR, hazard ratio; CI, confidence interval; Ref, reference; RCC: renal cell carcinoma
Multivariate survival analysis of distant metastases sites
On multivariable Cox regression, ethnicity, gender and married status were not the independent factors for mRCC (P > 0.05). As for metastatic site, liver metastasis was still the worst prognostic metastasis. Meanwhile, the interesting situation that moderately differentiated grade with better OS was reappeared on multivariate survival analysis. Sarcomatoid RCC had worse outcomes than other histological types as well. The anticipated event happened again when including the T stage on multivariate survival analysis that the patients of T3 showed better survival than patients with T1. Regional lymph nodes negative was the positive factor for patients with IV stage. (Table 4).
Table 4 Multivariate survival analysis of patients with four single metastases
Characteristics
|
Overall survival
|
|
HR (95% CI)
|
p-value
|
Metastasis site
|
|
|
Lung
|
1
|
Ref.
|
Bone
|
0.896 (0.765-1.050)
|
0.175
|
Liver
|
1.201 (0.932-1.546)
|
0.156
|
Brain
|
1.213 (0.878-1.675)
|
0.242
|
Race
|
|
|
White
|
1
|
Ref.
|
Black
|
0.862(0.661-1.124)
|
0.273
|
Other
|
0.827(0.649-1.052)
|
0.124
|
Gender
|
|
|
Male
|
1
|
Ref.
|
Female
|
1.052(0.911-1.214)
|
0.489
|
Grade
|
|
|
Well
|
1
|
Ref.
|
Moderate
|
0.934(0.594-1.470)
|
0.769
|
Poorly
|
1.109(0.709-1.733)
|
0.651
|
Undifferentiated
|
1.335(0.848-2.102)
|
0.212
|
Histology
|
|
|
Clear cell RCC
|
1
|
Ref.
|
Papillary RCC
|
1.509 (1.159-1.964)
|
0.002
|
Chromophobe RCC
|
0.968 (0.567-1.652)
|
0.905
|
Sarcomatoid RCC
|
2.072 (1.662-2.585)
|
< 0.001
|
Collecting duct RCC
|
2.457 (1.429-4.225)
|
0.001
|
T stage
|
|
|
T1
|
1
|
Ref.
|
T2
|
1.061(0.833-1.351)
|
0.634
|
T3
|
1.125(0.915-0.382)
|
0.264
|
T4
|
1.745(1.345-2.265)
|
<0.001
|
N stage
|
|
|
N0
|
1
|
Ref.
|
N1
|
1.749(1.514-2.021)
|
<0.001
|
Married status
|
|
|
Married
|
1
|
Ref.
|
Unmarried
|
1.145(0.998-1.314)
|
0.054
|
Abbreviations: HR, hazard ratio; CI, confidence interval; Ref, reference; RCC: renal cell carcinoma
Construction of prognosis model for distant metastases sites
Meaningful factors were selected for the nomogram model construction relied on the multivariate survival analysis and clinical availability. The included factors were as follow: age, grade, T/N stage, histology and distant metastases sites. Every factor had its score corresponding to the points at the top of the nomogram. For instance, in N stage, the N0 scores 0 points and the N1 scores 32 points. 1-year survival rate, 3-year survival rate and 5-year survival rate were acquired based on the commensurate points, respectively. If the total points is 160, the 1-year survival rate is 52%, the 3-year survival rate is 20% and the 5-year survival rate is 10% (Figure4)